# US 6,720,321 B2 · 1,4-disubstituted benzo-fused cycloalkyl urea compounds

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- Number: US 6,720,321 B2
- Document ID: US6720321B2
- Status: Granted
- Kind: B2
- Application number: 10/154,535
- Filed: 2002-05-24
- Published: 2003-05-29
- Granted: 2004-04-13
- Earliest claimed: 2001-06-05
- Assignees: Boehringer Ingelheim Pharmaceuticals, Inc.
- Inventors: Pier Francesco Cirillo; Eugene R. Hickey
- Web page: https://patentgrep.com/patent/US6720321B2

## CPC

- C07D 213/64: attached in position 2 or 6
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/08: Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock (artificial tears A61P27/04)
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- 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 11/06: Antiasthmatics
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/10: for osteoporosis
- 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 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
- C07D 213/36: Radicals substituted by singly-bound nitrogen atoms (nitro radicals C07D213/26)
- C07D 213/68: attached in position 4
- C07D 213/70: Sulfur atoms
- C07D 213/81: Amides; Imides
- C07D 239/34: One oxygen atom
- C07D 239/47: One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
- C07D 239/52: Two oxygen atoms
- C07D 251/46: with oxygen or sulfur atoms attached to the two other ring carbon atoms
- C07D 295/088: to an acyclic saturated chain
- C07D 295/13: to an acyclic saturated chain
- C07D 309/38: one oxygen atom in position 2 or 4, e.g. pyrones
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Disclosed are compounds of the formula (I) shown below which are active as anti-inflammatory agents. Also disclosed are methods of using and making such compounds. wherein n, X, A, L, J, p, Q, Y and z are described herein.

## Claims

### Claim 1

A compound of the formula (I):
wherein:
n is 1, 2, 3, 4 or 5 such that the cycloalkyl group is chosen from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, each optionally independently substituted by one to two R1 or R2;
X is O;
p is 0;
z is 0;
m is 0, 1 or 2;
ring A is:
fused saturated or unsaturated ring containing 3-5 carbon atoms wherein ring A or the phenyl ring to which it is fused is optionally substituted by one or more C1-6 branched or unbranched alkyl optionally partially or fully halogenated, acetyl, aroyl, C1-6 branched or unbranched alkoxy optionally partially or fully halogenated, halogen, methoxycarbonyl, phenylsulfonyl, hydroxy, amino, mono- or di-(C1-4 alkyl)amino, mono- or di-(C1-4 alkyl)amino-S(O)2, cyano, nitro or H2NSO2;
L is:
(i) an acyclic group chosen from —O—; —NH—; >C(O); >C(S);
C1-10 saturated or unsaturated branched or unbranched carbon chain;
wherein one or more carbon atoms are optionally independently replaced by heteroatoms chosen from O, N and S(O)m; and
wherein said acyclic group is optionally substituted with 0-2 oxo groups, one or more C1-4 branched or unbranched alkyl optionally substituted by one or more halogen atoms, hydroxy, amino or imino;
Q is
pyrimidinyl optionally substituted with one to three oxo, C1-6 alkyl, phenyl, C1-6 alkoxy or hydroxyl;
R1 is
phenyl, benzyl, naphthyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazoyl, [1,3,4]oxadiazol, triazolyl, tetrazolyl, thienyl, furanyl, tetrahydrofuranyl, tetrahydropyranyl, isoxazolyl, isothiazolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, each of the aforementioned is optionally substituted with one to three phenyl, naphthyl, heterocycle or heteroaryl as hereinabove described in this paragraph, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C3-7 cycloalkylC0-2 alkyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1-5 alkyl, naphthyl C1-5 alkyl, halogen, hydroxy, oxo, nitrile, C1-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heterocyclic or heteroaryl moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C1-3alky)lamino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl heterocyclic moiety is as hereinabove described in this paragraph, NH2C(O), a mono- or di-(C1-3alkyl) aminocarbonyl, C1-5 alkyl-C(O)—C1-4 alkyl, amino-C1-5 alkyl, mono- or di-(C1-5alkyl)amino, mono- or di -(C1-3alkyl)amino-C1-5 alkyl, C1-5 alkyl-S(O)m, amino-S(O)m, di-(C1-3alkyl)amino-S(O)m, R3—C1-5 alkyl, R3—C1-5 alkoxy, R3—C(O)—C1-5 alkyl, R3—C1-5 alkyl(R4)N, C1-6 acyl, C1-6 alkoxyCl-3 acyl, carboxy-mono- or di-(C1-5alkyl)-amino;
C3-7 cycloalkylC0-5 alkyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally be partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups;
cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C1-3 alkyl groups;
C1-4 alkyl-phenyl-C(O)—C1-4 alkyl-, C1-4 alkyl-C(O)—C1-4 alkyl- or C1-4 alkyl-phenyl-S(O)m—C1-4 alkyl-;
C1-6 alkyl or C1-6 alkoxy each of which is branched or unbranched and optionally partially or fully halogenated or optionally substituted with R3;
R2, is
a C1-6 branched or unbranched alkyl optionally partially or fully halogenated, C1-6acyl, aroyl, C1-4 branched or unbranched alkoxy, each being optionally partially or fully halogenated, carboxy, nitrile, nitro, halogen, C1-6 alkoxycarbonyl, C1-6 alkyl-S(O)m optionally partially or fully halogenated, phenyl-S(O)m, amino or aminocarbonyl wherein the N atom is optionally mono-or-disubstituted by C1-6 branched or unbranched alkyl, C1-6acyl, phenyl or benzyl;
each R3 is independently:
nitrile, C3-7 cycloalkyl, phenyl or NR5R6;
each R4 is independently:
hydrogen or C1-4 alkyl optionally partially or fully halogenated;
Y, is covalently attached to Q, and is
C1-5 alkyl branched or unbranched, optionally substituted by one to three hydroxy, oxo, C1-4 alkyl, C1-3 alkoxy, C1-4 acyl, C1-5 alkoxycarbonyl, NR5R6 or NR5R6—C(O)—;
wherein Y is further covalently attached to morpholinyl optionally substituted by one to three hydroxy, oxo, C1-3 alkyl, C1-3 alkoxy, C1-5 alkoxycarbonyl, NR5R6 or NR5R6—C(O)—;
each R5 and R6 are independently hydrogen, C3-7 cycloalkylC0-4 alkyl, arylC0-3 alkyl optionally subtituted by halogen, C1-3 alkyl or diC1-5 alkyl amino, or R5 and R6 are C1-3 acyl, aroyl or C1-6 branched or unbranched alkyl optionally substituted by C1-5 alkoxy, hydroxy, mono- or di-C1-3alkylaminocarbonyl or mono or diC1-3 alkyl amino wherein said C1-6 alkyl optionally partially or fully halogenated;
and the pharmaceutically acceptable salts, tautomers or stereoisomers thereof.

### Claim 2 (depends on 1)

The compound according to claim 1 wherein:
n is 1, 2 or 3, such that the cycloalkyl group is chosen from cyclopropyl, cyclobutyl and cyclopentyl, each optionally independently substituted by one to two R1 or R2;
ring A is:
R1 is
phenyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazoyl, [1,3,4]oxadiazol, triazolyl, tetrazolyl, isoxazolyl or isothiazolyl each of the aforementioned is optionally substituted with one to three phenyl, naphthyl, heterocycle or heteroaryl as hereinabove described in this paragraph, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C3-7 cycloalkyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1-5 alkyl, naphthyl C1-5 alkyl, halogen, hydroxy, oxo, nitrile, C1-3 alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heterocyclic or heteroaryl moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C1-3alky)lamino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl heterocyclic moiety is as hereinabove described in this paragraph, NH2C(O), a mono- or di-(C1-3alkyl) aminocarbonyl, C1-5 alkyl-C(O)—C1-4 alkyl, amino-C1-5 alkyl, mono- or di-(C1-5alkyl)amino, mono- or di-(C1-3alkyl)amino-C1-5 alkyl, amino-S(O)2 or di-(C1-3alkyl)amino-S(O)2;
C3-7 cycloalkyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally be partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups;
cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C1-3 alkyl groups;
C1-6 alkyl branched or unbranched and optionally partially or fully halogenated;
R2, is
a C1-6 branched or unbranched alkyl optionally partially or fully halogenated, C1-6acyl, aroyl, C1-4 branched or unbranched alkoxy, each being optionally partially or fully halogenated, carboxy, nitrile, nitro, halogen.

### Claim 3 (depends on 2)

The compound according to claim 2 wherein:
n is 1, such that the cycloalkyl group is cyclopropyl optionally independently substituted by one to two R1 or R2;
ring A is:
L is:
—O—, —S—, >C(O), >C(S), —OCH2—, —CH2—, —CH2CH2—, —CH2CH2CH2—, —C(CH3)2—, —CH(OH)—, —CH2CH(OH)—, —CH(OH)CH2—, —OCH2CH2—, —OCH2CH2CH2—, —OCH2CH2(CH3)—, —OCH2(CH3)CH2—, —OCH2C(O)—, —CH═CH—CH2—, —CH═CHCH2CH2, —NH—, —NHCH2—, —NHCH2CH2—, —S(O)m—, —S(O)mCH2—, —S(O)mCH2CH2— and —S(O)mCH2CH2CH2—;
Q is
pyrimidinyl optionally substituted with one to three C1-4 alkyl, phenyl, C1-4 alkoxy or hydroxy;
R1 is
phenyl optionally substituted with one to three C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C3-7 cycloalkyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, halogen, hydroxy, oxo, nitrile, C1-3 alkoxy optionally partially or fully halogenated, nitro, amino or mono- or di-(C1-3alky)lamino;
C3-7 cycloalkyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally be partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups;
cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C1-3 alkyl groups;
C1-6 alkyl branched or unbranched and optionally partially or fully halogenated; and
R2, is
a C1-6 branched or unbranched alkyl optionally partially or fully halogenated, C1-4 branched or unbranched alkoxy, each being optionally partially or fully halogenated, carboxy, nitrile, nitro, halogen.

### Claim 4 (depends on 3)

The compound according to claim 3 wherein:
L is:
—O—, —S—, >C(O), —OCH2—, —CH2—, —CH2CH2—, —CH2CH2CH2—, —CH(OH)—, —CH2CH(OH)—, —CH(OH)CH2—, —OCH2CH2—, —OCH2CH2CH2—, —OCH2CH2(CH3)—, —OCH2(CH3)CH2—, —S(O)m—, —S(O)mCH2—, —S(O)mCH2CH2— and —S(O)mCH2CH2CH2—;
Q is
pyrimidinyl, optionally substituted with one to two C1-4 alkoxy or C1-4 alkyl;
R1 is
phenyl, C3-7 cycloalkyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally be partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups;
C1-6 alkyl branched or unbranched and optionally partially or fully halogenated; and
R2, is
a C1-6 branched or unbranched alkyl optionally partially or fully halogenated, C1-4 branched or unbranched alkoxy, each being optionally partially or fully halogenated, carboxy, nitrile, nitro, halogen.

### Claim 5 (depends on 4)

The compound according to claim 4 wherein:
n is 1, such that the cycloalkyl group is cyclopropyl which is substituted by one R1;
L is:
—O—, —S—, >C(O) and —OCH2CH2—;
R1 is
phenyl, C3-6 cycloalkyl or neopentyl each being optionally partially or fully halogenated.

### Claim 6 (depends on 5)

The compound according to claim 5 wherein:
Q is
pyrimidin-4-yl optionally substituted with one to two C1-4 alkoxy or C1-4 alkyl; and
R1 is
phenyl, cyclohexyl or neopentyl each being optionally partially or fully halogenated.

### Claim 7 (depends on 6)

The compound according to claim 6 wherein:
Y is:
optionally substituted by one to two acetyl, methyl, ethyl, halogen or hydroxy;
each R5 and R6 are independently hydrogen, C3-5 cycloalkylC1-2 alkyl, benzyl each optionally subtituted by chlorine, bromine, fluorine or C1-2 alkyl, acetyl, benzoyl or C1-4 branched or unbranched alkyl;
L is:
—O—, —S—, >C(O) and —OCH2CH2—;
R1 is
phenyl, C3-6 cycloalkyl or neopentyl each being optionally partially or fully halogenated.

### Claim 8 (depends on 7)

The compound according to claim 7 wherein:
L is —O—;
R1 is cyclohexyl and
each R5 and R6 are independently hydrogen, cyclopropylmethyl, benzyl, benzoyl or C1-3 alkyl.

### Claim 9

A compound selected from:
1-[4(2-Morpholin-4-yl-ethoxy)-naphthalen-1-yl]-3-(2-phenyl-cyclopropyl)-urea;
1-(2-Cyclohexyl-cyclopropyl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea and
1-[2-(2,2-Dimethyl-propyl)-cyclopropyl]-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea;
or the pharmaceutically acceptable salts, tautomers or stereoisomers thereof.

### Claim 10

A compound selected from:
1-(2-Cyclohexyl cyclopropyl)-3-[4(6methyl-2-morpholin-4-ylmethyl-pyrimidin-4-yloxy) -naphthalen-1-yl]urea;
or the pharmaceutically acceptable derivatives thereof.

### Claim 11 (depends on 1)

A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to claim 1.

### Claim 12 (depends on 1)

A method of treating a cytokine mediated disease or condition which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 1.

### Claim 13 (depends on 12)

The method according to claim 12 wherein cytokine mediated disease or condition is selected from rheumatoid arthritis, inflammatory bowel disease, septic shock, osteoarthritis, Crohn's disease, ulcerative colitis, multiple sclerosis, Guillain-Barre syndrome, psoriasis, graft versus host disease, systemic lupus erythematosus, percutaneous transluminal coronary angioplasty, diabetes, toxic shock syndrome, Alzheimer's disease, acute and chronic pain, contact dermatitis, atherosclerosis, traumatic arthritis, glomerulonephritis, reperfusion injury, sepsis, bone resorption diseases, chronic obstructive pulmonary disease, congestive heart failure, asthma, stroke, myocardial infarction, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ injury secondary to trauma, dermatoses with acute inflammatory components, acute purulent meningitis, necrotizing entrerocolitis, syndromes associated with hemodialysis, leukopherisis and granulocyte transfusion.

### Claim 14 (depends on 13)

The method according to claim 13 wherein the disease is selected from rheumatoid arthritis, osteoarthritis, Crohn's disease, psoriasis, ulcerative colitis, osteoporosis, chronic obstructive pulmonary disease, percutaneous transluminal coronary angioplasty and congestive heart failure.

### Claim 15 (depends on 14)

The method according to claim 14 wherein the disease is selected from rheumatoid arthritis, Crohn's disease, psoriasis, chronic obstructive pulmonary disease, percutaneous transluminal coronary angioplasty and congestive heart failure.

### Claim 16 (depends on 1)

A process of making a compound of the formula (I) according to claim 1,
wherein n is 1, and the cyclopropyl group has the stereochemistry shown above;
said process comprising
reacting the aldehyde bearing R1 or R2 (VI) with the carbethoxymethylene triphenylphosphorane in a suitable solvent to provide the alpha, beta-unsaturated ester (VII);
reacting compound (VII) with diazomethane in the presence of palladium (II) acetate in a suitable solvent at a temperature of about 0° C. to room temperature to provide the cyclopropane carboxylic acid ester (VIII);
hydrolyzing the ester (VIII) under suitable conditions to provide the carboxylic acid (IX) compound;
reacting carboxylic acid compound (IX) under suitable conditions for converting via Curtius rearrangement to provide the isocyanate (X);
reacting the isocyante (X) with the intermediate (IV) to provide compounds of the formula (I) with the stereochemistry indicated in the formula (I) shown above and subsequently isolating the product compound.