# US 2019/0167681 A1 · Sulfonyl pyridyl trp inhibitors

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- Number: US 2019/0167681 A1
- Document ID: US20190167681A1
- Status: Published application
- Kind: A1
- Application number: 16/269,973
- Filed: 2019-02-07
- Published: 2019-06-06
- Earliest claimed: 2016-08-12
- Assignees: Genentech, Inc.
- Applicants: Genentech, Inc.
- Inventors: Vishal VERMA; Matthew VOLGRAF; Baihua HU
- Web page: https://patentgrep.com/patent/US20190167681A1

## CPC

- A61K 31/506: not condensed and containing further heterocyclic rings
- A61P 11/00: Drugs for disorders of the respiratory system
- C07D 401/14: containing three or more hetero rings
- C07D 491/048: the oxygen-containing ring being five-membered
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The invention provides compounds of formula I: and pharmaceutically acceptable salts thereof where R1 is a substituted or unsubstituted phenyl or a fused bicyclic comprising a substituted or unsubstituted phenyl. In addition, the present invention relates to methods of manufacturing and methods of using the compounds of formula I as well as pharmaceutical compositions containing such compounds. The compounds may be useful in treating diseases and conditions mediated by TRPA1, such as pain.

## Claims

### Claim 1

A compound of formula I
wherein:
B is selected from B1, B2 and B3;
B1 is a 5-membered heteroaryl comprising 2 nitrogen atoms in the ring, wherein each 5-membered heteroaryl is unsubstituted or substituted with one or more groups independently selected from halogen, CN, (C1-6)alkyl, (C1-6)haloalkyl, O(C1-6)alkyl, and O(C1-6)haloalkyl;
B2 is phenyl, wherein each phenyl is unsubstituted or substituted with one or more groups independently selected from halogen, CN, (C1-6)alkyl, (C1-6)haloalkyl, O(C1-6)alkyl, and O(C1-6)haloalkyl;
B3 is 6-membered heteroaryl, wherein each 6-membered heteroaryl is unsubstituted or substituted with one or more groups independently selected from halogen, CN, (C1-6)alkyl, (C1-6)haloalkyl, O(C1-6)alkyl, O(C1-6)haloalkyl, 5 or 6-membered heteroaryl, (C3-7)cycloalkyl, and 4, 5, 6, or 7-membered heterocyclyl, wherein any of the 5 or 6-membered heteroaryl, (C3-7)cycloalkyl, or 4, 5, 6, or 7-membered heterocyclyl groups is unsubstituted or substituted with one or more groups independently selected from halogen, CN, (C1-6)alkyl, (C1-6)haloalkyl, O(C1-6)alkyl, and O(C1-6)haloalkyl;
R1 is selected from the group consisting of:
(i) unsubstituted pyridyl selected from
(ii) a pyridyl selected from
wherein said pyridyl is substituted with one or more groups independently selected from halogen, CN, (C1-6)alkyl, and (C1-6)haloalkyl,
wherein, when the pyridyl is
(a) and wherein said pyridyl is substituted with fluorine, the substituted pyridyl is selected from
(b) and wherein said pyridyl is substituted with chlorine, the substituted pyridyl is selected from
(c) and wherein said pyridyl is substituted with cyano, the substituted pyridyl is selected from
and
(iii) a fused bicyclic ring system comprising a 2-pyridyl, 3-pyridyl or 4-pyridyl ring and a fused saturated, partially saturated or unsaturated ring having from 4 to 6 atoms and 1 or 2 heteroatoms independently selected from N, O and S, wherein the bicyclic ring system is unsubstituted or is substituted with one or more groups independently selected from halogen, CN, (C1-6)alkyl;
R2 is selected from (C1-6)alkyl, (C1-6)haloalkyl, (C3-7)cycloalkyl, and (C1-6)alkyl-(C3-7)cycloalkyl, wherein (C1-6)alkyl is optionally substituted with O(C1-C6)alkyl;
R3 is H or (C1-6)alkyl or R2 and R3 together with the atoms to which they are attached form a (C3)cycloalkyl;
R4 is selected from H, F and CN;
R5 is H or (C1-6)alkyl, or one of R2 and R3 and one of R4 and R5 together with the atoms to which they are attached form a (C3)cycloalkyl;
R6 is phenyl, (C3-7)cycloalkyl, 5 or 6-membered heteroaryl, or 4, 5, 6 or 7-membered heterocycle, wherein any phenyl, (C3-7)cycloalkyl, 5 or 6-membered heteroaryl, or 4, 5, 6 or 7-membered heterocycle of R6 is optionally substituted with one or more groups independently selected from halogen, CN, SF5, (C1-6)alkyl, (C1-6)haloalkyl, O(C1-6)alkyl and O(C1-6)haloalkyl, or R6 is O—CH2—R7;
R7 is (C1-6)alkyl, 4, 5, 6, or 7-membered heterocycle, (C3-7)cycloalkyl, or 6-membered heteroaryl, wherein any (C1-6)alkyl, 4, 5, 6, or 7-membered heterocycle, (C3-7)cycloalkyl, or 6-membered heteroaryl is optionally substituted with one or more groups independently selected from halogen, CN, (C1-6)alkyl, (C1-6)haloalkyl, O(C1-6)alkyl, (C3-7)cycloalkyl, and O(C1-6)haloalkyl;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein B1 is unsubstituted or substituted pyrazolyl, optionally selected from:

### Claim 3 (depends on 1)

The compound of claim 1, wherein B2 is selected from:

### Claim 4 (depends on 1)

The compound of claim 1, wherein B3 is selected from:

### Claim 5 (depends on 1)

The compound of claim 1, wherein B is selected from:

### Claim 6 (depends on 1)

The compound of claim 1, wherein R1 is substituted with one or more groups independently selected from Br, Cl, F, CN, CH3, CF2H and CF3.

### Claim 7 (depends on 1)

The compound of claim 1, wherein R1 is selected from:

### Claim 8 (depends on 1)

The compound of claim 1, wherein R2 is selected from:
(i) (C1-6)alkyl, optionally selected from CH3, CH2CH3 and C(CH3)3;
(ii) (C1-6)haloalkyl, optionally C(CF3)3;
(iii) CH2OCH3; and
(iv) cyclopropyl.

### Claim 9 (depends on 1)

The compound of claim 1, wherein R2 and R3 together with the atoms to which they are attached form a (C3)cycloalkyl or a spirocyclopropyl.

### Claim 10 (depends on 1)

The compound of claim 1, wherein: R3 is H; R4 is H, F or CN; and R5 is H.

### Claim 11 (depends on 1)

The compound of claim 1, wherein the group
is selected from:

### Claim 12 (depends on 1)

The compound of claim 1, wherein R6:
(i) is a substituted or unsubstituted 5-membered heteroaryl, optionally of the structure
or
(ii) is a substituted or unsubstituted 6-membered heteroaryl, optionally selected from
(a) a pyridinyl, optionally selected from
(b) a pyrimidinyl, optionally of the structure
and
(c) a pyrazinyl, optionally of the structure

### Claim 13 (depends on 1)

The compound of claim 1, wherein R6 is selected from:
a substituted or unsubstituted 4-membered heterocycle, optionally of the structure
(ii) a substituted or unsubstituted 5-membered heterocycle;
(iii) a substituted or unsubstituted 6-membered heterocycle, optionally selected from
and
(iv) a substituted or unsubstituted 7-membered heterocycle.

### Claim 14 (depends on 1)

The compound of claim 1 wherein R6 is selected from:
(i) substituted or unsubstituted (C3-7)cycloalkyl, optionally of the structure
(ii) substituted or unsubstituted phenyl, optionally of the structure
and
(iii) the structure

### Claim 15 (depends on 1)

The compound of claim 1 wherein:
R2 is CH3, R3 is H, R4 is F, R5 is H, and R6 is
R1 is selected from
and
B is selected from

### Claim 16

A compound selected from:

### Claim 17 (depends on 1)

A pharmaceutical composition, comprising a compound as described in claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

### Claim 18 (depends on 1)

A method for the treatment of a disease or condition mediated by TRPA1 activit, the method comprising administering to a subject in need thereof an effective amount of a compound of claim 1.

### Claim 19 (depends on 18)

The method of claim 18, wherein the disease or condition is a respiratory disorder.