US Pat. No. 9,359,313

USE OF METFORMIN IN COMBINATION WITH A GLUCOKINASE ACTIVATOR AND COMPOSITIONS COMPRISING METFORMIN AND A GLUCOKINASE ACTIVATOR

vTv Therapeutics LLC, Hi...

1. A method of treating type 2 diabetes in a human comprising: administering to a subject {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic
acid or a pharmaceutically acceptable salt thereof in combination with metformin, wherein the metformin is administered in
an amount of less than 1000 mg/day.
US Pat. No. 9,393,245

TRICYCLIC COMPOUNDS AS MODULATORS OF TNF-ALPHA SYNTHESIS AND AS PDE4 INHIBITORS

vTv Therapeutics LLC, Hi...

1. A method of treating atopic dermatitis comprising administering to a human a compound, wherein the compound is
1-cyclopentyl-7-methoxy-3-(4-methyl-thiophen-2-yl)-1H-pyrimido[5,4-c]quinoline-2,4-dione,
1-cyclopentyl-7-methoxy-3-m-tolyl-1H-pyrimido[5,4-c]quinoline-2,4-dione,
3-(3-chloro-phenyl)-1-(1-methane-sulfonyl-piperidin-4-yl)-7-methoxy-1H-pyrimido[5,4-c]-quinoline-2,4-dione,
trans-4-[3-(3-chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimido-[5,4-c]quinolin-1-yl]-cyclohexanecarboxylic acid,
3-(3-chloro-phenyl)-1-((R)-1-methane-sulfonyl-pyrrolidin-3-yl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione,
3-(3-chloro-phenyl)-1-((S)-1-methane-sulfonyl-pyrrolidin-3-yl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione,
3-(3-chloro-phenyl)-1-(1-ethanesulfonyl-piperidin-4-yl)-7-methoxy-1H-pyrimido-[5,4-c]quinoline-2,4-dione,
N-{4-[(S)-3-(3-chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimido[5,4-c]quinolin-1-yl]trans-cyclohexyl}-methanesulfonamide,
or a pharmaceutically acceptable salt thereof.

US Pat. No. 9,163,022

TRICYCLIC COMPOUNDS AS MODULATORS OF TNF-? SYNTHESIS AND AS PDE4 INHIBITORS

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1. A method of treating rheumatoid arthritis comprising administering to a human a compound of Formula (I) or a pharmaceutically
acceptable salt thereof:

wherein:
A1 is O or S;

A2 is O or S;

U is N;
V is C—(CH2)vRV;

W is C—(CH2)wRW;

X is C—(CH2)xRX;

Y is C—(CH2)yRY;

Z is C—(CH2)zRZ;

R1 is —(CH2)qRQ;

R2 is —(CH2)sRS;

wherein
each of q, s, w, x, y, and z individually is 0, 1, 2, 3, or 4;
v is zero;
RQ is selected from the group consisting of:

alkyl,
cycloalkyl,
phenyl,
benzyl,
tetrahydrofuranyl,
tetrahydropyranyl,
pyrrolidinyl,
piperidinyl, and
—OR8, wherein

the cycloalkyl is optionally substituted with one or more Rc;

the phenyl and benzyl are each independently optionally substituted with one or more Ra; and

the tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl and piperidinyl are each independently optionally substituted with
one or more Rhc;

RV is chloro or —OCH3;

each of RS, RW, RX, RY, and RZ is independently selected from the group consisting of

alkyl;
alkenyl;
alkynyl;
aryl;
aryl substituted with one or more Ra;

azido;
cyano;
cycloalkyl;
cycloalkyl substituted with one or more Rc;

fused cycloalkylaryl substituted with one or more Rf1;

fused arylcycloalkyl substituted with one or more Rf2;

fused heterocyclyaryl substituted with one or more Rf3;

fused arylheterocyclyl substituted with one or more Rf4;

fused cycloalkylheteroaryl substituted with one or more Rf5;

fused heteroarylcycloalkyl substituted with one or more Rf6;

fused heterocyclylheteroaryl substituted with one or more Rf7;

halogen;
haloalkyl;
heterocyclyl;
heterocyclyl substituted with one or more Rhc;

heteroaryl;
heteroaryl substituted with one or more Rha;

hydrogen;
—NR3R4;

—C(O)NR3R4;

—C(O)R5;

—C(O)2R6;

—S(O)nR7;

—OR8; and

nitro;
wherein
each of R3 and R4 is independently selected from the group consisting of H, acyl, alkyl, alkoxy, alkoxyalkyl, alkylsulfonyl, aryl, cycloalkyl,
heterocyclyl and heteroaryl;

j is 0, 1, or 2;
each R5, R6, R7, and R8 is independently selected from the group consisting of

 hydrogen;
 alkyl;
 alkenyl;
 alkynyl;
 alkoxy;
 aryl;
 aryl substituted with one or more Ra;

 cycloalkyl;
 cycloalkyl substituted with one or more Rc;

 halogen;
 haloalkyl;
 heterocyclyl;
 heterocyclyl substituted with one or more Rhc;

 heteroaryl; and
 heteroaryl substituted with one or more Rha;

 wherein each of Ra, Rc, Rf1, Rf2, Rf3, Rf4, Rf5, Rf6, Rf7, Rhc and Rha is independently selected from the group consisting of acyl, alkyl, alkenyl, alkynyl, alkoxy, amide, amino, aryl, cyano, cycloalkyl,
halogen, haloalkyl, haloalkoxy, heteroaryl, hydroxy, nitro, —C(O)OR9, —SO2R10, —SR11, —C(O)R12, —C(O)NR13, —NH—SO2—R14, —SO2—NR15R16, and —SO2—CH2—SO2—CH3; and wherein

 each of R9, R10, R11, R12, R13 R14, R15, and R16 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl,
and heteroaryl.

US Pat. No. 9,598,375

SUBSTITUTED IMIDAZOLE DERIVATIVES AND METHODS OF USE THEREOF

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1. A method for treating Alzheimer's disease comprising administering to a subject a compound of Formula (I) or a pharmaceutically
acceptable salt thereof,
wherein
R1 and R2 are independently selected from the group consisting of: —CH3, —CH2CH3, —CH(CH3)2, and —CH2CH2CH3; and

Q1 is selected from the group consisting of —CH2OCH2CH3 and —CH2CH2CH2CH3.

US Pat. No. 10,030,011

SUBSTITUTED FUSED IMIDAZOLE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS, AND METHODS OF USE THEREOF

vTv Therapeutics LLC, Hi...

1. A method of treating a disease comprising administering to a human subject a compound,wherein the disease is a neurodegenerative disease;
wherein the compound is a compound of Formula (I) or a pharmaceutically acceptable salt thereof

wherein
one of X1, X2, X3, and X4 is
and the remaining members of X1, X2, X3, and X4 are independently N or
G is hydrogen, —C1-8 alkyl, —C3-10 cycloalkyl, —C1-6 alkylene-C3-10 cycloaklyl, heterocyclyl, —C1-6 alkylene-C3-10 heterocyclyl, phenyl, heteroaryl, or NRh Rk, where the alkyl, alkylene, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rc;
L is —CH2—C(O)N(R6)—, —C(O)N(R6)—, —C(O)—O—, —SO2—, —C(O)—, heteroarylene optionally substituted one or more times with substituents independently selected from Rx, or heterocyclylene optionally substituted one or more times with substituents independently selected from Rx; or the group -L-G is -cyano;
R1 is hydrogen, Ra, phenyl, or heteroaryl, where the phenyl and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rx;
R2 is Rb;
R3 is hydrogen, —C1-6 alkyl, or —C1-6 alkylene-C3-10 cycloaklyl, where the alkyl, alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from Rz;
R4 is —C1-6 alkyl or —C1-6 alkylene-C3-10 cycloaklyl, where the alkyl, alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from Ry;
R6 is hydrogen, —C1-6 alkyl, —C1-6 alkylene-C3-10 cycloaklyl, where the alkyl, alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from Rx;
Ra is
a) -halogen,
b) —C1-6 alkyl,
c) —C3-10 cycloalkyl,
d) -heterocyclyl,
e) -cyano,
f) —CF3,
g) —OCF3,
h) —O—Rd,
i) —S(O)w—Rd,
j) —S(O)2O—Rd,
k) —NRdRe,
l) —C(O)—Rd,
m) —C(O)—O—Rd,
n) —OC(O)—Rd,
O) —C(O)NRd Re,
p) —C(O)-heterocyclyl,
q) —NRd C(O)Re,
r) —OC(O)NRd Re,
s) —NRd C(O)ORd, or
t) —NRd C(O)NRd Re,
where the alkyl, cycloalkyl, and heterocyclyl groups are optionally substituted one or more times with substituents independently selected from Ry;
Rb is
a) -halogen,
b) —C1-6 alkyl,
c) —C3-10 cycloalkyl,
d) -heterocyclyl,
e) -phenyl,
f) -heteroaryl,
g) -cyano,
h) —CF3,
i) —OCF3,
j) —O—Rf,
k) —S(O)w—Rf,
l) —S(O)2O—Rf,
m) —NRfRg,
n) —C(O)—Rf,
o) —C(O)—O—Rf,
p) —OC(O)—Rf,
q) —C(O)NRfRg,
r) —C(O)-heterocyclyl,
s) —NRf C(O)Rg,
t) —OC(O)NRf Rg,
u) —NRf C(O)ORf, or
v) —NRf C(O)NRf Rg,
where the alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rz;
Rc is
a) -halogen,
b) —C1-6 alkyl,
c) —C3-10 cycloalkyl,
d) -heterocyclyl,
e) -cyano,
f) —CF3,
g) —OCF3,
h) —O—Rh,
i) —S(O)w—Rh,
j) —S(O)2O—Rh,
k) —NRhRk,
l) —C(O)—Rh,
m) —C(O)—O—Rh,
n) —OC(O)—Rh,
o) —C(O)NRh Rk,
p) —C(O)-heterocyclyl,
q) —NRh C(O)Rk,
r) —OC(O)NRh Rk,
s) —NRh C(O)ORk,
t) —NRh C(O)NRh Rk,
u) —NRh S(O)wRk,
v) -phenyl,
w) -heteroaryl, or
x) —O(C1-4 alkylene)-O—(C1-4 alkylene)-N(Rh)C(O)—ORk,
where the alkylene, alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rx;
Rd and Re are independently hydrogen, C1-6 alkyl, or C3-10 cycloalkyl, where the alkyl and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from Ry; or, if Rd and Re are both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents independently selected from Ry;
Rf and Rg are independently hydrogen, C1-6 alkyl, C3-10 cycloalkyl, phenyl, or heteroaryl, where the alkyl, cycloalkyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rz; or, if Rf and Rg are both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents independently selected from Rz;
Rh and Rk are independently hydrogen, C1-6 alkyl, C3-10 cycloalkyl, heterocyclyl, phenyl, or heteroaryl, where the alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rx; or, if Rh and Rk are both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents independently selected from Rx;
Ry is
a) -halogen,
b) —NH2,
c) -cyano,
d) -carboxy,
e) -hydroxy,
f) -thiol,
g) —CF3,
h) —OCF3,
i) —C(O)—NH2,
j) —S(O)2—NH2,
k) oxo,
l) —C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
m) -heterocyclyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
n) —C3-10 cycloalkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
o) —O—C1-6 alkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
p) —O—C3-10 cycloalkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
q) —NH—C1-6 alkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
r) —N(C1-6 alkyl)2 optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
s) —C(O)—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
t) —C(O)—O—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
u) —S—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
v) —S(O)2—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
w) —C(O)—NH—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
x) —C(O)—N(C1-6 alkyl)2, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
y) —S(O)2—NH—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
z) —S(O)2—N(C1-6 alkyl)2, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
aa) —NH—C(O)—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2, or
bb) —NH—S(O)2—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2;
Rx is
a) —Ry
b) -phenyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
c) -heteroaryl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
d) —O-phenyl,
e) —O-heteroaryl,
f) —C(O)-phenyl,
g) —C(O)-heteroaryl,
h) —C(O)—O-phenyl, or
i) —C(O)—O-heteroaryl;
Rz is
a) —Ry
b) -phenyl,
c) -heteroaryl;
d) —O-phenyl,
e) —O-heteroaryl,
f) —C(O)-phenyl,
g) —C(O)-heteroaryl,
h) —C(O)—O-phenyl, or
i) —C(O)—O-heteroaryl;
v is an integer from 0 to 4, and
w is an integer from 0 to 2.
US Pat. No. 9,855,251

USE OF METFORMIN IN COMBINATION WITH A GLUCOKINASE ACTIVATOR AND COMPOSITIONS COMPRISING METFORMIN AND A GLUCOKINASE ACTIVATOR

vTv Therapeutics LLC, Hi...

1. A method of lowering blood glucose in a subject comprising:
administering to the subject {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid or
a pharmaceutically acceptable salt thereof in combination with metformin, wherein the metformin is administered in an amount
of less than 1000 mg/day.

US Pat. No. 9,855,274

PHENOXY ACETIC ACIDS AND PHENYL PROPIONIC ACIDS AS PPAR DELTA AGONISTS

vTv Therapeutics LLC, Hi...

1. A method of reducing blood glucose levels, of reducing triglyceride levels, or of increasing insulin sensitivity in a subject
suffering from type II diabetes, the method comprising administering to a subject in need thereof an effective amount of a
compound according to formula (I) or a pharmaceutically acceptable salt thereof:

wherein is a double bond, with either E or Z substitution;
X1 is C1-6-alkyl substituted with morpholino;

X2 is phenylene;

X3 is phenyl substituted with one or more halogens;

Ar is phenylene optionally substituted with methyl;
Y1 is O;

Y2 is O;

Z is CH2;

R1 is hydrogen; and

R2 is hydrogen.

US Pat. No. 9,707,239

COMPOUNDS THAT MODULATE OXIDATIVE STRESS

vTv Therapeutics LLC, Hi...

1. A method of selectively inducing an oxidative stress response in a cell, the method comprising:
contacting a cell with a selective inducer compound,
wherein the selective inducer compound
i) is a non-naturally-occurring organic compound,
ii) induces expression in the cell of at least the oxidative stress-responsive genes heme oxygenase 1 (HMOX1), NAD(P)H:quinine
oxidoreductase (NQO1), and thioredoxin reductase 1 (TXNRD 1);

iii) does not significantly activate the cellular stress response in the cell, wherein activation of the cellular stress response
comprises inducing expression of at least the cellular stress genes Growth arrest and DNA-damage-inducible, alpha (GADD45A)
and Heatshock 70kDa protein 6 (HSPA6); and

iv) does not significantly activate nuclear factor-kappaB (NF-?B) in the cell, wherein activation of NF-?B is determined by
measuring the induction of expression of intercellular adhesion molecule (ICAM-1);

wherein the cell is selected from the group consisting of a lymphocyte, a granulocyte, a monocyte, a macrophage, a mast cell,
a thrombocyte, an erythrocyte, a megakaryocyte, a dendritic cell, a glial cell, a pneumocyte, a Clara cell, a goblet cell,
a myocardiocyte, a pericyte, a hepatocyte, a Kupffer cell, a Paneth cell, an osteoblast, an osteocyte, a chondroblast, a chondrocyte,
a keratinocyte, a melanocyte, a myocyte, an adipocyte, a fibroblast, a tendon cell, an epithelial cell, an endothelial cell,
a smooth muscle cell, a skeletal muscle cell, an embryonic stem cell, a neural stem cell, a skin stem cell, a mesenchymal
stem cell, a hematopoietic stem cell, a stromal stem cell, and an epithelial stem cell.

US Pat. No. 9,487,493

USE OF A PPAR-DELTA AGONIST FOR TREATING MUSCLE ATROPHY

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1. A method for reducing disuse-associated muscle atrophy in a subject in need thereof comprising administering to the subject
an effective amount of a PPAR? agonist, wherein the PPAR? agonist is (E)-[4-[3-(4-Fluorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic
acid or a pharmaceutically acceptable salt thereof.
US Pat. No. 9,447,468

COMPOUNDS THAT MODULATE OXIDATIVE STRESS

vTv Therapeutics LLC, Hi...

1. A method of identifying compounds that decrease oxidative stress by selectively inducing oxidative stress response in a
biological sample, the method comprising:
(a) contacting the biological sample with one or more non-naturally occurring compounds;
(b) determining whether the one or more non-naturally occurring compounds induce an oxidative stress response in the biological
sample, wherein induction of the oxidative stress response comprises inducing expression of at least the oxidative stress-responsive
genes heme oxygenase 1 (HMOX 1), NAD(P)H:quinine oxidoreductase (NQO1), and thioredoxin reductase 1 (TXNRD1);

(c)(1) determining whether the one or more non-naturally occurring compounds activate a cellular stress response in the biological
sample, wherein activation of the cellular stress response comprises inducing expression of at least the cellular stress genes
Growth arrest and DNA-damage-inducible, alpha (GADD45A) and Heatshock 70 kDa protein 6 (HSPA6);

(c)(2) determining whether the one or more non-naturally occurring compounds activate nuclear factor-kappaB (NF-?B) in the
biological sample, wherein activation of NF-?B is determined by measuring the induction of expression of intercellular adhesion
molecule (ICAM-1); and

(d) selecting for the one or more non-naturally occurring compounds that induce the oxidative stress response but that do
not significantly activate the cellular stress response in the biological sample and that do not significantly activate NF-?B
in the biological sample.

US Pat. No. 9,198,901

TRIS(HYDROXYMETHYL)AMINOMETHANE SALTS OF A SMALL-MOLECULE GLP1R AGONIST AND PHARMACEUTICAL COMPOSITIONS AND USES THEREOF

vTv Therapeutics LLC, Hi...

1. A tris(hydroxymethyl)aminomethane salt of (S)-3-(4?-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic
acid.

US Pat. No. 9,175,003

SUBSTITUTED AZOANTHRACENE DERIVATIVES AND INTERMEDIATES FOR PREPARATION THEREOF

vTv Therapeutics LLC, Hi...

1. A compound of the formula:

wherein
R1 is hydrogen or methyl, and

R2 is —CO2-tert-butyl, or -1-(phenyl)-propyl.

US Pat. No. 9,162,963

PHENYLGLYOXYLIC ACID DERIVATIVES AND THEIR PREPARATION AND USE

vTv Therapeutics LLC, Hi...

1. A compound of Formula (I)

wherein:
R1 is hydrogen, fluoro, chloro, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, or trifluoromethoxy;

R5 —is hydrogen, fluoro, chloro, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, or trifluoromethoxy;

R3 is hydroxyl, cyano, fluoro chloro, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, or trifluoromethoxy;

one of R2 and R4 is hydrogen, hydroxyl, cyano, fluoro, chloro, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, or trifluoromethoxy,
while the other is hydrogen hydroxyl, cyano, fluoro, chloro, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl,
or trifluoromethoxy;

R6 , R7 , R8 , R9 are hydrogen;

R10 is hydrogen, C1-6 alkyl, or an alkali metal cation; and

Z is— unsubstituted methylene or unsubstituted 1,2 -ethylene.

US Pat. No. 9,120,813

OXADIAZOANTHRACENE COMPOUNDS FOR THE TREATMENT OF DIABETES

vTv Therapeutics LLC, Hi...

1. A method of treating hyperglycaemia comprising administering to a subject a compound of Formula (I) or a pharmaceutically
acceptable salt thereof:

wherein
R is —(CH2)p-G1-L1-G2, wherein

L1 is selected from the group consisting of: a direct bond, —CH2—, —O—, —N(R16)—, —C(O)—, —CON(R16)—, —N(R16)C(O)—, —N(R16)SO2—, —SO2N(R16)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O)2—, and —C?C—, wherein

R16 is selected from the group consisting of: -hydrogen, -alkyl, -aryl, -alkylene-aryl;

G1 is selected from the group consisting of: alkynylene, arylene, heteroarylene, fused arylcycloalkylene, fused cycloalkylarylene,
fused cycloalkylheteroarylene, fused heterocyclylarylene, and fused heterocyclylheteroarylene, wherein G1 is optionally substituted 1-4 times with substituents independently selected from R10, wherein

R10 is Rb,

G2 is selected from the group consisting of: -aryl, -heteroaryl, -fused arylcycloalkyl, -fused cycloalkylaryl, -fused cycloalkylheteroaryl,
-fused heterocyclylaryl, and -fused heterocyclylheteroaryl, wherein G2 is optionally substituted 1-4 times with substituents independently selected from R11, wherein

R11 is Rb,

R1 is selected from the group consisting of: —CO2H, —CO2R12, —C(O)NH2, —C(O)NHR12, -tetrazole, and acid isostere, wherein

R12 is selected from the group consisting of: —C1-10 alkyl, -cycloalkyl, and -aryl, wherein R12 is optionally substituted 1-4 times with a group independently selected from Rc;

R2 is selected from the group consisting of: -hydrogen, -alkyl, -phenyl, -cycloalkyl, -alkylene-cycloalkyl, and -alkylene-phenyl,
wherein alkyl, phenyl, and cycloalkyl groups are optionally substituted 1-4 times with a group independently selected from
Rc;

R3 is selected from Ra;

R4 is selected from Ra; and

R5 is -G3-L2-Q2-L3-G4, wherein

L2 and L3 are independently selected from the group consisting of: a direct bond, —CH2—, —O—, —N(R26)—, —C(O)—, —CON(R26)—, —N(R26)C(O)—, —N(R26)CON(R27)—, —N(R26)C(O)O—, —OC(O)N(R26)—, —N(R26)SO2—, —SO2N(R26)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O)2—, and —N(R26)SO2N(R27)—, wherein

R26 and R27 are independently selected from the group consisting of: hydrogen, -alkyl, -aryl, and -alkylene-aryl, wherein R26 and R27 are optionally substituted 1-4 times with Rc, or R26 and R27 are taken together with the atoms to which they are attached to form a heterocyclic ring of 5 to 7 members containing 0-2
additional heteroatoms independently selected from oxygen, nitrogen, and sulfur;

Q2 is selected from the group consisting of: a direct bond, C1-10 alkylene, C2-10 alkenylene, and C2-10 alkynylene,

G3 is selected from the group consisting of: -arylene, -cycloalkylene, -heterocyclylene, -heteroarylene, -fused arylcycloalkylene,
-fused cycloalkylarylene, -fused cycloalkylheteroarylene, -fused heterocyclylarylene, and -fused heterocyclylheteroarylene,
wherein

G3 is optionally substituted 1-4 times with substituents independently selected from R8, wherein R8 is selected from Rb,

G4 is selected from the group consisting of: -aryl, -cycloalkyl, -heterocyclyl, -heteroaryl, -fused arylcycloalkyl, -fused cycloalkylaryl,
-fused cycloalkylheteroaryl, -fused heterocyclylaryl, and -fused heterocyclylheteroaryl, wherein

G4 is optionally substituted 1-4 times with substituents independently selected from R9, wherein R9 is selected from Rb,

Rings B and C are optionally substituted 1-4 times with substituents independently selected from the group consisting of Rb;

Ra is selected from the group consisting of:

a) -hydrogen,
b) —S(O)mRd,

c) —S(O)2ORd,

d) —S(O)mNRdRe,

e) —C(O)Rd,

f) —CO2Rd,

g) —C(O)NRdRe,

h) -haloalkyl,
i) -cycloalkyl,
j) -heterocyclyl,
k) —C1-10 alkyl,

l) —C2-10 alkenyl,

m) —C2-10 alkynyl,

n) -aryl,
o) -heteroaryl,
p) —C1-10 alkylene-aryl,

q) —C2-10 alkynylene-aryl,

r) —C1-10 alkylene-heteroaryl,

s) —C2-10 alkynylene-heteroaryl, and

t) —C(RfRg)n-aryl,

wherein alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, and cycloalkyl groups are optionally substituted 1-4 times
with a group independently selected from Re;

Rb is selected from the group consisting of:

a) -cycloalkyl,
b) -cyano,
c) —ORd,

d) —NO2,

e) -halogen,
f) —S(O)mRd,

g) —SRd,

h) —S(O)2ORd,

i) —S(O)mNRdRe,

j) —NRdRe,

k) —O(CRfRg)nNRdRe,

l) —C(O)Rd,

m) —CO2Rd,

n) —OC2(CRfRg)—CONRdRe,

o) —OC(O)Rd,

p) —C(O)NRdRe,

q) —NRd C(O)Re,

r) —OC(O)NRdRe,

s) —NRd C(O)ORe,

t) —NRd C(O)NRdRe,

u) —CF3,

v) —OCF3,

w) -haloalkyl,
x) -haloalkoxy,
y) —C1-10 alkyl,

z) —C2-10 alkenyl,

aa) —C2-10 alkynyl,

ab) —C1-10 alkylene-aryl,

ac) —C1-10 alkylene-heteroaryl, and

ad) -heteroaryl,
wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl, and cycloalkyl groups are optionally substituted 1-4 times with a group
independently selected from Rc;

Rc is selected from the group consisting of:

a) -halogen,
b) -amino,
c) -carboxy,
d) -cyano,
e) —C1-4 alkyl,

f) —O—C1-4 alkyl,

g) —O—CF3,

h) -cycloalkyl,
i) —O-cycloalkyl,
j) -aryl,
k) —C1-4 alkylene-aryl,

l) -hydroxy,
m) —CF3,

n) -haloalkyl,
o) -haloalkoxy,
p) —O-aryl,
q) -heteroaryl,
r) -heteroarylene-C1-10 alkyl,

s) -heterocyclyl,
t) —CO2—C1-10 alkyl,

u) —CO2—C1-10 alkyl-aryl,

v) -fused arylcycloalkyl,
w) -alkynylene-heteroaryl,
x) -alkylene-aryl,
y) -alkynylene-aryl,
z) -nitro,
aa) —N(H)—C(O)—C1-6-alkyl, and

bb) —S—C1-6-alkyl;

Rd and Re are independently selected from the group consisting of: hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, cycloalkyl, —C1-10 alkylene-cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl
groups are optionally substituted with one to four substituents independently selected from Rc; or Rd and Re together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms
independently selected from oxygen, sulfur and nitrogen and optionally substituted with 1-3 times with Rc,

Rf and Rg are independently selected from the group consisting of: hydrogen, C1-10 alkyl, cycloalkyl, —C1-10 alkylene-cycloalkyl, -carboxy, and aryl, wherein alkyl, cycloalkyl, and aryl groups are optionally substituted with one to
four substituents independently selected from Rc; or Rf and Rg together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently
selected from oxygen, sulfur and nitrogen optionally substituted with 1-3 times with Rc;

m is an integer from 1 to 2;
n is an integer from 1 to 10; and
p is an integer from 0 to 2.

US Pat. No. 9,663,481

PHENOXY ACETIC ACIDS AND PHENYL PROPIONIC ACIDS AS PPAR? AGONISTS

vTv Therapeutics LLC, Hi...

1. A method of arresting development of a disease-state, slowing development of a disease state, causing regression of a disease-state,
or causing regression of a symptom of a disease-state, wherein the disease-state is type I diabetes, type II diabetes, impaired
glucose tolerance, insulin resistance, or obesity, the method comprising administering to a subject in need thereof an effective
amount of a compound according to formula (I) or a pharmaceutically acceptable salt thereof:

wherein is a double bond, with either E or Z substitution;
X1 is C1-6-alkyl substituted with morpholino;

X2 is phenylene;

X3 is phenyl substituted with one or more halogens;

Ar is phenylene optionally substituted with methyl;
Y1 is O;

Y2 is O;

Z is CH2;

R1 is H; and

R2 is H.

US Pat. No. 10,085,990

TRICYCLIC COMPOUNDS AS MODULATORS OF TNF-? SYNTHESIS AND AS PDE4 INHIBITORS

vTv Therapeutics LLC, Hi...

1. A method of treating ulcerative colitis or Crohn's disease comprising administering to a human a compound, wherein the compound is selected from the group consisting of1-cyclopentyl-7-methoxy-3-(4-methyl-thiophen-2-yl)-1H-pyrimido[5,4-c]quinoline-2,4-dione,
1-cyclopentyl-7-methoxy-3-m-tolyl-1H-pyrimido[5,4-c]quinoline-2,4-dione,
3-(3-chloro-phenyl)-1-(1-methane-sulfonyl-piperidin-4-yl)-7-methoxy-1H-pyrimido[5,4-c]-quinoline-2,4-dione,
trans-4-[3-(3-chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimido-[5,4-c]quinolin-1-yl]-cyclohexanecarboxylic acid methyl ester,
3-(3-chloro-phenyl)-1-((R)-1-methane-sulfonyl-pyrrolidin-3-yl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione,
3-(3-chloro-phenyl)-1-((S)-1-methane-sulfonyl-pyrrolidin-3-yl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione,
3-(3-chloro-phenyl)-1-(1-ethanesulfonyl-piperidin-4-yl)-7-methoxy-1H-pyrimido-[5,4-c]quinoline-2,4-dione, and
N-{4-[(S)-3-(3-chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimido[5,4-c]quinolin-1-yl]-trans-cyclohexyl}-methanesulfonamide,
or a pharmaceutically acceptable salt thereof.
US Pat. No. 9,833,457

TRICYCLIC COMPOUNDS AS MODULATORS OF TNF-? SYNTHESIS AND AS PDE4 INHIBITORS

vTv Therapeutics LLC, Hi...

1. A method of treating psoriatic arthritis comprising administering to a human a compound, wherein the compound is selected
from the group consisting of
1-cyclopentyl-7-methoxy-3-(4-methyl-thiophen-2-yl)-1H-pyrimido[5,4-c]quinoline-2,4-dione,
1-cyclopentyl-7-methoxy-3-m-tolyl-1H-pyrimido[5,4-c]quinoline-2,4-dione,
3-(3-chloro-phenyl)-1-(1-methane-sulfonyl-piperidin-4-yl)-7-methoxy-1H-pyrimido[5,4-c]-quinoline-2,4-dione,
trans-4-[3-(3-chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimido-[5,4-c]quinolin-1-yl]-cyclohexanecarboxylic acid
methyl ester,

3-(3-chloro-phenyl)-1-((R)-1-methane-sulfonyl-pyrrolidin-3-yl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione,
3-(3-chloro-phenyl)-1-((S)-1-methane-sulfonyl-pyrrolidin-3-yl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione,
3-(3-chloro-phenyl)-1-(1-ethanesulfonyl-piperidin-4-yl)-7-methoxy-1H-pyrimido-[5,4-c]quinoline-2,4-dione, and
N-{4-[(S)-3-(3-chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimido[5,4-c]quinolin-1-yl]-trans-cyclohexyl}-methanesulfonamide,
or a pharmaceutically acceptable salt thereof.
US Pat. No. 9,717,710

TREATMENT OF MILD AND MODERATE ALZHEIMER'S DISEASE

vTv THERAPEUTICS LLC, Hi...

1. A method of treating Alzheimer's disease comprising administering to a human in need thereof an amount of about 5 mg per
day of [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl amine, wherein the human
is suffering from mild Alzheimer's disease.
US Pat. No. 9,687,489

TRICYCLIC COMPOUNDS AS MODULATORS OF TNF-? SYNTHESIS AND AS PDE4 INHIBITORS

vTv Therapeutics LLC, Hi...

1. A method of treating psoriasis comprising administering to a human a compound, wherein the compound is
1-cyclopentyl-7-methoxy-3-(4-methyl-thiophen-2-yl)-1H-pyrimido[5,4-c]quinoline-2,4-dione,
1-cyclopentyl-7-methoxy-3-m-tolyl-1H-pyrimido[5,4-c]quinoline-2,4-dione,
3-(3-chloro-phenyl)-1-(1-methane-sulfonyl-piperidin-4-yl)-7-methoxy-1H-pyrimido[5,4-c]-quinoline-2,4-dione,
trans-4-[3-(3-chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimido-[5,4-c]quinolin-1-yl]-cyclohexanecarboxylic acid,
3-(3-chloro-phenyl)-1-((R)-1-methane-sulfonyl-pyrrolidin-3-yl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione,
3-(3-chloro-phenyl)-1-((S)-1-methane-sulfonyl-pyrrolidin-3-yl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione,
3-(3-chloro-phenyl)-1-(1-ethanesulfonyl-piperidin-4-yl)-7-methoxy-1H-pyrimido-[5,4-c]quinoline-2,4-dione, or
N-{4-[(S)-3-(3-chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimido[5,4-c]quinolin-1-yl]-trans-cyclohexyl}-methanesulfonamide,
or a pharmaceutically acceptable salt thereof.
US Pat. No. 9,968,613

USE OF A PPAR-DELTA AGONIST FOR REDUCING LOSS OF MUSCLE STRENGTH, MUSCLE MASS, OR TYPE I MUSCLE FIBERS IN AN IMMOBILIZED LIMB

VTV THERAPEUTICS LLC, Hi...

1. A method of treatment comprising administering to a human subject (E)-[4-[3-(4-Fluorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic acid or a pharmaceutically acceptable salt thereof,wherein the human subject has an immobilized limb, and
wherein the amount of (E)-[4-[3-(4-Fluorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic acid or a pharmaceutically acceptable salt thereof administered is sufficient to reduce the rate of loss of muscle strength in the muscle tissue of the immobilized limb of the subject relative to a control,
wherein muscle strength is measured by a muscle strength test.
US Pat. No. 10,004,782

GLUCOKINASE ACTIVATOR COMPOSITIONS FOR THE TREATMENT OF DIABETES

vTv Therapeutics LLC, Hi...

1. A pharmaceutical composition comprising: i) {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid or a pharmaceutically acceptable salt thereof, ii) a GLP-1 analog or a pharmaceutically acceptable salt thereof; and iii) at least one pharmaceutically acceptable carrier, excipient, diluent or mixture thereof.
US Pat. No. 10,064,846

USE OF METFORMIN IN COMBINATION WITH A GLUCOKINASE ACTIVATOR AND COMPOSITIONS COMPRISING METFORMIN AND A GLUCOKINASE ACTIVATOR

vTv Therapeutics LLC, Hi...

1. A method of improving insulin sensitivity in a subject comprising:administering to the subject {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid or a pharmaceutically acceptable salt thereof in combination with metformin, wherein the metformin is administered in an amount of less than 1000 mg/day.
US Pat. No. 10,363,244

COMPOSITIONS COMPRISING METFORMIN AND A GLUCOKINASE ACTIVATOR

vTv Therapeutics LLC, Hi...

1. A pharmaceutical composition comprising:(a) {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid or a pharmaceutically acceptable salt thereof,
(b) less than 1000 mg of metformin, and
(c) at least one pharmaceutically acceptable carrier, excipient, diluent, or a mixture thereof.
US Pat. No. 10,391,097

TRICYCLIC COMPOUNDS AS MODULATORS OF TNF-ALPHA SYNTHESIS AND AS PDE4 INHIBITORS

vTv Therapeutics LLC, Hi...

1. A method of treating ankylosing spondylitis comprising administering to a human a compound, wherein the compound is selected from the group consisting of1-cyclopentyl-7-methoxy-3-(4-methyl-thiophen-2-yl)-1H-pyrimido[5,4-c]quinoline-2,4-dione,
1-cyclopentyl-7-methoxy-3-m-tolyl-1H-pyrimido[5,4-c]quinoline-2,4-dione,
3-(3-chloro-phenyl)-1-(1-methane-sulfonyl-piperidin-4-yl)-7-methoxy-1H-pyrimido[5,4-c]-quinoline-2,4-dione,
trans-4-[3-(3-chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimido-[5,4-c]quinolin-1-yl]-cyclohexanecarboxylic acid methyl ester,
3-(3-chloro-phenyl)-1-((R)-1-methane-sulfonyl-pyrrolidin-3-yl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione,
3-(3-chloro-phenyl)-1-((S)-1-methane-sulfonyl-pyrrolidin-3-yl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione,
3-(3-chloro-phenyl)-1-(1-ethanesulfonyl-piperidin-4-yl)-7-methoxy-1H-pyrimido-[5,4-c]quinoline-2,4-dione, and
N-{4-[(S)-3-(3-chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimido[5,4-c]quinolin-1-yl]-trans-cyclohexyl}-methanesulfonamide,
or a pharmaceutically acceptable salt thereof.

US Pat. No. 10,364,233

PIPERIDINE DERIVATIVE AND METHODS OF USE THEREOF

vTv Therapeutics LLC, Hi...

1. A compound, wherein the compound is a compound of Formula (I)
or a pharmaceutically acceptable salt thereof.

US Pat. No. 10,363,241

SUBSTITUTED IMIDAZOLE DERIVATIVES AND METHODS OF USE THEREOF

vTv Therapeutics LLC, Hi...

1. A compound of Formula (X)
wherein
Q1 is selected from the group consisting of —CH2OCH2CH3 and —CH2CH2CH2CH3.

US Pat. No. 10,287,284

SUBSTITUTED FUSED IMIDAZOLE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS, AND METHODS OF USE THEREOF

vTv Therapeutics LLC, Hi...

1. A method of treating a disease comprising administering to a human subject a compound,wherein the disease is a fibrotic disease of the lung, a fibrotic disease of the liver, or a fibrotic disease of the skin;
wherein the compound is a compound of Formula (I) or a pharmaceutically acceptable salt thereof

wherein
one of X1, X2, X3, and X4 is
and the remaining members of X1, X2, X3, and X4 are independently N or
G is hydrogen, —C1-8 alkyl, —C3-10 cycloalkyl, —C1-6 alkylene-C3-10 cycloaklyl, heterocyclyl, —C1-6 alkylene-C3-10 heterocyclyl, phenyl, heteroaryl, or NRhRk, where the alkyl, alkylene, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rc;
L is —CH2—C(O)N(R6)—, —C(O)N(R6)—, —C(O)—O—, —SO2—, —C(O)—, heteroarylene optionally substituted one or more times with substituents independently selected from Rx, or heterocyclylene optionally substituted one or more times with substituents independently selected from Rx; or the group -L-G is -cyano;
R1 is hydrogen, Ra, phenyl, or heteroaryl, where the phenyl and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rx;
R2 is Rb;
R3 is hydrogen, —C1-6 alkyl, or —C1-6 alkylene-C3-10 cycloaklyl, where the alkyl, alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from Rz;
R4 is —C1-6 alkyl or —C1-6 alkylene-C3-10 cycloaklyl, where the alkyl, alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from RY;
R6 is hydrogen, —C1-6 alkyl, —C1-6 alkylene-C3-10 cycloaklyl, where the alkyl, alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from Rx;
Ra is
a) -halogen,
b) —C1-6 alkyl,
c) —C3-10 cycloalkyl,
d) -heterocyclyl,
e) -cyano,
f) —CF3,
g) —OCF3,
h) —O—Rd,
i) —S(O)w—Rd,
j) —S(O)2O—Rd,
k) —NRdRe,
l) —C(O)—Rd,
m) —C(O)—O—Rd,
n) —OC(O)—Rd,
o) —C(O)NRdRe,
p) —C(O)-heterocyclyl,
q) —NRd C(O)Re,
r) —OC(O)NRdRe,
s) —NRd C(O)ORd, or
t) —NRd C(O)NRdRe,
where the alkyl, cycloalkyl, and heterocyclyl groups are optionally substituted one or more times with substituents independently selected from Ry;
Rb is
a) -halogen,
b) —C1-6 alkyl,
c) —C3-10 cycloalkyl,
d) -heterocyclyl,
e) -phenyl,
f) -heteroaryl,
g) -cyano,
h) —CF3,
i) —OCF3,
j) —O—Rf,
k) —S(O)w—Rf,
l) —S(O)2O—Rf,
m) —NRfRg,
n) —C(O)—Rf,
o) —C(O)—O—Rf,
p) —OC(O)—Rf,
q) —C(O)NRfRg,
r) —C(O)-heterocyclyl,
s) —NR C(O)Rg,
t) —OC(O)NRfRg,
u) —NRfC(O)ORf, or
v) —NRfC(O)NRfRg,
where the alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from RZ;
Rc is
a) -halogen,
b) —C1-6 alkyl,
c) —C3-10 cycloalkyl,
d) -heterocyclyl,
e) -cyano,
f) —CF3,
g) —OCF3,
h) —O—Rh,
i) —S(O)w—Rh,
j) —S(O)2O—Rh,
k) —NRhRk,
l) —C(O)—Rh,
m) —C(O)—O—Rh,
n) —OC(O)—Rh,
o) —C(O)NRhRk,
p) —C(O)-heterocyclyl,
q) —NRhC(O)Rk,
r) —OC(O)NRhRk,
s) —NRhC(O)ORk,
t) —NRhC(O)NRhRk,
u) —NRh S(O)wRk,
v) -phenyl,
w) -heteroaryl, or
x) —O—(C1-4 alkylene)-O—(C1-4 alkylene)-N(Rh)C(O)—ORk,
where the alkylene, alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rx;
Rd and Re are independently hydrogen, C1-6 alkyl, or C3-10 cycloalkyl, where the alkyl and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from Ry; or, if Rd and Re are both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents independently selected from Ry;
Rf and Rg are independently hydrogen, C1-6 alkyl, C3-10 cycloalkyl, phenyl, or heteroaryl, where the alkyl, cycloalkyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rz; or, if Rf and Rg are both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents independently selected from Rz;
Rh and Rk are independently hydrogen, C1-6 alkyl, C3-10 cycloalkyl, heterocyclyl, phenyl, or heteroaryl, where the alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rx; or, if Rh and Rk are both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents independently selected from Rx;
Ry is
a) -halogen,
b) —NH2,
c) -cyano,
d) -carboxy,
e) -hydroxy,
f) -thiol,
g) —CF3,
h) —OCF3,
i) —C(O)—NH2,
j) —S(O)2—NH2,
k) oxo,
l) —C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
m) -heterocyclyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
n) —C3-10 cycloalkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
o) —O—C1-6 alkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
p) —O—C3-10 cycloalkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
q) —NH—C1-6 alkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
r) —N(C1-6 alkyl)2 optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
s) —C(O)—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
t) —C(O)—O—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
u) —S—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
v) —S(O)2—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
w) —C(O)—NH—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
x) —C(O)—N(C1-6 alkyl)2, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
y) —S(O)2—NH—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
z) —S(O)2—N(C1-6 alkyl)2, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
aa) —NH—C(O)—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2, or
bb) —NH—S(O)2—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2;
Rx is
a) —Ry
b) -phenyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
c) -heteroaryl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
d) —O-phenyl,
e) —O-heteroaryl,
f) —C(O)-phenyl,
g) —C(O)-heteroaryl,
h) —C(O)—O-phenyl, or
i) —C(O)—O-heteroaryl;
Rz is
a) —Ry
b) -phenyl,
c) -heteroaryl;
d) —O-phenyl,
e) —O-heteroaryl,
f) —C(O)-phenyl,
g) —C(O)-heteroaryl,
h) —C(O)—O-phenyl, or
i) —C(O)—O-heteroaryl;
v is an integer from 0 to 4, and
w is an integer from 0 to 2.

US Pat. No. 10,172,840

BACH1 INHIBITORS IN COMBINATION WITH NRF2 ACTIVATORS AND PHARMACEUTICAL COMPOSITIONS THEREOF

vTv Therapeutics LLC, Hi...

1. A method of treatment of a condition, comprising administering an Nrf2 activator and a Bach1 Inhibitor to a subject in need thereof,wherein the condition is selected from the group consisting of psoriasis, scleroderma, chronic kidney disease (CKD), asthma, chronic obstructive pulmonary disorder (COPD), fibrosis, inflammatory arthritis disease, inflammatory bowel disease (IBD), multiple sclerosis, clinically isolated syndrome (CIS), amyotrophic lateral sclerosis, Alzheimer's disease, dementia, Huntington's disease, and Parkinson's disease;
wherein the Nrf2 Activator is selected from the group consisting of
a fumaric acid mono- and/or dialkyl ester, methyl 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate, ethyl 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate, 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oic acid, 1[2-Cyan-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole, and 2-cyano-N-methyl-3,12-dioxooleana-1,9(11)-dien-28 amide,
wherein the Bach1 Inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof,

wherein
X1 is ?CH—;
G is hydrogen, —C1-8 alkyl, —C3-10 cycloalkyl, —C1-6 alkylene-C3-10 cycloaklyl, heterocyclyl, —C1-6 alkylene-C3-10 heterocyclyl, phenyl, heteroaryl, or NRhRk, where the alkyl, alkylene, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rc; or G is —CH2Y3, —CH2CH2Y3, —CH2CH2CH2Y3, —CH(CH3)CH2Y3, —CH2CH(Y3)CH3, —CH(Y3)CH3, —CH2C(Y3)(CH3)2, —C(Y3)(CH3)2, or
where Y3 is cyclopropyl, —CF3, —OCF3, —OCH3, —OCH2CH3, —F, —Cl, —OH, —O(CH2)2—OH, —O(CH2)2—F, —SCH3, —S(O)2—CH3, —SCH2CH3, —S(O)2CH2CH3, —NH—CH3, —NH—CH2CH3, —N(CH3)2, tetrahydropyran-4-yl, tetrahydrofuran-2-yl, morpholin-2-yl, morpholin-4-yl, piperidin-1-yl, 4-hydroxy-piperidin-1-yl, 3-hydroxy-piperidin-1-yl, —NH—C(O)—CH3, —NH—C(O)—CH2CH3, tetrahydrofuran-2-yl-methyloxy, or —C(O)—Y4, where Y4 is —OH, —OCH3, —OCH2CH3, —OC(CH3)3, —NH2, —NH—CH3, —NH—CH2CH3, —N(CH3)2, —N(CH2CH3)2, morpholin-4-yl, 4-methyl-piperazin-1-yl, pyrrolidin-1-yl, or piperazin-1-yl;L is —CH2—C(O)N(R6)—, —C(O)N(R6)—, —C(O)—O—, —SO2—, —C(O)—, heteroarylene optionally substituted one or more times with substituents independently selected from Rx, or heterocyclylene optionally substituted one or more times with substituents independently selected from Rx; or the group -L-G is -cyano;
R1 is hydrogen, Ra, phenyl, or heteroaryl, where the phenyl and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rx;
R2 is Rb;
R3 is hydrogen, —C1-6 alkyl, or —C1-6 alkylene-C3-10 cycloaklyl, where the alkyl, alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from Rz;
R4 is —C1-6 alkyl or —C1-6 alkylene-C3-10 cycloaklyl, where the alkyl, alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from Ry;
R6 is hydrogen, —C1-6 alkyl, —C1-6 alkylene-C3-10 cycloaklyl, where the alkyl, alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from Rx;
Ra is
a) -halogen,
b) —C1-6 alkyl,
c) —C3-10 cycloalkyl,
d) -heterocyclyl,
e) -cyano,
f) —CF3,
g) —OCF3,
h) —O—Rd,
i) —S(O)w—Rd,
j) —S(O)2O—Rd,
k) —NRdRe,
l) —C(O)—Rd,
m) —C(O)—O—Rd,
n) —OC(O)—Rd,
o) —C(O)NRdRe,
p) —C(O)-heterocyclyl,
q) —NRdC(O)Re,
r) —OC(O)NRdRe,
s) —NRdC(O)ORd, or
t) —NRdC(O)NRdRe,
where the alkyl, cycloalkyl, and heterocyclyl groups are optionally substituted one or more times with substituents independently selected from Ry;
Rb is
a) -halogen,
b) —C1-6 alkyl,
c) —C3-10 cycloalkyl,
d) -heterocyclyl,
e) -phenyl,
f) -heteroaryl,
g) -cyano,
h) —CF3,
i) —OCF3,
j) —O—Rf,
k) —S(O)w—Rf,
l) —S(O)2O—Rf,
m) —NRfRg,
n) —C(O)—Rf,
o) —C(O)—O—Rf,
p) —OC(O)—Rf,
q) —C(O)NRfRg,
r) —C(O)-heterocyclyl,
s) —NRf C(O)Rg,
t) —OC(O)NRfRg,
u) —NRf C(O)ORf, or
v) —NRf C(O)NRfRg,
where the alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rz;
Rc is
a) -halogen,
b) —C1-6 alkyl,
c) —C3-10 cycloalkyl,
d) -heterocyclyl,
e) -cyano,
f) —CF3,
g) —OCF3,
h) —O—Rh,
i) —S(O)w—Rh,
j) —S(O)2O—Rh,
k) —NRhRk;
l) —C(O)—Rh,
m) —C(O)—O—Rh,
n) —OC(O)—Rh,
o) —C(O)NRhRk,
p) —C(O)-heterocyclyl,
q) —NRhC(O)Rk,
r) —OC(O)NRhRk,
s) —NRhC(O)ORk,
t) —NRhC(O)NRhRk,
u) —NRh S(O)wRk,
v) -phenyl,
w) -heteroaryl, or
x) —O—(C1-4 alkylene)-O—(C1-4 alkylene)-N(Rh)C(O)—ORk,
where the alkylene, alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rx;
Rd and Re are independently hydrogen, C1-6 alkyl, or C3-10 cycloalkyl, where the alkyl and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from Ry; or, if Rd and Re are both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents independently selected from Ry;
Rf and Rg are independently hydrogen, C1-6 alkyl, C3-10 cycloalkyl, phenyl, or heteroaryl, where the alkyl, cycloalkyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rz; or, if Rf and Rg are both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents independently selected from Rz;
Rh and Rk are independently hydrogen, C1-6 alkyl, C3-10 cycloalkyl, heterocyclyl, phenyl, or heteroaryl, where the alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rx; or, if Rh and Rk are both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents independently selected from Rx;
Ry is
a) -halogen,
b) —NH2,
c) -cyano,
d) -carboxy,
e) -hydroxy,
f) -thiol,
g) —CF3,
h) —OCF3,
i) —C(O)—NH2,
j) —S(O)2—NH2,
k) oxo,
l) —C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
m) -heterocyclyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
n) —C3-10 cycloalkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
o) —O—C1-6 alkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
p) —O—C3-10 cycloalkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
q) —NH—C1-6 alkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
r) —N(C1-6 alkyl)2 optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
s) —C(O)—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
t) —C(O)—O—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
u) —S—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
v) —S(O)2—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
w) —C(O)—NH—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
x) —C(O)—N(C1-6 alkyl)2, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
y) —S(O)2—NH—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
z) —S(O)2—N(C1-6 alkyl)2, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
aa) —NH—C(O)—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2, or
bb) —NH—S(O)2—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2;
Rx is
a) -Ry
b) -phenyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
c) -heteroaryl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
d) —O-phenyl,
e) —O-heteroaryl,
f) —C(O)-phenyl,
g) —C(O)-heteroaryl,
h) —C(O)—O-phenyl, or
i) —C(O)—O-heteroaryl;
Rz is
a) -Ry
b) -phenyl,
c) -heteroaryl;
d) —O-phenyl,
e) —O-heteroaryl,
f) —C(O)-phenyl,
g) —C(O)-heteroaryl,
h) —C(O)—O-phenyl, or
i) —C(O)—O-heteroaryl;
v is an integer from 0 to 4, and
w is an integer from 0 to 2.

US Pat. No. 10,463,652

BACH1 INHIBITORS IN COMBINATION WITH NRF2 ACTIVATORS AND PHARMACEUTICAL COMPOSITIONS THEREOF

vTv Therapeutics LLC, Hi...

1. A method of treatment of a condition, comprising administering an Nrf2 activator and a Bach1 Inhibitor to a subject in need thereof,wherein the condition is selected from the group consisting of psoriasis, scleroderma, chronic kidney disease (CKD), asthma, chronic obstructive pulmonary disorder (COPD), fibrosis, inflammatory arthritis disease, inflammatory bowel disease (IBD), multiple sclerosis, clinically isolated syndrome (CIS), amyotrophic lateral sclerosis, Alzheimer's disease, dementia, Huntington's disease, and Parkinson's disease;
wherein the Nrf2 Activator is selected from the group consisting of
a fumaric acid mono- and/or dialkyl ester, methyl 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate, ethyl 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate, 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oic acid, 1[2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole, and 2-cyano-N-methyl-3,12-dioxooleana-1,9(11)-dien-28 amide,
wherein the Bach1 Inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof,

wherein
X1 is ?N—;
G is hydrogen, —C1-8 alkyl, —C3-10 cycloalkyl, —C1-6 alkylene-C3-10 cycloaklyl, heterocyclyl, —C1-6 alkylene-C3-10 heterocyclyl, phenyl, heteroaryl, or NRhRk, where the alkyl, alkylene, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rc; or G is —CH2Y3, —CH2CH2Y3, —CH2CH2CH2Y3, —CH(CH3)CH2Y3, —CH2CH(Y3)CH3, —CH(Y3)CH3, —CH2C(Y3)(CH3)2, —C(Y3)(CH3)2, or
where Y3 is cyclopropyl, —CF3, —OCF3, —OCH3, —OCH2CH3, —F, —Cl, —OH, —O(CH2)2—OH, —O(CH2)2—F, —SCH3, —S(O)2—CH3, —SCH2CH3, —S(O)2CH2CH3, —NH—CH3, —NH—CH2CH3, —N(CH3)2, tetrahydropyran-4-yl, tetrahydrofuran-2-yl, morpholin-2-yl, morpholin-4-yl, piperidin-1-yl, 4-hydroxy-piperidin-1-yl, 3-hydroxy-piperidin-1-yl, —NH—C(O)—CH3, —NH—C(O)—CH2CH3, tetrahydrofuran-2-yl-methyloxy, or —C(O)—Y4, where Y4 is —OH, —OCH3, —OCH2CH3, —OC(CH3)3, —NH2, —NH—CH3, —NH—CH2CH3, —N(CH3)2, —N(CH2CH3)2, morpholin-4-yl, 4-methyl-piperazin-1-yl, pyrrolidin-1-yl, or piperazin-1-yl;L is —CH2—C(O)N(R6)—, —C(O)N(R6)—, —C(O)—O—, —SO2—, —C(O)—, heteroarylene optionally substituted one or more times with substituents independently selected from Rx, or heterocyclylene optionally substituted one or more times with substituents independently selected from Rx; or the group -L-G is -cyano;
R1 is hydrogen, Ra, phenyl, or heteroaryl, where the phenyl and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rx;
R2 is Rb;
R3 is hydrogen, —C1-6 alkyl, or —C1-6 alkylene-C3-10 cycloaklyl, where the alkyl, alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from Rz;
R4 is —C1-6 alkyl or —C1-6 alkylene-C3-10 cycloaklyl, where the alkyl, alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from BY;
R6 is hydrogen, —C1-6 alkyl, —C1-6 alkylene-C3-10 cycloaklyl, where the alkyl, alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from Rx;
Ra is
a) -halogen,
b) —C1-6 alkyl,
c) —C3-10 cycloalkyl,
d) -heterocyclyl,
e) -cyano,
f) —CF3,
g) —OCF3,
h) —O—Rd,
i) —S(O)w—Rd,
j) —S(O)2O—Rd,
k) —NRdRe,
l) —C(O)—Rd,
m) —C(O)—O—Rd,
n) —OC(O)—Rd,
o) —C(O)NRdRe,
p) —C(O)-heterocyclyl,
q) —NRdC(O)Re,
r) —OC(O)NRdRe,
s) —NRdC(O)ORd, or
t) —NRdC(O)NRdRe,
where the alkyl, cycloalkyl, and heterocyclyl groups are optionally substituted one or more times with substituents independently selected from BY;
Rb is
a) -halogen,
b) —C1-6 alkyl,
c) —C3-10 cycloalkyl,
d) -heterocyclyl,
e) -phenyl,
f) -heteroaryl,
g) -cyano,
h) —CF3,
i) —OCF3,
j) —O—Rf,
k) —S(O)w—Rf,
l) —S(O)2O—Rf,
m) —NRfRg,
n) —C(O)—Rf,
o) —C(O)—O—Rf,
p) —OC(O)—Rf,
q) —C(O)NRfRg,
r) —C(O)-heterocyclyl,
s) —NRfC(O)Rg,
t) —OC(O)NRfRg,
u) —NRfC(O)ORf, or
v) —NRfC(O)NRfRg,
where the alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rz;
Rc is
a) -halogen,
b) —C1-6 alkyl,
c) —C3-10 cycloalkyl,
d) -heterocyclyl,
e) -cyano,
f) —CF3,
g) —OCF3,
h) —O—Rh,
i) —S(O)w—Rh,
j) —S(O)2O—Rh,
k) —NRhRk,
l) —C(O)—Rh,
m) —C(O)—O—Rh,
n) —OC(O)—Rh,
o) —C(O)NRhRk,
p) —C(O)-heterocyclyl,
q) —NRhC(O)Rk,
r) —OC(O)NRhRk,
s) —NRhC(O)ORk,
t) —NRhC(O)NRhRk,
u) —NRh S(O)wRk,
v) -phenyl,
w) -heteroaryl, or
x) —O—(C1-4 alkylene)-O—(C1-4 alkylene)-N(Rh)C(O)—ORk,
where the alkylene, alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rx;
Rd and Re are independently hydrogen, C1-6 alkyl, or C3-10 cycloalkyl, where the alkyl and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from Ry; or, if Rd and Re are both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents independently selected from Ry;
Rf and Rg are independently hydrogen, C1-6 alkyl, C3-10 cycloalkyl, phenyl, or heteroaryl, where the alkyl, cycloalkyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rz; or, if Rf and Rg are both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents independently selected from Rz;
Rh and Rk are independently hydrogen, C1-6 alkyl, C3-10 cycloalkyl, heterocyclyl, phenyl, or heteroaryl, where the alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rx; or, if Rh and Rk are both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents independently selected from Rx;
Ry is
a) -halogen,
b) —NH2,
c) -cyano,
d) -carboxy,
e) -hydroxy,
f) -thiol,
g) —CF3,
h) —OCF3,
i) —C(O)—NH2,
j) —S(O)2—NH2,
k) oxo,
l) —C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
m) -heterocyclyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
n) —C3-10 cycloalkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
o) —O—C1-6 alkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
p) —O—C3-10 cycloalkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
q) —NH—C1-6 alkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
r) —N(C1-6 alkyl)2 optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
s) —C(O)—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
t) —C(O)—O—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
u) —S—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
v) —S(O)2—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
w) —C(O)—NH—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
x) —C(O)—N(C1-6 alkyl)2, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
y) —S(O)2—NH—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
z) —S(O)2—N(C1-6 alkyl)2, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
aa) —NH—C(O)—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2, or
bb) —NH—S(O)2—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2;
Rx is
a) —Ry
b) -phenyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
c) -heteroaryl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
d) —O-phenyl,
e) —O-heteroaryl,
f) —C(O)-phenyl,
g) —C(O)-heteroaryl,
h) —C(O)—O-phenyl, or
i) —C(O)—O-heteroaryl;
Rz is
a) —Ry
b) -phenyl,
c) -heteroaryl;
d) —O-phenyl,
e) —O-heteroaryl,
f) —C(O)-phenyl,
g) —C(O)-heteroaryl,
h) —C(O)—O-phenyl, or
i) —C(O)—O-heteroaryl;
v is an integer from 0 to 4, and
w is an integer from 0 to 2.

US Pat. No. 10,471,066

PHENOXY ACETIC ACIDS AND PHENYL PROPIONIC ACIDS AS PPAR DELTA AGONISTS

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1. A method of improving mitochondrial energy output in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein is a double bond, with either E or Z substitution;
X1 is C1-6 alkyl substituted with morpholino;
X2 is phenylene;
X3 is phenyl substituted with one or more halogens;
Ar is phenylene optionally substituted with methyl;
Y1 is O;
Y2 is CH2;
Z is CH2;
R1 is hydrogen; and
R2 is hydrogen.
US Pat. No. 10,456,406

USE OF A PPAR-? AGONIST FOR REDUCING LOSS OF MUSCLE STRENGTH, MUSCLE MASS, OR TYPE I MUSCLE FIBERS IN AN IMMOBILIZED LIMB

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1. A method of treating muscle atrophy in a subject comprising administering to the subject in need thereof (E)-[4-[3-(4-fluorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic acid, or a pharmaceutically acceptable salt thereof.