IP Library › Patent Application 17307985

Patent Application

App. No. 17/307,985

HETEROCYCLIC MODULATORS OF LIPID SYNTHESIS

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Patent No.: US None
App. No.: 17/307,985

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Abstract

Compounds that are fatty acid synthesis modulators are provided. The compounds may be used to treat disorders characterized by dysregulation of the fatty acid synthase function by modulating the function and/or the fatty acid synthase pathway. Methods are provided for treating such disorders including viral infections, such as hepatitis C infection, cancer and metabolic disorders, such as non-alcoholic steatohepatitis (NASH).

Claims (603)

1 . A method of treating a disorder characterized by dysregulation in the fatty acid synthase function in a subject in need thereof, the method comprising administering to the subject a fatty acid synthase inhibitor having a formula of:

(a) Formula (IX)

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl) wherein:

C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and

when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;

each R 2 is independently hydrogen, halogen or C 1 -C 4 straight or branched alkyl;

R 3 is H, —OH, or halogen;

R 21 is H, halogen, C 1 -C 4 straight or branched alkyl, C 3 -C 5 cycloalkyl wherein the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;

R 22 is H, halogen, or C 1 -C 2 alkyl;

R 24 is H, C 1 -C 4 straight or branched alkyl, —(C 1 -C 4 alkyl) t -OH, —(C 1 -C 4 alkyl) t -O t —(C 3 -C 5 cycloalkyl), or —(C 1 -C 4 alkyl) t -O—(C 1 -C 4 straight or branched alkyl) wherein:

t is 0 or 1;

the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;

L 1 is CR 23 or N;

L 2 is CH or N;

at least one of L 1 or L 2 is N; and

R 23 is H or C 1 -C 4 straight or branched alkyl; or

(b) Formula (X):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl) wherein:

the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and

when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;

each R 2 is independently hydrogen, halogen or C 1 -C 4 straight or branched alkyl;

R 3 is H, —OH or halogen;

L 3 is C(R 60 ) 2 or NR 50 ;

each R 11 is independently H, —OH, —CN, —O t —(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl), or —C(O)—N(R 601 ) 2 wherein:

t is 0 or 1, and

the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;

each R 2 is independently H, —C(O)—O t —(C 1 -C 4 straight or branched alkyl), —C(O)—O t —(C 3 -C 5 cyclic alkyl), —C 3 -C 5 cyclic alkyl optionally containing an oxygen or nitrogen heteroatom, —C(O)—N(R 1 ) 2 , C 1 -C 4 straight or branched alkyl wherein:

t is 0 or 1, and

the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;

n is 1, 2 or 3;

m is 1 or 2;

R 21 is H, halogen, C 1 -C 4 straight or branched alkyl, C 3 -C 5 cycloalkyl wherein the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom

R 22 is H, halogen, C 1 -C 2 alkyl;

each R 26 is independently —OH, —CN, halogen, C 1 -C 4 straight or branched alkyl, —(C 1 -C 4 alkyl) t -O t —(C 3 -C 5 cycloalkyl), —(C 1 -C 4 alkyl) t -O—(C 1 -C 4 straight or branched alkyl), —C(O)—O t —(C 1 -C 4 alkyl), or —C(O)—N(R 501 ) 2 wherein:

t is 0 or 1, and

the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;

s is 0, 1 or 2;

each R 601 and R 501 is independently H or C 1 -C 4 straight or branched alkyl; and

wherein two of R 26 , R 60 , R 50 , R 501 and R 601 optionally join to form a ring wherein the two of R 26 , R 60 , R 50 , R 501 and R 601 may be two R 26 , two R 60 , two R 50 , two R 501 or two R 601 ; or

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl) wherein:

the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and

when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;

each R 2 is independently H, halogen or C 1 -C 4 straight or branched alkyl;

R 3 is H, —OH, or halogen;

R 21 is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R 22 is H, halogen, or C 1 -C 2 alkyl;

R 35 is —C(O)—R 351 , —C(O)—NHR 35 , —C(O)—O—R 35 or S(O) 2 R 351 ; and

R 351 is C 1 -C 6 straight or branched alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; or

(d) Formula (XII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle) or —O—(C 1 -C 4 alkyl), wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogens;

each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;

R 3 is H or F;

R 11 is H or —CH 3 ;

R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;

R 22 is H, halogen, or C 1 -C 2 alkyl;

R 24 is H, —CN, —(C 1 -C 4 alkyl)-CN, C 1 -C 4 alkyl, —(C 1 -C 4 alkyl)-OH, —(C 1 -C 4 alkyl)-N(R 241 ) 2 , —(C 1 -C 4 alkyl) t -O u —(C 3 -C 6 cycloalkyl), —(C 1 -C 4 alkyl) t -O u -(4- to 6-membered heterocycle) or —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

with the proviso that when u is 1, t is 1; and

each R 24 1 is independently H or C 1 -C 2 alkyl; and

R 25 is halogen, —CN, —(C 1 -C 4 alkyl)-CN, C 1 -C 2 alkyl or cyclopropyl; or

(e) Formula (XIII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;

R 3 is H or F;

R 11 is H or —CH 3 ;

R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;

R 22 is H, halogen or C 1 -C 2 alkyl; and

each R 24 and R 25 is independently H, halogen, —CN, —(C 1 -C 4 alkyl)-CN, C 1 -C 4 alkyl, —(C 1 -C 4 alkyl)-OH, —(C 1 -C 4 alkyl)-N(R 241 ) 2 , —(C 1 -C 4 alkyl)-O(C 3 -C 5 cycloalkyl), —(C 1 -C 4 alkyl) t -O u -(4- to 6-membered heterocycle) or —(C 1 -C 4 alkyl) t -O—(C 1 -C 4 alkyl), wherein:

each t is independently 0 or 1;

each u is independently 0 or 1; and

each R 24 1 is independently H or C 1 -C 2 alkyl; or

(f) Formula (XIV):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;

R 3 is H or F;

R 11 is H or —CH 3 ;

R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;

R 22 is H, halogen, or C 1 -C 2 alkyl; and

R 24 is H, C 1 -C 4 alkyl, —(C 1 -C 4 alkyl)-OH, —(C 1 -C 4 alkyl)-N(R 241 ) 2 , —(C 1 -C 4 alkyl) t -O t —(C 3 -C 5 cycloalkyl), —(C 1 -C 4 alkyl) t -O t -(4- to 6-membered heterocycle) or —(C 1 -C 4 alkyl) t -O—(C 1 -C 4 alkyl), wherein:

each t is independently 0 or 1; and

each R 24 1 is independently H or C 1 -C 2 alkyl; or

(g) Formula (XV):

or pharmaceutically acceptable salts thereof, wherein:

L 3 is —CH 2 —, —CHR 50 —, —O—, —NR 50 —, —NC(O)R 50 — or —NC(O)OR 50 —, wherein R 50 is C 1 -C 6 alkyl, C 3 -C 5 cycloalkyl, or 4- to 6-membered heterocycle;

n is 1, 2, or 3;

m is 1 or 2 with the proviso that n+m≥3;

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6 membered heteroaryl;

each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;

R 3 is H or F;

R 11 is H or —CH 3 ;

R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or a 4- to 6-membered heterocycle; and

R 22 is H, halogen, or C 1 -C 2 alkyl; or

(h) Formula (XVI):

or pharmaceutically acceptable thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;

R 3 is H or F;

R 11 is H or —CH 3 ;

R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;

R 22 is H, halogen or C 1 -C 2 alkyl; and

each of R 24 and R 25 is independently H, —C 1 -C 4 alkyl, or halogen; or

(i) Formula (XVII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;

R 3 is H or F;

R 11 is H or —CH 3 ;

R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;

R 22 is H, halogen or C 1 -C 2 alkyl; and

R 24 is H, C 1 -C 4 alkyl, —(C 1 -C 4 alkyl)-OH, —(C 1 -C 4 alkyl)-N(R 241 ) 2 , —(C 1 -C 4 alkyl) t -O u —(C 3 -C 5 cycloalkyl), —(C 1 -C 4 alkyl) t -O u -(4- to 6-membered heterocycle) or —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

with the proviso that when u is 1, t is 1; and

R 24 1 is H or C 1 -C 2 alkyl; or

(j) Formula (XVIII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

L 2 is —NHR 35 or —C(O)NHR 351 , wherein R 351 is C 1 -C 6 alkyl, C 3 -C 5 cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;

Het is a 5- to 6-membered heteroaryl;

R 1 is H, —CN, halogen, C 1 -C 4 alkyl, —O—(C 3 -C 5 cycloalkyl), —O-(4- to 6-membered heterocycle), —O—(C 1 -C 4 alkyl) wherein when R 1 is not H, —CN or halogen, R 1 is optionally substituted with one or more halogens;

each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;

R 3 is H or F;

R 11 is H or —CH 3 ;

R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;

R 22 is H, halogen, or C 1 -C 2 alkyl; and

R 35 is —C(O)R 351 , —C(O)NHR 351 , C(O)OR 351 or S(O) 2 R 351 wherein R 351 is C 1 -C 6 alkyl, C 3 -C 5 cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl; or

(k) Formula (XIX):

or pharmaceutically acceptable salts thereof, wherein:

each W, X, Y and Z is independently —N— or —CR 26 — with the proviso that not more than 2 of W, X, Y and Z are —N—;

each R 26 is independently H, C 1 -C 4 alkyl, —O—(C 1 -C 4 alkyl), —N(R 27 ) 2 , —S(O) 2 —(C 1 -C 4 alkyl), or —C(O)—(C 1 -C 4 alkyl);

each R 27 is independently H or C 1 -C 4 alkyl or both R 27 are C 1 -C 4 alkyl and join to form a 3- to 6-membered ring together with the N to which they are attached and wherein the ring optionally includes one oxygen atom as one of the members of the ring;

Ar is

Het is a 5- to 6-membered heteroaryl;

each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;

R 3 is H or F;

R 11 is H or —CH 3 ;

R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or a 4- to 6-membered heterocycle; and

R 22 is H, halogen or C 1 -C 2 alkyl; or

(l) Formula (XX):

or a pharmaceutically acceptable salt thereof, wherein:

L-Ar is

Ar is

each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;

R 3 is H or F;

R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;

R 22 is H, halogen or C 1 -C 2 alkyl;

R 24 is —O—(C 1 -C 4 alkyl), —O—(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), —O—(C 3 -C 5 cycloalkyl) or —O-(4- to 6-membered heterocycle), wherein R 24 is optionally substituted with one or more hydroxyl or halogen; and

R 25 is H, halogen, C 1 -C 4 alkyl or C 3 -C 5 cycloalkyl, wherein R 25 is optionally substituted with one or more halogen; or

(m) Formula (XI):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl) wherein:

the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and

when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;

each R 2 is independently H, halogen or C 1 -C 4 straight or branched alkyl;

R 3 is H, —OH, or halogen;

R 21 is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R 22 is H, halogen, C 1 -C 2 alkyl; and

R 351 is C 1 -C 2 alkyl or C 2 —O—(C 1 or C 2 alkyl).

2 . The method of claim 1 , wherein the disorder is a fatty liver disease.

3 . The method of claim 2 , wherein the fatty liver disease is selected from non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

4 . The method of claim 1 , wherein the disorder is non-alcoholic steatohepatitis (NASH).

5 . The method of claim 4 , wherein treating the non-alcoholic steatohepatitis comprises preventing the progression of at least one symptom of non-alcoholic steatohepatitis.

6 . The method of claim 5 , wherein the symptom is selected from elevated levels of AST; elevated levels of ALT; elevated levels of liver triglycerides; elevated levels of cholesterol;

liver steatosis; liver inflammation; liver ballooning; liver fibrosis; and NAFLD activity score.

7 . The method of claim 1 , wherein the disorder is non-alcoholic fatty liver disease (NAFLD).

8 . The method of claim 1 , wherein the disorder is metabolic syndrome.

9 . The method of claim 1 , wherein the disorder is liver cirrhosis.

10 . The method of claim 1 , wherein the disorder is liver fibrosis.

11 . The method of claim 1 , wherein the disorder is liver cancer.

12 . The method of claim 1 , wherein the disorder is a disease or condition in which interleukin 1 beta (IL1β) levels are elevated.

13 . The method of claim 12 , wherein the disease or condition is selected from Familial Mediterranean fever (FMF), Pyogenic arthritis, pyoderma gangrenosum, acne (PAPA), Cryopyrin-associated periodic syndromes (CAPS), Hyper IgD syndrome (HIDS), Adult and juvenile Still disease, Schnitzler syndrome, TNF receptor-associated periodic syndrome (TRAPS), Blau syndrome; Sweet syndrome, Deficiency in IL-1 receptor antagonist (DIRA), Recurrent idiopathic pericarditis, Macrophage activation syndrome (MAS), Urticarial vasculitis, Antisynthetase syndrome, Relapsing chondritis, Beheet disease, Erdheim-Chester syndrome (histiocytosis), Synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO), Rheumatoid arthritis, Periodic fever, aphthous stomatitis, pharyngitis, adenitis syndrome (PFAPA), Urate crystal arthritis (gout), Type 2 diabetes, Smoldering multiple myeloma, Postmyocardial infarction heart failure, Osteoarthritis, Transfusion-related acute lung injury, Ventilator-induced lung injury, Pulmonary fibrosis including Idiopathic, Chronic obstructive pulmonary disease and Asthma.

14 . The method of claim 1 , wherein disease is a disease or condition in which t-helper (T h ) cell levels are elevated.

15 . The method of claim 14 , wherein the disease or condition is selected from Psoriasis, Rheumatoid arthritis, Multiple sclerosis, Ankylosing spondylitis, inflammatory bowel disease, asthma, tumorigenesis and transplant rejection.

16 . The method of claim 1 , wherein the disorder is a disease or condition in which regulatory t cells (T K g) are reduced or suppressed.

17 . The method of claim 16 , wherein the disease or condition is selected from Psoriasis, Rheumatoid arthritis, Multiple sclerosis, Ankylosing spondylitis, inflammatory bowel disease, asthma, tumorigenesis and transplant rejection.

18 . The method of claim 1 , wherein the disorder is skin fibrosis.

19 . A method of reversing established non-alcoholic steatohepatitis (NASH), the method comprising administering to a subject in need thereof a fatty acid synthase inhibitor having a formula of:

(a) Formula (IX)

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl) wherein:

C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and

when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;

each R 2 is independently hydrogen, halogen or C 1 -C 4 straight or branched alkyl;

R 3 is H, —OH, or halogen;

R 21 is H, halogen, C 1 -C 4 straight or branched alkyl, C 3 -C 5 cycloalkyl wherein the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;

R 22 is H, halogen, or C 1 -C 2 alkyl;

t is 0 or 1;

the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;

L 1 is CR 23 or N;

L 2 is CH or N;

at least one of L 1 or L 2 is N; and

R 23 is H or C 1 -C 4 straight or branched alkyl; or

(b) Formula (X):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl) wherein:

the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and

when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;

each R 2 is independently hydrogen, halogen or C 1 -C 4 straight or branched alkyl;

R 3 is H, —OH or halogen;

L 3 is C(R 0 ) 2 , O or NR′;

each R 11 is independently H, —OH, —CN, —O t —(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl), or —C(O)—N(R 601 ) 2 wherein:

t is 0 or 1, and

the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;

each R S is independently H, —C(O)—O—(C 1 -C 4 straight or branched alkyl), —C(O)—O—(C 3 -C 5 cyclic alkyl), —C 3 -C 5 cyclic alkyl optionally containing an oxygen or nitrogen heteroatom, —C(O)—N(R 1 ) 2 , C 1 -C 4 straight or branched alkyl wherein:

t is 0 or 1, and

the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;

n is 1, 2 or 3;

m is 1 or 2;

R 21 is H, halogen, C 1 -C 4 straight or branched alkyl, C 3 -C 5 cycloalkyl wherein the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom

R 22 is H, halogen, C 1 -C 2 alkyl;

t is 0 or 1, and

the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;

s is 0, 1 or 2;

each R 601 and R 501 is independently H or C 1 -C 4 straight or branched alkyl; and

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl) wherein:

the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and

when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;

each R 2 is independently H, halogen or C 1 -C 4 straight or branched alkyl;

R 3 is H, —OH, or halogen;

R 21 is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R 22 is H, halogen, or C 1 -C 2 alkyl;

R 35 is —C(O)—R 351 , —C(O)—NHR 35 , —C(O)—O—R 35 or S(O) 2 R 351 ; and

R 351 is C 1 -C 6 straight or branched alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; or

(d) Formula (XII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;

R 3 is H or F;

R 11 is H or —CH 3 ;

R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;

R 22 is H, halogen, or C 1 -C 2 alkyl;

R 24 is H, —CN, —(C 1 -C 4 alkyl)-CN, C 1 -C 4 alkyl, —(C 1 -C 4 alkyl)-OH, —(C 1 -C 4 alkyl)-N(R 241 ) 2 , —(C 1 -C 4 alkyl) t -O—(C 3 -C 6 cycloalkyl), —(C 1 -C 4 alkyl) t -O u -(4- to 6-membered heterocycle) or —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), wherein:

t is 0 or 1;

u is 0 or 1;

with the proviso that when u is 1, t is 1; and

each R 24 1 is independently H or C 1 -C 2 alkyl; and

R 25 is halogen, —CN, —(C 1 -C 4 alkyl)-CN, C 1 -C 2 alkyl or cyclopropyl; or

(e) Formula (XIII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;

R 3 is H or F;

R 11 is H or —CH 3 ;

R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;

R 22 is H, halogen or C 1 -C 2 alkyl; and

each R 24 and R 25 is independently H, halogen, —CN, —(C 1 -C 4 alkyl)-CN, C 1 -C 4 alkyl, —(C 1 -C 4 alkyl)-OH, —(C 1 -C 4 alkyl)-N(R 241 ) 2 , —(C 1 -C 4 alkyl) t -O—(C 3 -C 5 cycloalkyl), —(C 1 -C 4 alkyl) t -O u -(4- to 6-membered heterocycle) or —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), wherein:

each t is independently 0 or 1;

each u is independently 0 or 1; and

each R 24 1 is independently H or C 1 -C 2 alkyl; or

(f) Formula (XIV):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;

R 3 is H or F;

R 11 is H or —CH 3 ;

R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;

R 22 is H, halogen, or C 1 -C 2 alkyl; and

each t is independently 0 or 1; and

each R 24 1 is independently H or C 1 -C 2 alkyl; or

(g) Formula (XV):

or pharmaceutically acceptable salts thereof, wherein:

L 3 is —CH 2 —, —CHR 50 —, —O—, —NR 50 —, —NC(O)R 50 — or —NC(O)OR 50 —, wherein R is C 1 -C 6 alkyl, C 3 -C 5 cycloalkyl, or 4- to 6-membered heterocycle;

n is 1, 2, or 3;

m is 1 or 2 with the proviso that n+m≥3;

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;

R 3 is H or F;

R 11 is H or —CH 3 ;

R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or a 4- to 6-membered heterocycle; and

R 22 is H, halogen, or C 1 -C 2 alkyl; or

(h) Formula (XVI):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;

R 3 is H or F;

R 11 is H or —CH 3 ;

R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;

R 22 is H, halogen or C 1 -C 2 alkyl; and

each of R 24 and R 25 is independently H, —C 1 -C 4 alkyl, or halogen; or

(i) Formula (XVII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;

R 3 is H or F;

R 11 is H or —CH 3 ;

R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;

R 22 is H, halogen or C 1 -C 2 alkyl; and

t is 0 or 1;

u is 0 or 1;

with the proviso that when u is 1, t is 1; and

R 24 1 is H or C 1 -C 2 alkyl; or

(j) Formula (XVIII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

L 2 is —NHR 35 or —C(O)NHR 351 , wherein R 351 is C 1 -C 6 alkyl, C 3 -C 5 cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;

Het is a 5- to 6-membered heteroaryl;

each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;

R 3 is H or F;

R 11 is H or —CH 3 ;

R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;

R 22 is H, halogen, or C 1 -C 2 alkyl; and

R 35 is —C(O)R 351 , —C(O)NHR 351 , C(O)OR 351 or S(O) 2 R 351 wherein R 351 is C 1 -C 6 alkyl, C 3 -C 5 cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl; or

(k) Formula (XIX):

or pharmaceutically acceptable salts thereof, wherein:

each W, X, Y and Z is independently —N— or —CR 26 — with the proviso that not more than 2 of W, X, Y and Z are —N—;

each R 26 is independently H, C 1 -C 4 alkyl, —O—(C 1 -C 4 alkyl), —N(R 27 ) 2 , —S(O) 2 —(C 1 -C 4 alkyl), or —C(O)—(C 1 -C 4 alkyl);

Ar is

Het is a 5- to 6-membered heteroaryl;

each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;

R 3 is H or F;

R 11 is H or —CH 3 ;

R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or a 4- to 6-membered heterocycle; and

R 22 is H, halogen or C 1 -C 2 alkyl; or

(l) Formula (XX):

or a pharmaceutically acceptable salt thereof, wherein:

L-Ar is

Ar is

each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;

R 3 is H or F;

R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;

R 22 is H, halogen or C 1 -C 2 alkyl;

R 25 is H, halogen, C 1 -C 4 alkyl or C 3 -C 5 cycloalkyl, wherein R 25 is optionally substituted with one or more halogen; or

(m) Formula (XI):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl) wherein:

the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and

when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;

each R 2 is independently H, halogen or C 1 -C 4 straight or branched alkyl;

R 3 is H, —OH, or halogen;

R 21 is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R 22 is H, halogen, C 1 -C 2 alkyl; and

R 351 is C 1 -C 2 alkyl or C 2 —O—(C 1 or C 2 alkyl).

20 . A method of reducing fibrotic gene expression, the method comprising administering to a subject in need thereof a fatty acid synthase inhibitor having a formula of:

(a) Formula (IX)

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl) wherein:

C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and

when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;

each R 2 is independently hydrogen, halogen or C 1 -C 4 straight or branched alkyl;

R 3 is H, —OH, or halogen;

R 21 is H, halogen, C 1 -C 4 straight or branched alkyl, C 3 -C 5 cycloalkyl wherein the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;

R 22 is H, halogen, or C 1 -C 2 alkyl;

R 24 is H, C 1 -C 4 straight or branched alkyl, —(C 1 -C 4 alkyl) t -OH, —(C 1 -C 4 alkyl) t -O t —(C 3 -C 5 cycloalkyl), or —(C 1 -C 4 alkyl) t -O t —(C 1 -C 4 straight or branched alkyl) wherein:

t is 0 or 1;

the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;

L 1 is CR 23 or N;

L 2 is CH or N;

at least one of L 1 or L 2 is N; and

R 23 is H or C 1 -C 4 straight or branched alkyl; or

(b) Formula (X):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl) wherein:

the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and

when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;

each R 2 is independently hydrogen, halogen or C 1 -C 4 straight or branched alkyl;

R 3 is H, —OH or halogen;

L 3 is C(R 6 ) 2 , O or NR 50 ;

each R 60 is independently H, —OH, —CN, —O t —(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl), or —C(O)—N(R 601 ) 2 wherein:

t is 0 or 1, and

the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;

each R 50 is independently H, —C(O)—O t —(C 1 -C 4 straight or branched alkyl), —C(O)—O t —(C 3 -C 5 cyclic alkyl), —C 3 -C 5 cyclic alkyl optionally containing an oxygen or nitrogen heteroatom, —C(O)—N(R 501 ) 2 , C 1 -C 4 straight or branched alkyl wherein:

t is 0 or 1, and

the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;

n is 1, 2 or 3;

m is 1 or 2;

R 21 is H, halogen, C 1 -C 4 straight or branched alkyl, C 3 -C 5 cycloalkyl wherein the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom

R 22 is H, halogen, C 1 -C 2 alkyl;

t is 0 or 1, and

the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;

s is 0, 1 or 2;

each R 601 and R 501 is independently H or C 1 -C 4 straight or branched alkyl; and

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl) wherein:

the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and

when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;

each R 2 is independently H, halogen or C 1 -C 4 straight or branched alkyl;

R 3 is H, —OH, or halogen;

R 21 is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R 22 is H, halogen, or C 1 -C 2 alkyl;

R 35 is —C(O)—R 351 , —C(O)—NHR 35 , —C(O)—O—R 35 or S(O) 2 R 351 ; and

R 351 is C 1 -C 6 straight or branched alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; or

(d) Formula (XII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;

R 3 is H or F;

R 11 is H or —CH 3 ;

R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;

R 22 is H, halogen, or C 1 -C 2 alkyl;

t is 0 or 1;

u is 0 or 1;

with the proviso that when u is 1, t is 1; and

each R 24 1 is independently H or C 1 -C 2 alkyl; and

R 25 is halogen, —CN, —(C 1 -C 4 alkyl)-CN, C 1 -C 2 alkyl or cyclopropyl; or

(e) Formula (XIII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;

R 3 is H or F;

R 11 is H or —CH 3 ;

R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;

R 22 is H, halogen or C 1 -C 2 alkyl; and

each R 24 and R 25 is independently H, halogen, —CN, —(C 1 -C 4 alkyl)-CN, C 1 -C 4 alkyl, —(C 1 -C 4 alkyl)-OH, —(C 1 -C 4 alkyl)-N(R 241 ) 2 , —(C 1 -C 4 alkyl) t -O u —(C 3 -C 5 cycloalkyl), —(C 1 -C 4 alkyl) t -O u -(4- to 6-membered heterocycle) or —(C 1 -C 4 alkyl) t -O—(C 1 -C 4 alkyl), wherein:

each t is independently 0 or 1;

each u is independently 0 or 1; and

each R 24 1 is independently H or C 1 -C 2 alkyl; or

(f) Formula (XIV):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;

R 3 is H or F;

R 11 is H or —CH 3 ;

R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;

R 22 is H, halogen, or C 1 -C 2 alkyl; and

each t is independently 0 or 1; and

each R 24 1 is independently H or C 1 -C 2 alkyl; or

(g) Formula (XV):

or pharmaceutically acceptable salts thereof, wherein:

L 3 is —CH 2 —, —CHR 50 —, —O—, —NR 50 —, —NC(O)R 50 — or —NC(O)OR 50 —, wherein R is C 1 -C 6 alkyl, C 3 -C 5 cycloalkyl, or 4- to 6-membered heterocycle;

n is 1, 2, or 3;

m is 1 or 2 with the proviso that n+m≥3;

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;

R 3 is H or F;

R 11 is H or —CH 3 ;

R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or a 4- to 6-membered heterocycle; and

R 22 is H, halogen, or C 1 -C 2 alkyl; or

(h) Formula (XVI):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

Het is a 5- to 6-membered heteroaryl;

each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;

R 3 is H or F;

R 11 is H or —CH 3 ;

R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;

R 22 is H, halogen or C 1 -C 2 alkyl; and

each of R 24 and R 25 is independently H, —C 1 -C 4 alkyl, or halogen; or

(i) Formula (XVII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

Het is a 5- to 6-membered heteroaryl;

each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;

R 3 is H or F;

R 11 is H or —CH 3 ;

R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;

R 22 is H, halogen or C 1 -C 2 alkyl; and

t is 0 or 1;

u is 0 or 1;

with the proviso that when u is 1, t is 1; and

R 241 is H or C 1 -C 2 alkyl; or

(j) Formula (XVIII):

or pharmaceutically acceptable salts thereof, wherein:

L-Ar is

Ar is

with the proviso that when L-Ar is

Ar is not

L 2 is —NHR 35 or —C(O)NHR 351 , wherein R 351 is C 1 -C 6 alkyl, C 3 -C 5 cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl;

Het is a 5- to 6-membered heteroaryl;

each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;

R 3 is H or F;

R 11 is H or —CH 3 ;

R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;

R 22 is H, halogen, or C 1 -C 2 alkyl; and

R 35 is —C(O)R 351 , —C(O)NHR 351 , C(O)OR 351 or S(O) 2 R 351 wherein R 351 is C 1 -C 6 alkyl, C 3 -C 5 cycloalkyl, 4- to 6-membered heterocycle, aryl or heteroaryl; or

(k) Formula (XIX):

or pharmaceutically acceptable salts thereof, wherein:

each W, X, Y and Z is independently —N— or —CR 26 — with the proviso that not more than 2 of W, X, Y and Z are —N—;

each R 26 is independently H, C 1 -C 4 alkyl, —O—(C 1 -C 4 alkyl), —N(R 27 ) 2 , —S(O) 2 —(C 1 -C 4 alkyl), or —C(O)—(C 1 -C 4 alkyl);

Ar is

Het is a 5- to 6-membered heteroaryl;

each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;

R 3 is H or F;

R 11 is H or —CH 3 ;

R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or a 4- to 6-membered heterocycle; and

R 22 is H, halogen or C 1 -C 2 alkyl; or

(l) Formula (XX):

or a pharmaceutically acceptable salt thereof, wherein:

L-Ar is

Ar is

each R 2 is independently hydrogen, halogen or C 1 -C 4 alkyl;

R 3 is H or F;

R 21 is H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 4- to 6-membered heterocycle;

R 22 is H, halogen or C 1 -C 2 alkyl;

R 25 is H, halogen, C 1 -C 4 alkyl or C 3 -C 5 cycloalkyl, wherein R 25 is optionally substituted with one or more halogen; or

(m) Formula (XI):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl) wherein:

the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and

when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;

each R 2 is independently H, halogen or C 1 -C 4 straight or branched alkyl;

R 3 is H, —OH, or halogen;

R 21 is cyclobutyl, azetidin-1-yl, or cyclopropyl;

R 22 is H, halogen, C 1 -C 2 alkyl; and

R 351 is C 1 -C 2 alkyl or C 2 —O—(C 1 or C 2 alkyl).

Assignments (2)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 14, 2021

From: BUCKLEY, DOUGLAS I.; DUKE, GREGORY; WAGMAN, ALLAN S.; EVANCHIK, MARC; MCDOWELL, ROBERT S.

To: 3-V BIOSCIENCES, INC.

Reel/Frame 056249/0606 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 14, 2021

From: 3-V BIOSCIENCES, INC.

To: SAGIMET BIOSCIENCES INC.

Reel/Frame 056306/0976 →