# US 7,745,638 B2 · 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators

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- Number: US 7,745,638 B2
- Document ID: US7745638B2
- Status: Granted
- Kind: B2
- Application number: 11/875,470
- Filed: 2007-10-19
- Published: 2008-10-30
- Granted: 2010-06-29
- Earliest claimed: 2003-07-22
- Assignees: Astex Therapeutics Limited; The Institute of Cancer Research: Royal Cancer Hospital; Cancer Research Technology Limited
- Inventors: Valerio Berdini; Michael Alistair O'Brien; Maria Grazia Carr; Theresa Rachel Early; Adrian Liam Gill; Gary Trewartha; Alison Jo-Anne Woolford; Andrew James Woodhead; Paul Graham Wyatt
- Web page: https://patentgrep.com/patent/US7745638B2

## CPC

- C07D 231/38: Nitrogen atoms (nitro radicals C07D231/16)
- A61K 31/415: 1,2-Diazoles
- A61K 31/4152: having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
- A61K 31/4155: non condensed and containing further heterocyclic rings
- A61K 31/416: condensed with carbocyclic ring systems, e.g. indazole
- A61K 31/4178: not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
- A61K 31/4196: 1,2,4-Triazoles
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/541: Non-condensed thiazines containing further heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/12: of the kidneys
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/10: Antimycotics
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61P 31/18: for HIV
- A61P 31/20: for DNA viruses
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C04B 35/632: Organic additives
- C07D 231/14: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D 231/40: Acylated on said nitrogen atom
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 409/14: containing three or more hetero rings
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: containing three or more hetero rings
- C07D 453/02: containing not further condensed quinuclidine ring systems
- C07D 471/04: Ortho-condensed systems
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C04B: LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE {(roofing granules E04D7/005)}; CERAMICS (devitrified glass-ceramics C03C10/00); REFRACTORIES; TREATMENT OF NATURAL STONE

## Abstract

The invention provides compounds of the formula (0) or salts or tautomers or N-oxides or solvates thereof for use in the prophylaxis or treatment of disease states and conditions such as cancers mediated by cyclin-dependent kinase and glycogen synthase kinase-3. In formula (0): X is a group R1—A—NR4— or a 5- or 6-membered carbocyclic or heterocyclic ring; A is a bond, SO2, C═O, NRg(C═O) or O(C═O) wherein Rg is hydrogen or C1-4 hydrocarbyl optionally substituted by hydroxy or C1-4 alkoxy; Y is a bond or an alkylene chain of 1, 2 or 3 carbon atoms in length; R1 is hydrogen; a carbocyclic or heterocyclic group having from 3 to 12 ring members; or a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from halogen (e.g. fluorine), hydroxy, C1-4 hydrocarbyloxy, amino, mono- or di-C1-4 hydrocarbylamino, and carbocyclic or heterocyclic groups having from 3 to 12 ring members, and wherein 1 or 2 of the carbon atoms of the hydrocarbyl group may optionally be replaced by an atom or group selected from O, S, NH, SO, SO2; R2 is hydrogen; halogen; C1-4 alkoxy (e.g. methoxy); or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy); R3 is selected from hydrogen and carbocyclic and heterocyclic groups having from 3 to 12 ring members; and R4 is hydrogen or a C1-4 hydrocarbyl group optionally substituted by halogen (e.g. fluorine), hydroxyl or C1-4 alkoxy (e.g. methoxy).

## Claims

### Claim 1

A compound having the formula (II):
or salts or tautomers or N-oxides thereof;
wherein Y is a bond or an alkylene chain of 1, 2 or 3 carbon atoms in length;
R1 is a substituted or unsubstituted phenyl group;
R2 is hydrogen; halogen; C1-4 alkoxy; or a C1-4 hydrocarbyl group optionally substituted by halogen or C1-4 alkoxy;
R3 is selected from carbocyclic groups and heterocyclic groups having from 3 to 12 ring members wherein R3 is not unsubstituted piperidin-4-yl, N-methyl piperidin-4-yl, an N-unsubstituted piperidin-4-yl substituted by C3 alkyl or an N-methyl piperidin-4-yl substituted by C1-3 alkyl.

### Claim 2 (depends on 1)

A compound according to claim 1 wherein R3 is selected from monocyclic carbocyclic and heterocyclic groups having from 3 to 6 ring members.

### Claim 3 (depends on 1)

A compound according to claim 1 wherein R2 is hydrogen or methyl.

### Claim 4 (depends on 3)

A compound according to claim 3 wherein R2 is hydrogen.

### Claim 5 (depends on 1)

A compound according to claim 1 wherein Y is a bond.

### Claim 6 (depends on 5)

A compound according to claim 5 wherein R2 is hydrogen.

### Claim 7 (depends on 1)

A compound according to claim 1 wherein R1 is a phenyl ring having 1, 2 or 3 substituents located at the 2-, 3-, 4-, 5- or 6-positions around the ring.

### Claim 8 (depends on 7)

A compound according to claim 7 wherein:
(a) the phenyl group is 2-monosubstituted, 3-monosubstituted, 2,6-disubstituted, 2,3-disubstituted, 2,4-disubstituted 2,5-disubstituted, 2,3,6-trisubstituted or 2,4,6-trisubstituted; or
(b) the phenyl group is:
(i) monosubstituted at the 2-position, or disubstituted at positions 2- and 3-, or disubstituted at positions 2- and 6- with substituents selected from fluorine, chlorine and Ra-Rb, where Ra is O and Rb is C1-4 alkyl; or
(ii) monosubstituted at the 2-position with a substituent selected from fluorine; chlorine; C1-4 alkoxy optionally substituted by one or more fluorine atoms; or disubstituted at the 2- and 5-positions with substituents selected from fluorine, chlorine and methoxy.

### Claim 9 (depends on 1)

A compound according to claim 1 wherein R1 is a phenyl group substituted by one or more substituent group selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C1-4 hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members; a group Ra-Rb wherein Ra is a bond, O, CO, X1C(X2), C(X2)X1, X1C(X2)X1, S, SO, SO2, NRc, SO2NRc or NRcSO2 and Rb is selected from hydrogen, carbocyclic and heterocyclic groups having from 3 to 12 ring members, and a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C1-4 hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members and wherein one or more carbon atoms of the C1-8 hydrocarbyl group may optionally be replaced by O, S, SO, SO2, NRc, X1C(X2), C(X2)X1 or X1C(X2)X1;
Rc is selected from hydrogen and C1-4 hydrocarbyl; and
X1 is O, S or NRc and X2 is ═O, ═S or ═NRc.

### Claim 10 (depends on 9)

A compound according to claim 9 wherein the phenyl group is substituted by one or more substituent group selected from halogen, hydroxy, trifluoromethyl, a group Ra-Rb wherein Ra is a bond or O, and Rb is selected from hydrogen and a C1-4 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxyl, halogen, and 5 and 6 membered saturated carbocyclic and heterocyclic groups.

### Claim 11 (depends on 1)

A compound according to claim 1 wherein:
(a) R1 is phenyl optionally substituted by one or more substituents selected from fluorine; chlorine; hydroxy; C1-3 hydrocarbyloxy; and C1-3 hydrocarbyl wherein the C1-3 hydrocarbyl group is optionally substituted by one or more substituents chosen from hydroxy, fluorine, C1-2 alkoxy, amino, mono and di-C1-4 alkylamino, saturated carbocyclic groups having 3 to 7 ring members or saturated heterocyclic groups of 5 or 6 ring members and containing up to 2 heteroatoms selected from O, S and N; or
(b) R1 is an unsubstituted phenyl group or a 2-monosubstituted, 3-monosubstituted, 2,3 disubstituted, 2,5 disubstituted or 2,6 disubstituted phenyl group or 2,3-dihydro-benzo[1,4]dioxine, where the substituents are selected from halogen; hydroxyl; C1-3 alkoxy; and C1-3 alkyl groups wherein the C1-3 alkyl group is optionally substituted by hydroxy, fluorine, C1-2 alkoxy, amino, mono and di-C1-4 alkylamino, or saturated carbocyclic groups having 3 to 6 ring members and/or saturated heterocyclic groups of 5 or 6 ring members and containing 1 or 2 heteroatoms selected from N and O; or
(c) R1 is selected from unsubstituted phenyl, 2-fluorophenyl, 2-hydroxyphenyl, 2-methoxyphenyl, 2-methylphenyl, 2-(2-(pyrrolidin-1-yl)ethoxy)-phenyl, 3-fluorophenyl, 3-methoxyphenyl, 2,6-difluorophenyl, 2-fluoro-6-hydroxyphenyl, 2-fluoro-3-methoxyphenyl, 2-fluoro-5-methoxyphenyl, 2-chloro-6-methoxyphenyl, 2-fluoro-6-methoxyphenyl, 2,6-dichlorophenyl and 2-chloro-6-fluorophenyl; and is optionally further selected from 5-fluoro-2-methoxyphenyl; or
(d) R1 is selected from 2,6-difluorophenyl, 2-fluoro-6-methoxyphenyl, 2,6-dichlorophenyl and 2-chloro-6-fluorophenyl.

### Claim 12 (depends on 1)

A compound according to claim 1 wherein R3 is selected from monocyclic carbocyclic and heterocyclic groups having from 3 to 6 ring members.

### Claim 13 (depends on 1)

A compound according to claim 1 wherein R3 is an aryl or heteroaryl group.

### Claim 14 (depends on 1)

A compound according to claim 1 wherein R3 is selected from non-aromatic groups.

### Claim 15 (depends on 12)

A compound according to claim 12 wherein the monocyclic carbocyclic and heterocyclic groups are substituted by 1, 2 or 3 substituents selected from:
(i) halogen;
(ii) C1-4 alkoxy optionally substituted by one or substituents selected from halogen, hydroxy, C1-2 alkoxy and five and six membered saturated heterocyclic rings containing 1 or 2 heteroatoms selected from O, N and S, the heterocyclic rings being optionally further substituted by one or more C1-4 groups and wherein the S, when present, is S, SO or SO2;
(iii) C1-4 alkyl optionally substituted by one or more substituents selected from halogen, hydroxy, C1-4 alkoxy, amino, C1-4 alkylsulphonylamino, 3 to 6 membered cycloalkyl groups, phenyl (optionally substituted by one or more substituents selected from halogen, methyl, methoxy and amino) and five and six membered saturated heterocyclic rings containing 1 or 2 heteroatoms selected from O, N and S, the heterocyclic rings being optionally further substituted by one or more C1-4 groups and wherein the S, when present, is S, SO or SO2;
(iv) hydroxy;
(v) amino, mono-C1-4 alkylamino, di-C1-4 alkylamino, benzyloxycarbonylamino and C1-4 alkoxycarbonylamino;
(vi) carboxy and C1-4 alkoxycarbonyl;
(vii) C1-4 alkylaminosulphonyl and C1-4 alkylsulphonylamino;
(viii) C1-4 alkylsulphonyl;
(ix) a group O-Hets or NH-Hets where Hets is a five or six membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from O, N and S, the heterocyclic rings being optionally further substituted by one or more C1-4 groups and wherein the S, when present, is S, SO or SO2;
(x) five and six membered saturated heterocyclic rings containing 1 or 2 heteroatoms selected from O, N and S, the heterocyclic rings being optionally further substituted by one or more C1-4 groups and wherein the S, when present, is S, SO or SO2;
(xi) oxo; and
(xii) six membered aryl and heteroaryl rings containing up to two nitrogen ring members and being optionally substituted by one or more substituents selected from halogen, methyl and methoxy.

### Claim 16

A pharmaceutical composition comprising a compound having the formula (II):
or salts or tautomers or N-oxides thereof, and a pharmaceutically acceptable carrier, wherein
Y is a bond or an alkylene chain of 1, 2 or 3 carbon atoms in length;
R1 is a substituted or unsubstituted phenyl group;
R2 is hydrogen; halogen; C1-4 alkoxy; or a C1-4 hydrocarbyl group optionally substituted by halogen or C1-4 alkoxy, and
R3 is selected from carbocyclic groups having from 3 to 12 ring members wherein R3 is not unsubstituted piperidin-4-yl, N-methyl piperidin-4-yl, an N-unsubstituted piperidin-4-yl substituted by C1-3 alkyl, or an N-methyl piperidin-4-yl substituted by C1-3 alkyl.

### Claim 17 (depends on 1)

A compound according to claim 1 having the formula (IV):
or salts or tautomers or N-oxides thereof;
wherein R1 and R2 are as defined in claim 1;
an optional second bond may be present between carbon atoms numbered 1 and 2;
one of U and T is selected from CH2, CHR13, CR11R13, NR14, N(O)R15, O and S(O)t; and
the other of U and T is selected from, NR14, O, CH2, CHR11, C(R11)2, and C═O; r is 0, 1, 2, 3 or 4; t is 0, 1 or 2;
R11 is selected from hydrogen, halogen, C1-3 alkyl and C1-3 alkoxy;
R13 is selected from hydrogen, NHR14, NOH, NOR14 and Ra-Rb;
R14 is selected from hydrogen and Rd-Rb;
Rd is selected from a bond, CO, C(X2)X1, SO2 and SO2NRc;
Ra is a bond, O, CO, X1C(X2), C(X2)X1, X1C(X2)X1, S, SO, SO2, NRc, SO2NRc or NRcSO2;
Rb is selected from hydrogen, carbocyclic and heterocyclic groups having from 3 to 12 ring members, and a C1-8 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C1-4 hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members and wherein one or more carbon atoms of the C1-8 hydrocarbyl group may optionally be replaced by O, S, SO, SO2, NRc, X1C(X2), C(X2)X1 or X1C(X2)X1;
Rc is selected from hydrogen and C1-4 hydrocarbyl; and
X1 is O, S or NRc and X2 is ═O, ═S or ═NRc; and
R15 is selected from C1-4 saturated hydrocarbyl optionally substituted by hydroxy, C1-2 alkoxy, halogen or a monocyclic 5- or 6-membered carbocyclic or heterocyclic group, provided that U and T cannot be O simultaneously.

### Claim 18 (depends on 17)

A compound according to claim 17 wherein one of U and T is selected from CH2, CHR13, CR11R13, NR14, N(O)R15, O and S(O)t; and the other of U and T is selected from CH2, CHR11, C(R11)2, and C═O;
r is 0, 1 or 2;
t is 0, 1 or 2;
R11 is selected from hydrogen and C1-3 alkyl;
R13 is selected from hydrogen and Ra-Rb;
R14 is selected from hydrogen and Rd-Rb;
Rd is selected from a bond, CO, C(X2)X1, SO2 and SO2NRc; and
R15 is selected from C1-4 saturated hydrocarbyl optionally substituted by hydroxy, C1-2 alkoxy, halogen or a monocyclic 5- or 6-membered carbocyclic or heterocyclic group.

### Claim 19 (depends on 18)

A compound according to claim 18 wherein T is selected from CH2, CHR13, CH11R13, NR14, N(O)R15, O and S(O)t.

### Claim 20 (depends on 18)

A compound according to claim 18 wherein U is selected from CH2, CHR11, C(R11)2, and C═O.

### Claim 21 (depends on 18)

A compound according to claim 18 wherein R11 is selected from hydrogen and methyl.

### Claim 22 (depends on 18)

A compound according to claim 18 having the formula (Va):
or salts or tautomers or N-oxides thereof;
wherein R14a is selected from hydrogen, C1-4 alkyl optionally substituted by fluoro, cyclopropylmethyl, phenyl-C1-2 alkyl, C1-4 alkoxycarbonyl, phenyl-C1-2 alkoxycarbonyl, C1-2-alkoxy-C1-2 alkyl, and C1-4 alkylsulphonyl, wherein the phenyl moieties when present are optionally substituted by one to three substituents selected from fluorine, chlorine, C1-4 alkoxy optionally substituted by fluoro or C1-2-alkoxy, and C1-4 alkyl optionally substituted by fluoro or C1-2-alkoxy;
w is 0, 1, 2 or 3;
R2 is hydrogen or methyl; and
R19 is selected from fluorine; chlorine; C1-4 alkoxy optionally substituted by fluoro or C1-2-alkoxy; and C1-4 alkyl optionally substituted by fluoro or C1-2-alkoxy.

### Claim 23 (depends on 1)

A compound according to claim 1 of formula