Substituted aldehyde compounds and methods for their use in increasing tissue oxygenation

Patent metadata

Field	Value
Publication number	US-10100043-B2
Application number	US-201414776723-A
Country	US
Kind code	B2
Filing date	Mar 14, 2014
Priority date	Mar 15, 2013
Publication date	Oct 16, 2018
Grant date	Oct 16, 2018

Abstract

Provided are cycloalkyl- and cycloalkenyl-substituted benzaldehydes and heteroaldehydes of formula (I) that act as allosteric modulators of hemoglobin, methods and intermediates for their preparation, pharmaceutical compositions containing the modulators, and methods for their use in treating disorders mediated by hemoglobin and disorders that would benefit from increased tissue oxygenation.

First claim

What is claimed is:

1. A compound of Formula (I):

a tautomer, a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein:
Q is cycloalkyl or cycloalkenyl, each of which is substituted with one to three R a ;
Y is CR 1a R 1b , wherein
R 1a is H or halo, and
R 1b is H or halo;

X is 0;
T 1 , T 2 , T 3 , and T 4 are independently C or N provided that at least one of T 1 , T 2 , T 3 , and T 4 is C; wherein when T 1 , T 2 , T 3 , or T 4 are N, then R 2 , R 3 , R 4 , or R 5 , respectively, are absent;
R 2 , R 3 , and R 4 are independently hydrogen, halo, R b , OR d , or NR d NR d ;
R 5 is selected from the group consisting of hydrogen, halo, R b , OR d , —O(CH 2 ) z OR d , —O(CH 2 ) z NR d R d , OC(O)R e , SR d , CN, NO 2 , CO 2 R d , CONR d R d , C(O)R d , OC(O)NR d R d , NR d R d , NR d C(O)R e , NR d C(O) 2 R e , NR d C(O)NR d R d , S(O)R e , S(O) 2 R e , NR d S(O) 2 R e , S(O) 2 NR d R d , and N 3 ; wherein z is 0, 1, 2, 3, 4, 5, or 6; or
R 5 is —(CH 2 ) p R 5a , wherein p is 0 or 1 and R 5a is OH;
R 6 and R 7 together form oxo or an aldehyde protecting group, or
R 6 together with R 1b or R 5 forms a cyclic ether, wherein
one of R 1b or R 5a is O, R 6 is a bond, and
R 7 is selected from the group consisting of OH, C 1-8 alkoxy, and haloC 1-8 alkoxy;

each R a is independently selected from the group consisting of halo, R b , OR d , —(CH 2 ) k CO 2 (C 1-8 alkyl)OH, —(CH 2 ) k CO 2 R d , —(CH 2 ) k CONR d R d , —(CH 2 ) k C(O)R d , —(CH 2 ) k aryl optionally substituted with one to three R c , —(CH 2 ) k heteroaryl optionally substituted with one to three R c , and —(CH 2 ) k heterocycloalkyl optionally substituted with one to three R c ; wherein k is 0, 1, 2, 3, 4, 5, or 6; and wherein at least one of R a is selected from the group consisting of OR d , —(CH 2 ) k CO 2 (C 1-8 alkyl)OH, —(CH 2 ) k CO 2 R d , —(CH 2 ) k CONR d R d , —(CH 2 ) k C(O)R d , —(CH 2 ) k aryl optionally substituted with one to three R c , —(CH 2 ) k heteroaryl optionally substituted with one to three R c , —(CH 2 ) k heterocycloalkyl optionally substituted with one to three R c , substituted C 1-8 alkyl, substituted C 2-8 alkenyl, and substituted C 2-8 alkynyl; wherein the substituted C 1-8 alkyl, substituted C 2-8 alkenyl, and substituted C 2-8 alkynyl are each substituted with one to three halo, OR d , or NR d R d ;
each R b is independently selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, and C 2-8 alkynyl, each optionally independently substituted with one to three halo, OR d , or NR d R d ;
each R c is independently selected from the group consisting of halo, C 1-8 alkyl, haloC 1-8 alkyl, C 2-8 alkenyl, haloC 2-8 alkenyl, C 2-8 alkynyl, haloC 2-8 alkynyl, (CH 2 ) m OR f , heteroaryl, cycloalkyl, and heterocycloalkyl; wherein m is selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6;
each R d is independently selected from the group consisting of hydrogen, C 1-8 alkyl, haloC 1-8 alkyl, C 2-8 alkenyl, haloC 2-8 alkenyl, C 2-8 alkynyl, haloC 2-8 alkynyl, —(CH 2 ) k heterocycloalkyl, and —(CH 2 ) u O—(CH 2 ) u H; wherein k is 0, 1, 2, 3, 4, 5, or 6 and each u is independently 1, 2, 3, 4, 5, or 6;
each R f is independently selected from the group consisting of hydrogen, C 1-8 alkyl, haloC 1-8 alkyl, C 2-8 alkenyl, haloC 2-8 alkenyl, C 2-8 alkynyl, and haloC 2-8 alkynyl; and
R e is C 1-8 alkyl, haloC 1-8 alkyl, C 2-8 alkenyl, haloC 2-8 alkenyl, C 2-8 alkynyl, or haloC 2-8 alkynyl;
provided that:
at least one of R 4 and R 5 is other than hydrogen or
T 1 and T 3 are C; T 2 is N and T 4 is C, or T 2 is C and T 4 is N.

2. The compound according to claim 1 , a tautomer, a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein:
T 1 , T 2 , T 3 , and T 4 are C.

3. The compound according to claim 2 , a tautomer, a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein:
R 2 , R 3 , R 4 , and R 5 are independently hydrogen, halo, R b , or OR d .

4. The compound according to claim 3 , a tautomer, a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein Y is CH 2 .

5. The compound according to claim 1 , a tautomer, a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R 5 is OH; and R 2, R 3 and R 4 are hydrogen.

6. The compound according to claim 5 , a tautomer, a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein Q is cyclopentyl or cyclohexyl.

7. The compound according to claim 6 , a tautomer, a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein each R a is independently selected from the group consisting of R b , OR d , —(CH 2 ) k CO 2 R d , —(CH 2 ) k aryl optionally substituted with one to three R c , —(CH 2 )kheteroaryl optionally substituted with one to three R c , and —(CH 2 ) k heterocycloalkyl optionally substituted with one to three R c ; wherein k is 0, 1, 2, 3, 4, 5, or 6; and wherein at least one of R a is selected from the group consisting of OR d , —(CH 2 ) k CO 2 R d , —(CH 2 )karyl optionally substituted with one to three R c , —(CH 2 ) k heteroaryl optionally substituted with one to three R c , —(CH 2 ) k heterocycloalkyl optionally substituted with one to three R c , substituted C 1-8 alkyl, substituted C 2-8 alkenyl, and substituted C 2-8 alkynyl, wherein the substituted C 1-8 alkyl, substituted C 2-8 alkenyl, and substituted C 2-8 alkynyl are each substituted with one to three halo, OR d , or NR d R d .

8. The compound according to claim 6 , a tautomer, a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein Q is substituted with one R a which is heteroaryl optionally substituted with one to three R c .

9. The compound according to claim 8 , a tautomer, a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R a is selected from the group consisting of pyridinyl, pyrazolyl, and imidazolyl, and wherein each R c is independently selected from the group consisting of halo, OR f , C 1-8 alkyl, haloC 1-8 alkyl, cycloalkyl, and heterocycloalkyl.

10. A compound according to claim 8 , a tautomer, a stereoisomer, a mixture of stereoisomers, a pharmaceutically acceptable salt thereof, wherein R a is selected from the group consisting of 2-chloropyridin-3-yl, 2-methoxypyridin-3-yl, 2-cyclobutylpyrazol-3-yl, 2-cyclopentylpyrazol-3-yl, 2-cyclopropylpyrazol-3-yl, 2-ethylpyrazol-3-yl, 2-propan-2-ylpyrazol-3-yl, 2-propylpyrazol-3-yl, 2-(2,2,2-trifluoroethyl)pyrazol-3-yl, 2-(2,2-difluoroethyl)pyrazol-3-yl, 2-(3,3,3-trifluoropropyl)pyrazol-3-yl, 2-(oxetan-3-yl)pyrazol-3-yl, 2-propan-2-ylpyrazol-3-yl, 2-propylpyrazol-3-yl, and 3-propan-2-ylimidazol-4yl.

11. The compound according to claim 5 , a tautomer, a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein Q is cyclopentenyl or cyclohexenyl.

12. The compound according to claim 11 , a tautomer, a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein each R a is independently selected from the group consisting of R b , OR d , —(CH 2 ) k CO 2 R d , —(CH 2 ) k aryl optionally substituted with one to three R c , —(CH 2 ) k heteroaryl optionally substituted with

Assignees

• Global Blood Therapeutics Inc
• Cytokinetics Inc

Inventors

• Metcalf Brian
• Chuang Chihyuan
• Li Zhe

Classifications

• C07D413/14

  containing three or more hetero rings · CPC title

• C07C47/565

  all hydroxy groups bound to the ring · CPC title

• C07C47/575

  containing ether groups, [IMAGE cpc-sch-C07C-0958.gif] groups,[IMAGE cpc-sch-C07C-0959.gif] groups, or[IMAGE cpc-sch-C07C-0960.gif] groups · CPC title

• C07C2601/14

  The ring being saturated · CPC title

• C07D213/69

  Two or more oxygen atoms · CPC title