IP Library › Patent Application 15966076

Patent Application

App. No. 15/966,076

Pro-Neurogenic Compounds

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Patent No.: US None
App. No.: 15/966,076

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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 (442)

1 . A compound having formula (I):

wherein:

each of R 1 , R 2 , R 3 , 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 and R′ are defined according to (1), (2), (3) or (4) 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

(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 ; or

(3) R and R′ together with C 2 and C 3 , respectively, form a fused heterocyclic ring containing from 5-6 ring atoms, wherein from 1-2 of the ring atoms is independently selected from N, NH, N(C 1 -C 6 alkyl), NC(O)(C 1 -C 6 alkyl), O, and S; and wherein said heterocyclic ring is optionally substituted with from 1-3 independently selected R a ; or

(4) each of R and R′ is, independently, hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

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 each of R A1 and R A2 is independently selected from hydrogen, halo, C 1 -C 3 alkyl, 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, or a double bond formed between A and one of L 1 and L 2 ; or

(ii) C═O; or

(iii) C 3 -C 5 cycloalkylene that is (a) substituted with 1 oxo; and (b) optionally further substituted with from 1-4 independently selected R a ; or

(iv) heterocycloalkylene containing from 3-5 ring atoms, wherein from 1-2 of the ring atoms is independently selected from N, NH, N(C 1 -C 3 alkyl), O, and S; and wherein said heterocycloalkylene is (a) substituted with 1 oxo; and (b) is optionally further substituted with from 1-4 independently selected R a .

Z is:

(i) —NR 10 R 11 ; or

(ii) —C(O)NR 10 R 11 ; or

(iii) —OR 12 ; or

(iv) —S(O) n R 13 , wherein n is 0, 1, or 2; or

(v) heterocycloalkenyl containing from 5-6 ring atoms, wherein from 1-3 of the ring atoms is independently selected from N, NH, N(C 1 -C 6 alkyl), NC(O)(C 1 -C 6 alkyl), O, and S; and wherein said heterocycloalkenyl is optionally substituted with from 1-4 independently selected R a ; or

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

(vii) 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 independently selected R b ; or

(viii) C 8 -C 14 arylcycloalkyl, wherein:

(1) the aryl portion is optionally substituted with from 1-4 independently selected R b , and

(2) the cycloalkyl portion is optionally substituted with from 1-4 independently selected R a ; or

(ix) arylheterocyclyl containing from 8-14 ring atoms, wherein:

(1) the aryl portion from is optionally substituted with from 1-4 independently selected R b , and

(2) from 1-2 of the ring atoms of the heterocyclyl portion is independently selected from N, NH, N(C 1 -C 6 alkyl), NC(O)(C 1 -C 6 alkyl), O, and S; and wherein said heterocyclyl portion is optionally substituted with from 1-3 independently selected R a ; or

(x) heteroarylheterocyclyl containing from 8-14 ring atoms, wherein:

(1) from 1-2 of the ring atoms of the heteroaryl portion is independently selected from N, NH, N(C 1 -C 3 alkyl), O, and S; and wherein said heteroaryl portion is optionally substituted with from 1-3 independently selected R b ; and

(xi) heteroarylcycloalkyl containing from 8-14 ring atoms, wherein:

(2) the cycloalkyl portion is optionally substituted with from 1-4 independently selected R a ;

each of R 10 and R 11 is independently selected from the substituents delineated collectively in (a) through (1) below:

(a) hydrogen;

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

(c) 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 1 );

(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);

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

(g) C 8 -C 14 arylcycloalkyl, wherein:

(1) the aryl portion is optionally substituted with from 1-4 independently selected R b , and

(2) the cycloalkyl portion is optionally substituted with from 1-4 independently selected R a ;

(h) arylheterocyclyl containing from 8-14 ring atoms, wherein:

(1) the aryl portion from is optionally substituted with from 1-4 independently selected R b , and

(i) heteroarylheterocyclyl containing from 8-14 ring atoms, wherein:

(j) heteroarylcycloalkyl containing from 8-14 ring atoms, wherein:

(2) the cycloalkyl portion is optionally substituted with from 1-4 independently selected R a ;

(k) C 3 -C 8 cycloalkyl or C 3 -C 8 cycloalkenyl, each of which is optionally substituted with from 1-4 independently selected R a ; and

(l) C 7 -C 12 aralkyl, wherein the aryl portion is optionally substituted with from 1-4 independently selected R b ,

provided that one of R 10 and R 11 must be selected from (b), (c), (g), (h), (i), (j), and (k); R 12 is:

(i) C 6 -C 1 ° 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 ; or

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

(iv) C 8 -C 14 arylcycloalkyl, wherein:

(1) the aryl portion is optionally substituted with from 1-4 independently selected R b , and

(2) the cycloalkyl portion is optionally substituted with from 1-4 independently selected R a ; or

(v) arylheterocyclyl containing from 8-14 ring atoms, wherein:

(1) the aryl portion from is optionally substituted with from 1-4 independently selected R b , and

(vi) heteroarylheterocyclyl containing from 8-14 ring atoms, wherein:

(vii) heteroarylcycloalkyl containing from 8-14 ring atoms, wherein:

(2) the cycloalkyl portion is optionally substituted with from 1-4 independently selected R a ;

R 13 is:

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

(iii) C 8 -C 14 arylcycloalkyl, wherein:

(1) the aryl portion is optionally substituted with from 1-4 independently selected R b , and

(2) the cycloalkyl portion is optionally substituted with from 1-4 independently selected Ra; or

(iv) arylheterocyclyl containing from 8-14 ring atoms, wherein:

(1) the aryl portion from is optionally substituted with from 1-4 independently selected R b , and

(v) heteroarylheterocyclyl containing from 8-14 ring atoms, wherein:

(vi) heteroarylcycloalkyl containing from 8-14 ring atoms, wherein:

(2) the cycloalkyl portion is optionally substituted with from 1-4 independently selected R a ;

R a at each occurrence is, independently selected from halo, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, oxo, thioxo, ═NH, ═N(C 1 -C 6 alkyl), 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 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 ;

(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 wherein each of said phenyl and heterocyclyl is optionally substituted with from 1-3 independently selected R a ; 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)—;

or a pharmaceutically acceptable salt thereof;

provided that R 3 and R 6 cannot both be hydrogen when A is CH 2 , and R and R′ are defined according to definition (1);

provided that R 3 cannot be hydrogen when A is CH 2 , and R and R′ are defined according to definition (2);

provided that R 3 and R 6 cannot both be chloro when A is CH 2 , R and R′ are defined according to definition (1), Z is OR 12 , and R 12 is unsubstituted phenyl;

provided that R 3 and R 6 cannot both be bromo when A is CH 2 , R and R′ are defined according to definition (1), Z is OR 12 , and R 12 is phenyl that is substituted with pyridyl or alkyl that is substituted with from 1-3 R e ;

provided that R 3 and R 6 cannot both be hydrogen when A is CH(CH 3 ), R and R′ are defined according to definition (1), Z is NR 10 R 11 is CH 3 , and R 11 is unsubstituted phenyl; and

provided that when A is CR A1 R A2 , and one of R A1 and R A2 is OH, then the other of R A1 and R A2 is C 1 -C 3 alkyl.

2 . The compound of claim 1 , wherein A is:

(i) CR A1 R A2 , wherein each of R A1 and R A2 is independently selected from hydrogen, halo, C 1 -C 3 alkyl, 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 a double bond formed between A and one of L 1 and L 2 ; or

(ii) C═O.

3 . The compound of claim 1 , wherein A is CR AIR A2, wherein each of R A1 and R A2 is, independently, hydrogen, halo, C 1 -C 3 alkyl, OR 9 , or a double bond formed between A and one of L 1 and L 2 .

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

5 . The compound according to claim 4 , wherein the carbon attached to R A1 and R A2 is substituted with four different substituents.

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

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

9 . The compound 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 compound of claim 1 , 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.

11 . The compound of claim 1 , wherein R 3 is halo or C 1 -C 6 alkyl.

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

13 . The compound of claim 12 , 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.

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

15 . The compound of claim 1 , wherein Z is:

(i) —NR 10 R 11 ; or

(ii) —C(O)NR 10 R 11 ; or

(iii) —OR 12 ; or

(iv) —S(O) n R 13 , wherein n is 0, 1, or 2;

wherein each of R 10 , R 11 , R 12 , and R 13 is independently selected from:

(a) hydrogen;

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

wherein 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);

(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 ;

(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.

16 . The compound of claim 1 , selected from:

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

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

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

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

N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)-N-(3-methoxyphenyl)acetamide;

5-((3,6-dibromo-9H-carbazol-9-yl)methyl)-3-(3-methoxyphenyl)-oxazolidin-2-one;

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

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-one;

N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-methoxypropyl)-3-methoxyaniline;

1-(3,6-Dimethyl-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol;

1-(3-Bromo-6-methyl-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol;

1-(3,6-Dichloro-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol;

1-(5-bromo-2,3-dimethyl-1H-indol-1-yl)-3-(phenylamino)propan-2-ol;

1-(3,6-Dibromo-9H-pyrido [3 ,4-b]indol-9-yl)-3-(phenylamino)propan-2-ol;

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

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

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

3-(3,6-Dibromo-9H-carbazol-9-yl)-2-hydroxy-N-(3-methoxyphenyl)-propanamide;

Ethyl 5-(2-Hydroxy-3-(3-methoxyphenylamino)propyl)-8-methyl-3 ,4-dihydro-1H-pyrido [4,3-b]indole-2(5H)-carboxylate;

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

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

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-methoxyphenyl)(methyl)-amino)propan-2-ol;

3-(3,6-dibromo-9H-carbazol-9-yl)-1-(3-methoxyphenylamino)-1-(methylthio)propan-2-one;

3-amino-1-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)pyridinium;

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

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

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

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

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

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

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

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3 ,5-dimethyl-1H-pyrazol-1-yl)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-bromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol;

N-(5-(3-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropylamino)phenoxy)pentyl)-2-(7-(dimethylamino)-2-oxo-2H-chromen-4-yl)acetamide;

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

N-(2-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropoxy)ethyl)-acetamide;

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;

1-(2,8-dimethyl-3,4-dihydro-1H-pyrido [4,3-b]indol-5 (2H)-yl)-3-(phenylamino)propan-2-ol;

N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2,2-difluoropropyl)-3-methoxyaniline;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3,5-dimethylphenylamino)propan-2-ol;

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

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(2,5-dimethylphenylamino)propan-2-ol;

1-(4-bromophenylamino)-3-(2,3-dimethyl-1H-indol-1-yl)propan-2-ol;

1-(2,3-dimethyl-1H-indol-1-yl)-3-(4-methoxyphenylamino)propan-2-ol;

1-(2,3-dimethyl-1H-indol-1-yl)-3-(4-ethoxyphenylamino)propan-2-ol;

1-(2,3-dimethyl-1H-indol-1-yl)-3-(p-tolylamino)propan-2-ol;

1-(2,3-dimethyl-1H-indol-1-yl)-3-(phenylamino)propan-2-ol oxalate;

1-(1H-indol-1-yl)-3-(4-methoxyphenylamino)propan-2-ol hydrochloride;

1-(1H-indol-1-yl)-3-(phenylamino)propan-2-ol oxalate;

1-(3,4-dihydro-1H-carbazol-9(2H)-yl)-3-(m-tolylamino)propan-2-ol;

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

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

1-(9H-carbazol-9-yl)-3-(p-tolylamino)propan-2-ol;

1-(3,6-dichloro-9H-carbazol-9-yl)-3-(p-tolylamino)propan-2-ol;

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

N-(4-(3-(9H-carbazol-9-yl)-2-hydroxypropoxy)phenyl)acetamide;

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

1-(9H-carbazol-9-yl)-3-(4-methoxyphenylamino)propan-2-ol;

1-(benzylamino)-3-(9H-carbazol-9-yl)propan-2-ol;

methyl 4-(3-(9H-carbazol-9-yl)-2-hydroxypropoxy)benzoate;

1-(9H-carbazol-9-yl)-3-(4-methoxyphenoxy)propan-2-ol;

1-amino-3-(3,6-dibromo-9H-carbazol-9-yl)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-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-2-methylpropan-2-ol;

1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(3-methoxyphenylamino)propan-2-ol;

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

1-(3-azido-6-bromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol;

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

1-(3,6-dichloro-9H-carbazol-9-yl)-3-(phenylsulfonyl)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;

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

1-(3,6-diethynyl-9H-carbazol-9-yl)-3-(3-methoxyphenylamino) propan-2-ol;

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

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-methoxyaniline;

N-(2-bromo-3-(3,6-dibromo-9H-carbazol-9-yl)propyl)-N-(4-methoxyphenyl)-4-nitrobenzenesulfonamide;

Ethyl 2-(4-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropylamino)phenoxy)acetate; and

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

N-(2-(2-(4-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropylamino)phenoxy)acetamido)ethyl)-5-(2-oxohexahydro-1H-thieno [3,4-d]imidazol-4-yl)pentanamide;

2-(4-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropylamino)phenoxy)-N,N-dimethylacetamide;

2-(4-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropylamino)phenoxy)-N-(2-hydroxyethyl)acetamide;

(E)-3,6-dibromo-9-(3-phenoxyallyl)-9H-carbazole;

(E)-3,6-dibromo-9-(3-phenoxyprop-1-en-1-yl)-9H-carbazole;

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

1-(2,8-Dibromo-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-3-(3-methoxyphenylamino)propan-2-ol;

1-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylthio)propan-2-ol;

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

3,6-Dibromo-9-(2-fluoro-3-(3-methoxyphenylthio)propyl)-9H-carbazole;

3,6-Dibromo-9-(2-fluoro-3-(4-methoxyphenylthio)propyl)-9H-carbazole;

3,6-Dibromo-9-(2-fluoro-3-(3-methoxyphenylsulfonyl)propyl)-9H-carbazole;

1-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylsulfonyl)propan-2-ol;

3,6-Dibromo-9-(2-fluoro-3-(4-methoxyphenylsulfonyl)propyl)-9H-carbazole;

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

3-(3-(3,6-D ibromo-9H-carbazol-9-yl)-2-hydroxypropylthio)phenol;

4-(3-(3,6-D ibromo-9H-carbazol-9-yl)-2-hydroxypropylthio)phenol;

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

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

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

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

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

N-Benzyl-2-(3-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropylthio)-phenoxy)acetamide;

N-Benzyl-2-(4-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropylthio)-phenoxy)acetamide;

3-(3-(3,6-D ibromo-9H-carbazol-9-yl)-2-fluoropropylsulfonyl)phenol;N-B enzyl-2-(3-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropylsulfonyl)-phenoxy)acetamide;

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

5-(5-(3-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropylamino)phenoxy)pentylcarbamoyl)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid;

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

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

8-bromo-5-(2-hydroxy-3-phenoxypropyl)-3,4-dihydro-1H-pyrido [4,3-b]indole-2(5H)-carbonitrile;

8-bromo-5-(2-fluoro-3-phenoxypropyl)-2,3,4,5-tetrahydro-1H-pyrido [4,3-b]indole;

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

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

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

(R)—N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-3-methoxyaniline

(S)—N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-3-methoxyaniline

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

2-(6-Amino-3-imino-3H-xanthen-9-yl)-4-(6-(5-(3-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropylamino)phenoxy)pentylamino)-6-oxohexylcarbamoyl)benzoic acid AND 2-(6-amino-3-imino-3H-xanthen-9-yl)-5-(6-(5-(3-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropylamino)phenoxy)pentylamino)-6-oxohexylcarbamoyl)benzoic acid;

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

6-((4-bromophenyl)(2-hydroxy-3-phenoxypropyl)amino)nicotinonitrile;

1-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)pyridin-2(1H)-one;

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

tert-butyl (5-(4-((3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)sulfonyl)phenoxy)pentyl)carbamate;

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

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

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

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

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

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

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

tert-butyl 3-(2-(2-(2-(3-43-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)amino)phenoxy)ethoxy)ethoxy)ethoxy)propanoate;

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

1-(3,6-dibromo-1,8-dimethyl-9H-carbazol-9-yl)-3-(phenylamino)propan-2-ol;

2-(3,6-dibromo-9H-carbazol-9-yl)acetic acid;

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;

9-(2-hydroxy-3-phenoxypropyl)-9H-pyrido[3,4-b]indole-3-carboxylic acid;

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

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

(E)-N-(3-(3,6-dibromo-9H-carbazol-9-yl)prop-1-en-1-yl)-1, 1, 1-trifluoro-N-(3-methoxyphenyl)methane sulfonamide;

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

1-(3,6-dibromo-9H-1-carbazol-9-yl)-3-((6-methoxypyridin-2-yl)amino)propan-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;

8-bromo-5-(2-hydroxy-3-phenoxypropyl)-5H-pyrido[4,3-b]indole 2-oxide;

8-bromo-5-(2-hydroxy-3-phenoxypropyl)-5H-pyrido[3,2-b]indole 1-oxide;

(6-bromo-9H-pyrido [3,4-b]indol-3-yl)methanol;

ethyl 6-bromo-9H-pyrido [3,4-b]indole-3-carboxylate;

tert-butyl (3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)carbamate;

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

3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropan-1-amine hydrochloride;

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

2-(3,6-dibromo-9H-carbazol-9-yl)propanamide;

6-bromo-9H-pyrido[3,4-b]indole -3-carbonitrile;

6-bromo-3-methyl-9H-pyrido[3,4-b]indole;

methyl (2-(3,6-dibromo-9H-carbazol-9-yl)acetyl)carbamate;

N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-1,1,1-trifluoro-N-(3-methoxyphenyl)methane sulfonamide;

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

N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)-1, 1, 1-trifluoro-N-(3-methoxyphenyl)methane sulfonamide;

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

N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)-2,2,2-trifluoroacetamide;

tert-butyl (3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)carbamate;

5-(2-hydroxy-3-phenoxypropyl)-5H-pyrimido[5,4-b]indole -2-carboxylic acid;

N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)acetamide;

ethyl (3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)carbamate;

6-bromo-9-(3-(4-bromophenoxy)-2-hydroxypropyl)-9H-carbazole -3-carbonitrile;

methyl 9-(2-hydroxy-3-phenoxypropyl)-9H-pyrido [3,4-b]indole-3-carboxylate; and

N-(3-(3-bromo-6-methyl-9H-carbazol-9-yl)-2-fluoropropyl)-6-methoxypyridin-2-amine;

or a pharmaceutically acceptable salt thereof.

17 . A pharmaceutical composition comprising the compound or salt of claim 1 and a pharmaceutically acceptable carrier.

18 . A method for the treatment of a disease, disorder, or condition associated with unwanted neuronal cell death or insufficient neurogenesis, the method comprising administering an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

19 . The method of claim 18 , wherein the disease, disorder, or condition is a neuropsychiatric and/or neurodegenerative disease selected from the group consisting of: 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, and cognitive decline associated with normal aging, and chemotherapy.

20 . A method of treating a disease, disorder, or condition associated with unwanted neuronal cell death or insufficient neurogenesis, the method comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof:

wherein:

R and R′ are defined according to (1), (2), (3) or (4) below:

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

(4) each of R and R′ is, independently, hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;

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 each of R A1 and R A2 is independently selected from hydrogen, halo, C 1 -C 3 alkyl, Ole, wherein R 9 is hydrogen or C 1 -C 3 alkyl that is optionally substituted with hydroxyl or C 1 -C 3 alkoxy, or a double bond formed between A and one of L 1 and L 2 ; or

(ii) C═O; or

(iii) C 3 -C 5 cycloalkylene that is (a) substituted with 1 oxo; and (b) optionally further substituted with from 1-4 independently selected R a ; or

Z is:

—NR 10 R 11 ; or