IP Library › Granted Patent US 10,183,011

Granted Patent B2

US 10,183,011 · App. 15/440,396 · Granted Jan 22, 2019

Anti-depression compounds

Inventors: Steven L. McKnight (Dallas, TX); Andrew A. Pieper (Iowa City, IA); Joseph M. Ready (Carrollton, TX); Jef K. De Brabander (Flower Mound, TX); Jeffrey M. Zigman (Dallas, TX)

Assignee: Board of Regents of The University of Texas System

A61K31/4045 A61K31/403 A61K31/404 A61K31/41 A61K31/4155 A61K31/4188 A61K31/4192 A61K31/422 A61K31/429 A61K31/437 A61K31/44 A61K31/4425 A61K31/4439 A61K31/506 A61K31/5377 A61K31/69 C07D209/04 C07D209/08 C07D209/82 C07D209/86 C07D209/88 C07D401/06 C07D401/12 C07D403/06 C07D403/12 C07D403/14 C07D405/12 C07D407/06 C07D413/06 C07D413/14 C07D471/04 C07D487/04 C07D495/04 C07F5/022 C07F7/0812

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Quick Facts

Patent No.: US 10,183,011
App. No.: 15/440,396
Granted: Jan 22, 2019
Kind: B2

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Abstract

This technology relates generally to compounds and methods for stimulating neurogenesis (e.g., post-natal neurogenesis, including post-natal hippocampal and hypothalamic neurogenesis) and/or protecting neuronal cell from cell death. Various compounds are disclosed herein. In vivo activity tests suggest that these compounds may have therapeutic benefits in neuropsychiatric and/or neurodegenerative diseases such as schizophrenia, major depression, bipolar disorder, normal aging, epilepsy, traumatic brain injury, post-traumatic stress disorder, Parkinson's disease, Alzheimer's disease, Down syndrome, spinocerebellar ataxia, amyotrophic lateral sclerosis, Huntington's disease, stroke, radiation therapy, chronic stress, abuse of a neuro-active drug, retinal degeneration, spinal cord injury, peripheral nerve injury, physiological weight loss associated with various conditions, as well as cognitive decline associated with normal aging, chemotherapy, and the like.

Claims (185)

1. A method for treating a depressive disorder, comprising administering to a subject in need thereof an effective amount of a compound, or a pharmaceutically acceptable salt thereof, having formula (I):

wherein:

each of R 1 , R 2 , and R 4 is independently selected from hydrogen, halo, hydroxyl, sulfhydryl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkynyl, cyclopropyl, —N 3 , cyano, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), and nitro;

R 3 is selected from fluoro, bromo, hydroxyl, sulfhydryl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkynyl, cyclopropyl, —N 3 , cyano, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), and nitro;

R and R′ are defined according to (1) or (2) below:

(1) R and R′ together with C 2 and C 3 , respectively, form a fused phenyl ring having formula (II):

wherein each of R 5 , R 7 , and R 8 is independently selected from hydrogen, halo, hydroxyl, sulfhydryl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkynyl, cyclopropyl, —N 3 , cyano, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), and nitro;

R 6 is selected from halo, hydroxyl, sulfhydryl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkynyl, cyclopropyl, —N 3 , cyano, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , and —NHC(O)(C 1 -C 6 alkyl); or

(2) R and R′ together with C 2 and C 3 , respectively, form a fused heteroaryl ring containing 6 ring atoms, wherein from 1-2 independently selected ring atoms is N; and wherein said heteroaryl ring is optionally substituted with from 1-2 independently selected R b ;

each of L 1 and L 2 is, independently, C 1 -C 3 alkylene, which is optionally substituted with from 1-2 independently selected R c ;

A is:

(i) CR A1 R A2 , wherein one of R A1 and R A2 is halo or OR 9 , wherein R 9 is hydrogen or C C 3 alkyl that is optionally substituted with hydroxyl or C 1 -C 3 alkoxy; and the other of R A1 and R A2 is hydrogen, halo, or C 1 -C 3 alkyl; or

(ii) C═O;

Z is:

—NR 10 R 11 ; or

—OR 12 ; or

—S(O) n R 13 , wherein n is 1, or 2;

each of R 10 and R 11 is independently selected from:

(a) hydrogen;

(b) C 6 -C 10 aryl that is optionally substituted with from 1-4 R b ;

(c) heteroaryl containing 6 ring atoms, wherein 1-2 of the ring atoms is N; and wherein said heteroaryl is optionally substituted with from 1-4 R b ;

(d) C 1 -C 6 alkyl or C 1 -C 6 haloalkyl, each of which is optionally substituted with from 1-3 R d ;

(e) —C(O)(C 1 -C 6 alkyl), —C(O)(C 1 -C 6 haloalkyl), or —C(O)O(C 1 -C 6 alkyl); or

(f) C 2 -C 6 alkenyl or C 2 -C 6 alkynyl;

wherein one of R 10 and R 11 is selected from (b) or (c) and the other of R 10 and R 11 is selected from (a), (d), (e) or (f);

R 12 is:

(i) C 6 -C 10 aryl that is optionally substituted with from 1-4 R b ; or

(ii) heteroaryl containing 6 ring atoms, wherein 1-2 of the ring atoms is N; and wherein said heteroaryl is optionally substituted with from 1-4 R b ;

R 13 is:

C 6 -C 10 aryl that is optionally substituted with from 1-4 R b ;

R b at each occurrence is independently selected from the substituents delineated in (aa) through (dd) below:

(aa) C 1 -C 6 haloalkoxy; C 1 -C 6 thioalkoxy; C 1 -C 6 thiohaloalkoxy; —O—(CH 2 ) 1-3 —[O(CH 2 ) 1-3 ] 1-3 —H; —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , wherein the alkyl portion of each is unsubstituted or substituted with from 1-3 independently selected R e ;

(bb) hydroxyl; cyano; —NH 2 ; azido; sulfhydryl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; —C(O)H; —C(O)(C 1 -C 6 alkyl); —C(O)(C 1 -C 6 haloalkyl); —C(O)O(C 1 -C 6 alkyl); —C(O)NH 2 ; —C(O)NH(C 1 -C 6 alkyl); —C(O)N(C 1 -C 6 alkyl) 2 ; —SO 2 (C 1 -C 6 alkyl); —SO 2 NH 2 ; —SO 2 NH(C 1 -C 6 alkyl); —SO 2 N(C 1 -C 6 alkyl) 2 ;

(cc) C 3 -C 6 cycloalkyl or heterocyclyl containing from 5-6 ring atoms, wherein from 1-2 of the ring atoms of the heterocyclyl is independently selected from N, NH, N(C 1 -C 6 alkyl), NC(O)(C 1 -C 6 alkyl), O, and S; and

(dd) phenyl or heteroaryl containing from 5-6 ring atoms, wherein from 1-2 of the ring atoms of the heteroaryl is independently selected from N, NH, N(C 1 -C 3 alkyl), O, and S; wherein each of said phenyl and heteroaryl is optionally substituted with from 1-3 substituents independently selected from halo; hydroxyl; cyano; nitro; —NH 2 ; —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), C 1 -C 6 alkoxy; C 1 -C 6 haloalkoxy; C 1 -C 6 thioalkoxy; C 1 -C 6 thiohaloalkoxy; C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;

R c at each occurrence is, independently selected from halo, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), and cyano;

R d at each occurrence is, independently selected from hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), and cyano; and

R e at each occurrence is, independently selected from hydroxyl, C 1 -C 6 alkoxy; C 1 -C 6 thioalkoxy; C 1 -C 6 haloalkoxy; C 1 -C 6 thiohaloalkoxy; —NH 2 ; —NH(C 1 -C 6 alkyl); —N(C 1 -C 6 alkyl) 2 ; —NHC(O)(C 1 -C 6 alkyl); cyano; —C(O)H; —C(O)(C 1 -C 6 alkyl); —C(O)(C 1 -C 6 haloalkyl); —C(O)OH; —C(O)O(C 1 -C 6 alkyl); —C(O)NH 2 ; —C(O)NH(C 1 -C 6 alkyl); —C(O)N(C 1 -C 6 alkyl) 2 ; —SO 2 (C 1 -C 6 alkyl); —SO 2 NH 2 ; —SO 2 NH(C 1 -C 6 alkyl); —SO 2 N(C 1 -C 6 alkyl) 2 ; and L 3 -(C 1 -C 6 alkylene)-biotin, where in L 3 is a —O—, —NH—, —NCH 3 —, —C(O)—, —C(O)NH—, —C(O)NCH 3 —, —NHC(O)—, or —NCH 3 C(O)—;

wherein when R and R′ are (1), each of L 1 and L 2 is CH 2 , one of R A1 and R A2 is OH and the other is hydrogen, Z is —NHR 10 , R 3 and R 6 are both halo, each of R 1 , R 2 , R 4 , R 5 , and R 8 is hydrogen, and R 10 is C 6 -C 10 aryl that is optionally substituted with 1 to 4 R b , then R 10 is phenyl substituted with 1 R b .

2. The method of claim 1 , wherein A is CR A1 R A2 , wherein one of R A1 and R A2 is halo or OR 9 wherein R 9 is hydrogen or C 1 -C 3 alkyl, and the other of R A1 and R A2 is hydrogen, halo, or C 1 -C 3 alkyl.

3. The method of claim 1 , wherein A is CR A1 R A2 , wherein one of R A1 and R A2 is halo or OR 9 , wherein R 9 is hydrogen or C 1 -C 3 alkyl; and the other of R A1 and R A2 is hydrogen or C 1 -C 3 alkyl.

4. The method of claim 1 , wherein A is CR A1 R A2 , wherein one of R A1 and R A2 is halo; and the other of R A1 and R A2 is hydrogen or C 1 -C 3 alkyl.

5. The method of claim 1 , wherein the carbon attached to R A1 and R A2 is substituted with four different substituents.

6. The method of claim 5 , wherein the carbon attached to R A1 and R A2 is (R) or (5) configured.

7. The method of claim 6 , wherein the (R) configured compound is substantially free of a compound that is (S) configured at the carbon atom attached to R A1 and R A2 , and wherein the (S) configured compound is substantially free of a compound that is (R) configured at the carbon atom attached to R A1 and R A2 .

8. The method of claim 5 , wherein the compound is (+) (dextrorotatory) or (−) (levororotatory).

9. The method of claim 8 , wherein the (+) (dextrorotatory) compound is substantially free of a compound that is (−) (levororotatory), and wherein the (−) (levororotatory) compound is substantially free of a compound that is (+) (dextrorotatory).

10. The method of claim 1 , wherein R 3 is fluoro, bromo or C 1 -C 6 alkyl.

11. The method of claim 1 , wherein R and R′ together with C 2 and C 3 , respectively, form a fused phenyl ring having formula (II):

12. The method of claim 11 , wherein R 6 is selected from halo, hydroxyl, sulfhydryl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkynyl, cyclopropyl, —N 3 , cyano, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), and nitro.

13. The method of claim 12 , wherein R 6 is halo or C 1 -C 6 alkyl.

14. The method of claim 1 , wherein R b at each occurrence is independently selected from:

(bb) hydroxyl; cyano; —NH 2 ; azido; sulfhydryl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; —C(O)H; —C(O)(C 1 -C 6 alkyl); —C(O)(C 1 -C 6 haloalkyl); —C(O)O(C 1 -C 6 alkyl); —C(O)NH 2 ; —C(O)NH(C 1 -C 6 alkyl); C(O)N(C 1 -C 6 alkyl) 2 ; —SO 2 (C 1 -C 6 alkyl); —SO 2 NH 2 ; —SO 2 NH(C 1 -C 6 alkyl); —SO 2 N(C 1 -C 6 alkyl) 2 ;

15. The method of claim 1 , wherein the compound is selected from:

1-(3-Azidophenylamino)-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol;

4-(3,6-dibromo-9H-carbazol-9-yl)-1-(phenylamino)butan-2-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-4-(phenylamino)butan-2-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(pyridin-2-ylamino)propan-2-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(pyrimidin-2-ylamino)propan-2-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylsulfinyl)propan-2-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylsulfonyl)propan-2-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-phenoxypropan-2-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(pyridin-3-ylamino)propan-2-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(pyridin-4-ylamino)propan-2-ol;

(S)-1-(3,6-dibromo-9H-carbazol-9-yl)-3-phenoxypropan-2-ol;

(R)-1-(3,6-dibromo-9H-carbazol-9-yl)-3-phenoxypropan-2-ol;

3,6-dibromo-9-(2-fluoro-3-phenoxypropyl)-9H-carbazole;

1-(4-azidophenylamino)-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol;

3,6-dibromo-9-(2-fluoro-3-(phenylsulfonyl)propyl)-9H-carbazole;

(S)-1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylsulfonyl) propan-2-ol;

(R)-1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylsulfonyl) propan-2-ol;

1-(3,6-dicyclopropyl-9H-carbazol-9-yl)-3-(phenylamino) propan-2-ol;

N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)aniline;

3,6-dibromo-9-(2,2-difluoro-3-phenoxypropyl)-9H-carbazole;

N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-4-(2-(2-methoxyethoxy)ethoxy)aniline;

1-(3,6-bis(trifluoromethyl)-9H-carbazol-9-yl)-3-(phenylamino)propan-2-ol;

3-(3-(3,6-Dibromo-9H-carbazol-9-yl)-2-hydroxypropylsulfonyl)phenol;

4-(3-(3,6-Dibromo-9H-carbazol-9-yl)-2-hydroxypropylsulfonyl)phenol;

3-(3-(3,6-Dibromo-9H-carbazol-9-yl)-2-fluoropropylsulfonyl)phenol;

4-(3-(3,6-Dibromo-9H-carbazol-9-yl)-2-fluoropropylsulfonyl)phenol;

9-(2-hydroxy-3-phenoxypropyl)-9H-carbazole-3,6-dicarbonitrile;

6-bromo-9-(2-hydroxy-3-phenoxypropyl)-9H-carbazole-3-carbonitrile;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(pyridin-2-yloxy)propan-2-ol;

6-bromo-9-(2-hydroxy-3-phenoxypropyl)-9H-pyrido[2,3-b]indole-3-carbonitrile;

tert-butyl 3-(2-(2-(2-(3-((3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)amino)phenoxy)ethoxy)ethoxy)ethoxy)propanoate;

1-(6-bromo-3-methoxy-1-methyl-9H-carbazol-9-yl)-3-(phenylamino)propan-2-ol;

1-(4,6-dibromo-3-methoxy-1-methyl-9H-carbazol-9-yl)-3-(phenylamino)propan-2-ol;

1-(3,6-dibromo-4-methoxy-9H-carbazol-9-yl)-3-(phenylamino)propan-2-ol;

ethyl 6-bromo-9-(2-hydroxy-3-phenoxypropyl)-9H-pyrido[3,4-b]indole-3-carboxylate;

9-(2-fluoro-3-phenoxypropyl)-9H-carbazole-3,6-dicarbonitrile;

9-(2-hydroxy-2-methyl-3-phenoxypropyl)-9H-carbazole-3,6-dicarbonitrile;

1-(3,6-dibromo-9H-pyrido[2,3-b]indol-9-yl)-3-phenoxypropan-2-ol;

1-(8-bromo-5H-pyrido[4,3-b]indol-5-yl)-3-phenoxypropan-2-ol;

6-bromo-9-(2-hydroxy-3-phenoxypropyl)-9H-pyrido[3,4-b]indole-3-carboxamide;

or a pharmaceutically acceptable salt thereof.

16. The method of claim 1 , wherein when A is CHOH and Z is NR 10 R 11 , one or more of the following apply:

each of R 3 and R 6 is CH 3 ;

one of R 3 and R 6 is CH 3 and the other of R 3 and R 6 is bromo;

each of R 10 and R 11 is other than hydrogen;

one of R 10 and R 11 is (c); or

one or both of L 1 and L 2 is C 2 -C 3 alkylene that is optionally substituted with from 1-2 independently selected R c .

17. The method of claim 11 , wherein R 6 is selected from fluoro, chloro, bromo, hydroxyl, sulfhydryl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkynyl, cyclopropyl, —N 3 , cyano, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), and nitro.

18. The method of claim 1 , wherein the compound is N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-6-methoxypyridin-2-amine.

19. A method for treating a depressive disorder, comprising administering to a subject in need thereof an effective amount of a compound, or a pharmaceutically acceptable salt thereof, having formula (I):

wherein:

R 3 is selected from halo, hydroxyl, sulfhydryl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkynyl, cyclopropyl, —N 3 , cyano, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), and nitro;

R and R′ are defined according to (1) or (2) below:

(1) R and R′ together with C 2 and C 3 , respectively, form a fused phenyl ring having formula (II):

wherein each of R 5 , R 6 , R 7 , and R 8 is independently selected from hydrogen, halo, hydroxyl, sulfhydryl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkynyl, cyclopropyl, —N 3 , cyano, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), and nitro; or

each of L 1 and L 2 is, independently, C 1 -C 3 alkylene, which is optionally substituted with from 1-2 independently selected R c ;

A is:

(i) CR A1 R A2 , wherein one of R A1 and R A2 is halo, and the other of R A1 and R A2 is hydrogen, halo, or C 1 -C 3 alkyl; or

(ii) C═O;

Z is:

—NR 10 R 11 ; or —OR 12 ; or —OR 12 ; or —S(O) n R 13 , wherein n is 0, 1, or 2;

each of R 10 and R 11 is independently selected from:

(a) hydrogen;

(b) C 6 -C 10 aryl that is optionally substituted with from 1-4 R b ;

(c) heteroaryl containing 6 ring atoms, wherein 1-2 of the ring atoms is N; and wherein said heteroaryl is optionally substituted with from 1-4 R b ;

(d) C 1 -C 6 alkyl or C 1 -C 6 haloalkyl, each of which is optionally substituted with from 1-3 R d ;

(e) —C(O)(C 1 -C 6 alkyl), —C(O)(C 1 -C 6 haloalkyl), or —C(O)O(C 1 -C 6 alkyl); or

(f) C 2 -C 6 alkenyl or C 2 -C 6 alkynyl;

wherein one of R 10 and R 11 is selected from (b) or (c);

R 12 is:

(i) C 6 -C 10 aryl that is optionally substituted with from 1-4 R b ; or

(ii) heteroaryl containing 6 ring atoms, wherein 1-2 of the ring atoms is N; and wherein

said heteroaryl is optionally substituted with from 1-4 R b ;

R 13 is:

(i) C 6 -C 10 aryl that is optionally substituted with from 1-4 R b ; or

(ii) heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(C 1 -C 3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 R b ;

R b at each occurrence is independently selected from the substituents delineated in (aa) through (dd) below:

(aa) C 1 -C 6 alkoxy; C 1 -C 6 haloalkoxy; C 1 -C 6 thioalkoxy; C 1 -C 6 thiohaloalkoxy; —O—(CH 2 ) 1-3 —[O(CH 2 ) 1-3 ] 1-3 —H; —C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), wherein the alkyl portion of each is optionally substituted with from 1-3 independently selected R e ;

(bb) halo; hydroxyl; cyano; nitro; —NH 2 ; azido; sulfhydryl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; —C(O)H; —C(O)(C 1 -C 6 alkyl); —C(O)(C 1 -C 6 haloalkyl); —C(O)OH; —C(O)O(C 1 -C 6 alkyl); —C(O)NH 2 ; —C(O)NH(C 1 -C 6 alkyl); —C(O)N(C 1 -C 6 alkyl) 2 ; —SO 2 (C 1 -C 6 alkyl); —SO 2 NH 2 ; —SO 2 NH(C 1 -C 6 alkyl); —SO 2 N(C 1 -C 6 alkyl) 2 ;

20. The method of claim 19 , wherein A is CR A1 R A2 , wherein one of R A1 and R A2 is halo; and the other of R A1 and R A2 is hydrogen or C 1 -C 3 alkyl.

21. The method of claim 19 , wherein the carbon attached to R A1 and R A2 is substituted with four different substituents and is (R) or (S) configured; and wherein the compound is (+) (dextrorotatory) or (−) (levororotatory).

22. The method of claim 21 , wherein the (R) configured compound is substantially free of a compound that is (S) configured at the carbon atom attached to R A1 and R A2 , and wherein the (S) configured compound is substantially free of a compound that is (R) configured at the carbon atom attached to R A1 and R A2 .

23. The method of claim 22 , wherein the (+) (dextrorotatory) compound is substantially free of a compound that is (−) (levororotatory), and wherein the (−) (levororotatory) compound is substantially free of a compound that is (+) (dextrorotatory).

24. The method of claim 19 , wherein R and R′ together with C 2 and C 3 , respectively, form a fused phenyl ring having formula (II):

25. The method of claim 24 , wherein R 3 is selected from fluoro, chloro, bromo, hydroxyl, sulfhydryl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkynyl, cyclopropyl, —N 3 , cyano, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), and nitro.

26. The method of claim 24 , wherein R 6 is selected from halo, hydroxyl, sulfhydryl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkynyl, cyclopropyl, —N 3 , cyano, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), and nitro.

27. The method of claim 24 , wherein R 6 is selected from fluoro, chloro, bromo, hydroxyl, sulfhydryl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkynyl, cyclopropyl, —N 3 , cyano, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), and nitro.

28. A method for treating a depressive disorder, comprising administering to a subject in need thereof an effective amount of a compound, or a pharmaceutically acceptable salt thereof, having formula (I):

wherein:

R and R′ are defined according to (1) or (2) below:

(1) R and R′ together with C 2 and C 3 , respectively, form a fused phenyl ring having formula (II):

each of L 1 and L 2 is, independently, C 1 -C 3 alkylene, which is optionally substituted with from 1-2 independently selected R c ;

A is:

(i) CR A1 R A2 , wherein one of R A1 and R A2 is halo or OR 9 , wherein R 9 is hydrogen or C 1 -C 3 alkyl that is optionally substituted with hydroxyl or C 1 -C 3 alkoxy; and the other of R A1 and R A2 is hydrogen, halo, or C 1 -C 3 alkyl; or

(ii) C═O;

Z is:

—OR 12 or —S(O) n R 13 , wherein n is 1, or 2;

R 12 is:

(i) C 6 -C 10 aryl that is optionally substituted with from 1-4 R b ; or

(ii) heteroaryl containing 6 ring atoms, wherein 1-2 of the ring atoms is N; and wherein said heteroaryl is optionally substituted with from 1-4 R b ;

R 13 is:

C 6 -C 10 aryl that is optionally substituted with from 1-4 R b ;

R b at each occurrence is independently selected from the substituents delineated in (aa) through (dd) below:

(aa) C 1 -C 6 alkoxy; C 1 -C 6 haloalkoxy; C 1 -C 6 thioalkoxy; C 1 -C 6 thiohaloalkoxy; —O—(CH 2 ) 1-3 —[O(CH 2 ) 1-3 ] 1-3 —H; C 1 -C 6 haloalkyl, —NH(C 1 -C 6 alkyl), —NHC(O)(C 1 -C 6 alkyl), wherein the alkyl portion of each is unsubstituted or substituted with from 1-3 independently selected R e ;

(bb) halo; cyano; nitro; —NH 2 ; azido; sulfhydryl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; —C(O)H; —C(O)(C 1 -C 6 alkyl); —C(O)(C 1 -C 6 haloalkyl); —C(O)OH; —C(O)O(C 1 -C 6 alkyl); —C(O)NH 2 ; —C(O)NH(C 1 -C 6 alkyl); —C(O)N(C 1 -C 6 alkyl) 2 ; —SO 2 (C 1 -C 6 alkyl); —SO 2 NH 2 ; —SO 2 NH(C 1 -C 6 alkyl); —SO 2 N(C 1 -C 6 alkyl) 2 ;

(dd) phenyl or heteroaryl containing from 5-6 ring atoms, wherein from 1-2 of the ring atoms of the heteroaryl is independently selected from N, NH, N(C 1 -C 3 alkyl), 0, and S; wherein each of said phenyl and heteroaryl is optionally substituted with from 1-3 substituents independently selected from halo; hydroxyl; cyano; nitro; —NH 2 ; —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), C 1 -C 6 alkoxy; C 1 -C 6 haloalkoxy; C 1 -C 6 thioalkoxy; C 1 -C 6 thiohaloalkoxy; C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;

29. The method of claim 28 , wherein A is CR A1 R A2 , wherein one of R A1 and R A2 is halo; and the other of R A1 and R A2 is hydrogen, halo or C 1 -C 3 alkyl.

30. The method of claim 28 , wherein the carbon attached to R A1 and R A2 is substituted with four different substituents and is (R) or (5) configured; and wherein the compound is (+) (dextrorotatory) or (−) (levororotatory).

31. The method of claim 30 , wherein the (R) configured compound is substantially free of a compound that is (S) configured at the carbon atom attached to R A1 and R A2 , and wherein the (S) configured compound is substantially free of a compound that is (R) configured at the carbon atom attached to R A1 and R A2 .

32. The method of claim 30 , wherein the (+) (dextrorotatory) compound is substantially free of a compound that is (−) (levororotatory), and wherein the (−) (levororotatory) compound is substantially free of a compound that is (+) (dextrorotatory).

33. The method of claim 28 , wherein R and R′ together with C 2 and C 3 , respectively, form a fused phenyl ring having formula (II):

34. The method of claim 33 , wherein R 3 is selected from fluoro, chloro, bromo, hydroxyl, sulfhydryl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkynyl, cyclopropyl, —N 3 , cyano, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), and nitro.

35. The method of claim 33 , wherein R 6 is selected from halo, hydroxyl, sulfhydryl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkynyl, cyclopropyl, —N 3 , cyano, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), and nitro.

36. The method of claim 33 , wherein R 6 is selected from fluoro, chloro, bromo, hydroxyl, sulfhydryl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkynyl, cyclopropyl, —N 3 , cyano, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), and nitro.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 24, 2018

From: MCKNIGHT, STEVEN L.; PIEPER, ANDREW A.; READY, JOSEPH M.; DE BRABANDER, JEF K.; ZIGMAN, JEFFREY M.

To: BOARD OF REGENTS OF THE UNIVERSITY OF TEXAS SYSTEM

Reel/Frame 045621/0076 →

Continuity (9)

Continuation 14886332 · Oct 19, 2015

Continuation 14339772 · Jul 24, 2014

Continuation In Part 13594223 · Aug 24, 2012

Continuation In Part 13177981 · Jul 7, 2011

Continuation In Part 12832056 · Jul 7, 2010

Continuation In Part 12685652 · Jan 11, 2010

Provisional Application 61958282 · Jul 24, 2013

Provisional Application 61143755 · Jan 9, 2009

Related Publication 20170157092A1 · Jun 8, 2017

Cited By (1)

US 12,679,843