US2022354848A9PendingUtilityA9
Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase
Est. expiryNov 20, 2038(~12.3 yrs left)· nominal 20-yr term from priority
C07D 213/70A61K 31/4418C07D 409/04A61P 13/12C07D 239/56A61P 25/28A61P 3/00C07D 409/14C07D 401/12C07D 213/85A61K 31/506A61P 1/16A61K 31/4436C07D 409/12A61K 31/513A61P 29/00A61K 31/5377C07D 413/12C07D 413/14A61P 39/06A61P 25/00C07D 409/06C07D 403/12
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Claims
Abstract
The present disclosure discloses compounds capable of modulating the activity of α-amino-β-carboxymuconic acid semialdehyde decarboxylase (ACMSD), which are useful for the prevention and/or the treatment of diseases and disorders associated with defects in NAD+ biosynthesis, e.g., metabolic disorders, neurodegenerative diseases, chronic inflammatory diseases, kidney diseases, and diseases associated with ageing. The present application also discloses pharmaceutical compositions comprising said compounds and the use of such compounds as a medicament.
Claims
exact text as granted — not AI-modified1 . A compound represented by Formula (II):
or a pharmaceutically acceptable salt or tautomer thereof, wherein:
X is H, S, SR 2 , NR 2 , NR 2 R 2′ , O, OH, OR h , F, Br, or Cl ;
W is N or C;
(i) when W is N, then: L is —(C(R 5 ) 2 ) m CH═CH(C(R 5 ) 2 ) p —,
—(C(R 5 ) 2 ) m Y 1 (C(R 5 ) 2 ) p —, —(C(R 5 ) 2 ) m Y 1 (C(R 5 ) 2 ) p -cyclopropyl-, —(C(R 5 ) 2 ) m Y 1 CH═CH—, —(C(R 5 ) 2 ) m NR 3 C═(O)(C(R 5 ) 2 ) p —, —(C(R 5 ) 2 ) m phenyl(C(R 5 ) 2 ) p —, —(C(R 5 ) 2 ) m pyridinyl(C(R 5 ) 2 ) p —, or —(C(R 5 ) 2 ) m thiophenyl(C(R 5 ) 2 ) p —;
(ii) when W is C, then: L is —(C(R 5 ) 2 ) m CH═CH(C(R 5 ) 2 ) p —, —(C(R 5 ) 2 ) o —, —(C(R 5 ) 2 ) m Y 1 (C(R 5 ) 2 ) p —,
—(C(R 5 ) 2 ) m Y 1 CH═CH—, —(C(R 5 ) 2 ) m C═(O)(CH 2 ) p —, —(C(R 5 ) 2 ) m C═(O)O(C(R 5 ) 2 ) p —, —(C(R 5 ) 2 ) m C═(O)NR 3 (C(R 5 ) 2 ) p —, —(C(R 5 ) 2 ) m NR 3 C═(O)(C(R 5 ) 2 ) p —, —(C(R 5 ) 2 ) m phenyl(C(R 5 ) 2 ) p —, —(C(R 5 ) 2 ) m pyridinyl(C(R 5 ) 2 ) p —, or —(C(R 5 ) 2 ) m thiophenyl(C(R 5 ) 2 ) p —;
Y 1 is O, NR 4 , or S(O) q ;
each Y 2 is independently O, NH or S;
R 1 is absent, C 6 -C 10 arylene, heteroarylene, or C 3 -C 8 cycloalkylene, wherein the heteroarylene comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O and S, and wherein the C 6 -C 10 arylene, heteroarylene, and C 3 -C 8 cycloalkylene are optionally substituted with one to two R e ;
R 2 is H or C 1 -C 4 alkyl;
R 2′ is H, C 1 -C 4 alkyl, or C 3 -C 7 cycloalkyl; or
R 2 and R 2′ together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycloalkyl ring comprising 1-3 additional heteroatoms selected from N, O and S;
R 3 is H or C 1 -C 4 alkyl;
R 4 is H or C 1 -C 4 alkyl;
each R 5 is independently at each occurrence H or C 1 -C 4 alkyl;
each R 6 is independently at each occurrence H or C 1 -C 4 alkyl;
R 7 is H, A, B, or C;
A is —(C(R 6 ) 2 ) r CO 2 R x , —Y 2 (C(R 6 ) 2 ) r CO 2 R x , —(C(R 6 ) 2 ) r tetrazole, —(C(R 6 ) 2 ) r oxadiazolone, —(C(R 6 ) 2 ) r tetrazolone, —(C(R 6 ) 2 ) r thiadiazolol, —(C(R 6 ) 2 ) r isoxazol-3-ol, —(C(R 6 ) 2 ) r P(O)(OH)OR x , —(C(R 6 ) 2 ) r S(O) 2 OH, —(C(R 6 ) 2 ) r C(O)NHCN, or —(C(R 6 ) 2 ) r C(O)NHS(O) 2 alkyl, wherein —(C(R 6 ) 2 ) r tetrazole, —(C(R 6 ) 2 ) r oxadiazolone, —(C(R 6 ) 2 ) r tetrazolone, —(C(R 6 ) 2 ) r thiadiazolol, —(C(R 6 ) 2 ) r isoxazol-3-ol are optionally substituted with C 1 -C 6 alkyl,
B is —(C(R 6 ) 2 ) r S(O) 2 OC 1 -C 4 alkyl, —O(C(R 6 ) 2 ) r S(O) 2 OC 1 -C 4 alkyl, —Y 2 (C(R 6 ) 2 ) r C(O)NR g R g′ , —Y 2 (C(R 6 ) 2 ) r S(O) 2 NR g R g′ , —(C(R 6 ) 2 ) r C(O)NR g R g′ , —(C(R 6 ) 2 ) r S(O) 2 NR g R g′ , —(C(R 6 ) 2 ) r C(O)NHS(O) 2 NR g R g′ , —(C(R 6 ) 2 ) r CO 2 R r , —(C(R 6 ) 2 ) r NH 2 CO 2 R x , —(C(R 6 ) 2 ) r P(O)(OR x ) 2 , —O(C(R 6 ) 2 ) r P(O)(OR x ) 2 , —(C(R 6 ) 2 ) r S(O) 2 OH, —O(C(R 6 ) 2 ) r S(O) 2 OH, —(C(R 6 ) 2 ) r P(O) 2 OR x , or —O(C(R 6 ) 2 ) r P(O) 2 OR x ,
C is —(CH 2 ) r CN, —(CH 2 ) s OH, halogen, —(C(R)) 2 ) r C 6 -C 10 aryl, —(C(R 6 ) 2 ) r S—C 6 -C 10 aryl, —(C(R 6 ) 2 ) r heteroaryl, —O(C(R 6 ) 2 ) r heteroaryl, —O(C(R 6 ) 2 ) r heterocycloalkyl, —O(C(R 6 ) 2 ) r OH, —OR y , —(C(R 6 ) 2 ) r C(O)NHCN, —CH═CHCO 2 R x , or —(C(R 6 ) 2 ) r C(O)NHS(O) 2 C 1 -C 4 alkyl, wherein the aryl and heteroaryl are substituted with one to three substituents each independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halogen, and OH, and wherein the heterocycloalkyl is substituted with one to two ═O or ═S;
R c is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halogen, —CN, —OR x , or —CO 2 R x ;
R d is methyl, CF 3 , CR f F 2 , —(C(R 6 ) 2 ) t C 6 -C 10 aryl, —(C(R 6 ) 2 ) t -5- or 6-membered heteroaryl, —(C(R 6 ) 2 ) t -5- or 6-membered cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered cycloalkyl;
each R e is independently at each occurrence C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl, —NHR z , —OH, or —CN;
R f is absent, H, or methyl;
R g is H, C 1 -C 6 alkyl, OH, —S(O) 2 (C 1 -C 6 alkyl), or S(O) 2 N(C 1 -C 6 alkyl) 2 ;
R g′ is H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from N, O and S, C 6 -C 10 aryl, or 5- to 7-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein the alkyl is optionally substituted with one or more substituents independently selected from halogen and —OH, and wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents independently selected from C 1 -C 6 alkyl, halogen, and —OH;
R h is H, C 1 -C 4 alkyl, or 3- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from N, O and S, wherein the alkyl is optionally substituted with one or more substituents each independently selected from NH 2 , C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, and C(O)NH 2 ; and wherein the heterocycloalkyl is optionally substituted with one or more substituents each independently selected from C 1 -C 6 alkyl and C 1 -C 6 haloalkyl;
R i is (i) —(CH 2 ) s OC(O)C 1 -C 6 alkyl, wherein the alkyl is substituted with one or more NH 2 ;
(ii) (CH 2 CH 2 O) n CH 2 CH 2 OH; or (iii) C 1 -C 6 alkyl substituted with one or more substituents each independently selected from OH and 4- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, or S;
R j is absent, H, C 1 -C 6 alkyl, or —CN;
each R x is independently at each occurrence H, C 1 -C 6 alkyl, or C 6 -C 10 aryl;
each R y and R z is independently H, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
each m, p, q, r, and t is independently 0, 1 or 2;
n is 0, 1, 2, or 3;
s is 1 or 2;
is 0, 1, 2, 3, or 4; and
represents a single bond or a double bond; and
provided that
when X is O; R f is H; W is C; R j is —CN; L is —SCH 2 —; R 1 is phenylene or pyridine; then R 7 is not —COOH;
when X is O; R f is H; W is C; R i is —CN; L is —SCH 2 —; R 1 is phenylene or pyridine; and R 7 is tetrazole; then R c is not H;
when X is O; R f is H; W is C; R i is —CN; L is —S—C(R 5 ) 2 or —SCH 2 CH 2 —; R 1 is absent; then R 7 is not COOH or tetrazole;
when X is O, R f is H; W is N; R i is absent; R d is methyl, optionally substituted 5- to 10-membered aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered cycloalkyl; L is —SCH 2 — or —OCH 2 —; and R 1 is phenylene; then R 7 is not —COOH, —CH 2 COOH,
and
when X is O, R f is H, W is N, R i is absent, L is —NHCH 2 —, —CH 2 NH—, or —NH—C(O)—, and R 1 is phenylene, then R d is not phenyl.
2 . A compound represented by Formula (I):
or a pharmaceutically acceptable salt or tautomer thereof,
wherein:
X is H, S, SR 2 , NR 2 , NR 2 R 2′ , O, OH, OR h , F, Br, or Cl ;
W is N or C;
(i) when W is N, then:
L is —(C(R 5 ) 2 ) m CH═CH(C(R 5 ) 2 ) p —,
—(C(R 5 ) 2 ) m Y 1 (C(R 5 ) 2 ) p —, —(C(R 5 ) 2 ) m Y 1 (C(R 5 ) 2 ) p -cyclopropyl-, —(C(R 5 ) 2 ) m Y 1 CH═CH—, —(C(R 5 ) 2 ) m NR 3 C═(O)(C(R 5 ) 2 ) p —, —(C(R 5 ) 2 ) m phenyl(C(R 5 ) 2 ) p —, —(C(R 5 ) 2 ) m pyridinyl(C(R 5 ) 2 ) p —, or —(C(R 5 ) 2 ) m thiophenyl(C(R 5 ) 2 ) p —;
(ii) when W is C, then:
L is —(C(R 5 ) 2 ) m CH═CH(C(R 5 ) 2 ) p —, —(C(R 5 ) 2 ) o —, —(C(R 5 ) 2 ) m Y 1 (C(R 5 ) 2 ) p —,
—(C(R 5 ) 2 ) m Y 1 CH═CH—, —(C(R 5 ) 2 ) m C═(O)(CH 2 ) p —, —(C(R 5 ) 2 ) m C═(O)O(C(R 5 ) 2 ) p —, —(C(R 5 ) 2 ) m C═(O)NR 3 (C(R 5 ) 2 ) p —, —(C(R 5 ) 2 ) m NR 3 C═(O)(C(R 5 ) 2 ) p —, —(C(R 5 ) 2 ) m phenyl(C(R 5 ) 2 ) p —, —(C(R 5 ) 2 ) m pyridinyl(C(R 5 ) 2 ) p —, or —(C(R 5 ) 2 ) m thiophenyl(C(R 5 ) 2 ) p —;
Y 1 is O, NR 4 , or S(O) q ;
each Y 2 is independently O, NH or S;
R 1 is absent or C 6 -C 10 arylene or heteroarylene, wherein the heteroarylene comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O and S, and wherein the C 6 -C 10 arylene or heteroarylene are optionally substituted with one to two R e ;
R 2 is H or C 1 -C 4 alkyl;
R 2′ is H, C 1 -C 4 alkyl, or C 3 -C 7 cycloalkyl; or
R 2 and R 2′ together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocycloalkyl ring comprising 1-3 additional heteroatoms selected from N, O and S;
R 3 is H or C 1 -C 4 alkyl;
R 4 is H or C 1 -C 4 alkyl;
each R s is independently at each occurrence H or C 1 -C 4 alkyl;
each R 6 is independently at each occurrence H or C 1 -C 4 alkyl;
R 7 is H, A, B, or C;
A is —(C(R 6 ) 2 ) r CO 2 R x , —Y 2 (C(R 6 ) 2 ) r CO 2 R x , —(CH 2 ) r tetrazole, —(CH 2 ) r oxadiazolone, —(CH 2 ) r tetrazolone, —(CH 2 ) r thiadiazolol, —(CH 2 ) r isoxazol-3-ol, —(CH 2 ) r P(O)(OH)OR x , —(CH 2 ) r S(O) 2 OH, —(CH 2 ) r C(O)NHCN, or —(CH 2 ) r C(O)NHS(O) 2 alkyl, wherein —(CH 2 ) r tetrazole, —(CH 2 ) r oxadiazolone, —(CH 2 ) r tetrazolone, —(CH 2 ) r thiadiazolol, —(CH 2 ) r isoxazol-3-ol are optionally substituted with C 1 -C 6 alkyl,
B is —(C(R 6 ) 2 ) r S(O) 2 OC 1 -C 4 alkyl, —O(C(R 6 ) 2 ) r S(O) 2 OC 1 -C 4 alkyl, —Y 2 (C(R 6 ) 2 ) r C(O)NR g R g′ , —Y 2 (C(R 6 ) 2 ) r S(O) 2 NR g R g′ , —(CH 2 ) r C(O)NR g R g′ , —(CH 2 ) r S(O) 2 NR g R g′ , —(CH 2 ) r C(O)NHS(O) 2 NR g R g′ , —(C(R 6 ) 2 ) r CO 2 R i , —(C(R 6 ) 2 ) r NH 2 CO 2 R x , —(C(R 6 ) 2 ) r P(O)(OR x ) 2 , —O(C(R 6 ) 2 ) r P(O)(OR x ) 2 , —(C(R 6 ) 2 ) r S(O) 2 OH, —O(C(R 6 ) 2 ) r S(O) 2 OH, —(C(R 6 ) 2 ) r P(O) 2 OR x , or —O(C(R 6 ) 2 ) r P(O) 2 OR x ,
C is —(CH 2 ) r CN, —(CH 2 ) s OH, halogen, —(C(R 6 ) 2 ) r C 6 -C 10 aryl, —(C(R 6 ) 2 ) r S—C 6 -C 10 aryl, —(C(R 6 ) 2 ) r heteroaryl, —O(C(R 6 ) 2 ) r heteroaryl, —O(C(R 6 ) 2 ) r heterocycloalkyl, —O(C(R 6 ) 2 ) r OH, —OR y , —(C(R 6 ) 2 ) r C(O)NHCN, —CH═CHCO 2 R x , or —(C(R 6 ) 2 ) r C(O)NHS(O) 2 C 1 -C 4 alkyl, wherein the aryl and heteroaryl are substituted with one to three substituents each independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halogen, and OH, and wherein the heterocycloalkyl is substituted with one to two ═O or ═S;
R c is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halogen, —CN, —OR x , or —CO 2 R x ;
R d is methyl, CF 3 , CR f F 2 , —(C(R 6 ) 2 ) t C 6 -C 10 aryl, —(C(R 6 ) 2 ) t -5- or 6-membered heteroaryl, —(C(R 6 ) 2 ) t -5- or 6-membered cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered cycloalkyl;
each R e is independently at each occurrence C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl, —NHR z , —OH, or —CN;
R f is absent, H, or methyl;
R g is H, C 1 -C 6 alkyl, OH, —S(O) 2 (C 1 -C 6 alkyl), or S(O) 2 N(C 1 -C 6 alkyl) 2 ;
R g′ is H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, 4- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from N, O and S, C 6 -C 10 aryl, or 5- to 7-membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S, wherein the alkyl is optionally substituted with one or more substituents independently selected from halogen and —OH, and wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents independently selected from C 1 -C 6 alkyl, halogen, and —OH;
R h is H, C 1 -C 4 alkyl, or 3- to 7-membered heterocycloalkyl ring comprising 1-3 heteroatoms selected from N, O and S, wherein the alkyl is optionally substituted with one or more substituents each independently selected from NH 2 , C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, and C(O)NH 2 ; and wherein the heterocycloalkyl is optionally substituted with one or more substituents each independently selected from C 1 -C 6 alkyl and C 1 -C 6 haloalkyl;
R i is (i) —(CH 2 ) s OC(O)C 1 -C 6 alkyl, wherein the alkyl is substituted with one or more NH 2 ; (ii) (CH 2 CH 2 O) n CH 2 CH 2 OH; or (iii) C 1 -C 6 alkyl substituted with one or more substituents each independently selected from OH and 4- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, or S;
R i is absent, H, C 1 -C 6 alkyl, or —CN;
each R x is independently at each occurrence H, C 1 -C 6 alkyl, or C 6 -C 10 aryl;
each R y and R z is independently H, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
each m, p, q, r, and t is independently 0, 1 or 2;
n is 0, 1, 2, or 3;
s is 1 or 2;
is 0, 1, 2, 3, or 4; and
represents a single bond or a double bond; and
provided that
when X is O; R f is H; W is C; R i is —CN; L is —SCH 2 —; R 1 is phenylene or pyridine; then R 7 is not —COOH;
when X is O; R f is H; W is C; R i is —CN; L is —SCH 2 —; R 1 is phenylene or pyridine; and R 7 is tetrazole; then R c is not H;
when X is O; R f is H; W is C; R i is —CN; L is —S—C(R 5 ) 2 or —SCH 2 CH 2 —; R 1 is absent; then R 7 is not COOH or tetrazole;
when X is O, R f is H; W is N; R i is absent; R d is methyl, optionally substituted 5- to 10-membered aryl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered cycloalkyl; L is —SCH 2 — or —OCH 2 —; and R 1 is phenylene; then R 7 is not —COOH, —CH 2 COOH,
and
when X is O, R f is H, W is N, R j is absent, L is —NHCH 2 —, —CH 2 NH—, or —NH—C(O)—, and R 1 is phenylene, then R d is not phenyl.
3 . The compound of claim 1 , wherein X is O, OH, OR h , F, Br, or Cl.
4 . The compound of claim 1 , wherein X is H, S, SR 2 , NR 2 , or NR 2 R 2′ .
5 . The compound of claim 1 , wherein R f is absent.
6 . The compound of claim 1 , wherein R f is H or methyl.
7 . The compound of claim 1 , wherein W is N.
8 . The compound of claim 7 , wherein R j is absent.
9 . The compound of claim 1 , wherein W is C.
10 . The compound of claim 9 , wherein R j is H, C 1 -C 6 alkyl, or —CN.
11 . The compound of claim 9 , wherein R j is —CN.
12 . The compound of claim 1 , wherein R c is C 1 -C 6 alkyl, —CN, or halogen.
13 . The compound of claim 1 , wherein R c is —CN or halogen.
14 . The compound of claim 1 , wherein R c is —CN.
15 . The compound of claim 1 , wherein R d is methyl.
16 . The compound of claim 1 , wherein R d is optionally substituted 5- to 10-membered aryl.
17 . The compound of claim 1 , wherein R d is optionally substituted 5- or 6-membered heteroaryl.
18 . The compound of claim 1 , wherein R d is optionally substituted 5- or 6-membered cycloalkyl.
19 . The compound of claim 1 , wherein R d is methyl, cyclohexyl, pyridinyl, thiazolyl, phenyl, or thienyl.
20 . The compound of claim 1 , wherein R d is methyl, cyclohexyl, pyridinyl, thiazolyl, thienyl, or optionally substituted phenyl.
21 . The compound of claim 1 , wherein R d is methyl.
22 . The compound of claim 1 , wherein R d is —CF 3 .
23 . The compound of claim 1 , wherein R d is CR f F 2 .
24 . The compound of claim 1 , wherein R d is —(C(R 6 ) 2 ) r C 6 -C 10 aryl, —(C(R 6 ) 2 ) r -5- or 6-membered heteroaryl, —(C(R 6 ) 2 ) r -5- or 6-membered cycloalkyl.
25 . The compound of claim 1 , wherein R d is —(C(R 6 ) 2 ) r C 6 -C 10 aryl.
26 . The compound of claim 1 , wherein L is —(C(R 5 ) 2 ) m Y 1 (C(R 5 ) 2 ) p —.
27 . The compound of claim 26 , wherein Y i is S.
28 . The compound of claim 1 , wherein L is —(C(R 5 ) 2 ) m NR 3 C═(O)(C(R 5 ) 2 ) p — or —(C(R 5 ) 2 ) m Y 1 (C(R 5 ) 2 ) p -cyclopropyl-.
29 . The compound of claim 1 , wherein R 1 is C 6 -C 10 arylene.
30 . The compound of claim 1 , wherein R 1 is heteroarylene.
31 . The compound of claim 1 , wherein R 1 is absent.
32 . The compound of claim 1 , wherein R 7 is A.
33 . The compound of claim 32 , wherein A is —(C(R 6 ) 2 ) r CO 2 R x or —(CH 2 ) r tetrazole, wherein the —(CH 2 ) r tetrazole is optionally substituted with C 1 -C 6 alkyl.
34 . The compound of claim 1 , wherein R 7 is B.
35 . The compound of claim 32 , wherein B is —(CH 2 ) r C(O)NR g R g′ , or —(CH 2 ) r S(O) 2 NR g R g′ ,
36 . The compound of claim 1 , wherein R 7 is C.
37 . The compound of claim 32 , wherein C is —(CH 2 ) r CN, —(CH 2 ) s OH, or —(C(R 6 ) 2 ) r C 6 -C 10 aryl, wherein the aryl is substituted with one to three substituents each independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halogen, and OH.
38 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, selected from the group consisting of:
Cpd
No.
Structure
I-1
I-2
I-3
I-4
I-5
I-6
I-7
I-8
I-9
I-10
I-11
I-12
I-13
I-14
I-15
I-16
I-17
I-18
I-19
I-20
I-21
I-22
I-23
I-24
I-25
I-26
I-27
I-28
I-29
I-30
I-31
I-32
I-33
I-34
I-35
I-36
39 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, selected from the group consisting of:
40 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, selected from the group consisting of:
41 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one of a pharmaceutically acceptable carrier, diluent, or excipient.
42 . The pharmaceutical composition according to claim 41 , which comprises one or more further therapeutic agents.
43 . A method of treating, preventing, or reducing the risk of a disease or disorder inhibited by α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) comprising administering to the subject suffering from or susceptible to developing the disease or disorder a therapeutically effective amount of one or more compounds of any-ene claim 1 , or a pharmaceutically acceptable salt thereof.
44 . A method of treating, preventing, or reducing the risk of a disease or disorder associated with reduced nicotinamide adenine dinucleotide (NAD + ) levels comprising administering to the subject suffering from or susceptible to developing a disease or disorder associated with reduced NAD + levels a therapeutically effective amount of one or more compounds of claim 1 , or a pharmaceutically acceptable salt thereof.
45 . The method of claim 44 , wherein the disease is chronic liver disease selected from primary biliary cirrhosis (PBC), cerebrotendinous xanthomatosis (CTX), primary sclerosing cholangitis (PSC), drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver transplant associated graft versus host disease, living donor transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren's syndrome, Sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, and alpha 1-antitrypsin deficiency.
46 . A method of treating a disorder associated with mitochondrial dysfunction comprising administering to the subject suffering from or susceptible to developing a metabolic disorder a therapeutically effective amount of one or more compounds of claim 1 , or a pharmaceutically acceptable salt thereof, that increases intracellular nicotinamide adenine dinucleotide (NAD + ).
47 . The method of claim 46 , wherein said disorder associated with mitochondrial dysfunction is an inherited mitochondrial disease, a common metabolic disorder, a neurodegenerative disease, an aging related disorder, a kidney disorder, or a chronic inflammatory disease.
48 . The method of claim 47 , wherein the common metabolic disorder is obesity or type II diabetes.
49 . A method of promoting oxidative metabolism comprising administering to the subject suffering from or susceptible to developing a metabolic disorder a therapeutically effective amount of one or more compounds of claim 1 , or a pharmaceutically acceptable salt thereof, that increases intracellular nicotinamide adenine dinucleotide (NAD + ).
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