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CN-122003400-A - 3- (2- (Dimethylamino) ethyl) -1H-indol-4-yl derivatives

CN122003400ACN 122003400 ACN122003400 ACN 122003400ACN-122003400-A

Abstract

Provided herein are compounds of formula (I), (I) A compound selected from any one of the compounds in table 1, table 2, table 3, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R 1 、R 2 、R 3 and R 4 are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of formula (I) or a compound selected from any one of the compounds of table 1, table 2, table 3, or a pharmaceutically acceptable salt or deuterated form thereof, and methods of using a compound of formula (I) or a pharmaceutically acceptable salt or deuterated form thereof, e.g., to treat a 5-HT 2 a receptor-related disease or disorder.

Inventors

  • MORPHY JOHN RICHARD
  • T.M. Beck
  • A.W. BROWN

Assignees

  • 指南针探路者有限公司

Dates

Publication Date
20260508
Application Date
20240823
Priority Date
20230825

Claims (20)

  1. 1. A compound of formula (I) (I), Or a pharmaceutically acceptable salt or deuterated form thereof, Wherein: R 2 and R 3 are independently alkyl; R 4 is H or C (=O) Oalkyl, and R 1 is defined according to i, ii, iii or iv: i. R 1 is-OR 8 , wherein R 8 is alkynyl-substituted NR 5 R 6 , OR- (CH 2 CH 2 O) m- alkyl) wherein m is 1, 2, 3, 5 OR 6; R 5 and R 6 are independently H, alkyl, C (=o) alkyl, alkylene-aryl or S (O) 2 alkyl; R 1 is-R 9A , wherein R 9A is-C (R A ) 2 NR 5 R 6 、-C(R A ) 2 -O-alkyl, -C (R A ) 2 -O-cycloalkyl, cycloalkyl substituted by-O alkyl, heterocyclyl substituted by-C (=O) O alkyl, alkenylene-aryl wherein aryl is substituted by 1-4R 7A , alkenylene-heteroaryl wherein heteroaryl is substituted by 0-4R 7A , aryl substituted by NR 5 R 6 , or 5 membered heteroaryl substituted by 1-4 groups selected from alkyl, OH, halogen, haloalkyl, O alkyl or O-haloalkyl; each R A is independently H, halo, unsubstituted alkyl or alkylene-OH, or Two R A together with the carbon to which they are attached form a cycloalkylene or heterocycloalkylene group, Provided that at least one R A is not H; r 5 and R 6 are independently H, alkyl, or Or C (=o) alkyl in which the alkyl group is optionally substituted with NH 2 , NH (alkyl), N (alkyl) 2 , C (=o) aryl, C (=o) oalkyl, S (O) 2 alkyl, or alkylene-heterocyclyl; r 7A is OH, halo, alkyl, haloalkyl, O-alkyl, OC (=o) alkyl, si (alkyl) 3 , aryl, NH (c=o) alkyl, NH 2 , NH (alkyl), N (alkyl) 2 , or heterocyclyl; provided that R 9A is not 。 R 1 is- (CH 2 ) n -R 9B ) in which N is 1,2,3, 4, 5 or 6; R 9B is-O-alkylene-OH, -C (=O) -alkylene-NR 5 R 6 , alkylene-aryl substituted by 1-4R 7B , si (alkyl) 3 or- (OCH 2 CH 2 ) m -Oalkyl wherein m is 2 or 3, provided that when R 9B is Si (alkyl) 3 or When n is not 1; r 5 and R 6 are independently H, alkyl, C (=o) aryl, C (=o) oalkyl, S (O) 2 alkyl, alkylene-heterocyclyl; R 7B is-OP (=o) OH 2 ,C 1-6 alkyl; r 1 is-N (R 5A )(R 6A ), wherein R 5A and R 6A are independently H, C 1-6 alkyl optionally substituted by-COOH, -OC (=O) alkyl or-O-alkylene-OH, Provided that when one of R 5A and R 6A is H, the other cannot be H, CH 2 CH(CH 3 ) 2 or (CH 2 ) 5 CH 3 , and When one of R 5A and R 6A is CH 3 , the other cannot be H, CH 3 or CH 2 CH 3 、CH 2 CH(CH 3 ) 2 or 。
  2. 2. The compound of claim 1, wherein the compound is of formula (II): (II), or a pharmaceutically acceptable salt or deuterated form thereof, Wherein: R 8 is alkynyl-NR 5 R 6 or- (CH 2 CH 2 O) m- alkyl); m is 1,2, 3, 5 or 6; R 2 and R 3 are independently alkyl; R 4 is H or C (=O) Oalkyl, and R 5 and R 6 are independently H, alkyl, C (=o) H, C (=o) alkyl, alkylene-heteroaryl, alkylene-aryl, alkylene-carbocyclyl, alkylene-heterocyclyl, S (=o) alkyl, or S (=o) 2 alkyl.
  3. 3. The compound of claim 1 or 2, wherein R 8 is: C1-6 alkynyl substituted by N (C 1-6 alkyl) 2 , or - (CH 2 CH 2 O) m -CH 3 ) wherein m is 1,2 or 3.
  4. 4. A compound according to any one of claims 1-3, wherein R 8 is - (CH 2 CH 2 O)-CH 3 、-(CH 2 CH 2 O) 2 -CH 3 or- (CH 2 CH 2 O) 3 -CH 3 ).
  5. 5. The compound of claim 1, wherein the compound is of formula (III): (III), or a pharmaceutically acceptable salt or deuterated form thereof, Wherein: R 9A is-C (R A ) 2 NR 5 R 6 、-C(R A ) 2 -O-alkyl, -C (R A ) 2 -O-cycloalkyl, cycloalkyl substituted by Oalkyl, heterocyclyl substituted by C (=O) Oalkyl, alkenylene-aryl wherein aryl is substituted by 1-4R 7A , alkenylene-heteroaryl wherein heteroaryl is substituted by 0-4R 7A , aryl substituted by NR 5 R 6 , or 5 membered heteroaryl substituted by 1-4 groups selected from alkyl, OH, halogen, haloalkyl, oalkyl or O-haloalkyl; each R A is independently H, halo, unsubstituted alkyl or alkylene-OH, or Two R A together with the carbon to which they are attached form a cycloalkylene or heterocycloalkylene group, Provided that at least one R A is not H; R 2 and R 3 are independently alkyl; R 4 is H or C (=o) oalkyl; R 5 and R 6 are independently H, alkyl, Or C (=o) alkyl in which the alkyl group is optionally substituted with NH 2 , NH (alkyl), or N (alkyl) 2 ; R 7A is OH, halo, alkyl, haloalkyl, O-alkyl, OC (=O) alkyl, si (alkyl) 3 , aryl, NH (C=O) alkyl, NH 2 , NH (alkyl), N (alkyl) 2 or heterocyclyl, Provided that R 9A is not 。
  6. 6. The compound according to claim 5, wherein R 9A is selected from-C (R A ) 2 NR 5 R 6 、-C(R A ) 2 -O-C 1-6 alkyl, -C (R A ) 2 -O-C 3-6 cycloalkyl, cyclopropyl substituted with OC 1-6 alkyl, heterocyclyl substituted with C (=o) OC 1-6 alkyl, C 1-6 alkenylene-aryl wherein aryl is substituted with 1-4R 7A , C 1-6 alkenylene-heteroaryl, arylene-NR 5 R 6 , or 5 membered heteroaryl comprising two N atoms wherein heteroaryl is substituted with C 1-3 alkyl; each R A is independently H or unsubstituted alkyl, provided that at least one R A is not H, R 2 and R 3 are independently alkyl; R 4 is H or C (=o) oalkyl; R 5 and R 6 are independently H, alkyl, Or C (=o) alkyl in which the alkyl group is optionally substituted with NH 2 , NH (alkyl), or N (alkyl) 2 ; R 7A is OH, halo, alkyl, haloalkyl, O-alkyl, OC (=o) alkyl, si (alkyl) 3 , aryl, NH (c=o) alkyl, NH 2 , NH (alkyl), N (alkyl) 2 , or heterocyclyl.
  7. 7. The compound of any one of claims 1 or 5-6, wherein R 9A is 、 、 、 、 、 、 、 、 Or (b) 。
  8. 8. The compound of claim 1, wherein the compound is of formula (IV): (IV), or a pharmaceutically acceptable salt or deuterated form thereof, Wherein: n is 1,2,3, 4, 5 or 6; R 9B is-O-alkylene-OH, -C (=O) -alkylene-NR 5 R 6 , alkylene-aryl in which the aryl group is substituted with 1-4R 7B , si (alkyl) 3 or- (OCH 2 CH 2 ) m -Oalkyl; m is 2 or 3; R 2 and R 3 are independently alkyl; R 4 is H or C (=o) oalkyl; R 5 and R 6 are independently H, alkyl, C (=o) aryl, C (=o) oalkyl, S (O) 2 alkyl, or alkylene-heterocyclyl; r 7B is-OP (=o) OH 2 ,C 1-6 alkyl, With the proviso that when R 9B is Si (alkyl) 3 or When n is not 1.
  9. 9. The compound according to any one of claims 1 or 8, wherein N is 1, 2 or 3; R 9B is-O-C 1-6 alkylene-OH or-C (=O) -C 1-6 alkylene-NR 5 R 6 , C 1-6 alkylene-aryl in which the aryl group is substituted by 1 to 4R 7B , si (C 1-6 alkyl) 3 or- (OCH 2 CH 2 ) m -Oalkyl; m is 2 or 3; R 2 and R 3 are independently alkyl; R 4 is H or C (=o) OC 1-6 alkyl; R 5 and R 6 are independently H or alkyl.
  10. 10. The compound of any one of claims 1 or 8-9, wherein R 9B is 、 、Si(CH 3 ) 3 、 Or (b) 。
  11. 11. The compound of any one of claims 1 or 8-10, wherein n is 1,2, or 3, and R 9B is 、 、Si(CH 3 ) 3 、 Or (b) 。
  12. 12. The compound of claim 1, wherein the compound is of formula (V): (V), Or a pharmaceutically acceptable salt or deuterated form thereof, Wherein: R 2 and R 3 are independently alkyl; R 4 is H or C (=o) oalkyl; R 5A and R 6A are independently H, C 1-6 alkyl optionally substituted by-COOH, -OC (=O) alkyl or-O-alkylene-OH, Provided that neither R 5A nor R 6A is H, and when one of R 5A and R 6A is H, the other cannot be H, - (CH 2 ) 5 CH 3 or CH 2 CH(CH 3 ) 2 , and With the further proviso that when one of R 5A and R 6A is CH 3 , the other cannot be H, CH 3 or CH 2 CH 3 、CH 2 CH(CH 3 ) 2 , Or (b) 。
  13. 13. The compound of claim 1 or 12, wherein R5a And R6A is independently H, CH 3 , 、 、 、 、 Or (b) 。
  14. 14. A compound of formula (VI) (V), or a pharmaceutically acceptable salt or deuterated thereof Wherein: r is NR 5 R 6 ; R 2 and R 3 are independently alkyl; R 4 is H or C (=o) oalkyl; R 5 and R 6 are independently H, alkyl, haloalkyl or C (=o) haloalkyl.
  15. 15. The compound of claim 14, wherein R 5 is H and R 6 is C (=o) CF 3 .
  16. 16. A compound of formula (VII) (VII), Or a pharmaceutically acceptable salt or deuterated form thereof, Wherein: R 2 and R 3 are independently alkyl; r c is OH or OC (=o) alkyl; R 10 is NR 5A R 6A , O-alkylene-OC (=o) alkyl, O-alkylene-Si (alkyl) 2 , heterocycle or aryl; R 5A and R 6A are independently alkyl or alkylene-OC (=o) alkyl.
  17. 17. The compound according to claim 16, wherein R c is OH or OC (=o) C 1-6 alkyl; R 10 is NR 5A R 6A 、O-C 1-6 alkylene-OC (=O) C 1-6 alkyl, -O-C 1-6 alkylene-Si (C 1-6 alkyl) 2 , a 3-8 membered heterocycle, or aryl; R 5A and R 6A are independently C 1-6 alkyl or C 1-6 alkylene-OC (=o) C 1-6 alkyl.
  18. 18. The composition of claim 16 or 17, wherein R c is OH or OC (=O) CH 3 , and R 10 is 、 、 、 、 、 Or (b) 。
  19. 19. The compound of any one of claims 1-18, wherein R 2 and R 3 are independently C 1-6 alkyl.
  20. 20. The compound of any one of claims 1-19, wherein R 2 and R 3 are-CH 3 .

Description

3- (2- (Dimethylamino) ethyl) -1H-indol-4-yl derivatives Cross Reference to Related Applications The present application claims priority from U.S. provisional application No. 63/578,791 filed on 8/25 of 2023, the disclosure of which is incorporated herein by reference in its entirety for all purposes. Background Over 50% of american adults will be diagnosed with a psychotic disorder at some point in their lifetime. Nearly one fifth of people suffer from mental disorders, and nearly twenty-five people suffer from severe mental disorders such as major depressive disorder, schizophrenia, or bipolar disorder. The hallucinogens exhibit promising activity in the treatment of psychotic disorders. New hallucinogen compounds are needed to treat psychotic disorders. Disclosure of Invention In some embodiments, the present disclosure provides compounds of formula (I): (I), Or a pharmaceutically acceptable salt or deuterated form thereof, Wherein: R 2 and R 3 are independently alkyl; R 4 is H or C (=O) Oalkyl, and R 1 is defined according to i, ii, iii or iv: i.R 1 is-OR 8, wherein R 8 is alkynyl-substituted NR 5R6, OR- (CH 2CH2O)m- alkyl), wherein m is 1, 2,3,5 OR 6; R 5 and R 6 are independently H, alkyl, C (=o) alkyl, alkylene-aryl or S (O) 2 alkyl; R 1 is-R 9A, wherein R 9A is-C (R A)2NR5R6、-C(RA)2 -O-alkyl, -C (R A)2 -O-cycloalkyl, cycloalkyl substituted by O alkyl, heterocyclyl substituted by C (=O) O alkyl, alkenylene wherein aryl is substituted by 1-4R 7A, alkenylene wherein heteroaryl is substituted by 0-4R 7A, or aryl substituted by NR 5R6; each R A is independently H, halo, unsubstituted alkyl or alkylene-OH, or Two R A together with the carbon to which they are attached form a cycloalkylene or heterocycloalkylene group, Provided that at least one R A is not H; r 5 and R 6 are independently H, alkyl, or Or C (=o) alkyl in which the alkyl group is optionally substituted with NH 2, NH (alkyl), N (alkyl) 2, C (=o) aryl, C (=o) oalkyl, S (O) 2 alkyl, or alkylene-heterocyclyl; r 7A is OH, halo, alkyl, haloalkyl, O-alkyl, OC (=o) alkyl, si (alkyl) 3, aryl, NH (c=o) alkyl, NH 2, NH (alkyl), N (alkyl) 2, or heterocyclyl; provided that R 9A is not , R 1 is- (CH 2)n-R9B) in which N is 1,2,3, 4, 5 or 6; R 9B is-O-alkylene-OH, -C (=O) -alkylene-NR 5R6, alkylene-aryl substituted by 1-4R 7B, si (alkyl) 3 or- (OCH 2CH2)m -Oalkyl wherein m is 2 or 3,5 or 6, provided that when R 9B is Si (alkyl) 3 or When n is not 1; r 5 and R 6 are independently H, alkyl, C (=o) aryl, C (=o) oalkyl, S (O) 2 alkyl, alkylene-heterocyclyl; R 7B is-OP (=o) OH 2,C1-6 alkyl; R 1 is-N (R 5A)(R6A), where R 5A and R 6A are independently H, C 1-6 alkyl optionally substituted by-COOH, -OC (=O) alkyl or-O-alkylene-OH, Provided that when one of R 5A and R 6A is H, the other cannot be H, CH 2CH(CH3)2 or (CH 2)5CH3, and With the further proviso that when one of R 5A and R 6A is CH 3, the other cannot be H, CH 3 or CH 2CH3、CH2CH(CH3)2,Or (b)。 In some embodiments, the present disclosure provides compounds of formula (I) (I), Or a pharmaceutically acceptable salt or deuterated form thereof, Wherein: R 2 and R 3 are independently alkyl; R 4 is H or C (=O) Oalkyl, and R 1 is defined according to i, ii or iii: i.R 1 is-OR 8, wherein R 8 is- (CH 2CH2O)m- alkyl) m is 2,3, 5 OR 6; R 1 is-R 9A, wherein R 9A is-C (R A)2 -O-alkyl, -C (R A)2 -O-cycloalkyl, cycloalkyl substituted with OC 1-6 alkyl, heterocyclyl substituted with C (=o) O alkyl, a 5 membered heteroaryl containing two N atoms, wherein the heteroaryl is substituted with C 1-3 alkyl, or arylene-NR 5R6; R 5 and R 6 are independently H, alkyl, Or C (=O) alkyl in which the alkyl group is optionally substituted by NH 2, NH (alkyl) or N (alkyl) 2, Each R A is independently H, halo, unsubstituted alkyl or alkylene-OH, or Two R A together with the carbon to which they are attached form a cycloalkylene or heterocycloalkylene group, Provided that at least one R A is not H; R 1 is- (CH 2)n-R9B) in which N is 1,2,3, 4, 5 or 6; R 9B is-branched alkylene-aryl wherein aryl is substituted with 1-4R 7B, si (alkyl) 3 or- (OCH 2CH2)m -Oalkyl; r 7B is-OP (=o) OH 2,C1-6 alkyl, With the proviso that when R 9B is Si (alkyl) 3 orWhen n is not 1. Detailed Description Definition of the definition Unless otherwise indicated, the following terms as used herein have the following meanings: "cyano" refers to a CN group. "Hydroxyl" refers to the-OH group. "Oxo" refers to an =o substituent. "Alkyl" or "alkyl group" refers to a fully saturated straight or branched hydrocarbon chain group having one to twelve carbon atoms, and which is attached to the remainder of the molecule by a single bond. Including alkyl groups containing any number from 1 to 12 carbon atoms. The alkyl group containing up to 12 carbon atoms is a C 1-C12 alkyl group, the alkyl group containing up to 10 carbon atoms is a C 1-C10 alkyl group, the alkyl group containing up to 6 carbon atoms is a C 1-C6 alkyl group, and the alkyl group containing up to 5 carbon atoms is