Indazole-carboxamide compounds

1. A compound of formula (I):

wherein:

R 1 is hydrogen, halo, hydroxy, C 1-4 alkyl, or C 1-4 alkoxy;

R 2 is C 3-4 alkyl, or C 3-6 cycloalkyl;

R 3 is hydroxy, C 1-3 alkoxy, hydroxy-substituted C 1-4 alkyl, or —OC(O)NR a R b ;

R 4 is hydrogen or C 1-4 alkyl;

W is selected from

(a) Y, wherein Y is selected from —N(R 8a )C(O)R 9 , —N(R 8a )S(O) 2 R 10 , —N(R 8a )C(O)OR 12 , —N(R 8a )C(O)NR 13 R 14 , and —N(R 8a )S(O) 2 NR 13 R 14 ; and

(b) a moiety of formula (b):

 wherein:

X is selected from —N(R 8 )C(O)R 9 , —N(R 8 )S(O) 2 R 10 , —S(R 11 )O 2 , —N(R 8 )C(O)OR 12 , —N(R 8 )C(O)NR 13 R 14 , —N(R 8 )S(O) 2 NR 13 R 14 , —C(O)NR 13 R 14 , —OC(O)NR 13 R 14 , —C(O)OR 12 , —OR 15 , —NR 8 R 16 , cyano, —SR 15 , CF 3 , pyridinyl, pyrrolyl, pyrimidinyl, thiomorpholinyl, thiazolidinyl, 1,1-dioxo isothiazolidinyl, imidazolyl, indolyl, tetrahydrofuranyl, pyrrolidinyl and piperidinyl, wherein pyrrolidinyl is optionally substituted with oxo and piperidinyl is optionally substituted with 1 to 3 halo;

R 5 is hydrogen or C 1-4 alkyl, wherein C 1-4 alkyl is optionally substituted with hydroxy, C 1-3 alkoxy, or cyano;

R 6 and R 7 at each occurrence are independently selected from hydrogen, hydroxy, halo, cyano, and C 1-4 alkyl, wherein C 1-4 alkyl is optionally substituted with 1 to 2 substituents selected from hydroxy, C 1-3 alkoxy, halo, and cyano;

R 8 and R 8a are hydrogen or C 1-4 alkyl;

or R 5 and R 8 , R 5 and R 6 , or R 6 and R 8 taken together form C 2-5 alkylenyl, wherein C 2-5 alkylenyl is optionally substituted with hydroxy, halo, hydroxy-substituted C 1-3 alkyl, or C 1-3 alkoxy;

or R 5 and R 6 taken together form —(CH 2 ) q —Q—(CH 2 ) q , wherein Q is oxygen or sulfur and q is independently 0, 1, or 2;

or R 7 and X taken together form —NHC(O)NHC(O)— or —C(O)NHC(O)NH—;

R 9 is selected from hydrogen, furanyl, tetrahydrofuranyl, pyridinyl, or C 1-4 alkyl, wherein C 1-4 alkyl is optionally substituted with hydroxy or with from 1 to 3 halo;

R 10 is selected from hydrogen, C 1-4 alkyl, pyridinyl, and imidazolyl, wherein C 1-4 alkyl is optionally substituted with —S(O) 2 R c , C 3-6 cycloalkyl, or with from 1 to 3 halo, and imidazolyl is optionally substituted with C 1-3 alkyl;

or R 8 and R 10 taken together form C 3 alkylenyl;

R 11 is —NR a R b , or C 1-4 alkyl, where C 1-4 alkyl is optionally substituted with from 1 to 3 halo;

or R 5 and R 11 or R 6 and R 11 taken together form C 2-5 alkylenyl;

R 12 is C 1-4 alkyl;

R 13 and R 14 are independently hydrogen or C 1-4 alkyl;

R 15 is hydrogen or C 1-4 alkyl, wherein C 1-4 alkyl is optionally substituted with hydroxy;

or when X is —SR 15 , R 5 and R 15 taken together form C 1-4 alkylenyl;

R 16 is —(CH 2 ) r —R 17 , wherein r is 0, 1, 2, or 3; and R 17 is selected from hydrogen, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, —C(O)NR a R b , —C(O)-morpholinyl, pyridinyl, pyrrolyl, pyrimidinyl, morpholinyl, and tetrahydrofuranyl, wherein C 1-3 alkoxy is optionally substituted with hydroxy; provided that when r is 0, R 17 is selected from hydrogen, C 1-3 alkyl, pyridinyl, and pyrimidinyl; and when r is 1, R 17 is hydrogen or R 17 forms a carbon-carbon bond with the —(CH 2 ) r — carbon atom;

R 18 is —C(O)O—C 1-3 alkyl, —S(O) 2 —C 1-3 alkyl, or —C(O)—C 1-3 alkyl;

R a , R b , and R c are independently hydrogen or C 1-3 alkyl;

a is 1; and

n is an integer of 1, 2, 3, 4, or 5; provided that when n is 1, X is —SR 15 , or X forms a carbon-carbon bond with the carbon atom bearing the substituents R 6 and R 7 ;

or a pharmaceutically-acceptable salt or stereoisomer thereof.

2. The compound of claim 1 wherein R 1 is hydrogen or halo, R 2 is isopropyl or C 4-5 cycloalkyl, and R 4 is hydrogen.

3. The compound of claim 2 wherein R 3 is hydroxy, methoxy, hydroxymethyl, —OC(O)NHCH 3 , or —OC(O)N(CH 3 ) 2 —.

4. The compound of claim 1 , which is a compound of formula (I-a):

wherein:

R 1 is hydrogen, halo or C 1-4 alkyl;

R 2 is isopropyl or C 4-5 cycloalkyl;

R 3 is hydroxy, C 1-3 alkoxy, or OC(O)NR a R b ;

W is selected from

(a) Y, wherein Y is selected from —N(R 8a )C(O)R 9 , —N(R 8a )S(O) 2 R 10 , —N(R 8a )C(O)OR 12 , —N(R 8a )C(O)NR 13 R 14 , and —N(R 8a )S(O) 2 NR 13 R 14 ; and

(b) a moiety of formula (b):

wherein

X is selected from —N(R 8 )C(O)R 9 , —N(R 8 )S(O) 2 R 10 , —S(R 11 )O 2 , —N(R 8 )C(O)OR 12 , —N(R 8 )C(O)NR 13 R 14 , —N(R 8 )S(O) 2 NR 13 R 14 , —C(O)NR 13 R 14 , —OC(O)NR 13 R 14 , —C(O)OR 12 , —OR 15 , —NR 8 R 16 , cyano, —SR 15 , CF 3 , pyridinyl, pyrrolyl, 1,1-dioxoisothiazolidinyl, imidazolyl, and pyrrolidinyl, wherein pyrrolidinyl is optionally substituted with oxo;

R 5 is hydrogen, C 1-3 alkyl, or C 1-3 alkyl substituted at the terminal position with hydroxy;

R 6 and R 7 at each occurrence are independently hydrogen, hydroxy, halo or cyano;

R 8 and R 8a are hydrogen or C 1-3 alkyl;

or R 5 and R 8 or R 5 and R 6 together form a C 2-5 alkylene;

R 9 is hydrogen, tetrahydrofuranyl, pyridinyl, or C 1-3 alkyl;

R 10 is C 1-3 alkyl, wherein C 1-3 alkyl is optionally substituted with —S(O) 2 C 1-3 alkyl, or with from 1 to 3 halo;

R 11 is —NR a R b , or C 1-3 alkyl, where C 1-3 alkyl is optionally substituted with from 1 to 3 halo;

or R 5 and R 11 or R 6 and R 11 taken together form C 2-5 alkylenyl;

R 12 is C 1-3 alkyl;

R 13 , R 14 , and R 15 are independently hydrogen or C 1-3 alkyl;

R 16 is —CH 2 —C(O)NR a R b , —CH 2 —C(O)-morpholinyl, —CH 2 -pyridinyl, —CH 2 -pyrimidinyl, or —CH 2 -tetrahydrofuranyl;

R 18 is —C(O)OCH 3 , —S(O) 2 CH 3 , or —C(O)CH 3 ;

R a and R b are independently hydrogen or C 1-3 alkyl;

a is 1; and

n is an integer of 1, 2, or 3; provided that when n is 1, X is —SR 15 , or X forms a carbon-carbon bond with the carbon atom bearing the substituents R 6 and R 7 ;

or a pharmaceutically-acceptable salt or stereoisomer thereof.

5. The compound of claim 4 wherein W is selected from:

(a) Y, wherein Y is selected from —N(R 8a )C(O)R 9 , —N(R 8a )S(O) 2 R 10 , and —N(R 8a )C(O)NR 13 R 14 ; and

(b) a moiety of formula (b) wherein X is selected from —N(R 8 )C(O)R 9 , —N(R 8 )S(O) 2 R 10 , —N(R 8 )C(O)OR 12 , —N(R 8 )C(O)NR 13 R 14 , —N(R 8 )S(O) 2 NR 13 R 14 , —C(O)NR 13 R 14 , —OR 15 , and cyano.

6. The compound of claim 4 wherein W is selected from Y, wherein R 8a is hydrogen or methyl; R 9 is hydrogen, tetrahydrofuranyl, pyridinyl, or methyl; R 10 and R 12 are methyl or ethyl; and R 13 and R 14 are independently hydrogen or methyl.

7. The compound of claim 4 wherein W is selected from —NHC(O)H, —N(CH 3 )C(O)H, —NHC(O)CH 3 , —N(CH 3 )C(O)CH 3 , —N(CH 3 )S(O) 2 CH 3 , —N(CH 3 )C(O)NHCH 3 , and —N(CH 3 )CH 2 CH 2 CN.

8. A compound selected from the group consisting of:

1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[2-hydroxy-3-(methanesulfonylrnethylaniino)propyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[3-(acetyl-methylaniino)-2-hydroxypropyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[3-(formyl-methylamino)-2-hydroxypropyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[3-(1 ,3-dimethylureido)-2hydroxypropyl]-8-azabicyclo[3.2.1]oct-3-yl}amide;

1-isopropyl-1H-indazole-3-carboxylic acid ((1S,3R,5R)-8-{2-hydroxy-3-[(pyridine-4-carbonyl)amino]propyl}-8-azabicyclo[3.2.1]oct-3-yl)amide;

1-isopropyl-1H-indazole-3-carboxylic acid [(1S,3R,5R)-8-(3-formylamino-2-hydroxypropyl)-8-azabicyclo[3.2.1]oct-3-yl]-amide; and

1-isopropyl-1H-indazole-3-carboxylic acid {(1S,3R,5R)-8-[(R)-2-hydroxy-3-(methanesulfonylmethylamino)propyl]-8-azabicyclo[3.2.1]oct-3-yl}amide; and

pharmaceutically-acceptable salts and stereoisomers thereof.

9. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier.

10. A process for preparing a compound of formula (I), wherein R 1 , R 2 , R 3 , R 4 , and W are defined as in claim 1 , or a salt or stereoisomer thereof, the process comprising:

(a) reacting a compound of formula (II):

 with a compound of formula (III):

H—W  (III);

 or

(b) reacting a compound of formula (IV):

 with a compound of formula (V):

 to provide a compound of formula (I), or a salt or stereoisomer thereof.

11. A process for preparing a compound of formula (I), wherein R 3 is hydroxy and R 1 , R 2 , R 4 , and W are defined as in claim 1 , or a salt or stereoisomer thereof, the process comprising:

(a) reacting a compound of formula (II):

 with a compound of formula (III):

H—W  (III);

(b) reacting a compound of formula (IV):

 with a compound of formula (V):

(c) reacting a compound of formula (VI):

 or a salt thereof, with a compound of formula (III):

H—W  (III)

 and a compound of formula (VII):

 wherein L is a leaving group;

 or

(d) reacting a compound of formula (VI) with a compound of formula (VIII):

 to provide a compound of formula (I), or a salt or stereoisomer thereof.

12. A process for preparing a compound of formula (I), wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8a , R 9 , R 10 , R 12 , R 13 , R 14 , R 18 , a, n, W and X are as defined in claim 1 ; or a salt or stereoisomer thereof, the process comprising:

reacting a compound of formula (IX):

wherein R 19 is R 5 , R 8a , or R 18 ;

with a compound of formula (X):

L-W″  (X)

 wherein:

L is a leaving group; and

(a) when R 19 is R 8a , W″ is selected from —C(O)R 9 , —S(O) 2 R 10 , —C(O)OR 12 , —C(O)NR 13 R 14 , and —S(O) 2 NR 13 R 14 ; and

(b) when R 19 is R 18 , W″ is —(CH 2 ) 2 —N(R 5 )(CR 6 R 7 ) n —X

to provide a compound of formula (I) or a salt or stereoisomer thereof.