US Pat. No. 9,198,947

SMALL MOLECULE CONJUGATES FOR INTRACELLULAR DELIVERY OF NUCLEIC ACIDS

HOFFMANN-LA ROCHE INC., ...

1. A conjugate of formula IV

wherein siRNA comprises
an antisense strand with the modification pattern 5?-(w)-(Z1)-(Z2)-(Z3)na-3? and

a sense strand with the modification pattern 5?-(Z3)ns-3?, wherein

w is independently a 5?-phosphate or 5?-phosphothioate or H,
Z1 is independently a 2?-modified nucleotide.
Z2 is independently a 2?-deoxy nucleotide or 2?-Fluoro-modified nucleotide,
Z3 is independently a 2?-modified nucleotide,
na is 8-23 nucleotides and ns is 8-25 nucleotides.

US Pat. No. 9,056,866

[1,2,3]TRIAZOLO[4,5-D]PYRIMIDINE DERIVATIVES

Hoffmann-La Roche Inc., ...

30. A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.
US Pat. No. 9,339,560

METHOD FOR DETERMINING THE ANTI-TUMOR EFFICACY OF MONOCLONAL ANTIBODIES

Hoffmann-La Roche Inc., ...

1. Method for testing the anti-tumor efficacy of a monoclonal antibody comprising the consecutive steps of
a) application of tumor-cells to a rodent;
b) measurement of the tumor size of said rodent in dependency of the time until the tumor size exceeds 100 mm3;
c) application of hybridomas producing said monoclonal antibody to said rodent; and
d) measurement of the tumor size of said tumor-bearing rodent in dependency of the time.

US Pat. No. 9,403,805

ANTIVIRAL COMPOUNDS

Hoffmann-La Roche Inc., ...

1. A method for the treatment of HCV infection of a subject in need thereof which method comprises administering to such subject
an effective amount of a compound of formula I

wherein:
A is CH or N;
n is 1 or 2;
R1 is lower alkyl, cycloalkyl, phenyl, or heterocycloalkyl;

R2 is —C(?O)OR2?, —C(?O)N(R2?)2, monocyclic or bicyclic heteroaryl, optionally substituted with one or more R2?;

each R2? is independently H, lower alkyl or heterocycloalkyl;

R3 is H or lower alkyl;

R4 is hydroxyl or amino; and

X is CH2 or C(?O);

or a pharmaceutically acceptable salt thereof.

US Pat. No. 9,067,924

1,4 THIAZEPINES/SULFONES AS BACE1 AND/OR BACE2 INHIBITORS

HOFFMANN-LA ROCHE INC., ...

1. A compound of formula

wherein
R1 is selected from the group consisting of

hydrogen,
halogen, and
C1-6-alkyl;

R2 is selected from the group consisting of

hydrogen,
C1-6-alkyl, and

halogen-C1-6-alkyl;

R3 is selected from the group consisting of

hydrogen and
C1-6-alkyl;

R4 is selected from the group consisting of

hydrogen and
C1-6-alkyl;

R5 is heteroaryl unsubstituted or substituted by one or two substituents individually selected from the group consisting of

C1-6-alkyl,

halogen,
C1-6-alkoxy, and

halogen-C1-6-alkyl;

R6 is hydrogen;

R7 is hydrogen;

R8 is hydrogen;

R9 is hydrogen;

or R6 and R8 together form a 5-6 membered heterocyclyl; and

X is selected from the group consisting of
—S and
—SO2;

or a pharmaceutically acceptable salt thereof.
US Pat. No. 9,221,909

ANTIBODIES AGAINST HUMAN EPO RECEPTOR

Hoffmann-La Roche Inc., ...

1. An antibody that binds to human erythropoietin (EPO) receptor, wherein said antibody comprises a heavy chain CDR3 region
of SEQ ID NO:17, a heavy chain CDR2 region of SEQ ID NO:18, a heavy chain CDR1 region of SEQ ID NO:19, a light chain CDR3
region of SEQ ID NO:20, a light chain CDR2 region of SEQ ID NO:21, and a light chain CDR1region of SEQ ID NO:22.
US Pat. No. 9,067,943

[1,2,3]TRIAZOLO[4,5-D]PYRIMIDINE DERIVATIVES

HOFFMANN-LA ROCHE INC., ...

1. A compound selected from the group consisting of
5-tert-Butyl-2-(2-chloro-benzyl)-7-morpholin-4-yl-2H-[1,2,3]triazolo[4,5-d]pyrimidine;
5-tert-Butyl-2-(2-chloro-4-fluoro-benzyl)-7-morpholin-4-yl-2H-[1,2,3]triazolo[4,5-d]pyrimidine;
5-tert-Butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine;
5-tert-Butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-(2-methoxy-ethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine;
2-[5-tert-Butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl]-ethanol;
5-tert-Butyl-2-cyclohexylmethyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine;
5-tert-Butyl-2-(3-chloro-benzyl)-7-(3,3-difluoro-pyrrolidin-1-yl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine;
5-tert-Butyl-2-(4-chloro-benzyl)-7-(3,3-difluoro-pyrrolidin-1-yl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine;
5-tert-Butyl-2-(2,3-dichloro-benzyl)-7-(3,3-difluoro-pyrrolidin-1-yl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine;
5-tert-Butyl-2-(2,4-dichloro-benzyl)-7-(3,3-difluoro-pyrrolidin-1-yl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine;
5-tert-Butyl-2-(2,5-dichloro-benzyl)-7-(3,3-difluoro-pyrrolidin-1-yl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine;
5-tert-Butyl-2-(2,6-dichloro-benzyl)-7-(3,3-difluoro-pyrrolidin-1-yl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine;
5-tert-Butyl-2-(2-chloro-4-fluoro-benzyl)-7-(3,3-difluoro-pyrrolidin-1-yl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine;
5-tert-Butyl-2-(2-chloro-6-fluoro-benzyl)-7-(3,3-difluoro-pyrrolidin-1-yl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; and
5-tert-Butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-pyridin-2-ylmethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine.

US Pat. No. 9,150,594

PROCESSES FOR THE MANUFACTURE OF PROPANE-1-SULFONIC ACID {3-[5-(4-CHLORO-PHENYL)-1H-PYRROLO[2,3-B]PYRIDINE-3-CARBONYL]-2,4-DIFLUORO-PHENYL}-AMIDE

Hoffmann-La Roche Inc., ...

1. A process for the manufacture of a compound of formula A

said process being characterized in that
a) a compound of formula B

is reacted in the presence of a halogenation reagent, optionally followed by the introduction of amino-protecting groups,
to give a compound of formula C


b) the compound of formula C is further reacted in the presence of a palladium catalyst, a base, and a compound of formula
7


to give the compound of formula F

c) the compound of formula F is further treated with a strong base;
to give a compound of formula A; wherein
R is phenyl, which is unsubstituted or once or several times substituted by halogen;
X is —Br or —I; and
Y1 and Y2 are independently selected from the group consisting of benzyl, trifluoroacetyl, acetyl, and hydrogen.

US Pat. No. 9,334,278

PYRROLO[2,3-B]PYRAZINES AS SYK INHIBITORS

Hoffmann-La Roche Inc., ...

1. A compound of Formula I:

wherein:
R1 is H, halo, or lower alkyl;

R2 is lower alkyl;

R3 is H or lower alkyl;

A is monocyclic or bicyclic heteroaryl or phenyl, optionally substituted with one or more A?; and
each A? is independently lower alkyl, halo, lower alkyl sulfonyl, amido, lower hydroxyalkyl, lower alkoxy, amino lower alkyl,
or deuterium;

or a pharmaceutically acceptable salt thereof.

US Pat. No. 9,115,130

PROCESS FOR THE PREPARATION OF 2-PHENYL-[1,2,4]TRIAZOLO[1,5-A]PYRIDINE DERIVATIVES

HOFFMANN-LA ROCHE INC., ...

1. A process for the preparation of 2-phenyl-[1,2,4]triazolo[1,5-a]pyridine derivatives of formula I or of a salt thereof
wherein,
R1 stands for hydrogen, a halogen, for an optionally protected hydroxyl group or for an optionally protected amino group and

R2 is hydrogen or a halogen,
which comprises the conversion of a pyridine compound of formula II or of a salt thereof,
wherein, R1 and R2 are as above,with benzonitrile in the presence of a Cu-catalyst, a 1,10-phenanthroline derivative and of a mixture O2/N2, characterized in that no other solvent than the reactant benzonitrile is present in the process.

US Pat. No. 9,067,926

FLUOROMETHYL-5,6-DIHYDRO-4H-[1,3]OXAZINES

HOFFMANN-LA ROCHE INC., ...

1. A compound of formula I,

wherein
R1 is selected from the group consisting of

i) aryl,
ii) aryl substituted by 1-4 substituents individually selected from cyano, cyano-C1-6-alkyl, halogen, halogen-C1-6-alkoxy, halogen-C1-6-alkyl, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, C2-6-alkynyl-C1-6-alkoxy, C2-6-alkynyl and C1-6-alkyl,

iii) heteroaryl, and
iv) heteroaryl substituted by 1-4 substituents individually selected from cyano, cyano-C1-6-alkyl, halogen, halogen-C1-6-alkoxy, halogen-C1-6-alkyl, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, C2-6-alkynyl-C1-6-alkoxy, C2-6-alkynyl and C1-6-alkyl;

R2 is selected from the group consisting of

i) hydrogen,
ii) C1-6-alkyl, and

iii) halogen;
R3 is selected from the group consisting of

i) C1-6-alkyl, and

ii) halogen-C1-6-alkyl,

R4 is halogen-C1-6-alkyl;

or pharmaceutically acceptable salts thereof.
US Pat. No. 9,266,861

METHOD OF SYNTHESIZING THYROID HORMONE ANALOGS AND POLYMORPHS THEREOF

Madrigal Pharmaceuticals,...

1. A morphic form of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile
(“Compound A”) (Form I) characterized by an X-ray powder diffraction pattern including peaks at about 10.5, 18.7, 22.9, 23.6,
and 24.7 degrees 2?.

US Pat. No. 9,255,110

PYRAZOLO[1,5A]PYRIMIDINE DERIVATIVES AS IRAK4 MODULATORS

ROCHE PALO ALTO LLC, Pal...

1. A compound, wherein said compound is of formula Ia or IIa:

wherein:
R4 is halo:

R3 is: halo-C1-4alkyl; C1-6alkenyl; C1-6alkoxy; halo-C1-6alkoxy; hydroxy-C1-6alkyl; hydroxy-C1-6alkylamino; C1-6alkyl-amino; amino; amino-C1-6alkyl; aminocarbonyl; hydroxy-C1-6alkoxy; hydroxy-C1-6alkenyl; C1-6alkoxy-C1-6alkoxy; C1-6alkylsulfonyl; C1-6alkylsulfanyl; piperidinyl wherein the piperidinyl moiety is optionally substituted with hydroxy, amino, amino-C1-6alkyl, hydroxy-C1-6alkyl or aminocarbonyl; phenylaminocarbonyl; hydroxy-C1-6alkylamino; cyclohexyloxy wherein the cyclohexyl moiety thereof is optionally substituted with hydroxy, amino, amino-C1-6alkyl or hydroxy-C1-6alkyl; cyclopentyloxy wherein the cyclopentyl moiety thereof is optionally substituted with hydroxy, amino, amino-C1-6alkyl or hydroxy-C1-6alkyl; piperidinyloxy wherein the piperidinyl moiety thereof is optionally substituted with hydroxy, amino, amino-C1-6alkyl, hydroxy-C1-6alkyl or aminocarbonyl; phenyl wherein the phenyl moiety is optionally substituted with amino, hydroxy, amino-C1-6alkyl, hydroxy-C1-6alkyl or aminocarbonyl; pyrrolidinyl wherein the pyrrolidinyl moiety is optionally substituted with hydroxy, amino, amino-C1-6alkyl, hydroxy-C1-6alkyl or aminocarbonyl; pyrrolidinyloxy wherein the pyrrolidinyl moiety is optionally substituted with hydroxy, amino, amino-C1-6alkyl, hydroxy-C1-6alkyl or aminocarbonyl; piperazinyl wherein the piperazinyl moiety is optionally substituted with C1-6alkyl; oxazol-C1-6alkoxy wherein the oxazol moiety thereof is optionally substituted with C1-6alkyl; morpholinyl; hydroxy-C1-6alkylaminocarbonyl; C3-6cycloalkyl; azepanyl wherein the azepanyl moiety is optionally substituted with hydroxy, amino, amino-C1-6alkyl, hydroxy-C1-6alkyl or aminocarbonyl; benzyl wherein the phenyl moiety thereof is optionally substituted with amino, hydroxy, amino-C1-6alkyl, hydroxy-C1-6alkyl or aminocarbonyl; C1-6alkoxycarbonyl-C1-6alkoxy; or C1-6alkylcabonylamino; and

R1 is: hydrogen, C1-6alkyl, C1-6alkoxy, hydroxy, hydroxy-C1-6alkyl, C1-6alkyl-amino, amino-C1-6alkyl amino-C1-6alkyl-amino, hydroxy-C1-6alkylamino, C3-6cycloalkylamino, aminocarbonyl, halo, hydroxy-C1-6alkyl or hydroxy-C1-6alkoxy,
or a pharmaceutically acceptable salt thereof.

US Pat. No. 9,353,102

NON-ANNULATED THIOPHENYLAMIDES

Hoffmann-La Roche Inc., ...

1. A compound of formula (I)

wherein
R1 and R2 are independently selected from H, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, halocycloalkyl,
halocycloalkylalkyl, substituted aryl, substituted arylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl,
substituted heteroaryl, substituted heteroarylalkyl, substituted aminocarbonyl, alkoxycarbonyl, haloalkoxycarbonyl and carboxy,
wherein substituted aryl, substituted arylalkyl, substituted heterocycloalkyl, substituted heterocycloalkylalkyl, substituted
heteroaryl and substituted heteroarylalkyl are substituted with R14, R15 and R16, and wherein substituted aminocarbonyl is substituted on the nitrogen atom with one to two substituents independently selected
from H, alkyl, cycloalkyl, haloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, hydroxyalkyl and alkoxyalkyl;

R3 is pyrrolidinyl, substituted [1,2,4]-oxadiazolyl, oxazolyl, substituted thiazolyl, substituted [1,2,4]thiadiazol-5-yl, or
pyrimidinyl, wherein substituted [1,2,4]-oxadiazolyl, substituted [1,2,4]thiadiazol-5-yl and substituted thiazolyl are substituted
with R17
R4 is H or alkyl;

R5 and R6 are independently selected from H, alkyl and cycloalkyl;

R7 is H, alkyl or cycloalkyl;

A is NR8 or CR9R10;

E is NR11 or CR12R13;

R8 and R11 are independently selected from H, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, cycloalkylalkyl or halocycloalkylalkyl;

R9, R10, R12 and R13 are independently selected from H, halogen, alkyl, haloalkyl or cycloalkyl;

or R5 and R12 together with the carbon atoms to which they are attached form a substituted cycloalkyl, substituted cycloalkenyl, substituted
aryl, substituted heterocycloalkyl or substituted heteroaryl, wherein substituted cycloalkyl, substituted cycloalkenyl, substituted
aryl, substituted heterocycloalkyl and substituted heteroaryl are substituted with R20 and can be further substituted with R21 and/or R22, wherein in case R5 and R12 together with the carbon atoms to which they are attached form a substituted aryl or substituted heteroaryl, then R6 and R13 are absent;

or R8 and R12 together with the nitrogen and carbon atoms to which they are attached form a substituted heterocycloalkyl or substituted
heteroaryl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with R20 and can be further substituted with R21 and/or R22, wherein in case R8 and R12 together with the carbon atoms to which they are attached form a substituted heteroaryl, then R13 is absent;

or R9 and R11 together with the nitrogen and carbon atoms to which they are attached form a substituted heterocycloalkyl or substituted
heteroaryl, wherein substituted heterocycloalkyl and substituted heteroaryl are substituted with R20 and can be further substituted with R21 and/or R22, wherein in case R9 and R11 together with the carbon atoms to which they are attached form a substituted heteroaryl, then R10 is absent;

or R9 and R12 together with the carbon atoms to which they are attached form a substituted cycloalkyl, substituted cycloalkenyl, substituted
aryl, substituted heterocycloalkyl or substituted heteroaryl, wherein substituted cycloalkyl, substituted cycloalkenyl, substituted
aryl, substituted heterocycloalkyl and substituted heteroaryl are substituted with R20 and can be further substituted with R21 and/or R22, wherein in case R9 and R12 together with the carbon atoms to which they are attached form a substituted aryl or substituted heteroaryl, then R10 and R13 are absent;

or R10 and R13 together with the carbon atoms to which they are attached form a substituted cycloalkyl, substituted cycloalkenyl, substituted
aryl, substituted heterocycloalkyl or substituted heteroaryl, wherein substituted cycloalkyl, substituted cycloalkenyl, substituted
aryl, substituted heterocycloalkyl and substituted heteroaryl are substituted with R23 and can be further substituted with R24 and/or R25, wherein in case R10 and R13 together with the carbon atoms to which they are attached form a substituted aryl or substituted heteroaryl, then R9 and R12 are absent;

or R10 and R13 together with the carbon atoms to which they are attached form a double bond;

R14, R15, R16, R17, R20, R21, R23, R24 and R25 are independently selected from H, hydroxy, oxo, halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy,
alkoxyalkyl, haloalkoxyalkyl, alkoxycarbonyl, carboxy and amino substituted on the nitrogen atom with one to two substituents
independently selected from H alkyl, cycloalkyl, haloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, hydroxyalkyl
and alkoxyalkyl;

n is zero or 1;
or a pharmaceutically acceptable salt thereof.

US Pat. No. 9,309,265

BENZOPYRAN AND BENZOXEPIN PI3K INHIBITOR COMPOUNDS AND METHODS OF USE

Genentech, Inc., South S...

1. A method of treating breast cancer, prostate cancer or pharynx cancer in a mammal comprised of administering to said mammal
a pharmaceutical formulation comprised of:
(i) a pharmaceutically acceptable carrier, glidant, diluent, or excipient; and
(ii) a compound of Formula I:

or a stereoisomer, geometric isomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
Z1 is CR1;

Z2 is CR2;

Z3 is CR3;

Z4 is CR4;

where X1 is S and X2 is CR7;

R1, R2, R3, R4, and R7 are independently selected from H, F, Cl, Br, I, —CN, —CF3, —CH2OR10, —CH2R10, —(C1-C12 alkylene)NR10R11, —(C1-C12 alkylene)NR12C(?O)R10, —(C1-C12 alkylene)C(?O)OR10, —(C1-C12 alkylene)OR10, —CO2R10, —C(?O)N(R10)OR11, —NO2, —NR10R11, —OR10, —S(O)2R10, —C(?O)NR10R11, —C(?O)NR10 (C1-C12 alkylene)NR10R11, —C(?O)NR10(C1-C12 alkylene)NR10C(?O)OR11, —C(?O)NR10 (C1-C12 alkylene)NR10C(?O)R11, —C(?O)NR10(C1-C12 alkylene)R10, —C(?NR10)NR10R11, —NR12C(?O)R10, —NR12C(?O)OR11, —NR12C(?O)NR10R11, —NR12C(?O) (C1-C12 alkylene)NR10R11, —NR12(C1-C12 alkylene)NR10R11, —NR12(C1-C12 alkylene)OR10, —NR12(C1-C12 alkylene)C(?O)NR10R11, —C?CR10, —CH?CHR10, C2-C20 heterocyclyl, C1-C20 heteroaryl, and phenyl, where heterocyclyl, heteroaryl, phenyl and alkylene are optionally substituted with one or more groups
selected from F, Cl, Br, I, —CH2OH, —(CH2)2OH, —CH2CO2H, —CN, —CH2NH2, —(CH2)2N(CH3)2, —CH3, —C(?O)CH3, —C(?O)NHCH3, —CO2H, —CH2CO2CH3, —NH2, —OCH3, —S(O)2CH3, 4-methylpiperazin-1-yl, and 4-morpholinyl;

A is selected from —C(?O)NR5R6, C2-C20 heterocyclyl and C1-C20 heteroaryl wherein C2-C20 heterocyclyl and C1-C20 heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CH2OH, —CH2CO2H, —CH(CH3)CH2OCH3, —CN, C1-C12 alkyl, —(C1-C12 alkylene)NR10R11, —(C1-C12 alkylene)OR10, —CH3, —C(?O)CH3, —C(?O)NHCH3, —C(?O)N(CH3)2, —CO2H, —CO2CH3, —CH2CO2CH3, —NH2, —NHC(?O)CH3, —OCH3, —S(O)2CH3, 1-methylpiperid-4-yl, 4-methylpiperazin-1-yl, 4-morpholinyl, isopropyl, isobutyl, cyclopropyl, cyclopropylmethyl, cyclobutyl,
triazolylmethyl, benzyl, and phenyl, where alkyl, alkylene, benzyl and phenyl are optionally substituted with one or more
groups independently selected from F, Cl, Br, I, —CF3, —CH2OH, —CH2CO2H, —CN, —CH2NH2, —CH3, —C(?O)CH3, —C(?O)NHCH3, —CO2H, —CH2CO2CH3, —NH2, —OH, —OCH3, —S(O)2CH3, 1-methylpiperid-4-yl, (4-methylpiperazin-1-yl)carboxamide, —CH2(1H-1,2,4-triazol-5-yl), 4-methylpiperazin-1-yl, and 4-morpholinyl;

R5 is selected from H, C1-C12 alkyl, optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CN, —CO2H, —CONH2, —CONHCH3, —NH2, —NO2, —N(CH3)2, —NHCOCH3, —NHS(O)2CH3, —OH, —OCH3, —OCH2CH3, —S(O)2NH2, and —S(O)2CH3;

R6 is selected from C1-C12 alkyl, C3-C12 carbocyclyl, C2-C20 heterocyclyl, C1-C20 heteroaryl, and C6-C20 aryl, each optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CH2OH, —CH2C6H5, —CN, —CF3, —CO2H, —C(?O)NR10R11, —NH2, —NO2, —N(CH3)2, —NHCOCH3, —NHS(O)2CH3, —OH, —OCH3, —OCH2CH3, —S(O)2NH2, —S(O)2CH3, —C(?O)NR10(C1-C12 alkylene)NR10R11, morpholin-4-yl, piperidin-1-yl, piperazinyl, piperazin-4-yl-2-one, piperazin-4-yl-3-one, pyrrolidin-1-yl, thiomorpholin-4-yl,
S-dioxothiomorpholin-4-yl, —C?CR13, —CH?CHR13, and —C(?O)NR10R11;

or R5 and R6 together with the nitrogen atom to which they are attached form morpholin-4-yl, piperidin-1-yl, piperazinyl, piperazin-4-yl-2-one,
piperazin-4-yl-3-one, pyrrolidin-1-yl, thiomorpholin-4-yl or S-dioxothiomorpholin-4-yl, each optionally substituted with one
or more groups selected from F, Cl, Br, I, —CH2OH, —CH2C6H5, —CN, —CF3, —CO2H, —CONH2, —CONHCH3, —NO2, —N(CH3)2, —NHCOCH3, —NHS(O)2CH3, —OH, —OCH3, —OCH2CH3, —S(O)2NH2, and —S(O)2CH3;

R10, R11 and R12 are independently selected from H, C1-C12 alkyl, C1-C12 alkylene-C2-C20 heterocyclyl, C1-C12 alkylene-C6-C20 aryl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C12 carbocyclyl, C2-C20 heterocyclyl, C6-C20 aryl, and C1-C20 heteroaryl, where C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C12 carbocyclyl, C2-C20 heterocyclyl, C6-C20 aryl, and C1-C20 heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CH2OH, —CH2C6H5, —CN, —CF3, —CO2H, —CONH2, —CONHCH3, —NO2, —N(CH3)2, —NHCOCH3, —NHS(O)2CH3, —OH, —OCH3, —OCH2CH3, 2-oxopyrrolidin-1-yl, —S(O)2NH2, and —S(O)2CH3;

or R10 and R11 together with the nitrogen atom to which they are attached form a C2-C20 heterocyclyl ring or C1-C20 heteroaryl each optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CH3, —CH2OH, —CH2C6H5, —CN, —CF3, —CO2H, —CONH2, —CONHCH3, —NO2, —N(CH3)2, —NHCOCH3, —NHS(O)2CH3, —OH, oxo, —OCH3, —OCH2CH3, —S(O)2NH2, and —S(O)2CH3; and

R13 is selected from H, F, Cl, Br, I, —CH3, —CH2CH3, —CN, —CF3, —CH2N(CH3)2, —CH2OH, —CO2H, —CONH2, —CON(CH3)2, —NO2, and —S(O)2CH3.

US Pat. No. 9,388,172

SUBSTITUTED CARBAMATE COMPOUNDS

Hoffmann-La Roche Inc., ...

1. A compound of formula (I):
wherein:
X is —CH2— or oxygen; and

R1 is benzoimidazolyl, benzimidazole ring substituted with a halogen, benzooxazolyl, benzoxazole ring substituted with a halogen,
an unsubstituted 5-membered heteroaryl ring or a 5-membered heteroaryl ring substituted with halo-phenyl, methyl-pyridinyl
or halo-pyridinyl, or a pharmaceutically acceptable salt thereof.

US Pat. No. 9,371,280

SUBSTITUTED PYRROLIDINE-2-CARBOXAMIDES

HOFFMANN-LA ROCHE INC., ...

1. A compound selected from the group consisting of:
2-(Phosphonooxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate,
trifluoroacetate salt,

(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic
acid [4-(2-hydroxy-1-methyl-ethylcarbamoyl)-2-methoxy-phenyl]-amide,

4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic
acid 2-diethylamino-ethyl ester,

4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic
acid 1-methyl-piperidin-4-yl ester,

4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic
acid 1-methyl-piperidin-4-ylmethyl ester,

4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic
acid 2-(4-methyl-piperazin-1-yl)-ethyl ester,

4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic
acid [1,2,3]triazolo[4,5-b]pyridin-3-yl ester,

4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic
acid 1-methyl-2-morpholin-4-yl-ethyl ester,

4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic
acid 2-morpholin-4-yl-ethyl ester,

(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic
acid [4-(2-diethylamino-ethylcarbamoyl)-2-methoxy-phenyl]-amide, hydrochloride, and

4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic
acid dimethylcarbamoylmethyl ester, hydrochloride.

US Pat. No. 9,353,081

BICYCLIC DIHYDROQUINOLINE-2-ONE DERIVATIVES

Hoffmann-La Roche Inc., ...

1. A compound of formula (I):

wherein:
R1 is C1-C7-alkyl;

R2 is H;

R3 is H;

R4 is H;

R5 is H;

R6 is H, halogen or C1-C7-alkyl;

R7 is H;

R8 is H;

R9 is H;

R10 is H;

R11 is H;

R12 is H or halogen;

A1 is CR13;

A2 is NR14 or CR15R16;

A3 is CR17;

R13 is H or halogen;

R14 is —(CR20R21)q—(CR22R23)r—(CR24R25)p—NR26R27, wherein the sum of q, r and p is at least 2;

R15 is —(CR20R21)q—(CR22R23)r—(CR24R25)p—NR26R27;

R16 is H;

or R6 and R16 together with the carbon atoms to which they are attached form a double bond;

R17 is H;

R20 is H;

R21 is H;

R22 is H;

R23 is H;

R24 is H;

R25 is H;

R26 is H;

R27 is H, —S(O)2R31, —C(O)R31 or —C(O)OR31, wherein in case R26 is H and R27 is H, then the sum of q, r and p is at least 1;

R31 is C1-C7-alkyl, chloropyridinyl, hydroxyl-C1-C7-alkyl or C3-C8-cycloalkyl;

n is zero or 1;
p is zero or 1;
q is zero or 1; and
r is zero or 1;
or a pharmaceutically acceptable salt or ester thereof.

US Pat. No. 9,334,480

COMPOUNDS FOR IMPROVED STEM CELL DIFFERENTIATION INTO HEPATOCYTES

Hoffmann-La Roche Inc., ...

1. A method for differentiating stem cells into hepatocytes comprising administering to said stem cells a compound of formula
I:
or a pharmaceutically acceptable salt or ester thereof; wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are independently hydrogen or halogen; and R11 is hydrogen or hydroxy.

US Pat. No. 9,315,502

IMIDAZOPYRIDINE DERIVATIVES

Hoffmann-La Roche Inc., ...

1. A compound of formula I
wherein
Ar is phenyl or pyridinyl;
X1 is N or CH,

X2 is N or CH, with the proviso that only one of X1 or X2 is N and the other is CH;

R1 is hydrogen, halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, cyano or S(O)2-lower alkyl;

R2 is hydrogen, halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen or cyano;

n is 1 or 2;or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers
thereof.
US Pat. No. 9,382,218

N-HETEROARYL SUBSTITUTED ANILINE DERIVATIVES AS HCV-ANTIVIRALS

Hoffmann-La Roche Inc., ...

1. A compound
wherein said compound is
N5-(3,5-Dichloro-phenyl)-1H-pyrazole-3,5-diamine;

N5-(3,5-Dichloro-4-fluoro-phenyl)-1H-pyrazole-3,5-diamine;

(3,5-Dichloro-phenyl)-(5-methyl-[1,3,4]oxadiazol-2-yl)-amine;
N3-(3-Trifluoromethyl-phenyl)-[1,2,4]oxadiazole-3,5-diamine;

N5-(3,5-Dichloro-phenyl)-[1,2,4]oxadiazole-3,5-diamine;

N3-(3,5-Dichloro-phenyl)-[1,2,4]oxadiazole-3,5-diamine;

N5-(3-Chloro-5-trifluoromethyl-phenyl)-[1,2,4]oxadiazole -3,5-diamine;

N3-(3-Chloro-5-trifluoromethyl-phenyl)-[1,2,4]oxadiazole-3,5-diamine;

N-[4?-(3-Amino-[1,2,4]oxadiazol-5-ylamino)-6?-chloro-2?-trifluoromethyl-biphenyl-3-yl]-methanesulfonamide;
N-[4?-(5-Amino-[1,2,4]oxadiazol-3-ylamino)-6?-chloro-2?-trifluoromethyl-biphenyl-3-yl]-methanesulfonamide; or
N2-(3,5-Dichloro-phenyl)-oxazole-2,5-diamine, or a pharmaceutically acceptable salt thereof.

US Pat. No. 9,359,301

ETHYNYL DERIVATIVES

Hoffmann-La Roche Inc., ...

1. A compound of formula I
wherein
Y is N or CH;
R1 is fluoro or chloro;
or a pharmaceutically acceptable acid addition salt, racemic mixture, enantiomer, optical isomer or stereoisomer thereof.

US Pat. No. 9,073,881

BENZOIC ACID DERIVATIVES

HOFFMANN-LA ROCHE INC., ...

1. A compound of formula I:

wherein R1 is selected from the group consisting of
bromothienyl, thienyl, pyridyl and phenyl optionally substituted with one or two members selected from the group consisting
of fluoro, chloro, bromo, methyl, methoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxy, —S(O)2-methyl, and cyano;
R2 is selected from the group consisting of
thienyl optionally substituted by a member selected from the group consisting of methyl, acetyl, and chloro;
pyridyl optionally substituted by one or two members selected from the group consisting of amido, methoxy, methyl, fluoro,
chloro, and cyano;

pyrimidinyl optionally substituted with a member selected from the group consisting of ethoxy, methoxy, hydroxy, and isopropyl;
and

phenyl optionally substituted with one to three members selected from the group consisting of methyl, cyano, hydroxy, acetyl,
C(O)NH2, methoxy, ethoxy, trifluoromethoxy, C(O)H, chloro, fluoro, trifluoromethyl, nitro, —C(O)OH,

—C(O)—X1, wherein X1 is a member selected from the group consisting of
and
—NH—X2, wherein X2 is a member selected from the group consisting of —CH(CH3)-phenyl and —(CH2)n-X4, wherein n is 1, 2 or
3 and X4 is a member selected from the group consisting of —N(methyl)2, —N(ethyl)2, pyridyl, thienyl, morpholinyl, and phenyl optionally substituted with a member selected from the group consisting of methyl,
methoxy, fluoro, and trifluoromethyl;

or a pharmaceutically acceptable salt thereof.

US Pat. No. 9,409,866

PYRIDINE-2-AMIDES USEFUL AS CB2 AGONISTS

HOFFMANN-LA ROCHE INC., ...

1. A compound of formula (I)

wherein
R1 is halogen, halophenyl, cycloalkylalkoxy, halophenylalkyl, oxetanyloxy, haloalkoxy, halophenylalkoxy or alkyloxetanylalkoxy;

R2 is halogen, cycloalkyl, haloazetidinyl, halopyrrolidinyl, cycloalkenyl, halocycloalkyl or halooxetanyl;

one of R3 and R4 is hydrogen or alkyl and the other one is —(CR5R6)—(CR7R8)n—R9;

or R3 and R4 together with the nitrogen atom to which they are attached form 2-oxo-5-aza-spiro[3.4]octyl, haloazetidinyl or halopyrrolidinyl;

R5 and R6 are independently selected from hydrogen, alkyl, cycloalkylalkyl, haloalkyl, cycloalkyl, alkylsulfonylalkyl, phenylalkoxyalkyl,
hydroxyalkyl, haloazetidinylalkyl, haloazetidinylcarbonyl, 2-oxa-6-azaspiro[3,3]heptanylcarbonyl, alkylaminocarbonyl, di alkylaminocarbonyl,
aminocarbonyl, azetidinylcarbonyl, oxetanyl alkyl and alkyl oxetanyl;

or R5 and R6 together with the carbon atom to which they are attached form cycloalkyl, oxetanyl, oxanyl or dioxothietanyl;

R7 and R8 are independently selected from hydrogen, alkyl and cycloalkyl;

or R7 and R8 together with the carbon atom to which they are attached form cycloalkyl;

R9 is alkyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, aminocarbonyl, cyano, pyridinyl, alkylaminocarbonyl, thiazol-2-yl, oxazol-2-yl,
5-alkyl-[1,2,4]oxadiazol-3-yl, alkyltetrazolyl, alkylthiazol-2-yl, 1H-tetrazolyl, 5-amino-[1,2,4]-oxadiazol-3-yl, 5-alkyl-[1,3,4]-oxadiazol-2-yl,
azetidinylcarbonyl, haloazetidinylcarbonyl, 6-oxa-1-azaspiro[3.3]heptanyl, 5-phenyl-[1,3,4]-oxadiazol-2-yl or haloalkylaminocarbonyl;
and

n is 0 or 1;
provided that when R3 and R4 are both alkyl at the same time, then R1 and R2 are not both halogen at the same time;

or a pharmaceutically acceptable salt or ester thereof.

US Pat. No. 9,216,170

COMBINATION THERAPY FOR PROLIFERATIVE DISORDERS

HOFFMANN-LA ROCHE INC., ...

1. A method of treating a patient suffering from a proliferative disorder, comprising administering to the patient, either
concomitantly or sequentially: (i) a first component comprising, as an active agent, vemurafenib, or a pharmaceutically-acceptable
salt thereof, and (ii) a second component comprising, as an active agent, an MDM2 inhibitor, or a pharmaceutically: acceptable
salt thereof; the amount of said active agents being such that the combination thereof is therapeutically effective in the
treatment of said proliferative disorder; wherein said proliferative disorder is a melanoma or a colorectal cancer that involves
a tumor comprising b-Raf having the V600E mutation; and
said MDM2 inhibitor is Compound II:

or Compound III:

or a pharmaceutically-acceptable salt thereof.

US Pat. No. 9,206,191

INDAZOLES FOR THE TREATMENT AND PROPHYLAXIS OF RESPIRATORY SYNCYTIAL VIRUS INFECTION

Hoffmann-La Roche Inc., ...

1. A compound of formula (I)

wherein
R1 is hydrogen or halogen;

R2 is hydrogen or halogen;

R3 is azetidinyl; C1-6alkoxypyridinyl; C1-6alkylsulfonyl-CxH2x—; carboxycycloalkyl; difluorocycloalkyl; 1,1-dioxo-tetrahydrothienyl; halopyridinyl; hydroxy-CyH2y—; hydroxy-CxH2x-cycloalkyl; hydroxy-CyH2y—O—CyH2y—; hydroxycycloalkyl-CzH2z—, unsubstituted or substituted by C1-3 alkyl, hydroxy or hydroxy-CxH2x—; 4-hydroxypiperidin-1-yl-CyH2y—; 3-hydroxy-pyrrolidin-1-yl-CyH2y—; morpholinyl-CyH2y—; oxetanyl; oxetanyl-CxH2x—, unsubstituted or substituted by C1-3alkyl; piperidinyl; oxo-piperidinyl; oxo-pyrrolidinyl; pyrrolidinyl, unsubstituted or substituted by C1-6alkylcarbonyl, C1-6alkylsulfonyl, hydroxy-CyH2y—, hydroxy-CxH2x-carbonyl, amino-CxH2x-carbonyl or trifluoromethyl-CxH2x—; tetrahydrofuran-3-yl-CzH2z—; tetrahydropyranyl; trifluoromethyl-CxH2x—;


R4 is C1-6alkyl or cycloalkyl;

R5 is hydrogen or halogen;

R7 is hydrogen or C1-6alkyl;

A1 is —N— or —CH;

A2 is —N—, —NO or —CH;

A3 is —N— or —CH;

x is 1-6;
y is 2-6;
z is 0-6;or a pharmaceutically acceptable salt thereof.

US Pat. No. 9,090,615

ADAMANTYL DERIVATIVES AS CANNABINOID RECEPTOR 2 AGONISTS

HOFFMANN-LA ROCHE INC., ...

1. A compound of formula (I)

wherein
A1 is —CH2— or —C(O)—;

one of R1 and R2 is hydrogen and the other one is -A2-C(O)—R3;

A2 is —NH— or absent;

R3 is (A), (B) or (C);




A3 is —CR18R19—, —NR20— or —C(O)—;

A4 is nitrogen or —CR12—;

R4 is hydrogen or alkoxycarbonyl;

R5 is hydrogen or alkyl;

R6 and R7 are independently selected from hydrogen and alkyl;

R8 and R9 are independently selected from hydrogen and alkyl;

R10, R11, R12 and R13 are independently selected from hydrogen, alkyl, nitro, fluoro, chloro, haloalkyl and alkoxy, provided that they are not all
hydrogen at the same time;

or R13 is alkoxycarbonyl and R10, R11 and R12 are all hydrogen at the same time;

or R10, R11, R12 and R13 are all hydrogen at the same time, provided that:

at least two of R6, R7, R8 and R9 are alkyl and the other ones are hydrogen;

or A1 is —C(O)—;

or R1 is hydrogen and R2 is is -A2-C(O)—R3;

R14 and R17 are independently selected from hydrogen and halogen;

R15 and R16 are independently selected from hydrogen, morpholinyl and halogen;

one of R18 and R19 is hydrogen and the other one is independently selected from alkylaminocarbonyl, hydroxyalkyl, alkyl, alkoxy and alkoxyalkoxy;

or one of R18 and R19 is hydroxyalkyl and the other one is alkyl;

or R18 and R19 are both hydrogen at the same time, provided that R4 is alkoxycarbonyl or R5 is alkyl; and

R20 is alkyl;

or a pharmaceutically acceptable salt thereof.

US Pat. No. 9,067,911

PIPERIDINE DERIVATIVES

Hoffmann-La Roche Inc., ...

1. A compound of formula I

wherein
R1 is hydrogen, lower alkyl, CD3,—(CH2)n—CHO,—(CH2)n—O-lower alkyl,—(CH2)n—OH, —(CH2)n-cycloalkyl or heterocycloalkyl;

R2 is hydrogen, halogen, hydroxy, lower alkyl, di-lower alkyl, —OCH2—O-lower alkyl, or lower alkoxy; or the piperidin ring together with R2 forms 4-aza-spiro[2.5]oct-6-yl;

Ar is phenyl substituted by one or two CF3 groups and optionally substituted by one or two substituents selected from halogen, lower alkyl, lower alkyl substituted by
halogen, lower alkoxy halogen, cycloalkyl, lower alkoxy, S-lower alkyl, heteroaryl, heterocycloalkyl, and phenyl optionally
substituted by R?, to give no more than three substituents total on Ar;

R? is lower alkyl, lower alkoxy, lower alkoxy substituted by halogen, or heteroaryl;
R is phenyl optionally substituted by one or two R?; and
n is 0, 1 2 or 3;
or a pharmaceutically acceptable acid addition salt, racemic mixture, enantiomer, or optical isomer thereof.

US Pat. No. 9,328,070

ETHYNYL DERIVATIVES

Hoffmann-La Roche Inc., ...

1. A compound of formula I

wherein
Y is CH
or a pharmaceutically acceptable acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer
and/or stereoisomer thereof.

US Pat. No. 9,309,319

ANTIBODIES AGAINST HUMAN IL33R AND USES THEREOF

HOFFMANN-LA ROCHE INC., ...

1. A method of treating asthma comprising administering a therapeutically effective amount of an anti-human IL33R antibody
to a patient in need of therapy, wherein said antibody is selected from:
(a) An anti-human IL33R antibody comprising a heavy chain variable domain comprising a CDR3 region of SEQ ID NO:24, a CDR2
region of SEQ ID NO:23 and a CDR1 region of SEQ ID NO:22 and a light chain variable domain comprising a CDR3 region of SEQ
ID NO:33, a CDR2 region of SEQ ID NO:32 and a CDR1 region of SEQ ID NO:31;

(b) An anti-human IL33R antibody comprising a heavy chain variable domain comprising SEQ ID NO:21 and a light chain variable
domain comprising SEQ ID NO:30;

(c) An anti-human IL33R antibody comprising a heavy chain variable domain comprising SEQ ID NO:7 and a light chain variable
domain comprising SEQ ID NO:8;

(d) An anti-human IL33R antibody according to (a)-(c) having a human IgG1 or IgG4 isotype but modified in the hinge region
at one or more amino acid position between 216-240 and/or in the second inter-domain region at one or more amino acid position
between 327-331 between CH2 and CH3;

(e) An anti-human IL33R antibody according to (d), wherein said hinge region is modified by replacing the amino acid at position
234 and the amino acid at position 235 with alanine;

(f) An anti-human IL33R antibody according to (d), wherein said hinge region is modified by replacing the amino acid at position
235 and the amino acid at position 228 with glutamic acid and proline, respectively; and

(g) An anti-human IL33R antibody according to (a)-(f) which is a chimeric antibody, a humanized antibody or a T cell epitope-depleted
antibody.

US Pat. No. 9,169,259

IMIDAZOPYRIDAZINE COMPOUNDS

HOFFMANN-LA ROCHE INC., ...

1. A compound of Formula I

wherein:
A is pyridyl, pyrrolidinyl, or pyrazolyl, substituted with one or more A?;
each A? is independently pyrrolidinyl or piperidinyl, optionally substituted with lower alkyl;
n is 0, 1 or 2;
B is phenyl, pyridyl, pyrrolidinyl, or piperidinyl;
each R is independently halo, hydroxy, lower alkyl, lower alkoxy, lower haloalkyl, cyano, heterocycloalkyl lower alkyl, —NH(C?O)R1, —C(?O)R1, —C(?O)OR?, —O(CH2)pR1, CH2R1, CH2NHR1, or —C(?O)NHR1;

or two R together form a bicyclic heteroaryl or heterocycloalkyl ring system;
R1 is H or R1?;

R1? is lower alkyl, phenyl, indolyl, indazolyl, heteroaryl lower alkyl, or heterocycloalkyl, optionally substituted with one
or more R1?;

each R1? is hydroxy, lower alkyl, lower alkoxy, carboxy, amido, amino, dialkyl amino, or oxo; and

p is 0, 1, or 2;
or a pharmaceutically acceptable salt thereof.

US Pat. No. 9,102,689

PROCESS FOR THE PREPARATION OF BORONIC ACID INTERMEDIATES

HOFFMANN-LA ROCHE INC., ...

1. A process for the preparation of a compound of formula (I)

or salts or esters thereof, comprising
a) adding a compound of formula (II)

wherein R1 and R2 each independently is C1-6 alkyl,

to a solution of a compound of formula (III)

and an immobilized acidic catalyst in a polar aprotic organic solvent with a boiling point above 100° C., wherein Hal is F,
Cl, Br or I;

to form a compound of formula (IV)

b) reacting a mixture of a compound of formula (IV) and a compound of formula (V) with a metalation reagent

wherein R3, R4 and R5 each independently is C1-6 alkyl;

in a polar aprotic organic solvent at a temperature of ?90° C. to ?95° C.
to a compound of formula (VI)
and
c) hydrolyzing the compound of formula (VI) to produce the compound of formula (I)

or salts or esters thereof.
US Pat. No. 9,080,183

PROMOTER

HOFFMANN-LA ROCHE INC., ...

1. A method for the selection of a cell expressing a heterologous polypeptide to the cell expressing it comprising the following
steps:
a) transfecting an isolated eukaryotic cell with a nucleic acid comprising
i) a first expression cassette comprising a nucleic acid encoding a heterologous polypeptide,
ii) a second expression cassette comprising a first nucleic acid comprising the sequence of SEQ ID NO: 04 and a second nucleic
acid encoding a selectable marker selected from the group consisting of hygromycin phosphotransferase, neomycin and G418 aminoglycoside
phosphotransferase, dLNGFR and GFP, whereby said first and second nucleic acid are operably linked,

b) cultivating said transfected cell under conditions suitable for the growth of non-transfected cell; and
c) cultivating said cells under selective culture conditions;
d) selecting a cell propagating in step b) and under selective culture conditions in step c).

US Pat. No. 9,456,998

SELECTIVE INHIBITORS OF UNDIFFERENTIATED CELLS

Yissum Research Developme...

1. A method of inhibiting undifferentiated cells, the method being effected by contacting undifferentiated cells with the
following compound:
said undifferentiated cells being selected from the group consisting of pluripotent stem cells, cancer stem cells and Grade
4 undifferentiated cancer cells.

US Pat. No. 9,447,086

6-AMINO ACID HETEROARYLDIHYDROPYRIMIDINES FOR THE TREATMENT AND PROPHYLAXIS OF HEPATITIS B VIRUS INFECTION

Hoffmann-LA Roche INC., ...

1. A compound selected from

US Pat. No. 9,365,881

PROCESS FOR ANTIBODY G1 GLYCOFORM PRODUCTION

Hoffmann-La Roche Inc., ...

1. A method for producing an immunoglobulin or immunoglobulin fragment or immunoglobulin fusion, having a G1 glycostructure,
comprising the following steps:
incubating an affinity chromatography column eluate containing the immunoglobulin or immunoglobulin fragment or immunoglobulin
fusion with a galactosyltransferase to obtain a galactosyltransferase reaction product,

incubating the galactosyltransferase reaction product with a sialyltransferase to obtain a sialytransferase reaction product,
incubating the sialyltransferase reaction product with a beta-1,4-galactosidase to obtain a beta-1,4-galactosidase reaction
product,

removing or inactivating the beta-1,4-galactosidase, and
incubating the beta-1,4-galactosidase reaction product, in which the beta-1,4-galactosidase has been removed or inactivated,
with a sialidase and thereby producing the immunoglobulin or immunoglobulin fragment or immunoglobulin fusion with the G1
glycostructure.

US Pat. No. 9,278,918

UREA DERIVATIVES AND THEIR USE AS FATTY-ACID BINDING PROTEIN (FABP) INHIBITORS

Hoffmann-La Roche Inc., ...

1. Compounds of formula (I)

wherein
R1 and R2 together with the carbon they are attached to form a cycloalkyl;

R3 is H, alkyl or cycloalkyl;

R4 is H, alkyl or cycloalkyl;

W is a bond, —O—, —S—, —NR5—, —C(O)—, —S(O)2—, —C(O)—NR5— or —CR6R7—;

R5 is H, alkyl or cycloalkyl;

R6 and R7 are independently selected from H, alkyl or cycloalkyl;

A is substituted phenyl, substituted thiophenyl, substituted benzothiophenyl, substituted thienopyridinyl, wherein substituted
phenyl, substituted thiophenyl, substituted benzothiophenyl and substituted thienopyridinyl are substituted with R8, R9 and R10;

B is substituted cycloalkyl, substituted cycloalkenyl, substituted pyridinyl, substituted phenyl, substituted thiophenyl,
substituted benzothiophenyl, substituted thienopyridinyl, wherein substituted cycloalkyl, substituted cycloalkenyl, substituted
pyridinyl, substituted phenyl, substituted thiophenyl, substituted benzothiophenyl and substituted thienopyridinyl are substituted
with R11, R12 and R13;

R8, R9, R10 are independently selected from H, alkyl, alkenyl, alkinyl, hydroxyalkyl, haloalkyl, hydroxyhaloalkyl, cycloalkyl, cycloalkenyl,
cycloalkylalkyl, cycloalkenylalkyl, cycloalkylalkoxy, cycloalkoxy, cycloalkoxyalkyl, cycloalkylalkoxyalkyl, alkoxy, alkoxyalkyl,
haloalkoxy, haloalkoxyalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, phenyl, substituted phenyl, pyridinyl, substituted pyridinyl,
halogen, hydroxy, cyano, substituted aminosulfonyl, substituted aminocarbonyl, substituted amino and substituted aminoalkyl,
wherein substituted aminosulfonyl, substituted aminocarbonyl, substituted amino and substituted aminoalkyl are substituted
on the nitrogen atom with one to two substituents independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,
hydroxyalkyl, alkoxyalkyl, alkylcarbonyl and cycloalkylcarbonyl and wherein substituted phenyl and substituted pyridinyl are
substituted with one to three substituent selected from alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, alkoxy, haloalkoxy, halogen,
hydroxy and cyano;

R11, R12 and R13 are independently selected from H, alkyl, alkenyl, alkinyl, hydroxyalkyl, haloalkyl, hydroxyhaloalkyl, cycloalkyl, cycloalkenyl,
cycloalkylalkyl, cycloalkenylalkyl, cycloalkylalkoxy, cycloalkoxy, cycloalkoxyalkyl, cycloalkylalkoxyalkyl, alkoxy, alkoxyalkyl,
haloalkoxy, haloalkoxyalkyl, alkoxyalkoxy, alkoxyalkoxyalkyl, phenyl, substituted phenyl, pyridinyl, substituted pyridinyl,
halogen, hydroxy, cyano, substituted aminosulfonyl, substituted aminocarbonyl, substituted amino and substituted aminoalkyl,
wherein substituted aminosulfonyl, substituted aminocarbonyl, substituted amino and substituted aminoalkyl are substituted
on the nitrogen atom with one to two substituents independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,
hydroxyalkyl, alkoxyalkyl, alkylcarbonyl and cycloalkylcarbonyl and wherein substituted phenyl and substituted pyridinyl are
substituted with one to three substituent selected from alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, alkoxy, haloalkoxy, halogen,
hydroxy and cyano;

or pharmaceutically acceptable salts.
US Pat. No. 9,169,323

ANTIBODIES AGAINST HUMAN CSF-1R

HOFFMANN-LA ROCHE INC., ...

15. An antibody, or antibody fragment thereof, that binds to human CSF-1R, obtained from or produced by hybridoma cell line
7H5.2G10.

US Pat. No. 9,090,599

HETEROARYLMETHYL AMIDES

HOFFMANN-LA ROCHE INC., ...

1. A compound of formula I,

wherein:
A1 is N;

A2 and A3 are CH;

R1 is selected from the group consisting of:

lower alkyl,
cycloalkyl,
lower cycloalkylalkyl,
lower hydroxyalkyl,
lower alkoxyalkyl,
lower halogenalkyl,
lower carbamoylalkyl,
lower alkylcarbonylaminoalkyl,
lower phenylalkyl,
lower heterocyclylalkyl wherein the heterocyclyl group is unsubstituted or substituted by oxo,
lower heteroarylalkyl wherein the heteroaryl group is unsubstituted or mono- or di-substituted by lower alkyl, and
phenyl which is unsubstituted or mono- or di-substituted by halogen;
R2 and R6 independently from each other are hydrogen or halogen;

R3 and R5 independently from each other are selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halogen, lower
halogenalkyl, lower halogenalkoxy and cyano;

R4 is selected from the group consisting of hydrogen, lower alkoxy, halogen, lower halogenalkyl, lower halogenalkoxy and cyano;

or R4 and R5 together with the C atoms they are attached to form a five- or six-membered carbocycle or a five- or six-membered heterocycle
containing one, two or three heteroatoms selected from the group consisting of N, O and S, said carbocycle or heterocycle
being unsubstituted or substituted by one or two substituents independently selected from the group consisting of lower alkyl,
lower alkoxy, halogen, lower halogenalkyl, lower halogenalkoxy and cyano;

R7 and R7? independently from each other are hydrogen or lower alkyl; and

R8 is a five- or six-membered heteroaryl group containing one, two or three heteroatoms selected from the group consisting of
N, O and S, said heteroaryl group being unsubstituted or substituted by one or two substituents independently selected from
the group consisting of lower alkyl, lower alkoxy, halogen, lower halogenalkyl and cycloalkyl;

or a pharmaceutically acceptable salt thereof.

US Pat. No. 9,346,786

PYRROLIDINE COMPOUNDS

Hoffmann-La Roche Inc., ...

1. A compound of formula I

wherein
R1 is hydrogen, halogen, cyano, lower alkyl or lower alkyl substituted by halogen;

n is 1, 2 or 3, wherein when n is 2 or 3, each R1 is the same or different;

R2 is C2-7-alkyl or C3-6-cycloalkyl;

R3 is the group


wherein
X is CH or N;
R5 is hydrogen, —C(O)-lower alkyl, —C(O)O-lower alkyl, S(O)2-lower alkyl, —C(O)CH2O-lower alkyl, —C(O)—CH2—CN, or is

—C(O)-cycloalkyl, cycloalkyl, or —CH2-cycloalkyl,

wherein the cycloalkyl groups are optionally substituted by lower alkyl, —CH2—O-lower alkyl, lower alkoxy, CF3, halogen or cyano, or is

—C(O)-heterocycloalkyl, heterocycloalkyl, —C(O)-heteroaryl, heteroaryl, —C(O)-aryl, or aryl,
which heterocycloalkyl, heteroaryl or aryl groups are optionally substituted by halogen, lower alkyl, ?O, lower alkoxy, lower
alkyl substituted by halogen, lower alkyl substituted by hydroxy, —C(O)—CH2—N(di-lower alkyl), C(O)NH-lower alkyl, C(O)NH2, —O—C(O)-lower alkyl, C(O)-lower alkyl, S(O)2-lower alkyl or cyano;

R4 is aryl, which is optionally substituted by halogen, hydroxy, lower alkyl, lower alkyl substituted by halogen, S(O)2-lower alkyl, cyano or by lower alkoxy;

or a pharmaceutically active salt thereof.

US Pat. No. 9,133,170

INHIBITORS OF HCV NS5A

HOFFMANN-LA ROCHE INC., ...

1. A compound of Formulae I-III

wherein:
each A is independently selected from the group consisting of

each R1 and R2 are independently selected from the group consisting of H, lower alkyl, or aryl;

each R3 is independently selected from the group consisting of H, lower alkyl, or C(?O)OR4;

R4 is lower alkyl;

each X is independently selected from the group consisting of H and Cl; and
each Y1 and Y2 are independently selected from the group consisting of H or F;

or a pharmaceutically acceptable salt thereof.

US Pat. No. 9,409,882

PYRIDINE DERIVATIVES

Hoffmann-La Roche Inc., ...

1. A compound of formula (I)

wherein
A1 is —S— or —S(O)2—;

A2 is nitrogen or —(CH)—;

R1 is halogen or haloalkyl;

R2 is hydrogen or halogen;

R3 is hydrogen, halogen, haloalkyl, pyrazolyl, [1,2,3]-triazolyl or [1,2,4]-triazolyl;

R4 and R6 are independently selected from hydrogen, alkyl, haloalkyl and halophenyl; and

R5 is hydrogen, halogen, haloalkyl, alkoxy, haloalkoxy, alkylpyridinyl, halopyridinyl or alkylpyrazolyl;

or a pharmaceutically acceptable salt thereof.
US Pat. No. 9,290,567

USE OF AN ANTI-TAU PS422 ANTIBODY FOR THE TREATMENT OF BRAIN DISEASES

Hoffmann-La Roche Inc., ...

1. An antibody, which specifically binds to Tau phosphorylated at serine 442 (Tau pS422) and to the phosphorylated Tau fragment
of SEQ ID NO:9 but does not bind to either wild-type Tau or to the phosphorylated human mitotic centromere-associated kinesin
(MCAK) fragment of SEQ ID NO:17, and which comprises the complementary determining regions (CDRs): CDR1H of SEQ ID NO:55,
CDR2H of SEQ ID NO:56, CDR3H of SEQ ID NO:57, CDR1L of SEQ ID NO:59, CDR2L of SEQ ID NO:60, and CDR3L of SEQ ID NO:61, wherein
the antibody is a variant antibody that has been humanized.

US Pat. No. 9,273,042

5-AMINO[1,4]THIAZINES AS BACE 1 INHIBITORS

HOFFMANN-LA ROCHE INC., ...

1. A compound of formula I:

wherein:
R1 is selected from the group consisting of

i) aryl,
ii) aryl substituted by 1-4 substituents individually selected from cyano, cyano-C1-6-alkyl, halogen, halogen-C1-6-alkoxy, halogen-C1-6-alkyl, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, C2-6-alkynyl-C1-6-alkoxy, C2-6-alkynyl and C1-6-alkyl,

iii) heteroaryl, and
iv) heteroaryl substituted by 1-4 substituents individually selected from cyano, cyano-C1-6-alkyl, halogen, halogen-C1-6-alkoxy, halogen-C1-6-alkyl, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, C2-6-alkynyl-C1-6-alkoxy, C2-6-alkynyl and C1-6-alkyl;

R2 is selected from the group consisting of

i) hydrogen,
ii) C1-6-alkyl, and

iii) halogen;
R3 is selected from the group consisting of

i) C1-6-alkyl, and

ii) halogen-C1-6-alkyl;

R4 is selected from the group consisting of halogen-C1-6-alkyl and hydrogen;

R5 is selected from the group consisting of halogen-C1-6-alkyl and hydrogen; and

x is 0 or 2,
or pharmaceutically acceptable salts thereof.

US Pat. No. 9,242,943

1,4 OXAZINES AS BACE1 AND/OR BACE2 INHIBITORS

SIENA BIOTECH S.P.A., Si...

1. A compound of formula I
wherein
R1 is selected from the group consisting of
i) hydrogen,
ii) halogen, and
iii) C1-6-alkyl,

R2 is C1-6-alkyl,

R3 is selected from the group consisting of

i) aryl,
ii) aryl substituted by 1-4 substituents individually selected from cyano, cyano-C1-6-alkyl, halogen, halogen-C1-6-alkoxy, halogen-C1-6-alkyl, C1-6-alkoxy, C1-6-alkoxy- C1-6-alkyl and C1-6-alkyl,

iii) aryl-C1-6-alkyl,

iv) aryl-C1-6-alkyl, wherein the aryl is substituted by 1-4 substituents individually selected from cyano, cyano-C1-6-alkyl, halogen, halogen-C1-6-alkoxy, halogen-1 C1-6-alkyl, C1-6-alkoxy, C1-6-alkoxy- C1-6-alkyl and C1-6-alkyl,

v) heteroaryl,
vi) heteroaryl substituted by 1-4 substituents individually selected from amido, cyano, cyano-C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C2-6-alkenyl, C37-cycloalkyl-C2-6-alkynyl, C3-7-cycloalkyl-C1-6 -alkyl, C3-7-cycloalkyl-C1-6-alkoxy, halogen, halogen-C1-6-alkoxy, halogen-C1 6-alkyl, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C1-6-alkyl and nitro,

vii) heteroaryl-C1-6-alkyl,

viii) heteroaryl-C1-6-alkyl, wherein the heteroaryl is substituted by 1-4 substituents individually selected from amido, cyano, cyano-C1-6-alkyl, C3-7-cycloalkyl,C3-7-cycloalkyl-C2-6-alkenyl, C3-7-cycloalkyl-C2-6-alkynyl, C3-7-cycloalkyl-C1-6-alkyl, C3-7-cycloalkyl-C1-6-alkoxy, halogen, halogen-C1-6-alkoxy, halogen-C1-6-alkyl, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C1-6-alkyl and nitro,

ix) C1-6-alkyl,

x) C1-6-alkyl substituted by 1-5 substituents individually selected from cyano, halogen, ydroxyl, C1-6-alkyl—S—and C1-6-alkoxy,

xi) C3-7-cycloalkyl,

xii) C3-7-cycloalkyl substituted by 1-4 substituents individually selected from cyano, cyano-C1-6-alkyl, halogen, halogen-C1-6-alkoxy, halogen-C1-6-alkyl, ydroxyl, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl and C1-6-alkyl,

xiii) C3-7-cycloalkyl-C1-6-alkyl,

xiv) C3-7-cycloalkyl-C1-6-alkyl, wherein the C3-7-cycloalkyl is substituted by 1-4 substituents individually selected from cyano, cyano-C1-6-alkyl, halogen, halogen-C1-6-alkoxy, halogen-C1-6-alkyl, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl and C1-6-alkyl,

xv) heterocyclyl,
xvi) heterocyclyl substituted by 1-4 substituents individually selected from ano, cyano-C1-6-alkyl, halogen, halogen-C1-6-alkoxy, halogen-C1-6-alkyl, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl and C1-6-alkyl,

xvii) heterocyclyl-C1-6-alkyl, and

xviii) heterocyclyl-C1-6-alkyl, wherein the heterocyclyl is substituted by 1-4 substituents individually selected from cyano, cyano-C1-6-alkyl, halogen, halogen-C1-6-alkoxy, halogen-C1-6-alkyl, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl and C1-6-1 alkyl; and

R4 is hydrogen;

or a pharmaceutically acceptable salt thereof.

US Pat. No. 9,260,408

DIHYDROQUINOLINE-2-ONE DERIVATIVES

Hoffmann-La Roche Inc., ...

43. A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

US Pat. No. 9,328,090

ARYLETHYNYL DERIVATIVES

Hoffmann-La Roche Inc., ...

1. An ethynyl derivative of formula I

wherein
R1 is phenyl, which is optionally substituted by 1-2 halogen atoms, selected from fluorine or chlorine;

or a pharmaceutically acceptable acid addition salt in enantiomerically pure form.

US Pat. No. 9,139,593

AZETIDINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE

HOFFMANN-LA ROCHE INC., ...

1. A compound of Formula (I):
R1-L1-A-L2-R2  (I)
wherein
A is selected from the group consisting of Ia, and Ic:
wherein
X is N or CH;
Y is NH or CH2; and

wherein
L1 is selected from the group consisting of a bond, —(CH2)1-3—, —NH—(CH2)0-3—C(O)—, —(CH2)0-3—C(O)—, —(CH2)0-3—SO2— and —(CH2)0-3—NR3—C(O)—;

L2 is selected from the group consisting of a bond, —(CH2)1-3—, —(CH2)0-3—C(O)—NH—, —NH—(CH2)0-3—C(O)—NH—, —(CH2)0-3—C(O)—, —(CH2)0-3—SO2— and —(CH2)0-3—NR3—C(O)—;

R1 is selected from the group consisting of phenyl, 5- or 6-membered heteroaryl, adamantyl and —(CH2)1-3-phenyl, wherein said phenyl, heteroaryl or adamantyl is unsubstituted or substituted by one to three R5 groups;

R2 is selected from the group consisting of phenyl, 5- or 6-membered heteroaryl and —(CH2)1-3-phenyl, wherein said phenyl or heteroaryl is unsubstituted or substituted by one to three R5 groups;

R3 is hydrogen or lower alkyl;

R4 is hydrogen or lower alkyl; and

R5 is selected from the group consisting of halogen, lower alkyl, lower haloalkyl, lower haloalkoxy, and —C(O)OR4, or

a stereoisomer, tautomer or pharmaceutically acceptable salt thereof,
with the proviso that said compound is not 2,6-bis[(4-methylphenyl)sulfonyl]-2,6-diazaspiro[3,3]heptane or 2-phenyl-6-(phenylmethyl)-2,6-diazaspiro[3,3]heptane,
and the further provisos that when L2 is —C(O)—NH—, L1 is not —CH2—; when L2 is —CH2—, L1 is not a bond; when L2 is —SO2—, L1 is not —CH2—; and L1 and L2 are different.

US Pat. No. 9,073,911

PYRAZOLE DERIVATIVES

HOFFMANN-LA ROCHE INC., ...

1. A compound of formula IA or IB

wherein
R1 is hydrogen,

phenyl substituted by halogen, CN, lower alkoxy or lower alkoxy substituted by halogen;
R2 is hydrogen or lower alkyl;

R3 is hydrogen,

lower alkyl,
phenyl substituted by one or more substituents selected from halogen, cyano and lower alkoxy substituted by halogen,
pyridinyl optionally substituted by halogen or lower alkyl substituted by halogen, pyrimidinyl optionally substituted by lower
alkyl substituted by halogen, or pyrazinyl optionally substituted by halogen, cyano or lower alkyl substituted by halogen;

R4 is hydrogen, lower alkyl or phenyl; and

Z is a bond, —CH2— or —O—;

or a pharmaceutically suitable acid addition salt thereof.

US Pat. No. 9,359,337

ACETAMIDE DERIVATIVES

Hoffmann-La Roche Inc., ...

1. A compound of formula (I)

wherein:
X is —CH2— or oxygen;

Y is —(CH2)n—;

R1 is phenyl optionally substituted with halogen;
R2 is lower alkyl;
R3 is trifluoromethyl-phenyl, trifluoromethyl-pyridinyl, trifluoromethyl-pyridazinyl, trifluoromethyl-pyrimidinyl or trifluoromethyl-pyrazinyl;
and

n is 0 or 1, provided that n is not 0 when X is oxygen;
or a pharmaceutically acceptable salt thereof.
US Pat. No. 9,132,136

PHARMACEUTICAL COMBINATION

HOFFMANN-LA ROCHE INC., ...

1. A combination comprising a therapeutically effective amount of each of olanzapine and,
(S)-4-(3-fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine, or a pharmaceutically suitable acid addition additional salt
thereof, said combination being characterized by a reduced incidence of the metabolic syndrome associated with the administration
of atypical antipsychotic medications.

US Pat. No. 9,187,455

SUBSTITUTED PYRIDAZINES AS PDE10A INHIBITORS

Hoffmann-La Roche Inc., ...

24. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I)
wherein
R1 is pyridinyl, quinolinyl, or isoquinolinyl, each of which is optionally substituted with 1 to 4 substituents independently
selected from the group consisting of lower-alkyl, lower-alkoxy, fluoro-lower-alkyl, fluoro-lower-alkoxy, lower-alkyl-SO2, fluoro-lower-alkyl-SO2, halogen, lower-alkoxy-lower-alkyl, cyano, NO2, morpholinyl, NH2—SO2, NH(lower-alkyl)-SO2, N(lower-alkyl)2-SO2, pyrrolidinyl-SO2, piperidinyl-SO2, morpholinyl-SO2, hydroxy, COOH, COO-lower-alkyl, lower-alkyl-C(O)O, CO-lower-alkyl, CONH2, CONH(lower-alkyl), CON(lower-alkyl)2, lower-alkyl-CO—NH, lower-alkyl-CO—N(lower-alkyl), NH2—CO-lower-alkyl, NH(lower-alkyl)-CO-lower-alkyl, N(lower-alkyl)2-CO-lower-alkyl, NH2, NH(lower-alkyl), N(lower-alkyl)2, NH2-lower-alkyl, NH(lower-alkyl)-lower-alkyl, N(lower-alkyl)2-lower-alkyl, cycloalkyl, piperidinyl, piperazinyl and (N-lower-alkyl)-piperazinyl;

R2 is aryl or heteroaryl, each of which is optionally substituted with 1 to 4 substituents independently selected from the group
consisting of halogen, cyano, lower-alkyl, lower-alkoxy, fluoro-lower-alkyl, lower-alkynyl, lower-alkyl-SO2, COOH, CONH2, NH2—SO2, COO-lower-alkyl, lower-alkoxy-lower-alkyl, CONH(lower-alkyl), CON(lower-alkyl)2, NH(lower-alkyl)-SO2, N(lower-alkyl)2-SO2, lower-alkenyl, hydroxy, NO2, morpholinyl, piperidinyl, piperazinyl, (N-lower-alkyl)-piperazinyl, pyrrolidinyl, lower-alkyl-C(O)O, lower-alkyl-CO—NH,
lower-alkyl-CO—N(lower-alkyl), NH2—CO-lower-alkyl, NH(lower-alkyl)-CO-lower-alkyl, N(lower-alkyl)2-CO-lower-alkyl, CO-lower-alkyl, NH2, NH(lower-alkyl), N(lower-alkyl)2, NH2-lower-alkyl, NH(lower-alkyl)-lower-alkyl, N(lower-alkyl)2-lower-alkyl, tri(lower-alkyl)silyl-loweralkynyl and cycloalkyl,

or wherein two substituents at adjacent positions on the aryl or heteroaryl are bound together to form a ring and said two
bound substituents are lower-alkylene, dioxy-lower-alkylene, dioxy-fluoro-lower-alkylene, NH-lower-alkylene, N(lower alkyl)-lower-alkylene,
lower-alkylene-NH-lower-alkylene, lower-alkylene-N(lower alkyl)-lower-alkylene, NH—C(O)-lower-alkylene, N(lower alkyl)-C(O)-lower-alkylene,
lower-alkylene-NH—C(O)-lower-alkylene, lower-alkylene-N(lower alkyl)-C(O)-lower-alkylene, C(O)—NH-lower-alkylene or C(O)—N(lower-alkyl)-lower-alkylene;

R3 is hydrogen, lower-alkyl, fluoro-lower-alkyl, lower-alkoxy, fluoro-lower-alkoxy, halogen, hydroxy or phenyl; and

R4 is hydrogen, lower-alkyl, fluoro-lower-alkyl, lower-alkoxy, fluoro-lower-alkoxy, halogen, hydroxy or phenyl;

or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable carrier.
US Pat. No. 9,192,667

METHOD OF TREATING CANCER BY ADMINISTERING CSF-1R ANTIBODIES AND A TLR9 AGONIST

HOFFMANN-LA ROCHE INC., ...

1. A method of treating cancer, the method comprising administering to a patient in need thereof an effective amount of
i) an antibody which binds to human CSF-1R, and
ii) a TLR9 agonist.
US Pat. No. 9,290,451

PYRIDINE DERIVATIVES AS AGONISTS OF THE CB2 RECEPTOR

Hoffmann-La Roche Inc., ...

1. A compound selected from the group consisting of:
Methyl 2-methyl-2-(5-methyl-6-(2,2,2-trifluoroethoxy)picolinamido)propanoate;
2-[(6-Cyclohexyl-pyridine-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester;
2-{[6-Cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carbonyl]amino}-2-methyl-propionic acid methyl ester;
6-Cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid [1-methyl-1(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;6-(3-Chloro-phenyl)-pyridine-2-carboxylic
acid piperidin-1-ylamide;

2-{[6-Cyclopropylmethoxy-5-(1H-pyrazol-3-yl)-pyridine-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester;
6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide;
2-[(6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester;
6-Cyclopropylmethoxy-5-(2-methyl-pyrrolidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
6-Cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;
6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid (1,1-dimethyl-3-moipholin-4-yl-propyl)-amide;
6-Cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid (1-methyl-1-methylcarbamoyl-ethyl)-amide;
6-(Tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid piperidin-1-ylamide;
5-Cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-methyl-1-methylcarbamoyl-ethyl)-amide;
6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid piperidin-1-ylamide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-methyl-1-methylcarbamoyl-ethyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
6-Cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid piperidin-1-ylamide;
5-Cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
5-Cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
5-Cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;
6-Cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
6-Cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid ((S)-2-cyclopropyl-1-thiazol-2-yl-ethyl)-amide;
6-Cyclopropylmethoxy-5-(2-oxo-pyrrolidin-1-yl)-pyridine-2-carboxylic acid (1-methyl-1-oxazol-2-yl-ethyl)-amide;
6-Cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;
6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid [1-(4,5-dihydro-oxazol-2-yl)-1-methyl-ethyl]-amide;
6-Cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid ((S)-3-methyl-1-thiazol-2-yl-butyl)-amide;
6-Cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid ((S)-2-cyclopropyl-1-thiazol-2-yl-ethyl-amide;
6-Cyclopropylmethoxy-pyridine-2-carboxylic acid piperidin-1-ylamide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-methyl-1-[1,2,4]oxadiazol-3-yl-ethyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
6-Cyclopropylmetboxy-5-(3-hydroxy-azetidin-1-yl)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;
6-(4-Chloro-phenyl)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
6-(Cyclopropylmethoxy)-5-(1,1-dioxido-1,2-isothiazolidin-2-yl)-N-[2-(1,3-thiazol-2-yl) propan-2-yl]pyridine-2-carboxamide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-pyrrolidin-1-yl)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-pyrrolidin-1-yl)-pyridine-2-carboxylic acid (1-methyl-1-methylcarbamoybethyl)-amide;
6-(3-Chloro-phenyl)-5-methoxy-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;
5-Chloro-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-methyl-1-[1,2,4]oxadiazol-3-yl-ethyl)-amide;
6-Cyclohexyl-pyridine-2-carboxylic acid (2-hydroxy-cyclohexyl)-amide;
6-Cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-methyl-1-methylcarbamoyl-ethyl)-amide;
2-[(6-Cyclohexyl-pyridine-2-carbonyl)-amino]-cyclohexanecarboxylic acid methyl ester;
6-Cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid (1-methyl-1-oxazol-2-yl-ethyl)-amide;
6-Cyclopentyl-pyridine-2-carboxylic acid piperidin-1-ylamide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-2-cyclopropyl-1-thiazol-2-yl-ethyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;
5-Cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;
5-Chloro-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
5-Chloro-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
5-Bromo-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;
5-Cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-pyrrolidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;
6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;
6-Cyclopropylmethoxy-5-(tetrahydro-furan-3-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
6-Cyclopropylmethoxy-5-(tetrahydro-furan-2-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-amide;
6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (1-methyl-1-[1,2,4]oxadiazol-3-yl-ethyl)-amide;
6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;
6-Cyclohexyl-pyridine-2-carboxylic acid (2-hydroxymethyl-cyclohexyl)-amide;
6-Cyclopropylmethoxy-5-(tetrahydro-furan-2-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
6-Cyclopropylmethoxy-5-(tetrahydro-furan-3-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (1-methyl-1-oxazol-2-yl-ethyl)-amide;
6-Cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;
6-Cyclopropylmethoxy-5-(3-hydroxy-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
5-Cyclopropylamino-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;
5-Cyclopropylamino-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-cyclopropylmethyl-2-hydroxy-2-methyl-propyl)-amide;
6-Cyclopropylmethoxy-5-(tetrahydro-furan-3-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (2-hydroxy-cyclohexyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-cyclopropylmethyl-2-hydroxy-2-methyl-propyl)-amide;
6-Cyclopropylmethoxy-5-(tetrahydro-furan-3-yl)-pyridine-2-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide;
5-Cyclopropyl-6-(2-methoxy-ethoxy)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-2-cyclopropyl-1-thiazol-2-yl-ethyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (pyridin-2-ylmethyl)-amide;
[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-methanone;
6-Cyclopropylmethoxy-5-(3-hydroxy-oxetan-3-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
5-Cyclopropyl-6-(2-methoxy-ethoxy)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1,1-dimethyl-3-morpholin-4-yl-propyl)-amide;
5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(2-methoxy-ethoxymethyl)-ethyl]-amide;
5-Cyclopropylamino-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide;
6-Cyclopropylmethoxy-5-(1-hydroxy-cyclobutyl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
5-Cyclopropyl-6-(2-methoxy-ethoxy)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;
5-[Bis-(2,2,2-trifluoro-ethyl)-amino]-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
5-[Bis-(2,2,2-trifluoro-ethyl)-amino]-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
N-(2-Cyanopropan-2-yl)-5-cyclopropyl-6-(cyclopropylmethoxy)picolinamide;
(S)-5-Cyclopropyl-6-(cyclopropylmethoxy)-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)picolinamide;
N-(1-Amino-2,3-dimethyl-1-oxobutan-2-yl)-5-cyclopropyl-6-(cyclopropylmethoxy)picolinamide;
N-(1-Amino-2-methyl-1-oxobutan-2-yl)-5-cyclopropyl-6-(cyclopropylmethoxy)picolinamide;
5-Cyclopropyl-6-(cyclopropylmethoxy)-N-(1-(5-methyl-1,2,4-oxadiazol-3-yl)cyclobutyl)picolinamide;
(S)-N-(2-Amino-2-oxo-1-phenylethyl)-5-cyclopropyl-6-(cyclopropylmethoxy)picolinamide;
(R)-N-(2-Amino-2-oxo-1-phenylethyl)-5-cyclopropyl-6-(cyclopropylmethoxy)picolinamide;
(R)-5-Cyclopropyl-6-(cyclopropylmethoxy)-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide;
5-Cyclopropyl-6-(cyclopropylmethoxy)-N-(1-(hydroxymethyl)cyclopentyl)picolinamide;
5-Cyclopropyl-6-(cyclopropylmethoxy)-N-(2-(3-methyl-1,2,4-oxadiazol-5-yl)propan-2-yl)picolinamide;
5-Bromo-6-(4-fluoro-phenoxy)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
N-(1-Amino-2,4-dimethyl-1-oxopentan-2-yl)-5-cyclopropyl-6-(cyclopropylmethoxy)picolinamide;
N-(1-Amino-3,3-dimethyl-1-oxobutan-2-yl)-5-cyclopropyl-6-(cyclopropylmethoxy)picolinamide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (4-carbamoyl-tetrahydro-pyran-4-yl)-amide;
(S)-5-Cyclopropyl-6-(cyclopropylmethoxy)-N-(4-methyl-1-(methylamino)-1-oxopentan-2-yl)picolinamide;
(S)-5-Cyclopropyl-6-(cyclopropylmethoxy)-N-(4,4-dimethyl-1-(methylamino)-1-oxopentan-2-yl)picolinamide;
5-Cyclopropyl-N-((S)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-6-((tetrahydrofuran-2-yl)methoxy)picolinamide;
5-Cyclopropyl-N-((S)-4-methyl-1-(methylamino)-1-oxopentan-2-yl)-6-((tetrahydrofuran-2-yl)methoxy)picolinamide;
5-Cyclopropyl-N-((S)-4,4-dimethyl-1-(methylamino)-1-oxopentan-2-yl)-6-((tetrahydrofuran-2-yl)methoxy)picolinamide;
N-((S)-1-Amino-4-methyl-1-oxopentan-2-yl)-5-cyclopropyl-6-((tetrahydrofuran-2-yl)methoxy)picolinamide;
5-Cyclopropyl-6-(4-fluoro-phenoxy)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
5-Bromo-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid ((S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-amide;
5-Cyclopropyl-N-(1-(5-methyl-1,2,4-oxadiazol-3-yl)cyclobutyl)-6-(pyridin-2-ylmethoxy)picolinamide;
5-Cyclopropyl-N-(cyclopropyl(5-methyl-1,2,4-oxadiazol-3-yl)methyl)-6-(cyclopropylmethoxy)picolinamide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((R)-1-hydroxymethyl-1,2-dimethyl-propyl)-amide;
5-Cyclopropyl-6-(cyclopropylmethoxy)-N-(4-hydroxy-2-methylbutan-2-yl)picolinamide;
(S)-5-Cyclopropyl-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)picolinamide;
(S)-5-Cyclopropyl-N-(4,4-dimethyl-1-(methylamino)-1-oxopentan-2-yl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)picolinamide;
(?)-5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide;
(+)-5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide;
5-Cyclopropyl-N-(2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl)-6-(pyridin-2-ylmethoxy)picolinamide;
(S)-N-(1-Amino-4-methyl-1-oxopentan-2-yl)-5-cyclopropyl-6-(pyridin-2-ylmethoxy)picolinamide;
(S)-5-Cyclopropyl-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-6-(pyridin-2-ylmethoxy)picolinamide;
5-Cyclopropyl-N-(2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)picolinamide;
(S)-5-Cyclopropyl-N-(4-methyl-1-(methylamino)-1-oxopentan-2-yl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)picolinamide;
2-(6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinamido)-2-ethylbutanoic acid;
(S)-6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)picolinamide;
(S)-6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-(4,4-dimethyl-1-(methylamino)-1-oxopentan-2-yl)picolinamide;
(S)-N-(4-Methyl-1-(methylamino)-1-oxopentan-2-yl)-6-(3-(trifluoromethyl)phenyl)picolinamide;
(S)-N-(3,3-Dimethyl-1-(methylamino)-1-oxobutan-2-yl)-6-(3-(trifluoromethyl)phenyl)picolinamide;
(S)-5-Cyclopropyl-6-(cyclopropylmethoxy)-N-(2,2,2-trifluoro-1-(pyridin-3-yl)ethyl)picolinamide;
(R)-5-Cyclopropyl-6-(cyclopropylmethoxy)-N-(2,2,2-trifluoro-1-(pyridin-3-yl)ethyl)picolinamide;
5-Cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methy]-amide;
2-({5-[Bis-(2,2,2-trifluoro-ethyl)-amino]-6-cyclopropylmethoxy-pyridine-2-carbonyl}-amino)-2-ethyl-butyric acid methyl ester;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-2-cyclopropyl-1-dimethylcarbamoyl-ethyl)-amide;
5-Cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylic acid (2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((?)-methylcarbamoyl-phenyl-methyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((+)-dimethylcarbamoyl-phenyl-methyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((?)-dimethylcarbamoyl-phenyl-methyl)-amide;
6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3-dimethyl-1-methylcarbamoyl-butyl)-amide;
6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide;
6-(Tetrahydro-pyran-4-ylmethoxy)-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3-dimethyl-1-methylcarbamoyl-butyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-dimethylcarbamoyl-3-methyl-butyl)-amide;
2-{[5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carbonyl]-amino}-2-ethyl-butyric acid methyl ester;
6-Cyclopropylmethoxy-5-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-pyridine-2-carboxylic acid ((S)-3,3-dimethyl-1-methylcarbamoyl-butyl)-amide;
6-Cyclopropylmethoxy-5-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
6-Cyclopropylmethoxy-5-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxlic acid ((R)-2,2,2-trifluoro-1-pyridin-3-yl-ethyl)-amide;
2-Ethyl-2-{[6-(tetrahydro-pyran-4-ylmethoxy)-5-trifluoromethyl-pyridine-2-carbonyl]-amino}-butyric acid methyl ester;
(S)-2-[(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-3,3-dimethyl-butyric acid methyl ester;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(?)-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(+)-3-methyl-1-(5-methyl-[1,2,4]oxadiazol -3-yl)-butyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(+)-3-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-butyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(+)-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-propyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(?)-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-propyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((?)-cyano-methyl-methyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((?)-1-cyano-3-methyl-butyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((+)-cyano-cyclopropyl-methyl)-amide;
2-[(6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid methyl ester;
5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
2-[(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid methyl ester;
2-[(6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid;
6-(Tetrahydro-pyran-4-ylmethoxy)-5-trifluoromethyl-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
2-Ethyl-2-{[6-(tetrahydro-furan-2-ylmethoxy)-5-trifluoromethyl-pyridine-2-carbonyl]-amino}-butyric acid ethyl ester;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (dimethylcarbamoyl-phenyl-methyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-2-cyclopropyl-1-dimethylcarbamoyl-ethyl)-amide;
2-[(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid ethyl ester;
(S)-3-Cyclopropyl-2-[(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-propionic acid methyl ester;
6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
6-(Tetrahydro-pyran-4-ylmethoxy)-5-trifluoromethyl-pyridine-2-carboxylic acid (1-dimethylcarbamoyl-1-ethyl-propyl)-amide;
2-{[6-Cyclopropylmethoxy-5-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-pyridine-2-carbonyl]amino}-2-ethyl-butyric acid ethyl ester;
6-(Tetrahydro-furan-2-ylmethoxy)-5-trifluoromethyl-pyridine-2-carboxylic acid (1-dimethylcarbamoyl-1-ethyl-propyl)-amide;
2-[(5-Bromo-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid ethyl ester;
2-{[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-amino}-2-ethyl-butyric acid ethyl ester;
2-{[6-Cyclopropylmethoxy-5-(3,3-difluoro-2-oxo-azetidin-1-yl)-pyridine-2-carbonyl]-amino}-2-ethyl-butyric acid methyl ester;
(S)-2-[(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-4-methyl-pentanoic acid methyl ester;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-cyano-3-methyl-butyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [3-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-butyl]-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-hydroxymethyl-1,3-dimethyl-butyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-(azetidine-1-carbonyl)-1-ethyl-propyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-ethyl-1-(2-methoxy-ethylcarbamoyl)-propyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-ethyl-1-(ethyl-methyl-carbamoyl)-propyl]-amide;
6-(4-Fluoro-benzyl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
6-(4-Fluoro-benzyl)-pyridine-2-carboxylic acid ((R)-2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-hydroxymethyl-1,2-dimethyl-propyl)-amide;
5-Bromo-6-(3-methyl-oxetan-3-ylmethoxy)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;
5-Bromo-6-(3-methyl-oxetan-3-ylmethoxy)-pyridine-2-carboxylic acid (3-thiazol-2-yl-oxetan-3-yl)-amide;
5-Bromo-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (3-thiazol-2-yl-oxetan-3-yl)-amide;
5-Bromo-6-(3-methyl-oxetan-3-ylmethoxy)-pyridine-2-carboxylic acid (2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-(cyclopropylmethyl-carbamoyl)-1-ethyl-propyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-methyl-1-pyridin-2-yl-ethyl)-amide;
6-(4-Fluoro-benzyl)-pyridine-2-carboxylic acid ((S)-3,3-dimethyl-1-methylcarbamoyl-butyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-(3,3-difluoro-azetidine-1-carbonyl)-1-ethyl-propyl]-amide;
2-[(6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid ethyl ester;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-methyl-5-oxo-pyrrolidin-3-yl)-amide;
2[(6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1,1-dioxo-tetrahydro-1?6-thiophen-3-yl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid N?-(1,1-dioxo-tetrahydro-1?6-thiophen-3-yl)-hydrazide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-methyl-1-(4-methyl-thiazol-2-yl)-ethyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-(5-amino-[1,2,4]oxadiazol-3-yl)-1-methyl-ethyl]-amide;
6-(2,2,3,3,3-Pentafluoro-propoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
5-Cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
5-Cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid ((S)-3,3-dimethyl-1-methylcarbamoyl-butyl)-amide;
5-Cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
5-Cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid ((S)-carbamoyl-phenyl-methyl)-amide;
5-Cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide;
5-Cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide;
5-Cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (3-thiazol-2-yl-oxetan-3-yl)-amide;
5-Cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;
5-Cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (2,2-dimethyl-1-thiazol-2-yl-propyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [1-(3,3-difluoro-azetidine-1-carbonyl)-1-ethyl-propyl]-amide;
6-(4-Fluoro-benzyl)-pyridine-2-carboxylic acid N?-(1,1-dioxo-tetrahydro-1?6-thiophen-3-yl)-hydrazide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-(3-amino-[1,2,4]oxadiazol-5-yl)-1-methyl-ethyl]-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [(S)-1-(3,3-difluoro-azetidine-1-carbonyl)-2,2-dimethyl-propyl]-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [(S)-1-(3,3-difluoro-azetidine-1-carbonyl)-3-methyl-butyl]-amide;
2-[(6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid ethyl ester;
5-Cyclopropyl-6-((R)-3-hydroxy-1-trifluoromethyl-propoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
5-Cyclopropyl-6-((R)-4,4,4-trifluoro-3-hydroxy-butoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (3-methyl-1-pyridin-2-yl-butyl)-amide;
6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid [1-(3,3-difluoro-azetidine-1-carbonyl)-1-ethyl-propyl]-amide;
6-[(4-Fluoro-phenyl)-hydroxy-methyl]-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
6-[(4-Fluoro-phenyl)-hydroxy-methyl]-pyridine-2-carboxylic acid [(S)-3-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-butyl]-amide;
5-Cyclopropyl-6-((S)-3-hydroxy-1-trifluoromethyl-propoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
5-Cyclopropyl-6-((S)-4,4,4-trifluoro-3-hydroxy-butoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (3-methyl-1-pyridazin-3-yl-butyl)-amide;
6-Cyclopropylmethoxy-5-(3-oxo-azetidin-1-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(+)-1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(?)-1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (3-methyl-1-pyridin-3-yl-butyl)-amide;
5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;
5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(S)-carbamoyl-(4-fluoro-phenyl)-methyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(S)-carbamoyl-(4-chloro-phenyl)-methyl]-amide;
6-(2-Methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
6-Isobutylsulfanyl-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid ((S)-2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide;
2-{[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carbonyl]-amino}-2-ethyl-butyric acid;
6-Cyclopropylmethoxy-5-(3-oxo-pyrrolidin-1-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide,
6-(2-Methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid [(S)-3-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-butyl]-amide;
(S)-2-{[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carbonyl]-amino}-4-methyl-pentanoic acid;
2-{[5-Cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carbonyl]-amino}-2-ethyl-butyric acid;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-methyl-1-(4-methyl-5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (3-methyl-1-pyrimidin-2-yl-butyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methylsulfanyl-propyl)-amide;
6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid {(S)-3-methyl-1-[(7-nitro-benzo[1,2,5]oxadiazol-4-ylamino)-methyl]-butyl}-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methanesulfonyl-propyl)-amide;
5-Cyclopropyl-6-isobutylsulfanyl-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
6-(4-Fluoro-3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (3-methanesulfonyl-1,1-dimethyl-propyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-thiazol-2-yl)-ethyl]-amide;
5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-thiazol-2-yl)-ethyl]-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((R)-3-methyl-1-pyridazin-3-yl-butyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-3-methyl-1-pyridazin-3-yl-butyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-ethyl-1-(2-hydroxy-ethylcarbamoyl)-propyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(+)-2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(?)-2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid tert-butylamide;
2-{[5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carbonyl]-amino}-2-ethyl-butyric acid ethyl ester;
5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid ((S)-3,3-dimethyl-1-methylcarbamoyl-butyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-2-oxo-tetrahydro-furan-3-yl)-amide;
N?-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-N-cyclopropylmethyl-hydrazinecarboxylic acid tert-butyl ester;
5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid ((S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-amide;
5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid ((S)-2,2,2-trifluoro-1-pyridin-3-yl-ethyl)-amide;
(S)-2-[(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-4-methyl-pentanoic acid tert-butyl ester;
5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid tert-butylamide;
5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid tert-butylamide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (3-methyl-oxetan-3-yl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (2-oxo[1,3]oxazinan-3-yl)-amide;
5-Cyclopropyl-6-(2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3methyl-butyl)-amide;
5-Cyclopropyl-6-(2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid [1-methyl-1(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((+)-carbamoyl-cyclopropyl-methyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((?)-carbamoyl-cyclopropyl-methyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((+)-carbamoyl-cyclopropyl-methyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((?)-carbamoyl-cyclopropyl-methyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-trifluoromethyl-cyclopropyl)-amide;
(+)-5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(3-hydroxy-pyrrolidin-1-ylcarbamoyl)-ethyl]-amide;
(?)-5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(3-hydroxy-pyrrolidin-1-ylcarbamoyl)-ethyl]-amide;
(+)-5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid [1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
and

(?)-5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid [1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide.

US Pat. No. 9,340,573

AZAINDOLINES

Hoffmann-La Roche Inc., ...

1. A compound of Formula I:

wherein:
W is selected from the group
a) H,
b) C1-6-alkyl that optionally includes 1-3 deuterium atoms,

c) C1-6-alkyl that optionally may be substituted with SO2R5 and OR5
Y is C1-6-alkyl that optionally may be substituted with OR5;

Z is N;
R1 is selected from the group

a) C1-6-alkyl that optionally may be substituted with SO2R5,

b) C3-7-cycloalkyl,

c) heterocyclic, and
d) aryl;
R2 is C1-6-alkyl that optionally may be substituted with NHC(O)R6, NHSO2R5, NHCOOR6 and NHR6;

R3 and R4 may be the same or different and each is independently selected from the group

a) H, and
b) C1-6-alkyl;

R5 is selected from the group

a) H,
b) C1-6-alkyl,

c) NR7R8, and

d) aryl;
R6 is selected from the group

a) H
b) aryl that optionally may be substituted with C1-6-alkyl, OR5, halogen, C(O)OR5, C(O)NR7R8, aryl, heterocyclyl, C(O)R9, SO2R5, cyano and CF3,

c) C1-6-alkyl that optionally may be substituted with CF3, SO2R5 and aryl that optionally may be substituted with C1-6-alkyl and halogen,

d) OR5,

e) NR7R8,

f) heteroaryl that optionally may be substituted with C1-6-alkyl, OR5, halogen, aryl and oxo, and

g) heterocyclyl;
R7 and R8 may be the same or different and each is independently selected from the group

a) H,
b) C1-6-alkyl, and

c) aryl; and
R9 is selected from the group

a) C1-6-alkyl, and

b) aryl;
or a pharmaceutically acceptable salt thereof.

US Pat. No. 9,403,768

INDOLINES

Hoffmann-La Roche Inc., ...

1. A compound of Formula I:

wherein
W is selected from the group
a) C1-6-alkyl that optionally includes 1-3 deuterium atoms,

b) C1-6-alkyl that optionally may be substituted with SO2R5 and OR5
Y is C1-6-alkyl;

Z is CH;
R1 is selected from the group

a) C1-6-alkyl, and

b) aryl;
R2 is CONHR6;

R3 and R4 may be the same or different and each is independently selected from the group

a) H, and
b) C1-6-alkyl;

R5 is selected from the group

a) C1-6-alkyl, and

b) aryl;
R6 is selected from the group

a) H
b) aryl that optionally may be substituted with C1-6-alkyl, OR5, halogen, aryl, and C(O)R7, and

c) C1-6-alkyl that optionally may be substituted with aryl that optionally may be substituted with C1-6-alkyl and halogen;

R7 is selected from the group

a) C1-6-alkyl, and

b) aryl;
or a pharmaceutically acceptable salt thereof.

US Pat. No. 9,266,904

6-BRIDGED HETEROARYLDIHYDROPYRIMIDINES FOR THE TREATMENT AND PROPHYLAXIS OF HEPATITIS B VIRUS INFECTION

Hoffmann-La Roche Inc., ...

1. A compounds of formula (I)
wherein
R1 is C1-6alkyl;

R2 is phenyl, which is once or twice or three times substituted by halogen or C1-6alkyl;

R3 is hydrogen or C1-6alkyl;

R4 is


wherein one of R5a and R6a is hydrogen or halogen, and the other one is hydrogen, halogen or hydroxy;

one of R5b and R6b is hydrogen or halogen, and the other one is hydrogen or halogen;

R9 is hydrogen or carboxy;

one of R17 and R18 is hydrogen, halogen, hydroxy, amino, C1-6alkylsulfonylamino or trifluoromethylcarbonylamino, the other one is hydrogen, halogen, hydroxy-CyH2y—, C1-6alkylcarbonyl-O—, C1-6alkoxycarbonyl-CyH2y—, carboxy-CyH2y—O—, carboxy-CyH2y—, C1-6alkylcarbonyl-NH—, C1-6alkylsulfonyl-NH—, aminocarbonyl-NH— or aminosulfonyl-NH—;

wherein —CyH2y— is unsubstituted once or more times substituted by hydroxy;

or R6a and R17 together with the carbon atoms, to which they are attached, form a ring of isoxazolyl, pyrazolyl or oxo-dihydropyrazolyl,
which ring is unsubstituted or once or more times substituted by C1-6alkyl;

or R17 and R18 together with the carbon atom, to which they are attached, form diazirinyl;

X is oxygen; sulfur; —N(carbonylC1-6alkyl)-; or —C(R15R16)—, wherein one of R15 and R16 is hydrogen or hydroxy, and the other one is hydrogen or carboxy-CyH2y—;

r is 0 or 1;
m is 0 or 1;
n is 0 or 1;
y is 0-6;
or R4 is


wherein R7 is hydrogen or halogen;

R8 is hydrogen or halogen;

R10 is hydrogen, halogen, hydroxy-CyH2y— or C1-6alkylcarbonylamino-CyH2y—;

R11 is hydrogen or carboxy;

R12 is hydrogen or carboxy;

W is a bond, oxygen, —CH2—, —CF2— or —N(carbonylC1-6alkyl)-;

t is 1 or 2;
y is 0-6;
with the proviso that

is excluded;
or R4 is


wherein R19 is hydrogen; C1-6alkyl, which is unsubstituted or once or more times substituted by halogen; C1-6alkoxycarbonyl-CyH2y—; hydroxy-CyH2y-carbonyl; carboxy-CyH2y-carbonyl; C1-6alkylaminosulfonyl; C1-6alkylcarbonyl; C1-6alkylsulfonyl; aminocarbonyl; or aminosulfonyl;

Y is carbonyl or —CH2—;

u is 0 or 1;
y is 0-6;
or R4 is


wherein M is a bond, —CH2— or —N(R14)—CH2—;

R14 is C1-6alkoxycarbonyl;
or pharmaceutically acceptable salts, or tautomerism isomers, or enantiomers, or diastereomers thereof.
US Pat. No. 9,187,564

ANTIBODIES AGAINST HUMAN TWEAK AND USES THEREOF

HOFFMANN-LA ROCHE INC., ...

1. A chimeric, humanized or T-cell epitope depleted variant antibody binding to human TWEAK, comprising
a) a variable light chain of SEQ ID NO:1 and a variable heavy chain of SEQ ID NO:5,
b) a variable light chain of SEQ ID NO:9 and a variable heavy chain of SEQ ID NO:13 or
c) a variable light chain of SEQ ID NO:17 and a variable heavy chain of SEQ ID NO:21.

US Pat. No. 9,181,218

COMPOUNDS FOR IMPROVED STEM CELL DIFFERENTIATION INTO HEPATOCYTES

Hoffmann-La Roche Inc., ...

1. A compound of formula I:

or a pharmaceutically acceptable salt or ester thereof; wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are independently hydrogen or halogen; and R11 is hydrogen or hydroxy.

US Pat. No. 9,657,054

IMMUNOGLOBULIN AGGREGATE REMOVAL

Hoffmann-La Roche Inc., ...

1. A method for obtaining an immunoglobulin in monomeric form, characterized in that the method comprises the following steps:
a) incubating a solution comprising the polypeptide in monomeric form and in aggregated form with underivatized controlled
pore glass with a surface of 100 m 2 to 150 m 2 per gram of immunoglobulin at a pH value of from pH 4.5 to pH 5.5, wherein the incubating is by applying the solution to a
chromatography column comprising the “underivatized”controlled pore glass, and

b) recovering a flow-through and thereby obtaining the immunoglobulin in monomeric form.

US Pat. No. 9,458,106

PHENYL-PYRIDINE/PYRAZINE AMIDES FOR THE TREATMENT OF CANCER

Hoffmann-La Roche Inc., ...

1. Compounds of formula (I)

wherein
R1 is phenyl, pyridinyl, thienyl, pyrimidinyl, pyrazolyl, pyridinonyl or pyrrolyl; which is unsubstituted or once or twice substituted
by C1-6alkoxy, C1-6alkyl, halogen or trifluoromethyl;

R2 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl or C1-6alkylsulfonyl;

A is phenyl, pyridinyl, pyridinonyl, thienyl, pyrazolyl or pyrrolyl; which is unsubstituted or once or twice or thrice substituted
by C1-6alkoxy, C1-6alkyl, cyano, halogen, hydroxy or trifluoromethyl;

W is —N— or —CH;
or pharmaceutically acceptable salt thereof.

US Pat. No. 9,284,321

PIPERAZINO[1,2-A]INDOL-1-ONES AND [1,4]DIAZEPINO[1,2-A]INDOL-1-ONE

Hoffmann-La Roche Inc., ...

1. A compound of formula I

wherein
R1 is hydrogen, halogen, lower alkyl, lower alkoxy, lower alkoxy substituted by halogen or cyano;

R2 is hydrogen, lower alkyl or lower alkyl substituted by halogen;

R3 is phenyl, benzo[1,3]dioxolyl, 2,3-dihydro-benzofuran-5-yl or a 5- and 6-membered heteroaryl, wherein phenyl and the 5- and
6-membered heteroaryl groups may be substituted by one or more substituents, selected from cyano, nitro, amino and lower di-alkylamino,
lower alkyl sulfonyl, lower alkoxy, lower alkoxy substituted by halogen, halogen, lower alkyl, lower alkyl substituted by
halogen or lower alkyl substituted by hydroxyl;

X is —CH(lower alkyl)-, —CH2—, —CH2CH2— or —CH(lower alkyl)CH2—;

R is hydrogen or lower alkyl;
n is 1 or 2;
or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers
thereof.

US Pat. No. 9,481,706

PURIFICATION OF NON-GLYCOSYLATED POLYPEPTIDES

Hoffmann-La Roche Inc., ...

1. A method for purifying a non-glycosylated polypeptide, wherein the non-glycosylated polypeptide is interferon, the method
comprising a sequence of three successive chromatography steps comprising
a) a first chromatography step consisting of hydrophobic interaction chromatography;
b) a second chromatography step consisting of anion exchange chromatography; and
c) a third chromatography step consisting of cation exchange chromatography.

US Pat. No. 10,246,460

SYNTHESIS OF TRANS-8-CHLORO-5-METHYL-1-[4-(PYRIDIN-2-YLOXY)-CYCLOHEXYL]-5,6-DIHYDRO-4H-2,3,5,10B-TETRAAZA-BENZO[E]AZULENE AND CRYTALLINE FORMS THEREOF

Hoffmann-La Roche Inc., ...

1. A process to synthesize compound formula I, comprising reacting compound formula III with compound formula VI
US Pat. No. 9,587,006

IGF-I POLY (ETHYLENE GLYCOL) CONJUGATES

Hoffmann-La Roche Inc., ...

1. A polypeptide consisting of the amino acid sequence of SEQ ID NO: 28 that is conjugated to poly (ethylene glycol) at the
C-terminal lysine residue of the polypeptide.
US Pat. No. 9,297,025

CONVERSION OF SOMATIC CELLS TO INDUCED REPROGRAMMED NEURAL STEM CELLS (IRNSCS)

HOFFMANN-LA ROCHE INC., ...

1. A method of producing Neural Stem Cells (NSCs), comprising:
a) providing human somatic cells selected from the group consisting of fibroblasts, adipocytes, or keratinocytes,
b) reprogramming said cells to NSCs by introducing a first and a second gene, wherein the first gene is Sox2, and the second
gene is selected from the group consisting of Bmi1, Mash 1, Sox11, Emx2, Foxg1 and Pax6; and

c) culturing the cells of step (b) in medium comprising growth factors selected from the group consisting of FGF2, EGF and
BDNF and a small molecule inhibitor of Rho-associated coiled-coil forming protein serine/threonine kinase (ROCK inhibitor),
to produce NSCs.

US Pat. No. 9,233,978

6-FUSED HETEROARYLDIHYDROPYRIMIDINES FOR THE TREATMENT AND PROPHYLAXIS OF HEPATITIS B VIRUS INFECTION

HOFFMANN-LA ROCHE INC., ...

1. A compound of formula (I)

wherein
R1 is hydrogen, halogen or C1-6alkyl;

R2 is hydrogen or halogen;

R3 is hydrogen or halogen;

R4 is C1-6alkyl;

R5 is hydrogen, hydroxyC1-6alkyl, aminocarbonyl, C1-6alkoxycarbonyl or carboxy;

R6 is hydrogen, C1-6alkoxycarbonyl or carboxy-CmH2m—;

X is carbonyl or sulfonyl;
Y is —CH2—, —O— or —N(R7)—,

wherein R7 is hydrogen, C1-6alkyl, haloC1-6alkyl, C3-7cycloalkyl-CmH2m—, C1-6alkoxycarbonyl-CmH2m—, —CtH2t—COOH, -haloC1-6alkyl-COOH, —(C1-6alkoxy)C1-6alkyl-COOH, —C1-6alkyl-O—C1-6alkyl-COOH, —C3-7cycloalkyl-CmH2m—COOH, —CmH2m—C3-7cycloalkyl-COOH, hydroxy-CtH2t, carboxyspiro[3.3]heptyl, carboxyphenyl-CmH2m— or carboxypyridinyl-CmH2m—;

W is —CH2—, —C(C1-6alkyl)2-, —O— or carbonyl;

n is 0 or 1;
m is 0-7; and
t is 1-7;
or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.
US Pat. No. 9,403,896

SERPIN-FINGER FUSION POLYPEPTIDE

Hoffmann-La Roche Inc., ...

1. A fusion polypeptide comprising in an N-terminal to C-terminal direction a serpin-finger polypeptide, wherein the amino
acid sequence of the serpin-finger polypeptide is selected from the group consisting of SEQ ID NO:1, 2, 3, 4, 5, 6, 7, 8,
9, 10, 11, 15, 16 ,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 82, and 83, fused to an HIV fusion inhibitor
polypeptide, wherein the amino acid sequence of the HIV fusion inhibitor polypeptide is selected from the group consisting
of SEQ ID NO:13, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, and 42.
US Pat. No. 9,187,563

ANTI-HUMAN EPO RECEPTOR ANTIBODIES AND METHODS OF USE

Hoffmann-La Roche Inc., ...

1. An isolated antibody that specifically binds to human erythropoietin (EPO) receptor, characterized in that the antibody
binds to human EPO receptor fragment of SEQ ID NO: 1 and does not specifically bind to a protein obtainable from human endothelial
cells that has a molecular weight of about 66 kD.

US Pat. No. 9,226,916

PYRROLIDINE DERIVATIVES

HOFFMANN-LA ROCHE INC., ...

1. A compound of formula I

wherein
R1 is hydrogen, halogen, cyano, lower alkyl or lower alkyl substituted by halogen;

n is 1, 2 or 3, wherein when n is 2 or 3, each R1 is the same or different;

R2 is hydrogen or methyl;

R3 is (CH2)r—C(O)NH2 or (CH2)r—CN, wherein r is 1 or 2, or

is a non aromatic heterocyclic group

wherein
X is N or CH;
Y is —C(R)(R7)—; —N(R7?)—, —S(O)2 or O;

R6 is hydrogen, di-lower alkyl or ?O;

o and m are each independently 0, 1 or 2;
p is 0, 1 or 2;
R is hydrogen, halogen, or lower alkyl;
R7 is hydrogen, halogen, hydroxy, lower alkyl substituted by hydroxy, cyano, or lower alkoxy;

R7? is hydrogen, —C(O)-lower alkyl, —C(O)O-lower alkyl, —C(O)CH2O-lower alkyl,

—C(O)CH2CN, or is

—C(O)-cycloalkyl, cycloalkyl or —CH2-cycloalkyl,

wherein the cycloalkyl groups are optionally substituted by halogen, lower alkoxy, lower alkyl substituted by halogen, cyano,
—CH2O-lower alkyl, or lower alkyl, or is

—C(O)-heterocycloalkyl, heterocycloalkyl, —C(O)-heteroaryl or heteroaryl,
which heterocycloalkyl or heteroaryl groups are optionally substituted by halogen, lower alkyl, ?O, lower alkoxy, lower alkyl
substituted by halogen, C(O)NH-lower alkyl, C(O)NH2,C(O)-lower alkyl, S(O)2— lower alkyl or cyano;

Z is —O—
R4 is

lower alkyl substituted by halogen,
lower alkyl substituted by hydroxy,
lower alkyl substituted by cycloalkyl,
(CH2)s—O-lower alkyl, wherein s is 2 or 3,

CH(CH3)CH2—O-lower alkyl,

(CH2)qCN, bicyclo[2.2.1]heptanyl,

(CH2)q-cycloalkyl optionally substituted by lower alkyl, lower alkyl substituted by halogen, lower alkoxy or by halogen, or is

(CH2)q-heterocycloalkyl, (CH2)q-aryl, CH(lower alkyl)-aryl, CH(cycloalkyl)-aryl, or (CH2)q-heteroaryl,

which heterocycloalkyl, aryl or heteroaryl rings are optionally substituted by halogen, hydroxy, lower alkyl, lower alkyl
substituted by halogen, S(O)2-lower alkyl, cyano or by lower alkoxy;

q is 0, 1 or 2;
or a pharmaceutically active salt thereof.
US Pat. No. 9,221,910

ANTIBODIES AGAINST HUMAN CSF-1R

HOFFMANN-LA ROCHE INC., ...

1. An isolated antibody binding to human macrophage colony-stimulating factor 1 receptor (CSF-1R), or an antibody fragment
thereof, wherein the antibody comprises
a heavy chain variable domain comprising a CDR3 region of SEQ ID NO: 1, a CDR2 region of SEQ ID NO: 2, and a CDR1 region of
SEQ ID NO:3, and a light chain variable domain comprising a CDR3 region of SEQ ID NO: 4, a CDR2 region of SEQ ID NO:5, and
a CDR1 region of SEQ ID NO:6.

US Pat. No. 9,458,153

DIHYDROQUINOLIZINONES FOR THE TREATMENT AND PROPHYLAXIS OF HEPATITIS B VIRUS INFECTION

Hoffmann-La Roche INC., ...

1. A compound of formula IA,

wherein
R1 is hydrogen, halogen or C1-6alkoxy;

R2 is hydrogen, halogen, C1-6alkyl, C1-6alkoxy, C3-7cycloalkyl, hydroxy or phenyl-CxH2x—O—;

R4 is hydrogen or halogen;

R5 is hydrogen or C1-6alkyl;

R6 is hydrogen; C1-6alkyl, which is unsubstituted or once, twice or three times substituted by fluoro; C3-7cycloalkyl; C1-6alkylC3-7cycloalkyl; or phenyl-CxH2x—;

R7 is hydrogen; C1-6alkyl, which is unsubstituted or substituted with one to three substituents independently selected from fluoro, hydroxy and
ethenyl; C1-6alkoxyC1-6alkyl; C1-6alkoxyC1-6alkoxyC1-6alkyl; aminoC1-8alkyl; C1-6alkylcarbonylaminoC1-8alkyl; C1-6alkylsulfonylaminoC1-8alkyl; C1-6alkylsulfanylC1-6alkyl; C1-6alkylsulfonylC1-6alkyl; cyanoC1-6alkyl; C3-7cycloalkylC1-6alkyl; cyanoC3-7cycloalkylC1-6alkyl; phenylC1-6alkyl; pyrrolidinylcarbonylC1-6alkyl; C2-6alkynyl; hydroxyC1-6alkylC2-6alkynyl; aminoC1-6alkoxyC1-6alkyl; C1-6alkylaminoC1-6alkoxyC1-6alkyl; carboxyC1-6alkyl; C1-6 alkoxycarbonylaminoC1-8alkyl; heteroarylC1-6alkyl, wherein heteroaryl is N-containing monocyclic heteroaryl; or heterocycloalkylC1-6alkyl, wherein heterocycloalkyl is monocyclic heterocycloalkyl;

x is 1-6;
or pharmaceutically acceptable salts, or enantiomers thereof.

US Pat. No. 9,187,429

PHENYL-TETRAHYDROISOQUINOLINE DERIVATIVES

HOFFMANN-LA ROCHE INC., ...

1. A compound of formula (I)

wherein
R1, R2, R3 and R4 are independently selected from H, halogen, cyano, nitro, alkoxycarbonyl, cycloalkoxycarbonyl, substituted aminocarbonyl,
substituted aminosulfonyl, alkyl, haloalkyl, cycloalkyl, alkoxy, haloalkoxy and cycloalkoxy, wherein substituted aminocarbonyl
and substituted aminosulfonyl are substituted on the nitrogen atom with one to two substituents independently selected from
H, alkyl, cycloalkyl, hydroxyalkyl and alkoxyalkyl;

R5 is H, halogen, alkyl or cycloalkyl;

R6 is H, alkyl, haloalkyl, cycloalkyl, substituted aryl or substituted heteroaryl, wherein substituted aryl or substituted heteroaryl
are substituted with R19, R20 and R21;

R7, R8, R9, R10, R11 and R12 are independently selected from H, halogen, alkyl and haloalkyl;

A is —(CR13R14)p—NR15R16 or —(CR13R14)p—OR16;

R13 and R14 are independently selected from H, alkyl, haloalkyl, cycloalkyl and halocycloalkyl;

R15 is H, alkyl, haloalkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl or haloalkoxyalkyl;

R16 is H, alkyl, haloalkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, oxetanylalkyl, —CH2—C(O)OH, —CH2—C(O)OR17, —CH2—C(O)—NR17R18, —S(O)R17, —S(O)2R17, —S(O)2OR17, —S(O)2NR17R18, —C(O)R17, —C(O)OR17 or —C(O)NR17R18;

R17 is alkyl, hydroxyalkyl, haloalkyl, cycloalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, cycloalkylalkyl, cycloalkoxyalkyl, cycloalkylalkoxyalkyl,
alkoxyalkyl, haloalkoxyalkyl, alkoxyalkoxyalkyl or substituted heteroaryl, wherein substituted heteroaryl is substituted with
R22, R23 and R24;

R18 is H, alkyl, haloalkyl, cycloalkyl, alkoxyalkyl, haloalkoxyalkyl or hydroxyalkyl;

R19, R20, R21, R22, R23 and R24 are independently selected from H, halogen, alkyl, haloalkyl, cycloalkyl, alkoxy and haloalkoxy;

n is zero, 1 or 2;
p is zero or 1;
or a pharmaceutically acceptable salt or ester thereof.

US Pat. No. 9,809,599

ARYL-QUINOLINE DERIVATIVES

Hoffmann-La Roche Inc., ...

1. A compound according to formula (I),

wherein
R1 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, halocycloalkyl, haloalkoxy, cycloalkoxy, halocycloalkoxy,
hydroxyalkyl, heterocycloalkyl, substituted heterocycloalkyl, substituted amino, aminocarbonyl or substituted aminocarbonyl,
wherein substituted heterocycloalkyl is substituted with one to three substituents independently selected from the group consisting
of oxo, halogen, alkyl, cycloalkyl and haloalkyl, and wherein substituted amino and substituted aminocarbonyl are substituted
on the nitrogen atom with one to two substituents independently selected from the group consisting of alkyl, cycloalkyl, haloalkyl,
alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, hydroxyalkyl and alkoxyalkyl, with the proviso that R1 is not methyl or ethyl;

R2 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy,
cycloalkoxy, halocycloalkoxy, nitro, cyano, amino, aminoalkyl, substituted amino and substituted aminoalkyl, wherein substituted
amino and substituted aminoalkyl are substituted on the nitrogen atom with one to two substituents independently selected
from the group consisting of alkyl, cycloalkyl, haloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, hydroxyalkyl
and alkoxyalkyl;

R3 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy,
cycloalkoxy, halocycloalkoxy, nitro, cyano, amino, aminoalkyl, substituted amino and substituted aminoalkyl, wherein substituted
amino and substituted aminoalkyl are substituted on the nitrogen atom with one to two substituents independently selected
from the group consisting of alkyl, cycloalkyl, haloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, hydroxyalkyl
and alkoxyalkyl;

R4 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy,
cycloalkoxy, halocycloalkoxy, nitro, cyano, amino, aminoalkyl, substituted amino and substituted aminoalkyl, wherein substituted
amino and substituted aminoalkyl are substituted on the nitrogen atom with one to two substituents independently selected
from the group consisting of alkyl, cycloalkyl, haloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, hydroxyalkyl
and alkoxyalkyl;

R5 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy,
cycloalkoxy, halocycloalkoxy, nitro, cyano, amino, aminoalkyl, substituted amino and substituted aminoalkyl, wherein substituted
amino and substituted aminoalkyl are substituted on the nitrogen atom with one to two substituents independently selected
from the group consisting of alkyl, cycloalkyl, haloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, hydroxyalkyl
and alkoxyalkyl;

R6 is selected from the group consisting of phenyl, substituted phenyl, pyridinyl and substituted pyridinyl, wherein substituted
phenyl and substituted pyridinyl are substituted with one to three substituent independently selected from the group consisting
of alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, cycloalkoxy, cycloalkoxyalkyl,
alkylcycloalkylalkyl, halocycloalkyl, halocycloalkylalkyl, halogen, cyano, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl,
haloalkoxy, hydroxyalkoxy, alkoxyalkoxy, alkoxyalkoxyalkyl, hydroxyhaloalkyl, amino and substituted amino, wherein substituted
amino is substituted with one to two substituents independently selected from the group consisting of alkyl, cycloalkyl, haloalkyl,
alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, hydroxyalkyl and alkoxyalkyl;

R7 is selected from the group consisting of —COOH, 3H-[1,3,4]oxadiazol-2-on-5-yl, 3H-[1,3,4]oxadiazole-2-thion-5-yl, 4H-[1,2,4]oxadiazol-5-on-3-yl,
4H-[1,2,4]oxadiazole-5-thion-3-yl, 3H-[1,2,3,5]oxathiadiazole-2-oxide-4-yl, 4H-[1,2,4]thiadiazol-5-on-3-yl, isoxazol-3-ol-5-yl,
5-alkylisoxazol-3-ol-4-yl, 5-cycloalkylisoxazol-3-ol-4-yl, furazan-3-ol-4-yl, 5-alkylsulfonylamino-[1,3,4]oxadiazol-2-yl,
5-cycloalkylsulfonylamino-[1,3,4]oxadiazol-2-yl, 5-alkylsulfonylamino-2H-[1,2,4]triazol-3-yl, 5-cycloalkylsulfonylamino-2H-[1,2,4]triazol-3-yl,
5-alkylisothiazol-3-ol-4-yl, 5-cycloalkylisothiazol-3-ol-4-yl, [1,2,5]thiadiazol-3-ol-4-yl, 1,4-dihydro-tetrazol-5-on-1-yl,
2H-tetrazol-5-ylcarbamoyl, 2H-tetrazole-5-carbonyl, [1,2,4]oxadiazolidine-3,5-dion-2-y, 4H-[1,2,4]oxadiazol-5-on-3-yl, 2,4-dihydro-[1,2,4]triazol-3-on-5-sulfanyl,
4H-[1,2,4]triazole-3-sulfanyl, 4H-[1,2,4]triazole-3-sulfinyl, 4H-[1,2,4]triazole-3-sulfonyl, 4-alkyl-pyrazol-1-ol-5-yl, 4-cycloalkyl-pyrazol-1-ol-5-yl,
4-alkyl-[1,2,3]triazol-1-ol-5-yl, 4-cycloalkyl-[1,2,3]triazol-1-ol-5-yl, 5-alkyl-imidazol-1-ol-2-yl, 5-cycloalkyl-imidazol-1-ol-2-yl,
4-alkyl-imidazol-1-ol-5-yl, 4-cycloalkyl-imidazol-1-ol-5-yl, 4-alkyl-1,1-dioxo-1%-[1,2,5]thiadiazolidin-3-on-5-yl, 4,4-dialkyl-1,1-dioxo-1?6-[1,2,5]thiadiazolidin-3-on-5-yl, 4-cycloalkyl-1,1-dioxo-1?6-[1,2,5]thiadiazolidin-3-on-5-yl, 4,4-dicycloalkyl-1,1-dioxo-1?61,2,5]thiadiazolidin-3-on-5-yl, thiazolidine-2,4-dion-5-yl, oxazolidine-2,4-dion-5-yl, 3-[1-Hydroxy-meth-(E)-ylidene]-pyrrolidine-2,4-dion-1-yl,
3-[1-Hydroxy-meth-(Z)-ylidene]-pyrrolidine-2,4-dion-1-yl, 5-methyl-4-hydroxy-5H-furan-2-on-3-yl, 5,5-dialkyl-4-hydroxy-5H-furan-2-on-3-yl,
5-cycloalkyl-4-hydroxy-5H-furan-2-on-3-yl, 5,5-dicycloalkyl-4-hydroxy-5H-furan-2-on-3-yl, 3-hydroxy-cyclobut-3-ene-1,2-dion-4-yl
and 3-hydroxy-cyclobut-3-ene-1,2-dion-4-amino; and

n is zero or 1;with the proviso that at least one of R2, R3, R4 and R5 is different from hydrogen and that said compound is not 6-methoxy-4-phenyl-2-trifluoromethyl-quinoline-3-carboxylic acid
or 4-(3,4-dimethoxy-phenyl)-2-hydroxymethyl-6,7-dimethoxy-quinoline-3-carboxylic acid; or a pharmaceutically acceptable salt
thereof.
US Pat. No. 9,624,302

NUCLEIC ACIDS ENCODING ANTIBODIES AGAINST HUMAN CSF-1R

HOFFMANN-LA ROCHE INC., ...

1. An isolated nucleic acid encoding an antibody binding to human macrophage colony-stimulating factor 1 receptor (CSF-1R),
or an antibody fragment thereof, wherein the antibody, or antibody fragment thereof, comprises:
a heavy chain variable domain comprising a CDR3 region of SEQ ID NO: 1, a CDR2 region of SEQ ID NO: 2, and a CDR1 region of
SEQ ID NO:3; and a light chain variable domain comprising a CDR3 region of SEQ ID NO: 4, a CDR2 region of SEQ ID NO:5, and
a CDR1 region of SEQ ID NO:6.

US Pat. No. 9,493,548

IMMUNOGLOBULIN PURIFICATION

Hoffmann-La Roche Inc., ...

1. A method for obtaining an immunoglobulin in monomeric form from a solution comprising the immunoglobulin in monomeric and
in aggregated form, comprising the steps of:
a) applying an aqueous, buffered solution comprising said immunoglobulin in monomeric and in aggregated form to a cation exchange
membrane under conditions whereby at least 90% of said immunoglobulin in monomeric form does not bind to said cation exchange
membrane, and

b) recovering said immunoglublin in monomeric form from said aqueous, buffered solution after the contact with said cation
exchange membrane,
wherein said step a) is a chromatography step operated in flow-through mode and said aqueous, buffered solution has a pH value
of from pH 5 to pH 8 and said aqueous, buffered solution of step a) has a conductivity of from 4.0 to 10.0 mS/cm and the sum
of pH value and conductivity in mS/cm of the aqueous, buffered solution in step a) is in the range of from 10 to 15.

US Pat. No. 9,458,135

DIHYDROQUINOLINE-2-ONE DERIVATIVES

Hoffmann-La Roche Inc., ...

1. A Compound of formula (I)

wherein
R1 is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl;

R2 is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl;

R3 is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl;

R4 is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl;

or R3 and R4 together with the carbon atoms to which they are attached form a double bond;

R5 is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl;

R6 is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl;

R7 is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl;

or R6 and R7 together with the carbon atom to which they are attached form a cycloalkyl;

A is —C(O)NR8—, —S—, —O—;

R8 is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl;

R9 is a substituted aryl or substituted heteroaryl, wherein substituted aryl and substituted heteroaryl are substituted with
one to three substitutents independently selected from H, halogen, oxo, cyano, alkyl, haloalkyl, cycloalkyl and halocycloalkyl;

R10 is H, halogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl;

R11 is H, halogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl;

or pharmaceutically acceptable salts or esters.

US Pat. No. 9,464,049

INDOLE-CARBOXAMIDES

Hoffmann-La Roche Inc., ...

1. A compound of formula I

wherein
R1 is aryl or heteroaryl, which are optionally substituted by one, two or three substituents, selected from lower alkyl, halogen,
lower alkyl substituted by halogen, hydroxyl, lower alkoxy, lower alkoxy substituted by halogen, cyano or nitro;

R2 is halogen, lower alkyl or cyano;

R3 is hydrogen or lower alkyl;

R4 is hydrogen or lower alkyl;

R5, R6 are independently hydrogen or lower alkyl, or R5 and R6 together with the N-atom to which they are attached form a heterocycloalkyl ring;

or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers
thereof.

US Pat. No. 9,303,075

CELL-PENETRATING PEPTIDES AND USES THEREOF

HOFFMANN-LA ROCHE INC., ...

1. A peptide capable of being internalized into a cell, wherein the peptide:
(a) has an amino acid sequence selected from the group consisting of: GAAEAAARVYDLGLRRLRQRRRLRRERVRA (SEQ ID NO: 2); and
an amino acid sequence having over its total length at least 80% overall sequence identity with SEQ ID NO: 2; and
(b) is internalized into a cell with an efficacy being at least 200% of the internalization efficacy of the TAT peptide having
the amino acid sequence GRKKRRQRRRPPQ (SEQ ID NO: 1).

US Pat. No. 9,212,171

ETHYNYL COMPOUNDS

HOFFMANN-LA ROCHE INC., ...

1. A compound of formula
wherein
X is N;
G is CH;
R1 is phenyl or pyridinyl, each of which is optionally substituted by halogen;

R2 is hydrogen, lower alkyl, hydroxy, lower alkoxy or C(O)O-benzyl;

R3, R3?, R4, R4?, R6, and R6? are each independently hydrogen or lower alkyl;

or R6 and R4 together with the carbon atom to which they are attached form a C4-6-cycloalkyl ring, when m is 0 and n is 1 or 2;

R5 is hydrogen or lower alkyl;

n is 0, 1 or 2; and
m is 0 or 1; with the proviso that n and m are not simultaneously 0;or a pharmaceutically acceptable acid addition salt, a racemic mixture, its corresponding enantiomer or stereoisomer thereof.
US Pat. No. 9,499,624

ANTIBODIES AGAINST HUMAN CSF-1R AND USES THEREOF

Hoffmann-La Roche Inc., ...

1. An isolated antibody binding to human CSF-1R, wherein the antibody comprises a heavy chain variable domain and a light
chain variable domain, and wherein the heavy chain variable domain comprises SEQ ID NO: 15 and the light chain variable domain
comprises SEQ ID NO: 16.

US Pat. No. 9,856,247

4-METHYL-DIHYDROPYRIMIDINES FOR THE TREATMENT AND PROPHYLAXIS OF HEPATITIS B VIRUS INFECTION

Hoffmann-La Roche Inc., ...

1. A method for the treatment of hepatitis B virus infection, which method comprises administering to a patient in need thereof
a therapeutically effective amount of a compound of formula (I)

wherein:
R1 is C1-2 alkoxycarbonyl or cyano;

R2 is phenyl, which is substituted by halogen;

R3 is thiazolyl, thienyl, imidazolyl, isoxazolyl or pyridinyl; which is unsubstituted or substituted by halogen or C1-6alkyl;

X is oxygen or —NR7;

R4 and R5 are independently selected from hydrogen, C1-6alkyl and trifluoroC1-6alkyl; or

R4 and R5, together with the carbon atom to which they are attached, form a 3 to 7 membered cycloalkyl; or

when X is —NR7, one of R4 and R5 is hydrogen or C1-6alkyl, and the other of R4 and R5 along with R and the atoms to which R4 or R5 and R7 are attached form a pyrrolidinyl, morpholinyl or piperidinyl ring, which pyrrolidinyl, morpholinyl or piperidinyl ring is
unsubstituted or substituted by fluoro;

M is C1-6alkoxycarbonyl, carboxy, di-C1-6alkylaminoC2-6alkoxycarbonyl, aminocarbonyl, C1-6alkylaminocarbonyl, di-C1-6alkylaminocarbonyl, C1-6alkylsulfonylaminocarbonyl, 2-thiazolylaminocarbonyl, hydroxy-CyH2y—,


R7 is C1-6alkyl or trifluoroC1-6alkyl; and

y is 1-6;
or a pharmaceutically acceptable salt, or tautomer thereof.

US Pat. No. 9,657,000

ETHYNYL DERIVATIVES

HOFFMANN-LA ROCHE INC., ...

1. A compound of formula I

wherein
Y is CH;
R1 is hydrogen, fluoro or chloro; and

R2 is hydrogen or lower alkyl;

or a pharmaceutically acceptable acid addition salt thereof.

US Pat. No. 9,663,494

INHIBITORS OF BRUTON'S TYROSINE KINASE

Hoffmann-La Roche Inc., ...

13. A pharmaceutical composition, comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, admixed with at least one pharmaceutically acceptable carrier, excipient
or diluent.

US Pat. No. 9,440,962

BENZISOXAZOLES

Hoffmann-La Roche Inc., ...

1. A compound of formula
wherein
Ar1/Ar2 are phenyl or a 5 or 6-membered heteroaryl;

R1/R2 is hydrogen, halogen, lower alkyl, CF3 or lower alkoxy;

n,m are 1 or 2;
or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers
thereof, with the exception of the compound 2,1-benzisoxazole, 3-(4-chlorophenyl)-5-(1-phenyl-1H-pyrazol-5-yl).

US Pat. No. 9,422,331

2-OXO-2,3,4,5-TETRAHYDRO-1 H-BENZO[B]DIAZEPINES AND THEIR USE IN THE TREATMENT OF CANCER

HOFFMANN-LA ROCHE INC., ...

1. A compound of Formula I
wherein
W is selected from H and C1-6-alkyl that optionally may be substituted with 1-3 deuterium atoms;

Y is C1-6-alkyl that optionally may be substituted with OR6,

R1, R2 and R3 are the same or different and each is independently selected from H and cyano;
R4 is C1-6-alkyl;

R5 is selected from the group
a) C1-6-alkyl that optionally may be substituted with SO2R6 and OR6,

b) heterocyclyl, and
c) aryl that optionally may be substituted with C(O)R7, halo and cyano;
Z is selected from the group
a) aryl that optionally may be substituted with C1-6-alkyl, OR6, halogen and aryl that optionally may be substituted with halogen,

b) heteroaryl that optionally may be substituted with C1-6-alkyl, C3-7-cycloalkyl, OR6, halogen, oxo and aryl that optionally may substituted with cyano, and

c) aryl fused with heterocyclyl, wherein the aryl optionally may be substituted with OR6 and halogen, and the heterocyclyl
optionally may be substituted with oxo, and

d) heterocyclyl;
R6 is selected from H and C1-6-alkyl that optionally may be substituted with halogen and deuterium; and

R7 is C1-6-alkyl;

or a pharmaceutically acceptable salt thereof.

US Pat. No. 9,394,304

IMIDAZOPYRIDINE DERIVATIVES

Hoffmann-La Roche Inc., ...

1. A compound of formula (I):

wherein R1 is cyclopropyl;
R2 and R2?, independently of each other, are hydrogen, halogen, lower alkyl or lower haloalkyl, and
R3 and R3?, independently of each other, are hydrogen, halogen, cyano or ethynyl,
or a pharmaceutically acceptable salt thereof.

US Pat. No. 9,505,742

3,4-DIHYDRO-2H-ISOQUINOLINE-1-ONE AND 2,3-DIHYDRO-ISOINDOL-1-ONE COMPOUNDS

Hoffmann-La Roche Inc., ...

1. A Compound of formula (I)
wherein
R1, R2, R3 and R4 are independently selected from H, alkyl and cycloalkyl;

R5, R6, R7 and R9 are independently selected from H, alkyl, halogen and hydroxy;

R8 and R11 together form —CH2—CH2—;

R10 is H or R10 and R11 together form —(CH2)w—;

A is —C(O)— or —S(O)2—;

B is —C— or —N—;
R12 is alkyl, cycloalkyl or substituted heteroaryl, wherein substituted heteroaryl is substituted with one to three substituent
independently selected from H, alkyl, cycloalkyl, hydroxy, alkoxy, cyano and halogen;

R13 is halogen, cyano, alkoxy or haloalkoxy;

R14 is H, alkyl or halogen;

m, n and p are independently selected from zero and 1;
w is 1, 2 or 3;
with the proviso that 2-[5-(1-acetyl-pyrrolidin-3-yl)-pyridin-3-yl]-5-chloro-3,3-dimethyl-2,3-dihydro-isoindol-1-one and 2-(1?-acetyl-1?,2?,3?,4?,5?,6?-hexahydro-[3,4?]bipyridinyl-5-yl)-5-chloro-3,3-dimethyl-2,3-dihydro-isoindol-1-one
are excluded;
or a and pharmaceutically acceptable salt thereof.
US Pat. No. 9,394,337

ION EXCHANGE CHROMATOGRAPHY WITH IMPROVED SELECTIVITY FOR THE SEPARATION OF POLYPEPTIDE MONOMERS, AGGREGATES AND FRAGMENTS BY MODULATION OF THE MOBILE PHASE

Hoffmann-La Roche Inc., ...

1. A method for producing an antibody of the IgG class in monomeric form comprising the following steps:
applying a first solution that optionally comprises poly(ethylene glycol) and sorbitol to a cation exchange chromatographic
material, thereby equilibrating the material;

applying a solution comprising an antibody of the IgG class to the equilibrated cation exchange chromatography material, thereby
loading the chromatography material;

applying a solution comprising poly (ethylene glycol) having a concentration of about 10% by weight and sorbitol having a
concentration of from 5% to 20% by weight to the cation exchange chromatographic material, thereby separating the antibody
of the IgG class in monomeric form from the antibody in aggregate form and obtaining the antibody in monomeric form.

US Pat. No. 9,121,067

PREDICTIVE MARKER FOR EGFR INHIBITOR TREATMENT

HOFFMANN-LA ROCHE INC., ...

1. A method of treating a human NSCLC patient that will derive clinical benefit from treatment with erlotinib, said method
comprising:
(i) assaying, in vitro, the level of protein tyrosine phosphatase receptor type F (PTPRF) RNA in a tumor sample of a human
NSCLC patient,

(ii) comparing the level of PTPRF RNA in the tumor sample to a value representative of the level of PTPRF RNA in tumors of
a population of human NSCLC patients that derive no clinical benefit from erlotinib treatment,

(iii) determining that the level of PTPRF RNA in the tumor sample of the human NSCLC patient is higher than the value representative
of the level of PTPRF RNA in tumors of a population of human NSCLC patients that derive no clinical benefit from erlotinib
treatment and that the human NSCLC patient will derive clinical benefit from erlotinib treatment; and

(iv) administering a therapeutically effective amount of erlotinib to the human NSCLC patient.

US Pat. No. 9,441,008

3-SUBSTITUTED 5-AMINO-6H-THIAZOLO[4,5-D]PYRIMIDINE-2,7-DIONE COMPOUNDS FOR THE TREATMENT AND PROPHYLAXIS OF VIRUS INFECTION

Hoffmann-LA Roche Inc., ...

1. A compound of formula (I),

wherein
R1 is hydroxy, C1-6alkyl, haloC1-6alkyl, C1-6alkylcarbonyl-O—, C1-6alkyl-S—, azido, cyano, C2-6alkenyl, C1-6alkylsulfonyl-NH—, (C1-6alkyl)2N—, C1-6alkylcarbonyl-NH— or heterocyclic amino;

R2 is hydrogen, C1-6alkyl, C1-6alkoxyC1-6alkyl, C3-7cycloalkyl, C2-6alkynyl, C2-6alkenyl, benzyl and thiophenyl;

R3 is hydrogen or C1-6alkylcarbonyl;

or pharmaceutically acceptable salt, enantiomer or diastereomer thereof;
with the proviso that 5-amino-7-hydroxy-3-[3-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]thiazolo[4,5-d]pyrimidin-2-one;
[2-(5-amino-7-hydroxy-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-5-(hydroxymethyl)tetrahydrofuran-3-yl]acetate; [4-acetoxy-5-(5-amino-7-hydroxy-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2-yl]methyl
acetate and their diastereomers are excluded.

US Pat. No. 9,427,427

PHARMACEUTICAL COMPOSITION WITH IMPROVED BIOAVAILABILITY

HOFFMANN-LA ROCHE INC., ...

1. A physically stable solid dispersion comprising compound (A):

and a stabilizing polymer, wherein said stabilizing polymer is Poly(methacylic acid)-co-methyl methacrylate or Poly(vinylpyrrolidone-co-vinyl
acetate)(6+4).

US Pat. No. 9,422,332

AZAHETEROCYCLES AS BIR2 AND/OR BIR3 INHIBITORS

HOFFMANN-LA ROCHE INC., ...

1. A compound of Formula I:

wherein:
R1 is halogen;

R2 is selected from

aryl that optionally may be substituted with C1-6-alkyl, OR4, and halogen,

aryl that is fused with C3-7-cycloalkyl, and

heteroaryl that optionally may be substituted with C1-6-alkyl;

R3 is selected from

C1-6-alkyl that optionally may be substituted with OR4 and aryl,

C3-7-cycloalkyl,

heterocyclyl, and
aryl;
R4 is selected from H and C1-6-alkyl;

n is 1 or 2;
m is 0 or 1; and
q is 0, 1 or 2;
or a pharmaceutically acceptable salt thereof.
US Pat. No. 9,303,076

CELL-PENETRATING PEPTIDES AND USES THEREOF

HOFFMANN-LA ROCHE INC., ...

1. Composition comprising at least one peptide being attached to one or more nucleic acid molecules, the peptide being capable
to be internalized into a cell, wherein the peptide:
(a) has an amino acid sequence selected from the group consisting of:
GAAEAAARVYDLGLRRLRQRRRLRRERVRA (SEQ ID NO: 2);
IREIMEKFGKQPVSLPARRLKLRGRKRRQR (SEQ ID NO: 3);
YLKVVRKHHRVIAGQFFGHHHTDSFRMLYD (SEQ ID NO: 4); and
an amino acid sequence having over its total length at least 70% overall sequence identity with any one of SEQ ID NO: 2 to
SEQ ID NO: 4; and

(b) is internalized into a cell with an efficacy being at least 200% of the internalization efficacy of the TAT peptide having
the amino acid sequence GRKKRRQRRRPPQ (SEQ ID NO: 1); and
wherein the attachment is accomplished by a linkage selected from the group consisting of a covalent linkage and a non-covalent
linkage.

US Pat. No. 9,199,938

ARYL-QUINOLINE DERIVATIVES

HOFFMANN-LA ROCHE INC., ...

1. A compound according to formula (I),

wherein
R1 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy,
hydroxyalkyl, heterocycloalkyl, substituted heterocycloalkyl, substituted amino, aminocarbonyl and substituted aminocarbonyl,
wherein substituted heterocycloalkyl is substituted with one to three substituents independently selected from the group consisting
of oxo, halogen, alkyl, cycloalkyl and haloalkyl, and wherein substituted amino and substituted aminocarbonyl are substituted
on the nitrogen atom with one to two substituents independently selected from the group consisting of alkyl, cycloalkyl, haloalkyl,
alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, hydroxyalkyl and alkoxyalkyl, with the proviso that R1 is not methyl or ethyl;

R2 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy,
cycloalkoxy, halocycloalkoxy, nitro, cyano, amino, aminoalkyl, substituted amino and substituted aminoalkyl, wherein substituted
amino and substituted aminoalkyl are substituted on the nitrogen atom with one to two substituents independently selected
from the group consisting of alkyl, cycloalkyl, haloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, hydroxyalkyl
and alkoxyalkyl;

R3 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy,
cycloalkoxy, halocycloalkoxy, nitro, cyano, amino, aminoalkyl, substituted amino and substituted aminoalkyl, wherein substituted
amino and substituted aminoalkyl are substituted on the nitrogen atom with one to two substituents independently selected
from the group consisting of alkyl, cycloalkyl, haloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, hydroxyalkyl
and alkoxyalkyl;

R4 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy,
cycloalkoxy, halocycloalkoxy, nitro, cyano, amino, aminoalkyl, substituted amino and substituted aminoalkyl, wherein substituted
amino and substituted aminoalkyl are substituted on the nitrogen atom with one to two substituents independently selected
from the group consisting of alkyl, cycloalkyl, haloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, hydroxyalkyl
and alkoxyalkyl;

R5 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy,
cycloalkoxy, halocycloalkoxy, nitro, cyano, amino, aminoalkyl, substituted amino and substituted aminoalkyl, wherein substituted
amino and substituted aminoalkyl are substituted on the nitrogen atom with one to two substituents independently selected
from the group consisting of alkyl, cycloalkyl, haloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, hydroxyalkyl
and alkoxyalkyl;

R6 is selected from the group consisting of phenyl, substituted phenyl, pyridinyl and substituted pyridinyl, wherein substituted
phenyl and substituted pyridinyl are substituted with one to three substituent independently selected from the group consisting
of alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, cycloalkoxy, cycloalkoxyalkyl,
alkylcycloalkylalkyl, halocycloalkyl, halocycloalkylalkyl, halogen, cyano, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl,
haloalkoxy, hydroxyalkoxy, alkoxyalkoxy, alkoxyalkoxyalkyl, hydroxyhaloalkyl, amino and substituted amino, wherein substituted
amino is substituted with one to two substituents independently selected from the group consisting of alkyl, cycloalkyl, haloalkyl,
alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, hydroxyalkyl and alkoxyalkyl;

R7 is 1H-tetrazol-5-yl or 2H-tetrazol-5-yl; and

n is zero or 1;
with the proviso that at least one of R2, R3, R4 and R5 is different from hydrogen;

or a pharmaceutically acceptable salt or ester thereof.
US Pat. No. 9,107,836

FORMULATION

HOFFMANN-LA ROCHE INC., ...

1. A composition, consisting of:
a) 48% to 55% by weight of S-[2-([[1-(2-ethylbutyl)-cyclohexyl]-carbonyl]amino)phenyl]2-methylpropanethioate;
b) 24% to 26% by weight of microcrystalline cellulose;
c) 11% to 12% by weight of crospovidone micronized;
d) 4% to 5% by weight of hydroxypropylmethyl cellulose;
e) 4% to 6% by weight of croscarmellose sodium;
f) 0 to 1% by weight of magnesium stearate;
g) 0 to 1% by weight of colloidal silicon dioxide; and
h) 0 to 1% by weight of sodium stearyl fumarate.

US Pat. No. 9,802,886

PROCESS FOR MAKING LYSINE-GLUTAMIC ACID DIPEPTIDE DERIVATIVES

Hoffmann-La Roche Inc., ...

1. A process for the preparation of compounds of formula I,

and enantiomers and salts thereof, wherein:
R1 is hydrogen or an ester protecting group;

R2 is hydrogen;

R3 is hydrogen or an amino protecting group and

R4 is C12-20-alkyl;

the process comprising:
a) coupling the glutamic acid derivative of formula II

or a salt thereof with a lysine derivative of formula III

wherein R2? is an ester protecting group, or a salt thereof to form a compound of the formula Ic;


and
b) removing the ester protecting group R2? to provide the compound of formula I.

US Pat. No. 9,505,759

PD-CATALYZED COUPLING OF PYRAZOLE AMIDES

Hoffmann-La Roche Inc., ...

1. A process for the preparation of imidazo[1,2-a]pyridine compounds of the formula (I)

wherein
R1 is C1-4-alkoxy or NR4R5 wherein

R4 and R5 are independently hydrogen or C1-4-alkyl, or,

R4 and R5, together with the nitrogen atom to which they are attached, form a saturated 4- to 6-membered heterocyclic ring which may
contain one additional heteroatom selected from nitrogen or oxygen;

R2 is C1-4-alkyl, C1-4-alkoxycarbonyl, halogen, phenyl which is optionally substituted with C1-4-alkyl, C1-4-alkoxy or halogen or is NR4R5 wherein

R4 and R5 are independently hydrogen or C1-4-alkyl or

R4 and R5, together with the nitrogen atom to which they are attached, form a saturated 4- to 6-membered heterocyclic ring which may
contain one further heteroatom selected from nitrogen or oxygen;

R3 is C1-4-alkyl and

X is nitrogen or CH;
comprising the reaction of a pyrazole carboxamide derivative of formula (II)

wherein R1 and R3 are as above;

with a halogen imidazo[1,2-a]pyridine derivative of the formula

wherein R2 and X are as above and Y is halogen, C1-4-alkylsulfonyloxy, mono- or polyhalogen-C1-4-alkylsulfonyloxy, mono- or poly-C1-4-alkylphenylsulfonyloxy or phenylsulfonyloxy;

in the presence of a palladium catalyst, a base and an organic solvent.

US Pat. No. 9,405,069

METHOD FOR PREPARING AN OUTER SURFACE OF A PLANAR WAVEGUIDE TO BE CAPABLE OF BINDING TARGET SAMPLES ALONG A PLURALITY OF PREDETERMINDED LINES AND A PLANAR WAVEGUIDE

HOFFMANN-LA ROCHE INC., ...

1. A method for preparing an outer surface of a planar waveguide so as to be capable of binding target samples along a plurality
of predetermined lines, the method comprising the steps of:
providing a planar waveguide having an outer surface adapted for attachment of a linker molecule to the outer surface;
sequentially applying at least one plurality of linker molecules to the outer surface, each plurality of the at least one
plurality of linker molecules assembling to form an individual layer of linker molecules with individual layers being formed
one above the other starting from the outer surface of the planar waveguide, each linker molecule comprising a functional
group and a head group, the head group being capable of attaching to the outer surface of the planar waveguide or to the functional
groups of the preceding layer of linker molecules, and wherein the functional groups of the linker molecules of the uppermost
layer are bound to photo-labile protecting groups so that each functional group of the uppermost layer bound to a said photo-labile
protecting group is incapable of attaching a complementary functional group of a further molecule; and

exposing those photo-labile protecting groups of the uppermost layer arranged along a plurality of predetermined lines to
light of a predetermined wavelength to remove the exposed photo-labile protecting groups from the functional groups to make
these functional groups capable of attaching a complementary functional group of a further molecule.

US Pat. No. 9,340,609

ANTIBODIES AGAINST HUMAN ANGIOPOIETIN 2

Hoffmann-La Roche Inc., ...

1. A method of inhibiting tumor growth in a patient comprising administering, to a patient in need thereof, an antibody which
binds specifically to human angiopoietin-2 (ANG-2), wherein said antibody comprises: (A) a heavy chain variable domain which
comprises the CDR3 region of SEQ ID NO: 1, the CDR2 region of SEQ ID NO: 2 and the CDR1 region of SEQ ID NO: 3; and (B) a
light chain variable domain which comprises the CDR3 region of SEQ ID NO: 4, the CDR2 region of SEQ ID NO: 5 and the CDR1
region of SEQ ID NO: 6.

US Pat. No. 9,180,193

ANTIVIRAL COMPOUNDS

HOFFMANN-LA ROCHE INC., ...

1. A compound of formula I or II

wherein:
X is lower alkyl;
each R is independently lower alkyl, or benzyl;
each R? is lower alkyl;
B and D are independently selected from the group consisting of

Q1 and Q2 are independently H or F;

or Q1 and Q2 together form heterocycloalkyl; and

L is
or a pharmaceutically acceptable salt thereof.

US Pat. No. 9,090,559

ANTIVIRAL COMPOUNDS

HOFFMANN-LA ROCHE INC., ...

1. A compound of Formula I

wherein:
A is CH or N;
n is 1 or 2;
R1 is lower alkyl, cycloalkyl, phenyl, or heterocycloalkyl;

R2 is —C(?O)OR2?, —C(?O)N(R2?)2, monocyclic or bicyclic heteroaryl, optionally substituted with one or more R2?;

each R2? is independently H, lower alkyl or heterocycloalkyl;

R3 is H or lower alkyl;

R4 is hydroxyl or amino; and

X is CH2 or C(?O);

or a pharmaceutically acceptable salt thereof.

US Pat. No. 9,593,107

DIHYDROQUINOLINE-2-ONE DERIVATIVES

Hoffmann-La Roche Inc., ...

1. A Compound of formula (I)

wherein
R1 is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl;

R2 is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl;

R3 is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl;

R4 is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl;

or R3 and R4 together with the carbon atoms to which they are attached form a double bond;

R5 is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl;

R6 is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl;

R7 is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl;

or R6 and R7 together with the carbon atom to which they are attached form a cycloalkyl;

R8 and R9 together with the nitrogen atom to which they are attached form a heteroaryl substituted with an oxo substituent and one to
three substitutents independently selected from H, halogen, cyano, alkyl, haloalkyl, cycloalkyl and halocycloalkyl;

R10 is H, halogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl;

R11 is H, halogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl;

or pharmaceutically acceptable salts or esters.

US Pat. No. 9,290,465

SUBSTITUTED ISOXAZOLE AMINE COMPOUNDS AS INHIBITORS OF SCD1

HOFFMANN-LA ROCHE INC., ...

1. A compound of formula (I)

wherein
A is —CH— or nitrogen;
R1 is —O(CH2)nR4, —CH2NHR4, —CH2CH2R4, —OCH2C(O)R4 or —CH2OR4;

R2 is hydrogen or halogen;
R3 is hydrogen or lower alkyl;
R4 is phenyl, pyridinyl, 1,1-dioxo-2,3-dihydro-1H-1lambda*6*-benzo[b]thiophenyl or 1,1-dioxo-1H-1lambda*6*-benzo[b]thiophenyl,
said phenyl optionally mono- or bi-substituted independently with halogen, lower alkyl, alkoxy, —C(O)OCH3, —S(O)2CH3, —NO2, —CN, —CF3, —OCF3, —SCH3, —SO2-phenyl, —SCF3 or —SO2CH2CH3; and

n is 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.

US Pat. No. 9,079,919

SPIRO-[1,3]-OXAZINES AND SPIRO-[1,4]-OXAZEPINES AS BACE1 AND/OR BACE2 INHIBITORS

HOFFMANN-LA ROCHE INC., ...

1. A compound of formula I,

wherein
V is —CR7aR7b—;

W is —CR2aR2b—;

X is —CR1aR1b—; —O—, —S— or —SO2—;

Y —NH—C?O—;
Z is selected from the group consisting of
heteroaryl substituted by 1-4 substituents individually selected from R8,

aryl, and
aryl substituted by 1-4 substituents individually selected from R8;

R1a is selected from the group consisting of

hydrogen,
halogen, and
C1-6-alkyl;

R1b is selected from the group consisting of

hydrogen,
halogen, and
C1-6-alkyl;

R2a is selected from the group consisting of

hydrogen, and
C1-6-alkyl;

R2b is selected from the group consisting of

hydrogen,
aryl, and C1-6-alkyl;

or R2a and R2b together with the C to which they are attached form a heterocyclyl;

R3 is

halogen,
R4 is selected from the group consisting of

hydrogen, and
halogen,
R5 is selected from the group consisting of

hydrogen and
C1-6-alkyl;

R6 is selected from the group consisting of

hydrogen and
C1-6-alkyl;

R7a is selected from the group consisting of

hydrogen and
C1-6-alkyl;

R7b is selected from the group consisting of

hydrogen and
C1-6-alkyl;

R8 is selected from the group consisting of

cyano,
cyano-C1-6-alkyl,

halogen,
halogen-C1-6-alkoxy,

halogen-C1-6-alkyl,

C1-6-alkoxy,

C1-6-alkoxy-C1-6-alkyl,

C2-6-alkynyl, and

C1-6-alkyl;

n is 0;
m is 0 or 1; and
p is 0 or 1;
or a pharmaceutically acceptable salt thereof.
US Pat. No. 9,724,425

CONJUGATES OF INSULIN-LIKE GROWTH FACTOR-1 AND POLY(ETHYLENE GLYCOL)

HOFFMANN-LA ROCHE INC., ...

1. A conjugate comprising an IGF-I (insulin-like growth factor I) variant and poly(ethylene glycol), wherein the IGF-I variant
has amino acid alterations from wild-type IGF-I at positions 27 and 65 or at positions 27 and 68, and the amino acid alterations
do not reduce in vitro binding affinity for an IGF-I binding protein and in vitro IGF-I receptor phosphorylation; wherein
the IGF-I variant selected from the group consisting of R27, R37, R65, K68 (RRRK) and R27, R37, K65, R68 (RRKR) and wherein
the poly(ethylene glycol) is conjugated to the IGF-1 variant via a lysine primary amino group without poly(ethylene glycol)
being conjugated to the N-terminus of the IGF-I variant.

US Pat. No. 9,617,260

INHIBITORS OF BRUTON'S TYROSINE KINASE

Hoffmann-La Roche Inc., ...

20. The method of claim 16, further comprising administering an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative
agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating
cardiovascular disease, an agent for treating diabetes, or an agent for treating immunodeficiency disorders.

US Pat. No. 9,464,058

IMIDAZOLYLKETONE DERIVATIVES

Hoffmann-La Roche Inc., ...

1. A Compound of formula (I)

wherein
R1 is methyl, ethyl, isopropyl, pentan-3-yl or cyanophenyl;

R2 is H, halogen, cyano, nitro, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, cycloalkylalkyl, halocycloalkylalkyl, alkoxy, haloalkoxy,
alkoxyalkyl, haloalkoxyalkyl, cycloalkoxy, halocycloalkoxy or hydroxyalkyl;

R3 is H, chloro, fluoro, cyano, or methoxy;

R4 is H, halogen, cyano, nitro, substituted amino, alkyl, cycloalkyl, halocycloalkyl, cycloalkyl alkyl, halocycloalkylalkyl,
alkynyl, alkoxy, haloalkoxy, alkylsulfanyl, cycloalkylsulfanyl, haloalkylsulfanyl, alkylsulfonyl, cycloalkylsulfonyl, haloalkylsulfonyl,
alkoxyalkyl, haloalkoxyalkyl, cycloalkoxy, halocycloalkoxy or hydroxyalkyl, wherein substituted amino is substituted with
R8 and R9;

or R3 and R4 together form —CH2—CH2—C(O)—N(CH3)— or —CH?CH—S—

R5, R6 and R7 are independently selected from H, halogen, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, cycloalkylalkyl, halocycloalkyl
alkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, cycloalkoxy, halocycloalkoxy and hydroxyalkyl;

R8 is alkyl, cycloalkyl, formyl, alkylcarbonyl or alkoxycarbonyl;

R9 is H, alkyl or cycloalkyl;

or a pharmaceutically acceptable salt thereof;
with the proviso that at least one of R2, R3 and R4 is different from H and that (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)-methanone, 2-fluoro-4-[(1-methyl-1H-imidazol-5-yl)carbonyl]-benzonitrile,
4-[(1-methyl-1H-imidazol-5-yl)carbonyl]-benzonitrile, 2-bromo-4-[(1-methyl-1H-imidazol-5-yl)carbonyl]-benzonitrile, (4-chlorophenyl)[1-(1-methyl
ethyl)-1H-imidazol-5-yl]-methanone, [4-(1-methyl ethyl)phenyl](1-methyl-1H-imidazol-5-yl)-methanone, (4-ethylphenyl)(1-methyl-1H-imidazol-5-yl)-methanone,
(1-methyl-1H-imidazol-5-yl)(4-methylphenyl)-methanone, (4-chlorophenyl)(1-ethyl-1H-imidazol-5-yl)-methanone, (4-chloro-3-methylphenyl)(1-methyl-1H-imidazol-5-yl)methanone,
(1-methyl-1H-imidazol-5-yl)[3-(trifluoromethyl)phenyl]-methanone, (4-chloro-2-fluoro-5-methoxyphenyl)(1-methyl-1H-imidazol-5-yl)-methanone,
(2-fluorophenyl)(1-methyl-1H-imidazol-5-yl)-methanone, and (3-bromophenyl)(1-methyl-1H-imidazol-5-yl)-methanone are excluded.

US Pat. No. 9,409,888

DIMERIC COMPOUNDS

Hoffmann-La Roche Inc., ...

1. A compound of Formula I

wherein
Z is selected from the group
a) aryl that optionally is substituted with OR3, halogen and C1-6-alkyl, and

b) heteroaryl that optionally is substituted with aryl that optionally is substituted with cyano;
X is selected from the group
a) C1-6-alkyl,

b) C1-6-alkyl-aryl-C1-6-alkyl

c) aryl that optionally is substituted with C1-6-alkyl and -O-aryl, and

d) heteroaryl;
Q is selected from

R1 is selected from the group H and cyano;

R2 is selected from the group

a) C1-6-alkyl that optionally is substituted with aryl,

b) C3-7-cycloalkyl that optionally is fused with phenyl,

c) phenyl, and
d) C3-7-cycloalkylaryl; and

R3 is C1-6-alkyl;

or a pharmaceutically acceptable salt thereof.

US Pat. No. 9,359,345

THIAZOLE DERIVATIVES AS INHIBITORS OF BRUTON'S TYROSINE KINASE

HOFFMANN-LA ROCHE INC., ...

1. A compound of Formula I,

wherein:
A is lower alkyl, phenyl, CH2R1, OR4,


R1 is H,


R2 is H or halo;

R3 is halo;

R4 is lower alkyl;

R5 is lower alkyl;

R6 is H or halo;

X is C(?O) or S(?O)2; and

Y is CH or N;
or a pharmaceutically acceptable salt thereof.

US Pat. No. 9,309,248

AZAINDOLINES

HOFFMANN-LA ROCHE INC., ...

1. A compound of Formula I:

wherein:
W is selected from the group
a) H,
b) C1-6-alkyl that optionally includes 1-3 deuterium atoms, and

c) C1-6-alkyl that optionally may be substituted with SO2R5 and OR5;

Y is C1-6-alkyl that optionally may be substituted with OR5;

Z is N;
R1 is selected from the group

a) C1-6-alkyl that optionally may be substituted with SO2R5,

b) C3-7-cycloalkyl,

c) heterocyclyl, and
d) aryl;
R2 is selected from the group

a) H
b) C(O)NHR6,

c) heterocyclyl, and
d) heteroaryl;
R3 and R4 may be the same or different and each is independently selected from the group

a) H, and
b) C1-6-alkyl;

R5 is selected from the group

a) H,
b) C1-6-alkyl,

c) NR7R8, and

d) aryl;
R6 is selected from the group

a) H,
b) aryl that optionally may be substituted with C1-6-alkyl, OR5, halogen, C(O)OR5, C(O)NR7R8, aryl, heterocyclyl, C(O)R9, SO2R5, cyano and CF3,

c) C1-6-alkyl that optionally may be substituted with CF3, SO2R5 and aryl that optionally may be substituted with C1-6-alkyl and halogen,

d) heteroaryl that optionally may be substituted with C1-6-alkyl, OR5, halogen, aryl and oxo, and

e) heterocyclyl;
R7 and R8 may be the same or different and each is independently selected from the group

a) H,
b) C1-6-alkyl, and

c) aryl;
R9 is selected from the group

a) C1-6-alkyl, and

b) aryl;
or a pharmaceutically acceptable salt thereof.

US Pat. No. 9,862,763

HUMANIZED ANTI-TAU(PS422) ANTIBODIES AND METHODS OF USE

Hoffmann-La Roche Inc., ...

1. A humanized antibody that specifically binds to human Tau(pS422), wherein the antibody comprises
in the heavy chain variable domain the HVRs of SEQ ID NO: 08, 09 and 10, and
in the light chain variable domain
the HVRs of SEQ ID NO: 71, 73 and 15;
the HVRs of SEQ ID NO: 70, 72 and 15; or
the HVRs of SEQ ID NO: 12, 14 and 74.

US Pat. No. 9,845,322

TETRAHYDROPYRIDOPYRIMIDINES AND TETRAHYDROPYRIDOPYRIDINES FOR THE TREATMENT AND PROPHYLAXIS OF HEPATITIS B VIRUS INFECTION

Hoffmann-La Roche Inc., ...

1. A compound of formula I,

wherein
R1 is C1-6alkyl, C3-7cycloalkyl, haloC1-6alkyl, hydroxyC1-6alkyl, nitroC1-6alkyl, C1-6alkoxycarbonylC1-6alkyl, carboxyC1-6alkyl, di(C1-6alkoxycarbonyl)methylenyl, cyanoC1-6alkyl, C3-7cycloalkylC1-6alkyl, phenylC1-6alkyl, C1-6alkylsulfanylC1-6alkyl, C1-6alkylsufonylC1-6alkyl, aminoC1-6alkyl, C1-6alkylcarbonylaminoC1-6alkyl, C1-6alkylsufonylaminoC1-6alkyl, C1-6alkoxycarbonyl aminoC1-6alkyl, aminocarbonylC1-6alkyl, diC1-6alkylaminocarbonylC1-6alkyl, monocyclic heterocycloalkylC1-6alkyl or imidazolylC1-6alkyl;

R2 is aryl or heteroaryl, said aryl or heteroaryl being unsubstituted, or substituted by one, two, three or four substituents
independently selected from C1-6alkyl, C3-7cycloalkyl, halogen, haloC1-6alkyl, cyano, nitro, hydroxy, haloC1-6alkoxy, —O—CxH2x—R3, —O—Cy—H2y—NHR6, —NR9R10, —SO2—R11, —SO2—NR12R13, carboxy, C1-6alkoxycarbonyl, —C(?O)—NR12R13, aryl, heteroaryl, monocyclic heterocycloalkyl and —O-monocyclic heterocycloalkyl; wherein monocyclic heterocycloalkyl is
unsubstituted or substituted by C1-6alkyl, C3-7cycloalkyl, C1-6alkylcarbonyl, C1-6alkylsufonyl or C1-6alkoxycarbonyl;

R3 is hydrogen; C3-7cycloalkyl; haloC3-7cycloalkyl; hydroxy; hydroxyC1-6alkylC3-7cycloalkyl; C1-6alkoxy; monocyclic heterocycloalkyl; monocyclic heterocycloalkyl substituted by C1-6alkyl, C1-6alkylcarbonyl, C1-6alkylsufonyl, C3-7cycloalkyl or C1-6alkoxycarbonyl; —C(?O)—R4; C1-6alkylsulfinyl; —SO2—R5; —C(NHR7)—C(?O)—R8; carboxyC1-6alkoxy or aminocarbonylC1-6alkoxy; wherein

R4 is hydroxy, C1-6alkoxy, amino, C1-6alkylamino, diC1-6alkylamino, tetrahydrofuranylamino, pyrrolidinyl or morpholinyl;

R5 is C1-6alkyl, C3-7cycloalkyl, hydroxy, amino, C1-6alkylamino or diC1-6alkylamino;

R7 is hydrogen or C1-6alkoxycarbonyl;

R8 is hydroxy or C1-6alkoxy;

R6 is hydrogen, C1-6alkylcarbonyl, haloC1-6alkylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylsulfonyl, C3-7cycloalkylsulfonyl or C1-6alkoxyC1-6alkylsulfonyl;

R9 and R10 are independently selected from hydrogen, C1-6alkyl, C3-7cycloalkyl, C1-6alkylcarbonyl, C1-6alkylsulfonyl, C3-7cycloalkylcarbonyl and C3-7cycloalkylsulfonyl; or

R9 and R10 together with the nitrogen to which they are attached form monocyclic heterocycloalkyl;

R11 is C1-6alkyl, haloC1-6alkyl, C3-7cycloalkyl, haloC3-7cycloalkyl, hydroxyC1-6alkyl, C1-6alkoxyC1-6alkyl, haloC1-6alkoxyC1-6alkyl, C3-7cycloalkylC1-6alkyl, aminoC1-6alkyl, C1-6alkylaminoC1-6alkyl, diC1-6alkylaminoC1-6alkyl, C1-6alkylcarbonylaminoC1-6alkyl, C1-6alkylsulfonylaminoC1-6alkyl, C1-6alkoxycarbonylaminoC1-6alkyl, C1-6alkylsulfenylC1-6alkyl, C1-6alkylsulfanylC1-6alkyl or C1-6alkylsulfonylC1-6alkyl;

R12 and R13 are independently selected from hydrogen, C1-6alkyl, C1-6alkoxyC1-6alkyl, haloC1-6alkyl, C3-7cycloalkyl and haloC3-7cycloalkyl; or

R12 and R13 together with the nitrogen to which they are attached form monocyclic heterocycloalkyl;

x is 1, 2, 3, 4, 5, 6, 7 or 8;
y is 1, 2, 3, 4, 5, 6, 7 or 8;
U, W and Z are independently selected from CH and N;
one of X and Y is N, and the other one is N;
or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

US Pat. No. 9,822,065

BENZAZEPINE DICARBOXAMIDE COMPOUNDS

Hoffmann-La Roche Inc., ...

1. A process for the preparation of 2-amino-8-methoxycarbonyl-3H-1-benzazepine-4-carboxylic acid (I) comprising the step of
deprotection of

4-tert-butyl 8-methyl 2-amino-3H-benzo[b]azepine-4,8-dicarboxylate (II) under acidic conditions.

US Pat. No. 9,611,224

ANTIPROLIFERATIVE BENZO [B] AZEPIN-2-ONES

HOFFMANN-LA ROCHE INC., ...

1. A compound of Formula 1:

wherein:
W and X are the same or different and each is independently selected from the group
a) H,
b) alkyl that optionally may be substituted with OR5, aryl, alkenyl, alkynyl and cycloalkyl,

c) cycloalkyl, and
d) heterocycle,
or alternatively, X and W together with the nitrogen to which they are bound can form a C2-C9 heterocycle, or W together with the nitrogen to which it is bound and Y together with the carbon to which it is bound can
form a C3-C9 heterocycle;

Y is selected from the group
a) alkyl that optionally may be substituted with OR5 and cycloalkyl, and

b) cycloalkyl;
Z is selected from the group
a) lower alkyl that optionally may be substituted with aryl,
b) aryl that optionally may be substituted with
1) lower alkyl that optionally may be substituted with OR5, aryl and heterocyclyl,

2) OR5,

3) halogen,
4) COOR5,

5) CONR6R7,

6) NR4C(O)R5,

7) C(O)R5,

8) CF3,

9) alkenyl
10) alkynyl that optionally may be substituted with heterocycle that optionally may be substituted with OR5,

11) heterocycle that optionally may be substituted with lower alkyl, oxo and OR5,

12) NH2C?N—NH2,

13) CONR5SO2R4,

14) cyano,
15) cycloalkyl,
16) aryl,
17) heteroaryl that optionally may be substituted with lower alkyl, oxo and CF3,

c) aryl fused with cycloalkyl, wherein the aryl may be substituted with OR5,

d) heteroaryl that optionally may be substituted with lower alkynyl, OR5, halogen, COOR5, CONR6R7, oxo, CF3, cycloalkyl, cyano and aryl, and

e) heterocyclyl;
R1, R2 and R3 are the same or different and each is independently selected from the group

a) H,
b) halogen,
c) alkyl that optionally may be substituted with aryl,
d) cyano,
e) aryl,
f) C(O)R5,

g) OR5,

h) N-acyl,
i) N-sulfonyl, and
j) OR5;

R4 is selected from the group

a) H, and
h) alkyl;
R5 is selected from the group

a) H,
b) lower alkyl that optionally may be substituted with aryl, cycloalkyl, and CF3,

c) cycloalkyl,
d) alkenyl,
e) aryl that optionally may be substituted with NR5R7, C(O)R7, CR1OR7, NO2 and OR7,

f) heterocyclyl,
g) CR4F2, and

h) CR6R7;

R6 and R7 are the same or different and each is independently selected from the group

a) H, and
b) alkyl that optionally may be substituted with aryl, heteroaryl and cycloalkyl; and
n is 0, 1 or 2;
or a pharmaceutically acceptable salt thereof.
US Pat. No. 9,540,345

ANTIVIRAL COMPOUNDS

HOFFMANN-LA ROCHE INC., ...

1. A compound selected from the group consisting of:
N3-[3,5-Dichloro-4-(6-methoxy-pyridin-3-yl)-phenyl]-1H-[1,2,4]triazole-3,5-diamine;

N3-[3,5-Dichloro-4-(5-methanesulfonyl-pyridin-3-yl)-phenyl]-1H-[1,2,4]triazole-3,5-diamine;

5-[4-(5-Amino-1H-[1,2,4]triazol-3-ylamino)-2,6-dichloro-phenyl]-1H-pyridin-2-one;
N3-[4-(6-Amino-pyridin-3-yl)-3,5-dichloro-phenyl]-1H-[1,2,4]triazole-3,5-diamine;

N3-[4-(2-Amino-pyrimidin-5-yl)-3,5-dichloro-phenyl]-1H-[1,2,4]triazole-3,5-diamine;

N3-[3,5-Dichloro-4-(2-methoxy-pyridin-4-yl)-phenyl]-1H-[1,2,4]triazole-3,5-diamine;
4-[4-(5-Amino-1H-[1,2,4]triazol-3-ylamino)-2,6-dichloro-phenyl]-1H-pyridin-2-one;
N-{5-[4-(5-Amino-1H-[1,2,4]triazol-3-ylamino)-2,6-dichloro-phenyl]-pyridin-2-yl}-methanesulfonamide;
N5-[3-Fluoro-4-(6-fluoro-pyridin-3-yl)-5-trifluoromethyl-phenyl]-1H-[1,2,4]triazole-3,5-diamine;

N5-(3-Fluoro-4-pyridin-3-yl-5-trifluoromethyl-phenyl)-1H-[1,2,4]triazole-3,5-diamine;

N3-[3,5-Dichloro-4-(6-methanesulfonyl-pyridin-3-yl)-phenyl]-1H-[1,2,4]triazole-3,5-diamine;

6-[4-(5-Amino-1H-[1,2,4]triazol-3-ylamino)-2,6-dichloro-phenyl]-2,6-diaza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester;
N3-(3-Chloro-4-pyridazin-3-yl-phenyl)-1H-[1,2,4]triazole-3,5-diamine;

N3-[3-Chloro-4-(1-methyl-1H-tetrazol-5-yl)-phenyl]-1H-[1,2,4]triazole-3,5-diamine;

N3-[3-Chloro-4-(2-methyl-2H-[1,2,4]triazol-3-yl)-phenyl]-1H-[1,2,4]triazole-3,5-diamine;

N3-(3,5-Dichloro-4-pyrazol-1-yl-phenyl)-1H-[1,2,4]triazole-3,5-diamine;

4-[4-(5-Amino-1H-[1,2,4]triazol-3-ylamino)-2,6-dichloro-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester;
N3-[3,5-Dichloro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-phenyl]-1H-[1,2,4]triazole-3,5-diamine;

4-[4-(5-Amino-1H-[1,2,4]triazol-3-ylamino)-2-chloro-6-trifluoromethyl-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl
ester;

N3-[3-Chloro-4-(1,2,3,6-tetrahydro-pyridin-4-yl)-5-trifluoromethyl-phenyl]-1H-[1,2,4]triazole-3,5-diamine;

N5-(3,5-Dichloro-4-[1,2,4]triazolo[4,3-a]pyridin-3-yl-phenyl)-1H-[1,2,4]triazole-3,5-diamine;

N-{3-Chloro-4-[6-(propane-2-sulfonyl)-pyridin-3-yl]-5-trifluoromethyl-phenyl}-4H-[1,2,4]triazole-3,5-diamine;
5-[4-(5-Amino-1H-[1,2,4]triazol-3-ylamino)-2-chloro-6-trifluoromethyl-phenyl]-pyridine-2-sulfonic acid tert-butylamide;
5-[4-(5-Amino-1H-[1,2,4]triazol-3-ylamino)-2-chloro-6-trifluoromethyl-phenyl]-pyridine-2-sulfonic acid (2,2,2-trifluoro-1,1-dimethyl-ethyl)-amide;
5-[4-(5-Amino-1H-[1,2,4]triazol-3-ylamino)-2-chloro-6-trifluoromethyl-phenyl]-pyridine-2-sulfonic acid adamantan-1-ylamide;
N3-[2-Chloro-4?-(4-methyl-piperazin-1-yl)-6-trifluoromethyl-biphenyl-4-yl]-1H-[1,2,4]triazole-3,5-diamine;

N3-(3-Chloro-4-pyridazin-3-yl-phenyl)-1H-[1,2,4]triazole-3,5-diamine;

1-[4-(5-Amino-1H-[1,2,4]triazol-3-ylamino)-phenyl]-1H-pyridin-2-one;
1-[4-(5-Amino-1H-[1,2,4]triazol-3-ylamino)-2-chloro-phenyl]-1H-pyridin-2-one;
1-[4-(5-Amino-1H-[1,2,4]triazol-3-ylamino)-2,6-dichloro-phenyl]-1H-pyridin-2-one;
5-[4-(5-Amino-1H-[1,2,4]triazol-3-ylamino)-2-chloro-6-trifluoromethyl-phenyl]-pyridine-2-carboxylic acid methylamide;
N3-(3,5-Dichloro-4-pyridazin-4-yl-phenyl)-1H-[1,2,4]-triazole-3,5-diamine;

1-{3-[4-(5-Amino-1H-[1,2,4]triazol-3-yl amino)-2,6-dichloro-phenyl]-thiophen-2-yl}-ethanone;
N3-(3,5-Dichloro-4-pyridin-4-yl-phenyl)-1H-[1,2,4]triazole-3,5-diamine;
N3-[3,5-Dichloro-4-(5-chloro-thiophen-2-yl)-phenyl]-1H-[1,2,4]triazole-3,5-diamine;
N3-(3,5-Dichloro-4-pyridin-3-yl-phenyl)-1H-[1,2,4]triazole-3,5-diamine;
N3-[3,5-Dichloro-4-(1H-pyrazol-3-yl)-phenyl]-1H-[1,2,4]triazole-3,5-diamine;
N3-(3,5-Dichloro-4-pyrimidin-5-yl-phenyl)-1H-[1,2,4]triazole-3,5-diamine;
N3-[3,5-Dichloro-4-(2-methoxy-pyrimidin-5-yl)-phenyl]-1H-[1,2,4]triazole-3,5-diamine;
N3-[3,5-Dichloro-4-(6-trifluoromethyl-pyridin-3-yl)-phenyl]-1H-[1,2,4]triazole-3,5-diamine;
N3-[3,5-Dichloro-4-(1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-phenyl]-1H-[1,2,4]triazole-3,5-diamine;
N3-[3,5-Dichloro-4-(5-chloro-pyridin-3-yl)-phenyl]-1H-[1,2,4]triazole-3,5-diamine; and
N3-[3,5-Dichloro-4-(6-methoxy-pyridin-2-yl)-phenyl]-1H-[1,2,4]triazole-3,5-diamine,
or a pharmaceutically acceptable salt thereof.

US Pat. No. 9,505,762

PURINE DERIVATIVES AS CB2 RECEPTOR AGONISTS

HOFFMANN-LA ROCHE INC., ...

1. A compound of formula (I)

wherein
A is CH2, CH2CH2, CH2CO or absent;

R1 is tert-butyl, tert-butylamino, or 2,2-dimethylpropyloxy;

R2 and R3, together with the nitrogen atom to which they are attached, form pyrrolidinyl, substituted pyrrolidinyl, thiazolidinyl,
alkylpiperazinyl, 2-oxa-7-azaspiro[3.4]octyl, 2-oxa-6-azaspiro[3.3]heptyl, azetidinyl, substituted azetidinyl, 2,2-dioxo-2?6-thia-6-azaspiro[3.3]heptyl or halo-5-azaspiro[2.4]heptyl, wherein substituted pyrrolidinyl is pyrrolidinyl substituted with
one to four substituents independently selected from halogen, hydroxyl, alkyl, hydroxyalkyl, cyano, alkylcarbonylamino, alkylcarbonyloxy
and haloalkyl and wherein substituted azetidinyl is azetidinyl substituted with one or two substituents selected from halogen,
hydroxyl, alkyl and haloalkyl; and

R4 is hydrogen, phenyl, halophenyl, alkylphenyl, haloalkylphenyl, pyridinyl, halopyridinyl, cycloalkyl, alkyl, alkyloxadiazolyl,
oxolanyl, alkyltetrazolyl, alkoxy, alkylsulfonylphenyl, haloalkyl, alkoxyphenyl, dioxothietanyl, cycloalkyltetrazolyl, haloalkyl-1H-pyrazolyl
or cycloalkylalkyltetrazolyl;

or a pharmaceutically acceptable salt or ester thereof.
US Pat. No. 9,499,626

ANTIBODIES AGAINST HUMAN CSF-1R AND USES THEREOF

HOFFMANN-LA ROCHE INC., ...

1. A method for treating a patient suffering from cancer associated with CSF-1R expression, the method comprising administering
to the patient an effective amount of an isolated antibody binding to human CSF-1R, wherein the antibody comprises a heavy
chain variable domain and a light chain variable domain, and wherein:
a) the heavy chain variable domain comprises a CDR3 region comprising the amino acid sequence of SEQ ID NO: 1, a CDR2 region
comprising the amino acid sequence of SEQ ID NO: 2, and a CDR1 region comprising the amino acid sequence of SEQ ID NO:3, and
the light chain variable domain comprises a CDR3 region comprising the amino acid sequence of SEQ ID NO: 4, a CDR2 region
comprising the amino acid sequence of SEQ ID NO:5, and a CDR1 region comprising the amino acid sequence of SEQ ID NO:6;

b) the heavy chain variable domain comprises a CDR3 region comprising the amino acid sequence of SEQ ID NO: 9, a CDR2 region
comprising the amino acid sequence of SEQ ID NO: 10, and a CDR1 region comprising the amino acid sequence of SEQ ID NO: 11,
and the light chain variable domain comprises a CDR3 region comprising the amino acid sequence of SEQ ID NO:12, a CDR2 region
comprising the amino acid sequence of SEQ ID NO: 13, and a CDR1 region comprising the amino acid sequence of SEQ ID NO: 14;

c) the heavy chain variable domain comprises a CDR3 region comprising the amino acid sequence of SEQ ID NO: 17, a CDR2 region
comprising the amino acid sequence of SEQ ID NO: 18, and a CDR1 region comprising the amino acid sequence of SEQ ID NO:19,
and the light chain variable domain comprises a CDR3 region comprising the amino acid sequence of SEQ ID NO: 20, a CDR2 region
comprising the amino acid sequence of SEQ ID NO:21, and a CDR1 region comprising the amino acid sequence of SEQ ID NO:22;

d) the heavy chain variable domain comprises a CDR3 region comprising the amino acid sequence of SEQ ID NO: 25, a CDR2 region
comprising the amino acid sequence of SEQ ID NO: 26, and a CDR1 region comprising the amino acid sequence of SEQ ID NO: 27,
and the light chain variable domain comprises a CDR3 region comprising the amino acid sequence of SEQ ID NO:28, a CDR2 region
comprising the amino acid sequence of SEQ ID NO: 29, and a CDR1 region comprising the amino acid sequence of SEQ ID NO: 30;

e) the heavy chain variable domain comprises a CDR3 region comprising the amino acid sequence of SEQ ID NO: 33, a CDR2 region
comprising the amino acid sequence of SEQ ID NO: 34, and a CDR1 region comprising the amino acid sequence of SEQ ID NO: 35,
and the light chain variable domain comprises a CDR3 region comprising the amino acid sequence of SEQ ID NO:36, a CDR2 region
comprising the amino acid sequence of SEQ ID NO: 37, and a CDR1 region comprising the amino acid sequence of SEQ ID NO: 38;

f) the heavy chain variable domain comprises a CDR3 region comprising the amino acid sequence of SEQ ID NO:41, a CDR2 region
comprising the amino acid sequence of SEQ ID NO: 42, and a CDR1 region comprising the amino acid sequence of SEQ ID NO:43,
and the light chain variable domain comprises a CDR3 region comprising the amino acid sequence of SEQ ID NO: 44, a CDR2 region
comprising the amino acid sequence of SEQ ID NO:45, and a CDR1 region comprising the amino acid sequence of SEQ ID NO:46;

g) the heavy chain variable domain comprises a CDR3 region comprising the amino acid sequence of SEQ ID NO: 49, a CDR2 region
comprising the amino acid sequence of SEQ ID NO: 50, and a CDR1 region comprising the amino acid sequence of SEQ ID NO: 51,
and the light chain variable domain comprises a CDR3 region comprising the amino acid sequence of SEQ ID NO:52, a CDR2 region
comprising the amino acid sequence of SEQ ID NO: 53, and a CDR1 region comprising the amino acid sequence of SEQ ID NO: 54;

h) the heavy chain variable domain comprises a CDR3 region comprising the amino acid sequence of SEQ ID NO:69, a CDR2 region
comprising the amino acid sequence of SEQ ID NO: 70, and a CDR1 region comprising the amino acid sequence of SEQ ID NO:71,
and the light chain variable domain comprises a CDR3 region comprising the amino acid sequence of SEQ ID NO: 72, a CDR2 region
comprising the amino acid sequence of SEQ ID NO:73, and a CDR1 region comprising the amino acid sequence of SEQ ID NO:74;
or

i) the heavy chain variable domain comprises a CDR3 region comprising the amino acid sequence of SEQ ID NO: 77, a CDR2 region
comprising the amino acid sequence of SEQ ID NO: 78, and a CDR1 region comprising the amino acid sequence of SEQ ID NO: 79,
and the light chain variable domain comprises a CDR3 region comprising the amino acid sequence of SEQ ID NO:80, a CDR2 region
comprising the amino acid sequence of SEQ ID NO: 81, and a CDR1 region comprising the amino acid sequence of SEQ ID NO: 82.

US Pat. No. 9,493,553

ANTI-ALPHA-SYNUCLEIN ANTIBODIES AND METHODS OF USE

Hoffmann-La Roche Inc., ...

1. A monoclonal antibody comprising a heavy chain variable domain comprising a CDRH1 sequence, a CDRH2 sequence, and a CDRH3
sequence, wherein the CDRH1 sequence is SEQ ID NO: 15 or 21, the CDRH2 sequence is SEQ ID NO: 16 or 22, and the CDRH3 sequence
is SEQ ID NO: 17, and a light chain variable domain comprising a CDRL1 sequence, a CDRL2 sequence, and a CDRL3 sequence, wherein
the CDRL1 sequence is SEQ ID NO: 18 or 23, the CDRL2 sequence is SEQ ID NO: 19 or 24, and the CDRL3 sequence is SEQ ID NO:
20 or 25.

US Pat. No. 9,447,035

INTEGRIN ANTAGONIST CONJUGATES FOR TARGETED DELIVERY TO CELLS EXPRESSING VLA-4

Hoffmann-La Roche Inc., ...

1. A compound of formula I:
or a pharmaceutically acceptable salt or ester thereof; wherein n is 1-24 and wherein:R1 is selected from the group consisting of:
(1) a compound of the formula:
wherein m is 0-3 and G is selected from the group consisting of:

(2) a compound of the formula:
wherein m is 0-3, R4 and R5 are independently hydrogen or halogen, W is O or CH2, and G is selected from the group consisting of:

(3) a compound of the formula:
R2 is selected from the group consisting of:
(1) a compound of the formula:

(2) a compound of the formula:

(3) a compound of the formula:
and
(4) a compound of the formula:
wherein R3 is a conjugated moiety and X represents either sulfur or a compound of the formula:

US Pat. No. 9,422,329

OPTIMIZED METHOD FOR ANTIBODY CAPTURING BY MIXED MODE CHROMATOGRAPHY

Hoffmann-La Roche Inc., ...

1. A method for producing an anti-IGF-1R antibody comprising the following steps:
a) applying a crude mammalian cell culture cultivation supernatant to a multimodal weak cation exchange chromatography material,
b) recovering the anti-IGF-1R antibody by applying a buffered solution comprising ethylene glycol and an inorganic salt to
the multimodal weak cation exchange chromatography material and thereby producing an anti-IGF-1R antibody.

US Pat. No. 9,272,031

ANTIBODIES AGAINST AMYLOID BETA 4 WITH GLYCOSYLATION IN THE VARIABLE REGION

F. Hoffmann-La Roche Inc....

1. A pharmaceutical composition comprising antibody molecules and a pharmaceutically acceptable carrier or diluent,
(a) wherein the antibody molecules comprise:
a CDR1 in the variable heavy chain as shown in SEQ ID NO:10,
a CDR2 in the variable heavy chain as shown in SEQ ID NO:12,
a CDR3 in the variable heavy chain as shown in SEQ ID NO:14,
a CDR1 in the variable light chain as shown in SEQ ID NO:16,
a CDR2 in the variable light chain as shown in SEQ ID NO:18, and
a CDR3 in the variable light chain as shown in SEQ ID NO:20;
(b) wherein the composition comprises, in admixture, antibody molecules that are mono-glycosylated in one but not both of
their heavy chains at the asparagine residue of position 52 of SEQ ID NO: 6 and antibody molecules that are double-glycosylated
in both of their heavy chains at the asparagine residue of position 52 of SEQ ID NO: 6; and

(c) wherein, if present, any antibody molecule that is not glycosylated in either of its heavy chains at the asparagine residue
of position 52 of SEQ ID NO: 6, is present in an amount of less than 5%.

US Pat. No. 9,139,640

SHORTENED TETRANECTIN-APOLIPOPROTEIN A-1 FUSION PROTEIN, A LIPID PARTICLE CONTAINING IT, AND USES THEREOF

Hoffmann-La Roche Inc., ...

1. A fusion protein comprising the amino acid sequence of SEQ ID NO: 01 or a variant thereof having at least 70% sequence
identity with the amino acid sequence of SEQ ID NO: 01, wherein the first four amino acid residues of the fusion protein are
PIVN (residues 1-4 of SEQ ID NO: 01).
US Pat. No. 9,090,700

TUMOR THERAPY WITH AN ANTIBODY FOR VASCULAR ENDOTHELIAL GROWTH FACTOR AND AN ANTIBODY FOR HUMAN EPITHELIAL GROWTH FACTOR RECEPTOR TYPE 2

Hoffmann-La Roche Inc., ...

1. A combined therapy method of treating a breast cancer disease in a patient who has failed prior therapy with an anti-VEGF
antibody, comprising administering to the patient a therapeutically effective amount of an anti-HER2 antibody and an anti-VEGF
antibody, wherein the breast cancer disease is characterized by an overexpression of the HER2 receptor protein, and wherein
said method demonstrates tumor regression.

US Pat. No. 9,969,754

COMPOUNDS FOR TREATING SPINAL MUSCULAR ATROPHY

HOFFMANN-LA ROCHE INC., ...

1. A compound of formula (I):
wherein
R1 is hydrogen or C1-7-alkyl;
R2 is hydrogen, cyano, C1-7-alkyl, C1-7-haloalkyl or C3-8-cycloalkyl;
R3 is hydrogen, C1-7-alkyl, or C3-8-cycloalkyl;
A is N-heterocycloalkyl or NR12R13, wherein N-heterocycloalkyl comprises 1 or 2 nitrogen ring atoms and is optionally substituted with 1, 2, 3 or 4 substituents selected from R14;
R12 is heterocycloalkyl comprising 1 nitrogen ring atom, wherein heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents selected from R14;
R13 is hydrogen, C1-7-alkyl or C3-8-cycloalkyl;
R14 is independently selected from hydrogen, C1-7-alkyl, amino, amino-C1-7-alkyl, C3-8-cycloalkyl and heterocycloalkyl or two R14 together form C1-7-alkylene;
with the proviso that if A is N-heterocycloalkyl comprising only 1 nitrogen ring atom, then at least one R14 substituent is amino or amino-C1-7-alkyl;
or a pharmaceutically acceptable salt thereof.

US Pat. No. 9,890,167

PYRAZINE COMPOUNDS FOR THE TREATMENT OF INFECTIOUS DISEASES

Hoffmann-La Roche Inc., ...

1. A compound of formula (I),

wherein
R1 is heterocyclyl, said heterocyclyl being unsubstituted or substituted with one, two or three substituents independently selected
from (C1-6alkyl)2aminocarbonyl, (C1-6alkyl)2morpholinylcarbonyl, C1-6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkoxycarbonyl, C1-6alkyl, C1-6alkyl(C1-6alkylsulfonyl)amino, C1-6alkylaminocarbonyl, C1-6alkylcarbonyl, C1-6alkylcarbonylamino, C1-6alkylimidazolyl, C1-6alkylmorpholinylcarbonyl, C1-6alkyloxadiazolyl, C1-6alkyloxazolyl, C1-6alkylpyrazolyl, C1-6alkylsulfonyl, C1-6alkylsulfonylamino, C1-6alkylsulfonylC1-6alkyl, carbamoyl, cyano, dioxopyrrolidinyl, haloC1-6alkyl, haloC1-6alkyloxadiazolyl, halogen, halopiperidinylcarbonyl, halopyridinyl, halopyrimidinylamino, halopyrimidinyloxy, halopyrrolidinylcarbonyl,
hydroxy, hydroxyazetidinylcarbonyl, hydroxyC1-6alkyl, hydroxyC1-6alkyl(C1-6alkyl)aminocarbonyl, hydroxyC1-6alkylaminocarbonyl, hydroxypyrrolidinylcarbonyl, morpholinylcarbonyl, oxadiazolyl, oxazolyl, oxazolylaminocarbonyl, oxazolyl(C1-6alkyl)aminocarbonyl, oxazolylcarbonyl, oxazolylcarbonyl(C1-6alkyl)amino, oxomorpholinyl, oxooxazolidinyl, oxopyrrolidinyl, phenyl, phenylcarbonyl, pyrazolylC1-6alkyl, pyridinyl, pyrimidinyl, pyrimidinylamino, pyrimidinyl(C1-6alkyl)amino, pyrimidinyloxy, pyrimidinyloxyC1-6alkyl, pyrrolidinylcarbonyl and thiazolyl;

heteroaryl, said heteroaryl being unsubstituted or substituted with one, two or three substituents independently selected
from halogen, cyano, C1-6alkyl, haloC1-6alkyl, hydroxy C1-6alkyl and C1-6alkoxyC1-6alkyl;

phenyl, said phenyl being unsubstituted or substituted with one, two or three substituents independently selected from halogen,
cyano, hydroxy, C1-6alkyl, C1-6alkoxy, C3-7cycloalkyl, haloC1-6alkoxy and haloC1-6alkyl; or

C3-7cycloalkyl;

R2 and R3 are independently selected from hydrogen and C1-6alkyl;

R4 is heteroaryl, said heteroaryl being unsubstituted or substituted with one, two or three substituents independently selected
from halogen, cyano, C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, C3-7cycloalkyl and (C1-6alkyl)2amino;

aryl, said aryl being unsubstituted or substituted with one, two or three substituents independently selected from halogen,
cyano, C3-7cycloalkyl, C1-6alkyl, C2-6alkynyl, C1-6alkoxy, haloC1-6alkyl and haloC1-6alkoxy;

phenylC1-6alkyl, said phenylC1-6alkyl being unsubstituted or substituted with one, two or three halogens; or

C3-7cycloalkyl; and

Y and Q are independently selected from CH and N;
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
US Pat. No. 9,663,580

ANTIBODIES AGAINST HUMAN CSF-1R AND USES THEREOF

HOFFMANN-LA ROCHE INC., ...

1. An isolated antibody binding to human CSF-1R, wherein the antibody comprises a heavy chain variable domain and a light
chain variable domain, and wherein the heavy chain variable domain comprises a CDR3 region comprising SEQ ID NO: 69, a CDR2
region comprising SEQ ID NO: 70, and a CDR1 region comprising SEQ ID NO: 71, and the light chain variable domain comprises
a CDR3 region comprising SEQ ID NO:72, a CDR2 region comprising SEQ ID NO: 73, and a CDR1 region comprising SEQ ID NO: 74.

US Pat. No. 9,586,903

ISOQUINOLINE DERIVATIVES

Hoffmann-La Roche Inc., ...

1. A method for the therapeutic treatment of depression, anxiety disorders, Parkinson's disease, dementia, Alzheimer's disease,
Down syndrome, autism spectrum disorders, amyotrophic lateral sclerosis, multiple sclerosis and Huntington's disease, comprising
administering to a patient in need thereof a therapeutically effective amount of a compound according formula (I)
wherein
R1 is phenyl or pyridinyl, which are optionally substituted by halogen, cyano or lower alkyl substituted by halogen, or is dihydro-pyran-4-yl;

R2 is hydrogen or lower alkyl;

R3 is —(CHR)n-phenyl, optionally substituted by lower alkoxy or S(O)2-lower alkyl,

or is heterocycloalkyl, optionally substituted by ?O and lower alkyl, or,
is —(CH2)n-five or six membered heteroaryl, optionally substituted by lower alkyl,

or is hydrogen, lower alkyl, lower alkyl substituted by halogen, lower alkyl substituted by hydroxy, —NR—S(O)2-lower alkyl, —(CH2)n-cycloalkyl or —(CH2)n—S(O)2-lower alkyl; or,

R2 and R3 form together with the N-atom to which they are attached a heterocycloalkyl ring, selected from the group consisting of 1,1-dioxo-thiomorpholinyl,
morpholinyl, or pyrrolidinyl, optionally substituted by hydroxy;

R is hydrogen or lower alkyl;
n is 0, 1 or 2;or, a pharmaceutically acceptable acid addition salt, or an enantiomer, a diastereomer or a mixture of enantiomers or diastereomers.

US Pat. No. 9,512,132

PYRAZOLE COMPOUNDS AS CB2 AGONISTS

Hoffmann-La Roche Inc., ...

1. A compound of formula (I)

wherein
A1 is CH or N;

A2 is CH or N;

A3 is —(CH2)n— or —CH2C(O)—;

R1 is alkyl, cycloalkyl, alkoxy or halogen;

R2 is substituted pyrrolidinyl or substituted dihydropyrrolyl, wherein substituted pyrrolidinyl and substituted dihydropyrrolyl
are pyrrolidinyl and dihydropyrrolyl substituted with one or two substituents independently selected from halogen, hydroxyl,
hydroxyalkyl, alkoxyalkyl and alkylfurazanylalkoxy;

R3 is phenyl, substituted phenyl, substituted furazanyl, pyridinyl, substituted pyridinyl, dioxothietanyl, tetrahydrofuranyl,
substituted tetrazolyl or substituted triazolyl, wherein substituted phenyl, substituted furazanyl, substituted pyridinyl
and substituted triazolyl are phenyl, pyridinyl and triazolyl substituted with one or two substituents independently selected
from alkyl, alkoxy, halogen, haloalkyl, alkylsulfonyl and cycloalkyl, and wherein substituted tetrazolyl and substituted furazanyl
are tetrazolyl and furazanyl substituted with one substituent selected from alkyl, alkoxy, halogen, haloalkyl, alkylsulfonyl
and cycloalkyl;

n is 0, 1 or 2;
provided that A1 and A2 are not both CH at the same time;

or a pharmaceutically acceptable salt or ester thereof.

US Pat. No. 9,499,548

INHIBITORS OF BRUTON'S TYROSINE KINASE

HOFFMANN-LA ROCHE INC., ...

17. A pharmaceutical composition comprising the compound of claim 1, admixed with at least one pharmaceutically acceptable carrier, excipient or diluent.

US Pat. No. 9,486,445

COMBINATION THERAPY FOR PROLIFERATIVE DISORDERS

HOFFMANN-LA ROCHE INC., ...

1. A method of treating a patient suffering from cancer, comprising administering to the patient, either concomitantly or
sequentially: (i) a first component comprising vemurafenib or a pharmaceutically-acceptable salt thereof, and (ii) a second
component comprising Compound II:

or Compound III:

or a pharmaceutically-acceptable salt thereof;
the amount of the first and second components being such that the combination thereof is therapeutically effective in the
treatment of said cancer;

wherein the cancer is sarcoma, thyroid cancer, or leukemia, and comprises b-Raf having the V600E mutation.

US Pat. No. 9,447,099

METHODS FOR THE PREPARATION OF 5-[2-[7 (TRIFLUOROMETHYL)-5-[4-(TRIFLUOROMETHYL)PHENYL]PYRAZOLO [1,5-A]PYRIMIDIN-3-YL[ETHYNYL]-2-PYRIDINAMINE

Hoffmann-La Roche Inc., ...

1. A method for preparing compound 9 having the formula:
which comprises:
(a) reacting compound 8;

 with 2-methyl-3-butyn-2-ol via a Sonogashira coupling reaction in an inert solvent to provide compound 13; and

b) deprotecting compound 13 with a base in an inert solvent to provide compound 9.

US Pat. No. 9,416,127

TRIAZOLE CARBOXAMIDES AND USES THEREOF

Hoffmann-La Roche Inc., ...

1. A compound of formula

wherein
R1 is phenyl or pyridinyl, optionally substituted by halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen and
lower alkoxy substituted by halogen;

X1 is —N? or CH;

X2 is CR2 or ?N—;

X3 is —N? or CH;

with the proviso that only two of XI, X2 or X3 are nitrogen;

wherein
is a triazole group, selected from

R2 is hydrogen or lower alkyl;

Z is a bond, —O— or —CH2—;

or a pharmaceutically suitable acid addition salts thereof.

US Pat. No. 9,394,311

TRIAZOLO COMPOUNDS AS PDE10 INHIBITORS

Hoffmann-La Roche Inc., ...

1. A compound of formula (Ia) or (Ib)

wherein
B is C2-alkylene, C2-alkenylene, or C2-alkynylene;

R1 and R2 together with the nitrogen atom to which they are attached, form a 4 to 7 membered heterocycloalkyl which can be substituted
by 1 to 3 substituents independently selected from the group consisting of halogen, C1-C7-alkyl, C1-C7-hydroxyalkyl, C1-C7 alkoxy, C1-C7 haloalkyl, hydroxyl, and oxo;

R3 is selected from hydrogen, C1-C7-alkyl, C3-C5-cycloalkyl, C1-C7-alkoxyalkyl, C1-C7-haloalkyl, —(CH2)1,2-aryl optionally substituted by C1-C7 alkoxy, and —(CH2)1,2—C3-C5-cycloalkyl;

R4 is a heteroaryl group selected from (a), (b), (c), (d) or (e)


each optionally substituted by 1 to 3 R5, wherein R5 is selected from halogen, C1-C7-alkyl, C1-C7-hydroxyalkyl, C1-C7-haloalkoxy, C1-C7-haloalkyl, C3-C5-cycloalkyl, cyano, amino, nitro, —O—R6—C(O)—R7, —SO2R8, or C1-C2-alkoxy optionally substituted by C1-C2-alkoxy, heterocycloalkyl;

R6 and R8 are each C1-C7-alkyl;

R7 is heterocycloalkyl.

US Pat. No. 9,365,550

BENZIMIDAZOLES AS CNS ACTIVE AGENTS

Hoffmann-La Roche Inc., ...

1. A Compound of formula I
wherein
R1 hydrogen, lower alkyl, halogen or lower alkyl substituted by halogen;

R2 is hydrogen or halogen;

X1 is N or CH;

X2 is N or CH;

with the proviso that only one of X1 or X2 is N;

X3 is C(R) or N;

and R is hydrogen, lower alkyl, halogen, lower alkyl substituted by halogen, lower alkoxy or SO2-lower alkyl;
or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers
thereof.
US Pat. No. 10,072,047

TAGGED HEPADNAVIRUS E ANTIGEN AND ITS USE IN SCREENING ANTIVIRAL SUBSTANCES

Drexel University, Phila...

1. A method for assessing the capacity of a candidate molecule to inhibit covalently closed circular (ccc) DNA of a hepadnavirus comprising the steps of(a) contacting a cell comprising a nucleic acid molecule comprising a nucleic acid sequence encoding a tagged hepadnavirus e antigen with said candidate molecule; wherein the nucleic acid molecule comprises a sequence encoding one or more tags, wherein the sequence is inserted into the epsilon structure as encoded by a hepadnavirus genome,wherein said nucleic acid molecule comprising a sequence encoding the one or more tag is inserted between nucleotides corresponding to position C1902 and position A1903 of the HBV genome,wherein said nucleic acid molecule comprises 5? of the sequence encoding the one or more tag a sequence that is capable of forming base pairs with the lower stem of the epsilon structure as encoded by a hepadnavirus genome and wherein the sequence that is capable of forming base pairs with said lower stem of the epsilon structure as encoded by a hepadnavirus genome is capable of forming base pairs with nucleotides corresponding to positions T1849 to A1854 of the HBV genome;(b) assessing the level of the tagged hepadnavirus e antigen; and
(c) selecting a candidate molecule when the level of tagged hepadnavirus e antigen is decreased compared to a control.

US Pat. No. 9,840,501

MORPHOLIN-PYRIDINE DERIVATIVES

Hoffmann-La Roche Inc., ...

1. A compound of formula

wherein
X is CR;
R is hydrogen, halogen or lower alkyl;
L is a bond, —C(O)— or —C(O)NH—;
Ar is phenyl or a five or six membered heteroaryl group, containing one or two N atoms;
R1 is halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen or cycloalkyl;

n is 0, 1, 2 or 3;
or, a pharmaceutically suitable acid addition salt thereof, a racemic mixture, an enantiomer or mixture thereof.

US Pat. No. 9,656,971

COMT INHIBITORS

Hoffmann-La Roche Inc., ...

1. A compound of formula

wherein
R1 is hydrogen;

R2 is heteroaryl, selected from the group consisting of pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, imidazolyl, isoxazolyl,
isothiazolyl, thiophenyl, 1-thia-3,4-diazolyl, imidazo[1,2-a]pyridinyl, indazolyl, quinolinyl or isoquinolinyl, and which
groups are optionally substituted by R5, or is C(O)-heteroaryl, selected from pyridinyl or thiophenyl, wherein the heteroaryl groups are optionally substituted by
lower alkyl;

R5 is halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, hydroxy, (CH2)1,2-lower alkoxy, CH2-di-lower alkyl amino, di-lower alkyl amino, morpholinyl, piperazinyl, pyrrolidin-1-yl, C(O)-piperidinyl, C(O)-4-methyl-piperazinyl,
phenyl optionally substituted by halogen, pyridinyl, S(O)2N(CH3)2, C(O)O-lower alkyl, NHC(O)-lower alkyl,

or is C(O)-heteroaryl, selected from pyridinyl or thiophenyl, wherein the heteroaryl groups are optionally substituted by
lower alkyl,

R3 is hydrogen;

and pharmaceutically acceptable salts thereof.
US Pat. No. 9,671,394

METHOD FOR THE DETECTION OF FREE BINDING PARTNER OF A MULTISPECIFIC BINDER

Hoffmann-La Roche Inc., ...

1. An in vitro method for the determination of the presence and/or amount of an antigen of a multispecific antibody in a sample,
whereby the antigen to be detected can be specifically bound by a first binding specificity of the multispecific antibody,
comprising the steps of:
incubating the sample comprising the multispecific antibody, multispecific antibody bound antigen and free antigen with an
anti-idiotypic antibody that specifically binds to a second binding specificity of the multispecific antibody, which is different
from the first binding specificity,

depleting the anti-idiotypic antibody-multispecific antibody-complex and anti-idiotypic antibody-multispecific antibody-antigen
complex from the sample prior to the determination of the presence and/or the amount of free antigen, and

determining the presence and/or the amount of free antigen in the multispecific antibody-depleted sample.

US Pat. No. 9,617,271

TRIAZOLO COMPOUNDS

Hoffmann-La Roche Inc., ...

1. A compound of formula (I)

wherein
B is C1-C4-alkylene, C2-C4-alkenylene, C2-C4-alkynylene, —O—(C1-C4-alkylene)-,
—S—(C1-C4-alkylene)-;
R is selected from the group consisting of:

R1 and R2 together with the nitrogen atom to which they are attached, form a bicyclic ring system or heterocycloalkyl which can be substituted
by 1 to 3 substituents independently selected from the group consisting of halogen, C1-C7-alkyl, C1-C7-hydroxyalkyl, C1-C7 alkoxy, C1-C7-haloalkyl, hydroxyl and oxo;

R3 is selected from hydrogen, C1-C7-alkyl, C1-C7-alkoxyalkyl, C1-C7-haloalkyl, (CH2)1,2—C3-C5-cycloalkyl, —(CH2)1,2-aryl optionally substituted by C1-C7 alkoxy;

R4 and R5 are independently selected from hydrogen, halogen, C1-C7-alkyl, C1-C7-haloalkyl, C1-C7-hydroxyalkyl, cyano, or R4 and R5 together form a C3-C8 cycloalkyl

R6 is selected from hydrogen, C1-C7-alkyl, C1-C7-haloalkoxy, C3-C8 cycloalkyl, C1-C7 alkoxy, hydroxyl, halogen, S(O)2—C1-C7-alkyl, —C(O)NR?R?, NR?R? wherein R? and R? are independently selected from hydrogen, C1-C7-alkyl or R? and R? together with the nitrogen atom to which they are attached from a heterocycloalkyl or R6 and R7 together form a C3-C8cycloalkyl,

X is C—R7 wherein R7 is selected from hydrogen, C1-C7-alkyl, C1-C7 alkoxy, C1-C7-haloalkyl, C3-C8 cycloalkyl, —C(O)NR?R? wherein R? and R? are independently selected from hydrogen and C1-C7-alkyl,

Y is N or C—R4.

US Pat. No. 9,556,150

INHIBITORS OF BRUTON'S TYROSINE KINASE

Hoffmann-La Roche Inc., ...

1. A compound of Formula 1,

wherein:
R is lower alkyl or

n is 0 or 1
R1 is absent, halo, cyano, lower alkyl, or —C(—O)N(CH3)2;

R2 is absent, halo, cyano, —C(?O)NH2, or —C(?O)N(CH3)2;

R3 is halo or —C(?O)R3a,

R3a is R3a? or R3a?;

R3a? is heterocycloalkyl, optionally substituted with lower alkyl, amino, alkyl amino, dialkyl amino, or N(CH3)C(?O)OC(CH3)3;

R3a? is —OR3b, NH(CH2)2R3c; NHCN, NHS(?O)2R3d, or NHR3e;

R3b is H or lower alkyl;

R3c is lower alkoxy, amino, alkyl amino or dialkyl amino;

R3d is lower alkyl or cycloalkyl;

R3e is heterocycloalkyl, lower alkyl heterocycloalkyl, or (CH2)2N(CH3)C(?O)OC(CH3)3;

R4 is absent, lower alkyl, lower alkoxy, cyano, hydroxy, or halo;

R5 is halo or lower alkyl;

R6 is absent, halo, lower alkyl, or lower alkoxy;

R7 is H or R7 and R4 come together to form —C(?O);

R8 is absent, lower alkyl, hydroxy, or halo;

R9 is absent or halo;

X is CH or N;
X? is CH or N; and
Y is CH or N;
or a pharmaceutically acceptable salt thereof.
US Pat. No. 9,499,625

ANTIBODIES AGAINST HUMAN CSF-1R AND USES THEREOF

Hoffmann-La Roche Inc., ...

1. An isolated nucleic acid encoding an antibody binding to human CSF-1R, wherein the antibody comprises a heavy chain variable
domain and a light chain variable domain, and wherein:
a) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:7 and the light chain variable domain comprises
the amino acid sequence of SEQ ID NO:8;

b) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:15 and the light chain variable domain comprises
the amino acid sequence of SEQ ID NO:16;

c) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:75 and the light chain variable domain comprises
the amino acid sequence of SEQ ID NO:76;

d) the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:83 and the light chain variable domain comprises
the amino acid sequence of SEQ ID NO84;

or a humanized version thereof.

US Pat. No. 9,464,098

SUBSTITUTED TRIAZOLE BORONIC ACID COMPOUNDS

HOFFMANN-LA ROCHE INC., ...

1. A compound of formula (I):

wherein:
R1, R1? and R1?, of each other, are hydrogen, alkoxy, halogen or —CF3; and

R2 is C1-7 alkyl or phenyl,

or a pharmaceutically acceptable salt thereof.

US Pat. No. 9,447,097

4-AMINO-IMIDAZOQUINOLINE COMPOUNDS

Hoffmann-La Roche Inc., ...

1. A method of treating cancer, an autoimmune disease or infectious disease, the method comprising administering to a patient
in need thereof a therapeutically effective amount of a compound of formula I
wherein
R1 is C1-7-alkyl or C1-7-alkoxy-C1-7-alkyl;

R2 is selected from the group consisting of hydrogen, halogen, hydroxyl, hydroxy-C1-7-alkyl, alkoxy-C1-7-alkyl, carboxyl, carboxyl-C1-7-alkyl, carboxyl-C2-7-alkenyl, aminocarbonyl-C1-7-alkyl, aminocarbonyl-C2-7-alkenyl, C1-7-alkylamino-carbonyl-C1-7-alkyl, C1-7-alkylamino-carbonyl-C2-7-alkenyl, C1-7-alkoxycarbonyl-C1-7-alkyl, C1-7-alkoxycarbonyl-C2-7-alkenyl, C1-7-alkyl-sulfonyl-C1-7-alkyl, sulfamoyl-C1-7-alkyl, C1-7-alkyl-sulfamoyl-C1-7-alkyl,

phenyl, said phenyl being unsubstituted or substituted with one, two or three groups selected from the group consisting of
C1-7-alkyl, C1-7-cycloalkyl, halogen, halogen-C1-7-alkyl, halogen-C1-7-alkoxy, hydroxy, hydroxy-C1-7-alkyl, C1-7-alkoxy, cyano, carboxyl, C1-7-alkoxycarbonyl, C1-7-alkoxycarbonyl-C1-7-alkyl, C1-7-alkylsulfonyl, hydroxy-C1-7-alkylsulfonyl, C1-7-alkoxy-C1-7-alkylsulfonyl, carboxyl-C1-7-alkylsulfonyl, C1-7-alkoxy-carbonyl-C1-7-alkylsulfonyl, amino, C1-7-alkylamino, di-C1-7-alkylamino and nitro, and

phenoxy, said phenoxy group being unsubstituted or substituted with one, two or three groups selected from the group consisting
of C1-7-alkyl, C1-7-cycloalkyl, halogen, halogen-C1-7-alkyl, halogen-C1-7-alkoxy, hydroxy, hydroxy-C1-7-alkyl, C1-7-alkoxy, cyano, carboxyl, C1-7-alkoxycarbonyl, C1-7-alkoxycarbonyl-C1-7-alkyl, C1-7-alkyl-sulfonyl, hydroxy-C1-7-alkylsulfonyl, C1-7-alkoxy-C1-7-alkylsulfonyl, carboxyl-C1,7-alkylsulfonyl, C1-7-alkoxy-carbonyl-C1-7-alkylsulfonyl, amino, C1-7-alkylamino, di-C1-7-alkylamino and nitro;

R3 is hydrogen or halogen;

R4 is selected from the group consisting of

—O—(CH2)m-NHR5, and

—O—(CO)—(CH2)n-NHR6,

wherein
m is selected from 1, 2 or 3,
n is selected from 1 or 2,
R5 is selected from the group consisting of hydrogen, hydroxy-C1-7-alkyl, amino-C1-7-alkyl, C1-7-alkylcarbonyl, phenylcarbonyl, heteroarylcarbonyl, carboxyl, carboxyl-C1-7-alkyl and C1-7- alkoxycarbonyl-amino-C1-7-alkyl-carbonyl, and

R6 is selected from the group consisting of hydrogen, hydroxy-C1-7-alkyl, amino-C1-7-alkyl, C1-7-alkylcarbonyl, phenylcarbonyl, heteroarylcarbonyl, carboxyl, carboxyl-C1-7-alkyl and C1-7- alkoxycarbonyl-amino-C1-7-alkyl-carbonyl,
or a pharmaceutically acceptable salt thereof.
US Pat. No. 9,428,766

PROTEIN EXPRESSION FROM MULTIPLE NUCLEIC ACIDS

HOFFMANN-LA ROCHE INC., ...

1. A CHO cell secreting a heterologous immunoglobulin obtainable with the following method:
a) providing a CHO cell, which is
adapted to growth in suspension culture,
adapted to growth in serum-free medium, and
mycoplasma free,
b) providing a nucleic acid comprising
a prokaryotic origin of replication,
a first nucleic acid sequence conferring resistance to a prokaryotic selection agent,
a second nucleic acid sequence encoding the heavy chain of said heterologous immunoglobulin, and a third nucleic acid sequence
encoding the light chain of said heterologous immunoglobulin,

whereby a first transfection vector is provided which comprises said provided nucleic acid and an additional fourth nucleic
acid sequence conferring resistance to a first eukaryotic selection agent,

whereby a second transfection vector is provided which comprises said provided nucleic acid and an additional fourth nucleic
acid sequence conferring resistance to a second eukaryotic selection agent, whereby said second eukaryotic selection agent
is different to said first eukaryotic selection agent,

b1) providing a nucleic acid comprising
a prokaryotic origin of replication,
a first nucleic acid sequence conferring resistance to a prokaryotic selection agent,
a second nucleic acid sequence encoding the heavy chain of said heterologous immunoglobulin, and/or a third nucleic acid sequence
encoding the light chain of said heterologous immunoglobulin,

whereby a third transfection vector is provided which comprises said provided nucleic acid and an additional fourth nucleic
acid sequence conferring resistance to a third eukaryotic selection agent, whereby said third eukaryotic selection agent is
different to said first eukaryotic selection agent and is also different to said second eukaryotic selection agent,

c) transfecting said CHO cell, wherein said transfecting comprises the following steps in the following order:
(i) transfecting said CHO cell with said first transfection vector,
(ii) selecting a CHO cell transfected in (i) by selected growth in cultivation medium containing a first eukaryotic selection
agent to which the first transfection vector confers resistance,

(iii) transfecting said selected CHO cell in (ii) with said second transfection vector,
(iv) selecting a CHO cell transfected in (iii) by selected growth in cultivation medium containing said first eukaryotic selection
agent to which the first transfection vector confers resistance and said second eukaryotic selection agent to which the second
transfection vector confers resistance,

(v) transfecting said CHO cell selected in (iv) with said third transfections vector,
(vi) selecting a CHO cell transfected in (v) by selected growth in a cultivation medium containing said first eukaryotic selection
agent to which the first transfection vector confers resistance and said second eukaryotic selection agent to which the second
transfection vector confers resistance and said third eukaryotic selection agent to which the third transfection vector confers
resistance,

d) cultivating said transfected CHO cell in a medium in the presence of said first and said second eukaryotic selection agent,
under conditions suitable for the expression of said second, and/or third nucleic acid, wherein said transfected CHO cell
secretes the heterologous immunoglobulin and

e) recovering said secreted heterologous immunoglobulin from the cultivation medium and thereby producing a heterologous immunoglobulin
in a CHO cell which is secreted to the cultivation medium,
wherein said resultant CHO cell is stable in the absence of any or all selection agents, as used in the previous steps, for
up to generation 60.
US Pat. No. 9,409,961

CELL PENETRATING PEPTIDES TO TARGET EIF4E

Hoffmann-La Roche Inc., ...

1. A cell-penetrating peptide which binds mammalian initiation factor eIF4E (CPP-eIF4E), wherein the peptide comprises an
amino acid sequence selected from the group consisting of SEQ ID NOS: 7, 9-11, 12-26, 27-44 and 45-51.

US Pat. No. 9,090,565

1-PYRIDAZINYL-HYDROXYIMINO-3-PHENYL-PROPANES

Hoffmann-La Roche Inc., ...

1. A compound according to formula I,

wherein
R1 is a group selected from the group consisting of pyridazin-4-yl, 3-oxo -2,3-dihydro-pyridazin-4-yl “and 6-oxo-1,6-dihydropyridazin-3-yl,
said group”being unsubstituted or substituted by one, two or three groups independently selected from the group consisting
of C1-7-alkyl, halogen, halogen-C1-7-alkyl, hydroxy, hydroxy-C1-7-alkyl, C1-7-alkoxy and C1-7-alkoxy-C1-7-alkyl;

R2 is selected from the group consisting of C1-7-alkyl, C3-7-cycloalkyl, C2-7-alkenyl, halogen-C1-7-alkyl,

unsubstituted phenyl or phenyl substituted by one, two or three groups independently selected from the group consisting of
C1-7-alkyl, halogen, halogen-C1-7-alkyl, halogen-C1-7-alkoxy and C1-7-alkylsulfonyl, and

heteroaryl, said heteroaryl being unsubstituted or substituted by C1-7-alkyl or oxo,

R3 and R7 are independently from each other selected from the group consisting of hydrogen, halogen and C1-7-alkyl; and

R4, R5 and R6 are independently selected from the group consisting of hydrogen,

halogen, halogen-C1-7-alkyl,

cyano, cyano-C1-7-alkyl,

C1-7-alkyl, C3-7-alkenyl, C1-7-alkynyl,

C1-7-alkoxy, C1-7 -alkoxy-C1-7
hydroxy, hydroxy-C1-7-alkyl, hydroxy-C3-7-alkenyl, hydroxy-C3-7-alkynyl,

hydroxy-C1-7-alkoxy,

carboxyl, carboxyl-C1-7-alkyl, carboxyl-C3-7-alkenyl, carboxyl-C1-7-alkynyl,

carboxyl-C1-7-alkoxy,

tetrazolyl,
C1-7-alkoxycarbonyl,

C1-7-alkylsulfonyl, C1-7-alkylsulfonyloxy,

C1-7-alkylsulfonylamino, C3-7-cycloallcylsulfonylamino,

aminosulfonyl, (C1-7-alkyl)-aminosulfonyl, di-(C1-7-alkyl)-aminosulfonyl,

heterocyclylsulfonyl,
C1-7-alkyl-amino, di-(C1-7-alkyl)-amino, C1-7-alkoxy-C1-7-alkyl -amino,

C1-7-alkoxy-C1-7-alkyl-C1-7-alkyl-amino, C1-7-alkoxy-halogen-C1-7-alkyl-amino,

hydroxy-C1-7-alkyl-C1-7-alkyl-amino,

—NR—CHRA—COOH, wherein R is hydrogen or lower alkyl and RA is the side chain of a natural amino acid,

C3-7-cycloalkyl-amino, wherein C3-7-cycloalkyl is unsubstituted or substituted by hydroxy,

hydroxy-C1-7-alkyl or carboxyl,

carboxyl-C1-7-alkyl-aminocarbonyl, carboxyl-C1-7-alkyl-(C1-7-alkyl) -aminocarbonyl,

C1-7-alkoxycarbonyl-C1-7-alkyl-aminocarbonyl,

C1-7-alkyl-aminocarbonyl, di-(C1-7-alkyl)-aminocarbonyl,

C1-7-alkylsulfonyl-C1-7-alkyl-aminocarbonyl,

halogen-C1-7-alkyl-aminocarbonyl, hydroxy-C1-7-alkyl-aminocarbonyl,

hydroxy-C1-7-alkyl-C1-7-alkyl-aminocarbonyl, halogen-hydroxy-C1-7-alkyl -aminocarbonyl,

C1-7-alkoxy-C1-7-alkyl-aminocarbonyl,

C3-7-cycloalkylaminocarbonyl, wherein C3-7-cycloalkyl is unsubstituted or substituted by hydroxy, hydroxy-C1-7-alkyl or carboxyl,

heterocyclyl-aminocarbonyl, optionally substituted by C1-7-alkyl or oxo,

heterocyclyl-C1-7-alkyl-aminocarbonyl, optionally substituted by C1-7-alkyl or oxo,

hydroxy-C1-7-alkyl-aminocarbonyl-C1-7-alkyl,

C1-7-alkoxycarbonyl-C1-7-alkyl,

di-(C1-7-alkoxycarbonyl)-C1-7-alkyl,

C1-7-alkylcarbonylamino-C1-7-alkylaminocarbonyl,

C1-7-alkylcarbonylamino, carboxyl-C1-7-alkylcarbonylamino,

C1-7-alkoxycarbonyl-C1-7-alkylcarbonylamino,

C3-7-cycloalkyl, wherein C3-7-cycloalkyl is unsubstituted or substituted by hydroxy, hydroxy-C1-7-alkyl or carboxyl,

C3-7-cycloalkyl-C1-7-alkyl, wherein C3-7-cycloalkyl is unsubstituted or substituted by hydroxy, hydroxy-C1-7-alkyl or carboxyl,

heterocyclyl, optionally substituted by C1-7-alkyl,

halogen, hydroxy, hydroxy-C1-7-alkyl, C1-7-alkoxy, oxo, carboxyl, carboxyl -C1-7-alkyl, C1-7-alkoxycarbonyl, aminocarbonyl, C1-7-alkylsulfonyl, aminosulfonyl, C1-7-alkylcarbonyl,

carboxyl-C1-7-alkyl-aminocarbonyl or hydroxysulfonyl-C1-7-alkyl-aminocarbonyl,

heterocyclylcarbonyl, optionally substituted by C1-7alkyl, halogen, hydroxy, hydroxy-C1-7-alkyl, C1-7-alkoxy, oxo, carboxyl, carboxyl -C1-7-alkyl or C1-7-alkylsulfonyl,

heteroaryl, said heteroaryl being unsubstituted or substituted by C1-7-alkyl, C3 -7-cycloalkyl, tetrahydropyranyl, carboxyl, carboxyl-C1-7-alkyl, C1-7-alkoxy-C1-7-alkyl or C1-7-alkoxycarbonyl,

phenyloxy, wherein phenyl is unsubstituted or substituted by one to three groups selected from halogen or carboxyl, and
phenyl, said phenyl being unsubstituted or substituted by one to three groups selected from the group consisting of halogen,
C1-7-alkyl, hydroxy, hydroxy-C1-7-alkyl, cyano, cyano-C1-7-alkyl, amino, C1-7-alkoxy, carboxyl, carboxyl-C1-7-alkyl,

C1-7-alkoxy-carbonyl, tetrazolyl, carboxyl-C1-7-alkyl-carbonylamino,

C1-7-alkoxy-carbonyl-C1-7-alkyl-carbonylamino, C1-7-alkylsulfonyl,

C1-7-alkyl-sulfonylamino, aminosulfonyl, C1-7-alkyl-aminosulfonyl,

di-(C1-7-alkyl)-aminosulfonyl, heterocyclylsulfonyl, C1-7-alkoxycarbonyl-C1-7-alkoxy, C1-7-alkoxycarbonyl-C1-7-alkyl-aminocarbonyl, carboxyl-C1-7-alkyl-aminocarbonyl,

C1-7-alkoxycarbonyl-C1-7-alkyl-carbonylamino-C1-7-alkylsulfonyl,

phenyl-C1-7-alkyl-aminocarbonyl, tetrazolyl-aminocarbonyl,

tetrazolyl-C1-7-alkyl-aminocarbonyl and carboxyl-C1-7-alkyl-aminocarbonyl;

or a pharmaceutically acceptable salt thereof.

US Pat. No. 10,023,589

PYRAZOLO[1,5A]PYRIMIDINE DERIVATIVES AS IRAK4 MODULATORS

Hoffmann-La Roche Inc., ...

1. A compound of formula II:
or a pharmaceutically acceptable salt thereof,
wherein:
X is N or CH
m is 1 or 2;
Ar is:
optionally substituted aryl; or
optionally substituted heteroaryl;
R1 is:
hydrogen;
C1-6alkyl;
C1-6alkoxy;
hydroxy;
hydroxy-C1-6alkyl;
C1-6alkyl-amino;
amino-C1-6alkyl;
amino-C1-6alkyl-amino;
hydroxy-C1-6alkylamino;
amino-C3-6cycloalkylamino;
amino-C3-6heterocycloalkylamino;
aminocarbonyl;
halo;
hydroxy-C1-6alkyl; or
hydroxy-C1-6alkoxy; and
R2 is:
hydrogen; or
C1-6alkyl.

US Pat. No. 9,708,325

SULFONIMIDOYLPURINONE COMPOUNDS AND DERIVATIVES FOR THE TREATMENT AND PROPHYLAXIS OF VIRUS INFECTION

Hoffmann-La Roche Inc., ...

1. A compound of formula (I),

wherein
R1 is C1-6alkyl, haloC1-6alkyl, C3-7cylcoalkylC1-6alkyl, C1-6alkoxyC1-6alkyl or pyrrolidinylC1-6alkyl;

R2 is C1-6alkyl, phenylC1-6alkyl, pyridinylC1-6alkyl or pyrimidinylC1-6alkyl, said phenylC1-6alkyl, pyridinylC1-6alkyl and pyrimidinylC1-6alkyl are unsubstituted or substituted by one, two or three substituents independently selected from halogen, C1-6alkyl, C1-6alkoxy, cyano, carboxy, carbamoyl, haloC1-6alkyl, C1-6alkylsulfonyl, C1-6alkoxycarbonyl, C1-6alkoxyC1-6alkylaminocarbonyl, pyrrolidinylcarbonyl and piperidinylcarbonyl;

R3 is H;

or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.

US Pat. No. 9,636,680

SAMPLE HANDLING SYSTEM

HOFFMANN-LA ROCHE INC., ...

1. A sample handling system for handling samples contained in
tubes, each tube having a hollow body, a closed bottom and an open top for accessing the sample contained in the tube, the
system including a micro-plate comprising:

at least one separate grid insert and at least one further separate grid insert forming a stack of connected grid inserts
arranged one above the other in the stack, each of the at least one separate grid insert and the at least one further separate
grid insert having a plurality of compartments, each compartment including one or more side walls laterally confining a through-hole,
wherein the through-hole has a top opening and a bottom opening and extends between the top opening and the bottom opening,
and

a frame to which only an uppermost one of the at least one separate grid insert and the at least one further separate grid
insert of the stack is attached to form the microplate, the frame laterally confining a single through-opening dimensioned
to allow for accessing from above each compartment of the uppermost separate grid insert in the stack of connected grid inserts
that is attached to the frame and accessing from below each compartment of a lowermost separate grid insert in the stack of
connected grid inserts, and to allow for moving a tube into and out of each compartment through each of the top opening and
the bottom opening of the through-hole,

wherein:
each of the at least one separate grid insert and the at least one further separate grid insert includes one or more stacking
elements for connecting the at least one separate grid insert and the at least one further separate grid insert to form the
stack of connected grid inserts,

each stacking element includes at least one resilient locking member extending downwardly beyond a corresponding one of the
at least one separate grid insert and the at least one further separate grid insert and further includes at least one notch
arranged to lockingly receive the at least one resilient locking member of an above-arranged separate grid insert that is
one of the at least one further separate grid insert or the at least one separate grid insert, respectively, and

each compartment in each of the at least one separate grid insert is longitudinally aligned with a compartment of the at least
one further separate grid insert in the stack to form a joint through-hole through which a tube is moveable.

US Pat. No. 9,611,232

OXAZOLIDINONE AND IMIDAZOLIDINONE COMPOUNDS

Hoffmann-La Roche Inc., ...

21. A pharmaceutical composition comprising the compound of claim 1 admixed with at least one pharmaceutically acceptable carrier, excipient or diluent.

US Pat. No. 9,580,435

PYRROLO[2,3-D]PYRIMIDINE DERIVATIVES AS CB2 RECEPTOR AGONISTS

HOFFMANN-LA ROCHE INC., ...

1. A compound of formula (I)

wherein
A is CH2 or absent;

R1 and R2, together with the nitrogen atom to which they are attached form substituted pyrrolidinyl or 2-oxa-6-azaspiro[3.3]heptyl,
wherein substituted pyrrolidinyl is pyrrolidinyl substituted with one or two substituents independently selected from halogen,
hydroxyl and alkylcarbonyloxy; and

R3 is halophenyl, alkylsulfonylphenyl, haloalkylphenyl, halopyridinyl, alkyloxadiazolyl, alkyltriazolyl, alkyltetrazolyl, oxolanyl,
cycloalkyltetrazolyl or haloalkyl-1H-pyrazolyl;

or a pharmaceutically acceptable salt or ester thereof.
US Pat. No. 9,487,576

METHOD FOR REDUCTION OF 1->2 READING FRAME SHIFTS

HOFFMANN-LA ROCHE INC., ...

1. A method for reducing polypeptide by-product formation by 1?2 frameshift in the recombinant production of a human polypeptide
comprising the dipeptide AR (SEQ ID NO: 06), characterized in that the method comprises:
(a) substituting in the human polypeptide-encoding nucleic acid in the dipeptide AR encoding oligonucleotide gcg agg (SEQ
ID NO: 01), or gcg aga (SEQ ID NO: 02) to obtain the oligonucleotide gca cgt (SEQ ID NO: 03), or the oligonucleotide gcg cgt
(SEQ ID NO: 04), or the oligonucleotide gcc cgt (SEQ ID NO: 05), thereby producing a substituted polypeptide encoding nucleic
acid,

(b) expressing the substituted polypeptide-encoding nucleic acid using an E. coli host/vector, and

(c) recovering the polypeptide from the cells or the cultivation medium of a cultivation of a cell comprising a nucleic acid
encoding the polypeptide and thereby producing the polypeptide.

US Pat. No. 9,403,808

PYRAZINE DERIVATIVES

Hoffmann-La Roche Inc., ...

1. A compound, selected from the group consisting of:
6-(3-Chloro-phenyl)-5-cyclopropyl-pyrazine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]amide;
6-(3-Chloro-phenyl)-5-cyclopropyl-pyrazine-2-carboxylic acid (cyano-dimethyl-methyl)-amide;
6-(3-Chloro-phenyl)-5-cyclopropyl-pyrazine-2-carboxylic acid [1-(5-methyl-[1,2,4]oxadiazol-3-yl)-cyclobutyl]-amide;
6-(3-Chloro-phenyl)-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
5-Azetidin-1-yl-6-(3-chloro-phenyl)-pyrazine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
6-(3-Chloro-phenyl)-5-cyclopropyl-pyrazine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;
6-(3-Chloro-phenyl)-5-cyclopropyl-pyrazine-2-carboxylic acid piperidin-1-ylamide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid ((S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [1-(5-methyl-[1,2,4]oxadiazol-3-yl)-cyclobutyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (3-hydroxy-1,1-dimethyl-propyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1-hydroxymethyl-cyclobutyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [1-(5-methyl-[1,2,4]oxadiazol-3-yl)-cyclobutyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1-hydroxymethyl-1-methyl-propyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S)-carbamoyl-phenyl-methyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid ((S)-1-cyclopropylmethyl-2-hydroxy-2-methyl-propyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S)-1-cyclopropylmethyl-2-hydroxy-2-methyl-propyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid piperidin-1-ylamide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1-hydroxymethyl-2,2-dimethyl-propyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (1-cyclopropyl-2-hydroxy-ethyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid ((S)-carbamoyl-phenyl-methyl)-amide;
(S)-2-[(5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carbonyl)-amino]-3,3-dimethyl-butyric acid methyl ester;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S)-2-cyclopropyl-1-methylcarbamoyl-ethyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S)-2-cyclopropyl-1-dimethylcarbamoyl-ethyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S)-3-methyl-1-methylcarbamoyl-butyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S)-1-dimethylcarbamoyl-3-methyl-butyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
2-[(5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carbonyl)-amino]-2-ethyl-butyric acid methyl ester;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid ((S)-2-cyclopropyl-1-methylcarbamoyl-ethyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid ((S)-2-cyclopropyl-1-dimethylcarbamoyl-ethyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid ((S)-3-methyl-1-methylcarbamoyl-butyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid ((S)-1-dimethylcarbamoyl-3-methyl-butyl)-amide;
(S)-3-Cyclopropyl-2-[(5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carbonyl)-amino]-propionic acid methyl ester;
(S)-3-Cyclopropyl-2-{[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carbonyl]-amino}-propionic acid methyl
ester;

5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S)-1-carbamoyl-2-phenyl-ethyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid ((S)-1-carbamoyl-2-phenyl-ethyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [(S)-cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [(R)-cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [(S)-cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [(R)-cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide;
(S)-2-[(5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carbonyl)-amino]-3,3-dimethyl-butyric acid;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S)-1-pyridin-2-yl-ethyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid ((R)-2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid ((S)-2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S)-2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((R)-1-hydroxymethyl-1,2-dimethyl-propyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S)-1-hydroxymethyl-1,2-dimethyl-propyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [1-methyl-1-(4-methyl-thiazol-2-yl)-ethyl]-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [1-methyl-1-(4-methyl-thiazol-2-yl)-ethyl]-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [(R)-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [1-(5-amino-[1,2,4]oxadiazol-3-yl)-1-methyl-ethyl]amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [1-(5-amino-[1,2,4]oxadiazol-3-yl)-1-methyl-ethyl]-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid ((S)-1-carbamoyl-1-phenyl-ethyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [(S)-carbamoyl-(4-fluoro-phenyl)-methyl]-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [(S)-carbamoyl-(4-fluoro-phenyl)-methyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [(S)-3-methyl-1-(2,2,2-trifluoro-ethylcarbamoyl)-butyl]-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [(S)-carbamoyl-(4-chloro-phenyl)-methyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (4-hydroxy-1,1-dimethyl-butyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1,1-dimethyl-3-pyridin-4-yl-propyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [1,1-dimethyl-2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1,1-dimethyl-3-pyridin-4-yl-butyl)-amide;
1-{[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carbonyl]-amino}-cyclobutanecarboxylic acid methyl ester;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid [1-methyl-1-(5-methyl-thiazol-2-yl)-ethyl]-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [1-methyl-1-(5-methyl-thiazol-2-yl)-ethyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid ((S)-1-carbamoylmethyl-2-methyl-propyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid ((S)-1-carbamoylmethyl-2-methyl-propyl)-amide;
(+)-6-Cyclopropylrnethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
(?)-6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
2-Cyclopropyl-2-{[6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carbonyl]-amino}-propionic acid methyl ester;
(+)-6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid ((1R,2S)-rel-2-carbamoyl-cyclohexyl)-amide;
(?)-5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid cis-2-carbamoyl-cyclohexyl)-amide;
(+)-5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid cis-2-carbamoyl-cyclohexyl)-amide;
5-Cyclopropyl-6-cyclopropylinethoxy-pyrazine-2-carboxylic acid (3-carbamoylmethyl-oxetan-3-yl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (3-carbamoylmethyl-oxetan-3-yl)-amide;
(+)-6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
(?)-6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid [1-cyclopropyl-1-(5-methyl[1,2,4]oxadiazol-3-yl)-ethyl]amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (1-carbamoyl-2-methyl-propyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (1-carbamoyl-cyclohexyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (1-hydroxymethyl-cyclohexyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (1-dimethylcarbamoyl-2-methyl-propyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1-dimethylcarbamoyl-2-methyl-propyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (5-chloro-thiophen-2-yl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1-hydroxymethyl-cyclohexyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (3-methoxy-1,1-dimethyl-propyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (2-cyclobutyl-1-methylcarbarnoyl-ethyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (2-cyclobutyl-1-dimethylcarbamoyl-ethyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (2-cyclobutyl-1-methylcarbarnoyl-ethyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (3-methoxy-1,1-dimethyl-propyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (1-cyclobutylmethyl-2-hydroxy-ethyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (1-carbamoyl-2-cyclobutyl-ethyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (2-cyclobutyl-1-dimethylcarbamoyl-ethyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1-carbamoyl-2-cyclobutyl-ethyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (1-cyclobutylmethyl-2-hydroxy-ethyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (2-carbamoyl-1,1-dimethyl-ethyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (2-carbamoyl-1,1-dimethyl-ethyl)-amide;
(S)-2-{[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carbonyl]-amino}-4-methyl-pentanoic acid methyl ester;
and

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (1,1-dimethyl-3-phenyl-propyl)-amide.
US Pat. No. 9,321,727

PYRIDINE DERIVATIVES AS AGONISTS OF THE CB2 RECEPTOR

Hoffmann-La Roche Inc., ...

1. A compound selected from the group consisting of:
Methyl 2-methyl-2-(5-methyl-6-(2,2,2-trifluoroethoxy)picolinamido)propanoate;
2-[(6-Cyclohexyl-pyridine-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester;
2-{[6-Cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carbonyl]amino}-2-methyl-propionic acid methyl ester;
6-Cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid [1-methyl-1(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;6-(3-Chloro-phenyl)-pyridine-2-carboxylic
acid piperidin-1-ylamide;

2-{[6-Cyclopropylmethoxy-5-(1H-pyrazol-3-yl)-pyridine-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester;
6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide;
2-[(6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester;
6-Cyclopropylmethoxy-5-(2-methyl-pyrrolidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
6-Cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;
6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid (1,1-dimethyl-3-moipholin-4-yl-propyl)-amide;
6-Cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid (1-methyl-1-methylcarbamoyl-ethyl)-amide;
6-(Tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid piperidin-1-ylamide;
5-Cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-methyl-1-methylcarbamoyl-ethyl)-amide;
6-(3-Chloro-phenyl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid piperidin-1-ylamide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-methyl-1-methylcarbamoyl-ethyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
6-Cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid piperidin-1-ylamide;
5-Cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
5-Cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
5-Cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;
6-Cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
6-Cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid ((S)-2-cyclopropyl-1-thiazol-2-yl-ethyl)-amide;
6-Cyclopropylmethoxy-5-(2-oxo-pyrrolidin-1-yl)-pyridine-2-carboxylic acid (1-methyl-1-oxazol-2-yl-ethyl)-amide;
6-Cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;
6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid [1-(4,5-dihydro-oxazol-2-yl)-1-methyl-ethyl]-amide;
6-Cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid ((S)-3-methyl-1-thiazol-2-yl-butyl)-amide;
6-Cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid ((S)-2-cyclopropyl-1-thiazol-2-yl-ethyl-amide;
6-Cyclopropylmethoxy-pyridine-2-carboxylic acid piperidin-1-ylamide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-methyl-1-[1,2,4]oxadiazol-3-yl-ethyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
6-Cyclopropylmetboxy-5-(3-hydroxy-azetidin-1-yl)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;
6-(4-Chloro-phenyl)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
6-(Cyclopropylmethoxy)-5-(1,1-dioxido-1,2-isothiazolidin-2-yl)-N-[2-(1,3-thiazol-2-yl) propan-2-yl]pyridine-2-carboxamide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-pyrrolidin-1-yl)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-pyrrolidin-1-yl)-pyridine-2-carboxylic acid (1-methyl-1-methylcarbamoybethyl)-amide;
6-(3-Chloro-phenyl)-5-methoxy-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;
5-Chloro-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-methyl-1-[1,2,4]oxadiazol-3-yl-ethyl)-amide;
6-Cyclohexyl-pyridine-2-carboxylic acid (2-hydroxy-cyclohexyl)-amide;
6-Cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-methyl-1-methylcarbamoyl-ethyl)-amide;
2-[(6-Cyclohexyl-pyridine-2-carbonyl)-amino]-cyclohexanecarboxylic acid methyl ester;
6-Cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid (1-methyl-1-oxazol-2-yl-ethyl)-amide;
6-Cyclopentyl-pyridine-2-carboxylic acid piperidin-1-ylamide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-2-cyclopropyl-1-thiazol-2-yl-ethyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;
5-Cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;
5-Chloro-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
5-Chloro-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
5-Bromo-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;
5-Cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-pyrrolidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;
6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;
6-Cyclopropylmethoxy-5-(tetrahydro-furan-3-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
6-Cyclopropylmethoxy-5-(tetrahydro-furan-2-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-amide;
6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (1-methyl-1-[1,2,4]oxadiazol-3-yl-ethyl)-amide;
6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;
6-Cyclohexyl-pyridine-2-carboxylic acid (2-hydroxymethyl-cyclohexyl)-amide;
6-Cyclopropylmethoxy-5-(tetrahydro-furan-2-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
6-Cyclopropylmethoxy-5-(tetrahydro-furan-3-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (1-methyl-1-oxazol-2-yl-ethyl)-amide;
6-Cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;
6-Cyclopropylmethoxy-5-(3-hydroxy-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
5-Cyclopropylamino-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;
5-Cyclopropylamino-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-cyclopropylmethyl-2-hydroxy-2-methyl-propyl)-amide;
6-Cyclopropylmethoxy-5-(tetrahydro-furan-3-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (2-hydroxy-cyclohexyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-cyclopropylmethyl-2-hydroxy-2-methyl-propyl)-amide;
6-Cyclopropylmethoxy-5-(tetrahydro-furan-3-yl)-pyridine-2-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide;
5-Cyclopropyl-6-(2-methoxy-ethoxy)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-2-cyclopropyl-1-thiazol-2-yl-ethyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (pyridin-2-ylmethyl)-amide;
[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridin-2-yl]-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-methanone;
6-Cyclopropylmethoxy-5-(3-hydroxy-oxetan-3-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
5-Cyclopropyl-6-(2-methoxy-ethoxy)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1,1-dimethyl-3-morpholin-4-yl-propyl)-amide;
5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(2-methoxy-ethoxymethyl)-ethyl]-amide;
5-Cyclopropylamino-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide;
6-Cyclopropylmethoxy-5-(1-hydroxy-cyclobutyl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
5-Cyclopropyl-6-(2-methoxy-ethoxy)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;
5-[Bis-(2,2,2-trifluoro-ethyl)-amino]-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
5-[Bis-(2,2,2-trifluoro-ethyl)-amino]-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
N-(2-Cyanopropan-2-yl)-5-cyclopropyl-6-(cyclopropylmethoxy)picolinamide;
(S)-5-Cyclopropyl-6-(cyclopropylmethoxy)-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)picolinamide;
N-(1-Amino-2,3-dimethyl-1-oxobutan-2-yl)-5-cyclopropyl-6-(cyclopropylmethoxy)picolinamide;
N-(1-Amino-2-methyl-1-oxobutan-2-yl)-5-cyclopropyl-6-(cyclopropylmethoxy)picolinamide;
5-Cyclopropyl-6-(cyclopropylmethoxy)-N-(1-(5-methyl-1,2,4-oxadiazol-3-yl)cyclobutyl)picolinamide;
(S)-N-(2-Amino-2-oxo-1-phenylethyl)-5-cyclopropyl-6-(cyclopropylmethoxy)picolinamide;
(R)-N-(2-Amino-2-oxo-1-phenylethyl)-5-cyclopropyl-6-(cyclopropylmethoxy)picolinamide;
(R)-5-Cyclopropyl-6-(cyclopropylmethoxy)-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide;
5-Cyclopropyl-6-(cyclopropylmethoxy)-N-(1-(hydroxymethyl)cyclopentyl)picolinamide;
5-Cyclopropyl-6-(cyclopropylmethoxy)-N-(2-(3-methyl-1,2,4-oxadiazol-5-yl)propan-2-yl)picolinamide;
5-Bromo-6-(4-fluoro-phenoxy)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
N-(1-Amino-2,4-dimethyl-1-oxopentan-2-yl)-5-cyclopropyl-6-(cyclopropylmethoxy)picolinamide;
N-(1-Amino-3,3-dimethyl-1-oxobutan-2-yl)-5-cyclopropyl-6-(cyclopropylmethoxy)picolinamide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (4-carbamoyl-tetrahydro-pyran-4-yl)-amide;
(S)-5-Cyclopropyl-6-(cyclopropylmethoxy)-N-(4-methyl-1-(methylamino)-1-oxopentan-2-yl)picolinamide;
(S)-5-Cyclopropyl-6-(cyclopropylmethoxy)-N-(4,4-dimethyl-1-(methylamino)-1-oxopentan-2-yl)picolinamide;
5-Cyclopropyl-N-((S)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-6-((tetrahydrofuran-2-yl)methoxy)picolinamide;
5-Cyclopropyl-N-((S)-4-methyl-1-(methylamino)-1-oxopentan-2-yl)-6-((tetrahydrofuran-2-yl)methoxy)picolinamide;
5-Cyclopropyl-N-((S)-4,4-dimethyl-1-(methylamino)-1-oxopentan-2-yl)-6-((tetrahydrofuran-2-yl)methoxy)picolinamide;
N-((S)-1-Amino-4-methyl-1-oxopentan-2-yl)-5-cyclopropyl-6-((tetrahydrofuran-2-yl)methoxy)picolinamide;
5-Cyclopropyl-6-(4-fluoro-phenoxy)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
5-Bromo-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid ((S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-amide;
5-Cyclopropyl-N-(1-(5-methyl-1,2,4-oxadiazol-3-yl)cyclobutyl)-6-(pyridin-2-ylmethoxy)picolinamide;
5-Cyclopropyl-N-(cyclopropyl(5-methyl-1,2,4-oxadiazol-3-yl)methyl)-6-(cyclopropylmethoxy)picolinamide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((R)-1-hydroxymethyl-1,2-dimethyl-propyl)-amide;
5-Cyclopropyl-6-(cyclopropylmethoxy)-N-(4-hydroxy-2-methylbutan-2-yl)picolinamide;
(S)-5-Cyclopropyl-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)picolinamide;
(S)-5-Cyclopropyl-N-(4,4-dimethyl-1-(methylamino)-1-oxopentan-2-yl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)picolinamide;
(?)-5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide;
(+)-5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide;
5-Cyclopropyl-N-(2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl)-6-(pyridin-2-ylmethoxy)picolinamide;
(S)-N-(1-Amino-4-methyl-1-oxopentan-2-yl)-5-cyclopropyl-6-(pyridin-2-ylmethoxy)picolinamide;
(S)-5-Cyclopropyl-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-6-(pyridin-2-ylmethoxy)picolinamide;
5-Cyclopropyl-N-(2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-yl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)picolinamide;
(S)-5-Cyclopropyl-N-(4-methyl-1-(methylamino)-1-oxopentan-2-yl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)picolinamide;
2-(6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinamido)-2-ethylbutanoic acid;
(S)-6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)picolinamide;
(S)-6-(Cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)-N-(4,4-dimethyl-1-(methylamino)-1-oxopentan-2-yl)picolinamide;
(S)-N-(4-Methyl-1-(methylamino)-1-oxopentan-2-yl)-6-(3-(trifluoromethyl)phenyl)picolinamide;
(S)-N-(3,3-Dimethyl-1-(methylamino)-1-oxobutan-2-yl)-6-(3-(trifluoromethyl)phenyl)picolinamide;
(S)-5-Cyclopropyl-6-(cyclopropylmethoxy)-N-(2,2,2-trifluoro-1-(pyridin-3-yl)ethyl)picolinamide;
(R)-5-Cyclopropyl-6-(cyclopropylmethoxy)-N-(2,2,2-trifluoro-1-(pyridin-3-yl)ethyl)picolinamide;
5-Cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methy]-amide;
2-({5-[Bis-(2,2,2-trifluoro-ethyl)-amino]-6-cyclopropylmethoxy-pyridine-2-carbonyl}-amino)-2-ethyl-butyric acid methyl ester;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-2-cyclopropyl-1-dimethylcarbamoyl-ethyl)-amide;
5-Cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylic acid (2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((?)-methylcarbamoyl-phenyl-methyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((+)-dimethylcarbamoyl-phenyl-methyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((?)-dimethylcarbamoyl-phenyl-methyl)-amide;
6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3-dimethyl-1-methylcarbamoyl-butyl)-amide;
6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide;
6-(Tetrahydro-pyran-4-ylmethoxy)-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3-dimethyl-1-methylcarbamoyl-butyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-dimethylcarbamoyl-3-methyl-butyl)-amide;
2-{[5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carbonyl]-amino}-2-ethyl-butyric acid methyl ester;
6-Cyclopropylmethoxy-5-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-pyridine-2-carboxylic acid ((S)-3,3-dimethyl-1-methylcarbamoyl-butyl)-amide;
6-Cyclopropylmethoxy-5-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
6-Cyclopropylmethoxy-5-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-pyridine-2-carboxylic acid [cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methyl]-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxlic acid ((R)-2,2,2-trifluoro-1-pyridin-3-yl-ethyl)-amide;
2-Ethyl-2-{[6-(tetrahydro-pyran-4-ylmethoxy)-5-trifluoromethyl-pyridine-2-carbonyl]-amino}-butyric acid methyl ester;
(S)-2-[(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-3,3-dimethyl-butyric acid methyl ester;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(?)-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(+)-3-methyl-1-(5-methyl-[1,2,4]oxadiazol -3-yl)-butyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(+)-3-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-butyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(+)-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-propyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(?)-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-propyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((?)-cyano-methyl-methyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((?)-1-cyano-3-methyl-butyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((+)-cyano-cyclopropyl-methyl)-amide;
2-[(6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid methyl ester;
5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
2-[(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid methyl ester;
2-[(6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid;
6-(Tetrahydro-pyran-4-ylmethoxy)-5-trifluoromethyl-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
2-Ethyl-2-{[6-(tetrahydro-furan-2-ylmethoxy)-5-trifluoromethyl-pyridine-2-carbonyl]-amino}-butyric acid ethyl ester;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (dimethylcarbamoyl-phenyl-methyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-2-cyclopropyl-1-dimethylcarbamoyl-ethyl)-amide;
2-[(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid ethyl ester;
(S)-3-Cyclopropyl-2-[(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-propionic acid methyl ester;
6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
6-(Tetrahydro-pyran-4-ylmethoxy)-5-trifluoromethyl-pyridine-2-carboxylic acid (1-dimethylcarbamoyl-1-ethyl-propyl)-amide;
2-{[6-Cyclopropylmethoxy-5-(6-oxa-1-aza-spiro[3.3]hept-1-yl)-pyridine-2-carbonyl]amino}-2-ethyl-butyric acid ethyl ester;
6-(Tetrahydro-furan-2-ylmethoxy)-5-trifluoromethyl-pyridine-2-carboxylic acid (1-dimethylcarbamoyl-1-ethyl-propyl)-amide;
2-[(5-Bromo-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid ethyl ester;
2-{[6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carbonyl]-amino}-2-ethyl-butyric acid ethyl ester;
2-{[6-Cyclopropylmethoxy-5-(3,3-difluoro-2-oxo-azetidin-1-yl)-pyridine-2-carbonyl]-amino}-2-ethyl-butyric acid methyl ester;
(S)-2-[(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-4-methyl-pentanoic acid methyl ester;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-cyano-3-methyl-butyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [3-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-butyl]-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-hydroxymethyl-1,3-dimethyl-butyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-(azetidine-1-carbonyl)-1-ethyl-propyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-ethyl-1-(2-methoxy-ethylcarbamoyl)-propyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-ethyl-1-(ethyl-methyl-carbamoyl)-propyl]-amide;
6-(4-Fluoro-benzyl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
6-(4-Fluoro-benzyl)-pyridine-2-carboxylic acid ((R)-2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-1-hydroxymethyl-1,2-dimethyl-propyl)-amide;
5-Bromo-6-(3-methyl-oxetan-3-ylmethoxy)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;
5-Bromo-6-(3-methyl-oxetan-3-ylmethoxy)-pyridine-2-carboxylic acid (3-thiazol-2-yl-oxetan-3-yl)-amide;
5-Bromo-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (3-thiazol-2-yl-oxetan-3-yl)-amide;
5-Bromo-6-(3-methyl-oxetan-3-ylmethoxy)-pyridine-2-carboxylic acid (2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-(cyclopropylmethyl-carbamoyl)-1-ethyl-propyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (1-methyl-1-pyridin-2-yl-ethyl)-amide;
6-(4-Fluoro-benzyl)-pyridine-2-carboxylic acid ((S)-3,3-dimethyl-1-methylcarbamoyl-butyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-(3,3-difluoro-azetidine-1-carbonyl)-1-ethyl-propyl]-amide;
2-[(6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid ethyl ester;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-methyl-5-oxo-pyrrolidin-3-yl)-amide;
2[(6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1,1-dioxo-tetrahydro-1?6-thiophen-3-yl)-amide;

6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid N?-(1,1-dioxo-tetrahydro-1?6-thiophen-3-yl)-hydrazide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-methyl-1-(4-methyl-thiazol-2-yl)-ethyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-(5-amino-[1,2,4]oxadiazol-3-yl)-1-methyl-ethyl]-amide;
6-(2,2,3,3,3-Pentafluoro-propoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
5-Cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
5-Cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid ((S)-3,3-dimethyl-1-methylcarbamoyl-butyl)-amide;
5-Cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
5-Cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid ((S)-carbamoyl-phenyl-methyl)-amide;
5-Cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide;
5-Cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide;
5-Cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (3-thiazol-2-yl-oxetan-3-yl)-amide;
5-Cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (1-methyl-1-thiazol-2-yl-ethyl)-amide;
5-Cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (2,2-dimethyl-1-thiazol-2-yl-propyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [1-(3,3-difluoro-azetidine-1-carbonyl)-1-ethyl-propyl]-amide;
6-(4-Fluoro-benzyl)-pyridine-2-carboxylic acid N?-(1,1-dioxo-tetrahydro-1?6-thiophen-3-yl)-hydrazide;

5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-(3-amino-[1,2,4]oxadiazol-5-yl)-1-methyl-ethyl]-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [(S)-1-(3,3-difluoro-azetidine-1-carbonyl)-2,2-dimethyl-propyl]-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [(S)-1-(3,3-difluoro-azetidine-1-carbonyl)-3-methyl-butyl]-amide;
2-[(6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carbonyl)-amino]-2-ethyl-butyric acid ethyl ester;
5-Cyclopropyl-6-((R)-3-hydroxy-1-trifluoromethyl-propoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
5-Cyclopropyl-6-((R)-4,4,4-trifluoro-3-hydroxy-butoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (3-methyl-1-pyridin-2-yl-butyl)-amide;
6-Cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid [1-(3,3-difluoro-azetidine-1-carbonyl)-1-ethyl-propyl]-amide;
6-[(4-Fluoro-phenyl)-hydroxy-methyl]-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
6-[(4-Fluoro-phenyl)-hydroxy-methyl]-pyridine-2-carboxylic acid [(S)-3-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-butyl]-amide;
5-Cyclopropyl-6-((S)-3-hydroxy-1-trifluoromethyl-propoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
5-Cyclopropyl-6-((S)-4,4,4-trifluoro-3-hydroxy-butoxy)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (3-methyl-1-pyridazin-3-yl-butyl)-amide;
6-Cyclopropylmethoxy-5-(3-oxo-azetidin-1-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(+)-1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(?)-1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (3-methyl-1-pyridin-3-yl-butyl)-amide;
5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-2-cyclopropyl-ethyl)-amide;
5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(S)-carbamoyl-(4-fluoro-phenyl)-methyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(S)-carbamoyl-(4-chloro-phenyl)-methyl]-amide;
6-(2-Methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
6-Isobutylsulfanyl-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid ((S)-2,2,2-trifluoro-1-pyridin-2-yl-ethyl)-amide;
2-{[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carbonyl]-amino}-2-ethyl-butyric acid;
6-Cyclopropylmethoxy-5-(3-oxo-pyrrolidin-1-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide,
6-(2-Methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid [(S)-3-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-butyl]-amide;
(S)-2-{[5-Cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carbonyl]-amino}-4-methyl-pentanoic acid;
2-{[5-Cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carbonyl]-amino}-2-ethyl-butyric acid;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-methyl-1-(4-methyl-5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (3-methyl-1-pyrimidin-2-yl-butyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methylsulfanyl-propyl)-amide;
6-Cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid {(S)-3-methyl-1-[(7-nitro-benzo[1,2,5]oxadiazol-4-ylamino)-methyl]-butyl}-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methanesulfonyl-propyl)-amide;
5-Cyclopropyl-6-isobutylsulfanyl-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
6-(4-Fluoro-3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (3-methanesulfonyl-1,1-dimethyl-propyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-thiazol-2-yl)-ethyl]-amide;
5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3-methyl-butyl)-amide;
5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-thiazol-2-yl)-ethyl]-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((R)-3-methyl-1-pyridazin-3-yl-butyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((S)-3-methyl-1-pyridazin-3-yl-butyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-ethyl-1-(2-hydroxy-ethylcarbamoyl)-propyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(+)-2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(?)-2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid tert-butylamide;
2-{[5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carbonyl]-amino}-2-ethyl-butyric acid ethyl ester;
5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid ((S)-3,3-dimethyl-1-methylcarbamoyl-butyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((S)-2-oxo-tetrahydro-furan-3-yl)-amide;
N?-(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-N-cyclopropylmethyl-hydrazinecarboxylic acid tert-butyl ester;
5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid ((S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-amide;
5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid ((S)-2,2,2-trifluoro-1-pyridin-3-yl-ethyl)-amide;
(S)-2-[(5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-4-methyl-pentanoic acid tert-butyl ester;
5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid (1-ethyl-1-methylcarbamoyl-propyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid tert-butylamide;
5-Cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid tert-butylamide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (3-methyl-oxetan-3-yl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (2-oxo[1,3]oxazinan-3-yl)-amide;
5-Cyclopropyl-6-(2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid ((S)-1-carbamoyl-3methyl-butyl)-amide;
5-Cyclopropyl-6-(2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid [1-methyl-1(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((+)-carbamoyl-cyclopropyl-methyl)-amide;
5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid ((?)-carbamoyl-cyclopropyl-methyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((+)-carbamoyl-cyclopropyl-methyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid ((?)-carbamoyl-cyclopropyl-methyl)-amide;
6-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (1-trifluoromethyl-cyclopropyl)-amide;
(+)-5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(3-hydroxy-pyrrolidin-1-ylcarbamoyl)-ethyl]-amide;
(?)-5-Cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [(S)-2-cyclopropyl-1-(3-hydroxy-pyrrolidin-1-ylcarbamoyl)-ethyl]-amide;
(+)-5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid [1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide;
and

(?)-5-Cyclopropyl-6-(2-methyl-propane-1-sulfonyl)-pyridine-2-carboxylic acid [1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide.

US Pat. No. 9,289,699

MOVEABLE CHROMATOGRAPHY COLUMN SEPARATOR

Hoffmann-La Roche Inc., ...

1. A method to purify a polypeptide, comprising
providing a polypeptide to be purified in an aqueous buffered solution,
adding the polypeptide solution to a liquid chromatography column comprising
one or more chromatography column separators comprising
an O-shaped guide ring for use in the chromatography column, wherein the guide ring has a vertical cross-section comprising
two axially symmetric cross-section areas, wherein each of the axially symmetric cross-section areas has

i) a tapering structure, wherein the tapering is from the outside to the inside of the guide ring, and
ii) a notch with an opening directed to the inside of the guide ring for mounting a frit, wherein the notch is a rectangular
notch,

wherein further each of the cross-section areas has a triangular shape and the longest side has a length of at least 1.5 times
the diameter of the notch, and

a frit mounted into the guide ring,
wherein the one or more chromatography column separators divides the chromatography column into chambers,
wherein any chromatography column separator is in contact with a first chromatography material and in contact with a second
chromatography material, whereby the first and the second chromatography material are

i) chromatography materials with the same chromatographical functional group and of the same or different particle size, or
ii) chromatography materials with different chromatographical functional groups,
wherein the one or more chromatography column separators are freely moveable within the chromatography column and the chromatography
materials,

interaction of the polypeptide with the chromatography materials and obtaining an eluate therefrom, and
recovering the polypeptide from the eluate.
US Pat. No. 9,267,933

HANGING DROPLET PLATE

Hoffmann-La Roche Inc., ...

1. A hanging droplet plate comprising:
a predetermined number of droplet compartments each being capable of receiving a droplet of a liquid, each droplet compartment
having a cavity and a circumferential microfluidic wetting barrier surrounding the cavity such that a droplet is prevented
from spreading beyond the circumferential microfluidic wetting barrier, wherein

each droplet compartment comprises a separate and distinct closed bottom within the circumference of the circumferential microfluidic
wetting barrier and at least one additional circumferential microfluidic wetting barrier, each at least one additional circumferential
microfluidic wetting barrier surrounding a preceding circumferential microfluidic wetting barrier, with a wettable area being
arranged between two adjacently arranged microfluidic wetting barriers.

US Pat. No. 9,073,909

[1,3]OXAZINES

HOFFMANN-LA ROCHE INC., ...

1. A compound of formula I,

wherein
R1 is aryl or heteroaryl, each substituted by 1-4 substituents individually selected from halogen-C2-6-alkenyl, halogen-C2-6-alkynyl, C1-6-alkoxy-C2-6-alkenyl, C1-6-alkoxy-C2-6-alkynyl, C2-6-alkenyl-C1-6-alkoxy and C2-6-alkynyl-C1-6-alkoxy;

R2 is halogen;

R3 is C1-6-alkyl;

R4 is selected from the group consisting of

i) hydrogen,
ii) C1-6-alkyl, and

iii) halogen;
R5 is selected from the group consisting of

i) hydrogen,
ii) C1-6-alkyl, and

iii) halogen;
R6 is selected from the group consisting of

i) hydrogen, and
ii) C1-6-alkyl;

R7 is selected from the group consisting of

i) hydrogen, and
ii) C1-6-alkyl;

and when R1 is heteroaryl substituted by C2-6-alkynyl-C1-6-alkoxy, then R4 and R5 are both hydrogen or are both halogen;

or pharmaceutically acceptable salts thereof.
US Pat. No. 10,093,714

METHOD FOR PRODUCING SOLUBLE FCR AS FC-FUSION WITH INERT IMMUNOGLOBULIN FC-REGION AND USES THEREOF

Hoffmann-La Roche Inc., ...

1. A fusion polypeptide comprising the formula (I):R1-FC-R2  (formula I)
wherein:
R1 denotes a first Fc-receptor,
R2 denotes a second Fc-receptor, and
FC denotes a heavy chain Fc-region polypeptide,
wherein R1 or R2 or both are present,
wherein FC does not bind to R1 and/or R2,
wherein FC is selected from:
(i) human IgG1 heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO: 3 with
(1) the mutations L234A, L235A, and P329G,
(2) the mutations I253A, H310A, and H435A,
(3) the mutation T366W and optionally the mutation S354C,
(4) the mutations T366S, L368A, and Y407V, and optionally the mutation Y349C,
(5) the mutations L234A, L235A, P329G, T366W, and optionally the mutation S354C,
(6) the mutations I253A, H310A, H435A, T366W, and optionally the mutation S354C,
(7) the mutations L234A, L235A, P329G, T366S, L368A, and Y407V, and optionally the mutation Y349C,
(8) the mutations I253A, H310A, H435A, T366S, L368A, and Y407V, and optionally the mutation Y349C,
(9) the mutations L234A, L235A, P329G, I253A, H310A, H435A, T366W, and optionally the mutation S354C, or
(10) the mutations L234A, L235A, P329G, I253A, H310A, H435A, T366S, L368A, and Y407V, and optionally the mutation Y349C,
and
(ii) human IgG4 heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO 15 with
(1) the mutations S228P and L235E,
(2) the mutation T366W and optionally the mutation S354C,
(3) the mutations T366S, L368A, and Y 407V, and optionally the mutation Y349C,
(4) the mutations S228P, L235E, T366W, and optionally the mutation S354C, or
(5) the mutations S228P, L235E T366S, L368A, Y407V, and optionally the mutation Y349C.
US Pat. No. 10,087,246

ANTI-PDGF-B ANTIBODIES AND METHODS OF USE

Hoffmann-La Roche Inc., ...

1. An antibody that specifically binds to human PDGF-B, wherein the antibody comprises (a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 93, (b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 94, (c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 96, (d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 98, (e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 99, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 100.

US Pat. No. 9,890,155

AZA-OXO-INDOLES FOR THE TREATMENT AND PROPHYLAXIS OF RESPIRATORY SYNCYTIAL VIRUS INFECTION

Hoffmann-La Roche Inc., ...

1. Compounds of formula (I)

wherein
W is nitrogen or —CR9, wherein R9 is halogen;

X is nitrogen or —CR10, provided that

when X is —CR10, R1 is hydrogen, R2 is halogen, R3 is hydrogen, wherein R10 is C1-6alkylsulfonylphenyl;

when X is nitrogen, R1 is halogen, R2 is hydrogen, R3 is


R4 and R5, with the carbon atom to which they are attached, form cycloalkyl;

R6 is hydrogen or C1-6alkyl;

R7 is hydrogen, aminocarbonyl, C1-6 alkoxycarbonyl-CyH2y—, C1-6 alkylcarbonyl, C1-6 alkylsulfonyl, carboxy or cyano, wherein y is 0-6;

R8 is C1-6alkylsulfonyl, C1-6alkoxy, cyano or hydroxy;

or pharmaceutically acceptable salts thereof.

US Pat. No. 9,562,009

PROCESS TO MANUFACTURE N-[(3S)-1-[4-[(3-FLUOROPHENYL)METHOXY]PHENYL]-5-OXO-PYRROLIDIN-3-YL]ACETAMIDE

Hoffmann-La Roche Inc., ...

4. A crystalline form (polymorph B) of a compound of formula 1 characterized by an XRPD having characteristic peaks expressed
in values of degrees 2-theta at approximately 15.9, 21.3, 23.6 and 26.7.

US Pat. No. 9,522,874

LYSINE-GLUTAMIC ACID DIPEPTIDE DERIVATIVES

Hoffmann-La Roche Inc., ...

1. A compound of the formula

wherein,
R1 is t-butyl,

R2 is hydrogen or an ester protecting group,

R3 is hydrogen or an amino protecting group, and

R4 is C12-20-alkyl,

and enantiomers, diastereomers and salts thereof.
US Pat. No. 9,271,479

INFLAMMATION IN VIVO MODEL

Hoffmann-La Roche Inc., ...

1. A transgenic mouse comprising a deletion of at least one allele of the IL-33 gene, wherein the deletion is a deletion of
amino acids 1-67 of the expression product of the IL-33 gene, and wherein the transgenic mouse expresses the expression product
of the IL-33 gene with a deletion of amino acids 1-67.

US Pat. No. 10,093,657

INHIBITORS OF BRUTON'S TYROSINE KINASE

HOFFMANN-LA ROCHE INC., ...

1. A method for treating an inflammatory and/or autoimmune condition, comprising a step of administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I:
wherein:
R1 is H or halo;
R2 is H, halo, or cyano;
R3 is R4 or R5;
R4 is halo or cyano;
R5 is phenyl, heteroaryl, —C(?O)R5?, lower alkyl, or benzyl, optionally substituted with one or more R5?;
R5? is lower alkyl, cyano, hydroxyl, heterocycloalkyl, phenyl, amino, alkyl amino, dialkyl amino, or lower alkoxy; and
X is lower alkyl or halo;
or a pharmaceutically acceptable salt thereof.

US Pat. No. 9,802,944

BICYCLIC COMPOUNDS AS AUTOTAXIN (ATX) AND LYSOPHOSPHATIDIC ACID (LPA) PRODUCTION INHIBITORS

Hoffmann-La Roche Inc., ...

1. A compound of formula (I)

wherein
R1 is pyridinyl substituted with R3, R4, and R5;

A is —N—;
W is —C(O)—;
R2 is:


R3 is tetrahydropyranylmethoxy;

R4 is cycloalkyl;

R5 is H;

m, n, p and q are independently selected from 1 and 2; and
R9 is H, alkyl, halogen, haloalkyl or alkoxy;

or a pharmaceutically acceptable salt thereof.

US Pat. No. 9,790,213

IMIDAZOLES FOR THE TREATMENT AND PROPHYLAXIS OF RESPIRATORY SYNCYTIAL VIRUS INFECTION

Hoffmann-La Roche Inc., ...

1. Compounds of formula (I)
wherein
R1 is hydrogen, C1-6alkyl, C1-6alkoxy or halogen;

R2 is hydrogen, C1-6alkyl or halogen;

provided that R1 and R2 are not hydrogen simultaneously;

R3 is


wherein R4 is C1-6alkoxy, C1-6alkoxycarbonyl, carboxy or halogen;

R5 is hydrogen, C1-6alkyl or C1-6alkoxy;

R6 is hydrogen or C1-6alkoxy;

Q is

wherein R7 is hydrogen, C1-6alkyl, carboxy, hydroxy-CH2— or halogen;

R8 is hydrogen or C1-6alkyl;

R9 is C1-6alkyl;
or pharmaceutically acceptable salts thereof.

US Pat. No. 9,637,485

6,7-DIHYDROBENZO[A]QUINOLIZIN-2-ONE DERIVATIVES FOR THE TREATMENT AND PROPHYLAXIS OF HEPATITIS B VIRUS INFECTION

Hoffmann-LA Roche Inc., ...

1. A compound of formula (I)
wherein
R1, R2, R3 and R4 are independently selected from the group consisting of hydrogen, halogen, C1-6alkyl, diC1-6alkylamino, cyano, N-containing monocyclic heterocycloalkyl and OR7, wherein

R7 is hydrogen; C1-6alkyl; or C1-6alkyl which is substituted one or more times by fluoro, C3-7cycloalkyl, phenyl, hydroxyl, amino, C1-6alkoxy, C1-6alkylsulfanyl, C1-6alkylsulfonyl, diC1-6alkylamino, C1-6alkoxycarbonylamino, monocyclic heterocycloalkyl, pyrazoyl or imidazolyl;

R5 is hydrogen or C1-6alkyl;

R6 is hydrogen, C1-6alkyl, phenyl-CxH2x—, C1-6alkylcarbonyl, C1-6alkylsulfonyl, benzoyl or monocyclic heterocycloalkyl, wherein

x is 1-6;
W is a bond, CyH2yC(R8)(R9)CzH2z or CyH2yCH(R8)CH(R9)CzH2z, wherein

R8 and R9 are independently selected from the group consisting of hydrogen, fluoro, hydroxy and C1-6alkyl,

y is 0-6;
z is 0-6;
X is a bond; O; S; S(O)2; or NR10, wherein R10 is hydrogen or C1-6alkyl;

or R6 and R10, together with the nitrogen to which they are attached, form monocyclic heterocycloalkyl;

with the proviso that when X is a bond, R6 is not hydrogen, C1-6alkyl or phenyl-CxH2x—;

or a pharmaceutically acceptable salt, enantiomer, or diastereoisomer thereof.

US Pat. No. 9,605,006

5-ARYL-1-IMINO-1-OXO-[1,2,4]THIADIAZINES

Hoffmann-La Roche Inc., ...

1. A compound of formula I?,

wherein
R1 is selected from the group consisting of

i) C1-6-alkyl, and

ii) halogen-C1-6-alkyl;

R2 is selected from the group consisting of

i) hydrogen,
ii) halogen;
iii) —NH—C(?O)—R4,

iv) aryl,
v) aryl, substituted by 1-3 substituents individually selected from cyano, C1-6-alkyl, halogen-C1-6-alkyl and halogen

vi) heteroaryl,
vii) heteroaryl, substituted by 1-3 substituents individually selected from R6, and

viii) —C?C—R5;

R3 is halogen;

R4 is selected from the group consisting of

i) heteroaryl, and
ii) heteroaryl, optionally substituted by 1-3 substituents individually selected from R6,

R5 is selected from the group consisting of

i) aryl,
ii) aryl, optionally substituted by 1-3 substituents individually selected from cyano, C1-6-alkyl, halogen-C1-6-alkyl and halogen

iii) heteroaryl, and
iv) heteroaryl, optionally substituted by 1-3 substituents individually selected from cyano, C1-6-alkyl, halogen-C1-6-alkyl and halogen;

R6 is selected from the group consisting of

i) cyano,
ii) halogen;
iii) C1-6-alkyl,

iv) halogen-C1-6-alkyl,

v) C2-6-alkynyl-O—,

vi) heteroaryl, and
vii) heteroaryl, optionally substituted by 1-3 substituents individually selected from cyano, C1-6-alkyl, C1-6-alkoxy, halogen-C1-6-alkyl, halogen-C1-6-alkoxy and halogen;

R7 is selected from the group consisting of

i) halogen, and
ii) halogen-C1-6-alkyl;

m is 1 or 2;
n is 0 or 1; and
p is 0, 1 or 2;
or pharmaceutically acceptable salts thereof.

US Pat. No. 9,586,966

PIPERAZINO[1,2-A]INDOL-1-ONES AND [1,4]DIAZEPINO[1,2-A]INDOL-ONE

Hoffmann-La Roche Inc., ...

1. A compound of formula I

wherein
R1 is halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen or cyano;

R2 is hydrogen, CF3 or lower alkyl;

R3 is lower alkyl, lower alkenyl, lower alkynyl, heterocycloalkyl, lower alkyl substituted by cyano, cyano, benzyl substituted
by halogen, 2-oxa-6-aza-spiro[3.3]hept-6-yl or is lower alkoxy substituted by halogen;

X is —CH2— or —CH2—CH2—;
or a pharmaceutically acceptable acid addition salt, an enantiomer, diastereomer or a mixture of enantiomers or diastereomers.
US Pat. No. 9,562,091

HUMANIZED ANTI-TAU(PS422) ANTIBODIES AND METHODS OF USE

Hoffmann-La Roche Inc., ...

1. A humanized antibody that specifically binds to human Tau(pS422), wherein the antibody comprises
in the heavy chain variable domain the HVRs of SEQ ID NO: 08, 18 and 10, or
in the heavy chain variable domain the HVRs of SEQ ID NO: 08, 09 and 10; and
in the light chain variable domain the HVRs of SEQ ID NO: 13, 14 and 15, or
in the light chain variable domain the HVRs of SEQ ID NO: 12, 05 and 15.

US Pat. No. 9,540,397

BACE1 INHIBITORS

Hoffmann-La Roche Inc., ...

1. A compound of formula I:

wherein:
n is 1, 2 or 3;
R1 is selected from the group consisting of

i) C1-6-alkyl and

ii) halogen-C1-6-alkyl;

R2 is selected from the group consisting of

i) C1-6-alkyl, and

ii) halogen-C1-6-alkyl;

or R1 and R2 form together with the C-atom they are attached to, a C3-6-cycloalkyl-, wherein the C3-6-cycloalkyl- is optionally substituted by one or more substituents selected from the group consisting of halogen and hydroxyl;

R3 is each independently selected from the group consisting of

i) hydrogen,
ii) C1-6-alkyl, and

iii) halogen;
R4 is each independently selected from the group consisting of

i) hydrogen,
ii) C1-6-alkyl, and

iii) halogen;
or wherein R3 and R4 together are (CH2)m—, wherein m is 2, 3, 4 or 5,

R5 is hydrogen,

R6 is selected from the group consisting of

i) C1-6-alkyl, and

ii) halogen-C1-6-alkyl;

R7 is selected from the group consisting of

i) hydrogen, and
ii) halogen;
R8 is selected from the group consisting of

i) aryl,
ii) aryl substituted by 1-4 substituents individually selected from amino, cyano, halogen, halogen-C1-6-alkyl, halogen-C1-6-alkoxy, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, C2-6-alkynyl-C1-6-alkoxy, C2-6-alkynyl, C1-6-alkyl, COOR9, wherein R9 is H or C1-6-alkyl, CONR10R11, wherein R10 is H or C1-6-alkyl C3-6-cycloalkyl and R11 is H or C1-6-alkyl, C3-6-cycloalkyl that is optionally substituted by 1 to 4 substituents individually selected from the group consisting of halogen,
cyano, C1-6-alkyl and C1-6-alkoxy, C3-6-cycloalkyl-C1-6-alkoxy and C3-6-cycloalkyl-C1-6-alkoxy, wherein the cycloalkyl unit is substituted by 1 to 4 substituents individually selected from the group consisting
of halogen, cyano, C1-6-alkyl and C1-6-alkoxy;

iii) heteroaryl, and
iv) heteroaryl substituted by 1-4 substituents individually selected from amino, cyano, halogen, halogen-C1-6-alkyl, halogen-C1-6-alkoxy, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, C2-6-alkynyl-C1-6-alkoxy, C2-6-alkynyl, C1-6-alkyl, COOR9, wherein R9 is H or C1-6-alkyl, CONR10R11, wherein R10 is H or C1-6-alkyl C3-6-cycloalkyl and R11 is H or C3-6-cycloalkyl that is optionally substituted by 1 to 4 substituents individually selected from the group consisting of halogen,
cyano, C1-6-alkyl and C1-6-alkoxy, C3-6-cycloalkyl-C1-6-alkoxy and C3-6-cycloalkyl-C1-6-alkoxy, wherein the cycloalkyl unit is substituted by 1 to 4 substituents individually selected from the group consisting
of halogen, cyano, C1-6-alkyl and C1-6-alkoxy;

or pharmaceutically acceptable salts thereof.

US Pat. No. 9,487,501

PYRAZOLE CARBOXAMIDE COMPOUNDS AND USES THEREOF

Hoffmann-La Roche Inc., ...

1. A compound of formula

wherein
R1 is phenyl, optionally substituted by halogen, lower alkyl, lower cycloalkyl, lower alkoxy, cyano, lower alkyl substituted
by halogen, lower alkyl substituted by hydroxy, lower alkoxy substituted by halogen or lower alkoxy substituted by hydroxy;
or is pyridine-2, 3 or 4-yl, optionally substituted by halogen, lower alkyl, lower cycloalkyl, cyano, lower alkyl substituted
by halogen, lower alkyl substituted by hydroxyl, lower alkoxy, lower alkoxy substituted by halogen, or lower alkoxy substituted
by hydroxyl; or is

pyrimidin-2, 4 or 5-yl, optionally substituted by halogen, lower alkyl, lower cycloalkyl, lower alkyl substituted by hydroxy
or lower alkyl substituted by halogen, or is pyrazin-2-yl, optionally substituted by halogen, lower alkyl, lower cycloalkyl,
lower alkyl substituted by halogen, lower alkyl substituted by hydroxy or cyano, or is 2,2-difluorobenzo[d][1,3]dioxol-5-yl,
or is

thiazolyl, optionally substituted by lower alkyl substituted by halogen;
R2 is hydrogen or lower alkyl;

R3 is hydrogen, amino or lower alkyl;

Z is a bond, —CH2— or —O—;

or a pharmaceutically suitable acid addition salt thereof.
US Pat. No. 9,452,980

SUBSTITUTED BENZAMIDES

Hoffmann-La Roche Inc., ...

1. A compound selected from the group consisting of
(RS)-6-Pyrazol-1-yl-N-(4-pyrrolidin-3-yl-phenyl)-nicotinamide;
or a pharmaceutically suitable acid addition salt thereof.

US Pat. No. 9,181,230

MORPHOLINE COMPOUNDS AND USES THEREOF

Hoffmann-La Roche Inc., ...

1. A compound of formula

whereinR1 is a one or two membered heteroaryl group, selected from the group consisting of
R2 is hydrogen or halogen; orR1 and R2 may form together with the carbon atoms to with they are attached the following rings
R3 is hydrogen, halogen or lower alkyl;
n is 1 or 2;R4 is phenyl, optionally substituted by one or two substituents, selected from halogen or cyano, or is
pyridinyl, optionally substituted by halogen, or is
tetrahydropyran, or is
—NH—C(O)-phenyl, optionally substituted by halogen;R5 is hydrogen or halogen;R6-R13 are phenyl, optionally substituted by halogen:R14 is —NH—C(O)-phenyl, substituted by halogen;R15 is hydrogen, lower alkyl substituted by halogen or is halogen;R16 is hydrogen or lower alkoxy;R17 is pyridinyl, optionally substituted by lower alkoxy or lower alkyl substituted by halogen;or a pharmaceutically suitable acid addition salt thereof, all racemic mixtures, all their corresponding enantiomers and/or
optical isomers and all tautomeric forms of compounds of formula I.