Modulators of cystic fibrosis transmembrane conductance regulator

Patent metadata

Field	Value
Publication number	US-10738030-B2
Application number	US-201716089703-A
Country	US
Kind code	B2
Filing date	Mar 31, 2017
Priority date	Mar 31, 2016
Publication date	Aug 11, 2020
Grant date	Aug 11, 2020

Abstract

The present disclosure features a compound of formula I: or a pharmaceutically acceptable salt thereof, where R 1 , R 2 , W, X, Z, n, p, and Rings A and B are defined herein, for the treatment of CFTR mediated diseases, such as cystic fibrosis. The present disclosure also features pharmaceutical compositions, method of treating, and kits thereof.

First claim

The invention claimed is:

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence:
Ring A is a C 3 -C 14 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR;
Ring B is a C 3 -C 10 cycloalkyl ring; a C 6 -C 10 aryl ring; or a C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR;
W is O, S, or NR;
X is O or NR;
Z is NR or C(R) 2 ;
R 1 is halo; CN; NRR; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 3 -C 6 cycloalkyl; C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl;
R 2 is halo; NRR; CN; CO 2 R; C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl; C 1 -C 6 alkoxy or C 1 -C 6 fluoroalkoxy; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; or a (C 1 -C 9 alkylene)-R 3 wherein up to four CH 2 units are optionally and independently replaced with O, CO, S, SO, SO 2 or NR;
or two R 2 may form a ═CH 2 or ═O group;
R 3 is H; CF 3 ; CHF 2 ; OR; C≡CH; CO 2 R; OH; C 6 -C 10 aryl, C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C 3 -C 10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R;
R is independently H; OH; CO 2 H; CO 2 C 1 -C 6 alkyl; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 6 -C 10 aryl; C 3 -C 10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, or N; or C 3 -C 10 cycloalkyl;
n is 2 or 3;
p is 0, 1, 2, or 3; and
Provided that 1) when R 1 is adjacent to the C═W attached to Ring A, R 1 does not contain a ring moiety, 2) at least one R 1 is adjacent to the C═W attached to Ring A, and at least one R 1 is C 1 -C 6 alkyl or C 1 -C 6 fluoroalkyl, C 6 -C 10 aryl; C 3 -C 10 heteroaryl or C 3 -C 10 heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C 3 -C 10 cycloalkyl; 3) when Ring A is phenyl or six-membered mono-heteroaryl wherein anywhere from 1 to 3 ring atoms are N, R 1 is not 4,5-dihydroisoxazole; 4) when Ring A is phenyl, R 1 is not

 ureido, or aminocarbonyl; 5) when Ring A and the at least one R 1 is pyridine, R 1 (pyridine) is not further substituted by —CONHSO 2 —; and 6) when Ring A is pyridine or thiazole, and C═W wherein W is O in formula I is adjacent to the N on the pyridine or thiazole, R 1 which is adjacent to the N on the pyridine or on the thiazole is not

 wherein said compound of formula I modulates cystic fibrosis transmembrane conductance receptor activity.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring A is pyridyl, indole, indoline, isoindoline, pyrazole, pyrimidine, 1,2,3,4-tetrahydroquinoline, quinoline, 5,6,7,8-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, pyrrolodine, aza-indole, pyrrole, thiophene, oxazole, pyrazine, triazole, thiazole, indazole, 2,3,4,5-tetrahydro-1H-benzo[d]azepine, 1H-benzo[d]imidazole, imidazo[1,2-a]pyridine, or imidazole ring.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring A is

wherein the wavy line indicates point of attachment of Ring A to the C═W.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring B is a pyridyl, pyridine-2(1H)-one, pyrazole, indole, pyrrole, indoline, thiophene, dihydrobenzofuran, tetrahydrofuran, furan, pyrazine, indazole, thiazole, pyridine-4(1H)-one, pyrrolidinone, 3-azabicyclo[3.1.0]hexane, (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane, pyrrolidine, azetidine, piperidine, piperazine, imidazo[1,2-a]pyridine, or quinoline.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring B is

wherein the wavy line indicates point of attachment of Ring B to the X═S═O.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is independently halo, amino, OH, C 2 -C 6 alkenyl; C 2 -C 6 alkynyl, C 1 -C 6 fluoroalkyl, CN, C 1 -C 6 alkyl, C 1 -C 8 alkoxy or C 1 -C 8 fluoroalkoxy, a phenyl, C 3 -C 6 mono-cycloalkly, mono-C 4 -C 6 heterocyclic ring, 1,2,3,4-tetrahydroisoquinoline, pyridyl, pyrimidine, indole, aza-indole, pyrazole, pyrrole, or thiophene ring, or a (C 1 -C 9 alkylene)-R 3 , wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is CHF 2 CH 2 (CH 3 )N—, (CH 3 ) 2 CHCH 2 CH 2 O—, (CH 3 ) 3 CCH 2 CH 2 O—, (CH 3 ) 3 COCH 2 CH 2 O—, (CH 3 ) 2 CHO, CHF 2 CHF 2 CH(CH 3 )O—, —CF 3 , (CH 3 CH 2 ) 2 N—, CF 3 CH 2 CH(CH 3 )O—, CH 3 O—, CH 3 (CH 2 ) 4 O—, CH 3 CH 2 CH(CH 3 )CH(CH 3 )O—, CH 3 CH 2 OCH 2 CH 2 O—, CH 3 CH 2 NCH(CH 3 ) 2 , (CH 3 ) 3 CH 2 O—, (R)—CH 3 NCH(CH 3 )(CF 3 ), CH 3 OCH 2 CH(CH 2 CH 3 )O—, (CH 3 ) 2 N—, (S)—CH 3 OCH 2 CH(CH 3 )O—, CH 3 O(CH 2 ) 3 O—, CH 3 OC(CH 3 ) 2 (CH 2 ) 2 O, CH 3 OCH 2 CH(CH 3 )O, CH 3 CH(CH 3 )CH 2 CH(CH 3 )O—, (CH 3 ) 3 CCH(CH 3 )O, ((CH 3 ) 2 CH) 2 CHO—, CH 3 CH 2 CH 2 O, CH 3 CH═CHCH 2 O—, (S)—CH 3 CH 2 CH(CH 3 )O—, CH 3 CH 2 O, (CH 3 ) 2 CHNCH 3 , (CH 3 ) 3 CCH 2 O, (CF 3 ) 2 CHO—, (CH 3 ) 3 CCH(CH 2 CH 3 )O, CH 3 C≡CCH 2 CH 2 O, (CH 3 ) 3 CCH 2 CH(CH 3 )O—, (CH 3 ) 2 C═C(CH 3 ), CHF 2 CH 2 O—, CH 3 CH 2 CH 2 NH, (CH 3 ) 2 CHCH(CH 2 CH 3 )O, ((CH 3 ) 2 CH) 2 N, CH 2 ═CHCH(CH 3 )O, CH 2 ═CHCH 2 O—, CH 3 CH 2 C(CH 3 ) 2 O, (CH 3 CH 2 ) 2 CHO, CF 3 CH 2 O, CH 3 C(═CH 2 )CH 2 O, (CH 3 ) 3 CCH 2 CH 2 NH, CH 3 OCH 2 C(CH 3 ) 2 O, (CH 3 ) 3 CCH 2 N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 )NH, (CH 3 ) 2 CHO(CH 2 ) 2 O, CH 3 CH 2 CH 2 CH(CH 3 )O, CH 3 CF 2 CH 2 O, (CH 3 ) 3 CNH, (R)—CH 3 CH 2 CH(CH 3 )O, CH 3 OCH 2 CH 2 O, (CH 3 ) 2 CHCH 2 N(CH 3 ), CH 3 CH 2 CH 2 CH(CH 3 )CH(CH 3 )O, CH 3 CH 2 CH 2 CH 2 O, CH 3 CH 2 CH 2 N(CH 3 ), (R)—CH 3 OCH 2 CH(CH 3 )O, CF 3 CH 2 N(CH 3 ), CH 3 CH 2 N(CH 3 ), ((CH 3 ) 3 C) 2 CHO, (CH 3 CH 2 ) 2 CHN(CH 3 ), (CH 3 ) 2 CHN(CH 3 ), CH 3 CH 2 OCH 2 CH(CH 3 )O, (CH 3 ) 3 CCH 2 NH, CF 3 CH(CH 3 )O, CH 3 CH 2 NCH(CH 3 ) 2 , (R)—CF 3 CH(CH 3 )N(CH 3 ), (CH 3 ) 2 CHCH(CH 3 ), CH 3 CH 2 (CH 3 ) 2 CHCH 2 CH 2 O, (S)—CH 3 OCH(CH 3 )CH 2 O, HOCH(CH 3 ) 2 CH 2 CH 2 NH, CF 3 CH 2 CH 2 O, CF 3 CH 2 CH 2 CH 2 O, CF 3 CH═CHCH 2 O, CH 3 CH 2 CH 2 CH 2 CH 2 NH, CH 3 , Cl, F, CN, CH 2 CH 3 , CH(CH 3 ) 2 , OCH 2 CH 2 OCH 2 CH 3 ,

Assignees

• Vertex Pharma

Inventors

• Bear Brian
• Clemens Jeremy
• Cleveland Thomas
• Coon Timothy Richard
• Grootenhuis Peter Diederik Jan
• Frieman Bryan A
• Hadida Ruah Sara S
• Khatuya Haripada
• Krenitsky Paul J
• Miller Mark Thomas
• Silina Alina
• Uy Johnny
• Zhou Jinglan

Classifications

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D213/82

  in position 3 · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title