# US 11,897,887 B2 · sGC stimulators

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- Number: US 11,897,887 B2
- Document ID: US11897887B2
- Status: Granted
- Kind: B2
- Application number: 16/955,494
- Filed: 2018-12-19
- Published: 2020-12-03
- Granted: 2024-02-13
- Earliest claimed: 2017-12-19
- Assignees: Tisento Therapeutics Inc.
- Applicants: Tisento Therapeutics Inc.
- Inventors: Glen Robert Rennie; Paul Allan Renhowe; Takashi Nakai; Ara Mermerian; Helen Cumberbatch
- Web page: https://patentgrep.com/patent/US11897887B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61K 31/506: not condensed and containing further heterocyclic rings
- C07F 9/09: Esters of phosphoric acids
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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)
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The present disclosure relates to stimulators of soluble guanylate cyclase (sGC), pharmaceutically acceptable salts, pharmaceutical formulations comprising them as well as their phosphate ester prodrugs, and their uses alone or in combination with one or more additional agents, for treating various diseases, wherein an increase in the concentration of nitric oxide (NO) and/or an increase in the concentration of cyclic Guanosine Monophosphate (cGMP), or both, or the upregulation of the NO pathway is desirable. The compounds are of Formula I.

## Claims

### Claim 1

A compound of Formula I, or a pharmaceutically acceptable salt thereof,
wherein:
Y is independently N or C;
ring B is a phenyl or a 5 or 6-membered heteroaryl ring, containing 1 or 2 ring heteroatoms independently selected from N, O and S;
n is an integer selected from 0 to 3; and each JB is independently halogen, —CN, a C1-6 aliphatic or —ORB;
wherein each JB that is a C1-6 aliphatic is optionally and independently substituted with up to 3 instances of R3;
each RB is independently hydrogen or a C1-6 aliphatic; said C1-6 aliphatic represented by RB is optionally and independently substituted with up to 3 instances of R3a;
each R3 and R3a is, in each instance, independently halogen, —CN, C1-4 alkyl, C1-4 haloalkyl, —O(C1-4 alkyl) or —O(C1-4 haloalkyl);
Z is selected from the group consisting of hydrogen, —P(O)(OH)2, —P(O)(OH)O−M+, —P(O)(O−)2 (M+)2, —P(O)(O−)2 D2+and —P(O)(O-Benzyl)2; wherein M+ is a pharmaceutically acceptable monovalent cation and D2+is a pharmaceutically acceptable divalent cation;
m is 0 or 1;
R1 is C1-4 alkyl, C1-4 fluoroalkyl, —C(O)NH2 or hydrogen; and
R2 is C1-4 alkyl, C1-4 fluoroalkyl or hydrogen;
both instances of R4 are simultaneously hydrogen or both instances of R4, together with the carbon atom to which they are attached form a carbonyl group;
JD is hydrogen, halogen, methoxy or —CN
p is 1 or 2; and
each JC is independently hydrogen, halogen, C1-4 aliphatic, C1-4 alkoxy or —CN; wherein each said C1-4 aliphatic and each said C1-4 alkoxy is optionally and independently substituted by up to 3 instances of C1-4 alkoxy, C1-4 haloalkoxy, —OH or halogen.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein the compound is of Formula IA, Formula IB, Formula II, Formula IIA or Formula IIB:
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein (i) JD is hydrogen, chloro, fluoro, methoxy or —CN; (ii) JD is methoxy; (iii) JD is hydrogen, chloro, fluoro or —CN; (iv) JD is hydrogen, chloro or fluoro; (v) JD is fluoro or hydrogen; (vi) JD is hydrogen; (vii) JD is fluoro; (viii) JD is —CN; (ix) JD is chloro; (x) each JC is independently hydrogen, C1-2 alkyl, C1-2 alkoxy, C1-2 fluoroalkyl, C1-2 fluoroalkoxy, halogen or —CN, wherein each said C1-2 alkyl and C1-2 alkoxy is optionally and independently substituted by up to 3 instances of C1-4 alkoxy, C1-4 haloalkoxy, —OH or halogen; (xi) each JC is independently hydrogen, C1-2 alkyl, C1-2 alkoxy, C1-2 fluoroalkyl, C1-2 fluoroalkoxy, halogen or —CN; (xii) each JC is independently hydrogen or halogen; (xiv) each JC is hydrogen; or (xv) each JC is independently fluoro or chloro.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein the compound is of Formula IIIA, Formula IIIB, Formula IVA, Formula WB, Formula VA, Formula VIA, Formula VB or Formula VIB:
or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein (i) ring B is phenyl; (ii) ring B is a 5 or 6-membered heteroaryl ring, containing 1 or 2 ring heteroatoms independently selected from N, O and S; or (iii) ring B is a 6-membered heteroaryl ring, containing 1 to 2 ring nitrogen atoms.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein (i) n is 1, 2 or 3, and each JB is independently halogen or C1-6 aliphatic; (ii) n is 1 or 2 and each JB is independently halogen or C1-6 aliphatic; (iii) n is 1 or 2 and each JB is fluoro; (iv) n is 1 and JB is fluoro.

### Claim 7 (depends on 5)

The compound according to claim 5, wherein the compound is of Formula VIIA, Formula VIIIA, Formula VIIB or Formula VIIIB:
or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein (i) R1 is C1-2 alkyl, C1-2 fluoroalkyl, hydrogen or —C(O)NH2; (ii) R1 is C1-2 fluoroalkyl or —C(O)NH2; (iii) R2 is C1-2 fluoroalkyl, C1-2 alkyl or hydrogen; or (iv) R2 is C1-2 fluoroalkyl.

### Claim 9 (depends on 8)

The compound of claim 8, wherein (i) R1 is trifluoromethyl or —C(O)NH2 and R2 is trifluoromethyl; (ii) R1 and R2 are both hydrogen or C1-2 alkyl; or one of R1 and R2 is hydrogen and the other is C1-2 fluoroalkyl; (iii) R1 and R2 are both hydrogen; (iv) R1 and R2 are both methyl; or (v) one of R1 and R2 is hydrogen and the other is trifluoromethyl.

### Claim 10 (depends on 1)

The compound of claim 1 selected from:
wherein JD is selected from hydrogen or fluoro.

### Claim 11 (depends on 1)

The compound according to claim 1, wherein (i) Z is —P(O)(OH)2; (ii) Z is —P(O)(OH)O−M+or —P(O)(O−)2(M+)2; and M+is Na+, K+, Cs+or the monovalent cation of an organic amine; or (iii) Z is —P(O)(O−)2D2+; and D2+is Ca2+, Zn2+, Mg2+or the divalent cation of an organic amine.

### Claim 12 (depends on 1)

The compound according to claim 1 selected from the group consisting of

### Claim 13 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1 and at least one pharmaceutically acceptable excipient or carrier.

### Claim 14 (depends on 1)

A method of treating a disease in a subject in need thereof that would benefit from sGC stimulation or from an increase in the concentration of nitric oxide (NO) and/or cyclic guanosine monophosphate (cGMP), the method comprising administering a therapeutically effective amount of a compound of claim 1 to the subject in need of treatment.

### Claim 15 (depends on 14)

The method according to claim 14, further comprising administering to the subject an effective amount of a suitable therapeutic agent.

### Claim 16

A compound selected from:

### Claim 17

A compound represented by the following formula:
wherein:
n is an integer selected from 0 to 3; and each JB is independently halogen, —CN, a C1-6 aliphatic or —ORB;
wherein each JB that is a C1-6 aliphatic is optionally and independently substituted with up to 3 instances of R3;
each RB is independently hydrogen or a C1-6 aliphatic; said C1-6 aliphatic represented by RB is optionally and independently substituted with up to 3 instances of R3a;
each R3 and R3a is, in each instance, independently halogen, —CN, C1-4 alkyl, C1-4 haloalkyl, —O(C1-4 alkyl) or —O(C1-4 haloalkyl);
JC is independently hydrogen, halogen, C1-4 aliphatic, C1-4 alkoxy or —CN; wherein each said C1-4 aliphatic and each said C1-4 alkoxy is optionally and independently substituted by up to 3 instances of C1-4 alkoxy, C1-4 haloalkoxy, —OH or halogen; and
JD is hydrogen, halogen, methoxy or —CN.

### Claim 18 (depends on 17)

The compound of claim 17, wherein (i) JD is hydrogen, chloro, fluoro, methoxy or —CN; or (ii) JD is fluoro.

### Claim 19 (depends on 17)

The compound of claim 17, wherein (i) JC is hydrogen, C1-2 alkyl, C1-2 alkoxy, C1-2 fluoroalkyl, C1-2 fluoroalkoxy, halogen or —CN, wherein each said C1-2 alkyl and C1-2 alkoxy is optionally and independently substituted by up to 3 instances of C1-4 alkoxy, C1-4 haloalkoxy, —OH or halogen; (ii) JC is hydrogen or halogen; or (iii) JC is hydrogen.

### Claim 20 (depends on 17)

The compound of claim 17, wherein (i) n is 1, 2 or 3, and each JB is independently halogen or C1-6 aliphatic; (ii) n is 1 or 2 and each JB is independently halogen or C1-6 aliphatic; (iii) n is 1 or 2 and each JB is fluoro; or (iv) n is 1 and JB is fluoro.

### Claim 21 (depends on 10)

The compound of claim 10 selected from:

### Claim 22 (depends on 21)

The compound of claim 21 represented by formula:

### Claim 23 (depends on 12)

The compound of claim 12 represented by:

### Claim 24 (depends on 12)

The compound of claim 12 represented by