Androgen receptor modulators and methods of use thereof

1. A compound of structural formula I:

wherein:

X is selected from —O—, and —N(R 4 )—;

R 1 is selected from hydrogen, C 1-3 alkyl, cyclopropyl and trifluoromethyl;

R 2 is selected from:

(1) hydrogen,

(2) C 1-8 alkyl,

(3) C 3-8 cycloalkyl,

(4) C 3-8 cycloheteroalkyl,

(5) C 3-8 cycloalkyl-C 1-6 alkyl,

(6) C 3-8 cycloheteroalkyl-C 1-6 alkyl,

(7) aryl,

(8) aryl-C 1-6 alkyl,

(9) amino,

(10) amino-C 1-6 alkyl,

(11) C 1-3 acylamino,

(12) C 1-3 acylamino-C 1-6 alkyl,

(13) (C 1-6 alkyl) n amino,

(14) C 3-6 cycloalkyl-C 0-2 alkylamino,

(15) (C 1-6 alkyl) n amino-C 1-6 alkyl,

(16) C 1-6 alkoxy,

(17) C 1-4 alkoxy-C 1-6 alkyl,

(18) hydroxycarbonyl,

(19) hydroxycarbonyl-C 1-6 alkyl,

(20) C 1-3 alkoxycarbonyl,

(21) C 1-3 alkoxycarbonyl-C 1-6 alkyl,

(22) hydroxy,

(23) hydroxy-C 1-6 alkyl,

(24) nitro,

(25) cyano,

(26) trifluoromethyl,

(27) trifluoromethoxy,

(28) trifluoroethoxy,

(29) C 1-8 alkyl-S(O) p —,

(30) (C 1-8 alkyl) p aminocarbonyl,

(31) C 1-8 alkyloxycarbonylamino,

(32) (C 1-8 alkyl) n aminocarbonyloxy,

(33) (aryl C 1-3 alkyl) n amino,

(34) (aryl) n amino,

(35) aryl-C 1-3 alkylsulfonylamino, and

(36) C 1-8 alkylsulfonylamino;

R 3 is selected from hydrogen, C 1-8 alkyl, and trifluoromethyl;

or R 2 and R 3 together with the carbon atom to which they are attached form a carbonyl group, or join to form a 3- to 6-membered spiro-carbocyclic ring; and

wherein the alkyl groups in R 2 and R 3 are either unsubstituted or substituted with one to three R 5 substituents and wherein any of the aryl, cycloalkyl, or cycloheteroalkyl groups in R 2 are either unsubstituted or substituted with one to three R 6 substituents;

R 4 is selected from:

(1) hydrogen,

(2) aryl,

(3) aminocarbonyl,

(4) C 3-8 cycloalkyl,

(5) amino C 1-6 alkyl,

(6) (aryl) p aminocarbonyl,

(7) (aryl C 1-5 alkyl) p aminocarbonyl,

(8) hydroxycarbonyl C 1-6 alkyl,

(9) C 1-8 alkyl,

(10) perfluoro C 1-8 alkyl,

(11) aryl C 1-6 alkyl,

(12) (C 1-6 alkyl) p amino C 2-6 alkyl,

(13) (aryl C 1-6 alkyl) p amino C 2-6 alkyl,

(14) C 1-8 alkylsulfonyl,

(15) C 1-8 alkoxycarbonyl,

(16) aryloxycarbonyl,

(17) aryl C 1-8 alkoxycarbonyl,

(18) C 1-8 alkylcarbonyl,

(19) arylcarbonyl,

(20) aryl C 1-6 alkylcarbonyl,

(21) (C 1-8 alkyl) p aminocarbonyl,

(22) aminosulfonyl,

(23) C 1-8 alkylaminosulfonyl,

(24) (aryl) p aminosulfonyl,

(25) (aryl C 1-8 alkyl) p aminosulfonyl,

(26) arylsulfonyl,

(27) aryl C 1-6 alkylsulfonyl,

(28) C 1-6 alkylthiocarbonyl,

(29) arylthiocarbonyl, and

(30) aryl C 1-6 alkylthiocarbonyl,

wherein any of the alkyl groups of R 4 are either unsubstituted or substituted with one to three R 5 substituents and wherein any of the aryl, cycloalkyl, or cycloheteroalkyl groups in R 4 are either unsubtituted or substituted with one to three R 6 substituents;

each R 5 is independently selected from:

(1) halogen,

(2) C 1-8 alkyl,

(3) C 3-8 cycloalkyl,

(4) C 3-8 cycloheteroalkyl,

(5) C 3-8 cycloalkyl-C 1-6 alkyl,

(6) C 3-8 cycloheteroalkyl-C 1-6 alkyl,

(7) aryl,

(8) aryl-C 1-6 alkyl,

(9) amino,

(10) amino-C 1-6 alkyl,

(11) C 1-3 acylamino,

(12) C 1-3 acylamino-C 1-6 alkyl,

(13) (C 1-6 alkyl) n amino,

(14) C 3-6 cycloalkyl-C 0-2 alkylamino,

(15) (C 1-6 alkyl) n amino-C 1-6 alkyl,

(16) C 1-6 alkoxy,

(17) C 1-4 alkoxy-C 1-6 alkyl,

(18) hydroxycarbonyl,

(19) hydroxycarbonyl-C 1-6 alkyl,

(20) C 1-3 alkoxycarbonyl,

(21) C 1-3 alkoxycarbonyl-C 1-6 alkyl,

(22) hydroxy,

(23) hydroxy-C 1-6 alkyl,

(24) nitro,

(25) cyano,

(26) trifluoromethyl,

(27) trifluoromethoxy,

(28) trifluoroethoxy,

(29) C 1-8 alkyl-S(O) p —,

(30) (C 1-8 alkyl) p aminocarbonyl,

(31) C 1-8 alkyloxycarbonylamino,

(32) (C 1-8 alkyl) n aminocarbonyloxy,

(33) (aryl C 1-3 alkyl) n amino,

(34) (aryl) n amino,

(35) aryl-C 1-3 alkylsulfonylamino, and

(36) C 1-8 alkylsulfonylamino;

each R 6 is independently selected from:

(1) halogen,

(2) aryl,

(3) C 1-8 alkyl,

(4) C 3-8 cycloalkyl,

(5) C 3-8 cycloheteroalkyl,

(6) aryl C 1-6 alkyl,

(7) amino C 0-6 alkyl,

(8) C 1-6 alkylamino C 0-6 alkyl,

(9) (C 1-6 alkyl) 2 amino C 0-6 alkyl,

(10) aryl C 0-6 alkylamino C 0-6 alkyl,

(11) (aryl C 0-6 alkyl) 2 amino C 0-6 alkyl,

(12) C 1-6 alkylthio,

(13) aryl C 0-6 alkylthio,

(14) C 1-6 alkylsulfinyl,

(15) aryl C 0-6 alkylsulfinyl,

(16) C 1-6 alkylsulfonyl,

(17) aryl C 0-6 alkylsulfonyl,

(18) C 1-6 alkoxy C 0-6 alkyl,

(19) aryl C 0-6 alkoxy C 0-6 alkyl,

(20) hydroxycarbonyl C 0-6 alkyl,

(21) C 1-6 alkoxycarbonyl C 0-6 alkyl,

(22) aryl C 0-6 alkoxycarbonyl C 0-6 alkyl,

(23) hydroxycarbonyl C 1-6 alkyloxy,

(24) hydroxy C 0-6 alkyl,

(25) cyano,

(26) nitro,

(27) perfluoroC 1-4 alkyl,

(28) perfluoroC 1-4 alkoxy,

(29) oxo,

(30) C 1-6 alkylcarbonyloxy,

(31) aryl C 0-6 alkylcarbonyloxy,

(32) alkyl C 1-6 carbonylamino,

(33) aryl C 0-6 alkylcarbonylamino,

(34) C 1-6 alkylsulfonylamino,

(35) aryl C 0-6 alkylsulfonylamino,

(36) C 1-6 alkoxycarbonylamino,

(37) aryl C 0-6 alkoxycarbonylamino,

(38) C 1-6 alkylaminocarbonylamino,

(39) aryl C 0-6 alkylaminocarbonylamino,

(40) (C 1-6 alkyl) 2 aminocarbonylamino,

(41) (aryl C 0-6 alkyl) 2 aminocarbonylamino,

(42) (C 1-6 alkyl) 2 aminocarbonyloxy,

(43) (aryl C 0-6 alkyl) 2 aminocarbonyloxy,

(44) C 0-6 alkylcarbonyl C 0-6 alkyl, and

(45) aryl C 0-6 alkylcarbonyl C 0-6 alkyl;

n is selected from 1 and 2;

p is selected from 0, 1, and 2;

and pharmaceutically acceptable salts thereof.

2. The compound according to claim 1 , wherein:

X is selected from —O—, and —N(R 4 )—;

R 1 is selected from hydrogen, C 1-3 alkyl, cyclopropyl and trifluoromethyl;

R 2 is selected from:

(1) hydrogen,

(2) C 1-6 alkyl,

(3) C 3-8 cycloalkyl,

(4) C 4-6 cycloheteroalkyl,

(5) C 3-8 cycloalkyl-C 1-3 alkyl,

(6) C 4-6 cycloheteroalkyl-C 1-3 alkyl,

(7) phenyl,

(8) phenyl-C 1-3 alkyl,

(9) amino,

(10) amino-C 1-3 alkyl,

(11) C 1-3 acylamino,

(12) C 1-3 acylamino-C 1-3 alkyl,

(13) (C 1-3 alkyl) n amino,

(14) C 3-6 cycloalkyl-C 0-2 alkylamino,

(15) (C 1-3 alkyl) n amino-C 1-6 alkyl,

(16) C 1-6 alkoxy,

(17) C 1-3 alkoxy-C 1-6 alkyl,

(18) hydroxycarbonyl,

(19) hydroxycarbonyl-C 1-6 alkyl,

(20) C 1-3 alkoxycarbonyl,

(21) C 1-3 alkoxycarbonyl-C 1-6 alkyl,

(22) hydroxy,

(23) hydroxy-C 1-6 alkyl,

(24) nitro,

(25) cyano,

(26) trifluoromethyl,

(27) trifluoromethoxy,

(28) trifluoroethoxy,

(29) C 1-6 alkyl-S(O) p —,

(30) (C 1-6 alkyl) p aminocarbonyl,

(31) C 1-3 alkyloxycarbonylamino,

(32) (C 1-3 alkyl) n aminocarbonyloxy,

(33) (aryl C 1-3 alkyl) n amino,

(34) (aryl) 1-2 amino,

(35) aryl-C 1-3 alkylsulfonylamino, and

(36) C 1-6 alkylsulfonylamino;

R 3 is selected from hydrogen, C 1-8 alkyl, and trifluoromethyl;

or R 2 and R 3 together with the carbon atom to which they are attached to form a carbonyl group, or join to form a 3- to 6-membered spiro-carbocyclic ring;

R 4 is selected from:

(1) hydrogen,

(2) aryl,

(3) C 1-8 alkyl,

(4) perfluoro C 1-8 alkyl, and

(5) aryl C 1-6 alkyl;

wherein any of the alkyl groups of R 2 , R 3 and R 4 are either unsubstituted or substituted with one to three R 5 substituents;

and wherein any of the aryl, cycloalkyl, or cycloheteroalkyl groups of R 2 are either unsubstituted or substituted with one to three R 6 substituents, and wherein any of the aryl, groups of R 4 are either unsubstituted or substituted with one to three R 6 substituents;

n is selected from 1 and 2;

p is selected from 0, 1, and 2;

and pharmaceutically acceptable salts thereof.

3. The compound according to claim 1 , wherein:

R 1 is selected from hydrogen, methyl, cyclopropyl and trifluoromethyl;

R 2 is selected from hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl selected from cyclopropyl and cyclohexyl, C 3-8 cycloheteroalkyl selected from piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl, and piperazinyl, C 3-8 cycloalkyl-C 1-6 alkyl selected from cyclopropylmethyl, cyclopropylethyl, cyclopropyl-propyl, cyclohexylmethyl, cyclohexylethyl, and cyclohexylpropyl, C 3-8 cycloheteroalkyl-C 1-6 alkyl selected from piperidinylmethyl pyrrolidinylmethyl, azetidinylmethyl, morpholinylmethyl, piperazinylmethyl, piperidinylethyl, pyrrolidinylethyl, morpholinylethyl, piperazinylethyl, piperidinylpropyl, morpholinylpropyl, and piperazinylpropyl, aryl selected from phenyl and benzyl, aryl-C 1-6 alkyl selected from phenylethyl and phenylpropyl, hydroxy, methoxy, trifluoromethyl, trifluoromethyoxy, and trifluoroethoxy;

R 3 is selected from hydrogen, methyl and trifluoromethyl,

or R 2 and R 3 , together with the carbon atom to which they are attached, form a carbonyl group, or join to form a 3- to 6-membered spiro-carbocyclic ring;

wherein any of the alkyl groups of R 2 are either unsubstituted or substituted with one to three R 5 substituents;

R 4 is selected from hydrogen, methyl, ethyl, cyclopropyl, trifluoromethyl, and perfluoroethyl;

each R 5 is independently selected from:

(1) halogen,

(2) C 1-8 alkyl,

(3) C 3-8 cycloalkyl,

(4) C 3-8 cycloheteroalkyl,

(5) C 3-8 cycloalkyl-C 1-6 alkyl,

(6) aryl,

(7) amino,

(8) C 1-3 acylamino,

(9) (C 1-6 alkyl) n amino,

(10) C 3-6 cycloalkyl-C 0-2 alkylamino,

(11) C 1-6 alkoxy,

(12) hydroxycarbonyl,

(13) hydroxy,

(14) cyano,

(15) trifluoromethyl,

(16) trifluoromethoxy,

(17) trifluoroethoxy,

(18) (C 1-8 alkyl) p aminocarbonyl,

(19) C 1-8 alkyloxycarbonylamino,

(20) (C 1-8 alkyl) n aminocarbonyloxy,

(21) (aryl C 1-3 alkyl)n amino, and

(22) (aryl) n amino;

and wherein any of the aryl, cycloalkyl, or cycloheteroalkyl groups in R 2 are unsubstituted or substituted with one to three R 6 substituents,

each R 6 is independently selected from:

(1) halogen,

(2) phenyl,

(3) C 1-3 alkyl,

(4) C 4-6 cycloheteroalkyl,

(5) phenyl C 1-3 alkyl,

(6) amino C 0-3 alkyl,

(7) C 1-3 alkylamino C 0-3 alkyl,

(8) (C 1-3 alkyl) 2 amino C 0-3 alkyl,

(9) phenyl C 0-3 alkylamino C 0-3 alkyl,

(10) (phenyl C 0-3 alkyl) 2 amino C 0-3 alkyl,

(11) C 1-3 alkoxy C 0-3 alkyl,

(12) aryl C 0-3 alkoxy C 0-3 alkyl,

(13) hydroxycarbonyl C 0-3 alkyl,

(14) C 1-3 alkoxycarbonyl C 0-3 alkyl,

(15) phenyl C 0-3 alkoxycarbonyl C 0-3 alkyl,

(16) hydroxy C 0-3 alkyl,

(17) cyano,

(18) trifluoromethyl, and

(19) trifluoromethoxy;

n is selected from 1 and 2;

p is selected from 0, 1, and 2;

and pharmaceutically acceptable salts thereof.

4. The compound according to claim 1 , wherein:

X is selected from —O— and —NH—;

R 1 is selected from hydrogen, methyl, and trifluoromethyl;

R 2 is selected from hydrogen, C 1-3 alkyl, benzyl, and cyclopropylmethyl;

R 3 is selected from hydrogen and methyl;

or R 2 and R 3 , together with the carbon to which they are attached, join to form a spiro-cyclopropyl ring;

and pharmaceutically acceptable salts thereof.

5. The compound according to claim 1 selected from:

4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,

4-(trifluoromethyl)-1,6,7,8,9,10-hexahydro-2H-azepino[3,2-g]quinolin-2-one,

1,6,7,8,9,10-hexahydro-2H-azepino[3,2-g]quinolin-2-one,

8-(R)-methyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,

8-(S)-methyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,

8-spirocyclopropyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,

8-(R,S)-propyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,

8-(R,S)-dimethyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,

8-(R,S)-benzyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,

8-(R,S)-ethyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,

8-(R,S)-cyclopropylmethyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-]azepin-2(6H)-one,

4,8-dimethyl-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one, and

4-methyl-8-(R,S)-propyl-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,

and pharmaceutically acceptable salts thereof.

6. The compound according to claim 1 selected from:

4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,

4-(trifluoromethyl)-1,6,7,8,9,10-hexahydro-2H-azepino[3,2-g]quinolin-2-one,

8-(R)-methyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,

8-(S)-methyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,

8-spirocyclopropyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,

8-(R,S)-ethyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-b]azepin-2(6H)-one,

8-(R,S)-cyclopropylmethyl-4-(trifluoromethyl)-7,8,9,10-tetrahydrochromeno[7,6-]azepin-2(6H)-one,

and pharmaceutically acceptable salts thereof.

7. A method of treating a condition which is caused by androgen deficiency or which can be ameliorated by androgen administration selected from: osteoporosis, periodontal disease, bone fracture, bone damage following bone reconstructive surgery, sarcopenia, frailty, aging skin, male hypogonadism, female sexual dysfunction, post-menopausal symptoms in women, atherosclerosis, hypercholesterolemia, hyperlipidemia, aplastic anemia and other hematopoietic disorders, pancreatic cancer, renal cancer, prostate cancer, arthritis and joint repair, in a patient in need of such treatment, comprising administering a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

8. The method according to claim 7 wherein the condition is osteoporosis.

9. A method of treating osteoporosis in a patient in need of such treatment, comprising administering a therapeutically effective amount of a compound according to claim 5 or a pharmaceutically acceptable salt thereof.

10. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

11. A composition comprising a compound according to claim 5 and a pharmaceutically acceptable carrier.

12. The method according to claim 7 wherein the condition is selected from sarcopenia, frailty, and prostate cancer.

13. The method according to claim 12 wherein the condition is selected from sarcopenia, and frailty.