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CN-122029149-A - 3- (2- (Dimethylamino) ethyl) -1H-indol-4-yl oligoderivatives

CN122029149ACN 122029149 ACN122029149 ACN 122029149ACN-122029149-A

Abstract

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

Inventors

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

Assignees

  • 指南针探路者有限公司

Dates

Publication Date
20260512
Application Date
20240823
Priority Date
20230825

Claims (20)

  1. 1. A compound of formula (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; p is 2 or 3; R D is a divalent or trivalent radical selected from the group consisting of alkylene, alkenylene, alkylene-O-alkylene, - (CH 2 ) n -(OCH 2 CH 2 ) m -, cycloalkylene, or arylene, or Each of which is optionally substituted with 1-4 groups selected from halogen, OH, oalkyl, alkyl, NH 2 , NH (alkyl), N (alkyl) 2 , C (=o) OH, C (=o) oalkyl, OC (=o) alkyl, or C (=o) alkyl; n is 1, 2, 3, 4, 5, 6, 7 or 8; m is 1, 2, 3, 4, 5, 6, 7 or 8; r is 1, 2 or 3; Provided that when R 2 and R 3 are each non-deuterated alkyl, then R D is not CH 2 、(CH 2 ) 2 、(CH 2 ) 3 、(CH 2 ) 4 、(CH 2 ) 5 、(CH 2 ) 8 、 、 、 、 Or (b) , And provided that when R 2 and R 3 are each CD 3 , then R D is not (CH 2 ) 3 .
  2. 2. The compound of claim 1, wherein R D is a divalent or trivalent radical selected from the group consisting of C 1-12 alkylene, C 1-6 alkylene-O-C 1-6 alkylene, - (CH 2 ) n -(OCH 2 CH 2 ) m -、C 3-8 cycloalkylene, arylene, or Each of which is optionally substituted with 1 to 4 groups selected from C 1-3 alkyl, OH, OCH 3 、NH 2 , COOH or C (=O) alkyl.
  3. 3. The compound of claim 1, wherein R D is a divalent or trivalent radical selected from the group consisting of alkylene-O-alkylene, - (CH 2 ) n -(OCH 2 CH 2 ) m -, cycloalkylene, heterocyclylene, arylene, heteroarylene, or Each of which is optionally substituted with OH, OCH 3 、NH 2 , COOH, cycloalkyl or C (=o) alkyl.
  4. 4. A compound according to claim 1 or 3, wherein R D is a divalent or trivalent radical selected from the group consisting of C 1-6 alkylene-O-C 1-6 alkylene, - (CH 2 ) n -(OCH 2 CH 2 ) m -、C 3-8 cycloalkylene, 3-8 membered heterocyclylene, arylene, heteroarylene or Each of which is optionally substituted with OH, OCH 3 、NH 2 , COOH, cycloalkyl or C (=o) alkyl.
  5. 5. The compound of claim 1, wherein the compound is of formula (Ia) (Ia), Or a pharmaceutically acceptable salt or deuterated form thereof, Wherein: each R 2 and R 3 is independently alkyl; Each R 4 is independently H or C (=o) oxyalkyl; r E is a divalent radical selected from the group consisting of alkylene, cycloalkylene, arylene, alkylene-O-alkylene, - (CH 2 ) n -(OCH 2 CH 2 ) m -, or Each of which is optionally substituted with one or more groups selected from halogen, alkyl, oalkyl, NH 2 、NHC 1-6 alkyl, NC ( 1-6 alkyl) 2 , COOH, cycloalkyl and C (=o) oalkyl; n is 1, 2 or 3; m is 1, 2 or 3, and R is 1, 2 or 3.
  6. 6. The compound of claim 5, wherein R E is a divalent radical selected from the group consisting of C 1-12 alkylene, C 3-8 cycloalkylene, arylene, C 1-6 alkylene-O-C 1-6 alkylene, - (CH 2 ) n -(OCH 2 CH 2 ) m -, or Each of which is optionally substituted with one or more groups selected from halogen, C 1-3 alkyl, oalkyl, NH 2 、NHC 1-6 alkyl, NC ( 1-6 alkyl) 2 、COOH、C 3-8 cycloalkyl and C (=o) oalkyl.
  7. 7. The compound of any one of claims 5-6, wherein the alkylene group is linear or branched.
  8. 8. The compound of any one of claims 6-7, wherein the alkylene group is branched.
  9. 9. The compound of any one of claims 1-8, wherein R D or R E is 、 、 、 、 、-(CH 2 ) 2 -(OCH 2 CH 2 ) 2 -、-(CH 2 ) 2 -(OCH 2 CH 2 ) 3 -、 、 、 、 、 Or (b) 。
  10. 10. The compound of claim 1, wherein the compound is of formula (Ib) (Ib), Or a pharmaceutically acceptable salt or deuterated form thereof, Wherein: each R 2 and R 3 is independently alkyl; each R 4 is independently H or C (=O) Oalkyl, and R F is a trivalent cycloalkylene or alkylene group.
  11. 11. The compound of claim 10, wherein R F is trivalent C 3-8 cycloalkylene.
  12. 12. The compound of claim 10 or 11, wherein R F is 。
  13. 13. A compound of formula (IIa), (IIa), Or a pharmaceutically acceptable salt or deuterated form thereof, Wherein: each R 2 and R 3 is independently alkyl; Each R 4 is independently H or C (=o) oxyalkyl; R H is- - (CH 2 ) n -(OCH 2 CH 2 ) m - -or alkylene; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, and M is 1, 2 or 3; Provided that when R 2 and R 3 are each CH 3 , then R H is not- - (CH 2 ) 2 - -or- - (CH 2 ) 3 - -).
  14. 14. The compound of claim 13, wherein, N is 1,2,3, 4, 5, 6, 7, 8, and M is 1, 2 or 3.
  15. 15. The compound of claim 13 or 14, wherein R H is- (CH 2 ) 5 -、-(CH 2 ) 8 -or- (CH 2 ) 2 -(OCH 2 CH 2 ) 2 ).
  16. 16. A compound of formula (III) (III), 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 1 is alkylene-C (=o) OH, wherein the alkylene is optionally substituted with OH, C (=o) OH, -OC (=o) alkyl or NH 2 , alkenylene-C (=o) OH, wherein the alkenylene is optionally substituted with C (=o) OH, cycloalkylene-C (=o) OH, wherein the cycloalkylene is optionally substituted with C (=o) OH, arylene-C (=o) OH, wherein the arylene is optionally substituted with alkyl, oalkyl or C (=o) OH, - (CH 2 CH 2 O) m -(CH 2 CH 2 ) n -C (=o) OH, alkylene-O-alkylene-C (=o) OH, arylene-O (c=o) -alkylene-C (=o) OH, O-alkylene-OH, wherein the alkylene is optionally substituted with OH or- (OCH 2 CH 2 ) m -OH; m is 1, 2,3, and N is 1, 2 and 3, Provided that when R 2 and R 3 are each alkyl, then R 1 is not (CH 2 ) 2 C(=O)OH、(CH 2 ) 3 C (=o) OH, -ch=chc (=o) OH or 。
  17. 17. The compound of claim 16, wherein R 1 is C 1-10 alkylene-C (=o) OH, wherein the alkylene is optionally substituted with OH, C (=o) OH, -OC (=o) alkyl, or NH 2 、C 1-6 alkylene-C (=o) OH, wherein the alkylene is optionally substituted with C (=o) OH, C 3-6 cycloalkyl-C (=o) OH, wherein the cycloalkylene is optionally substituted with C (=o) OH, arylene-C (=o) OH, wherein the arylene is optionally substituted with alkyl, O alkyl, or C (=o) OH, - (CH 2 CH 2 O) m -(CH 2 CH 2 ) n -C(=O)OH、C 1-6 alkylene-O-C 1-6 alkylene-C (=o) OH, arylene-O (c=o) -C 1-6 alkylene-C (=o) O-arylene-C (=o) OH, O-C 1-10 alkylene-OH, wherein the alkylene is optionally substituted with OH or- (OCH 2 CH 2 ) m -OH.
  18. 18. The compound of claim 16 or 17, wherein R 1 is 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Or (b) 。
  19. 19. The compound of any one of claims 16-18, wherein R 1 is- (CH 2 CH 2 O) m -(CH 2 CH 2 ) n -C (=o) OH.
  20. 20. The compound of any one of claims 15-19, wherein R 1 is 、 Or (b) 。

Description

3- (2- (Dimethylamino) ethyl) -1H-indol-4-yl oligoderivatives Cross Reference to Related Applications The present application claims priority from U.S. provisional application No. 63/578,799 filed on 25 at 8/2023, the disclosure of which is incorporated 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. Approximately 1/5 suffers from psychological disorders and approximately 1/25 from severe psychological disorders, such as major depression, schizophrenia or bipolar disorder. Hallucinogens have shown promising activity in the treatment of psychological disorders. There is a need for novel hallucinogen compounds for the treatment of psychological disorders. Drawings Figure 1 shows pharmacokinetic data for compound 122 administered subcutaneously. Disclosure of Invention In some embodiments, the present disclosure provides a compound of formula (I): Or a pharmaceutically acceptable salt thereof, or deuterated form thereof, wherein: R 2 and R 3 are independently alkyl; R 4 is H or C (=o) oalkyl; p is 2 or 3; R D is a divalent or trivalent radical selected from the group consisting of alkylene, alkenylene, alkylene-O-alkylene, - (CH 2)n-(OCH2CH2)m -, cycloalkylene, or arylene, or Each of which is optionally substituted with 1 to 4 groups selected from halogen, OH, oalkyl, alkyl, NH 2, NH (alkyl), N (alkyl) 2, C (=o) OH, C (=o) oalkyl, OC (=o) alkyl, C (=o) alkyl, or cycloalkyl; n is 1, 2, 3, 4, 5, 6, 7 or 8; m is 1, 2, 3, 4, 5, 6, 7 or 8; r is 1, 2 or 3; With the proviso that when R 2 and R 3 are each alkyl, then R D is not CH2、(CH2)2、(CH2)3、(CH2)4、(CH2)5、(CH2)8、 、、、Or (b), And with the proviso that when R 2 and R 3 are each deuterated alkyl, then R D is not (CH 2)3. In some embodiments, the present disclosure provides a compound of formula (II): , 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; q is 2, 3 or 4; R G is- (CH 2)n-(OCH2CH2)m -, or a divalent, trivalent or tetravalent alkylene or alkenylene group; n is 1,2,3, 4, 5, 6, 7 or 8, and M is 0,1, 2, 3, 4, 5, 6, 7 or 8; Provided that when q is 2 and R 2 and R 3 are each CH 3, then R G is not- (CH 2)2 -or- (CH 2)3 -). In some embodiments, the present disclosure provides a compound of formula (III): Or a pharmaceutically acceptable salt thereof, or deuterated form thereof, wherein: R 2 and R 3 are independently alkyl; R 4 is H or C (=o) oalkyl; R 1 is alkylene-C (=o) OH, wherein the alkylene is optionally substituted with OH, C (=o) OH, -OC (=o) alkyl or NH 2, alkenylene-C (=o) OH, wherein the alkenylene is optionally substituted with C (=o) OH, cycloalkylene-C (=o) OH, wherein the cycloalkylene is optionally substituted with C (=o) OH, arylene-C (=o) OH, wherein the arylene is optionally substituted with alkyl, oalkyl or C (=o) OH, - (CH 2CH2O)m-(CH2CH2)n -C (=o) OH, alkylene-O-alkylene-C (=o) OH, arylene-O (c=o) -alkylene-C (=o) OH, O-alkylene-OH, wherein the alkylene is optionally substituted with OH or- (OCH 2CH2)m -OH; m is 1, 2 and 3, N is 1, 2 and 3, Provided that when R 2 and R 3 are each alkyl, then R 1 is not (CH 2)2、(CH2)3, -ch=ch-。 Detailed Description Definition of the definition The following terms, as used herein, have the following meanings, unless otherwise indicated: "cyano" refers to a-CN group. "Hydroxyl" refers to the-OH group. "Oxo" (oxo) refers to a =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 of carbon atoms from 1 to 12. 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 a C 1-C5 alkyl group. C 1-C5 alkyl includes C 5 alkyl, C 4 alkyl, C 3 alkyl, C 2 alkyl, and C 1 alkyl (i.e., methyl). C 1-C6 alkyl includes all of the moieties described above for C 1-C5 alkyl but also includes C 6 alkyl. C 1-C10 alkyl includes all of the moieties described above for C 1-C5 alkyl and C 1-C6 alkyl, but also includes C 7、C8、C9 and C 10 alkyl. Similarly, C 1-C12 alkyl includes all of the foregoing moieties, but also includes C 11 and C 12 alkyl. Non-limiting examples of C 1-C12 alkyl groups include methyl, ethyl, n-propyl, isopropyl, sec-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-dodecyl. Unless otherwise specifically indicated in the present specification, an alkyl group may be optionally substituted. "Alkylene" or "alkylene chain (ALKYLENE CHAIN)" refers to a fully saturated, straight or branched, multivalent