# US 10,765,676 B2 · Trk-inhibiting compound

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- Number: US 10,765,676 B2
- Document ID: US10765676B2
- Status: Granted
- Kind: B2
- Application number: 16/376,518
- Filed: 2019-04-05
- Published: 2019-08-01
- Granted: 2020-09-08
- Earliest claimed: 2013-02-19
- Assignees: Ono Pharmaceutical Co., Ltd.
- Applicants: Ono Pharmaceutical Co., Ltd.
- Inventors: Jun Takeuchi; Satoshi Itadani; Kazuya Hashimura; Masahiro Ikura; Masato Higashino; Tetsuya Yasuhiro; Takeshi Nagaura
- Web page: https://patentgrep.com/patent/US10765676B2

## CPC

- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/136: having the amino group directly attached to the aromatic ring, e.g. benzeneamine
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/663: Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07D 213/75: Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
- C07D 239/47: One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 405/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- 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
- 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)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The present invention provides a drug containing a compound having Trk-inhibiting activity as an active ingredient in prophylaxis and/or therapy for Trk-related diseases such as pain, pruritus, lower urinary tract dysfunction, asthma, allergic rhinitis, inflammatory bowel disease or Chagas disease. A compound represented by the general formula (I), wherein all symbols represent the same meanings as described in the specification, a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof is useful as a drug component having Trk-inhibiting activity in prophylaxis and/or therapy of diseases such as pain, pruritus, lower urinary tract dysfunction, asthma, allergic rhinitis, inflammatory bowel disease or Chagas disease.

## Claims

### Claim 1

A method for prophylaxis and/or treatment of Trk-related disease comprising, administering to a patient an effective amount of a compound of general formula (I) or a salt, an N-oxide, a solvate, or a prodrug thereof:
wherein:
Cy1 represents a ring selected from a C3-10 monocyclic or bicyclic carbocycle and a 4- to 10-membered monocyclic or bicyclic heterocycle;
Cy2 represents a 6- to 10-membered monocyclic or bicyclic heterocycle;
R1 represents:
(1) a halogen;
(2) a C1-6 alkyl group, C2-6 alkenyl group or C2-6 alkynyl group optionally substituted with a substituent selected from the group consisting of (i) a halogen and (ii) a hydroxy group;
(3) a C5-6 monocyclic carbocycle optionally substituted with one or two R5 groups;
(4) a 5- to 6-membered monocyclic heterocycle optionally substituted with one or two R5 groups;
(5) —S(O)m1-R6;
(6) —SO2NR7R8;
(7) —C(O)OR9;
(8) —NR10C(O)R11;
(9) —C(O)NR12R13;
(10) —OR14;
(11) —NR15R16;
(12) a cyano group; or
(13) a nitro group;
R5 represents:
(1) a halogen;
(2) —S(O)m2-R17;
(3) —SO2NR18R19;
(4) —C(O)OR20;
(5) —NR21C(O)R22;
(6) —C(O)NR23R24;
(7) —OR25;
(8) —NR26R27;
(9) a cyano group;
(10) a nitro group; or
(11) a C1-3 alkyl group optionally substituted with a substituent selected from the group consisting of (i) a halogen, (ii) a hydroxy group and (iii) an oxo group;
wherein, if two R5 groups are present, the R5 groups may be independently the same or different; and
wherein, if the two R5 groups are respectively and independently a C1-3 alkyl group or a hydroxy group, and are attached to carbon atoms adjacent to each other on the C5-6 monocyclic carbocycle or the 5- to 6-membered monocyclic heterocycle, the two R5 groups may, optionally, form a ring together;
R6 to R27 respectively and independently represent (1) a hydrogen atom or (2) a C1-6 alkyl group optionally substituted with (i) a halogen or (ii) a hydroxy group;
when R18 and R19 are respectively and independently a C1-6 alkyl group, R18 and R19 groups may together form a ring;
R2 represents:
(1) a halogen;
(2) a C1-6 alkyl group optionally substituted with (i) a halogen or (ii) a hydroxy group;
(3) a C3-6 cycloalkyl group optionally substituted with (i) a halogen or (ii) a hydroxy group;
(4) a C1-6 alkoxy group optionally substituted with a halogen;
(5) —NR28R29;
(6) a 3- to 7-membered monocyclic heterocycle; or
(7) —O-(3- to 7-membered monocyclic heterocycle);
R28 and R29 respectively and independently represent (1) a hydrogen atom or (2) a C1-6 alkyl group optionally substituted with (i) a halogen or (ii) a hydroxy group;
A1 and A2 respectively and independently represent ═CR3— or ═N—;
A3, A4, A5 and A6 respectively and independently represent ═CR4— or ═N—;
R3 and R4 respectively and independently represent a hydrogen atom or a halogen;
m1 is an integer from 0 to 2;
m2 is an integer from 0 to 2;
p is an integer from 0 to 7;
q is an integer of 0 from 7;
r is an integer of 0 from 2;
wherein, when p is 2 or more, each R1 may respectively and independently represent the same or different group;
when q is 2 or more, each R2 may respectively and independently represent the same or different group; and
when r is 2 or more, each R3 may respectively and independently represent the same or different group; and
wherein the Trk-related disease is pain, pruritus, lower urinary tract dysfunction, asthma, allergic rhinitis, inflammatory bowel disease, or Chagas disease.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the ring Cy2 is a 6- to 10-membered monocyclic or bicyclic aromatic heterocycle.

### Claim 3 (depends on 1)

The method according to claim 1, wherein the ring Cy2 is a pyridine ring, a pyrimidine ring, a pyrazolopyrimidine ring, an imidazopyridazine ring, an imidazopyridine ring, a pyrrolopyridine ring, an imidazopyrazine ring or a pyrazolopyridine ring.

### Claim 4 (depends on 1)

The method according to claim 1, wherein one of A1 and A2 is ═N— and the other is ═CH— or both are ═N— and A3, A4, A5 and A6 are ═CH—.

### Claim 5 (depends on 1)

The method according to claim 1, wherein the general formula (I) is represented by the general formula (I-i) or the general formula (I-ii):
wherein R2-a represents R2; q-a is an integer from 0 to 3; and t is an integer from 0 to 4, wherein, when q-a and t is 2 or more, R2-a and R4 may be respectively and independently the same or different.

### Claim 6 (depends on 1)

The method according to claim 1, wherein the general formula (I) is represented by the general formula (I-iii) or the general formula (I-iv):
wherein R2-b represents R2 and q-b represents an integer from 0 to 4, wherein, when q-b represents an integer of 2 or more, R2-b groups may be respectively and independently the same or different.

### Claim 7 (depends on 1)

The method according to claim 1, wherein the ring Cyi represents a benzene ring or a 5- to 6-membered monocyclic aromatic heterocycle.

### Claim 8 (depends on 1)

The method according to claim 1, wherein the ring Cyi represents a benzene ring, a pyridine ring, or a pyrazole ring.

### Claim 9 (depends on 1)

The method according to claim 1, wherein the compound is selected from the group consisting of:
(1) 1-(2-(1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)urea;
(2) 1-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(4-methyl-1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl)urea;
(3) 1-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(5-(trifluoromethyl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)urea;
(4) 1-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-chloro-5-(trifluoromethyl)phenyl)urea;
(5) 1-(2-(1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl-3-(6-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyridin-3-yl)urea;
(6) 1-(2-(1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl-3-(6-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyridin-3-yl)urea;
(7) 1-(6-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyridin-3-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea;
(8) 1-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)phenyl)urea;
(9) 1-(2-(1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-(2-amino-5-fluoropyridin-3-yl)phenoxy)pyrimidin-5-yl)urea;
(10) 1-(2-(1H-pyrazol-1-yl)-4-(trifluoromethyl)phenyl)-3-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)urea;
(11) 1-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-fluoro-4-(trifluoromethyl)phenyl)urea;
(12) 1-(2-(4-(2-amino-5-chloropyridin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-chloro-4-(trifluoromethyl)phenyl)urea;
(13) 1-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-{5-(trifluoromethyl)-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}urea;
(14) 1-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[4-(trifluoromethyl)-2-biphenylyflurea;
(15) 1-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[4-(trifluoromethyl)-2-biphenylyflurea;
(16) 1-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(4-chloro-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl]urea;
(17) 1-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-{5-chloro-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}urea;
(18) 1-{2-[4-(2-amino-5-chloro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2,4-bis(trifluoromethyl)phenyl]urea;
(19) 1-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[2-(4-chloro-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl]urea;
(20) 1-{2-[4-(2-amino-5-fluoro-3-pyridinyl)phenoxy]-5-pyrimidinyl}-3-[2-(methylsulfonyl)-5-(trifluoromethyl)phenyl]urea;
(21) 1-(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)-3-[2-(methylsulfonyl)-5-(trifluoromethyl)phenyl]urea; and
(22) 2-{[(2-{4-[2-amino-5-(trifluoromethyl)-3-pyridinyl]phenoxy}-5-pyrimidinyl)carbamoyl]amino}-N,N-dimethyl-4-(trifluoromethyl)benzenesulfonamide.

### Claim 10 (depends on 1)

The method according to claim 1, wherein the compound is selected from the group consisting of:
(1) 1-(2-(4-(5-(azetidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea;
(2) 1-(2-(4-(5-(azetidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)phenyl)urea;
(3) 1-(2-(4-(5-methoxypyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea;
(4) 1-(2-(4-(pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)pyrimidin-5-yl)-3-(2-(pyridin-3-yl)-5-(trifluoromethyl)phenyl)urea;
(5) 1-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-(3-pyridinyl)-5-(trifluoromethyl)phenyl]urea;
(6) 1-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)phenyl]urea;
(7) 1-{2-[4-(5-methylpyrazolo[1,5-a]pyrimidin-3-yl)phenoxy]-5-pyrimidinyl}-3-[2-(3-pyridinyl)-5-(trifluoromethyl)phenyl]urea;
(8) 1-(2-{4-[5-(ethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[3′-methyl-4-(trifluoromethyl)-2-biphenylyl]urea;
(9) 1-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl-3-[4-(trifluoromethyl)-2-biphenylyflurea;
(10) 1-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[3′-methyl-4-(trifluoromethyl)-2-biphenylyl]urea; and
(11) 1-(2-{4-[5-(dimethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenoxy}-5-pyrimidinyl)-3-[2′-methyl-4-(trifluoromethyl)-2-biphenylyl]urea.

### Claim 11 (depends on 1)

The method according to claim 1, wherein the pain is selected from the group consisting of pain of osteoarthritis, cancer pain, chronic low back pain, low back pain of osteoporosis, pain of bone fracture, pain of rheumatoid arthritis, neuropathic pain, postherpetic pain, pain of diabetic neuropathy, fibromyalgia, pain of pancreatitis, pain of interstitial cystitis, pain of endometriosis, pain of irritable bowel syndrome, migraine, postoperative pain and pain of pulpitis.

### Claim 12 (depends on 1)

The method according to claim 1, wherein the pain is pain of osteoarthritis.

### Claim 13 (depends on 1)

The method according to claim 1, wherein the pain is cancer pain.

### Claim 14 (depends on 1)

The method according to claim 1, wherein the pain is chronic low back pain.

### Claim 15 (depends on 1)

The method according to claim 1, wherein the pain is low back pain of osteoporosis.

### Claim 16 (depends on 1)

The method according to claim 1, wherein the pain is pain of bone fracture.

### Claim 17 (depends on 1)

The method according to claim 1, wherein the pain is pain of rheumatoid arthritis.

### Claim 18 (depends on 1)

The method according to claim 1, wherein the pain is neuropathic pain.

### Claim 19 (depends on 1)

The method according to claim 1, wherein the pain is postherpetic pain.

### Claim 20 (depends on 1)

The method according to claim 1, wherein the pain is pain of diabetic neuropathy.

### Claim 21 (depends on 1)

The method according to claim 1, wherein the pain is fibromyalgia.

### Claim 22 (depends on 1)

The method according to claim 1, wherein the pain is pain of pancreatitis.

### Claim 23 (depends on 1)

The method according to claim 1, wherein the pain is pain of interstitial cystitis.

### Claim 24 (depends on 1)

The method according to claim 1, wherein the pain is pain of endometriosis.

### Claim 25 (depends on 1)

The method according to claim 1, wherein the pain is pain of irritable bowel syndrome.

### Claim 26 (depends on 1)

The method according to claim 1, wherein the pain is migraine.

### Claim 27 (depends on 1)

The method according to claim 1, wherein the pain is postoperative pain.

### Claim 28 (depends on 1)

The method according to claim 1, wherein the pain is pain of pulpitis.