WO2007096151A2 - Inhibitors of p38-kinase for treatment of pulmonary hypertension - Google Patents

Inhibitors of p38-kinase for treatment of pulmonary hypertension Download PDF

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Publication number
WO2007096151A2
WO2007096151A2 PCT/EP2007/001508 EP2007001508W WO2007096151A2 WO 2007096151 A2 WO2007096151 A2 WO 2007096151A2 EP 2007001508 W EP2007001508 W EP 2007001508W WO 2007096151 A2 WO2007096151 A2 WO 2007096151A2
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amino
methyl
optionally substituted
benzoyl
alkyl
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PCT/EP2007/001508
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French (fr)
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WO2007096151A3 (en
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Christoph Walker
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Novartis Ag
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to organic compounds and their use as pharmaceuticals.
  • the invention relates, in one aspect, to the use of a compound of formula A
  • R 1 is hydrogen, acyl or -P(O)(OHIi;
  • R 2 is hydrogen, halo, optionally substituted alkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, optionally substituted alkoxy, optionally substituted heterocyclyloxy, or alkylamino;
  • G is an aryl, aralkyl, cycloalkyl, heteroaryl, heteroaralkyl or a heterocyclyl ring optionally fused to a phenyl ring, and is substituted with R 3 and R 4 , provided that the heterocyclyl ring is attached to the carbonyl group via a carbon ring atom, or G is OR 83 or NR 80 R 81 ;
  • B is an aryl or heteroaryl ring
  • C is a 5-membered heteroaryl ring containing one or two heteroatoms in the ring;
  • D is heteroaryl, optionally substituted heteroaryl or -C(O)NR 80 R 81 ;
  • each R 80 and R 81 is independently hydrogen, alkyl, optionally substituted cycloalkyl, alkoxy, hydroxy, heteroaryl or optionally substituted heteroaryl, or together from optionally substituted alkylene or heteroalkylene;
  • R 83 is hydrogen, alkyl, cycloalkyl, heteroaryl or optionally substituted heteroaryl; Case 50053A-HO 164
  • R 3 is selected from the group consisting of:
  • Y is a single bond, -O-, -NH- or -S(O) n - (where n is an integer from 0 to 2); and R 9 is halo, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -COOH, -COR 10 , -COOR", -CONR 12 R 13 , -SO 2 R 14 , -SO 2 NR 1S R 1 *, -NHSO 2 Ri 7 or -NHSO 2 NR 18 R 19 , where R 10 is alkyl or optionally substituted heterocycle, R 11 is alkyl, and R 12 , R' 3 , R 14 , R 15 , R 16 , R 17 R 18 and R 19 are, independently of each other, hydrogen, alkyl or heteroalkyl;
  • R 20 , R 21 and R 22 independently represent hydrogen, alkyl or hydroxy, or R 20 and R 21 together are -(CH 2 ) n -where n is 2 or 3 and R 22 is hydrogen or alkyl;
  • n is an integer from 0 to 2
  • R 27 is alley!, heteroalkyl, optionally substituted heterocyclylalkyl or -NR 28 R 29 where R 28 and R 29 are, independently of each other, hydrogen, alkyl or heteroalkyl;
  • R 40 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroarylium, optionally substituted cycloalkyl, optionally substituted heterocyclyl, C(L)R 56 , halo pseudohalo, OR 55 , SR 55 , NR 57 R 58 or SiR 52 R 53 R 54 ; where R 52 , R 53 and R 54 are selected as in (i) or (ii) as follows (i) R 52 , R 53 and R 54 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 55 or NR 62 R 63 ; or (ii) any two of R 52 , R 53 and R 54 together form al
  • R 57 and R 58 are selected as in (i) or (ii) as follows (i) R 57 and R 58 are each independently hydrogen, optionally substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 55 , NR 67 R 68 or C(L)R 6 ', where R 67 and R 68 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl or heterocyclyl, or together form alkylene, alkenylene, alkynylene, heteroalkylene; and R 69 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 70 or NR 62 R 63 , where R
  • R 4 is selected from the group consisting of:
  • R 3 and R 4 which substitute adjacent atoms on a ring, together form alkylenedioxy, thioalkylenoxy or alkylenedithioxy;
  • R 5 is selected from the group consisting of
  • R 6 is selected from the group consisting of:
  • the invention provides, in another aspect, a method of treating pulmonary hypertension, in a subject, particularly a human subject, in need of such treatment, which comprises administering to said subject an effective amount of a compound of formula A as hereinbefore defined.
  • the invention provides, in further aspect, a method of treating pulmonary hypertension, in a subject, particularly a human subject, in need of such treatment, which comprises administering to said subject an effective amount of a compound of formula A as hereinbefore defined in combination with a second active agent.
  • Treatment of pulmonary hypertension in accordance with the invention may be symptomatic or prophylactic.
  • Pulmonary hypertension to be treated in accordance with the invention includes primary pulmonary hypertension (PPH); secondary pulmonary hypertension (SPH); familial PPH; sporadic PPH; precapillary pulmonary hypertension; pulmonary arterial hypertension (PAH); pulmonary artery hypertension; idiopathic pulmonary hypertension; thrombotic pulmonary arteriopathy (TPA); plexogenic pulmonary arteriopathy; functional classes I to IV pulmonary hypertension; and pulmonary hypertension associated with, related to, or secondary to, left ventricular dysfunction, mitral valvular disease, constrictive pericarditis, aortic stenosis, cardiomyopathy, mediastinal fibrosis, anomalous pulmonary venous drainage, pulmonary Case 50053A-HO 164
  • venoocclusive disease collagen vasular disease, congenital heart disease, HIV virus infection, drugs and toxins such as fenfluramines, congenital heart disease, pulmonary venous hypertension, chronic obstructive pulmonary disease, interstitial lung disease, sleep- disordered breathing, alveolar hypoventilation disorder, chronic exposure to high altitude, neonatal lung disease, alveolar-capillary dysplasia, sickle cell disease, other coagulation disorder, chronic thromboemboli, connective tissue disease, lupus, schistosomiasis, sarcoidosis or pulmonary capillary hemangiomatosis.
  • drugs and toxins such as fenfluramines, congenital heart disease, pulmonary venous hypertension, chronic obstructive pulmonary disease, interstitial lung disease, sleep- disordered breathing, alveolar hypoventilation disorder, chronic exposure to high altitude, neonatal lung disease, alveolar-capillary dysplasia, sickle
  • Pulmonary hypertension to be treated in accordance with the invention is most particularly pulmonary hypertension associated with disorders of the respiratory system and/or hypoxemia, including chronic obstructive pulmonary disease, interstitial lung disease, sleep- disordered breathing, alveolar hypoventilation disorders, chronic exposure to high altitude, neonatal lung disease and alveolar-capillary dysplasia, but especially chronic obstructive pulmonary disease.
  • disorders of the respiratory system and/or hypoxemia including chronic obstructive pulmonary disease, interstitial lung disease, sleep- disordered breathing, alveolar hypoventilation disorders, chronic exposure to high altitude, neonatal lung disease and alveolar-capillary dysplasia, but especially chronic obstructive pulmonary disease.
  • p38 ⁇ refers to the enzyme disclosed in Han et al. (1995) Biochim. Biophys. Acta 1265 (2-3 ):224-7. As used herein, p38 ⁇ refers to the enzyme disclosed in Jiang et al. (1996) /. Biol. Chem. 271(30):17920-6. As used herein, p38 ⁇ refers to the enzyme disclosed in Li et al. (1996) Biochem. Biophys. Res. Comtnun. 228: 334-340. As used herein, p38 ⁇ refers to the enzyme disclosed in Wang et al. (1997) ]. Biol. Chem. 272(38):23668-74.
  • pharmaceutically acceptable derivatives of a compound include salts, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, Case 50053 A-HO 164
  • solvates, hydrates or prodrugs thereof Such derivatives may be readily prepared by those of skill in this art using known methods for such derivatization.
  • the compounds produced may be administered to animals or humans without substantial toxic effects and either are pharmaceutically active or are prodrugs.
  • salts include, but are not limited to, amine salts, such as but not limited to N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanoiamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N- benzylphenethylamine, l-para-chloro-benzyl-2-pyrrolidin-l'-ylmethyl-benzimidazole, diethylamine and other alkylami ⁇ es, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts, such as but not limited to lithium, potassium and sodium; alkali earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salts, such as but not limited to zinc; and other metal salts, such as but not limited to sodium hydrogen phosphate and disodium phosphate; and also including, but not limited to, nitrates,
  • esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl and heterocyclyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids, sulfinic acids and boronic acids.
  • Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent or water molecules, or 1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules.
  • AlkyP means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, pentyl, and the like.
  • cycloalkyl refers to a saturated or partially unsaturated nonaromatic cyclic hydrocarbon ring system, preferably containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C3-C7 carbocylic ring.
  • exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloctyl, cyclodecyl, cyclododecyl, and adamantyl.
  • a “substituted cycloalkyl” is substituted with one or more alkyl or substituted alkyl groups as described above, or one or more groups described above as alkyl substituents.
  • the expression “lower cycloalkyl” refers to an unsubstituted saturated or unsaturated nonaromatic cyclic hydrocarbon ring system containing 3 to 5 carbon atoms.
  • Alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, propylene, 2-methylpropyIene, pentylene, and the like.
  • Alkenyl means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g., ethenyl, propenyl, and the like.
  • Alkenylene means a linear divalent hydrocarbon radical of two to six carbon atoms or a branched divalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g., ethenylene, propenylene, and the like.
  • Alkynyl means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched divalent hydrocarbon radical of three to six carbon atoms, containing at least one triple bond, e.g., ethynyl, propynyl, and the like.
  • Alkynylene means a linear divalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one triple bond, e.g., ethynylene, propynylene, and the like.
  • Alkoxy means a radical -OR where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, 2-propoxy, the like.
  • Acyl means a radical -C(O)R where R is alkyl or haloalkyl e.g., acetyl, trifluoroaceryl, and the like.
  • Acylamino means a radical -NRC(O)R' where R is hydrogen or alkyl, and R' is alkyl, heteroalkyl or optionally substituted heterocyclylalkyl, e.g., acetylamino, 2-amino-2- methylpropionamide, and the like.
  • Halo means fluoro, chloro, bromo, or iodo, generally fluoro and chloro.
  • Haloalkyl means alkyl substituted with one or more same or different halo atoms, e.g., -CH 2 Cl, -CF 3 , -CH 2 CF 3 , -CH 2 CCl 3 , and the like.
  • Aryl means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms e.g., phenyl, 1-naphthyl, 2-naphthyl, and the like.
  • the aryl ring may optionally be fused to a 5-, 6- or 7- membered monocyclic saturated ring optionally containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen or sulfur, the remaining ring atoms being C where one or two C atoms are optionally replaced by a carbonyl group.
  • aryl radicals with fused rings include, but are not limited to, 2,3-dihydrobenzo[l,4]dioxan, chroman, isochroman, 2,3-dihydrobenzofuran, 1,3- dihydroisobenzofuran, benzo[l,3]dioxole, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4- tetrahydroquinoline, 2,3-dihydro-lH-indole, 2,3-dihydro-IH-isoindole, benzimidazol-2- one, 3H-benzoxazol-2-one, and the like.
  • Heteroaryl means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms containing one, two, or three ring heteroatoms selected from N, 0, or S, the remaining ring atoms being C.
  • the term also includes those radicals where a heteroatom within the ring has been oxidized or quaternized, such as, for example, to form an N-oxide or a quaternary salt.
  • Representative examples include, but are not limited to, thienyl, benzothienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, quinoxalinyl, imidazolyl, furanyl, benzofuranyl, thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, 2-pyridonyl, 4-pyridonyl, N-alkyl-2-pyridonyl, pyrazinonyl, pyridazinonyl, pyrimidinonyl, oxazolonyl, and their corresponding N-oxides, (e.g. pyridyl N-oxide, quinolinyl N-oxide), their quaternary salts and the like.
  • N-oxides e.
  • Heterocycle or “ heterocyclyl” means a cyclic nonaromatic radical of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, 0, or S(O) n , (where n is an Case 50053A-HO 164
  • ring nitrogen atom has been oxidized or quaternized, such as, for example, to form an N-oxide or a quaternary salt.
  • Representative examples include, but are not limited to, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidino, morpholino, piperazino, pyrrolidino, oxiranyl, dioxane, 1,3-dioxolanyl, 2,2-dimethyl-l,3-dioxalanyl, sulfolanyl, 2-oxazolidonyl, 2-imidazolidonyl, S,S-dioxo-thiomorpholino, and the like.
  • Heterocycloamino means a saturated monovalent cyclic group of 4 to 8 ring atoms, wherein at least one ring atom is N and optionally contains one additional ring atom selected from N or O, the remaining ring atoms being C.
  • the term includes groups such as pyrrolidino, piperidino, morpholino, piperazino and the like.
  • Optionally substituted alkyl, alkenyl, alkynyl, alkoxy or cycloalkyl means an aikyl, alkenyl, alkynyl, alkoxy or cycloalkyl group, as defined herein, which is optionally substituted independently with one or two substituents selected from alkyl, phenyl, benzyl, haloalkyl, heteroalkyl, halo, cyano, heterocyclyl, acyl, -OR (where R is hydrogen or alkyl), -NRR' (where R and R' are independently selected from hydrogen, acyl, or alkyl which is optionally substituted with hydroxy, alkoxy, cyano, halo or heterocyclyl), -NHCOR (where R is alkyl which is optionally substituted with hydroxy, alkoxy, cyano, halo or heterocyclyl), -NRS(O) n R' (where R is hydrogen or alkyl, n is
  • Optionally substituted aryl, heteroaryl or heterocyclyl means an aryl, heteroaryl or heterocyclyl ring as defined above, which is optionally substituted independently with one or two substituients selected from alkyl, phenyl, benzyl, haloalkyl, heteroalkyl, halo, cyano, Case 50053A-HO 164
  • acyl -OR (where R is hydrogen or alkyl), -NRR' (where R and R' are independently selected from hydrogen, alkyl or acyl), -NHCOR (where R is alkyl), -NRS(O) n R' (where R is hydrogen or alkyl, n is an integer from 0 to 2 and R 1 is hydrogen, alkyl or heteroalkyl), - NRS(O) n NR 1 R" (where R is hydrogen or alkyl, n is an integer from 0 to 2 and R 1 and R" are independently hydrogen, alkyl or heteroalkyl), -S(O) n R (where n is an integer from 0 to 2 and R is hydrogen, alkyl or heteroalkyl), -S(O) n NRR' (where n is an integer from 0 to 2 and R and R' are independently hydrogen, alkyl or heteroalkyl), -COOR, - (alkylene)COOR (where R is hydrogen or alkyl),
  • Heteroalkyl means an alkyl radical as defined above, carrying one, two or three substituents selected from -NR a R b , -OR C wherein R% R b and R c are independently of each other hydrogen, alkyl or acyl, or R" and R b together form heterocycloamino group.
  • Representative examples include, but are not limited to, hydroxymethyl, acetoxymethyl, 3- hydroxypropyl, 1,2-dihydroxyethyI, 2-methoxyethyl, 2-aminoethyl, 2-dimethylaminoethyl, 2- acetylaminoethyl, 3-[pyrrolidin-l-yl]ethyl and the like.
  • Heteroalkenyl means an alkenyl radical as defined above, carrying one or two substituents selected from -NR a R b , -OR C or -S(O) n R d wherein R a , R b and R c are independently of each other hydrogen or alkyl, and R d is alkyl or -NRR' (where R and R' are independently of each other hydrogen or alkyl.
  • Representative examples include, but are not limited to, 3-hydroxy- 1-propenyl, 3-aminoprop-l-enyl, 2-aminosulfonylethenyl, 2methyisulfonylethenyl, and the like.
  • Heteroalkynyl means an alkynyl radical as defined above, carrying one or two substituents selected -NR a R b , -OR C , -S(O) n R d or -S(O) n NRR 1 (where R and R' are independently of each other hydrogen or alkyl) wherein R a , R b and R c are independently of each other hydrogen or alkyl, and R d is alkyl and n is an integer from zero to two.
  • Representative examples include, but are not limited to, 3-hydroxy-l-propynyl, 3dimethylaminoprop-l-ynyl and the like.
  • Heteroalkoxy means a radical -OR where R is heteroalkyl group as defined above, e.g., 2- hydroxyethoxy, 3-hydroxypropoxy, 2,3-dihydroxypropoxy, 2-aminoethoxy, and the like.
  • Heteroalkylamino means a radical -NR a R b where R a is hydrogen or alkyl, and R b is a heteroalkyl group as defined above, e.g., 2-hydroxyethylamino, 3- dimethylaminopropylamino, and the like.
  • Case 50053A-HO 164 is a radical -NR a R b where R a is hydrogen or alkyl, and R b is a heteroalkyl group as defined above, e.g., 2-hydroxyethylamino, 3- dimethylaminopropylamino, and the like.
  • Optionally substituted heterocydylalkyl means a radical -R a R b where R a is an alkylene group, and R b is an optionally substituted heterocyclyl group as defined above e.g., 2- (morpholin-4-yI)ethyl, 3(piperidin-l-yI)-2-methylpropyl, and the like.
  • Optionally substituted heterocydylalkenyl means a radical -R a R b where R a is an alkenylene group and R b is an optionally substituted heterocyclyl group as defined above e.g., 3-(morpholin-4-yl)prop-l-enyll, 3-(piperidin-l-yl)prop-l-enyl, 3-(4-methylpiperazin-l- yl)prop-l-enyl, and the like.
  • Optionally substituted heterocyclylalkynyl means a radical -R a R b where R a is an alkynyl group and R b is an optionally substituted heterocyclyl group as defined above e.g., 3- (morpholin-4-yI)prop-l-ynyl, 3-(piperidin-l-yl)prop-l-ynyl, and the like.
  • Optionally substituted heterocyclylalkoxy means a radical -OR where R is an optionally substituted heterocydylalkyl group as defined above, e.g., 2-(morpholin-4-yl)-ethoxy, 3- (piperazin-l-yl)propoxy, 2-[2-oxopyrrolidin-l-yl]ethoxy, and the like.
  • Optionally substituted heterocyclylalkylamino means a radical -NR a R b where R a is hydrogen or alkyl and R & is an optionally substituted heterocydylalkyl group as defined above, e.g., 2-(pyrrolidin-2-yl)ethylamino, 3-(piperidin-l-yl)propylamino, and the like.
  • Optionally substituted heteroaralkyloxy means a radical -O-R a where R a is a heteroaralkyl radical e.g. 2-(pyridin-3-yl)ethoxy, 2-[3(2H)-pyridazon-l-yl]ethoxy and the like.
  • aryl group optionally mono- or di-substituted with an alkyl group means that the alkyl may but need not be present, and the description includes situations where the aryl group is mono- or disubstituted with an alkyl group and situations where the heterocyclo group is not substituted with the alkyl group.
  • Amino protecting group refers to those organic groups intended to protect nitrogen atoms against undesirable reactions during synthetic procedures e.g., benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trifluoroacetyl, and the like.
  • Case 50053A-HO 164 benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trifluoroacetyl, and the like.
  • All stereoisomers of the compounds provided herein are contemplated, either in admixture or in pure or substantially pure form.
  • the definition of compounds provided herein embraces all the possible stereoisomers and their mixtures. It embraces the racemic forms and the isolated optical isomers having the specified activity.
  • the racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography.
  • the individual optical isomers can be obtained from the racemates from the conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.
  • the invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula A wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen e.g. 2 H and 3 H, carbon e.g. 11 C, 13 C and 14 C, chlorine e.g. 36 Cl, fluorine e.g. 18 F, iodine e.g. 123 I and 125 I, nitrogen e.g. 13 N and 15 N, oxygen e.g. 15 O, 17 O and 18 O, and sulfur e.g. 35 S.
  • Certain isotopically-labelled compounds of formula A are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium ( 3 H) and carbon-14 ( 14 C) are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with heavier isotopes such as deuterium ( 2 H) may afford certain therapeutic advantages that result from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O, and 13 N can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • Isotopically-labelled compounds of formula A can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously used.
  • solvates in accordance with the invention include those wherein the solvent of crystallisation may be isotopically substituted e.g. D ⁇ O, d ⁇ -acetone or d «- DMSO.
  • the compounds provided herein may also have prodrug forms. Any compound that will be converted in vivo to provide the bioactive agent is a prodrug.
  • Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see, e.g.: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol.42, p. 309-396, edited by K. Widder, et al. (Acamedic Press, 1985); b) A Textbook of Drug Design and Development, edited by KrosgaardLarsen and H. Bundgaard, Chapter 5, "Design and Application of Prodrugs," by H. Bundgaard, p. 113-191 (1991); and c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992), each of which is incorporated herein by reference.
  • treatment means any manner in which one or more of the symptoms of a disease or disorder are ameliorated or otherwise beneficially altered.
  • amelioration of the symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the composition.
  • IC50 refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response, such as modulation of p38a kinase activity, in an assay that measures such response.
  • the compounds provided herein, or pharmaceutically acceptable derivative thereof, for use in the the manufacture of a medicament for the treatment of pulmonary hypertension are active in assays that measure p38 kinase activity, including, but not limited to, p38 ⁇ and p38 ⁇ kinase activity.
  • the invention relates to the use of compounds of formula IA, IB or IC respectively below : Case 50053A-HO 164
  • R 1 is hydrogen, acyl or -P(O)(OH) 2 ;
  • R 2 is hydrogen, halo, alkyl or alkylthio
  • A is an aryl, heteroaryl or a heterocyclyl ring optionally fused to a phenyl ring, provided that the heterocyclyl ring is attached to the carbonyl group via a carbon ring atom;
  • B is an aryl or heteroaryl ring
  • C is a 5-membered heteroaryl ring containing one or two heteroatoms in the ring;
  • D is heteroaryl, optionally substituted heteroaryl or -C(O)NR 80 R 81 , where R 80 and R 81 are independently hydrogen, alkyl, cycloalkyl, alkoxy, hydroxy, heteroaryl or optionally substituted heteroaryl; R 3 is selected from the group consisting of:
  • R 10 is alkyl or optionally substituted heterocycle
  • R 11 is alkyl
  • R 12 , R" , R 14 , R 15 , R l ⁇ , R 17 R 18 and R 19 are, independently of each other, hydrogen, alkyl or heteroalkyl
  • (u) -Q NR 20 MNR 21 R 22 ) where R 20 , R 21 and R 22 independently represent hydrogen, alkyl or hydroxy, or R 20 and R 21 together are -(CH 2 ) n -where n is
  • R 22 is hydrogen or alkyl;
  • R 30 , R 31 and R 32 are independently of each other, hydrogen, alkyl or heteroalkyl; Case 50053 A-HO 164
  • R 40 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroarylium, optionally substituted cycloalkyl, optionally substituted heterocyclyl, C(L)R 56 , halo pseudohalo, OR 5S , SR 55 , NR 57 R 58 or SiR 52 R 53 R 54 ; where R 52 , R 53 and R 54 are selected as in (i) or (ii) as follows (i) R 52 , R 53 and R 54 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR 55 or NR 62 R 63 ; or (ii) any two of R 52 , R 53 and R 54 together form
  • alkyl alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, or R 62 and R 65 together form alkylene, alkenylene, alkynylene, heteroalkylene; and (ii) optionally substituted alkyl;
  • R 4 is selected from the group consisting of:
  • R 5 is selected from the group consisting of (a) hydrogen
  • R 6 is selected from the group consisting of:
  • C is a 5-membered heteroaryl ring containing one or two heteroatoms in the ring.
  • C is selected from pyrazole, imidazole, pyrrole, thiazole, isothiazole, oxazole, isoxazole, furan and thiophene rings.
  • C is a pyrazole or imidazole ring.
  • C is an imidazole ring.
  • C is a pyrazole ring.
  • C is a pyrazole ring and thus the invention relates to the use of compounds of formula HA, IIB or IIC respectively below:
  • the hydrogen of the ring NH group may be replaced by one of the substituents shown in the structure (i.e., -C(O)-A(R 3 )(R 4 ), -R 2 , or -B(D)(R «)(R 5 )).
  • the compounds have formula DTA, DIB or IIC respectively below:
  • the compounds have formula IVA, IVB or IVC respectively below: Case 50053A-HO 164
  • the compounds have formula VA, VB or IVC respectively below:
  • the compounds have formula VA, VB or VC respectively below:
  • the compounds are imidazole-based compounds of formula VIA, VIB or VIC respectively below:
  • the hydrogen of the ring NH group may be replaced by one of the substituents shown in the structure structure (i.e., -C(O)-A(R 3 )(R 4 ), -R 2 , or -B(D)(R 6 )(R 5 ).
  • the compounds have formula VLIA, VIIB or VIIC respectively below:
  • the compounds have formula VIIIA, VHIB or VIIIC respectively below:
  • the compounds for use in the compositions and methods provided herein have the above formulae, or pharmaceutically acceptable derivatives thereof, where R 1 is hydrogen.
  • R 2 is hydrogen or lower alkyl. In another embodiment, R 2 is hydrogen.
  • G is OR 83 or NR 80 R 81 .
  • R 83 is alkyl or cycloalkyl. In another embodiment, R 83 is alkyl. In another embodiment, R 83 is ethyl.
  • R 80 and R 81 are each independently hydrogen, alky! or cycloalkyl. In another embodiment, R 80 and R 81 are each independently hydrogen or cycloalkyl. In another embodiment, R 80 and R 81 are each independently hydrogen or cyclohexyl. In another embodiment, G is NH2 or NH(cyclohexyl).
  • G is aryl, heteroaryl, cycloalkyl, heterocyclyl or heterocyclyl optionally fused to phenyl, and is substituted with R 3 and R 4 , provided that the heterocyclyl ring is attached to the carbonyl group via a carbon ring atom.
  • G is phenyl, cyclohexyl, cyclopentyl or benzyl, and is substituted with R 3 and R 4 .
  • G is phenyl and is substituted with R 3 and R 4 .
  • A is an aryl ring.
  • A is a phenyl ring.
  • B is an aryl ring. In another embodiment, B is a phenyl ring.
  • D is -C(O)NR 80 R 81 .
  • R 80 and R 81 are each independently hydrogen, cycloalkyl or alkoxy.
  • R 80 is hydrogen.
  • R 81 is cycloalkyl or alkoxy.
  • R 81 is Cj- ⁇ cycloalkyl or Ci- «alkoxy.
  • R 81 is cyclopropyl or methoxy.
  • D is optionally substituted heteroaryl. In another embodiment, D is optionally substituted triazolyl. In another embodiment, D is l,2,4-triazol-3-yl. Case 50053A-HO 164
  • R 3 is hydrogen, optionally substituted heterocyclyl, optionally substituted alkyl, C(L)R 40 , halo, pseudohalo or OR 41 ; where L is O, S or NR 55 ; R 40 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroarylium, optionally substituted cycloalkyl, optionally substituted heterocyclyl, C(L)R 56 , halo pseudohalo, OR 5S , SR 55 , NR 57 R 58 or SiR 52 R 53 R 54 ; R 41 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroarylium, optionally substituted cycloalkyl, optionally substituted heterocyclyl, C(L)
  • R 3 is hydrogen, optionally substituted heterocyclyl, optionally Case 50053 A-HO 164
  • R 3 is hydrogen, optionally substituted heterocyclyl, optionally substituted alkyl, C(L)R 40 , iodo, chloro or OR 41 .
  • R 3 is hydrogen, optionally substituted dioxolanyl, optionally substituted methyl, C(L)R 40 , iodo, chloro or OR 41 .
  • R 3 is hydrogen, 2-dioxolanyl, optionally substituted methyl, C(O)R 40 , iodo, chloro or OR 41 .
  • R 3 is hydrogen, 2-dioxolanyl, optionally substituted mediyl, CHO, iodo, chloro or OR 41 .
  • R 3 is hydrogen.
  • R 3 is optionally substituted methyl.
  • R 3 is methyl which is optionally substituted with heterocyclyl, hydroxy, aralkylamino or heterocyclylalkylamino.
  • R 3 is N-morpholinylmethyl, hydroxymethyl, N- (2-(3-chlorophenyl)-l-ethyl)aminomethyl, N-(2-morpholinyl-l-ethyl)aminomethyl or 4- piperizinylmethyl.
  • A is O.
  • R 40 is hydrogen, optionally substituted alkyl or cycloalkyl. In another embodiment, R 40 is hydrogen or alkyl. In another embodiment, R 40 is hydrogen.
  • R 41 is hydrogen or optionally substituted alkyl. In another embodiment, R 41 is hydrogen, or alkyl optionally substituted with heterocyclyl, aryl, dialkylamino, halo or hydroxy. In another embodiment, R 41 is hydrogen, or Ci-3alkyl optionally substituted with heterocyclyl, phenyl, dialkylamino, halo or hydroxy.
  • R 41 is hydrogen, 2-(N-morpholinyl)eth-l-yl, benzyl, 2-(N,N-di-(2-hydroxy-l- ethyl)amino)-l-ethyl, 2-bromo-l -ethyl, 2,2-dioxolan-4-ylmethyl, 2-(4-methylpiperazin-l-yl)- 1-ethyl or 2,3-dihydroxy-l-propyl.
  • R 41 is (S)-2,3-dihydroxy-l- propyl.
  • R 4 is hydrogen.
  • R 5 is alkyl.
  • R 5 is methyl.
  • R 6 is hydrogen.
  • the compounds for use in the compositions and methods have the above formulae, including formulae I-VIII, or a pharmaceutically acceptable derivative thereof, where:
  • R 1 is hydrogen, acyl or -P(O)(OH) 2 ;
  • R 2 is hydrogen, halo, alkyl or alkylthio; Case 50053 A-HO 164
  • A is an aryl, heteroaryl or a heterocyclyl ring optionally fused to a phenyl ring provided that the heterocyclyl ring is attached to the carbonyl group via a carbon ring atom;
  • B is an aryl or heteroaryl ring
  • D is heteroaryl, optionally substituted heteroaryl or -C(O)NR 80 R 81 (where R 80 and R 81 are independently hydrogen, alkyl, cycloalkyl, alkoxy, hydroxy, heteroaryl or optionally substituted heteroaryl);
  • R 3 is selected from the group consisting of:
  • R 4 is selected from the group consisting of:
  • R 5 is selected from the group consisting of
  • R 6 is selected from the group consisting of:
  • the compounds are those wherein:
  • R 1 is hydrogen or acyl
  • R 2 is hydrogen or alkyl
  • A is an aryl or heteroaryl ring.
  • the compounds are those wherein:
  • R 1 is hydrogen, acyl or -P(O)(OH) 2 ;
  • R 2 is hydrogen, halo, alkyl or alkylthio
  • A is an aryl, heteroaryl or a heterocyclyl ring optionally fused to a phenyl ring provided that the heterocyclyl ring is attached to the carbonyl group via a carbon ring atom;
  • B is an aryl or heteroaryl ring
  • R 3 is selected from the group consisting of: Case 50053 A-HO 164
  • heteroaryl optionally substituted with a substituent selected from halo, alkyl or alkoxy;
  • Y is a single bond, -O-, -NH- or - S(O) n - (where n is an integer from 0 to 2); and R 9 is cyano, heteroaryl, -COOH, -COR 10 , -COOR" - CONR i2 R", -SO 2 R 1 VSO 2 NR 15 R 16 , -NHSO 2 R 17 Or - NHSO 2 NR 18 R 19 where R 10 is alkyl or optionally substituted heterocyde, R 11 is alkyl, and R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 are, independently of each other, hydrogen, alkyl or heteroalkyl;
  • heterocyclylalkyl or R 25 and R 26 together with the nitrogen to which they are attached form an optionally substituted heterocyclyl ring;
  • R 4 is selected from the group consisting of:
  • R 5 is selected from the group consisting of:
  • R 6 is selected from a group consisting of:
  • R 12 , R 13 , R 14 , R 15 , R 16 R 17 , R 18 and R 19 are independently of each other heteroalkyl; hydrogen, alkyl or heteroalkyl; (x) cydoalkylalkyl, cycloalkylalkynyl and cycloalkylalkynyl, all optionally substituted with alkyl, halo, hydroxy or amino; (m) arylaminoalkylene or heteroarylaminoalkylene; or (n) Z-alkylene-NR 30 R 31 where Z is -NH-, -N(alkyl)- or -0-, and R 30 and
  • R 31 are independently of each other, hydrogen, alkyl or heteroalkyl.
  • the compounds are those where R 1 and R 2 are hydrogen and B is phenyl.
  • the compounds are those wherein R 4 is hydrogen and R s is halo or alkyl.
  • the compounds are those wherein R s is chloro, fluoro or methyl and R 6 is hydrogen, chloro, fluoro, methyl or methoxy.
  • the compounds are those wherein R 3 is optionally substituted heteroaryl.
  • the compounds are those wherein R 3 is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, N-oxidopyridin-2-yI, N-oxidopyridin-3-yl, Noxidopyridin-4-yl or pyridon-2-yl, all optionally substituted.
  • the compounds are those wherein R 3 is at the 3-position.
  • the compounds are those wherein R 5 is 4-F or 2-Me, and R 6 is hydrogen.
  • the compounds are those wherein R 3 is optionally substituted phenyl. Case 50053 A-HO 164
  • the compounds are those wherein R 3 is 3-sulfamoylphenyl, 3- methylsulfonylphenyl, 3-carboxyphenyl or 3-ethoxycarbonylphenyl.
  • the compounds are those wherein R 5 is 4-F and R 6 is hydrogen.
  • the compounds are those wherein R 3 is.
  • the compounds are those wherein R 3 is heteroalkyl.
  • the compounds are those wherein R 3 is at the 3-position and is selected from the group consisting of 2-dimethylaminoethyl, 3dimethylamtnopropyl, 4- dimethylaminobutyl, 2-dimethylaminoethylamino, 3-dimethylaminopropylamino, hydroxymethyl, 1,2-dihydroxyethyl, 3-hydroxy-3-methyl-l-butyl or 3-hydroxybutyl.
  • the compounds are those wherein R 5 is 2-F and R 6 is 4-F.
  • the compounds are those wherein R 5 is 2-Me and R 6 is hydrogen.
  • the compounds are those wherein R 9 is heteroalkoxy or heteroalkylamino.
  • the compounds are those wherein R 3 is at the 3-position and is selected from the group consisting of 3- dimethylaminopropoxy, 2dimethylaminoethoxy, 2-hydroxyethoxy, 2,3-dihydroxy- propoxy, 2-dimethylaminoethylamino and 3-dimethylaminopropylamino.
  • the compounds are those wherein R 3 is optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkoxy or optionally substituted Case 50053A-HO 164
  • the compounds are those wherein R 3 is at the 3-position and is selected from the group consisting of 3-(morpholin-4-yl)propoxy, 2-(morpholin-4-yl)ethoxy, 2-(2-oxo-pyrrolidin-l-yl)ethoxy, 3(morpholin-4-yl)propyI, 2- (morpholin-4-yl)ethyl, 4-(morpholin-4yl)butyl, 3-(morpholin-4-yl)propylamino, 2- (morpholin-4yl)ethylamino, 4-hydroxypiperidinylmethyl, 2-(S,S-dioxothiamorpholin-4- yl)ethyl, 3-(S,S-dioxo-thiamorpholin-4-yl)propyl and N-methylpiperazinylmethyl.
  • the compounds are those wherein R 3 is -Y-(alkylene)-R 9 where Y is a single bond, -O- or -NH- and R 9 is optionally substituted heteroaryl, - CONR 12 R 13 , -SO 2 R 14 , -SO 2 NR 15 R 1 S -NHSO 2 R 17 or -NHSO 2 NR 18 R 19 where R 12 , R 13 , R 14 , R 1S , R l ⁇ , R 17 , R 18 and R 19 are independently of each other hydrogen, alkyl or heteroalkyl.
  • the compounds are those wherein Y is a single bond and R 9 is - SO 2 R 14 or -SO 2 NR 15 R 16 .
  • the compounds are those wherein R 3 is 5-methylsulfonylethyl or sulfamoylethyl.
  • Specific preferred compounds of formula A for use in the manufacture of a medicament for the treatment of pulmonary hypertension include:
  • the invention relates most importantly to the use of 3-[5-Amino-4-(3-cyanobenzoyl)-pyrazol- l-yl]-N-cyclopropyI-4-methylbenzamide i.e. a compound of formula AA
  • the compounds of formula A are active in assays that measure p38 kinase activity, including, but not limited to, p38 ⁇ and p38 ⁇ kinase activity.
  • the invention provides a method of treating pulmonary hypertension, in a subject, particularly a human subject, in need of such treatment, which comprises administering to said subject an effective amount of a compound of formula A as hereinbefore defined.
  • the invention also provides a method of treating pulmonary hypertension, in a subject, particularly a human subject, in need of such treatment, which comprises administering to Case 50053A-HO 164
  • second or additional active agents include, but are not limited to, antiinflammatories, bronchodilators, antihistamines, decongestants, anti-tussives, anticoagulants, diuretics, cardiac glycosides, calcium channel blockers, vasodilators, prostacyclin analogues, endothelin antagonists, phosphodiesterase inhibitors, endopeptidase inhibitors, lipid lowering agents, thromboxane inhibitors, or other agents found, for example, in the Physician's Desk Reference 2003.
  • Second active agents can be large molecules (e.g., proteins) or small molecules (e.g., synthetic inorganic, organometallic, or organic molecules).
  • Compounds of formula I may be mixed with second or additional active agents in a fixed pharmaceutical composition or they may be administered separately, before, simultaneously with or after the second or additional active agents.
  • Examples of specific second active agents include, but are not limited to, amlodipine, diltiazem, nifedipine, adenosine, epoprostenol (FloranTM), treprostinil (RemodulinTM), bosentan (TracleerTM), warfarin, digoxin, nitric oxide, L- arginine, iloprost, betaprost, and sildenafil (ViagraTM).
  • Such anti-inflammatory drugs include steroids, in particular glucocorticosteroids such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate, or steroids described in WO 02/88167, WO 02/12266, WO 02/100879, WO 02/00679 (especially those of Examples 3, 11, 14, 17, 19, 26, 34, 37, 39, 51, 60, 67, 72, 73, 90, 99 and 101), WO 03/35668, WO 03/48181, WO 03/62259, WO 03/64445, WO 03/72592, WO 04/39827 and WO 04/66920; non-steroidal glucocorticoid receptor agonists, such as those described in DE 10261874, WO 00/00531, WO 02/10143, WO 03/82280, WO 03/82787, WO 03/86294, WO 03/104195, WO 03/101932,
  • WO 01/23399 WO 01/27130, WO 01/27131, WO 01/60835, WO 01/94368, WO 02/00676, WO 02/22630, WO 02/96462, WO 03/086408, WO 04/039762, WO 04/039766, WO 04/045618 and WO 04/046083; and A2b antagonists such as those described in WO 02/42298 and WO 03/042214.
  • Suitable PDE5 inhibitors include pyrazolopyrimidinones disclosed in EP 463756, EP 526004, WO 94/28902, WO 96/16657 or WO 98/49166; 5-substituted pyrazole [4,3-d]pyrimidin-7- ones disclosed in EP 201188; griseolic acid derivatives disclosed in EP 214708 and EP 319050; 2-phenylpurinone derivatives disclosed in EP 293063; phenylpyridone derivatives disclosed in EP 347027; fused pyrimidine derivatives disclosed in EP 347146; condensed pyrimidine derivatives disclosed in EP 349239; pyrimidopyrimidine derivatives disclosed in EP 351058; purine compounds disclosed in EP 352960; quinazolinone derivatives disclosed in EP 371731; phenylpyrimidone derivatives disclosed in EP 395328; imidazoquin-oxalinone derivatives or their aza analogues disclosed in EP 400583; phenyl
  • Suitable PDE4 inhibitors include cilomilast (Ariflo® GlaxoSmithKHne), Roflumilast (Byk Gulden),V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Case 50053A-HO 164
  • Arofylline Arofylline (Almirall Prodesfarma), PD189659 / PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID(TM) CC-10004 (Celgene), VM554/UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo), GRC 3886 (Oglemilast, Glenmark), WO 92/19594, WO 93/19749, WO 93/19750, WO 93/19751, WO 99/16766, WO 01/13953, WO 03/104204, WO 03/104205, WO 04/000814, WO 04/000839 and WO 04/005258 (Merck), WO 04018450, WO 04/018451, WO 04/018457, WO 04/018465, WO 04/
  • Such bronchodilatory drugs include beta-2 adrenoceptor agonists.
  • Suitable beta-2 adrenoceptor agonists include albuterol (salbutamol), metaproterenol, terbutaline, salmeterol, fenoterol, procaterol, and especially, formoterol, carmoterol, GSK159797 and pharmaceutically acceptable salts thereof, and compounds (in free or salt or solvate form) of formula I of WO 00/75114, which document is incorporated herein by reference, preferably compounds of the Examples thereof, especially a compound of formula
  • ⁇ -2- adrenoreceptor agonists include compounds, such as those described in and also compounds of EP 147719, EP 1440966, EP 1460064, EP 1477167, EP 1574501, JP 05025045, JP 2005187357, US 2002/0055651, US 2004/0242622, US 2004/0229904, US 2005/0133417, US 2005/5159448, US 2005/5159448, US 2005/171147, US 2005/182091, US 2005/182092, US 2005/209227, US 2005/256115, US 2005/277632, US 2005/272769, US 2005/239778, US 2005/215542, US 2005/215590, US 2006/19991, US 2006/58530, WO 93/18007, WO 99/64035, WO 01/42193
  • Such bronchodilatory drugs also include other anticholinergic or antimuscarinic agents, in particular ipratropium bromide, oxitropium bromide, tiotropium salts, glycopyrrolate, CHF 4226 (Chiesi) and SVT-40776, but also those described in EP 424021, US 3714357, US 5171744, US 2005/171147, US 2005/182091, WO 01/04118, WO 02/00652, WO 02/51841, WO 02/53564, WO 03/00840, WO 03/33495, WO 03/53966, WO 03/87094, WO 04/18422, WO 04/05285, WO 04/96800, WO 05/77361 and WO 06/48225.
  • ipratropium bromide oxitropium bromide
  • tiotropium salts glycopyrrolate
  • CHF 4226 Chiesi
  • SVT-40776 but also those described in EP 424021, US 3714357,
  • Suitable dual anti-inflammatory and bronchodilatory drugs include dual beta-2 adrenoceptor agonist / muscarinic antagonists such as those disclosed in US 2004/0167167, US 2004/0242622, US 2005/182092, US 2005/256114, US 2006/35933, WO 04/74246, WO 04/74812, WO 04/89892 and WO 06/23475.
  • Suitable antihistamine drug substances include cetirizine hydrochloride, levocetirizine, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, dimetinden, ebastine, epinastine, levocabastine, mizolastine and tefenadine as well as those disclosed in WO 03/099807, WO 04/026841 and JP 2004107299.
  • compounds of formula A, or pharmaceutically acceptable derivatives thereof may be administered by any appropriate route, for example orally, e.g. in tablet, capsule or liquid form, parenterally, for example in the form of an injectable solution or suspension, or intranasally, for example in the form of an aerosol or other atomisable formulation using an appropriate intranasal delivery device, e.g. a nasal spray such as those known in the art, or by inhalation.
  • an appropriate intranasal delivery device e.g. a nasal spray such as those known in the art, or by inhalation.
  • a compound of formula A or AA, or a pharmaceutically acceptable derivative thereof may be administered in a pharmaceutical composition together with a pharmaceutically acceptable diluent or carrier.
  • a pharmaceutical composition may be as described in WO 03/039544, for example dry powders, tablets, capsules and liquids, but also injection solutions, infusion solutions or Case 50053A-HO 164
  • inhalation suspensions which may be prepared using other formulating ingredients and techniques known in the art.
  • the dosage of the compound of formula A or AA, or a pharmaceutically acceptable derivative thereof can depend on various factors, such as the activity and duration of action of the active ingredient, the severity of the condition to be treated, the mode of administration, the species, sex, ethnic origin, age and weight of the subject and/or its individual condition.
  • the recommended daily dose range of the compound of formula for the conditions described herein lie within the range of from about 1 mg to about 10,000 mg per day, given as a single once-a-day dose, or in divided doses throughout a day.
  • a daily dose range should be from about 1 mg to about 5,000 mg per day, more specifically, between about 10 mg and about 2,500 mg per day, between about 100 mg and about 800 mg per day, between about 100 mg and about 1,200 mg per day, or between about 25 mg and about 2,500 mg per day.
  • a compound of formula A or a pharmaceutically acceptable derivative thereof is administered from about 1 to about 20 mg/day individually, for example, about 1 mg/day, about 2 mg/day, about 3 mg/day, about 4 mg/day, about 5 mg/day, about 6 mg/day, about 7 mg/day, about 8 mg/day, about 9 mg/day, about 10 mg/day, about 11 mg/day, about 12 mg/day, about 13 mg/day, about 14 mg/day, about 15 mg/day, about 16 mg/day, about 17 mg/day, about 18 mg/day, about 19 mg/day, or about 20 mg/day.
  • 3-[5- Amino-4-(3-cyanobenzoyl)-pyrazol-l -yl]-N-cyclopropyl-4-methylbenzamide or a pharmaceutically acceptable derivative thereof is administered in an amount of about 400, 800, 1,200, 2, 500, 5,000 or 10,000 mg a day in a single dose or as two divided doses.
  • Administration of a compound of formula A or a pharmaceutically acceptable derivative thereof and a second active agent to a patient can occur simultaneously or sequentially by the same or different routes of administration.
  • the suitability of a particular route of administration employed for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without decomposing prior to entering the blood stream) and the disease being treated.
  • a preferred route of administration for a compound of formula A is oral.
  • Another preferred route of administration for such a compound is parenteral, particularly for patients who are in a peri- transplant period or in an end stage of Case 50053A-HO 164
  • Preferred routes of administration for the second active agent of the invention are known to those of ordinary skill in the art such as in Physicians' Desk Reference (57th ed., 2003).
  • the specific amount of the second active agent will depend on the specific agent used, the type of pulmonary hypertension being treated or managed, the severity and stage of pulmonary hypertension, and the amount(s) of any optional additional active agents concurrently administered to the patient.
  • kits which, when used by the medical practitioner, can simplify the administration of appropriate amounts of active agents to a patient.
  • a typical kit of the invention comprises a dosage form of a compound of formula A, or a pharmaceutically acceptable derivative thereof, optionally further comprising a second active agent and/or a device or devices for administering the active agents e.g. syringes, drip bags, patches or inhalers.

Abstract

The use of a compound of formula A or a pharmaceutically acceptable derivative thereof for the manufacture of a medicament for the treatment of pulmonary hypertension, where R1, R2, R5, R6, B, C, D and G have the meanings described herein. Pharmaceutical compositions that contain the compounds are also described.

Description

ORGANIC COMPOUNDS
This invention relates to organic compounds and their use as pharmaceuticals.
The invention relates, in one aspect, to the use of a compound of formula A
Figure imgf000002_0001
or a pharmaceutically acceptable derivative thereof for the manufacture of a medicament for the treatment of pulmonary hypertension, where
R1 is hydrogen, acyl or -P(O)(OHIi;
R2 is hydrogen, halo, optionally substituted alkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, optionally substituted alkoxy, optionally substituted heterocyclyloxy, or alkylamino;
G is an aryl, aralkyl, cycloalkyl, heteroaryl, heteroaralkyl or a heterocyclyl ring optionally fused to a phenyl ring, and is substituted with R3 and R4, provided that the heterocyclyl ring is attached to the carbonyl group via a carbon ring atom, or G is OR83 or NR80R81;
B is an aryl or heteroaryl ring;
C is a 5-membered heteroaryl ring containing one or two heteroatoms in the ring;
D is heteroaryl, optionally substituted heteroaryl or -C(O)NR80R81;
where each R80 and R81 is independently hydrogen, alkyl, optionally substituted cycloalkyl, alkoxy, hydroxy, heteroaryl or optionally substituted heteroaryl, or together from optionally substituted alkylene or heteroalkylene;
R83 is hydrogen, alkyl, cycloalkyl, heteroaryl or optionally substituted heteroaryl; Case 50053A-HO 164
R3 is selected from the group consisting of:
(a) amino, alkylamino or dialkylamino;
(b) acylamino;
(c) optionally substituted heterocyclyl;
(d) optionally substituted aryl or heteroaryl;
(e) heteroalkyl;
(f) heteroalkenyl;
(g) heteroalkynyl; (h) heteroalkoxy;
(i) heteroalkylamino;
(j) optionally substituted heterocyclylalkyl;
(k) optionally substituted heterocyclylalkenyl;
(1) optionally substituted heterocyclylalkynyl;
(m) optionally substituted heterocyclylalkoxy or heterocyclyloxy;
(n) optionally substituted heterocyclylalkylamino;
(o) optionally substituted heterocyclylalkylcarbonyl;
(p) heteroalkylcarbonyl;
(q) -NHSO2R6 where Rβ is alkyl, heteroalkyl or optionally substituted heterocyclylalkyl;
(r) -NHSCbNR7R8 where R7 and R8 are, independently of each other, hydrogen, alkyl or heteroalkyl;
(s) -Y-(alkylene)-R9 where: Y is a single bond, -O-, -NH- or -S(O)n- (where n is an integer from 0 to 2); and R9 is halo, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -COOH, -COR10, -COOR", -CONR12R13, -SO2R14, -SO2NR1SR1*, -NHSO2Ri7 or -NHSO2NR18R19, where R10 is alkyl or optionally substituted heterocycle, R11 is alkyl, and R12, R'3 , R14, R15, R16, R17 R18 and R19 are, independently of each other, hydrogen, alkyl or heteroalkyl;
(t) -Q=NR20XNR21R22) where R20, R21 and R22 independently represent hydrogen, alkyl or hydroxy, or R20 and R21 together are -(CH2)n-where n is 2 or 3 and R22 is hydrogen or alkyl;
(u) -NHC(X)NR23R24 where X is -0- or -S-, and R23 and R24 are, independently of each other, hydrogen, alkyl or heteroalkyl;
(v) -CONR25R26 where R23 and R26 independently represent hydrogen, alkyl, heteroalkyl or optionally substituted heterocyclylalkyl, or R2S and R26 Case 50053 A-HO 164
together with the nitrogen to which they are attached form an optionally substituted heterocyclyl ring;
(w) -S(O)nR27 where n is an integer from 0 to 2, and R27 is alley!, heteroalkyl, optionally substituted heterocyclylalkyl or -NR28R29 where R28 and R29 are, independently of each other, hydrogen, alkyl or heteroalkyl;
(x) cycloalkylalkyl, cycloalkylalkynyl and cycloalkylalkynyl, all optionally substituted with alkyl, halo, hydroxy or amino;
(y) arylaminoalkylene or heteroarylaminoalkylene;
(z) Z-alkylene-NR30R31 or Z-alkylene-OR32 where Z is-NH-, -N(lower alkyl)- or -O-, and R30, R31 and R32 are independently of each other, hydrogen, alkyl or heteroalkyl;
(aa) -OC(O)-alkylene-CO2H or -OC(O)-NR1R" where R1 and R" are independently hydrogen or alkyl;
(bb) heteroarylalkenylene or heteroarylalkynylene;
(cc) hydrogen;
(dd) halo;
(ee) pseudohalo;
(ff) hydroxy;
(gg) optionally substituted alkoxy;
(hh) C(L)R40, where L is O, S or NR55; R40 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroarylium, optionally substituted cycloalkyl, optionally substituted heterocyclyl, C(L)R56, halo pseudohalo, OR55, SR55, NR57R58 or SiR52R53R54; where R52, R53 and R54 are selected as in (i) or (ii) as follows (i) R52, R53 and R54 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR55 or NR62R63; or (ii) any two of R52, R53 and R54 together form alkylene, alkenylene, alkynylene, heteroalkylene; and the other is selected as in (i); R55 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl or heterocyclyl; R56 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR55 or NR64R65; where R64 and R65 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR66 or NR6^R63, or R64 and R65 together form alkylene, alkenylene, alkynylene, heteroalkylene, where R66 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, Case 50053A-HO 164
heteroarylium, cycloalkyl or heterocyclyl; R57 and R58 are selected as in (i) or (ii) as follows (i) R57 and R58 are each independently hydrogen, optionally substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR55, NR67R68 or C(L)R6', where R67 and R68 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl or heterocyclyl, or together form alkylene, alkenylene, alkynylene, heteroalkylene; and R69 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR70 or NR62R63, where R70 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl; or (ii) R57 and R58 together form alkylene, alkenylene, alkynylene, heteroalkylene, or alkylenoxyalkylene; R62 and R63 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, or R62 and R63 together form alkylene, alkenylene, alkynylene, heteroalkylene; and (ii) optionally substituted alkyl;
R4 is selected from the group consisting of:
(a) hydrogen;
(b) halo;
(C) alkyl;
(d) alkoxy; and
(e) hydroxy;
or R3 and R4, which substitute adjacent atoms on a ring, together form alkylenedioxy, thioalkylenoxy or alkylenedithioxy;
R5 is selected from the group consisting of
(a) hydrogen;
(b) halo;
(C) alkyl;
(d) haloalkyl;
(e) thioalkyl;
(f) hydroxy;
(g) amino;
(h) alkylamino;
(i) dialkylamino; Case 50053 A-HO 164
(j) heteroalkyl;
(k) optionally substituted heterocycle;
(1) optionally substituted heterocyclylalkyl;
(m) optionally substituted heterocyclylalkoxy;
(n) alkylsulfonyl;
(o) aminosulfonyl, mono-alkylaminosulfonyl or di-alkylaminosulfonyl;
(p) heteroalkoxy; and
(q) carboxy; and
R6 is selected from the group consisting of:
(a) hydrogen;
(b) halo;
(c) alkyl; and
(d) alkoxy.
The invention provides, in another aspect, a method of treating pulmonary hypertension, in a subject, particularly a human subject, in need of such treatment, which comprises administering to said subject an effective amount of a compound of formula A as hereinbefore defined.
The invention provides, in further aspect, a method of treating pulmonary hypertension, in a subject, particularly a human subject, in need of such treatment, which comprises administering to said subject an effective amount of a compound of formula A as hereinbefore defined in combination with a second active agent.
Treatment of pulmonary hypertension in accordance with the invention may be symptomatic or prophylactic.
Pulmonary hypertension to be treated in accordance with the invention includes primary pulmonary hypertension (PPH); secondary pulmonary hypertension (SPH); familial PPH; sporadic PPH; precapillary pulmonary hypertension; pulmonary arterial hypertension (PAH); pulmonary artery hypertension; idiopathic pulmonary hypertension; thrombotic pulmonary arteriopathy (TPA); plexogenic pulmonary arteriopathy; functional classes I to IV pulmonary hypertension; and pulmonary hypertension associated with, related to, or secondary to, left ventricular dysfunction, mitral valvular disease, constrictive pericarditis, aortic stenosis, cardiomyopathy, mediastinal fibrosis, anomalous pulmonary venous drainage, pulmonary Case 50053A-HO 164
venoocclusive disease, collagen vasular disease, congenital heart disease, HIV virus infection, drugs and toxins such as fenfluramines, congenital heart disease, pulmonary venous hypertension, chronic obstructive pulmonary disease, interstitial lung disease, sleep- disordered breathing, alveolar hypoventilation disorder, chronic exposure to high altitude, neonatal lung disease, alveolar-capillary dysplasia, sickle cell disease, other coagulation disorder, chronic thromboemboli, connective tissue disease, lupus, schistosomiasis, sarcoidosis or pulmonary capillary hemangiomatosis.
Pulmonary hypertension to be treated in accordance with the invention is most particularly pulmonary hypertension associated with disorders of the respiratory system and/or hypoxemia, including chronic obstructive pulmonary disease, interstitial lung disease, sleep- disordered breathing, alveolar hypoventilation disorders, chronic exposure to high altitude, neonatal lung disease and alveolar-capillary dysplasia, but especially chronic obstructive pulmonary disease.
The terms used in the present specification have the following meanings:
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the invention(s) belong. All patents, patent applications, published applications and publications, Genbank sequences, databases, websites and other published materials referred to throughout the entire disclosure herein, unless noted otherwise, are incorporated by reference in their entirety. In the event that there are a plurality of definitions for terms herein, those in this section prevail. Where reference is made to a URL or other such identifier or address, it understood that such identifiers can change and particular information on the internet can come and go, but equivalent information can be found by searching the internet. Reference thereto evidences the availability and public dissemination of such information.
As used herein, p38α refers to the enzyme disclosed in Han et al. (1995) Biochim. Biophys. Acta 1265 (2-3 ):224-7. As used herein, p38β refers to the enzyme disclosed in Jiang et al. (1996) /. Biol. Chem. 271(30):17920-6. As used herein, p38γ refers to the enzyme disclosed in Li et al. (1996) Biochem. Biophys. Res. Comtnun. 228: 334-340. As used herein, p38δ refers to the enzyme disclosed in Wang et al. (1997) ]. Biol. Chem. 272(38):23668-74.
As used herein, pharmaceutically acceptable derivatives of a compound include salts, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, Case 50053 A-HO 164
solvates, hydrates or prodrugs thereof. Such derivatives may be readily prepared by those of skill in this art using known methods for such derivatization. The compounds produced may be administered to animals or humans without substantial toxic effects and either are pharmaceutically active or are prodrugs.
Pharmaceutically acceptable salts include, but are not limited to, amine salts, such as but not limited to N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanoiamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N- benzylphenethylamine, l-para-chloro-benzyl-2-pyrrolidin-l'-ylmethyl-benzimidazole, diethylamine and other alkylamiπes, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts, such as but not limited to lithium, potassium and sodium; alkali earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salts, such as but not limited to zinc; and other metal salts, such as but not limited to sodium hydrogen phosphate and disodium phosphate; and also including, but not limited to, nitrates, borates, methanesulfonates, benzene-sulfonates, toluenesulfonates, salts of mineral acids, such as but not limited to hydro-chlorides, hydrobromides, hydroiodides and sulfates; and salts of organic acids, such as but not limited to acetates, trifluoroacetates, oxalates, benzoates, salicylates, maleates, lactates, malates, tartrates, citrates, ascorbates, succinates, butyrates, valerates and fumarates. In addition, zwitterions ("inner salts") may be formed. In certain embodiments, salt forms of the compounds improve the compounds' dissolution rate and oral bioavailability.
Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl and heterocyclyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids, sulfinic acids and boronic acids. Pharmaceutically acceptable enol ethers include, but are not limited to, derivatives of formula C=C(OR) where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl or heterocyclyl. Pharmaceutically acceptable enol esters include, but are not limited to, derivatives of formula C=C(OC(O)R) where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl or heterocyclyl. Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent or water molecules, or 1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules. Case 50053 A-HO 164
"AlkyP means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, pentyl, and the like.
The term "cycloalkyl" refers to a saturated or partially unsaturated nonaromatic cyclic hydrocarbon ring system, preferably containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C3-C7 carbocylic ring. Exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloctyl, cyclodecyl, cyclododecyl, and adamantyl. A "substituted cycloalkyl" is substituted with one or more alkyl or substituted alkyl groups as described above, or one or more groups described above as alkyl substituents. The expression "lower cycloalkyl" refers to an unsubstituted saturated or unsaturated nonaromatic cyclic hydrocarbon ring system containing 3 to 5 carbon atoms.
"Alkylene" means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, propylene, 2-methylpropyIene, pentylene, and the like.
"Alkenyl" means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g., ethenyl, propenyl, and the like.
"Alkenylene" means a linear divalent hydrocarbon radical of two to six carbon atoms or a branched divalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g., ethenylene, propenylene, and the like.
"Alkynyl" means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched divalent hydrocarbon radical of three to six carbon atoms, containing at least one triple bond, e.g., ethynyl, propynyl, and the like.
"Alkynylene" means a linear divalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one triple bond, e.g., ethynylene, propynylene, and the like.
"Alkoxy" means a radical -OR where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, 2-propoxy, the like. Case S0053A-HO 164
"Acyl" means a radical -C(O)R where R is alkyl or haloalkyl e.g., acetyl, trifluoroaceryl, and the like.
"Acylamino" means a radical -NRC(O)R' where R is hydrogen or alkyl, and R' is alkyl, heteroalkyl or optionally substituted heterocyclylalkyl, e.g., acetylamino, 2-amino-2- methylpropionamide, and the like.
"Halo" means fluoro, chloro, bromo, or iodo, generally fluoro and chloro.
"Haloalkyl" means alkyl substituted with one or more same or different halo atoms, e.g., -CH2Cl, -CF3, -CH2CF3, -CH2CCl3, and the like.
"Aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms e.g., phenyl, 1-naphthyl, 2-naphthyl, and the like. The aryl ring may optionally be fused to a 5-, 6- or 7- membered monocyclic saturated ring optionally containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen or sulfur, the remaining ring atoms being C where one or two C atoms are optionally replaced by a carbonyl group. Representative aryl radicals with fused rings include, but are not limited to, 2,3-dihydrobenzo[l,4]dioxan, chroman, isochroman, 2,3-dihydrobenzofuran, 1,3- dihydroisobenzofuran, benzo[l,3]dioxole, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4- tetrahydroquinoline, 2,3-dihydro-lH-indole, 2,3-dihydro-IH-isoindole, benzimidazol-2- one, 3H-benzoxazol-2-one, and the like.
"Heteroaryl" means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms containing one, two, or three ring heteroatoms selected from N, 0, or S, the remaining ring atoms being C. The term also includes those radicals where a heteroatom within the ring has been oxidized or quaternized, such as, for example, to form an N-oxide or a quaternary salt. Representative examples include, but are not limited to, thienyl, benzothienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, quinoxalinyl, imidazolyl, furanyl, benzofuranyl, thiazolyl, isoxazolyl, benzisoxazolyl, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, 2-pyridonyl, 4-pyridonyl, N-alkyl-2-pyridonyl, pyrazinonyl, pyridazinonyl, pyrimidinonyl, oxazolonyl, and their corresponding N-oxides, (e.g. pyridyl N-oxide, quinolinyl N-oxide), their quaternary salts and the like.
"Heterocycle" or " heterocyclyl " means a cyclic nonaromatic radical of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, 0, or S(O)n, (where n is an Case 50053A-HO 164
10
integer from 0 to 2), the remaining ring atoms being C where one or two C atoms are optionally replaced by a carbonyl group. The term also includes those radicals where a ring nitrogen atom has been oxidized or quaternized, such as, for example, to form an N-oxide or a quaternary salt. Representative examples include, but are not limited to, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidino, morpholino, piperazino, pyrrolidino, oxiranyl, dioxane, 1,3-dioxolanyl, 2,2-dimethyl-l,3-dioxalanyl, sulfolanyl, 2-oxazolidonyl, 2-imidazolidonyl, S,S-dioxo-thiomorpholino, and the like.
"Heterocycloamino" means a saturated monovalent cyclic group of 4 to 8 ring atoms, wherein at least one ring atom is N and optionally contains one additional ring atom selected from N or O, the remaining ring atoms being C. The term includes groups such as pyrrolidino, piperidino, morpholino, piperazino and the like.
"Optionally substituted alkyl, alkenyl, alkynyl, alkoxy or cycloalkyl" means an aikyl, alkenyl, alkynyl, alkoxy or cycloalkyl group, as defined herein, which is optionally substituted independently with one or two substituents selected from alkyl, phenyl, benzyl, haloalkyl, heteroalkyl, halo, cyano, heterocyclyl, acyl, -OR (where R is hydrogen or alkyl), -NRR' (where R and R' are independently selected from hydrogen, acyl, or alkyl which is optionally substituted with hydroxy, alkoxy, cyano, halo or heterocyclyl), -NHCOR (where R is alkyl which is optionally substituted with hydroxy, alkoxy, cyano, halo or heterocyclyl), -NRS(O)nR' (where R is hydrogen or alkyl, n is an integer from 0 to 2; and R1 is hydrogen, alkyl or heteroalkyl, and is optionally substituted with hydroxy, alkoxy, cyano, halo or heterocyclyl), -NRS(O)nNR1R" (where R is hydrogen or alkyl, n is an integer from 0 to 2; and R' and R" are independently hydrogen, alkyl or heteroalkyl and are optionally substituted with hydroxy, alkoxy, cyano, halo or heterocyclyl), -S(O)nR (where n is an integer from 0 to 2; and R is hydrogen, alkyl or heteroalkyl and is optionally substituted with hydroxy, alkoxy, cyano, halo or heterocyclyl), -S(O)nNRR' (where n is an integer from 0 to 2; and R and R' are independently hydrogen, alkyl or heteroalkyl and are optionally substituted with hydroxy, alkoxy, cyano, halo or heterocyclyl), -COOR, -(alkylene)COOR (where R is hydrogen or alkyl), -CONR'R" or -(alkylene)CONR'R" (where R' and R" are independently hydrogen or alkyl, or together form a heterocyclyl ring with the nitrogen atom to which they are attached).
"Optionally substituted aryl, heteroaryl or heterocyclyl" means an aryl, heteroaryl or heterocyclyl ring as defined above, which is optionally substituted independently with one or two substituients selected from alkyl, phenyl, benzyl, haloalkyl, heteroalkyl, halo, cyano, Case 50053A-HO 164
11
acyl, -OR (where R is hydrogen or alkyl), -NRR' (where R and R' are independently selected from hydrogen, alkyl or acyl), -NHCOR (where R is alkyl), -NRS(O)nR' (where R is hydrogen or alkyl, n is an integer from 0 to 2 and R1 is hydrogen, alkyl or heteroalkyl), - NRS(O)nNR1R" (where R is hydrogen or alkyl, n is an integer from 0 to 2 and R1 and R" are independently hydrogen, alkyl or heteroalkyl), -S(O)nR (where n is an integer from 0 to 2 and R is hydrogen, alkyl or heteroalkyl), -S(O)nNRR' (where n is an integer from 0 to 2 and R and R' are independently hydrogen, alkyl or heteroalkyl), -COOR, - (alkylene)COOR (where R is hydrogen or alkyl), -CONR1R" or - (alkylene)CONR'R" (where R' and R" are independently hydrogen or alkyl).
"Heteroalkyl" means an alkyl radical as defined above, carrying one, two or three substituents selected from -NRaRb, -ORC wherein R% Rb and Rc are independently of each other hydrogen, alkyl or acyl, or R" and Rb together form heterocycloamino group. Representative examples include, but are not limited to, hydroxymethyl, acetoxymethyl, 3- hydroxypropyl, 1,2-dihydroxyethyI, 2-methoxyethyl, 2-aminoethyl, 2-dimethylaminoethyl, 2- acetylaminoethyl, 3-[pyrrolidin-l-yl]ethyl and the like.
"Heteroalkenyl" means an alkenyl radical as defined above, carrying one or two substituents selected from -NRaRb, -ORC or -S(O)nRd wherein Ra, Rb and Rc are independently of each other hydrogen or alkyl, and Rd is alkyl or -NRR' (where R and R' are independently of each other hydrogen or alkyl. Representative examples include, but are not limited to, 3-hydroxy- 1-propenyl, 3-aminoprop-l-enyl, 2-aminosulfonylethenyl, 2methyisulfonylethenyl, and the like.
"Heteroalkynyl" means an alkynyl radical as defined above, carrying one or two substituents selected -NRaRb, -ORC , -S(O)nRd or -S(O)nNRR1 (where R and R' are independently of each other hydrogen or alkyl) wherein Ra, Rb and Rc are independently of each other hydrogen or alkyl, and Rd is alkyl and n is an integer from zero to two. Representative examples include, but are not limited to, 3-hydroxy-l-propynyl, 3dimethylaminoprop-l-ynyl and the like.
"Heteroalkoxy" means a radical -OR where R is heteroalkyl group as defined above, e.g., 2- hydroxyethoxy, 3-hydroxypropoxy, 2,3-dihydroxypropoxy, 2-aminoethoxy, and the like.
"Heteroalkylamino" means a radical -NRaRb where Ra is hydrogen or alkyl, and Rb is a heteroalkyl group as defined above, e.g., 2-hydroxyethylamino, 3- dimethylaminopropylamino, and the like. Case 50053A-HO 164
12
"Optionally substituted heterocydylalkyl" means a radical -RaRb where Ra is an alkylene group, and Rb is an optionally substituted heterocyclyl group as defined above e.g., 2- (morpholin-4-yI)ethyl, 3(piperidin-l-yI)-2-methylpropyl, and the like.
"Optionally substituted heterocydylalkenyl " means a radical -RaRb where Ra is an alkenylene group and Rb is an optionally substituted heterocyclyl group as defined above e.g., 3-(morpholin-4-yl)prop-l-enyll, 3-(piperidin-l-yl)prop-l-enyl, 3-(4-methylpiperazin-l- yl)prop-l-enyl, and the like.
"Optionally substituted heterocyclylalkynyl" means a radical -RaRb where Ra is an alkynyl group and Rb is an optionally substituted heterocyclyl group as defined above e.g., 3- (morpholin-4-yI)prop-l-ynyl, 3-(piperidin-l-yl)prop-l-ynyl, and the like.
"Optionally substituted heterocyclylalkoxy " means a radical -OR where R is an optionally substituted heterocydylalkyl group as defined above, e.g., 2-(morpholin-4-yl)-ethoxy, 3- (piperazin-l-yl)propoxy, 2-[2-oxopyrrolidin-l-yl]ethoxy, and the like. "Optionally substituted heterocyclylalkylamino" means a radical -NRaRb where Ra is hydrogen or alkyl and R& is an optionally substituted heterocydylalkyl group as defined above, e.g., 2-(pyrrolidin-2-yl)ethylamino, 3-(piperidin-l-yl)propylamino, and the like.
"Optionally substituted heteroaralkyloxy means a radical -O-Ra where Ra is a heteroaralkyl radical e.g. 2-(pyridin-3-yl)ethoxy, 2-[3(2H)-pyridazon-l-yl]ethoxy and the like.
"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "aryl group optionally mono- or di-substituted with an alkyl group" means that the alkyl may but need not be present, and the description includes situations where the aryl group is mono- or disubstituted with an alkyl group and situations where the heterocyclo group is not substituted with the alkyl group.
"Amino protecting group" refers to those organic groups intended to protect nitrogen atoms against undesirable reactions during synthetic procedures e.g., benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trifluoroacetyl, and the like. Case 50053A-HO 164
13
Throughout the specification, groups and substituents thereof may be chosen by one skilled in the field to provide stable moieties and compounds. It is also understood that the chemical groups, as described herein, can be substituted or unsubstituted, branched or unbranched, as appropriate and desired.
All stereoisomers of the compounds provided herein are contemplated, either in admixture or in pure or substantially pure form. The definition of compounds provided herein embraces all the possible stereoisomers and their mixtures. It embraces the racemic forms and the isolated optical isomers having the specified activity. The racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemates from the conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.
The invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula A wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen e.g. 2H and 3H, carbon e.g. 11C, 13C and 14C, chlorine e.g. 36Cl, fluorine e.g. 18F, iodine e.g. 123I and 125I, nitrogen e.g. 13N and 15N, oxygen e.g. 15O, 17O and 18O, and sulfur e.g. 35S.
Certain isotopically-labelled compounds of formula A, for example those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium (3H) and carbon-14 (14C) are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium (2H) may afford certain therapeutic advantages that result from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as 11C, 18F, 15O, and 13N can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
Isotopically-labelled compounds of formula A can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously used. Case 50053A-HO 164
14
Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallisation may be isotopically substituted e.g. D∑O, dβ-acetone or d«- DMSO.
The compounds provided herein may also have prodrug forms. Any compound that will be converted in vivo to provide the bioactive agent is a prodrug. Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see, e.g.: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol.42, p. 309-396, edited by K. Widder, et al. (Acamedic Press, 1985); b) A Textbook of Drug Design and Development, edited by KrosgaardLarsen and H. Bundgaard, Chapter 5, "Design and Application of Prodrugs," by H. Bundgaard, p. 113-191 (1991); and c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992), each of which is incorporated herein by reference.
As used herein, treatment means any manner in which one or more of the symptoms of a disease or disorder are ameliorated or otherwise beneficially altered.
As used herein, amelioration of the symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the composition.
As used herein, IC50 refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response, such as modulation of p38a kinase activity, in an assay that measures such response.
The compounds provided herein, or pharmaceutically acceptable derivative thereof, for use in the the manufacture of a medicament for the treatment of pulmonary hypertension are active in assays that measure p38 kinase activity, including, but not limited to, p38α and p38β kinase activity.
In one embodiment, the invention relates to the use of compounds of formula IA, IB or IC respectively below : Case 50053A-HO 164
15
Figure imgf000016_0001
or a pharmaceutically acceptable derivative thereof for the manufacture of a medicament for the treatment of pulmonary hypertension, where:
R1 is hydrogen, acyl or -P(O)(OH)2;
R2 is hydrogen, halo, alkyl or alkylthio;
A is an aryl, heteroaryl or a heterocyclyl ring optionally fused to a phenyl ring, provided that the heterocyclyl ring is attached to the carbonyl group via a carbon ring atom;
B is an aryl or heteroaryl ring;
C is a 5-membered heteroaryl ring containing one or two heteroatoms in the ring;
D is heteroaryl, optionally substituted heteroaryl or -C(O)NR80R81, where R80 and R81 are independently hydrogen, alkyl, cycloalkyl, alkoxy, hydroxy, heteroaryl or optionally substituted heteroaryl; R3 is selected from the group consisting of:
(a) amino, alkylamino or dialkylamino;
(b) acylamino;
(c) optionally substituted heterocyclyl;
(d) optionally substituted aryl or heteroaryl;
(e) heteroalkyl;
(f) heteroalkenyl;
(g) heteroalkynyl; (h) heteroalkoxy;
(i) heteroalkylamino;
(j) optionally substituted heterocyclylalkyl; Case 50053 A-HO 164
16
(k) optionally substituted heterocydylalkenyl;
(1) optionally substituted heterocyclylalkynyl;
(m) optionally substituted heterocyclylalkoxy or heterocyclyloxy;
(n) optionally substituted heterocyclylalkylamino;
(o) optionally substituted heterocydylalkylcarbonyl;
(p) heteroalkylcarbonyl;
(q) -NHSO2R6 where R* is alkyl, heteroalkyl or optionally substituted heterocyclylalkyl; (r) -NHSOINR7R8 where R7 and R8 are, independently of each other, hydrogen, alkyl or heteroalkyl; (s) -Y-(alkylene)-R9 where: Y is a single bond, -O-, -NH- or -S(O)n- (where n is an integer from 0 to 2); and R9 is halo, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -COOH,
-COR10, -COOR", -CONR12R", -SO2R14, -SO2NR15R1*, -NHSO2R17 or
-NHSO2NR18R19, where R10 is alkyl or optionally substituted heterocycle, R11 is alkyl, and R12, R" , R14, R15, Rlβ, R17 R18 and R19 are, independently of each other, hydrogen, alkyl or heteroalkyl; (u) -Q=NR20MNR21R22) where R20, R21 and R22 independently represent hydrogen, alkyl or hydroxy, or R20 and R21 together are -(CH2)n-where n is
2 or 3 and R22 is hydrogen or alkyl; (u) -NHC(X)NR23R24 where X is -O- or -S-, and R23 and R24 are, independently of each other, hydrogen, alkyl or heteroalkyl; (v) -CONR25R26 where R25 and R25 independently represent hydrogen, alkyl, heteroalkyl or optionally substituted heterocyclylalkyl, or R25 and R26 together with the nitrogen to which they are attached form an optionally substituted heterocyclyl ring; (w) -S(O)nR27 where n is an integer from 0 to 2, and R27 is alkyl, heteroalkyl, optionally substituted heterocyclylalkyl or -NR28R29 where R28 and R29 are, independently of each other, hydrogen, alkyl or heteroalkyl; (x) cycloalkylalkyl, cycloalkylalkynyl and cycloalkylalkynyl, all optionally substituted with alkyl, halo, hydroxy or amino; (y) arylaminoalkylene or heteroarylaminoalkylene; (z) Z-alkylene-NR30R31 or Z-alkylene-OR32 where Z is-NH-, -N(Iower alkyl)- or
-O-, and R30, R31and R32 are independently of each other, hydrogen, alkyl or heteroalkyl; Case 50053 A-HO 164
17
(aa) -OC(O)-alkylene-CO2H or -OC(O)-NR1R" (where R1 and R" are independently hydrogen or alkyl);
(bb) heteroarylalkenylene or heteroarylalkynylene;
(cc) hydrogen;
(dd) halo;
(ee) pseudohalo;
(ff) hydroxy;
(gg) optionally substituted alkoxy;
(hh) C(L)R40, where L is O, S or NR55; R40 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroarylium, optionally substituted cycloalkyl, optionally substituted heterocyclyl, C(L)R56, halo pseudohalo, OR5S, SR55, NR57R58 or SiR52R53R54; where R52, R53 and R54 are selected as in (i) or (ii) as follows (i) R52, R53 and R54 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR55 or NR62R63; or (ii) any two of R52, R53 and R54 together form alkylene, alkenylene, alkynylene, heteroalkylene; and the other is selected as in (i); R55 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl or heterocyclyl; R56 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR55 or NR64R65; where R64 and R65 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR66 or NR62R63, or R64 and R65 together form alkylene, alkenylene, alkynylene, heteroalkylene, where R66 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl or heterocyclyl; R57 and R58 are selected as in (i) or (ii) as follows (i) R57 and R58 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR55, NR67R68 or C(L)R69, where R67 and R68 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl or heterocyclyl, or together form alkylene, alkenylene, alkynylene, heteroalkylene; and R69 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR70 or NR62R63, where R70 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl; or (ii) R57 and R58 together form alkylene, alkenylene, alkynylene, heteroalkylene; R62 and R63 are each independently hydrogen, Case 50053 A-HO 164
18
alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, or R62 and R65 together form alkylene, alkenylene, alkynylene, heteroalkylene; and (ii) optionally substituted alkyl;
R4 is selected from the group consisting of:
(a) hydrogen;
(b) halo; (C) alkyl;
(d) alkoxy; and
(e) hydroxy;
R5 is selected from the group consisting of (a) hydrogen;
(b) halo;
(c) alkyl;
(d) haloalkyl;
(e) thioalkyl;
(f) hydroxy;
(g) amino;
(h) alkylamino;
(i) dialkylamino;
(J) heteroalkyl;
(k) optionally substituted heterocycle;
(D optionally substituted heterocyclylalkyl;
(m) optionally substituted heterocyclylalkoxy;
(n) alkylsulfonyl;
(o) aminosulfonyl, mono-alkylaminosulfonyl or di-alkylamino-sulfonyl;
(P) heteroalkoxy; and
(q) carboxy; and
R6 is selected from the group consisting of:
(a) hydrogen;
(b) halo;
(c) alkyl; and
(d) alkoxy. Case 50053 A-HO 164
19
In one embodiment, C is a 5-membered heteroaryl ring containing one or two heteroatoms in the ring. In another embodiment, C is selected from pyrazole, imidazole, pyrrole, thiazole, isothiazole, oxazole, isoxazole, furan and thiophene rings. In another embodiment, C is a pyrazole or imidazole ring. In another embodiment, C is an imidazole ring. In another embodiment, C is a pyrazole ring.
Pyrazole-based compounds
In one embodiment, C is a pyrazole ring and thus the invention relates to the use of compounds of formula HA, IIB or IIC respectively below:
Figure imgf000020_0001
or a pharmaceutically acceptable derivative thereof for the manufacture of a medicament for the treatment of pulmonary hypertension, where the variables are as defined elsewhere herein. In this embodiment, the hydrogen of the ring NH group may be replaced by one of the substituents shown in the structure (i.e., -C(O)-A(R3)(R4), -R2, or -B(D)(R«)(R5)).
In another embodiment, the compounds have formula DTA, DIB or IIC respectively below:
Figure imgf000020_0002
III or a pharmaceutically acceptable derivative thereof, where the variables are as defined elsewhere herein.
In another embodiment, the compounds have formula IVA, IVB or IVC respectively below: Case 50053A-HO 164
20
Figure imgf000021_0001
IV or a pharmaceutically acceptable derivative thereof, where the variables are as defined elsewhere herein.
In another embodiment, the compounds have formula VA, VB or IVC respectively below:
Figure imgf000021_0002
or a pharmaceutically acceptable derivative thereof, where the variables are as defined elsewhere herein.
In another embodiment, the compounds have formula VA, VB or VC respectively below:
Figure imgf000021_0003
Va or a pharmaceutically acceptable derivative thereof, wherein A, D, R3, R4, and R6 are as defined elsewhere herein.
Imidazole-based compounds Case 50053 A-HO 164
21
In another embodiment, the compounds are imidazole-based compounds of formula VIA, VIB or VIC respectively below:
Figure imgf000022_0001
or a pharmaceutically acceptable derivative thereof, where the variables are as defined elsewhere herein. In this embodiment, the hydrogen of the ring NH group may be replaced by one of the substituents shown in the structure structure (i.e., -C(O)-A(R3)(R4), -R2, or -B(D)(R6)(R5).
In another embodiment, the compounds have formula VLIA, VIIB or VIIC respectively below:
Figure imgf000022_0002
VII or a pharmaceutically acceptable derivative thereof, where the variables are as defined elsewhere herein.
In another embodiment, the compounds have formula VIIIA, VHIB or VIIIC respectively below:
Figure imgf000022_0003
VIII Case 50053 A-HO 164
22
or a pharmaceutically acceptable derivative thereof, where the variables are as defined elsewhere herein.
Other embodiments
In other embodiments, the compounds for use in the compositions and methods provided herein have the above formulae, or pharmaceutically acceptable derivatives thereof, where R1 is hydrogen. In another embodiment, R2 is hydrogen or lower alkyl. In another embodiment, R2 is hydrogen.
In another embodiment, G is OR83 or NR80R81. In another embodiment, R83 is alkyl or cycloalkyl. In another embodiment, R83 is alkyl. In another embodiment, R83 is ethyl. In another embodiment, R80 and R81 are each independently hydrogen, alky! or cycloalkyl. In another embodiment, R80 and R81 are each independently hydrogen or cycloalkyl. In another embodiment, R80 and R81 are each independently hydrogen or cyclohexyl. In another embodiment, G is NH2 or NH(cyclohexyl).
In another embodiment, G is aryl, heteroaryl, cycloalkyl, heterocyclyl or heterocyclyl optionally fused to phenyl, and is substituted with R3 and R4, provided that the heterocyclyl ring is attached to the carbonyl group via a carbon ring atom. In another embodiment, G is phenyl, cyclohexyl, cyclopentyl or benzyl, and is substituted with R3 and R4. In another embodiment, G is phenyl and is substituted with R3 and R4. In another embodiment, A is an aryl ring. In another embodiment, A is a phenyl ring.
In another embodiment, B is an aryl ring. In another embodiment, B is a phenyl ring.
In another embodiment, D is -C(O)NR80R81. In another embodiment, R80 and R81 are each independently hydrogen, cycloalkyl or alkoxy. In another embodiment, R80 is hydrogen. In another embodiment, R81 is cycloalkyl or alkoxy. In another embodiment, R81 is Cj-βcycloalkyl or Ci-«alkoxy. In another embodiment, R81 is cyclopropyl or methoxy.
In another embodiment, D is optionally substituted heteroaryl. In another embodiment, D is optionally substituted triazolyl. In another embodiment, D is l,2,4-triazol-3-yl. Case 50053A-HO 164
23
In another embodiment, R3 is hydrogen, optionally substituted heterocyclyl, optionally substituted alkyl, C(L)R40, halo, pseudohalo or OR41; where L is O, S or NR55; R40 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroarylium, optionally substituted cycloalkyl, optionally substituted heterocyclyl, C(L)R56, halo pseudohalo, OR5S, SR55, NR57R58 or SiR52R53R54; R41 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroarylium, optionally substituted cycloalkyl, optionally substituted heterocyclyl, C(L)R59, NR60R*1 or SiR52R53R54; where R52, R53 and R54 are selected as in (i) or (ii) as follows (i) R52, R53 and R54 are each independently hydrogen, alkyl, aikenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR55 or NR62R63; or (ii) any two of R52, R53 and R54 together form alkylene, alkenylene, alkynylene, heteroalkylene; and the other is selected as in (i); R55 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl or heterocyclyl; R56 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR55 or NR64R65; where R64 and R65 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR66 or NR62R63, or R64 and R65 together form alkylene, alkenylene, alkynylene, heteroalkylene, where R66 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl or heterocyclyl; R57 and R58 are selected as in (i) or (ii) as follows (i) R57 and R58 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR55, NR67R68 or C(L)R69, where R67 and R68 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl or heterocyclyl, or together form alkylene, alkenylene, alkynylene, heteroalkylene; and R69 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR70 or NR62R63, where R70 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl; or (ii) R57 and R58 together form alkylene, alkenylene, alkynylene, heteroalkylene; R59 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR70 or NR62R63; R60 and R61 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl or C(L)R71, where R71 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR55 or NR62R63; or R60 and R61 together form alkylene, alkenylene, alkynylene, heteroalkylene; R62 and R63 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, or R62 and R63 together form alkylene, alkenylene, alkynylene, heteroalkylene.
In another embodiment, R3 is hydrogen, optionally substituted heterocyclyl, optionally Case 50053 A-HO 164
24
substituted alkyl, C(L)R40, halo or OR41. In another embodiment, R3 is hydrogen, optionally substituted heterocyclyl, optionally substituted alkyl, C(L)R40, iodo, chloro or OR41. In another embodiment, R3 is hydrogen, optionally substituted dioxolanyl, optionally substituted methyl, C(L)R40, iodo, chloro or OR41. In another embodiment, R3 is hydrogen, 2-dioxolanyl, optionally substituted methyl, C(O)R40, iodo, chloro or OR41. In another embodiment, R3 is hydrogen, 2-dioxolanyl, optionally substituted mediyl, CHO, iodo, chloro or OR41. In another embodiment, R3 is hydrogen.
In another embodiment, R3 is optionally substituted methyl. In another embodiment, R3 is methyl which is optionally substituted with heterocyclyl, hydroxy, aralkylamino or heterocyclylalkylamino. In another embodiment, R3 is N-morpholinylmethyl, hydroxymethyl, N- (2-(3-chlorophenyl)-l-ethyl)aminomethyl, N-(2-morpholinyl-l-ethyl)aminomethyl or 4- piperizinylmethyl.
In another embodiment, A is O. In another embodiment, R40 is hydrogen, optionally substituted alkyl or cycloalkyl. In another embodiment, R40 is hydrogen or alkyl. In another embodiment, R40 is hydrogen.
In another embodiment, R41 is hydrogen or optionally substituted alkyl. In another embodiment, R41 is hydrogen, or alkyl optionally substituted with heterocyclyl, aryl, dialkylamino, halo or hydroxy. In another embodiment, R41 is hydrogen, or Ci-3alkyl optionally substituted with heterocyclyl, phenyl, dialkylamino, halo or hydroxy. In another embodiment, R41 is hydrogen, 2-(N-morpholinyl)eth-l-yl, benzyl, 2-(N,N-di-(2-hydroxy-l- ethyl)amino)-l-ethyl, 2-bromo-l -ethyl, 2,2-dioxolan-4-ylmethyl, 2-(4-methylpiperazin-l-yl)- 1-ethyl or 2,3-dihydroxy-l-propyl. In another embodiment, R41 is (S)-2,3-dihydroxy-l- propyl.
In another embodiment, R4 is hydrogen. In another embodiment, R5 is alkyl. In another embodiment R5 is methyl. In another embodiment, R6 is hydrogen.
In another embodiment, the compounds for use in the compositions and methods provide herein have the above formulae, including formulae I-VIII, or a pharmaceutically acceptable derivative thereof, where:
R1 is hydrogen, acyl or -P(O)(OH)2;
R2 is hydrogen, halo, alkyl or alkylthio; Case 50053 A-HO 164
25
A is an aryl, heteroaryl or a heterocyclyl ring optionally fused to a phenyl ring provided that the heterocyclyl ring is attached to the carbonyl group via a carbon ring atom;
B is an aryl or heteroaryl ring;
D is heteroaryl, optionally substituted heteroaryl or -C(O)NR80R81 (where R80 and R81 are independently hydrogen, alkyl, cycloalkyl, alkoxy, hydroxy, heteroaryl or optionally substituted heteroaryl);
R3 is selected from the group consisting of:
(a) amino, alkylamino or dialkylamino;
(b) acylamino;
(c) optionally substituted heterocyclyl;
(d) optionally substituted aryl or heteroaryl;
(e) heteroalkyl;
(f) heteroalkenyl;
(g) heteroalkynyl; (h^ heteroalkoxy;
(i) heteroalkylamino;
(j) optionally substituted heterocyclylalkyl;
(k) optionally substituted heterocyclylalkenyl;
( 1 ) optionally substituted heterocyclylalkynyl;
(m) optionally substituted heterocyclylalkoxy or heterocyclyloxy;
(n) optionally substituted heterocyclylalkylamino;
(o) optionally substituted heterocyclylalkylcarbonyl;
(p) heteroalkylcarbonyl;
(q) -NHSO2R6 where R6 is alkyl, heteroalkyl or optionally substituted heterocyclylalkyl;
(r) -NHSO2NR7R8 where R7 and R8 are, independently of each other, hydrogen, alkyl or heteroalkyl;
(s) -Y-(alkylene)-R9 where: Y is a single bond, -O-, -NH- or - S(O)n (where n is an integer from 0 to 2); and R9 is cyano, optionally substituted heteroaryl, -COOH, -COR10, - COOR", -CONR12R", SO2R14, - SO2NR15R16, - NHSO2R17 or -NHSO2NR18R19, where R10 is alkyl or optionally substituted heterocycle, R11 is alkyl, and R12, Ri3 RH Ri5 RU R17 Ri8 ancj Ri9 are, independently of each other, hydrogen, alkyl or heteroalkyl; Case 50053A-HO 164
26
(v) -Q=NR20HNR21R22) where R20, R21 and R22 independently represent hydrogen, alkyl or hydroxy, or R20 and R21 together are -(CH2)n-where n is 2 or 3 and R22 is hydrogen or alkyl;
(u) -NHC(X)NR23R24 where X is -O- or -S-, and R23 and R24 are, independently of each other, hydrogen, alkyl or heteroalkyl; (v) -CONR25R26 where R25 and R2β independently represent hydrogen, alkyl, heteroalkyl or optionally substituted heterocyclylalkyl, or R25 and R2* together with the nitrogen to which they are attached form an optionally substituted heterocyclyl ring; (w) -S(O)nR27 where n is an integer from 0 to 2, and R27 is alkyl, heteroalkyl, optionally substituted heterocyclylalkyl or -NR28R29 where R28 and R2' are, independently of each other, hydrogen, alkyl or heteroalkyl;
(x) cydoalkylalkyl, cycloalkylalkynyl and cycloalkylalkynyl, all optionally substituted with alkyl, halo, hydroxy or amino;
(y) arylaminoalkylene or heteroarylaminoalkylene; (z) Z-alkylene-NR30R3i or Z-alkylene-OR32 where Z is-NH-, -N(lower alkyl)- or -O-, and R30, R31and R32 are independently of each other, hydrogen, alkyl or heteroalkyl;
(aa) -OC(O)-alkylene-CO2H or -OC(O)-NR1R" (where R1 and R" are independently hydrogen or alkyl); and (bb) heteroarylalkenylene or heteroarylalkynylene; R4 is selected from the group consisting of:
(a) hydrogen;
(b) halo; (C) alkyl;
(d) alkoxy; and
(e) hydroxy; R5 is selected from the group consisting of
(a) hydrogen;
(b) halo; Case 50053A-HO 164
27
(C) alkyl;
(d) haloalkyl;
(e) thioalkyl;
(f) hydroxy;
(g) amino;
(h) alkylamino;
(•) dialkylamino;
(J) heteroalkyl;
(k) optionally substituted heterocycle;
(D optionally substituted heterocyclylalkyl;
(m) optionally substituted heterocyclylalkoxy;
(n) alkylsulfonyl;
(o) aminosulfonyl, mono-alkylaminosulfonyl or di- alkylaminosulfonyl;
(P) heteroalkoxy; and
(q) carboxy;
R6 is selected from the group consisting of:
(a) hydrogen;
(b) halo;
(C) alkyl; and
(d) alkoxy; and prodrugs, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.
In another embodiment, the compounds are those wherein:
R1 is hydrogen or acyl;
R2 is hydrogen or alkyl; and
A is an aryl or heteroaryl ring.
In another embodiment, the compounds are those wherein:
R1 is hydrogen, acyl or -P(O)(OH)2;
R2 is hydrogen, halo, alkyl or alkylthio;
A is an aryl, heteroaryl or a heterocyclyl ring optionally fused to a phenyl ring provided that the heterocyclyl ring is attached to the carbonyl group via a carbon ring atom;
B is an aryl or heteroaryl ring;
R3 is selected from the group consisting of: Case 50053 A-HO 164
28
(a) amino;
(b) acylamino;
(c) optionally substituted heterocyde;
(d) heteroaryl optionally substituted with a substituent selected from halo, alkyl or alkoxy;
(e) heteroalkyl;
(f) heteroalkenyl;
(g) heteroalkynyl; (h) heteroalkoxy
(i) heteroalkylamino;
(j) optionally substituted heterocyclylalkyl;
(k) optionally substituted heterocyclylalkenyl;
(1) optionally substituted heterocyclylalkynyl;
(m) optionally substituted heterocyclylalkoxy;
(n) optionally substituted heterocyclylalkylamino;
(o) optionally substituted heterocyclylalkylcarbonyl;
(p) heteroalkylcarbonyl;
(q) -NHSO2R6 where R6 is alkyl, heteroalkyl or optionally substituted heterocyclylalkyl;
(r) -NHSO2NR7R8 where R7 and R8 are, independently of each other, hydrogen, alkyl or heteroalkyl;
(s) -Y-(alkylene)-R9 where: Y is a single bond, -O-, -NH- or - S(O)n- (where n is an integer from 0 to 2); and R9 is cyano, heteroaryl, -COOH, -COR10, -COOR" - CONRi2R", -SO2R1VSO2NR15R16, -NHSO2R17Or - NHSO2NR18R19 where R10 is alkyl or optionally substituted heterocyde, R11 is alkyl, and R12, R 13, R14, R15, R16, R17, R18 and R19 are, independently of each other, hydrogen, alkyl or heteroalkyl;
(t) -C(=NR20)(NR21R22) where R20, R21 and R22 independently represent hydrogen, alkyl or hydroxy, or R20 and R21 together are -(CH2)n- where n is 2 or 3 and R22 is hydrogen or alkyl;
(u) -NHC(X)NR23R24 where X is -0- or -S-, and R23 and R24 are, independently of each other, hydrogen, alkyl or heteroalkyl;
(v) -CONR25R2*- where R25 and R25 independently represent hydrogen, alkyl, heteroalkyl or optionally substituted Case 50053 A-HO 164
29
heterocyclylalkyl, or R25 and R26 together with the nitrogen to which they are attached form an optionally substituted heterocyclyl ring; (w) -S(O)nR27 where n is an integer from 0 to 2, and R27 is alkyl, heteroalkyl, optionally substituted heterocyclylalkyl or -NR28R29 where R28 and R29 are, independently of each other, hydrogen, alkyl or heteroalkyl; R4 is selected from the group consisting of:
(a) hydrogen;
(b) halo;
(c) alkyl; and
(d) alkoxy; R5 is selected from the group consisting of:
(a) hydrogen;
(b) halo;
(c) alkyl;
(d) haloalkyl;
(e) thioalkyl;
(f) hydroxy;
(g) amino;
(h) alkylamino; (i) dialkylamino; (j) heteroalkyl;
(k) optionally substituted heterocycle; (1) optionally substituted heterocyclylalkyl; and (m) optionally substituted heterocyclylalkoxy; and R6 is selected from a group consisting of:
(a) hydrogen;
(b) halo;
(c) alkyl; and
(d) alkoxy.
In another embodiment the compounds are those where R3 is:
(a) optionally substituted heterocyclyl;
(b) aryl or heteroaryl both optionally substituted with a substituent selected from halo, alkyl, amino, alkoxy, carboxy, lower alkoxy Case 50053 A-HO 164
30
carbonyl, SO2R1 (where R1 is alkyl) or -O2NHR1R" (where R1 and R" are independently hydrogen or alkyl);
(c) heteroalkyl;
(d) heteroalkenyl;
(e) heteroalkylamino;
(f) heteraloxy
(g) optionally substituted heterocyclylalkyl or heterocyclyloxy; (h) optionally substituted heterocydylalkenyl;
(i) optionally substituted heterocyclylalkynyl;
(j) optionally substituted heterocyclylalkoxy;
(k) optionally substituted heterocydylalkylamino;
(1) optionally substituted heterocyclylalkylcarbonyl:
(s) -Y-(alkylene)-R9 where Y is a single bond, -O or -NH- and R9 is optionally substituted heteroaryl, -CONR12R13, SO2R14, -SO2NR15R16
-NHSO2R17 or -NHSO2NR18R" where R12, R13, R14, R15, R16 R17, R18 and R19 are independently of each other heteroalkyl; hydrogen, alkyl or heteroalkyl; (x) cydoalkylalkyl, cycloalkylalkynyl and cycloalkylalkynyl, all optionally substituted with alkyl, halo, hydroxy or amino; (m) arylaminoalkylene or heteroarylaminoalkylene; or (n) Z-alkylene-NR30R31 where Z is -NH-, -N(alkyl)- or -0-, and R30 and
R31 are independently of each other, hydrogen, alkyl or heteroalkyl.
In still another embodiment, the compounds are those where R1 and R2 are hydrogen and B is phenyl. In an additional embodiment, the compounds are those wherein R4 is hydrogen and Rs is halo or alkyl. In another embodiment, the compounds are those wherein Rs is chloro, fluoro or methyl and R6 is hydrogen, chloro, fluoro, methyl or methoxy. In another embodiment, the compounds are those wherein R3 is optionally substituted heteroaryl.
In yet another embodiment, the compounds are those wherein R3 is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, N-oxidopyridin-2-yI, N-oxidopyridin-3-yl, Noxidopyridin-4-yl or pyridon-2-yl, all optionally substituted. In a further embodiment, the compounds are those wherein R3 is at the 3-position. In still another embodiment, the compounds are those wherein R5 is 4-F or 2-Me, and R6 is hydrogen. In another embodiment, the compounds are those wherein R3 is optionally substituted phenyl. Case 50053 A-HO 164
31
In a further embodiment, the compounds are those wherein R3 is 3-sulfamoylphenyl, 3- methylsulfonylphenyl, 3-carboxyphenyl or 3-ethoxycarbonylphenyl. In yet another embodiment, the compounds are those wherein R5 is 4-F and R6 is hydrogen.
In another embodiment, the compounds are those wherein R3 is.
(a) heteroalkyl;
(b) heteroalkoxy;
(c) heteroalkylamino;
(d) optionally substituted heterocyclylalkyl;
(e) optionally substituted heterocyclylalkoxy;
(f) optionally substituted heterocyclylalkylamino;
(g) Y-(alkylene)-R9 where Y is a single bond, -O- or -NH- and R9 is optionally substituted heteroaryl, -CONR12R13, -SO2R14, - SO2NRlsRlβ -NHSO2R17 or -NHSO2NR18R19 where Ri2, R13, R14, R15, R16, R17, R18 and R19 are independently of each other hydrogen, alkyl or heteroalkyl; or
(h) Z-alkylene-NR30R31 where Z is -NH-, -N(alkyl)- or -O-, and R30 and R31 are independently of each other, hydrogen, alkyl or heteroalkyl.
In a further embodiment, the compounds are those wherein R3 is heteroalkyl. In another embodiment, the compounds are those wherein R3 is at the 3-position and is selected from the group consisting of 2-dimethylaminoethyl, 3dimethylamtnopropyl, 4- dimethylaminobutyl, 2-dimethylaminoethylamino, 3-dimethylaminopropylamino, hydroxymethyl, 1,2-dihydroxyethyl, 3-hydroxy-3-methyl-l-butyl or 3-hydroxybutyl. In yet another embodiment, the compounds are those wherein R5 is 2-F and R6 is 4-F.
In still another embodiment, the compounds are those wherein R5 is 2-Me and R6 is hydrogen. In an additional embodiment, the compounds are those wherein R9 is heteroalkoxy or heteroalkylamino. In yet another embodiment, the compounds are those wherein R3 is at the 3-position and is selected from the group consisting of 3- dimethylaminopropoxy, 2dimethylaminoethoxy, 2-hydroxyethoxy, 2,3-dihydroxy- propoxy, 2-dimethylaminoethylamino and 3-dimethylaminopropylamino.
In yet another embodiment, the compounds are those wherein R3 is optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkoxy or optionally substituted Case 50053A-HO 164
32
heterocyclylalkylamino. In still another embodiment, the compounds are those wherein R3 is at the 3-position and is selected from the group consisting of 3-(morpholin-4-yl)propoxy, 2-(morpholin-4-yl)ethoxy, 2-(2-oxo-pyrrolidin-l-yl)ethoxy, 3(morpholin-4-yl)propyI, 2- (morpholin-4-yl)ethyl, 4-(morpholin-4yl)butyl, 3-(morpholin-4-yl)propylamino, 2- (morpholin-4yl)ethylamino, 4-hydroxypiperidinylmethyl, 2-(S,S-dioxothiamorpholin-4- yl)ethyl, 3-(S,S-dioxo-thiamorpholin-4-yl)propyl and N-methylpiperazinylmethyl.
In an additional embodiment, the compounds are those wherein R3 is -Y-(alkylene)-R9 where Y is a single bond, -O- or -NH- and R9 is optionally substituted heteroaryl, - CONR12R13, -SO2R14, -SO2NR15R1S -NHSO2R17 or -NHSO2NR18R19 where R12, R13, R14, R1S, Rlβ, R17, R18 and R19 are independently of each other hydrogen, alkyl or heteroalkyl. In a further embodiment, the compounds are those wherein Y is a single bond and R9 is - SO2R14 or -SO2NR15R16.
In an additional embodiment, the compounds are those wherein R3 is 5-methylsulfonylethyl or sulfamoylethyl.
Specific preferred compounds of formula A for use in the manufacture of a medicament for the treatment of pulmonary hypertension include:
5-amino-l-(4-fluorophenyl)-4-[3-(2-morpholin-4-ylethoxy)benzoyl]pyrazole, 5-amino-I-(2,4-difluoro-phenyl)-4-[3-(3-morpholin-4ylpropyl)benzoyl]pyrazole, 5-amino-4-(3-aminobenzoyI)-l-(4-fluorophenyl)pyrazole, 5-amino-l-(4-fluorophenyl)-4-[3-(3-morpholin-4-ylpropyl)benzoyl] pyrazole, 5-amino-4-[3-(2-aminosulfonylethenyl)benzoyl] -l-(4fluorophenyl)pyrazole, 5-amino-4-(3-acetyIaminobenzoyl)-l-phenylpyrazole, 5-amino-4-[3-(2-aminoethyl)benzoyl]-l-(4-fluorophenyl)pyrazole, 5-amino-l-(4-fluorophenyl)-4-[3-(3-morpholin-4-ylpropylamino) benzoyl] pyrazole, 5-amino-4-[3-(2-arninosulfonylethyl)benzoyl]-l-(4-fluorophenyl)pyrazole, 5-amino-l-(4-fluorophenyl)-4-(3-pyridin-3-ylbenzoyl)pyrazole, 5-amino-l-(2-methylphenyI)-4-[3-pyridin-3-yl)benzoyl]pyrazole, 5-amino-l-(2-methylphenyl)-4-[3-(N-oxidopyridin-3-yl)benzoyl]pyrazole, 5-arnino-4-[3-(2,3-dihydroxypropoxy)benzoyl]-l-(4-fluorophenyl) pyrazole, 5-amino-4-[3-(l,2-dihydroxyethyl)benzoyl]-l-(4-fluorophenyl) pyrazole, 5-amino-l-(4-fluorophenyl)-4-[3-(sulfamoylbenzoyl) pyrazole, 5-amino-l-(4-fluoro-phenyl)-4-[3-(3-hydroxy-3-methylbutyl) benzoyl]pyrazole, 5-amino-l-(4-fluorophenyl)-4-[3-(2-(l-hydroxycyclopentyl)ethyl) benzoyl]pyrazole, Case 50053A-HO 164
33
5-amino-4-[3-(2-methylsulfonylethyl)-benzoyl]-l-(4-fluorophenyl) pyrazole,
5-amino-l-(2,4-difluorophenyl)-4-[3-(2-hydroxyethyIsulfonyl) benzoyl]pyrazole,
3-[5-amino-4-(3-iodo-benzoyl)-pyrazoI-l-yl]-N-methoxy-4-methyl-benzamide,
3-(5-amino-4-benzoyl-pyrazol-l-yl)-N-methoxy-4-methyl-benzamide,
3-(5-amino-4-benzoyl-pyrazol-l-yl)-4-methyl-benzoic acid,
3-(5-amino-4-benzoyl-pyrazol-l-yl)-N-cyclopropyl-4-methyl-benzamide,
3-[5-amino-4-(3-iodo-benzoyl)-pyrazol-l-yl]-4-methyl-benzoic acid,
3-[5-amino-4-(3-iodo-benzoyl)-pyrazol-l-yl]-N-cyclopropyl-4-methyl-benzamide,
{5-amino-l-[2-methyl-5-(4H-[l,2,4]triazol-3-yl)-phenyl]-lH-pyrazol-4-yl}-phenyl-methanone,
3-[5-amino-4-(3-[l,3]dioxolan-2-yl-benzoyl)-pyrazol-l-yl]-N-cyclopropyl-4-methyl- benzamide,
3-[5-amino-4-(3-formyl-benzoyl)-pyrazol-l-yl]-N-cyclopropyl-4-methyl-benzainide,
3-[5-amino-4-(3-hydroxymethyl-benzoyl)-pyrazol-l-yl]-N-cyclopropyl-4-methyI-benzamide,
3-{5-amino-4-[3-(4-methyl-piperazin-l-ylmethyl)-benzoyl]-pyrazol-l-yl}-N-cycIopropyl-4- methyl-benzamide,
3-[5-amino-4-(3-morpholin-4-ylmethyl-benzoyI)-pyrazol-l-yl]-N-cyclopropyl-4-methyl- benzamide,
3-[5-amino-4-(3-morpholin-4-ylmethyl-benzoyl)-pyrazol-l-yl]-N-cycIopropyl-4-methyl- benzamide,
3-[5-amino-4-(3-benzyloxy-benzoyl)-pyrazoI-l-yl]-N-cyclopropyl-4-methyl-benzamide,
3-[5-amino-4-(3-hydroxy-benzoyI)-pyrazol-l-yl]-N-cyclopropyl-4-methyl-benzamide,
3-[5-amino-4-(4-methyl-benzoyl)-pyrazol-l-yI]-N-cyclopropyl-4-methyl-benzamide,
3-(5-amino-4-benzoyl-imidazol-l-yl)-N-cyclopropyl-4-methyl-benzamide,
3-[5-amino-4-(3-iodo-benzoyl)-pyrazoI-l-yl]-N-methoxy-4-methyl-benzamide,
3-(5-amino-4-benzoyl-pyrazol-l-yl)-N-methoxy-4-methyI-benzamide,
3-(5-amino-4-benzoyl-pyrazol-l-yl)-N-cycIopropyl-4-methyl-benzamide,
3-[5-amino-4-(3-iodo-benzoyl)-pyrazol-l-yI]-N-cyclopropyl-4-methyl-benzamide,
{5-amino-l-[2-methyl-5-(4H-[l,2,4]triazol-3-yl)-phenyl]-lH-pyrazol-4-yl}-phenyl-methanone,
3-[5-amino-4-(3-[l,3]dioxolan-2-yl-benzoyl)-pyrazol-l-yl]-N-cyclopropyl-4-methyl- benzamide,
3-[5-amino-4-(3-formyl-benzoyl)-pyrazol-l-yl]-N-cyclopropyl-4-methyl-benzamide,
3-[5-amino-4-(3-hydroxymethyl-benzoyl)-pyrazol-l-yl]-N-cyclopropyl-4-methyl-benzamide,
3-{5-amino-4-[3-(4-methyI-piperazin-l-ylmethyl)-benzoyl]-pyrazol-l-yl)-N-cyclopropyl-4- methyl-benzamide,
3-[5-amino-4-(3-morpholin-4-ylmethyl-benzoyl)-pyrazol-l-yl]-N-cyclopropyl-4-methyl- benzamide, Case 50053 A-HO 164
34
3-[5-amino-4-(3-morpholin-4-ylmethyl-benzoyI)-pyrazol-l-yl]-N-cyclopropyl-4-methyl- benzamide,
3-[5-amino-4-(3-benzyloxy-benzoyl)-pyrazol-l-yl]-N-cycIopropyl-4-methyl-benzamide,
S-tS-amino^-β-hydroxy-benzoyO-pyrazol-l-yll-N-cyclopropyM-methyl-benzamide,
3-[5-amino-4-(4-methyl-benzoyl)-pyrazol-l-yl]-N-cyclopropyl-4-methyl-benzamide,
3-(5-amino-4-benzoyl-imidazol-l-yl)-N-cyclopropyl-4-methyl-benzamide,
3-{5-Amino-4-[3-(2-dimethylamino-ethylcarbamoyI)-benzoyI]-imidazoi-l-yl}-N-cyclopropyI-
4-methyl-benzamide;
3-[5-Amiπo-4-(5-chloro-thiophene-2-carbonyl)-imidazol-l-yl]-N-cyclopropyl-4-methyl- benzamide,
3-[5-Amino-4-(3-hydrazinocarbonyl-benzoyl)-imidazol-l-yl]-N-cycIopropyl-4-methyl- benzamide,
3-(5-Amino-4-cyclohexanecarbonyl-imidazol-l-yl)-N-cyclopropyl-4-methyl-benzamide,
3-(5-Amino-4-cyclopentanecarbonyl-imidazol-l-yl)-N-cyclopropyl-4-methyl-benzamide,
3-(5-Amino-4-phenylacetyl-imidazol-l-yl)-N-cyclopropyl-4-methyl-benzamide,
3-[5-Amino-4-(tetrahydro-pyran-4-carbonyl)-imidazol-l-yI]-N-cyclopropyl-4-methyl- benzamide,
3-[5-Amino-4-(3-ethylcarbamoyl-benzoyl)-imidazol-l-yl]-N-cycIopropyl-4-methyl- benzamide,
3-[5-Amino-4-(3-isopropylcarbamoyl-benzoyl)-imidazol-l-yl]-N-cyclopropyI-4-methyl- benzamide,
5-Amino-l-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-methyl-lH-pyrazole-4-carboxyIic acid ethyl ester,
5-Amino-l-(5-cycIopropylcarbamoyl-2-methyl-phenyl)-lH-pyrazole-4-carboxylic acid ethyl ester,
3-(5-Amino-4-cydopentanecarbonyl-pyrazol-l-yl)-N-cyclopropyl-4-methyl-benzamide,
3-[5-Amino-4-(3-hydrazinocarbonyl-benzoyl)-pyrazol-l-yl]-N-cyclopropyl-4-methyl- benzamide,
5-Amino-l-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-lH-pyrazole-4-carboxylic acid beπzylamide,
3-(5-Amino-4-cyclohexanecarbonyl-pyrazol-l-yl)-N-cyclopropyl-4-methyl-benzamide,
5-Amino-l-(5-cyclopropylcarbamoyI-2-methyl-phenyl)-lH-pyrazole-4-carboxylic acid cyclohexylamide,
5-Amino-l-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-methylsulfanyl-lH-pyrazole-4- carboxylic acid amide, Case 50053A-HO 164
35
i-Amino-l-fS-cycIopropylcarbamoyl^-methyl-phenyOO-methanesulfonyl-lH-pyrazoIe^- carboxylic acid amide,
5-Aminc>-l-(5-cyclopropylcarbamoyI-2-methyl-phenyl)-3-methylsuIfanyl-lH-pyrazole-4- carboxyiic acid ethyl ester,
5-Amino-3-[(3-chloro-benzylcarbamoyl)-methoxy]-l-(5-cyclopropylcarbamoyl-2-methyI- phenyl)-lH-pyrazole-4-carboxylic acid ethyl ester,
3-[5-Amino-4-benzoyl-3-(piperidin-4-yloxy)-pyrazol-l-yl)-N-cycIopropyl-4-methyl- benzamide,
3-(5-Amino^-benzoyl-3-methanesuIfonyIφyrazol-l-yl)-N-cyclopropyl-4-methyl-benzarnide,
3-(5-Amino-4-benzoyl-3-methoxy-pyrazol-l-yl)-N-cyclopropyl-4-methyl-benzarnide,
5-Amino-l-(5-cycIopropyIcarbamoyl-2-methyl-phenyl)-3-(2-hydroxy-ethoxy)-lH-pyrazole-4- carboxylic acid ethyl ester,
4-[5-Amino-4-benzoyl-l-(5-cyclopropylcarbamoyl-2-methyl-pheπyl)-lH-pyrazol-3-yloxy]- piperidine-1 -carboxylic acid tert-butyl ester,
3-(5-Amino-4-benzoyl-3-methylsulfanyl-pyrazol-l-yl)-N-cyclopropyl-4-methyl-benzamide,
3-[5-Amino-4-benzoyl-3-(2-methoxy-ethoxy)-pyrazol-l-yl]-N-cyclopropyl-4-methyl- benzamide,
3-[5-Amino-4-(3-iodo-benzoyl)-pyrazol-l-yl]-N-methoxy-4-methyl-benzamide,
3-(5-Amino-4-benzoyl-pyrazol-l-yl)-N-methoxy-4-methyl-benzamide,
3-(5-amino-4-benzoyl-pyrazol-l-yl)-4-methyl-benzoic acid,
3-(5-amino-4-benzoyl-pyrazol-l-yl)-N-cyclopropyl-4-methyl-benzamide,
3-[5-amino-4-(3-iodo-benzoyI)-pyrazol-l-yl]-4-methyl-benzoic acid,
3-[5-amino-4-(3-iodo-benzoyl)-pyrazol-l-yl]-N-cyclopropyl-4-methyl-benzamide,
{5-amino-l-[2-methyl-5-(4H-[l,2,4]triazol-3-yl)-phenyl]-lH-pyrazoI-4-yl}-phenyl-methanone,
3-[5-amino-4-(3-[l,3]dioxolan-2-yl-benzoyl)-pyrazol-l-yl]-N-cyclopropyl-4-methyI- benzamide,
3-[5-amino-4-(3-formyl-benzoyl)-pyrazol-l-yI]-N-cyclopropyl-4-methyl-benzamide,
3-[5-amino-4-(3-hydroxymethyl-benzoyl)-pyrazol-l-yl]-N-cyclopropyl-4-methyl-benzamide,
3-{5-amino-4-[3-(4-methyl-piperazin-l-ylmethyl)-benzoyl]-pyrazol-l-yl}-N-cyclopropyl-4- methyl-benzamide,
3-[5-amino-4-(3-morpholin-4-ylmethyl-benzoyl)-pyrazol-l-yI]-N-cyclopropyl-4-methyl- benzamide,
3-{5-Amino-4-[3-(2-morpholin-4-yI-ethoxy)-benzoyl]-pyrazol-l-yl}-N-cyclopropyl-4-methyl- benzamide,
3-[5-amino-4-(3-benzyloxy-benzoyl)-pyrazoI-l-yl]-N-cyclopropyl-4-methyl-benzamide,
3-[5-amino-4-(3-hydroxy-benzoyl)-pyrazol-l-yl]-N-cyclopropyl-4-methyl-benzamide, Case 50053A-HO 164
36
3-[5-amino-4-(4-methyI-benzoyl)-pyrazol-l-yl]-N-cycIopropyl-4-methyl-benzamide,
3-(5-amino-4-benzoyl-imidazol-l-yl)-N-cyclopropyl-4-methyl-benzamide,
3-(5-Amino-4-cyclohexanecarbonyl-imidazol-l-yl)-N-cyclopropyl-4-methyl-benzamide,
3-(5-Amino-4-cyclopentanecarbonyl-iinidazol-l-yl)-N-cyclopropyl-4-πiethyl-benzamide,
3-(5-Amino-4-phenylacetyl-imidazol-l-yl)-N-cyclopropyl-4-methyl-benzamide,
3-[5-Amino-4-(3-isopropylcarbamoyl-benzoyl)-imidazol-l-yl]-N-cyclopropyl-4-methyl- benzamide,
3-{5-Amino-4-[3-(2-dimethylamino-ethyIcarbamoyl)-benzoyl]-imidazol-l-yl}-N-cyclopropyl-
4-methyl-benzamide,
3-[5-Amino-4-(3-ethylcarbamoyI-benzoyl)-imidazoI-l-yl]-N-cyclopropyl-4-methyl- benzamide,
3-[5-Amino-4-(3-methylcarbamoyl-benzoyl)-imidazol-l-yl]-N-cyclopropyl-4-methyl- benzamide,
3-[5-Amino-4-(3-cycIopropylcarbamoyl-benzoyl)-imidazol-l-yl]-N-cyclopropyI-4-methyl- benzamide,
3-[5-Amino-4-(3-cyclopentylcarbamoyl-benzoyl)-imidazol-l-yl]-N-cyclopropyl-4-methyl- benzamide,
3-{5-Amino-4-[3-(morpholine-4-carbonyl)-benzoyl]-imidazol-l-yl}-N-cyclopropyl-4-methyl- benzamide,
3-{5-Amino-4-[3-(cyclopropylmethyl-carbamoyl)-benzoyl]-imidazol-l-yl}-N-cyclopropyl-4- methyl-benzamide,
3-[5-Amino-4-(tetrahydro-pyran-4-carbonyl)-imidazol-l-yl]-N-cyclopropyl-4-inethyl- benzamide,
3-(5-amino-4-benzoyl-3-methoxy-pyrazol-l-yl)-N-cyclopropyl-4-methyl-benzamide,
3-(5-amino-4-benzoyl-3-ethoxy-pyrazol-l-yl)-N-cyclopropyl-4-methyl-benzamide,
3-[5-amino-4-benzoyl-3-(2-methoxy-ethoxy)-pyrazol-l-yl]-N-cyclopropyl-4-methyl- benzamide,
3-[5-amino-4-benzoyl-3-(2-benzyloxy-ethoxy)-pyrazol-l-yl]-N-cyclopropyl-4-methyl- benzamide,
4-[5-amino-4-benzoyl-l-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-lH-pyrazol-3-yloxy]- piperidine-1-carboxylic acid tert-butyl ester,
3-[5-amino-4-benzoyl-3-(piperidin-4-yloxy)-pyrazol-l-yl]-N-cyclopropyl-4-methyI- benzamide, trifluoroacetate salt,
3-(5-amino-4-benzoyl-3-methylsulfanyl-pyrazoI-l-yl)-N-cyclopropyl-4-methyl-benzamide,
3-(5-amino-4-benzoyl-3-methanesulfonyl-pyrazol-l-yl)-N-cyclopropyl-4-methyl-benzamide, Case 50053A-HO 164
37
5-amino-l-(5-cyclopropyIcarbamoyl-2-methyl-phenyl)-3-methylsulfanyl-lH-pyrazole-4- carboxylic acid amide,
5-amino-l-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-methanesulfonyl-lH-pyrazole-4- carboxylic acid amide, and i-amino-l-fS-cyclopropylcarbamoyl-Z-methyl-phenylJO-methylsulfanyl-lH-pyrazoIe^- carboxylic acid ethyl ester.
The invention relates most importantly to the use of 3-[5-Amino-4-(3-cyanobenzoyl)-pyrazol- l-yl]-N-cyclopropyI-4-methylbenzamide i.e. a compound of formula AA
Figure imgf000038_0001
or a pharmaceutically acceptable derivative thereof for the manufacture of a medicament for the treatment of pulmonary hypertension.
The compounds of formula A , or pharmaceutically acceptable derivatives thereof, are active in assays that measure p38 kinase activity, including, but not limited to, p38α and p38β kinase activity.
Compounds of formula A, in free or salt form, may be prepared as described in WO 2005/009973, the contents of which is incorporated herein by reference.
The invention provides a method of treating pulmonary hypertension, in a subject, particularly a human subject, in need of such treatment, which comprises administering to said subject an effective amount of a compound of formula A as hereinbefore defined.
The invention also provides a method of treating pulmonary hypertension, in a subject, particularly a human subject, in need of such treatment, which comprises administering to Case 50053A-HO 164
38
said subject an effective amount of a compound of formula A as hereinbefore defined or a pharmaceutically acceptable derivative thereof in combination with a second active agent. Examples of second or additional active agents include, but are not limited to, antiinflammatories, bronchodilators, antihistamines, decongestants, anti-tussives, anticoagulants, diuretics, cardiac glycosides, calcium channel blockers, vasodilators, prostacyclin analogues, endothelin antagonists, phosphodiesterase inhibitors, endopeptidase inhibitors, lipid lowering agents, thromboxane inhibitors, or other agents found, for example, in the Physician's Desk Reference 2003. Second active agents can be large molecules (e.g., proteins) or small molecules (e.g., synthetic inorganic, organometallic, or organic molecules). Compounds of formula I may be mixed with second or additional active agents in a fixed pharmaceutical composition or they may be administered separately, before, simultaneously with or after the second or additional active agents. Examples of specific second active agents include, but are not limited to, amlodipine, diltiazem, nifedipine, adenosine, epoprostenol (Floran™), treprostinil (Remodulin™), bosentan (Tracleer™), warfarin, digoxin, nitric oxide, L- arginine, iloprost, betaprost, and sildenafil (Viagra™).
Such anti-inflammatory drugs include steroids, in particular glucocorticosteroids such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate, or steroids described in WO 02/88167, WO 02/12266, WO 02/100879, WO 02/00679 (especially those of Examples 3, 11, 14, 17, 19, 26, 34, 37, 39, 51, 60, 67, 72, 73, 90, 99 and 101), WO 03/35668, WO 03/48181, WO 03/62259, WO 03/64445, WO 03/72592, WO 04/39827 and WO 04/66920; non-steroidal glucocorticoid receptor agonists, such as those described in DE 10261874, WO 00/00531, WO 02/10143, WO 03/82280, WO 03/82787, WO 03/86294, WO 03/104195, WO 03/101932, WO 04/05229, WO 04/18429, WO 04/19935, WO 04/26248 and WO 05/05452; LTB4 antagonists such as BIIL 284, CP-195543, DPC11870, LTB4 ethanolamide, LY 293111, LY 255283, CGS025019C, CP-195543, ONO-4057, SB 209247, SC-53228 and those described in US 5451700 and WO 04/108720; LTD4 antagonists such as montelukast, pranlukast, zafirlukast, accolate, SR2640, Wy-48,252, ICI 198615, MK-571, LY-171883, Ro 24-5913 and L-648051; Dopamine receptor agonists such as cabergoline, bromocriptine, ropinirole and 4-hydroxy-7-[2-[[2-[[3-(2-phenylethoxy)-propyl]suIfonyl]ethyl]amino]ethyl]-2(3H)- benzothiazolone and pharmaceutically acceptable salts thereof (the hydrochloride being Viozan® - AstraZeneca); A2a agonists such as those described in EP 409595A2, EP 1052264, EP 1241176, WO 94/17090, WO 96/02543, WO 96/02553, WO 98/28319, WO 99/24449, WO 99/24450, WO 99/24451, WO 99/38877, WO 99/41267, WO 99/67263, WO 99/67264, WO 99/67265, WO 99/67266, WO 00/23457, WO 00/77018, WO 00/78774, Case 50053A-HO 164
39
WO 01/23399, WO 01/27130, WO 01/27131, WO 01/60835, WO 01/94368, WO 02/00676, WO 02/22630, WO 02/96462, WO 03/086408, WO 04/039762, WO 04/039766, WO 04/045618 and WO 04/046083; and A2b antagonists such as those described in WO 02/42298 and WO 03/042214.
Suitable PDE5 inhibitors include pyrazolopyrimidinones disclosed in EP 463756, EP 526004, WO 94/28902, WO 96/16657 or WO 98/49166; 5-substituted pyrazole [4,3-d]pyrimidin-7- ones disclosed in EP 201188; griseolic acid derivatives disclosed in EP 214708 and EP 319050; 2-phenylpurinone derivatives disclosed in EP 293063; phenylpyridone derivatives disclosed in EP 347027; fused pyrimidine derivatives disclosed in EP 347146; condensed pyrimidine derivatives disclosed in EP 349239; pyrimidopyrimidine derivatives disclosed in EP 351058; purine compounds disclosed in EP 352960; quinazolinone derivatives disclosed in EP 371731; phenylpyrimidone derivatives disclosed in EP 395328; imidazoquin-oxalinone derivatives or their aza analogues disclosed in EP 400583; phenylpyrimidone derivatives disclosed in EP 400799; phenylpyridone derivatives disclosed in EP 428268; pyrimidopyrimidine derivatives disclosed in EP 442204; 4-aminoquinazoline derivatives disclosed in EP 579496; 4,5-dihydro-4-oxo-pyrrolo[l,2-a]quinoxaline derivatives or their aza analogues disclosed in EP 584487; polycyclic guanine derivatives disclosed in WO91/19717; nitrogenous heterocyclic compounds disclosed in WO93/07124; 2-benzyl-polycyclic guanine derivatives disclosed in WO94/19351; quinazoline derivatives disclosed in US 4060615; 6- heterocyclyl pyrazolo [3,4-d]pyrimidin-4-ones disclosed in US 5294612; benzimidazoles disclosed in Japanese Kokai 5-222000; cycloheptimidazoles disclosed in European Journal of Pharmacology, vol. 251, (1994), 1; N-containing heterocycles disclosed in WO 94/22855; pyrazolopyrimidine derivatives disclosed in EP 636626; 4-aminopyrimidine derivatives disclosed in EP 640599; imidazoquinazoline derivatives disclosed in EP 668280; anthranilic acid derivatives disclosed in EP 0686625; 4-aminoquinazoline derivatives disclosed in US 5436233; tetracyclic derivatives disclosed in WO 95/19978 (including tadafil); quinazoline compounds disclosed in EP 0669324; fused pyridazine compounds disclosed in EP 722936; imidazoquinoline compounds disclosed in EP 0758653; substituted pyrazoloquinolinamines disclosed in WO 96/28159; substituted pyrazolopyrimidinones disclosed in WO 96/28429; indole derivatives disclosed in WO 96/32379; benzimidazole derivatives disclosed in WO 97/03070; 2-phenyl substituted imidazotriazinone derivatives disclosed in WO 99/24433 (including vardenafil); as well as those described in WO 2001/77110.
Suitable PDE4 inhibitors include cilomilast (Ariflo® GlaxoSmithKHne), Roflumilast (Byk Gulden),V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Case 50053A-HO 164
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Arofylline (Almirall Prodesfarma), PD189659 / PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID(TM) CC-10004 (Celgene), VM554/UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo), GRC 3886 (Oglemilast, Glenmark), WO 92/19594, WO 93/19749, WO 93/19750, WO 93/19751, WO 99/16766, WO 01/13953, WO 03/104204, WO 03/104205, WO 04/000814, WO 04/000839 and WO 04/005258 (Merck), WO 04018450, WO 04/018451, WO 04/018457, WO 04/018465, WO 04/018431, WO 04/018449, WO 04/018450, WO 04/018451, WO 04/018457, WO 04/018465, WO 04/019944, WO 04/019945, WO 04/045607, WO 04/037805, WO 04/063197, WO 04/103998, WO 04/111044, WO 05012252, WO 05012253, WO 05/013995, WO 05/030212, WO 05/030725, WO 05/087744, WO 05/087745, WO 05/087749 and WO 05/090345 as well as those described in WO 98/18796 and WO 03/39544.
Such bronchodilatory drugs include beta-2 adrenoceptor agonists. Suitable beta-2 adrenoceptor agonists include albuterol (salbutamol), metaproterenol, terbutaline, salmeterol, fenoterol, procaterol, and especially, formoterol, carmoterol, GSK159797 and pharmaceutically acceptable salts thereof, and compounds (in free or salt or solvate form) of formula I of WO 00/75114, which document is incorporated herein by reference, preferably compounds of the Examples thereof, especially a compound of formula
Figure imgf000041_0001
and pharmaceutically acceptable salts thereof, as well as compounds (in free or salt or solvate form) of formula I of WO 04/16601 or of formula I of WO 04/087142. Further suitable β -2- adrenoreceptor agonists include compounds, such as those described in and also compounds of EP 147719, EP 1440966, EP 1460064, EP 1477167, EP 1574501, JP 05025045, JP 2005187357, US 2002/0055651, US 2004/0242622, US 2004/0229904, US 2005/0133417, US 2005/5159448, US 2005/5159448, US 2005/171147, US 2005/182091, US 2005/182092, US 2005/209227, US 2005/256115, US 2005/277632, US 2005/272769, US 2005/239778, US 2005/215542, US 2005/215590, US 2006/19991, US 2006/58530, WO 93/18007, WO 99/64035, WO 01/42193, WO 01/83462, WO 02/66422, WO 02/ 70490, WO 02/76933, WO 03/24439, WO 03/42160, WO 03/42164, WO 03/72539, WO 03/91204, WO 03/99764, WO 04/16578, WO 04/22547, WO 04/32921, WO 04/33412, WO 04/37768, Case 50053A-HO 164
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WO 04/37773, WO 04/37807, WO 04/39762, WO 04/39766, WO 04/45618 WO 04/46083 , WO 04/80964, WO 04/087142, WO 04/89892, WO 04/108675, WO 04/108676, WO 05/33121, WO 05/40103, WO 05/44787, WO 05/58867, WO 05/65650, WO 05/66140, WO 05/70908, WO 05/74924, WO 05/77361, WO 05/90288, WO 05/92860, WO 05/92887, WO 05/90287, WO 05/95328, WO 05/102350, WO 06/56471, WO 06/74897 or WO 06/8173.
Such bronchodilatory drugs also include other anticholinergic or antimuscarinic agents, in particular ipratropium bromide, oxitropium bromide, tiotropium salts, glycopyrrolate, CHF 4226 (Chiesi) and SVT-40776, but also those described in EP 424021, US 3714357, US 5171744, US 2005/171147, US 2005/182091, WO 01/04118, WO 02/00652, WO 02/51841, WO 02/53564, WO 03/00840, WO 03/33495, WO 03/53966, WO 03/87094, WO 04/18422, WO 04/05285, WO 04/96800, WO 05/77361 and WO 06/48225.
Suitable dual anti-inflammatory and bronchodilatory drugs include dual beta-2 adrenoceptor agonist / muscarinic antagonists such as those disclosed in US 2004/0167167, US 2004/0242622, US 2005/182092, US 2005/256114, US 2006/35933, WO 04/74246, WO 04/74812, WO 04/89892 and WO 06/23475.
Suitable antihistamine drug substances include cetirizine hydrochloride, levocetirizine, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, dimetinden, ebastine, epinastine, levocabastine, mizolastine and tefenadine as well as those disclosed in WO 03/099807, WO 04/026841 and JP 2004107299.
In the treatment of disorders in accordance with the invention, compounds of formula A, or pharmaceutically acceptable derivatives thereof, may be administered by any appropriate route, for example orally, e.g. in tablet, capsule or liquid form, parenterally, for example in the form of an injectable solution or suspension, or intranasally, for example in the form of an aerosol or other atomisable formulation using an appropriate intranasal delivery device, e.g. a nasal spray such as those known in the art, or by inhalation.
A compound of formula A or AA, or a pharmaceutically acceptable derivative thereof, may be administered in a pharmaceutical composition together with a pharmaceutically acceptable diluent or carrier. Such compositions may be as described in WO 03/039544, for example dry powders, tablets, capsules and liquids, but also injection solutions, infusion solutions or Case 50053A-HO 164
42
inhalation suspensions, which may be prepared using other formulating ingredients and techniques known in the art.
The dosage of the compound of formula A or AA, or a pharmaceutically acceptable derivative thereof, can depend on various factors, such as the activity and duration of action of the active ingredient, the severity of the condition to be treated, the mode of administration, the species, sex, ethnic origin, age and weight of the subject and/or its individual condition.
In one embodiment of the invention, the recommended daily dose range of the compound of formula for the conditions described herein lie within the range of from about 1 mg to about 10,000 mg per day, given as a single once-a-day dose, or in divided doses throughout a day. Specifically, a daily dose range should be from about 1 mg to about 5,000 mg per day, more specifically, between about 10 mg and about 2,500 mg per day, between about 100 mg and about 800 mg per day, between about 100 mg and about 1,200 mg per day, or between about 25 mg and about 2,500 mg per day. In managing the patient, the therapy should be initiated at a lower dose, perhaps about 1 mg to about 2,500 mg, and increased if necessary up to about 200 mg to about 5,000 mg per day as either a single dose or divided doses, depending on the patient's global response. In another embodiment of the invention, a compound of formula A or a pharmaceutically acceptable derivative thereof is administered from about 1 to about 20 mg/day individually, for example, about 1 mg/day, about 2 mg/day, about 3 mg/day, about 4 mg/day, about 5 mg/day, about 6 mg/day, about 7 mg/day, about 8 mg/day, about 9 mg/day, about 10 mg/day, about 11 mg/day, about 12 mg/day, about 13 mg/day, about 14 mg/day, about 15 mg/day, about 16 mg/day, about 17 mg/day, about 18 mg/day, about 19 mg/day, or about 20 mg/day. In a particular embodiment, 3-[5- Amino-4-(3-cyanobenzoyl)-pyrazol-l -yl]-N-cyclopropyl-4-methylbenzamide or a pharmaceutically acceptable derivative thereof is administered in an amount of about 400, 800, 1,200, 2, 500, 5,000 or 10,000 mg a day in a single dose or as two divided doses.
Administration of a compound of formula A or a pharmaceutically acceptable derivative thereof and a second active agent to a patient can occur simultaneously or sequentially by the same or different routes of administration. The suitability of a particular route of administration employed for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without decomposing prior to entering the blood stream) and the disease being treated. A preferred route of administration for a compound of formula A is oral. Another preferred route of administration for such a compound is parenteral, particularly for patients who are in a peri- transplant period or in an end stage of Case 50053A-HO 164
43
pulmonary hypertension. Preferred routes of administration for the second active agent of the invention are known to those of ordinary skill in the art such as in Physicians' Desk Reference (57th ed., 2003).
The specific amount of the second active agent will depend on the specific agent used, the type of pulmonary hypertension being treated or managed, the severity and stage of pulmonary hypertension, and the amount(s) of any optional additional active agents concurrently administered to the patient.
This present invention encompasses kits which, when used by the medical practitioner, can simplify the administration of appropriate amounts of active agents to a patient. A typical kit of the invention comprises a dosage form of a compound of formula A, or a pharmaceutically acceptable derivative thereof, optionally further comprising a second active agent and/or a device or devices for administering the active agents e.g. syringes, drip bags, patches or inhalers.

Claims

Case 50053A-HO 16444CLAIMS
1. The use of a compound of formula A
Figure imgf000045_0001
or a pharmaceutically acceptable derivative thereof for the manufacture of a medicament for the treatment of pulmonary hypertension, where
R1 is hydrogen, acyl or -P(O)(OH)2;
R2 is hydrogen, halo, optionally substituted alkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, optionally substituted alkoxy, optionally substituted heterocyclyloxy, or alkylamino;
G is an aryl, aralkyl, cycloalkyl, heteroaryl, heteroaralkyl or a heterocyclyl ring optionally fused to a phenyl ring, and is substituted with R3 and R4, provided that the heterocyclyl ring is attached to the carbonyl group via a carbon ring atom, or G is OR83 or NR80R81;
B is an aryl or heteroaryl ring;
C is a 5-membered heteroaryl ring containing one or two heteroatoms in the ring;
D is heteroaryl, optionally substituted heteroaryl or -C(O)NR80R81;
where each R80 and R81 is independently hydrogen, alkyl, optionally substituted cycloalkyl, alkoxy, hydroxy, heteroaryl or optionally substituted heteroaryl, or together from optionally substituted alkylene or heteroalkylene;
R83 is hydrogen, alkyl, cycloalkyl, heteroaryl or optionally substituted heteroaryl;
R3 is selected from the group consisting of:
(a) amino, alkylamino or dialkylamino;
(b) acylamino; Case 50053A-HO 164
45
(c) optionally substituted heterocyclyl;
(d) optionally substituted aryl or heteroaryl;
(e) heteroalkyl;
(f) heteroalkenyl;
(g) heteroalkynyl; (h) heteroalkoxy;
(i) heteroalkylamino;
(j) optionally substituted heterocyclylalkyl;
(k) optionally substituted heterocyclylalkenyl;
(1) optionally substituted heterocydylalkynyl;
(m) optionally substituted heterocyclylalkoxy or heterocyclyloxy;
(n) optionally substituted heterocyclylalkylamino;
(o) optionally substituted heterocyclylalkylcarbonyl;
(p) heteroalkylcarbonyl;
(q) -NHSO2R6 where R6 is alkyl, heteroalkyl or optionally substituted heterocyclylalkyl;
(r) -NHSOzNR7R8 where R7 and R8 are, independently of each other, hydrogen, alkyl or heteroalkyl;
(s) -Y-(alkylene)-R9 where: Y is a single bond, -O-, -NH- or -S(O)n- (where n is an integer from 0 to 2); and R9 is halo, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -COOH, -COR10, -COOR", -CONR12R", -SO2R14, -SO2NR15R1*, -NHSO2R17 or -NHSO2NR18R19, where R10 is alkyl or optionally substituted heterocycle, R11 is alkyl, and R12, R" , R14, R1S,R16, R17, R18 and R19 are, independently of each other, hydrogen, alkyl or heteroalkyl;
(w) -Q=NR20KNR21R22) where R20, R21 and R22 independently represent hydrogen, alkyl or hydroxy, or R20 and R21 together are -(CH2)n-where n is 2 or 3 and R22 is hydrogen or alkyl;
(u) -NHC(X)NR23R24 where X is -O- or -S-, and R23 and R24 are, independently of each other, hydrogen, alkyl or heteroalkyl;
(v) -CONR25R26 where R25 and R26 independently represent hydrogen, alkyl, heteroalkyl or optionally substituted heterocyclylalkyl, or R2S and R26 together with the nitrogen to which they are attached form an optionally substituted heterocyclyl ring; Case 50053A-HO 164
46
(w) -S(O)nR27 where n is an integer from 0 to 2, and R27 is alkyl, heteroalkyl, optionally substituted heterocyclylalkyl or -NR28R29 where R28 and R29 are, independently of each other, hydrogen, alkyl or heteroalkyl;
(x) cycloalkylalkyl, cycloalkylalkynyl and cycloalkylalkynyl, all optionally substituted with alkyl, halo, hydroxy or amino;
(y) arylaminoalkylene or heteroarylaminoalkylene;
(z) Z-alkylene-NR30R31 or Z-alkylene-OR32 where Z is-NH-, -N(lower alkyl)- or -O-, and R30, R31 and R32 are independently of each other, hydrogen, alkyl or heteroalkyl;
(aa) -OC(O)-alkylene-CO2H or -OC(O)-NR1R" where R1 and R" are independently hydrogen or alkyl;
(bb) heteroarylalkenylene or heteroarylalkynylene;
(cc) hydrogen;
(dd) halo;
(ee) pseudohalo;
(ff) hydroxy;
(gg) optionally substituted alkoxy;
(hh) C(L)R40, where L is O, S or NR55; R40 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroarylium, optionally substituted cycloalkyl, optionally substituted heterocyclyl, C(L)R56, halo pseudohalo, OR55, SR55, NR57R58 or SiR52R53R54; where R52, R53 and R54 are selected as in (i) or (ii) as follows (i) R52, R53 and R54 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR55 or NR62R63; or (ii) any two of R52, R53 and R54 together form alkylene, alkenylene, alkynylene, heteroalkylene; and the other is selected as in (i); R55 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl or heterocyclyl; R56 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR55 or NR64R65; where R64 and R65 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR66 or NR62R63, or R64 and R65 together form alkylene, alkenylene, alkynylene, heteroalkylene, where R66 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl or heterocyclyl; R57 and R58 are selected as in (i) or (ii) as follows (i) R57 and R58 are each independently hydrogen, Case 50053A-HO 164
47
optionally substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR55, NR67R68 or C(L)R69, where R67 and R68 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl or heterocyclyl, or together form alkylene, alkenylene, alkynylene, heteroalkylene; and Rβ* is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR70 or NR62R63, where R70 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl; or (ii) R57 and R58 together form alkylene, alkenylene, alkynylene, heteroalkylene, or alkylenoxyalkylene; R62 and R63 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, or R62 and R63 together form alkylene, alkenylene, alkynylene, heteroalkylene; and (ii) optionally substituted alkyl;
R4 is selected from the group consisting of:
(a) hydrogen;
(b) halo;
(c) alkyl;
(d) alkoxy; and
(e) hydroxy;
or R3 and R4, which substitute adjacent atoms on a ring, together form alkylenedioxy, thioalkylenoxy or alkylenedithioxy;
R5 is selected from the group consisting of
(a) hydrogen;
(b) halo;
(C) alkyl;
(d) haloalkyl;
(e) thioalkyl;
(0 hydroxy;
(g) amino;
(h) alkylamino;
(i) dialkylamino;
(J) heteroalkyl;
(k) optionally substituted heterocycle; Case 50053A-HO 164
48
(1) optionally substituted heterocyclylalkyl;
(m) optionally substituted heterocyclylalkoxy;
(n) alkylsulfonyl;
(o) aminosulfonyl, mono-alkylaminosulfonyl or di- alkylaminosulfonyl;
(p) heteroalkoxy; and
(q) carboxy; and
R6 is selected from the group consisting of:
(a) hydrogen;
(b) halo;
(c) alkyl; and
(d) alkoxy.
2. Use according to claim 1, wherein the compound of formula A is also a a compound of formula IA, IB or IC respectively below:
Figure imgf000049_0001
I or a pharmaceutically acceptable derivative thereof, where:
R1 is hydrogen, acyl or -P(O)(OH)2;
R2 is hydrogen, halo, alkyl or alkylthio;
A is an aryl, heteroaryl or a heterocyclyl ring optionally fused to a phenyl ring, provided that the heterocyclyl ring is attached to the carbonyl group via a carbon ring atom;
B is an aryl or heteroaryl ring;
C is a 5-membered heteroaryl ring containing one or two heteroatoms in the ring; Case 50053 A-HO 164
49
D is heteroaryl, optionally substituted heteroaryl or -C(O)NR80R81, where R80 and R81 are independently hydrogen, alkyl, cycloalkyl, alkoxy, hydroxy, heteroaryl or optionally substituted heteroaryl;
R3 is selected from the group consisting of:
(a) amino, alkylamino or dialkylamino;
(b) acylamino;
(c) optionally substituted heterocydyl;
(d) optionally substituted aryl or heteroaryl;
(e) heteroalkyl;
(f) heteroalkenyl;
(g) heteroalkynyl; (h) heteroalkoxy;
(i) heteroalkylamino;
(j) optionally substituted heterocydylalkyl;
(k) optionally substituted heterocydylalkenyl;
(1) optionally substituted heterocyclylalkynyl;
(m) optionally substituted heterocyclylalkoxy or heterocyclyloxy;
(n) optionally substituted heterocyclylalkylamino;
(o) optionally substituted heterocyclylalkylcarbonyl;
(p) heteroalkylcarbonyl;
(q) -NHSOzR6 where R6 is alkyl, heteroalkyl or optionally substituted heterocydylalkyl;
(r) -NHSOzNR7R8 where R7 and R8 are, independently of each other, hydrogen, alkyl or heteroalkyl;
(s) -Y-(alkylene)-R9 where: Y is a single bond, -O-, -NH- or -S(O)n- (where n is an integer from 0 to 2); and R9 is halo, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocydyl, -COOH, -COR10, -COOR", -CONR12R13, -SO2R14, -SO2NR15R1*, -NHSO2R17 or -NHSOzNR18R1', where R10 is alkyl or optionally substituted heterocycle, R11 is alkyl, and R12, R13 , R14, R15, R16, R17, R18 and R19 are, independently of each other, hydrogen, alkyl or heteroalkyl;
(x) -Cf=NR20XNR21R22) where R20, R21 and R22 independently represent hydrogen, alkyl or hydroxy, or R20 and R21 together are -(CH2)n-where n is 2 or 3 and R22 is hydrogen or alkyl; Case 50053 A-HO 164
50
(u) -NHC(X)NR23R24 where X is -O- or -S-, and R23 and R24 are, independently of each other, hydrogen, alkyl or heteroalkyl;
(v) -CONR25R26 where R25 and R26 independently represent hydrogen, alkyl, heteroalkyl or optionally substituted heterocyclylalkyl, or R25 and R26 together with the nitrogen to which they are attached form an optionally substituted heterocyclyl ring;
(w) -S(O)nR27 where n is an integer from 0 to 2, and R27 is alkyl, heteroalkyl, optionally substituted heterocyclylalkyl or -NR28R29 where R28 and R29 are, independently of each other, hydrogen, alkyl or heteroalkyl;
(x) cydoalkylalkyl, cycloalkylalkynyl and cycloalkylalkynyl, all optionally substituted with alkyl, halo, hydroxy or amino;
(y) arylaminoalkylene or heteroarylaminoalkylene;
(z) Z-alkylene-NR30R31 or Z-alkylene-OR32 where Z is-NH-, -N(lower alkyl)- or -O-, and R30, R31and R32 are independently of each other, hydrogen, alkyl or heteroalkyl;
(aa) -OC(O)-alkylene-CO2H or -OC(O)-NR1R" (where R1 and R" are independently hydrogen or alkyl);
(bb) heteroarylalkenylene or heteroarylalkynylene;
(cc) hydrogen;
(dd) halo;
(ee) pseudohalo;
(ff) hydroxy;
(gg) optionally substituted alkoxy;
(hh) C(L)R40, where L is O, S or NR55; R40 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroarylium, optionally substituted cycloalkyl, optionally substituted heterocyclyl, C(L)RS6, halo pseudohalo, OR55, SR55, NR57R58 or SiR52R53R54; where R52, R53 and R54 are selected as in (i) or (ii) as follows (i) R52, R53 and R54 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR55 or NR62R63; or (ii) any two of R52, R53 and R54 together form alkylene, alkenylene, alkynylene, heteroalkylene; and the other is selected as in (i); R55 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl or heterocyclyl; R56 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR55 or NR64R65; where R64 and Case 50053A-HO 164
51
R65 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR66 or NR62R63, or R64 and R65 together form alkylene, alkenylene, alkynylene, heteroalkylene, where R66 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl or heterocyclyl; R57 and R58 are selected as in (i) or (ii) as follows (i) RS7 and R58 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR55, NR67R68 or C(L)R69, where R67 and R68 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl or heterocyclyl, or together form alkylene, alkenylene, alkynylene, heteroalkylene; and R69 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, OR70 or NR62R63, where R70 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl; or (ii) RS7 and R58 together form alkylene, alkenylene, alkynylene, heteroalkylene; R62 and R63 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroarylium, cycloalkyl, heterocyclyl, or R*2 and R63 together form alkylene, alkenylene, alkynylene, heteroalkylene; and (ii) optionally substituted alkyl;
R4 is selected from the group consisting of:
(a) hydrogen;
(b) halo;
(c) alkyl;
(d) alkoxy; and
(e) hydroxy;
R5 is selected from the group consisting of
(a) hydrogen;
(b) halo;
(C) alkyl;
(d) haloalkyl;
(e) thioalkyl;
(f) hydroxy;
(g) amino;
(h) alkylamino; Case 50053A-HO 164
52
U) dialkylamino;
(J) heteroalkyl;
(k) optionally substituted heterocycle;
(D optionally substituted heterocyclylalkyl;
M optionally substituted heterocyclylalkoxy;
(n) alkylsulfonyl;
(o) aminosulfonyl, mono-alkylaminosulfonyl or di-alkylamino-sulfonyl;
(P) heteroalkoxy; and
(q) carboxy; and
R6 is selected from the group consisting of:
(a) hydrogen;
(b) halo;
(c) alkyl; and
(d) alkoxy.
3. Use according to claim 1 or 2, wherein the compound of formula A is selected from the group consisting of:
5-amino-l-(4-fluorophenyl)-4-[3-(2-morpholin-4-ylethoxy)benzoyl]pyrazole, 5-amino-l-(2,4-difluoro-phenyl)-4-[3-(3-morpholin-4ylpropyl)benzoyl]pyrazole, 5-amino-4-(3-aminobenzoyl)-l-(4-fluorophenyI)pyrazole, 5-amino-l-(4-fluorophenyl)-4-[3-(3-morpholin-4-ylpropyl)benzoyl] pyrazole, 5-amino-4-[3-(2-aminosulfonylethenyl)benzoyl] -l-(4fluorophenyl)pyrazole, 5-amino-4-(3-acetylaminobenzoyl)-l-phenylpyrazole, 5-amino-4-[3-(2-aminoethyl)benzoyl]-l-(4-fluorophenyl)pyrazole, 5-amino-l-(4-fluorophenyl)-4-[3-(3-morpholin-4-ylpropylamino) benzoyl] pyrazole, 5-amino-4-[3-(2-aminosulfonylethyl)benzoyl]-l-(4-fluorophenyl)pyrazole, 5-amino-l-(4-fluorophenyl)-4-(3-pyridin-3-ylbenzoyl)pyrazole, 5-amino-l-(2-methylphenyl)-4-[3-pyridin-3-yl)benzoyl]pyrazole, 5-amino-l-(2-methylphenyl)-4-[3-(N-oxidopyridin-3-yl)benzoyl]pyrazole, 5-amino-4-[3-(2,3-dihydroxypropoxy)benzoyl]-l-(4-fluorophenyl) pyrazole, 5-amino-4-[3-(l,2-dihydroxyethyl)benzoyl]-l-(4-fluorophenyl) pyrazole, 5-amino-I-(4-fluorophenyl)-4-[3-(sulfamoylbenzoyl] pyrazole, 5-amino-l-(4-fluoro-phenyl)-4-[3-(3-hydroxy-3-methylbutyl) benzoyl]pyrazole, 5-amino-l-(4-fluorophenyl)-4-[3-(2-(l-hydroxycyclopentyl)ethyI) benzoyl]pyrazole, 5-amino-4-[3-(2-methylsulfonylethyl)-benzoyl]-l-(4-fluorophenyl) pyrazole, Case 50053A-HO 164
53
5-amino-l-(2,4-difluorophenyl)-4-[3-(2-hydroxyethylsulfonyl) benzoyljpyrazole,
3-[5-amino-4-(3-iodo-benzoyl)-pyrazoI-l-yl]-N-methoxy-4-methyl-benzamide,
3-(5-amino-4-benzoyl-pyrazol-l-yl)-N-methoxy-4-rnethyl-benzamide,
3-(5-amino-4-benzoyl-pyrazol-l-yl)-4-methyl-benzoic acid,
3-(5-amino-4-benzoyI-pyrazol-l-yI)-N-cyclopropyl-4-methyl-benzamide,
3-[5-amino-4-(3-iodo-benzoyl)-pyrazoI-l-yl]-4-methyl-benzoic acid,
3-[5-amino-4-(3-iodo-benzoyI)-pyrazol-l-yl]-N-cyclopropyl-4-methyl-benzamide,
{5-amino-l-[2-methyl-5-(4H-[l,2,4]triazol-3-yl)-phenyl]-lH-pyrazol-4-yl}-phenyl-methanone,
3-[5-amino-4-(3-[l,3]dioxolan-2-yl-benzoyl)-pyrazol-l-yl]-N-cyclopropyl-4-methyl- benzamide,
3-[5-amino-4-(3-formyl-benzoyl)-pyrazol-l-yl]-N-cyclopropyl-4-methyl-benzamide,
3-[5-amino-4-(3-hydroxymethyl-benzoyl)-pyrazoI-l-yl]-N-cyclopropyl-4-methyl-benzamide,
3-{5-amino-4-[3-(4-methyl-piperazin-l-ylmethyI)-benzoyl]-pyrazol-l-yl}-N-cyclopropyl-4- methyl-benzamide,
3-[5-amino-4-(3-morpholin-4-ylmethyI-benzoyl)-pyrazol-l-yl]-N-cyclopropyl-4-methyI- benzamide,
3-[5-amino-4-(3-morpholin-4-ylmethyl-benzoyl)-pyrazol-l-yl]-N-cycIopropyl-4-methyl- benzamide,
3-[5-amino-4-(3-benzyloxy-benzoyl)-pyrazol-l-yl]-N-cyclopropyl-4-methyl-benzamide,
3-[5-amino-4-(3-hydroxy-benzoyl)-pyrazol-l-yl]-N-cyclopropyl-4-methyl-benzamide,
3-[5-amino-4-(4-methyl-benzoyl)-pyrazol-l-yl]-N-cyclopropyl-4-methyl-benzamide,
3-(5-amino-4-benzoyi-imidazol-l-yl)-N-cycIopropyl-4-methyl-benzamide,
3-[5-amino-4-(3-iodo-benzoyl)-pyrazol-l-yl]-N-methoxy-4-methyl-benzamide,
3-(5-amino-4-benzoyl-pyrazol-l-yl)-N-methoxy-4-methyl-benzamide,
3-(5-amino-4-benzoyI-pyrazoI-l-yl)-N-cyclopropyI-4-methyl-benzamide,
3-[5-amino-4-(3-iodo-benzoyl)-pyrazol-l-yl]-N-cyclopropyl-4-methyl-benzamide,
{5-amino-l-[2-methyl-5-(4H-[l,2,4]triazol-3-yl)-phenyl]-lH-pyrazol-4-yl}-phenyl-methanone,
3-[5-amino-4-(3-[l,3]dioxolan-2-yl-benzoyl)-pyrazol-l-yl]-N-cycIopropyl-4-methyl- benzamide,
3-[5-amino-4-(3-formyl-benzoyl)-pyrazol-l-yI]-N-cycIopropyl-4-methyl-benzainide,
3-[5-amino-4-(3-hydroxymethyl-benzoyI)-pyrazol-l-yl]-N-cyclopropyl-4-methyl-benzamide,
3-{5-amino-4-[3-(4-methyl-piperazin-l-ylmethyl)-benzoyl]-pyrazol-l-yl}-N-cyclopropyl-4- methyl-benzamide,
3-[5-amino-4-(3-morpholin-4-ylmethyl-benzoyl)-pyrazol-l-yl]-N-cyclopropyl-4-methyl- benzamide, Case 50053 A-HO 164
54
3-[5-amino-4-(3-morpholin-4-ylmethyl-benzoyl)-pyrazol-l-yl]-N-cyclopropyl-4-methyl- benzamide,
3-[5-amino-4-(3-benzyloxy-benzoyI)-pyrazol-l-yl]-N-cyclopropyl-4-methyl-benzamide,
3-[5-amino-4-(3-hydroxy-benzoyl)-pyrazol-l-yl]-N-cyclopropyl-4-methyl-benzamide,
3-[5-amino-4-(4-methyl-benzoyl)-pyrazol-l-yl]-N-cyclopropyl-4-methyl-benzamide,
3-(5-amino-4-benzoyl-imidazol-l-yl)-N-cyclopropyl-4-methyl-benzamide,
3-{5-Amino-4-[3-(2-dimethylamino-ethylcarbamoyl)-benzoyl]-imidazol-l-yl}-N-cyclopropyl-
4-methyl-benzamide,
3-[5-Amino-4-(5-ch!oro-thiopheπe-2-carbonyl)-imidazol-l-yl]-N-cyclopropyl-4-methyl- benzamide,
3-[5-Amino-4-(3-hydrazinocarbonyl-benzoyl)-imidazol-l-yl]-N-cyclopropyl-4-methyl- benzamide,
3-(5-Amino-4-cyclohexanecarbonyl-imidazol-l-yl)-N-cyclopropyl-4-methyl-benzamide,
3-(5-Amino-4-cyclopentanecarbonyl-imidazol-l-yl)-N-cyclopropyI-4-methyl-benzamide,
S-IS-Amino^-phenylacetyl-imidazol-l-ylJ-N-cyclopropyl^-methyl-benzamide,
3-[5-Amino-4-(tetrahydro-pyran-4-carbonyl)-imidazol-l-yl]-N-cyclopropyl-4-methyl- benzamide,
3-[5-Amino-4-(3-ethyIcarbamoyl-benzoyl)-imidazoH-yl]-N-cyclopropyl-4-methyl- benzamide,
3-[5-Amino-4-(3-isopropylcarbamoyl-benzoyl)-imidazol-l-yl]-N-cycIopropyl-4-methyl- benzamide,
5-Amino-l-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-methyl-lH-pyrazole-4-carboxylic acid ethyl ester,
5-Amino-l-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-lH-pyrazole-4-carboxylic acid ethyl ester,
3-(5-Amino-4-cyclopentanecarbonyl-pyrazol-l-yl)-N-cyclopropyl-4-methyl-benzamide,
3-[5-Amino-4-(3-hydrazinocarbonyl-benzoyl)-pyrazol-l-yl]-N-cyclopropyl-4-methyl- benzamide,
5-Amino-l-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-lH-pyrazole-4-carboxylic acid benzylamide,
3-(5-Amino-4-cyclohexanecarboπyl-pyrazol-l-yl)-N-cyclopropyl-4-methyl-benzamide,
5-Amino-l-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-lH-pyrazole-4-carboxylic acid cyclohexylamide,
S-Amino-l-fS-cyclopropylcarbamoyl^-methyl-phenyO-S-methylsulfanyl-lH-pyrazole^- carboxylic acid amide, Case 50053 A-HO 164
55
5-Atnino-l-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-methanesulfonyl-lH-pyrazole-4- carboxylic acid amide,
S-Amino-l-IS-cyclopropylcarbamoyl-Z-methyl-phenylJ-S-methylsulfanyl-lH-pyrazole^- carboxylic acid ethyl ester,
5-Amino-3-[(3-chloro-benzylcarbamoyl)-methoxy]-l-(5-cyclopropylcarbamoyl-2-methyl- phenyI)-lH-pyrazole-4-carboxylic acid ethyl ester,
3-[5-Amino-4-benzoyl-3-(piperidin-4-yloxy)-pyrazol-l-yl]-N-cyclopropyl-4-methyl- benzamide,
3-(5-Amino-4-benzoyl-3-methanesulfonyl-pyrazoI-l-yl)-N-cyclopropyl-4-methyl-benzamide,
3-(5-Amino-4-benzoyl-3-methoxy-pyrazol-l-yI)-N-cyclopropyl-4-methyl-benzamide,
5-Amino-l-(5-cyclopropylcarbamoyl-2-methyi-phenyl)-3-(2-hydroxy-ethoxy)-lH-pyrazole-4- carboxylic acid ethyl ester,
4-[5-Amino-4-benzoyl-l-(5-cyclopropylcarbamoyI-2-methyl-phenyl)-lH-pyrazol-3-yloxy]- piperidine-1-carboxylic acid tert-butyl ester,
3-(5-Amino-4-benzoyl-3-methylsulfanyl-pyrazol-l-yl)-N-cyclopropyl-4-methyl-benzamide,
3-[5-Amino-4-benzoyl-3-(2-methoxy-ethoxy)-pyrazol-l-yl]-N-cyclopropyI-4-methyl- benzamide,
3-[5-Arnino-4-(3-iodo-benzoyl)-pyrazol-l-yl]-N-methoxy-4-methyl-benzamide,
3-(5-Amino-4-benzoyl-pyrazol-l-yl)-N-methoxy-4-methyl-benzamide,
3-(5-amino-4-benzoyl-pyrazol-l-yl)-4-methyl-benzoic acid,
3-(5-amino-4-benzoyl-pyrazol-l-yl)-N-cyclopropyl-4-methyl-benzamide,
3-t5-amino-4-(3-iodo-benzoyl)-pyrazol-l-yl]-4-methyl-benzoic acid,
3-[5-amino-4-(3-iodo-benzoyl)-pyrazol-l-yl]-N-cyclopropyl-4-methyl-benzamide,
{5-amino-l-[2-methyl-5-(4H-[l,2,4]triazol-3-yl)-phenyl]-lH-pyrazol-4-yl}-phenyl-methanone,
S-^-amino^-JS-fl^Jdioxolan^-yl-benzoylJ-pyrazol-l-yll-N-cyclopropyM-methyl- benzamide,
3-[5-amino-4-(3-formyl-benzoyl)φyrazol-l-yl]-N-cyclopropyl-4-methyl-benzamide,
3-[5-amino-4-(3-hydroxymethyl-benzoyl)-pyrazol-l-yl]-N-cyclopropyl-4-methyl-benzamide,
3-{5-amino-4-f3-(4-methyl-piperazin-l-ylmethyl)-benzoyl]-pyrazol-l-yl}-N-cyclopropyl-4- methyl-benzamide,
3-[5-amino-4-(3-morpholin-4-ylmethyl-benzoyl)-pyrazol-l-yl]-N-cyclopropyl-4-πiethyl- benzamide,
3-{5-Amino-4-[3-(2-morpholin-4-yl-ethoxy)-benzoyl]-pyrazol-l-yl}-N-cyclopropyl-4-methyl- benzamide,
3-[5-amino-4-(3-benzyloxy-benzoyl)-pyrazol-l-yl]-N-cyclopropyl-4-methyl-benzamide,
3-[5-amino-4-(3-hydroxy-benzoyl)-pyrazol-l-yl]-N-cyclopropyl-4-methyl-benzamide, Case 50053 A-HO 164
56
3-[5-amino-4-(4-methyl-benzoyl)-pyrazol-l-yl]-N-cyclopropyl-4-methyl-benzamide,
3-(5-amino-4-benzoyl-imidazol-l-yl)-N-cyclopropyl-4-methyI-benzamide,
3-(5-Amino-4-cyclohexanecarbonyl-imidazol-l-yl)-N-cyclopropyl-4-methyl-benzamide,
3-(5-Amino-4-cyclopentanecarbonyl-imidazol-l-yl)-N-cyclopropyl-4-methyl-benzamide,
3-(5-Amino-4-phenylacetyl-imidazol-l-yI)-N-cyclopropyl-4-methyl-benzamide,
3-(5-Amino-4-(3-isopropylcarbamoyl-benzoyl)-imidazol-l-yl]-N-cyclopropyl-4-methyl- benzamide,
3-{5-Amino-4-[3-(2-dimethylamino-ethylcarbamoyl)-benzoyl]-imidazol-l-yl}-N-cyclopropyl-
4-methyl-benzamide,
3-[5-Amino-4-(3-ethylcarbamoyl-benzoyl)-imidazol-l-yl]-N-cyclopropyl-4-methyl- benzamide,
3-[5-Amino-4-(3-methylcarbamoyl-benzoyI)-imidazol-l-yl]-N-cyclopropyl-4-methyl- beπzamide,
3-[5-Amino-4-(3-cyclopropylcarbamoyl-benzoyl)-imidazol-l-yl]-N-cyclopropyl-4-methyl- beπzamide,
3-[5-Amino-4-(3-cyclopentyIcarbamoyl-benzoyl)-imidazol-l-yl]-N-cyclopropyl-4-methyl- benzamide,
3-{5-Amino-4-[3-(morpholine-4-carbonyl)-benzoyI]-imidazol-l-yl}-N-cyclopropyI-4-methyl- benzamide,
3-(5-Amino-4-[3-(cyclopropylmethyl-carbamoyl)-benzoyl]-iniidazol-l-yl}-N-cyclopropyl-4- methyl-benzamide,
3-[5-Amino-4-(tetrahydro-pyran-4-carbonyl)-imidazol-l-yl]-N-cyclopropyl-4-methyl- benzamide,
3-(5-amino-4-benzoyl-3-methoxy-pyrazol-l-yl)-N-cyclopropyl-4-methyl-benzamide,
3-(5-amino-4-benzoyl-3-ethoxy-pyrazol-l-yl)-N-cyclopropyl-4-methyl-benzamide,
3-[5-amino-4-benzoyl-3-(2-methoxy-ethoxy)-pyrazol-l-yl]-N-cyclopropyl-4-methyI- benzamide,
3-[5-amino-4-benzoyl-3-(2-benzyloxy-ethoxy)-pyrazol-l-yl]-N-cyclopropyl-4-methyl- benzamide,
4-[5-amino-4-benzoyl-l-(5-cycIopropylcarbamoyl-2-methyl-phenyl)-lH-pyrazol-3-yloxy]- piperidine-1-carboxylic acid tert-butyl ester,
3-[5-amino-4-benzoyl-3-(piperidin-4-yloxy)-pyrazol-l-yl}-N-cyclopropyl-4-πiethyl-benzamide trifluoroacetate salt,
3-(5-amino-4-benzoyl-3-methylsulfanyl-pyrazol-l-yl)-N-cyclopropyl-4-methyl-benzamide,
3-(5-amino-4-benzoyl-3-methanesulfonyl-pyrazol-l-yl)-N-cydopropyl-4-methyl-benzamide, Case 50053 A-HO 164
57
S-amino-l-fS-cyclopropylcarbamoyl-Z-methyl-phenyl^-methylsulfanyl-lH-pyrazole^- carboxylic acid amide,
J-amino-l-IS-cyclopropylcarbamoyl-l-methyl-phenylJ-S-methanesulfonyl-lH-pyrazole-^ carboxylic acid amide, and
5-amino-l-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-3-methylsulfanyl-lH-pyrazole-4- carboxylic acid ethyl ester.
4. Use according to any preceding claim, wherein the compound of formula A is 3-[5- Amino-4-(3-cyanobenzoyl)-pyrazol-l -yl]-N-cyclopropyl-4-methylbenzamide or a pharmaceutically acceptable derivative thereof.
5. Use according to any one of claims 1 to 4, in combination with a second active agent selected from the group consisting of antiinflammatories, bronchodilators, antihistamines, decongestants, anti-tussives, anticoagulants, diuretics, cardiac glycosides, calcium channel blockers, vasodilators, prostacyclin analogues, endothelin antagonists, phosphodiesterase inhibitors, endopeptidase inhibitors, lipid lowering agents and thromboxane inhibitors.
6. Use according to any one of claims 1 to 5, in which the pulmonary hypertension is primary pulmonary hypertension.
7. Use according to any one of claim 1 to 5, in which the pulmonary hypertension is associated with chronic obstructive pulmonary disease.
8. The use of 3-[5-Amino-4-(3-cyanobenzoyl)-pyrazol-l-yl]-N-cyclopropyl-4-methyl- benzamide or a pharmaceutically acceptable derivative thereof for the manufacture of a medicament for the treatment of primary pulmonary hypertension.
9. The use of S-tS-Amino^-β-cyanobenzoyO-pyrazol-l-ylJ-N-cyclopropyM-methyl- benzamide or a pharmaceutically acceptable derivative thereof for the manufacture of a medicament for the treatment of primary pulmonary hypertension associated with chronic obstructive pulmonary disease.
PCT/EP2007/001508 2006-02-23 2007-02-21 Inhibitors of p38-kinase for treatment of pulmonary hypertension WO2007096151A2 (en)

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