2-(benzothiazol-2-yl)-2-cyano-acetamide derivatives and their use as endothelial lipase inhibitors

Patent metadata

Field	Value
Publication number	US-10597370-B2
Application number	US-201716302158-A
Country	US
Kind code	B2
Filing date	Jun 5, 2017
Priority date	Jun 6, 2016
Publication date	Mar 24, 2020
Grant date	Mar 24, 2020

Abstract

The present invention provides compounds of Formula (I): as defined in the specification and compositions comprising any of such novel compounds. These compounds are endothelial lipase inhibitors which may be used as medicament.

First claim

What is claimed is:

1. A compound of Formula (I):

or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or a solvate thereof, wherein:
G is N or C;
R 1 is phenyl, a 5- or 6-membered heteroaryl, or a 5- or 6-membered non-aromatic heterocyclyl; wherein the heteroaryl or non-aromatic heterocyclyl each independently comprises one or more carbon atoms and 1 to 4 heteroatoms selected from N, NR a , O, and S(O) Z , and the phenyl, heteroaryl or non-aromatic heterocyclyl is each independently substituted with 0, 1, 2, or 3 R 6 ;
R 2 is, independently at each occurrence, selected from: halogen, OH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, NR b R c , NO 2 , CO 2 R d , and CONR b R c ;
R 3 is —(CH 2 ) Y —CONR e R 4 ;
R e is hydrogen, C 1-4 alkyl, or C 3-6 carbocyclyl;
R 4 is C 1-6 alkyl substituted with 0, 1, or 2 R 7 , —(CH 2 ) Q —(C 3-6 carbocyclyl substituted with 0, 1, or 2 R 7 ), or —(CH 2 ) Q -(4- to 6-membered heterocyclyl comprising one or more carbon atoms and 1 to 4 heteroatoms selected from N, NR a , O, and S(O) Z , wherein the heterocycle is substituted with 0, 1, or 2 R 7 ; or alternatively, R e and R 4 , taken together with the atoms to which they are attached, form a 5- or 6-membered azacyclyl comprising one or more carbon atoms and 1 to 4 heteroatoms selected from N, NR a , O, and S(O) Z , wherein the azacyclyl is substituted with 0, 1, or 2 R 5 ;
R 6 is, independently at each occurrence, selected from: OH, halogen, C 1-6 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, NR f R g , OPh, OBn, Ph, and —CONR h R i ; or alternatively, two R 6 , taken together with the atoms to which they are attached, form a 5- or 6-membered carbocyclyl, heteroaryl or non-aromatic heterocyclyl; wherein the heteroaryl or non-aromatic heterocyclyl each independently comprises one or more carbon atoms and 1 to 4 heteroatoms selected from N, NR a , O, and S(O) Z , and the carbocyclyl, heteroaryl or non-aromatic heterocyclyl is each independently substituted with 0, 1, 2, or 3 R 8 ;
R 5 , R 7 , R 8 , and R 9 are, independently at each occurrence, selected from: OH, halogen, C 1-6 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, NR j R k , OPh, OBn, Ph, and a 5- or 6-membered heteroaryl comprising one or more carbon atoms and 1 to 4 heteroatoms selected from N, NR a and O;
R a , R b , R c , R d , R e , R j , and R k are, independently at each occurrence, hydrogen, C 1-4 alkyl, or C 3-6 carbocyclyl;
R f and R g are independently hydrogen, C 1-4 alkyl, C 3-6 carbocyclyl, CO 2 R m , or CONR n R p ;
R h and R i are independently hydrogen, C 1-4 alkyl, C 3-6 carbocyclyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy; or alternatively, R h and R i , taken together with the atoms to which they are attached, form a 5- or 6-membered azacyclyl comprising one or more carbon atoms and 1 to 4 heteroatoms selected from N, NR a , O, and S(O) Z , wherein the azacyclyl is substituted with 0, 1, or 2 R 9 ;
R m , R n , and R p are independently hydrogen, C 1-4 alkyl, C 3-6 carbocyclyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, aryl, arylalkyl, or a 5- or 6-membered heteroaryl comprising one or more carbon atoms and 1 to 4 heteroatoms selected from N, NR a and O;
X is 0, 1, 2, or 3;
Y is 1, 2, or 3;
Z is, independently at each occurrence, 0, 1, or 2; and
Q is, independently at each occurrence, 0, 1, 2 or 3.

2. The compound according to claim 1 , wherein the compound is represented by Formula (IIa) or (IIb):

wherein:
G is N or C;
m is 0, 1, or 2; and
R 2 is, independently at each occurrence, selected from: halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy.

3. The compound according to claim 1 , wherein R 1 is phenyl, pyridinyl, pyrrolidinonyl, or pyridinonyl, each of which is independently substituted with 0, 1, 2, or 3 R 6 .

4. The compound according to claim 1 , wherein
R 3 is —(CH 2 ) Y —CONH(C 3-6 carbocyclyl substituted with 0, 1, or 2 R 7 ), —(CH 2 ) Y —CONH(4- to 6-membered heterocyclyl substituted with 0, 1, or 2 R 7 ), or —(CH 2 ) Y —CONR e R 4 ;
Y is 1 or 2; and
R e and R 4 , taken together with the atoms to which they are attached, form a 5- or 6-membered azacyclyl, which is substituted with 0, 1, or 2 R 5 .

5. The compound according to claim 4 , wherein
R 3 is —(CH 2 ) Y —CONH(C 3-6 cycloalkyl substituted with 0, 1, or 2 R 7 ), —(CH 2 ) Y —CONH(4- to 6-membered heterocycloalkyl substituted with 0, 1, or 2 R 7 ), or —(CH 2 ) Y —CONR e R 4 ;
Y is 1; and
R e and R 4 , taken together with the atoms to which they are attached, form azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl, each of which is substituted with 0, 1, or 2 R 5 .

6. The compound according to claim 1 , wherein
R 6 is not present or R 6 is OH, halogen, C 1-6 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, NH 2 , NHR g , and —CONR h R i ;
R g is C 1-4 alkyl, CO 2 R m , CONHR p , or CONR n R p ;
R h and R i are independently hydrogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy; or alternatively, R h and R i , taken together with the atoms to which they are attached, form a 5- or 6-membered azacyclyl comprising one or more carbon atoms and 1 to 4 heteroatoms selected from N, NR a , O, and S(O) Z , wherein the azacyclyl is substituted with 0, 1, or 2 R 9 ; and
R m , R n , and R p are independently C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, or C 1-4 haloalkoxy.

7. The compound according to claim 5 , wherein R 3 is —(CH 2 ) Y —CONHR 4 ; and R 4 is cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl, each of which is substituted with 0, 1, or 2 R 7 .

8. The compound according to claim 6 , wherein R h and R i are, taken together with the atoms to which they are attached, form azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl, each of which is independently substituted with 0, 1, or 2 R 9 .

9. The compound according to claim 1 , wherein the compound is represented by Formula (IIIa) or (IIIb):

wherein:
R 1 is phenyl, pyridinyl, pyrrolidinonyl, or pyridinonyl; wherein the phenyl, pyridinyl, or pyridinonyl is each independently substituted with 0 or 1 R 6 ;
R 2 is, independently at each occurrence, selected from: halogen, OH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, NH 2 , NH(C 1-4 alkyl), NO 2 , CO 2 H, CO 2 (C 1-4 alkyl), CONH 2 , and CONH(C 1-4 alkyl);
R 3 is —(CH 2 ) Y —CONH(C 3-6 carbocyclyl substituted with 0, 1, or 2 R 7 ), —(CH 2 ) Y —CONH(4- to 6-membered heterocyclyl substituted with 0, 1, or 2 R 7 ), or —(CH 2 ) Y —CONR e R 4 ;
R e and R 4 , taken together with the atoms to which they are attached, form a 5- or 6-membered azacyclyl comprising one or more carbon atoms and 1 to 4 heteroatoms selected from N, NR a , O, and S(O) Z , wherein the azacyclyl is substituted with 0, 1, or 2 R 5 ;
R 6 is, independently at each occurrence, selected from: OH, halogen, C 1-6 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, NH 2 , NHR g , OPh, OBn, Ph, —CONH 2 ; —CONHR i ; and —CONR h R i ; or alternatively, two R 6 , taken together with the atoms to which they are attached, form a 5- or 6-membered heterocyclyl; wherein the heterocyclyl comprises one or more carbon atoms and 1 to 4 heteroatoms select

Assignees

• Bristol Myers Squibb Co

Inventors

• Finlay Heather
• Meng Wei

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title