WO2005103010A2 - Pyrazole derivatives useful for the treatment of cancer - Google Patents

Pyrazole derivatives useful for the treatment of cancer Download PDF

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Publication number
WO2005103010A2
WO2005103010A2 PCT/GB2005/001512 GB2005001512W WO2005103010A2 WO 2005103010 A2 WO2005103010 A2 WO 2005103010A2 GB 2005001512 W GB2005001512 W GB 2005001512W WO 2005103010 A2 WO2005103010 A2 WO 2005103010A2
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Prior art keywords
formula
cancer
alkyl
compound
pharmaceutically acceptable
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PCT/GB2005/001512
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French (fr)
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WO2005103010A3 (en
Inventor
Paul Lyne
Bin Wang
Tao Wang
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Astrazeneca Ab
Astrazeneca Uk Limited
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Priority to EP05735572A priority Critical patent/EP1742921A2/en
Priority to JP2007508966A priority patent/JP2007533717A/en
Priority to US11/568,082 priority patent/US20090227648A1/en
Publication of WO2005103010A2 publication Critical patent/WO2005103010A2/en
Publication of WO2005103010A3 publication Critical patent/WO2005103010A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms

Definitions

  • the present invention relates to novel pyrazole derivatives, their pharmaceutical compositions and metliods of use.
  • the present invention relates to therapeutic methods for the treatment and prevention of cancers and to the use of these pyrazole derivatives in the manufacture of medicaments for use in the treatment and prevention of cancers.
  • RTK's Receptor tyrosine kinases
  • Trk's tropomyosin-related kinases
  • Trk's are the high affinity receptors activated by a group of soluble growth factors called neurotrophins (NT).
  • the Trk receptor family has three members - TrkA, TrkB and TrkC.
  • NTs nerve growth factor
  • TrkA nerve growth factor
  • TrkB brain-derived growth factor
  • TrkC neurotrophins
  • BDNF brain-derived growth factor
  • TrkC NT3 which activates TrkC.
  • Each Trk receptor contains an extra-cellular domain (ligand binding), a trans-membrane region and an intra-cellular domain (including kinase domain). Upon binding ofthe ligand, the kinase catalyzes auto-phosphorylation and triggers downstream signal transduction pathways.
  • Trk's are widely expressed in neuronal tissue during its development where Trk's are critical for the maintenance and survival of these cells.
  • Trk's play important role in both development and function ofthe nervous system (Patapoutian, A. et al Current Opinion in Neurobiology, 2001, 11, 272-280).
  • Trk's are expressed at low levels outside the nervous system in the adult, Trk expression is increased in late stage prostate cancers.
  • Trk inhibitors may yield a class of apoptosis-inducing agents specific for androgen- independent prostate cancer (Weeraratna, A. T. et al The Prostate, 2000, 45, 140-148).
  • Trk's are associated with secretory breast carcinoma (Cancer Cell, 2002, 2, 367-376), colorectal cancer (Bardelli et al Science, 2003, 300, 949-949) and ovarian cancer (Davidson, B. et al Clinical Cancer Research, 2003, 9, 2248-2259).
  • Trk tyrosine kinase inhibitors Cephalon described CEP-751, CEP-701 (George, D. et al Cancer Research, 1999, 59, 2395-2341) and other indolocarbazole analogues (WOOl 14380) as Trk inhibitors.
  • CEP-701 and/or CEP751 when combined with surgically or chemically induced androgen ablation, offered better efficacy compared with mono-therapy alone.
  • GlaxoSmithKline disclosed certain oxindole compounds as TrkA inhibitors in WO0220479 and WO0220513.
  • Japan Tobacco reported pyrazolyl condensed cyclic compounds as Trk inhibitors (JP2003231687A).
  • Vertex Pharmaceuticals have described pyrazole compounds as inhibitors of GSK3, Aurora, etc. in WO0250065, WO0262789 and WO03027111; and AstraZeneca have reported pyrazole compounds as inhibitors against IGF-1 receptor kinase (WO0348133).
  • novel pyrazole compounds, or pharmaceutically acceptable salts thereof which possess Trk kinase inhibitory activity and are accordingly useful for their anti-proliferation and/or proapoptotic (such as anti-cancer) activity and in methods of treatment ofthe human or animal body.
  • the invention also relates to processes for the manufacture of said pyrazole compounds, or pharmaceutically acceptable salts thereof, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments for use in the production of an anti-proliferation and/or proapoptotic effect in warm-blooded animals such as man.
  • the applicants provide methods of using such pyrazole compounds, or pharmaceutically acceptable salts thereof, in the treatment of cancer.
  • the properties ofthe compounds claimed in this invention are expected to be of value in the treatment of disease states associated with cell proliferation such as cancers (solid tumours and leukaemia), fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation.
  • cancers solid tumours and leukaemia
  • fibroproliferative and differentiative disorders such as cancers (solid tumours and leukaemia), fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic ne
  • the compounds, or pharmaceutically acceptable salts thereof, ofthe invention are expected to be of value in the treatment or prophylaxis of cancers selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, ewings tumour, neuroblastoma, kaposis sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, renal cancer, lymphoma and leukaemia; particularly ovarian cancer, breast cancer, colorectal cancer, prostate cancer and lung cancer - NSCLC and SCLC; more particularly prostate cancer; and more particularly hormone refractory prostate cancer.
  • cancers selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, ewings tumour, neuroblastoma, kaposis s
  • A is a direct bond or C ⁇ - 2 alkylene; wherein said C ⁇ . 2 alkylene may be optionally substituted by one or more R 22 ;
  • Ring C is carbocyclyl or heterocyclyl;
  • R 1 and R 4 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C ⁇ - 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 lkynyl, Ci- ⁇ alkoxy, C ⁇ - 6 alkanoyl, C ⁇ - 6 alkanoyloxy, N-(C ⁇ - 6 alkyl)amino, N,N-(C ⁇ - 6 alkyl) 2 amino, C ⁇ - 6 alkanoylamino, N-(C ⁇ - 6 alkyl)carbamoyl,
  • R may be optionally substituted on carbon by one or more R ; and wherein if said heterocyclyl contains an - ⁇ H- moiety that nitrogen may be optionally substituted by a group selected from R 11 ; R 3 is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci- ⁇ alkyl, C 2 . 6 alkenyl, C . 6 alkynyl, C ⁇ - 6 alkoxy,
  • R 6 independently of each other may be optionally substituted on carbon by one or more R 15 ; and wherein if said heterocyclyl contains an - ⁇ H- moiety that nitrogen may be optionally substituted by a group selected from R 16 ; or two adjacent R 6 groups together with the phenyl bond to which they are attached form a 5 or 6 membered carbocyclic ring or heterocyclic ring wherein said ring is fused to the phenyl of formula (I); and wherein said carbocyclic ring or heterocyclic ring may be optionally substituted on carbon by one or more R 17 ; and wherein if said heterocyclic ring contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R 18 ; n is 0, 1, 2 or 3; wherein the values of R 3 may be the same or different; m is 0-4; wherein the values of R 6 may be the same or different; R 8 , R 10 , R 12 , R 14 , R 15 , R 17 and
  • R is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbony
  • A is a direct bond.
  • A is C ⁇ - 2 alkylene.
  • A is C ⁇ - 2 alkylene; wherein said C ⁇ - 2 alkylene may be optionally substituted by one or more R .
  • Ring C is carbocyclyl.
  • Ring C is heterocyclyl.
  • Ring C is phenyl or pyridyl.
  • Ring C is phenyl.
  • R 1 and R 4 are independently selected from hydrogen and carbocyclyl.
  • R 1 and R 4 are independently selected from hydrogen and cyclopropyl.
  • R 1 and R 4 are independently selected from hydrogen, C ⁇ - 6 alkyl, d- 6 alkoxy and carbocyclyl.
  • R 1 and R 4 are independently selected from hydrogen, t-butyl, isopropoxy and cyclopropyl.
  • R 4 is hydrogen.
  • R 1 is cyclopropyl.
  • R 1 is selected from C ⁇ - 6 alkyl, C ⁇ . 6 alkoxy and carbocyclyl.
  • R 1 is selected from t-butyl, isopropoxy and cyclopropyl.
  • R 2 is selected from hydrogen or Ci- ⁇ alkyl; wherein R 2 may be optionally substituted on carbon by one or more R 10 .
  • 9 9 R is selected from hydrogen or C ⁇ - 6 alkyl; wherein R may be optionally substituted on carbon by one or more R 10 ; wherein R 10 is hydroxy.
  • R 9 is selected from hydrogen or methyl; wherein R 1 may be optionally substituted on carbon by one or more R 10 .
  • 9 9 R is selected from hydrogen or methyl; wherein R may be optionally substituted on carbon by one or more R 10 ; wherein R 10 is hydroxy.
  • R 2 is selected from hydrogen, methyl or hydroxymethyl.
  • R 2 is selected from hydrogen or hydroxymethyl.
  • R 3 is halo.
  • R 3 is fluoro.
  • R 5 is hydrogen.
  • R 6 is halo.
  • R 6 is chloro.
  • R 6 is independently selected from halo, nitro, cyano, amino and N-(C ⁇ - 6 alkyl)amino; wherein R 6 independently of each other may be optionally substituted on carbon by one or more R 15 ; wherein R 15 is selected from hydroxy.
  • R 6 is independently selected from fluoro, chloro, nitro, cyano, amino and ethylamino; wherein R 6 independently of each other may be optionally substituted on carbon by one or more R 15 ; wherein R 15 is selected from hydroxy.
  • R 6 is independently selected from fluoro, chloro, nitro, cyano, amino and 2-hydroxy ethylamino.
  • n is O or 1.
  • n 0.
  • n is 1.
  • m is 0 or 1.
  • m is 0.
  • m is 1. m is 2; wherein the values of R 6 may be the same or different. m is 3; wherein the values of R 6 may be the same or different. m is 0-3; wherein the values of R 6 may be the same or different. Therefore in a further aspect of the invention there is provided a compound of formula (I) (as depicted herein above) wherein: A is a direct bond; Ring C is carbocyclyl; R 1 and R 4 are independently selected from hydrogen and carbocyclyl; R 2 is selected from hydrogen or C ⁇ - 6 alkyl; wherein R 2 may be optionally substituted on carbon by one or more R 10 ; wherein R 10 is hydroxy; R 3 is halo; R 5 is hydrogen; R 6 is halo; n is 1; m is 0 or 1; or a pharmaceutically acceptable salt thereof. Therefore in a further aspect ofthe invention there is provided a compound of formula (I) (as depicted herein above) wherein: A is a direct bond; Ring
  • R 1 and R 4 are independently selected from hydrogen, C ⁇ - 6 alkyl, C ⁇ - 6 alkoxy and carbocyclyl;
  • R 2 is selected from hydrogen or C ⁇ - 6 alkyl; wherein R 2 may be optionally substituted on carbon by one or more R 10 ;
  • R 3 is halo;
  • R 5 is hydrogen;
  • R 6 is independently selected from halo, nitro, cyano, amino and N-(C ⁇ - 6 alkyl)amino; wherein R 6 independently of each other may be optionally substituted on carbon by one or more R 15 ;
  • n is 1;
  • m is 0-3; wherein the values of R 6 may be the same or different;
  • R 10 is hydroxy;
  • R 15 is selected from hydroxy; or a pharmaceutically acceptable salt thereof.
  • a compound of formula (I) (as depicted herein above) wherein: A is a direct bond; Ring C is phenyl; R 4 is hydrogen; R 1 is cyclopropyl; R 2 is selected from hydrogen or hydroxymethyl; R is fluoro; R 5 is hydrogen; R 6 is chloro; n is 1; m is 0 or 1; or a pharmaceutically acceptable salt thereof.
  • a compound of formula (I) (as depicted herein above) wherein: A is a direct bond; Ring C is phenyl; R 1 is selected from t-butyl, isopropoxy and cyclopropyl; R is selected from hydrogen, methyl or hydroxymethyl; R 3 is fluoro; R 4 is hydrogen; R 5 is hydrogen; R 6 is independently selected from fluoro, chloro, nitro, cyano, amino and 2-hydroxyethylamino; n is i; m is 0-3; wherein the values of R 6 may be the same or different; or a pharmaceutically acceptable salt thereof.
  • preferred compounds ofthe invention are any one ofthe Examples or a pharmaceutically acceptable salt thereof.
  • preferred compounds ofthe invention are any one of Examples 3, 9, 10, 13, 14 or 17 or a pharmaceutically acceptable salt thereof.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof which is a compound ofthe formula (la): da) wherein R a is amino or nitro and the other groups are as defined hereinabove.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof which is a compound ofthe formula (lb):
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the inhibition of Trk activity.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the treatment or prophylaxis of cancer.
  • the present invention provides a compound ofthe formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the treatment of cancer in a warm-blooded animal such as man.
  • the present invention provides a compound ofthe formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the treatment or prophylaxis of cancers (solid tumors and leukemia), fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis,, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation in a warm-blooded animal such as man.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the production of an anti-proliferative effect.
  • the present invention provides a method of inhibiting Trk activity comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method for the treatment of cancer comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method for the treatment or prophylaxis of cancer comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method for the treatment or prophylaxis of cancers (solid tumours and leukaemia), fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation in a warm-blooded animal such as man comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of producing an anti-proliferative effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, diluent or excipient for use in the inhibition of Trk activity.
  • the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, diluent or excipient for use in the treatment of cancer.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, diluent or excipient for use in the treatment or prophylaxis of cancer.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, diluent or excipient for use in the treatment or prophylaxis of cancers (solid tumours and leukaemia), fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation.
  • cancers solid tumours and leukaemia
  • fibroproliferative and differentiative disorders psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, diluent or excipient for use in the production of an anti-proliferative effect in a warm-blooded animal such as man.
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the inhibition of Trk activity.
  • the present invention provides a compound of formula
  • the present invention provides a compound ofthe formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in a warm-blooded animal such as man.
  • the present invention provides a compound ofthe formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of cancers (solid tumours and leukaemia), fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation in a warm-blooded animal such as man.
  • cancers solid tumours and leukaemia
  • fibroproliferative and differentiative disorders psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the production of an anti- proliferative effect.
  • Trk activity is referred to particularly this refers to the inhibition of TrkB activity.
  • the treatment (or prophylaxis) of cancer is referred to, particularly it refers to the treatment (or prophylaxis) of oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, ewings tumour, neuroblastoma, kaposis sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, renal cancer, lymphoma, leukaemia, tumours ofthe central and peripheral nervous system, melanoma, f ⁇ brosarcoma and osteosarcoma.
  • NSCLC non small cell lung cancer
  • SCLC small cell lung cancer
  • a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof which process (wherein variable groups are, unless otherwise specified, as defined in formula (I)) comprises of: Process a) reaction of a compound of formula (II): (II) wherein Pg is a nitrogen protecting group; with a compound of formula (III):
  • L is a displaceable group
  • Pg is a nitrogen protecting group
  • Process b) Compounds of formula (II) and (TV) may be reacted together under epoxide ring opening reaction conditions for example in the presence of a suitable catalyst such as LiClO 4 , NaClO 4 , Mg(ClO ) 2 and a suitable solvent such as CH 3 CN and at a temperature in the range
  • a suitable catalyst such as LiClO 4 , NaClO 4 , Mg(ClO ) 2 and a suitable solvent such as CH 3 CN
  • Process c) The s reaction may be carried out in a suitable solvent, for example, an alcohol such as ethanol or butanol at a temperature in the range from 50-120°C, in particular in the range from 70-100°C.
  • Compounds ofthe formula (V) may be prepared according to Scheme 2:
  • aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group.
  • modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.
  • a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
  • alkyl includes both straight and branched chain alkyl groups but references to individual alkyl groups such as “propyl” are specific for the straight chain version only.
  • C ⁇ - 6 alkyl and C ⁇ - 4 alkyl include methyl, ethyl, propyl, isopropyl and t-butyl.
  • references to individual alkyl groups such as 'propyl' are specific for the straight-chained version only and references to individual branched chain alkyl groups such as 'isopropyl' are specific for the branched-chain version only.
  • a similar convention applies to other radicals.
  • halo refers to fluoro, chloro, bromo and iodo.
  • a “heterocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 4-12 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH 2 - group can optionally be replaced by a -C(O)-, and a ring sulphur atom may be optionally oxidised to form the S-oxides.
  • heterocyclyl examples and suitable values ofthe term "heterocyclyl” are morpholino, piperidyl, pyridyl, pyranyl, pyrrolyl, isothiazolyl, indolyl, quinolyl, thienyl, 1,3-benzodioxolyl, thiadiazolyl, piperazinyl, thiazolidinyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, tetrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl, N-methylpyrrolyl, 4-pyridone, 1-isoquinolone, 2-pyrrolidone, 4-thiazolidone, pyridine-N-oxide and quinoline-N-oxide.
  • heterocyclyl is morpholino, piperazinyl and pyrrolidinyl.
  • a “heterocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 5 or 6 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, it may, unless otherwise specified, be carbon or nitrogen linked, a -CH 2 - group can optionally be replaced by a -C(O)-and a ring sulphur atom may be optionally oxidised to form the S-oxides.
  • a “carbocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic carbon ring that contains 3-12 atoms; wherein a -CH 2 - group can optionally be replaced by a -C(O)-. Particularly “carbocyclyl” is a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms.
  • Suitable values for "carbocyclyl” include cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or 1-oxoindanyl.
  • two adjacent R 6 groups together with the phenyl bond to which they are attached form a 5 or 6 membered carbocyclic ring or heterocyclic ring said ring is a partially saturated or unsaturated, mono or bicyclic carbon ring that contains 5 or 6 atoms two atoms of which are shared with the phenyl ring of formula (I); of which at least one atom is chosen from nitrogen, sulphur or oxygen; wherein a -CH 2 - group can optionally be replaced by a -C(O)-, and a ring sulphur atom may be optionally oxidized to form the S-oxides.
  • Said ring is fused to the phenyl ring of formula (I) to make a 9 or 10 membered bicyclic ring.
  • Suitable values for "two adjacent R 6 groups together with the phenyl bond to which they are attached form a 5 or 6 membered carbocyclic ring or heterocyclic ring" are naphthyl, quinolionyl and quinazolinyl, indole, isoindole, 3H-indole, indoline, benzofuran, benzothiophene, 1H- indazole, benzimidazole, benzthiazole, isoquinoline, cinnoline, phthalazine and quinoxaline.
  • C m - n or "C m - n group” used alone or as a prefix, refers to any group having m to n carbon atoms.
  • optionally substituted refers to either groups, structures, or molecules that are substituted and those that are not substituted.
  • An example of "C ⁇ - 6 alkanoyloxy” is acetoxy.
  • Examples of "C ⁇ - 6 alkoxycarbonyl” include C ⁇ - 4 alkoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl.
  • Examples of "d- ⁇ alkoxy” include C ⁇ - 4 alkoxy, C ⁇ - 3 alkoxy, methoxy, ethoxy and propoxy.
  • Examples of "Q- ⁇ alkoxyimino” include C M alkoxyimino, C ⁇ - 3 alkoxyimino, methoxyimino, ethoxyimino and propoxyimino.
  • Examples of “Q-ealkanoylamino” include formamido, acetamido and propionylamino.
  • Examples of "C 1 - 6 alkylS(O) a wherein a is 0 to 2” include C ⁇ - alkylsulphonyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl.
  • C ⁇ - 6 alkylthio examples include methylthio and ethylthio.
  • C ⁇ - 6 alkylsulphonylamino include methylsulphonylamino and ethylsulphsulphonylamino.
  • C ⁇ - 6 alkanoyl examples include propionyl and acetyl.
  • N-(C ⁇ -6alkyl)amino examples include methylamino and ethylamino.
  • N,N-(C ⁇ - 6 alkyl) 2 amino examples include di-N-methylamino, di-(N-ethyl)amino and N-ethyl-N-methylamino.
  • Examples of “C 2 - 6 alkenyl” are vinyl, allyl and 1-propenyl.
  • Examples of “C 2 - 6 alkynyl” are ethynyl, 1-propynyl and 2-propynyl. Examples of are N-(methyl)sulphamoyl and N-(ethyl)sulphamoyl.
  • Examples of “N-(C ⁇ - 6 alkyl) 2 sulphamoyl” are N,N-(dimethyl)sulphamoyl and
  • N-(methyl)-N-(ethyl)sulphamoyl N-(methyl)-N-(ethyl)sulphamoyl.
  • N-(C ⁇ - 6 alkyl)carbamoyl are N-(C ⁇ - 4 alkyl)carbamoyl, methylaminocarbonyl and ethylaminocarbonyl.
  • N,N-(Ci. 6 alkyl) 2 carbamoyl are N,N-(C ⁇ - 4 alkyl) carbamoyl, dimethylaminocarbonyl and methylethylaminocarbonyl.
  • RT or "rt” means room temperature.
  • a suitable pharmaceutically acceptable salt of a compound ofthe invention is, for example, an acid-addition salt of a compound ofthe invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid.
  • a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium or magnesium salt
  • an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation
  • a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxye
  • the pyrazoles claimed in this invention are capable to exist in different resonance structures and thus the pyrazoles claimed herein include all possible resonance structures, for example optical isomers, diastereoisomers and geometric isomers and all tautomeric forms ofthe compounds ofthe formula (I). It is also to be understood that certain compounds ofthe formula (I) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms.
  • Formulations Compounds ofthe present invention may be administered orally, parenteral, buccal, vaginal, rectal, inhalation, insufflation, sublingually, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints.
  • the dosage will depend on the route of administration, the severity ofthe disease, age and weight ofthe patient and other factors normally considered by the attending physician, when determining the individual regimen and dosage level as the most appropriate for a particular patient.
  • an effective amount of a compound ofthe present invention for use in therapy of cancer is an amount sufficient to symptomatically relieve in a warm-blooded animal, particularly a human the symptoms of cancer, to slow the progression of cancer, or to reduce in patients with symptoms of cancer the risk of getting worse.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • a solid carrier can be one or more substance, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.
  • the carrier is a finely divided solid, which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify.
  • Suitable carriers include magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like.
  • Some ofthe compounds ofthe present invention are capable of forming salts with various inorganic and organic acids and bases and such salts are also within the scope of this invention.
  • acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate, camphorsulfonate, choline, citrate, cyclohexyl sulfamate, diethylenediamine, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, maleate, methanesulfonate, meglumine, 2-naphthalenesulfonate, nitrate, oxalate, pamoate, persulf
  • Base salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as aluminum, calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, ornithine, and so forth.
  • basic nitrogen-containing groups may be quaternized with such agents as: lower alkyl halides, such as methyl, ethyl, propyl, and butyl halides; dialkyl sulfates like dimethyl, diethyl, dibutyl; diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl halides; aralkyl halides like benzyl bromide and others.
  • Non-toxic physiologically-acceptable salts are preferred, although other salts are also useful, such as in isolating or purifying the product.
  • the salts may be formed by conventional means, such as by reacting the free base form ofthe product with one or more equivalents ofthe appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion-exchange resin.
  • a compound ofthe formula (I) or a pharmaceutically acceptable salt thereof for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • composition of this invention may also contain, or be co-administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more disease conditions referred to herein.
  • composition is intended to include the formulation ofthe active component or a pharmaceutically acceptable salt with a pharmaceutically acceptable carrier.
  • this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols or nebulisers for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions.
  • Liquid form compositions include solutions, suspensions, and emulsions. Sterile water or water-propylene glycol solutions ofthe active compounds may be mentioned as an example of liquid preparations suitable for parenteral administration.
  • Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired.
  • Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
  • the pharmaceutical compositions can be in unit dosage form. In such form, the composition is divided into unit doses containing appropriate quantities ofthe active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities ofthe preparations, for example, packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.
  • Combinations The anti-cancer treatment defined herein may be applied as a sole therapy or may involve, in addition to the compound ofthe invention, conventional surgery or radiotherapy or _ _
  • Such chemotherapy may include one or more ofthe following categories of anti-tumour agents:
  • antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and
  • cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5 ⁇ -reductase such as finasteride; (iii) agents which inhibit cancer cell invasion (for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function
  • N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gef ⁇ tinib, AZD1839)
  • N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and
  • 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033)), for example inhibitors ofthe platelet-derived growth factor family and for example inhibitors ofthe hepatocyte growth factor family;
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [AvastinTM], compounds such as those disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds that work by other mechanisms (for example linomide, inhibitors of integrin ⁇ v ⁇ 3 function and angiostatin);
  • vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
  • antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
  • GDEPT gene-directed enzyme pro-drug therapy
  • immunotherapy approaches including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
  • cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor
  • approaches to decrease T-cell anergy approaches using transfected immune cells such as cytokine-transfected dendritic cells
  • approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies may be achieved by way ofthe simultaneous, sequential or separate dosing ofthe individual components ofthe treatment.
  • Such combination products employ the compounds of this invention, or pharmaceutically acceptable salts thereof
  • the compounds, or pharmaceutically acceptable salts thereof, ofthe present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis.
  • the compounds, or pharmaceutically acceptable salts thereof, ofthe present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the _ _
  • temperatures are given in degrees Celsius (°C); operations are carried out at room temperature or ambient temperature, that is, in a range of 18-25 °C;
  • chromatography means flash chromatography on silica gel; thin layer chromatography
  • yields are given for illustration only and are not necessarily those which can be obtained by diligent process development; preparations were repeated if more material was required; (vii) when given, NMR data is in the form of delta values for major diagnostic protons, given in part per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz in d6-DMSO unless otherwise stated; (viii) chemical symbols have their usual meanings; (ix) solvent ratio was given in volume: volume (v/v) terms.
  • Example 1 N 1 -( , 3-Cvclopropylpyrazol-5-ylVN 3 -(4-fluorobenzyl)benzene-1.3-diamine
  • Pd(OAc) 2 8 mg, 0.0355 mmol
  • 2-(di-tert-butylphosphino)biphenyl 21 mg, 0.071 mmol
  • ⁇ aO t Bu 85 mg, 0.888 mmol
  • Example 2-4 Following a similar procedure to Example 1, the following compounds were synthesized via reaction of a suitable aryl bromide (method is also listed) and a suitable amine.
  • Examples 6-8 Following a similar procedure to Example 5, the following compounds were synthesized from a suitable pyrazole by reacting it with a suitable amine.
  • Example 10 Following a similar procedure to Example 9, the following compounds were synthesized from a suitable pyrazole by reacting it with a suitable amine.
  • Example 13 rS)-N ; -(5-Cvclopropyl-lH-pyrazol-3-ylV4-fluoro-N 3 - -r4-fluorophenvnethylV6- nitrobenzene- 1.3-diamine
  • Example 16 Following a similar procedure to Example 15, the following compound was synthesized from a suitable pyrazole by reacting it with a suitable amine.
  • nitro compounds described herein may be reduced under standard reduction conditions to form the corresponding amino compounds.
  • they can be reduced using H 2 (atmospheric) with palladium on activated carbon or by using zinc dust with NH CI.
  • H 2 atmospheric
  • NH CI zinc dust with NH CI.
  • the following amino compounds were prepared by reducing the corresponding nitro compound.
  • starting materials are either commercially available or are readily prepared by standard methods from known materials. For example the following reactions are illustrations but not limitations of the preparation of some ofthe starting materials and examples used herein.
  • N-(5-Fluoro-2-nitrophenyl)-5-isopropoxy-lH-pyrazol-3-amine To the solution of 2,4-difluoro-l -nitrobenzene (1.80 g, 11.0 mmol) and DIEA (1.93 ml, 11.0 mmol) in T ⁇ F (20 ml) was added 5-isopropoxyl-lH-pyrazol-3-amine (1.30 g, 80% pure 7.4 mmol) at 25 °C. After addition, the reaction mixture was stirred at 105 °C for 48 hrs.
  • the compounds ofthe present invention have utility for the treatment of cancer by inhibiting the tyrosine kinases, particularly the Trks and more particularly Trk A and B.
  • Methods of treatment target tyrosine kinase activity, particularly the Trk activity and more particularly Trk A and B activity, which is involved in a variety of cancer related processes.
  • inhibitors of tyrosine kinase are expected to be active against neoplastic disease such as carcinoma ofthe breast, ovary, lung, colon, prostate or other tissues, as well as leukemias and lymphomas, tumours ofthe central and peripheral nervous system, and other tumour types such as melanoma, fibrosarcoma and osteosarcoma.
  • Tyrosine kinase inhibitors particularly the Trk inhibitors and more particularly Trk A and B inhibitors are also expected to be useful for the treatment other proliferative diseases including but not limited to autoimmune, inflammatory, neurological, and cardiovascular diseases.
  • Compounds ofthe present invention have been shown to inhibit tyrosine kinases, particularly the Trks and more particularly Trk A and B, as determined by the Trk B Assay described herein.
  • TrkB Assay Format TrkB kinase activity was measured for its ability to phosphorylate synthetic tyrosine residues within a generic polypeptide substrate using an Amplified Luminescent Proximity Assay (Alphascreen) technology (PerkinElmer, 549 Albany Street, Boston, MA).
  • TrkB kinase activity To measure TrkB kinase activity, the intracellular domain of a HIS-tagged human TrkB kinase (amino acids 455 to 822 of TrkB, Swiss-Prot Primary Accession Number Q 16620) was expressed in SF9 cells and purified using standard nickel column chromatography. After incubation ofthe kinase with a biotinylated substrate and adenosine triphosphate (ATP) for 45 minutes at room temperature, the kinase reaction was stopped by the addition of 30mM ethylenediaminetetraacetic acid (EDTA).
  • EDTA ethylenediaminetetraacetic acid
  • reaction was performed in 384 well microtitre plates and reaction products were detected with the addition of strepavidinb coated Donor Beads and phosphotyrosine-specific antibodie coated Acceptor Beads using a EnVision Multilabel Plate Reader after an overnight incubation at room temperature.
  • Trk A Assay Format Trk A kinase activity was measured for its ability to phosphorylate synthetic tyrosine residues within a generic polypeptide substrate using an Amplified Luminescent Proximity Assay (Alphascreen) technology (PerkinElmer, 549 Albany Street, Boston, MA).
  • Trk A kinase activity To measure Trk A kinase activity, the intracellular domain of a HIS-tagged human Trk A kinase (amino acids 442-796 of Trk A, Swiss-Prot Primary Accession Number P04629) was expressed in SF9 cells and purified using standard nickel column chromatography. After incubation ofthe kinase with a biotinylated substrate and adenosine triphosphate (ATP) for 20 minutes at room temperature, the kinase reaction was stopped by the addition of 30 mM ethylenediaminetetraacetic acid (EDTA).
  • EDTA ethylenediaminetetraacetic acid
  • reaction was performed in 384 well microtitre plates and the reaction products were detected with the addition of strepavidin coated Donor Beads and phosphotyrosine-specific antibodies coated Acceptor Beads using the EnNision Multilabel Plate Reader after an overnight incubation at room temperature.

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Abstract

This invention relates to novel compounds having the formul and to their pharmaceutical compositions and to their methods of use. These novel compounds provide a treatment for cancer.

Description

CHEMICAL COMPOUNDS
Field of the invention The present invention relates to novel pyrazole derivatives, their pharmaceutical compositions and metliods of use. In addition, the present invention relates to therapeutic methods for the treatment and prevention of cancers and to the use of these pyrazole derivatives in the manufacture of medicaments for use in the treatment and prevention of cancers. Background of the invention Receptor tyrosine kinases (RTK's) are a sub-family of protein kinases that play a critical role in cell signalling and are involved in a variety of cancer related processes including cell proliferation, survival, angiogenesis and metastasis. Currently up to 100 different RTK's including tropomyosin-related kinases (Trk's) have been identified. Trk's are the high affinity receptors activated by a group of soluble growth factors called neurotrophins (NT). The Trk receptor family has three members - TrkA, TrkB and TrkC. Among the NTs there are (i) nerve growth factor (NGF) which activates TrkA, (ii) brain-derived growth factor (BDNF) and NT-4/5 which activate TrkB and (iii) NT3 which activates TrkC. Each Trk receptor contains an extra-cellular domain (ligand binding), a trans-membrane region and an intra-cellular domain (including kinase domain). Upon binding ofthe ligand, the kinase catalyzes auto-phosphorylation and triggers downstream signal transduction pathways. Trk's are widely expressed in neuronal tissue during its development where Trk's are critical for the maintenance and survival of these cells. A post-embryonic role for the Trk/neurotrophin axis (or pathway), however, remains in question. There are reports showing that Trk's play important role in both development and function ofthe nervous system (Patapoutian, A. et al Current Opinion in Neurobiology, 2001, 11, 272-280). In the past decade, a considerable number of literature documentations linking Trk signalling with cancer have published. For example, while Trk's are expressed at low levels outside the nervous system in the adult, Trk expression is increased in late stage prostate cancers. Both normal prostate tissue and androgen- dependent prostate tumours express low levels of Trk A and undetectable levels of Trk B and C. However, all isoforms of Trk receptors as well as their cognate ligands are up-regulated in late stage, androgen- independent prostate cancer. There is additional evidence that these late stage prostate cancer cells become dependent on the Trk/neurotrophin axis for their survival. Therefore, Trk inhibitors may yield a class of apoptosis-inducing agents specific for androgen- independent prostate cancer (Weeraratna, A. T. et al The Prostate, 2000, 45, 140-148). Furthermore, very recent literature also shows that over-expression, activation, amplification and/or mutation of Trk's are associated with secretory breast carcinoma (Cancer Cell, 2002, 2, 367-376), colorectal cancer (Bardelli et al Science, 2003, 300, 949-949) and ovarian cancer (Davidson, B. et al Clinical Cancer Research, 2003, 9, 2248-2259). There are a few reports of selective Trk tyrosine kinase inhibitors. Cephalon described CEP-751, CEP-701 (George, D. et al Cancer Research, 1999, 59, 2395-2341) and other indolocarbazole analogues (WOOl 14380) as Trk inhibitors. It was shown that CEP-701 and/or CEP751, when combined with surgically or chemically induced androgen ablation, offered better efficacy compared with mono-therapy alone. GlaxoSmithKline disclosed certain oxindole compounds as TrkA inhibitors in WO0220479 and WO0220513. Recently, Japan Tobacco reported pyrazolyl condensed cyclic compounds as Trk inhibitors (JP2003231687A). In addition to the above, Vertex Pharmaceuticals have described pyrazole compounds as inhibitors of GSK3, Aurora, etc. in WO0250065, WO0262789 and WO03027111; and AstraZeneca have reported pyrazole compounds as inhibitors against IGF-1 receptor kinase (WO0348133). Summary of the invention In accordance with the present invention, the applicants have hereby discovered novel pyrazole compounds, or pharmaceutically acceptable salts thereof, which possess Trk kinase inhibitory activity and are accordingly useful for their anti-proliferation and/or proapoptotic (such as anti-cancer) activity and in methods of treatment ofthe human or animal body. The invention also relates to processes for the manufacture of said pyrazole compounds, or pharmaceutically acceptable salts thereof, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments for use in the production of an anti-proliferation and/or proapoptotic effect in warm-blooded animals such as man. Also in accordance with the present invention the applicants provide methods of using such pyrazole compounds, or pharmaceutically acceptable salts thereof, in the treatment of cancer. The properties ofthe compounds claimed in this invention are expected to be of value in the treatment of disease states associated with cell proliferation such as cancers (solid tumours and leukaemia), fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation. Furthermore, the compounds, or pharmaceutically acceptable salts thereof, ofthe invention are expected to be of value in the treatment or prophylaxis of cancers selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, ewings tumour, neuroblastoma, kaposis sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, renal cancer, lymphoma and leukaemia; particularly ovarian cancer, breast cancer, colorectal cancer, prostate cancer and lung cancer - NSCLC and SCLC; more particularly prostate cancer; and more particularly hormone refractory prostate cancer. Detailed description of the invention Accordingly, the present invention provides a compound of formula (I):
Figure imgf000004_0001
(i) wherein: A is a direct bond or Cι-2alkylene; wherein said Cι.2alkylene may be optionally substituted by one or more R22; Ring C is carbocyclyl or heterocyclyl; R1 and R4 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Cι-6alkyl, C2-6alkenyl, C2-6 lkynyl, Ci-βalkoxy, Cι-6alkanoyl, Cι-6alkanoyloxy, N-(Cι-6alkyl)amino, N,N-(Cι-6alkyl)2amino, Cι-6alkanoylamino, N-(Cι-6alkyl)carbamoyl,
N,N-(Cι-6alkyl)2carbamoyl, Cι-6alkylS(O)a wherein a is 0 to 2, Cι-6alkoxycarbonyl, N-(Cι-6alkyl)sulphamoyl, N,N-(Cι-6alkyι)2sulphamoyl, Cι-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R1 and R4 independently of each other may be optionally substituted on carbon by one or more R8; and wherein if said heterocyclyl contains an -ΝH- moiety that nitrogen may be optionally substituted by a group selected from R9; R2 is selected from hydrogen, halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Cι-6alkyl, C2-6alkenyl, C2-6alkynyl, Cι-6alkoxy,
Cι-6alkanoyl, Cι-6alkanoyloxy,
Figure imgf000005_0001
N,N-(C1-6alkyl)2amino, -galkanoylamino, N^ -ealkyfjcarbamoyl, N,N-(Cι-6alkyι)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, Cι-6alkoxycarbonyl, N-(Cι-6alkyl)sulphamoyl, N,N-(Cι-6alkyl)2sulphamoyl, Cι-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein
R may be optionally substituted on carbon by one or more R ; and wherein if said heterocyclyl contains an -ΝH- moiety that nitrogen may be optionally substituted by a group selected from R11; R3 is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci-βalkyl, C2.6alkenyl, C .6alkynyl, Cι-6alkoxy,
Cι-6alkanoyl, Cι-6alkanoyloxy, N-(Cι-6alkyl)amino, N,N-(Cι-6alkyl)2amino, -ealkanoylamino, N-(Cι-6alkyl)carbamoyl, N,N-(Cι-6alkyl)2carbamoyl, Cι-6alkylS(O)a wherein a is 0 to 2, Cι-6alkoxycarbonyl, N-(Cι-6alkyl)sulphamoyl,
N,N-(Cι-6alkyl)2sulphamoyl, -ealkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R3 may be optionally substituted on carbon by one or more R12; and wherein if said heterocyclyl contains an -ΝH- moiety that nitrogen may be optionally substituted by a group selected from R ; R5 is hydrogen or optionally substituted Cι-6alkyl; wherein said optional substituents are selected from one or more R14; R6 is independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, d-6alkyl, C2-6alkenyl, C2.6alkynyl, -βalkoxy, Cι-6alkanoyl, Cι-6alkanoyloxy, N-(Cι-6alkyl)amino, N,N-(Cι-6alkyl)2amino,
Cι-6alkanoylamino, N-(Cι-6alkyl)carbamoyl, N,N-(Cι-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, Cι-6alkoxycarbonyl, N-(Cι.6alkyl)sulphamoyl, N,N-(Cι-6alkyl)2sulphamoyl, Cι-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein
R6 independently of each other may be optionally substituted on carbon by one or more R15; and wherein if said heterocyclyl contains an -ΝH- moiety that nitrogen may be optionally substituted by a group selected from R16; or two adjacent R6 groups together with the phenyl bond to which they are attached form a 5 or 6 membered carbocyclic ring or heterocyclic ring wherein said ring is fused to the phenyl of formula (I); and wherein said carbocyclic ring or heterocyclic ring may be optionally substituted on carbon by one or more R17; and wherein if said heterocyclic ring contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R18; n is 0, 1, 2 or 3; wherein the values of R3 may be the same or different; m is 0-4; wherein the values of R6 may be the same or different; R8, R10, R12, R14, R15, R17 and R22 are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C^aU yl, C2.6alkenyl, C2.6alkynyl, C]-6alkoxy, Cι-6alkanoyl, Cι-6alkanoyloxy,
Figure imgf000006_0001
N,N-(Cι-6alkyl)2amino, Cι-6alkanoylamino,
Figure imgf000006_0002
N,N-(Cι-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, Cι-6alkoxycarbonyl, N-(Ci-6alkyl)sulphamoyl, N,N-(Cι-6alkyι)2sulphamoyl, Cι-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R , R , R , R , R , R and R independently of each other may be optionally substituted on carbon by one or more R19; and wherein if said heterocyclyl contains an -ΝH- moiety that nitrogen may be optionally substituted by a group selected from R20; R9, R11, R13, R16, R18 and R20 are independently selected from -ealkyl, Ci-6alkanoyl, Cι-6alkylsulphonyl, Cι-6alkoxycarbonyl, carbamoyl, N-(Cι-6alkyl)carbamoyl,
N,N-(Cι-6alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl; wherein R9, R11, R13, R16, R18 and R20 independently of each other may be optionally substituted on carbon by on or more R21; R19 and R21 are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Cι-6alkyl, C2.6alkenyl, C2-6alkynyl, -βalkoxy, d-ealkanoyl, Cι-6alkanoyloxy,
Figure imgf000006_0003
N,N-(C1.6alkyl)2amino, Cι-6alkanoylamino, N-(Cι-6alkyl)carbamoyl, N,N-(Cι-6alkyl)2carbamoyl, Cι-6alkylS(O)a wherein a is 0 to 2, Ci-βalkoxycarbonyl, N-(Cι-6alkyl)sulphamoyl, N,N-(C1-6alkyl)2sulphamoyl, Ci-ealkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R19 and R21 independently of each other may be optionally substituted on carbon by one or more R23; and wherein if said heterocyclyl contains an -ΝH- moiety that nitrogen may be optionally substituted by a group selected from R24; - o -
R is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl, N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl or N-methyl-N-ethylsulphamoyl; and R24 is selected from Cι-6alkyl, Cι-6alkanoyl, ^alkylsulphonyl, Cι-6alkoxycarbonyl, carbamoyl,
Figure imgf000007_0001
N,N-(Cι-6alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl; or a pharmaceutically acceptable salt thereof. Preferred values ofthe variable groups contained in formula (I) are as follows. Such values may be used, where appropriate, with any ofthe definitions, claims or embodiments defined hereinbefore or hereinafter. A is a direct bond. A is Cι-2alkylene. A is Cι-2alkylene; wherein said Cι-2alkylene may be optionally substituted by one or more R . Ring C is carbocyclyl. Ring C is heterocyclyl. Ring C is phenyl or pyridyl. Ring C is phenyl. R1 and R4 are independently selected from hydrogen and carbocyclyl. R1 and R4 are independently selected from hydrogen and cyclopropyl. R1 and R4 are independently selected from hydrogen, Cι-6alkyl, d-6alkoxy and carbocyclyl. R1 and R4 are independently selected from hydrogen, t-butyl, isopropoxy and cyclopropyl. R4 is hydrogen. R1 is cyclopropyl. R1 is selected from Cι-6alkyl, Cι.6alkoxy and carbocyclyl. R1 is selected from t-butyl, isopropoxy and cyclopropyl. R2 is selected from hydrogen or Ci-βalkyl; wherein R2 may be optionally substituted on carbon by one or more R10. 9 9 R is selected from hydrogen or Cι-6alkyl; wherein R may be optionally substituted on carbon by one or more R10; wherein R10 is hydroxy. R 9 is selected from hydrogen or methyl; wherein R 1 may be optionally substituted on carbon by one or more R10. 9 9 R is selected from hydrogen or methyl; wherein R may be optionally substituted on carbon by one or more R10; wherein R10 is hydroxy. R2 is selected from hydrogen, methyl or hydroxymethyl. R2 is selected from hydrogen or hydroxymethyl. R3 is halo. R3 is fluoro. R5 is hydrogen. R6 is halo. R6 is chloro. R6 is independently selected from halo, nitro, cyano, amino and N-(Cι-6alkyl)amino; wherein R6 independently of each other may be optionally substituted on carbon by one or more R15; wherein R15 is selected from hydroxy. R6 is independently selected from fluoro, chloro, nitro, cyano, amino and ethylamino; wherein R6 independently of each other may be optionally substituted on carbon by one or more R15; wherein R15 is selected from hydroxy. R6 is independently selected from fluoro, chloro, nitro, cyano, amino and 2-hydroxy ethylamino. n is O or 1. n is 0. n is 1. m is 0 or 1. m is 0. m is 1. m is 2; wherein the values of R6 may be the same or different. m is 3; wherein the values of R6 may be the same or different. m is 0-3; wherein the values of R6 may be the same or different. Therefore in a further aspect of the invention there is provided a compound of formula (I) (as depicted herein above) wherein: A is a direct bond; Ring C is carbocyclyl; R1 and R4 are independently selected from hydrogen and carbocyclyl; R2 is selected from hydrogen or Cι-6alkyl; wherein R2 may be optionally substituted on carbon by one or more R10; wherein R10 is hydroxy; R3 is halo; R5 is hydrogen; R6 is halo; n is 1; m is 0 or 1; or a pharmaceutically acceptable salt thereof. Therefore in a further aspect ofthe invention there is provided a compound of formula
(I) (as depicted herein above) wherein: A is a direct bond; Ring C is carbocyclyl; R1 and R4 are independently selected from hydrogen, Cι-6alkyl, Cι-6alkoxy and carbocyclyl; R2 is selected from hydrogen or Cι-6alkyl; wherein R2 may be optionally substituted on carbon by one or more R10; R3 is halo; R5 is hydrogen; R6 is independently selected from halo, nitro, cyano, amino and N-(Cι-6alkyl)amino; wherein R6 independently of each other may be optionally substituted on carbon by one or more R15; n is 1; m is 0-3; wherein the values of R6 may be the same or different; R10 is hydroxy; R15 is selected from hydroxy; or a pharmaceutically acceptable salt thereof. - y -
Therefore in a further aspect ofthe invention there is provided a compound of formula (I) (as depicted herein above) wherein: A is a direct bond; Ring C is phenyl; R4 is hydrogen; R1 is cyclopropyl; R2 is selected from hydrogen or hydroxymethyl; R is fluoro; R5 is hydrogen; R6 is chloro; n is 1; m is 0 or 1; or a pharmaceutically acceptable salt thereof. Therefore in a further aspect ofthe invention there is provided a compound of formula (I) (as depicted herein above) wherein: A is a direct bond; Ring C is phenyl; R1 is selected from t-butyl, isopropoxy and cyclopropyl; R is selected from hydrogen, methyl or hydroxymethyl; R3 is fluoro; R4 is hydrogen; R5 is hydrogen; R6 is independently selected from fluoro, chloro, nitro, cyano, amino and 2-hydroxyethylamino; n is i; m is 0-3; wherein the values of R6 may be the same or different; or a pharmaceutically acceptable salt thereof. In another aspect ofthe invention, preferred compounds ofthe invention are any one ofthe Examples or a pharmaceutically acceptable salt thereof. In another aspect ofthe invention, preferred compounds ofthe invention are any one of Examples 3, 9, 10, 13, 14 or 17 or a pharmaceutically acceptable salt thereof. In a further aspect ofthe invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof which is a compound ofthe formula (la):
Figure imgf000011_0001
da) wherein Ra is amino or nitro and the other groups are as defined hereinabove. In a further aspect ofthe invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof which is a compound ofthe formula (lb):
Figure imgf000011_0002
(lb) wherein R is ammo or nitro and the other groups are as defined hereinabove. In an additional embodiment the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament. In an additional embodiment the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the inhibition of Trk activity. In an additional embodiment the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the treatment or prophylaxis of cancer. In an additional embodiment the present invention provides a compound ofthe formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the treatment of cancer in a warm-blooded animal such as man. In an additional embodiment the present invention provides a compound ofthe formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the treatment or prophylaxis of cancers (solid tumors and leukemia), fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis,, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation in a warm-blooded animal such as man. In an additional embodiment the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the production of an anti-proliferative effect. In an additional embodiment the present invention provides a method of inhibiting Trk activity comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In an additional embodiment the present invention provides a method for the treatment of cancer comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In an additional embodiment the present invention provides a method for the treatment or prophylaxis of cancer comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In an additional embodiment the present invention provides a method for the treatment or prophylaxis of cancers (solid tumours and leukaemia), fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation in a warm-blooded animal such as man comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In an additional embodiment the present invention provides a method of producing an anti-proliferative effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. _ _
In an additional embodiment the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, diluent or excipient. In an additional embodiment the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, diluent or excipient for use in the inhibition of Trk activity. In an additional embodiment the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, diluent or excipient for use in the treatment of cancer. In an additional embodiment the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, diluent or excipient for use in the treatment or prophylaxis of cancer. In an additional embodiment the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, diluent or excipient for use in the treatment or prophylaxis of cancers (solid tumours and leukaemia), fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation. In an additional embodiment the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, diluent or excipient for use in the production of an anti-proliferative effect in a warm-blooded animal such as man. In an additional embodiment the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the inhibition of Trk activity. In an additional embodiment the present invention provides a compound of formula
(I), or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of cancer. In an additional embodiment the present invention provides a compound ofthe formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in a warm-blooded animal such as man. In an additional embodiment the present invention provides a compound ofthe formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of cancers (solid tumours and leukaemia), fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation in a warm-blooded animal such as man. In an additional embodiment the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the production of an anti- proliferative effect. Where the inhibition of Trk activity is referred to particularly this refers to the inhibition of TrkB activity. Where the treatment (or prophylaxis) of cancer is referred to, particularly it refers to the treatment (or prophylaxis) of oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, ewings tumour, neuroblastoma, kaposis sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, renal cancer, lymphoma, leukaemia, tumours ofthe central and peripheral nervous system, melanoma, fϊbrosarcoma and osteosarcoma. More particularly it refers to prostate cancer. In addition, more particularly it refers to SCLC, NSCLC, colorectal cancer, ovarian cancer and / or breast cancer. In a further aspect it refers to hormone refractory prostate cancer. In a further aspect ofthe present invention provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof which process (wherein variable groups are, unless otherwise specified, as defined in formula (I)) comprises of: Process a) reaction of a compound of formula (II):
Figure imgf000015_0001
(II) wherein Pg is a nitrogen protecting group; with a compound of formula (III):
Figure imgf000015_0002
(III) wherein L is a displaceable group;
Process b) for compounds of formula (I) wherein R2 is hydroxymethyl; reaction of a compound of formula (II) with an epoxide of formula (IV):
Figure imgf000015_0003
(IV)
Process c) reacting a compound of formula (V):
Figure imgf000015_0004
(V) with hydrazine;
Process d) reacting a compound of formula (VI):
Figure imgf000016_0001
(VI) wherein Pg is a nitrogen protecting group and L is a displaceable group; with a compound of formula (VII):
Figure imgf000016_0002
(VII)
Process e) reacting a compound of formula (VIII):
Figure imgf000016_0003
(vπi) wherein L is a displaceable group; with a compound of formula (IX):
Figure imgf000016_0004
(IX) wherein Pg is a nitrogen protecting group;
Process f) reacting a compound of formula (X):
Figure imgf000017_0001
(X) with a compound of formula (XI):
Figure imgf000017_0002
(XI) wherein L is a displaceable group and Pg is a nitrogen protecting group; and thereafter if necessary: i) converting a compound ofthe formula (I) into another compound ofthe formula (I); ii) removing any protecting groups; iii) forming a pharmaceutically acceptable salt. L is a displaceable group, suitable values for L are for example, a halo or sulphonyloxy group, for example a chloro, bromo, methanesulphonyloxy or toluene-4-sulphonyloxy group. Pg is a nitrogen protecting group. Suitable values for Pg are described herein below. Specific reaction conditions for the above reactions are as follows.
Process a) Compounds of formula (II) and (III) may be reacted together under standard nucleophilic addition reactions for example in the presence of a suitable base such as potassium carbonate and a suitable solvent such as DMF and at a temperature in the range from 25 to l00°C. Compounds ofthe formula (II) may be prepared according to Scheme 1:
Figure imgf000018_0001
Scheme 1 wherein Pg is a nitrogen protecting group. Suitable values for Pg are defined below; and wherein L is a displaceable group as defined above. Compounds of formula (in), (Ila) and (IΙb)are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art.
Process b) Compounds of formula (II) and (TV) may be reacted together under epoxide ring opening reaction conditions for example in the presence of a suitable catalyst such as LiClO4, NaClO4, Mg(ClO )2 and a suitable solvent such as CH3CN and at a temperature in the range
Figure imgf000018_0002
Compounds of formula (IV)are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art. Process c) The s reaction may be carried out in a suitable solvent, for example, an alcohol such as ethanol or butanol at a temperature in the range from 50-120°C, in particular in the range from 70-100°C. Compounds ofthe formula (V) may be prepared according to Scheme 2:
Scheme 2 Compounds ofthe formula (Va) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art. Process d) Compounds of formula (VI) and (VII) may be reacted together under the conditions given for Process a). Compounds ofthe formula (VI) may be prepared according to Scheme 3:
Figure imgf000019_0001
Scheme 3 Compounds ofthe formula (VII) and (Via) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art. Process e) Compounds of formula (VIII) and (IX) may be reacted together under the conditions given for Process a). Compounds ofthe formula (VIH) may be prepared according to Scheme 4: EtOH (Via) + (VII) *■ (VIII) Scheme 4 Compounds ofthe formula (IX) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art. Process e) Compounds of formula (X) and (XI) may be reacted together under the conditions given for Process a). Compounds ofthe formula (X) may be prepared according to Scheme 5:
Figure imgf000019_0002
Scheme 5 Compounds ofthe formula (XI) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art. _ _
It will be appreciated that certain ofthe various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group. Particular examples of modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl. It will also be appreciated that in some ofthe reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in the compounds. The instances where protection is necessary or desirable and suitable methods for protection are known to those skilled in the art. Conventional protecting groups may be used in accordance with standard practice (for illustration see T.W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactants include groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some ofthe reactions mentioned herein. A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine. A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon. A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon. The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art. Definitions In this specification the term "alkyl" includes both straight and branched chain alkyl groups but references to individual alkyl groups such as "propyl" are specific for the straight chain version only. For example, "Cι-6alkyl" and "Cι-4alkyl" include methyl, ethyl, propyl, isopropyl and t-butyl. However, references to individual alkyl groups such as 'propyl' are specific for the straight-chained version only and references to individual branched chain alkyl groups such as 'isopropyl' are specific for the branched-chain version only. A similar convention applies to other radicals. The term "halo" refers to fluoro, chloro, bromo and iodo. Where optional substituents are chosen from "one or more" groups it is to be understood that this definition includes all substituents being chosen from one ofthe specified groups or the substituents being chosen from two or more ofthe specified groups. A "heterocyclyl" is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 4-12 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH2- group can optionally be replaced by a -C(O)-, and a ring sulphur atom may be optionally oxidised to form the S-oxides. Examples and suitable values ofthe term "heterocyclyl" are morpholino, piperidyl, pyridyl, pyranyl, pyrrolyl, isothiazolyl, indolyl, quinolyl, thienyl, 1,3-benzodioxolyl, thiadiazolyl, piperazinyl, thiazolidinyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, tetrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl, N-methylpyrrolyl, 4-pyridone, 1-isoquinolone, 2-pyrrolidone, 4-thiazolidone, pyridine-N-oxide and quinoline-N-oxide. Further examples and suitable values ofthe term "heterocyclyl" are morpholino, piperazinyl and pyrrolidinyl. In one aspect ofthe invention a "heterocyclyl" is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 5 or 6 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, it may, unless otherwise specified, be carbon or nitrogen linked, a -CH2- group can optionally be replaced by a -C(O)-and a ring sulphur atom may be optionally oxidised to form the S-oxides. A "carbocyclyl" is a saturated, partially saturated or unsaturated, mono or bicyclic carbon ring that contains 3-12 atoms; wherein a -CH2- group can optionally be replaced by a -C(O)-. Particularly "carbocyclyl" is a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms. Suitable values for "carbocyclyl" include cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or 1-oxoindanyl. Where "two adjacent R6 groups together with the phenyl bond to which they are attached form a 5 or 6 membered carbocyclic ring or heterocyclic ring" said ring is a partially saturated or unsaturated, mono or bicyclic carbon ring that contains 5 or 6 atoms two atoms of which are shared with the phenyl ring of formula (I); of which at least one atom is chosen from nitrogen, sulphur or oxygen; wherein a -CH2- group can optionally be replaced by a -C(O)-, and a ring sulphur atom may be optionally oxidized to form the S-oxides. Said ring is fused to the phenyl ring of formula (I) to make a 9 or 10 membered bicyclic ring. Suitable values for "two adjacent R6 groups together with the phenyl bond to which they are attached form a 5 or 6 membered carbocyclic ring or heterocyclic ring" are naphthyl, quinolionyl and quinazolinyl, indole, isoindole, 3H-indole, indoline, benzofuran, benzothiophene, 1H- indazole, benzimidazole, benzthiazole, isoquinoline, cinnoline, phthalazine and quinoxaline. The term "Cm-n" or "Cm-n group" used alone or as a prefix, refers to any group having m to n carbon atoms. The term "optionally substituted" refers to either groups, structures, or molecules that are substituted and those that are not substituted. An example of "Cι-6alkanoyloxy" is acetoxy. Examples of "Cι-6alkoxycarbonyl" include Cι-4alkoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl. Examples of "d-βalkoxy" include Cι-4alkoxy, Cι-3alkoxy, methoxy, ethoxy and propoxy. Examples of "Q-δalkoxyimino" include CMalkoxyimino, Cι-3alkoxyimino, methoxyimino, ethoxyimino and propoxyimino. Examples of "Q-ealkanoylamino" include formamido, acetamido and propionylamino. Examples of "C1-6alkylS(O)a wherein a is 0 to 2" include Cι- alkylsulphonyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl. Examples of "Cι-6alkylthio" include methylthio and ethylthio. Examples of "Cι-6alkylsulphonylamino" include methylsulphonylamino and ethylsulphsulphonylamino. Examples of "Cι-6alkanoyl" include
Figure imgf000023_0001
propionyl and acetyl. Examples of "N-(Cι-6alkyl)amino" include methylamino and ethylamino. Examples of "N,N-(Cι-6alkyl)2amino" include di-N-methylamino, di-(N-ethyl)amino and N-ethyl-N-methylamino. Examples of "C2-6alkenyl" are vinyl, allyl and 1-propenyl. Examples of "C2-6alkynyl" are ethynyl, 1-propynyl and 2-propynyl. Examples of
Figure imgf000023_0002
are N-(methyl)sulphamoyl and N-(ethyl)sulphamoyl. Examples of "N-(Cι-6alkyl)2sulphamoyl" are N,N-(dimethyl)sulphamoyl and
N-(methyl)-N-(ethyl)sulphamoyl. Examples of "N-(Cι-6alkyl)carbamoyl" are N-(Cι-4alkyl)carbamoyl, methylaminocarbonyl and ethylaminocarbonyl. Examples of "N,N-(Ci.6alkyl)2carbamoyl" are N,N-(Cι-4alkyl) carbamoyl, dimethylaminocarbonyl and methylethylaminocarbonyl. "RT" or "rt" means room temperature. A suitable pharmaceutically acceptable salt of a compound ofthe invention is, for example, an acid-addition salt of a compound ofthe invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid. In addition a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine. It should be noted that the pyrazoles claimed in this invention are capable to exist in different resonance structures and thus the pyrazoles claimed herein include all possible resonance structures, for example optical isomers, diastereoisomers and geometric isomers and all tautomeric forms ofthe compounds ofthe formula (I). It is also to be understood that certain compounds ofthe formula (I) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms. Formulations Compounds ofthe present invention may be administered orally, parenteral, buccal, vaginal, rectal, inhalation, insufflation, sublingually, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints. The dosage will depend on the route of administration, the severity ofthe disease, age and weight ofthe patient and other factors normally considered by the attending physician, when determining the individual regimen and dosage level as the most appropriate for a particular patient. An effective amount of a compound ofthe present invention for use in therapy of cancer is an amount sufficient to symptomatically relieve in a warm-blooded animal, particularly a human the symptoms of cancer, to slow the progression of cancer, or to reduce in patients with symptoms of cancer the risk of getting worse. For preparing pharmaceutical compositions from the compounds of this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. A solid carrier can be one or more substance, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. For preparing suppository compositions, a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify. Suitable carriers include magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like.
Some ofthe compounds ofthe present invention are capable of forming salts with various inorganic and organic acids and bases and such salts are also within the scope of this invention. Examples of such acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate, camphorsulfonate, choline, citrate, cyclohexyl sulfamate, diethylenediamine, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, maleate, methanesulfonate, meglumine, 2-naphthalenesulfonate, nitrate, oxalate, pamoate, persulfate, phenylacetate, phosphate, diphosphate, picrate, pivalate, propionate, quinate, salicylate, stearate, succinate, sulfamate, sulfanilate, sulfate, tartrate, tosylate (p-toluenesulfonate), trifluoroacetate, and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as aluminum, calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, ornithine, and so forth. Also, basic nitrogen-containing groups may be quaternized with such agents as: lower alkyl halides, such as methyl, ethyl, propyl, and butyl halides; dialkyl sulfates like dimethyl, diethyl, dibutyl; diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl halides; aralkyl halides like benzyl bromide and others. Non-toxic physiologically-acceptable salts are preferred, although other salts are also useful, such as in isolating or purifying the product. The salts may be formed by conventional means, such as by reacting the free base form ofthe product with one or more equivalents ofthe appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion-exchange resin. In order to use a compound ofthe formula (I) or a pharmaceutically acceptable salt thereof for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. In addition to the compounds ofthe present invention, the pharmaceutical composition of this invention may also contain, or be co-administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more disease conditions referred to herein. The term composition is intended to include the formulation ofthe active component or a pharmaceutically acceptable salt with a pharmaceutically acceptable carrier. For example this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols or nebulisers for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions. Liquid form compositions include solutions, suspensions, and emulsions. Sterile water or water-propylene glycol solutions ofthe active compounds may be mentioned as an example of liquid preparations suitable for parenteral administration. Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution. Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired. Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art. The pharmaceutical compositions can be in unit dosage form. In such form, the composition is divided into unit doses containing appropriate quantities ofthe active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities ofthe preparations, for example, packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms. Combinations The anti-cancer treatment defined herein may be applied as a sole therapy or may involve, in addition to the compound ofthe invention, conventional surgery or radiotherapy or _ _
chemotherapy. Such chemotherapy may include one or more ofthe following categories of anti-tumour agents:
(i) antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin);
(ii) cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5α-reductase such as finasteride; (iii) agents which inhibit cancer cell invasion (for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function); (iv) inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab [Herceptin™] and the anti-erbbl antibody cetuximab [C225]) , farnesyl ransferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors ofthe epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as
N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefϊtinib, AZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and
6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033)), for example inhibitors ofthe platelet-derived growth factor family and for example inhibitors ofthe hepatocyte growth factor family; (v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [Avastin™], compounds such as those disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds that work by other mechanisms (for example linomide, inhibitors of integrin αvβ3 function and angiostatin);
(vi) vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213; (vii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
(viii) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
(ix) immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies. Such conjoint treatment may be achieved by way ofthe simultaneous, sequential or separate dosing ofthe individual components ofthe treatment. Such combination products employ the compounds of this invention, or pharmaceutically acceptable salts thereof, within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range. Synthesis The compounds, or pharmaceutically acceptable salts thereof, ofthe present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds, or pharmaceutically acceptable salts thereof, ofthe present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the _ _
art. Such methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety by reference. The novel compounds, or pharmaceutically acceptable salts thereof, of this invention may be prepared using the reactions and techniques described herein. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description ofthe synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration ofthe experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions ofthe molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents, which are compatible with the reaction conditions, will be readily apparent to one skilled in the art and alternate methods must then be used. The invention will now be further described with reference to the following illustrative examples in which, unless stated otherwise:
(i) temperatures are given in degrees Celsius (°C); operations are carried out at room temperature or ambient temperature, that is, in a range of 18-25 °C;
(ii) organic solutions were dried over anhydrous sodium sulfate; evaporation of organic solvent was carried out using a rotary evaporator under reduced pressure (4.5 - 30 mmHg) with a bath temperature of up to 60 °C;
(iii) chromatography means flash chromatography on silica gel; thin layer chromatography
(TLC) was carried out on silica gel plates;
(iv) in general, the course of reactions was followed by TLC or liquid chromatography/mass spectroscopy (LC/MS) and reaction times are given for illustration only;
(v) final products have satisfactory proton nuclear magnetic resonance (NMR) spectra and/or mass spectra data;
(vi) yields are given for illustration only and are not necessarily those which can be obtained by diligent process development; preparations were repeated if more material was required; (vii) when given, NMR data is in the form of delta values for major diagnostic protons, given in part per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz in d6-DMSO unless otherwise stated; (viii) chemical symbols have their usual meanings; (ix) solvent ratio was given in volume: volume (v/v) terms.
(x) Purification ofthe compounds were carried out using one or more ofthe following methods: a) flash chromatography on regular silica gel; b) flash chromatography on silica gel using Isco Combiflash® separation system: RediSep normal phase flash column, flow rate, 30-40 ml/min; c) Gilson semiprep HPLC separation system: YMC pack ODS-AQ column, 100x20mm, S 5μm 12 nm, water (0.1% trifluoroacetic acid) and acetonitrile (0.1% trifluoroacetic acid) as solvents, 20 min run; d) Chemical reaction involving microwave condition were carried out in Smith Synthesizer with Personal Chemistry vials; and
(xvi) the following abbreviations have been used: DMF dimethylformamide; EtOAc ethyl acetate; EtOH ethanol; THF tetrahydrofuran; DIEA diisopropylethylamine; and DCM dichloromethane.
Example 1 N1-(,3-Cvclopropylpyrazol-5-ylVN3-(4-fluorobenzyl)benzene-1.3-diamine To a microwave vial (Personal Chemistry) was added Pd(OAc)2 (8 mg, 0.0355 mmol), 2-(di-tert-butylphosphino)biphenyl (21 mg, 0.071 mmol) (Wolfe, J. P. et alJ. Org. Chem. 2000, 65, 1158-1174), and ΝaOtBu (85 mg, 0.888 mmol). The vial was evacuated and refilled with nitrogen. To the mixture was added a solution of 3-bromo-N-(4-fluorobenzyl)aniline (Method 1, 100 mg, 0.355 mmol) in toluene (2 ml) and a solution of 3 -cyclopropyl- 1H- pyrazole-5-amine (52 mg, 0.425 mmol) in toluene (2 ml). The vial was then sealed and the mixture was heated overnight at 95°C. EtOAc was added to the reaction mixture and the solution was washed with water, brine and was concentrated. Combiflash® column chromatography (from 50% EtOAc in hexanes to 100% EtOAc) gave desired product (17 mg, 15% yield). NMR (CDC13) δ 0.67 (m, 2 H), 0.93 (m, 2 H), 1.78 (m, 1 H), 4.25 (s, 2 H), 5.58 (s, 1 H), 6.15 (dd, J= 12.0, 3.0 Hz, 1 H), 6.39 (m, 2 H), 7.01 (m, 3 H), 7.30 (dd, J= 9.0, 6.0 Hz, 2 H).
Example 2-4 Following a similar procedure to Example 1, the following compounds were synthesized via reaction of a suitable aryl bromide (method is also listed) and a suitable amine.
Figure imgf000031_0001
Example 5
(S)-N3-r5-Cvclopropyl-lH-ρyrazol-3-ylVNi-α-r4-fluorophenvnethylV4-nitrobenzene-1.3- diamine A mixture of 5-cyclopropyl-N-(5-fluoro-2-nitrophenyl)-lH-pyrazol-3-amine (Method 6; 0.27 g, 1.03 mmol), (S)-l-(4-fluoro-phenyl)-ethylamine (0.72 g, 5.15 mmol), and DIEA (0.27 ml, 1.54 mmol) in «-BuOΗ (5 ml) was heated in a sealed tube at 230 °C for 23 hrs. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane : EtOAc = 1 : 2) to give the title compound as a yellow solid (0.38 g, 97%). ΝMR (400 MHz) 12.25 (s, 1H), 10.14 (s, 1H), 7.87 (d, J= 9.6 Hz, 1H), 7.76 (d, J= 6.4 Hz, IH), 7.36 (m, 2H), 7.15 (m, 2H), 6.68 (s, IH), 6.22 (d, J= 8.4 Hz, IH), 5.60 (br, IH), 4.57 (m, IH), 1.87 (m, IH), 1.44 (d, J= 6.8 Hz, 3H), 0.98 (m, 2H), 0.70 (m 2H). MS: Calcd. 381; Found: [M+H]+ 382.
Examples 6-8 Following a similar procedure to Example 5, the following compounds were synthesized from a suitable pyrazole by reacting it with a suitable amine.
Figure imgf000032_0001
Example 9 (S)-4-(5-Cyclopropyl-lH-pyrazol-3-ylamino)-2-('l-(4-fluorophenyl')ethylamino')-5- nitrobenzonitrile A mixture of 4-(5-cyclopropyl-lH-pyrazol-3-ylamino)-2-fluoro-5-nitrobenzonitrile (Method 8; 3.0 g, 10.4 mmol), (S)-l-(4-fluoro-phenyl)-ethylamine (1.60 g, 11.5 mmol), and DIEA (2.3 ml, 13.1 mmol) in n-BuOΗ (20 ml) was heated in a sealed tube at 230 °C for 2 hrs. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane : EtOAc = 1 : 2) to give the title compound as a yellow solid (4.1 g, 97%). NMR (400 MHz) 12.41 (s, IH), 9.95 (s, IH), 8.39 (s, IH), 7.44 (m, 2H), 7.38 (d, J= 6.4 Hz, IH), 7.13 (m, 2H), 6.95 (s, IH), 5.68 (s, IH), 4.56 (m, IH), 1.91 (m, IH), 1.55 (d, J= 6.8 Hz, 3H), 0.96 (m, 2H), 0.72 (m 2H). MS: Calcd.: 406; Found: [M+H]+ 407.
Example 10 Following a similar procedure to Example 9, the following compounds were synthesized from a suitable pyrazole by reacting it with a suitable amine.
Figure imgf000033_0001
Example 11 rS)-N3-C5-Cvclopropyl-lH-pyrazol-3-ylV2-fluoro-N -ri-r4-fluorophenvnethvn-4- nitrobenzene- 1 ,3-diamine A mixture of 5-cyclopropyl-N-(2,3-difluoro-6-nitrophenyl)-lH-pyrazol-3-amine (Method 10; 0.400 g, 1.43 mmol), (S)-l-(4-fluoro-ρhenyl)-ethylamine (0.209 g, 1.50 mmol, and DIEA (0.373 ml, 2.14 mmol) in Η-BUOΗ (3 ml) was heated in a sealed tube at 160 °C for 8 hrs. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane : EtOAc = 4 : 1) to give the title compound as an orange solid (0.40 g, 70%). ΝMR (400 MHz) 11.95 (s, IH), 8.74 (s, IH), 7.72 (d, J= 9.2 Hz, IH), 7.43 (t, J= 7.0 Hz, 2H), 7.25 (d, J= 6.4 Hz, IH), 7.15 (t, J= 8.8 Hz, 2H), 6.26 (t, J= 8.6 Hz, IH), 5.63 (s, IH), 4.78 (m, IH), 1.84 (m, IH), 1.48 (d, J= 6.8 Hz, 3H), 0.91 (m, 2H), 0.66 (m, 2H). MS: Calcd.: 399; Found: [M+H]+ 400. Example 12 R -2-(3-(5-Cvcloρropyl-lH-pyrazol-3-ylaminoV2-fluoro-4-nitrophenylamino -2-("4- fluoropheny ethanol A mixture of 5-cyclopropyl-N-(2,3-difluoro-6-nitroρhenyl)-lH-ρyrazol-3-amine (Method 10; 0.400 g, 1.43 mmol), (R)-2-amino-2-(4-fluorophenyl)ethanol (0.257 g, 1.50 mmol), and DIEA (0.373 ml, 2.14 mmol) in n-BuOΗ (3 ml) was heated in a sealed tube under microwave at 180° C for 150 min. It was then placed in an oil bath at 160 °C for another 4 hrs. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane : EtOAc = 1 : 1) to give the title compound as an orange solid (0.23 g, 39%). ΝMR (400 MHz) 11.95 (s, IH), 8.74 (s, IH), 7.72 (d, J= 9.6 Hz, IH), 7.42 (m, 2H), 7.15 (t, J= 8.8 Hz, 2H), 7.02 (d, J= 4.4 Hz, IH), 6.23 (t, J= 8.6 Hz, IH), 5.63 (s, IH), 5.04 (t, J= 5.8 Hz, IH), 4.65 (m, IH), 3.61-3.74 (m, 2H), 1.84 (m, IH), 0.91 (m, 2H), 0.66 (m, 2H). MS: Calcd.: 415; Found: [M+H]+ 416.
Example 13 rS)-N;-(5-Cvclopropyl-lH-pyrazol-3-ylV4-fluoro-N3- -r4-fluorophenvnethylV6- nitrobenzene- 1.3-diamine A mixture of 5-cyclopropyl-N-(4,5-difluoro-2-nitrophenyl)-lH-pyrazol-3 -amine (Method 11; 0.300 g, 1.07 mmol), (S)-l-(4-fluoro-phenyl)-ethylamine (0.164 g, 1.18 mmol), and DIEA (0.280 ml, 1.61 mmol) in n-BuOΗ (2 ml) was heated in a sealed tube at 160 °C for 16 hrs. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane : EtOAc = 3 : 1) to give the title compound as an orange solid (0.360 g, 84%). ΝMR (400 MHz) 12.29 (s, IH), 10.14 (s, IH), 7.75 (d, J= 12.8 Hz, IH), 7.63 (d, J= 6.4 Hz, IH), 7.41 (m, 2H), 7.14 (t, J= 8.8 Hz, 2H), 7.00 (d, J= 8.0 Hz, IH), 5.63 (s, IH), 4.55 (m, IH), 1.90 (m, IH), 1.52 (d, J= 6.8 Hz, 3H), 0.98 (m, 2H), 0.71 (m, 2H). MS: Calcd.: 399; Found: [M+H]+ 400.
Example 14
(R -2-(5-("5-Cvclopropyl-lH-pyrazol-3-ylaminoV2-fluoro-4-nitrophenylamino -2-(4- fluorophenyPethanol A mixture of 5-cyclopropyl-N-(4,5-difluoro-2-nitrophenyl)-lH-pyrazol-3-amine (Method 11; 0.300 g, 1.07 mmol), (R)-2-amino-2-(4-fluorophenyl)ethanol (0.183 g, 1.18 mmol), and DIEA (0.280 ml, 1.61 mmol) in n-BuOΗ (2 ml) was heated in a sealed tube at 160 °C for 16 hrs. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane : EtOAc = 1 : 1) to give the title compound as an orange solid (0.250 g, 56%). NMR (400 MHz) 12.29 (s, IH), 10.13 (s, IH), 7.77 (d, J= 12.8 Hz, IH), 7.41 (m, J= 6.4 Hz, 3H), 7.15 (t, J= 8.8 Hz, 2H), 7.04 (d, J= 8.0 Hz, IH), 5.60 (s, IH), 5.08 (t, J= 5.8 Hz, IH), 4.45 (m, IH), 3.62-3.80 (m, 2H), 1.90 (m, IH), 0.98 (m, 2H), 0.71 (m, 2H). MS: Calcd.: 415; Found: [M+H]+ 416.
Example 15 rS)-N1-(5-Cvclopropyl-lH-Pyrazol-3-ylV2.4-difluoro- N3- -r4-fluorophenvDethyl)-6- nitrobenzene- 1.3-diamine A mixture of 5-cyclopropyl-N-(2,3,4-trifluoro-6-nitrophenyl)-lH-pyrazol-3-amine (Method 12, 0.300 g, 1.01 mmol), (S)-l-(4-fluoro-phenyl)-ethylamine (0.154 g, 1.11 mmol) and DIEA (0.263 ml, 1.51 mmol) in π-BuOΗ (2 ml) was heated in a sealed tube placed in an oil bath set at 135 °C for 8 hours. The solvent was removed under reduced pressure and the residue was purified by chromatography (hexane-EtOAc = 3 : 1) to give the title compound as an orange solid (0.30 g, 71%). ΝMR (400 MHz) 11.89 (s, IH), 8.57 (s, IH), 7.69 (d, J= 13.6 Hz, IH), 7.35 (m, 2H), 7.14 (t, J= 8.8 Hz, 2H), 6.81 (d, J= 7.6 Hz, IH), 5.39 (s, IH), 5.00 (m, IH), 1.80 (m, IH), 1.49 (d, J= 6.8 Hz, 3H), 0.90 (m, 2H), 0.62 (m, 2H). MS: Calcd.: 417; Found: [M+H]+ 418.
Example 16 Following a similar procedure to Example 15, the following compound was synthesized from a suitable pyrazole by reacting it with a suitable amine.
Figure imgf000035_0001
Example 17
(S)-2-(3-(5-Cyclopropyl-lH-pyrazol-3-ylamino -5-('l-(4-fluorophenyl ethylaminoV2- nitrophenylamino')ethanol A mixture of 2-(3-(5-cyclopropyl-lH-pyrazol-3-ylamino)-5-fluoro-2- nitrophenylamino)ethanol (Method 13, 0.47 g, 1.50 mmol), (S)-l-(4-fluoro-phenyl)- ethylamine (1.0 g, 7.3 mmol) and DIEA (0.31 ml, 1.80 mmol) in n-BuOΗ (5 ml) was stirred at 200 °C for 25 hrs. The solvent was removed under reduced pressure and the residue was purified by chromatography (EtOAc) to give the title compound as a red solid (0.35 g, 54%). NMR (400 MHz) 12.18 (s, IH), 10.81 (b, IH), 9.04 (b, IH), 7.55 (d, J= 6.4 Hz, IH), 7.36 (m, 2H), 7.15 (m, 2H), 6.25 (s, IH), 5.66 (b, IH), 5.22 (b, IH), 4.91 (s, IH), 4.63 (b, IH), 3.57 (m, 2H), 3.03-3.18 (m, 2H), 1.87 (m, IH), 1.42 (d, J= 6.4 Hz, 3H), 0.95 (m, 2H), 0.71 (m, 2H). MS: Calcd.: 440; Found: [M+H]+ 441.
Example 18 rS)-3-(5-Cvclopropyl-lH-pyrazol-3-ylamino -5-('l-(4-fluorophenyl)ethylaminoV2- nitrobenzonitrile The mixture of 3 -(5 -cyclopropyl- lH-pyrazol-3 -ylamino)-5 -fluoro-2-nitrobenzonitrile (Method 15, 3.50 g, 12.2 mmol), (S)-l-(4-fluoro-phenyl)-ethylamine (1.87 g, 13.4 mmol) and DIEA (2.6 ml, 14.6 mmol) in n-BuOΗ (15 ml) was stirred at 185 °C for 11 hrs. The solvent was removed under reduced pressure and the residue was purified by chromatography
(EtOAc) to give the title compound as an orange solid (4.40 g, 89%). NMR (400 MHz) 12.38 (s, IH), 10.12 (b, IH), 8.07 (d, J= 6.4 Hz, IH), 7.34 (m, 2H), 7.16 (m, 2H), 6.89 (b, IH), 6.77 (s, IH), 5.64 (b, IH), 4.55 (b, IH), 1.90 (m, IH), 1.45 (d, J= 6.8 Hz, 3H), 0.96 (m, 2H), 0.70 (m, 2H). MS: Calcd.: 406; Found: [M+H]+ 407.
Examples 19-28 The nitro compounds described herein may be reduced under standard reduction conditions to form the corresponding amino compounds. For example they can be reduced using H2 (atmospheric) with palladium on activated carbon or by using zinc dust with NH CI. For example the following amino compounds were prepared by reducing the corresponding nitro compound.
Figure imgf000037_0001
Preparation of starting materials: The starting materials for the Examples contained herein are either commercially available or are readily prepared by standard methods from known materials. For example the following reactions are illustrations but not limitations ofthe preparation of some ofthe starting materials and examples used herein.
Method 1 3-Bromo-N-f4-fluorobenzyr)aniline To a microwave vial (Personal chemistry) was added K2CO3 (601 mg, 4.35 mmol) and DMF (3 ml). To the mixture was added 3-bromoaniline (500 mg, 2.9 mmol) and 4-fluorobenzylbromide (548 mg, 2.9 mmol). The vial was then sealed and was subjected to Smith Synthesizer (140°C, 900 seconds). To the mixture was added EtOAc. The mixture was then washed with water and was concentrated. Combiflash® column chromatography (from 10% EtOAc in hexanes to 20% EtOAc in hexanes) gave the desired product (191 mg, 47% yield). ΝMR (CDCU) δ 4.06 (br s, 1 H), 4.23 (m, 2 H), 6.50 (m, 1 H), 6.74 (s, 1 H), 6.80 (m, 1 H), 7.00 (m, 3 H), 7.25 (m, 2 H).
Method 2
2- [(3 -BromophenvDamino] -2-f 4-fluorophenvDethanol To a solution of 2-(4-fluorophenyl)oxirane (690 mg, 5.0 mmol) in CH3CΝ (4 ml) was added LiClO4 (1.06 g, 10.0 mmol) (Chini, M. et alJ. Org. Chem. 1991, 56, 5939-5942) and the solution was stirred until the salt was dissolved. To the solution was added 3-bromo-4- chloroaniline (860 mg, 5.0 mmol) and the reaction mixture was stirred at 60°C for 18 hrs. Water was added and the mixture was extracted with EtOAc three times. The combined organic layers were concentrated. Combiflash® column chromatography (from 25% EtOAc in hexanes to 50% EtOAc in hexanes) gave the desired product as an oil (1.26 g, 82%). NMR (CDCI3) δ 3.65 (m, 1 H), 3.89 (m, 1 H), 4.40 (m, 1 H), 4.65 (br s, 1 H), 6.42 (m, 1 H), 6.70 (m, 1 H), 6.80 (m, 1 H), 6.90 (m, 1 H), 7.00 (m, 2 H), 7.25 (m, 2 H).
Method 3
3 -Bromo-4-chloroaniline A suspension of 3-bromo-4-chloronitrobenzene (2.5 g, 10.6 mmol) and tin chloride dihydrate (12.0 g, 52.9 mmol) (Keana, J. F. W. et al J. Med. Chem. 1995, 38, 4367-4379) in EtOAc (38 ml) and EtOH (19 ml) was stirred at 70°C for 1 hr. The resulting solution was added to crushed ice and was carefully neutralized with Na2CO3. The suspension was then extracted with EtOAc three times. The combined organic layers were concentrated to give the _ _
title compound (2.14 g, 99%). NMR (CDC13) δ 3.70 (br s, 2 H), 6.55 (m, 1 H), 6.90 (s, 1 H), 7.18 (m, 1 H).
Method 4 (2R -2-r('3-Bromo-4-chlorophenyl)amino1-2- 4-fluorophenvPethanol To a solution of (2S)-2-(4-fluorophenyl)oxirane (Method 5, 470 mg, 3.41 mmol) in CH3CN (4 ml) was added LiClO4 (725 mg, 6.82 mmol) and the solution was stirred until the salt dissolved. To the solution was added 3-bromo-4-chloroaniline (Method 3; 701 mg, 3.41 mmol) and the reaction mixture was stirred at 60 °C for 18 hrs. Water was added and the mixture was extracted with EtOAc three times. The combined organic layers were concentrated. Combiflash® column chromatography (from 25% EtOAc in hexanes to 50% EtOAc in hexanes) gave the desired product as an oil (918 mg, 78%). NMR (CDC13) δ 3.74 (m, 1 H), 3.95 (m, 1 H), 4.40 (m, 1 H), 4.65 (m, 1 H), 6.40 (m, 1 H), 6.80 (s, 1 H), 7.04 (m, 3 H), 7.30 (m, 2 H).
Method 5
(2S)-2-(4-Fluorophenyl)oxirane To a solution of [(S, S)-N, N'-bis(3,5-di-tert-butylsalicylidene)-l,2- cyclohexanesdiamineato(2-)]cobalt (II) (87.5 mg, 0.145 mmol) (Schaus, S. E. et alJ. Am. Chem. Soc. 2002, 124, 1307-1315) in toluene (2 ml) was added acetic acid (83 μl, 1.45 mmol). The solution was allowed to stir at room temperature (open to air) for 30 min. The colour ofthe solution turned to brown from orange. The solution was concentrated in vacuo to give a brown solid. The solid was then dissolved in 2-(4-fluorophenyl)oxirane (2.00 g, 14.5 mmol) and THF (1.7 ml) at room temperature. The reaction mixture was cooled down to 0°C and water (0.14 ml, 7.96 mmol) was added dropwise over 5 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 48 hrs. Water was then added and the mixture was extracted with EtOAc. Combiflash® column chromatography (from 10% EtOAc in hexanes to 20% EtOAc in hexanes) gave desired product (500 mg, 50% ofthe theoretical yield). NMR (CDC13) δ 2.88 (m, 1 H), 3.15 (m, 1 H), 3.82 (m, 1 H), 7.03 (m, 2 H), 7.25 (m, 2 H). The ee ofthe product was determined to be 90% by chiral GC analysis:
SUPELCO ALPHA DEX 120 Fused Silica Capillary Column (30 m x 0.25 mm x 0.25 μm); flow rate, 1.0 ml/min; temperature, 3 °C/min from 80 °C to 150 °C; retention time (major): 12.18 minute, retention time (minor): 12.31 minute. Method 6
5 -Cyclopropyl-N-f 5 -fluoro-2-nitrophenylV lH-ρyrazol-3 -amine To a solution of 2,4-difluoro-l -nitrobenzene (1.76 g, 11.1 mmol) and DIEA (1.93 ml, 11.1 mmol) in TΗF (20 ml) was added dropwise the solution of 5-cyclopropyl-lH-pyrazol-3- amine (0.91 g, 7.39 mmol) in TΗF (5 ml) at 25 °C. After addition, the reaction mixture was stirred at 80 °C for 48 hrs. The solvent was removed under reduced pressure and the resulted residue was purified by column chromatography (hexane : DCM : EtOAc = 2 : 1 : 1) to give the title compound as a yellow solid (0.62 g, 32%). ΝMR (400 MHz) 12.37 (s, IH), 9.83 (s, IH), 8.25 (m, IH), 7.98 (d, J= 11.2 Hz, IH), 6.75 (m, IH), 5.95 (s, IH), 1.90 (m, IH), 0.96 (m, 2H), 0.72 (m, 2H).
Method 7
N-(5-Fluoro-2-nitrophenyl)-5-isopropoxy-lH-pyrazol-3-amine To the solution of 2,4-difluoro-l -nitrobenzene (1.80 g, 11.0 mmol) and DIEA (1.93 ml, 11.0 mmol) in TΗF (20 ml) was added 5-isopropoxyl-lH-pyrazol-3-amine (1.30 g, 80% pure 7.4 mmol) at 25 °C. After addition, the reaction mixture was stirred at 105 °C for 48 hrs. The solvent was removed under reduced pressure and the resulted residue was purified by column chromatography (hexane : EtOAc = 5 : 1) to give the title compound as a yellow solid (0.22 g, 66% pure, 7%). MS: Calcd.: 280; Found: [M+Η]+ 281.
Method 8
4-(5-Cyclopropyl-lH-pyrazol-3-ylaminoV2-fluoro-5-nitrobenzonitrile To a solution of 2,4-difluoro-5-nitrobenzonitrile (Method 9, 5.0 g, 27 mmol) and DIEA (5.4 ml, 31 mmol) in TΗF (20 ml) was added dropwise the solution of 5-cyclopropyl- lH-pyrazol-3 -amine (3.2 g, 26 mmol) in TΗF (5 ml) at 0 °C. After addition, the reaction mixture was stirred at 25 °C for 1 hr. The solvent was removed under reduced pressure and the resulted residue was purified by column chromatography (hexane : EtOAc = 3 : 1) to give the title compound as a yellow solid (5.5 g, 74%). ΝMR (400 MHz) 12.54 (s, IH), 10.13 (s, IH), 8.78 (d, J= 7.2 Hz, IH), 8.10 (d, J= 13.6 Hz, IH), 6.02 (s, IH), 1.91 (m, IH), 0.97 (m, 2H), 0.72 (m, 2H). MS: Calcd.: 287; Found: [M+H]+ 288. Method 9
2.4-Difluoro-5-nitrobenzonitrile Potassium nitrate (16.4 g, 147.4 mmol) was added to concentrated H2SO4 (85 ml, 1582 mmol) at 0 °C, followed by slow addition of 2,4-difluorobenzonitrile (11.0 g, 79.1 mmol). The suspension was stirred at this temperature for an additional 4 hrs and quenched ice / water (800 ml). The resulting solid was collected by filtration and dried to give the title compound (13.8 g, 95%) as a white solid. NMR (400 MHz, CDC13) 8.48 (m, IH), 7.24 (m, IH).
Method 10 5-Cyclopropyl-N-(2,3-difluoro-6-nitrophenyl)-lH-pyrazol-3-amine To a solution of l,2,3-trifluoro-4-nitrobenzene (3.2 g, 18 mmol) and DIEA (4.2 ml, 24 mmol) in dry TΗF (20 ml) was added dropwise the solution of 5-cyclopropyl-lH-pyrazol-3- amine (2.0 g, 16 mmol) in TΗF (5 ml) at 0 °C. After addition, the reaction mixture was stirred at 25 °C for 21 hrs. The solvent was removed under reduced pressure and the resulted residue was purified by column chromatography (hexane : EtOAc = 5 : 2). Recrystallization from EtOAc (10 ml) and hexanes (~100 ml) gave the title compound as red crystals (1.5 g, 33%). ΝMR (400 MHz) 11.90 (s, IH), 8.78 (s, IH), 7.86 (t, J= 1.6 Hz, IH), 7.08 (q, J= 8.7 Hz, IH), 5.60 (s, IH), 1.83 (m, IH), 0.89 (m, 2 H), 0.65 (m, 2H). MS: Calcd.: 280; Found: [M+H]+ 281.
Method 11
5 -Cvclopropyl-N-(4, 5 -difluoro-2-nitrophenylV lH-pyrazol-3 -amine To a solution of l,2,4-trifluoro-5-nitrobenzene (3.0 g, 18 mmol) and DIEA (4.2 ml, 24 mmol) in dry TΗF (20 ml) was added dropwise the solution of 5 -cyclopropyl- lH-pyrazol-3- amine (2.0 g, 16 mmol) in TΗF (5 ml) at 0 °C. After addition, the reaction mixture was stirred at 25 °C for 20 hrs. It was then heated to 40 °C for 40 hrs. The solvent was removed under reduced pressure and the resulted residue was purified by column chromatography (hexane : EtOAc = 5 : 2). Recrystallization from EtOAc (10 ml) and hexanes (~100ml) gave the title compound as red crystals (0.8 g, 18%). ΝMR (400 MHz) 12.36 (s, IH), 9.79 (s, IH), 8.27 (m, 2H), 5.93 (s, IH), 1.90 (m, IH), 0.93 (m, 2H), 0.72 (m, 2H). MS: Calcd.: 280; Found: [M+H]+ 281. _ _
Method 12
5-Cyclopropyl-N-(2,3 ,4-trifluoro-6-nitrophenyl')- lH-pyrazol-3 -amine To the solution of l,2,3,4-tetrafluoro-5-nitrobenzene (3.0 g, 15.4 mmol) and DIEA (3.7 ml, 21.0 mmol) in dry TΗF (20 ml) was added 5 -cyclopropyl- lH-pyrazol-3 -amine (1.7 g, 14.0 mmol) in TΗF (5 ml) drop wise at 0 °C. After addition, the reaction mixture was stirred at 25 °C for 16 hours. The solvent was removed under reduced pressure and the resulted residue was purified by column chromatography (hexane-EtOAc = 4 : 1). This was then recrystalized from Et O (20ml) and hexanes (~150ml) to give the title compound as red crystals (0.650 g, 16%). ΝMR (400 MHz) 11.84 (s, IH), 8.67 (s, IH), 8.06 (m, IH), 5.57 (s, IH), 1.82 (m, IH), 0.89 (m,2 H), 0.65 (m, 2H). MS: Calcd.: 298; Found: [M+H]+ 299.
Method 13
2-('3-r5-Cvclopropyl-lH-pyrazol-3-ylamino -5-fluoro-2-nitrophenylamino ethanol The mixture of 5-cyclopropyl-N-(3,5-difluoro-2-nitrophenyl)-lH-pyrazol-3-amine (Method 14, 0.50 g, 1.80 mmol), 2-aminoethanol (0.12 g, 2.0 mmol) and DIEA (0.37 ml, 2.1 mmol) in n-BuOΗ (10 ml) was stirred at 70 °C for 7 hours. After cooled to 25 °C, ether (5 ml) was added. The resulted solid was collected by filtration, washed with ether (20 ml) and dried to give the title compound as a red solid (0.48 g, 84%). ΝMR (400 MHz) 12.34 (s, IH), 10.44 (s, IH), 8.87 (s, IH), 7.02 (d, J= 12.8 Hz, IH), 6.06 (dd, J= 14.4 Hz & 2.4 Hz, IH), 5.89 (s, IH), 5.00 (t, J= 5.2 Hz, IH), 3.66 (m, 2H), 3.30 (m, 2H), 1.89 (m, IH), 0/94 (m, 2H), 0.71 (m, 2H). MS: Calcd.: 321; Found: [M+H]+ 322.
Method 14
5-Cyclopropyl-N-('3.5-difluoro-2-nitrophenyl)-lH-pyrazol-3-amine The solution of l,3,5-trifluoro-2-nitrobenzene (6.50 g, 37 mmol), 5 -cyclopropyl- 1H- pyrazol-3 -amine (3.50 g, 28 mmol) and DIEA (6.4 ml, 37 mmol) in TΗF (100 ml) was stirred at 25 °C for 80 hours. The solvent was removed under reduced pressure and the residue was purified by chromatography (DCM-EtOAc = 10 : 1) to give the title compound as yellow solid (4.9 g, 62%). ΝMR (400 MHz) 12.26 (s, IH), 9.09 (s, IH), 7.70 (d, J= 12.8 Hz, IH), 6.88 (m, IH), 5.80 (s, IH), 1.88 (m, IH), 0.93 (m, 2H), 0.69 (m, 2H). _ _
Method 15
3 -(5 -Cyclopropyl- lH-pyrazol-3 -ylaminoV 5-fluoro-2-nifrobenzonitrile The solution of 3,5-difluoro-2-nitrobenzonitrile (Method 16; 5.80 g, 31.5 mmol), 5- cyclopropyl-lH-pyrazol-3-amine (4.66 g, 37.8 mmol) and DIEA (5.5 ml, 31.5 mmol) in TΗF (100 ml) was stirred at 25 °C for 20 hours. The solvent was removed under reduced pressure and the residue was purified by chromatography (DCM-EtOAc = 10 : 1) to give the title compound as a yellow solid (5.50 g, 61%). NMR (400 MHz) 12.43 (s, IH), 9.70 (s, IH), 8.22 (d, J= 12.0 Hz, IH), 7.51 (d, J= 5.2 Hz, IH), 5.92 (s, IH), 1.89 (m, IH), 0.95 (m, 2H), 0.71 (m, 2H). Rt 3.19 min. MS: Calcd.: 287; Found: [M+H]+ 288.
Method 16
3,5-Difluoro-2-nitrobenzonitrile Potassium nitrate (6.56 g, 64.8 mmol) in concentrated sulfuric acid (34 ml, 633 mmol) was cooled to 0 °C. To which was added 3,5-diflouorobenzonitrile (4.40 g, 31.6 mmol) slowly. The resulting suspension was stirred at this temperature for an additional 3 hours. Ice water (500 ml) was added. The resulting solid was collected by filtration, washed with water (100 ml) and dried to give the title compound as white solid (5.55 g, 95%). 1H NMR (400 MHz, CDC13) δ 7.42-7.44 (m, IH), 7.33-7.38 (m, IH).
Utility The compounds ofthe present invention have utility for the treatment of cancer by inhibiting the tyrosine kinases, particularly the Trks and more particularly Trk A and B. Methods of treatment target tyrosine kinase activity, particularly the Trk activity and more particularly Trk A and B activity, which is involved in a variety of cancer related processes. Thus, inhibitors of tyrosine kinase, particularly the Trks and more particularly Trk A and B, are expected to be active against neoplastic disease such as carcinoma ofthe breast, ovary, lung, colon, prostate or other tissues, as well as leukemias and lymphomas, tumours ofthe central and peripheral nervous system, and other tumour types such as melanoma, fibrosarcoma and osteosarcoma. Tyrosine kinase inhibitors, particularly the Trk inhibitors and more particularly Trk A and B inhibitors are also expected to be useful for the treatment other proliferative diseases including but not limited to autoimmune, inflammatory, neurological, and cardiovascular diseases. Compounds ofthe present invention have been shown to inhibit tyrosine kinases, particularly the Trks and more particularly Trk A and B, as determined by the Trk B Assay described herein.
Compounds provided by this invention should also be useful as standards and reagents in determining the ability of a potential pharmaceutical to inhibit tyrosine kinases, particularly the Trks and more particularly Trk A and B. These would be provided in commercial kits comprising a compound of this invention TrkB Assay Format TrkB kinase activity was measured for its ability to phosphorylate synthetic tyrosine residues within a generic polypeptide substrate using an Amplified Luminescent Proximity Assay (Alphascreen) technology (PerkinElmer, 549 Albany Street, Boston, MA). To measure TrkB kinase activity, the intracellular domain of a HIS-tagged human TrkB kinase (amino acids 455 to 822 of TrkB, Swiss-Prot Primary Accession Number Q 16620) was expressed in SF9 cells and purified using standard nickel column chromatography. After incubation ofthe kinase with a biotinylated substrate and adenosine triphosphate (ATP) for 45 minutes at room temperature, the kinase reaction was stopped by the addition of 30mM ethylenediaminetetraacetic acid (EDTA). The reaction was performed in 384 well microtitre plates and reaction products were detected with the addition of strepavidinb coated Donor Beads and phosphotyrosine-specific antibodie coated Acceptor Beads using a EnVision Multilabel Plate Reader after an overnight incubation at room temperature.
Figure imgf000044_0001
Figure imgf000045_0001
Although the pharmacological properties ofthe compounds ofthe formula (I) vary with structural change, in general activity possessed by compounds ofthe formula (I) may be demonstrated at IC5o concentrations (concentrations to achieve 50% inhibition) or doses in the range of (0.01 μM to 10 μM). Trk A Assay Format Trk A kinase activity was measured for its ability to phosphorylate synthetic tyrosine residues within a generic polypeptide substrate using an Amplified Luminescent Proximity Assay (Alphascreen) technology (PerkinElmer, 549 Albany Street, Boston, MA). To measure Trk A kinase activity, the intracellular domain of a HIS-tagged human Trk A kinase (amino acids 442-796 of Trk A, Swiss-Prot Primary Accession Number P04629) was expressed in SF9 cells and purified using standard nickel column chromatography. After incubation ofthe kinase with a biotinylated substrate and adenosine triphosphate (ATP) for 20 minutes at room temperature, the kinase reaction was stopped by the addition of 30 mM ethylenediaminetetraacetic acid (EDTA). The reaction was performed in 384 well microtitre plates and the reaction products were detected with the addition of strepavidin coated Donor Beads and phosphotyrosine-specific antibodies coated Acceptor Beads using the EnNision Multilabel Plate Reader after an overnight incubation at room temperature.
Figure imgf000045_0002
Although the pharmacological properties ofthe compounds ofthe formula (I) vary with structural change, in general activity possessed by compounds ofthe formula (I) may be demonstrated at IC50 concentrations (concentrations to achieve 50% inhibition) or doses in the range of (0.01 μM to 10 μM). When tested in the above in- vitro assay the Trk A inhibitory activity ofthe following examples was measured at the following IC50S.
Figure imgf000046_0001

Claims

Claims:
A compound formula (I):
Figure imgf000047_0001
(I) wherein: A is a direct bond or Cι-2alkylene; wherein said Cι-2alkylene may be optionally substituted by one or more R22; Ring C is carbocyclyl or heterocyclyl; R1 and R4 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Cι-6alkyl, C2-6alkenyl, C2-6alkynyl, Cι-6alkoxy, Cι-6alkanoyl, Cι-6alkanoyloxy, N-(Cι-6alkyl)amino, N,N-(C1-6alkyl)2amino, Cι-6alkanoylamino,
Figure imgf000047_0002
N,N-(Cι-6alkyl)2carbamoyl, Cι-6alkylS(O)a wherein a is 0 to 2, Cι-6alkoxycarbonyl, ^(Ci.θalky^sulphamoyl, N,N-(Cι-6alkyl)2sulphamoyl, Cι.6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R1 and R4 independently of each other may be optionally substituted on carbon by one or more R8; and wherein if said heterocyclyl contains an -ΝH- moiety that nitrogen may be optionally substituted by a group selected from R9; » R2 is selected from hydrogen, halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Cι-6alkyl, C2-6alkenyl, C2-6alkynyl, Cι-6alkoxy, Cι-6alkanoyl, Cι-6alkanoyloxy,
Figure imgf000047_0003
N,N-(C1-6alkyl)2amino, Cι-6alkanoylamino, N-(Cι.6alkyl)carbamoyl, N,N-(Cι-6alkyl)2carbamoyl, Cι-6alkylS(O)a wherein a is 0 to 2, C ^alkoxycarbonyl, N-(Cι-6alkyl)sulphamoyl, N,N-(C1.6alkyl)2sulphamoyl, Ci-βalkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R2 may be optionally substituted on carbon by one or more R10; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R11; R3 is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Cι-6alkyl, C2-6alkenyl, C2-6alkynyl, -βalkoxy, Cι-6alkanoyl, C!-6alkanoyloxy, N-(Cι-6alkyl)amino, N,N-(C1-6alkyl)2amino,
Cι-6alkanoylamino, N-(Cι-6alkyl)carbamoyl, N,N-(Cι-6alkyι)2carbamoyl, Cι-6alkylS(O)a wherein a is 0 to 2, Cι-6alkoxycarbonyl, N-(Cι.6alkyl)sulphamoyl,
N,N-(Cι-6alkyl)2sulphamoyl, -ealkylsulphonylamino, carbocyclyl or heterocyclyl; wherein
R3 may be optionally substituted on carbon by one or more R12; and wherein if said heterocyclyl contains an -ΝH- moiety that nitrogen may be optionally substituted by a group selected from R13; R5 is hydrogen or optionally substituted Ci-βalkyl; wherein said optional substituents are selected from one or more R14; R6 is independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Cι-6alkyl, C2-6alkenyl, C2-6alkynyl, dialkoxy, Cι-6alkanoyl, Cι-6alkanoyloxy, N-(Cι-6alkyl)amino, N,N-(Cι-6alkyl)2amino, d-ealkanoylamino,
Figure imgf000048_0001
N,N-(Cι-6alkyl)2carbamoyl, Cι-6alkylS(O)a wherein a is 0 to 2, Cι-6alkoxycarbonyl, N-(Cι-6alkyl)sulphamoyl,
N,N-(Cι-6alkyl)2sulphamoyl, Cι-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R6 independently of each other may be optionally substituted on carbon by one or more R15; and wherein if said heterocyclyl contains an -ΝH- moiety that nitrogen may be optionally substituted by a group selected from R16; or two adjacent R6 groups together with the phenyl bond to which they are attached form a 5 or 6 membered carbocyclic ring or heterocyclic ring wherein said ring is fused to the phenyl of formula (I); and wherein said carbocyclic ring or heterocyclic ring may be optionally substituted on carbon by one or more R17; and wherein if said heterocyclic ring contains an -ΝH- moiety that nitrogen may be optionally substituted by a group selected from
R 18. n is 0, 1, 2 or 3; wherein the values of R3 may be the same or different; m is 0-4; wherein the values of R6 may be the same or different; R8, R10, R12, R14, R15, R17 and R22 are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C].6alkyl, C2.6alkenyl, C2.6alkynyl, Cι-6alkoxy, Cι-6alkanoyl, -βalkanoyloxy, N-(Cι-6alkyl)amino, N,N-(Cι-6alkyl)2amino, Cι-6alkanoylamino, N-(Cι-6alkyl)carbamoyl, N,N-(Cι-6alkyl)2carbamoyl, Cι-6alkylS(O)a wherein a is 0 to 2, Cι-6alkoxycarbonyl, N-(Cι-6alkyl)sulphamoyl, N,N-(C1-6alkyl)2sulphamoyl, Ci-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R8, R10, R12, R14, R15, R17 and R22 independently of each other may be optionally substituted on carbon by one or more R19; and wherein if said heterocyclyl contains an -ΝH- moiety that nitrogen may be optionally substituted by a group selected from R20; R9, R11, R13, R16, R18 and R20 are independently selected from Cι-6alkyl,
Figure imgf000049_0001
Cι-6alkylsulphonyl, Cι-6alkoxycarbonyl, carbamoyl, N-(Cι-6alkyl)carbamoyl, N,N-(Cι-6alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl; wherein R9, R11, R13, R16, R18 and R20 independently of each other may be optionally substituted on carbon by on or more R ; R19 and R21 are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Cι-6alkyl, C2-6alkenyl, C2-6alkynyl, Cι-6alkoxy, Cι-6alkanoyl, Cι-6alkanoyloxy, N-(Cι-6alkyl)amino, N,N-(Cι-6alkyl)2amino, Cι-6alkanoylamino, N-(Cι-6alkyl)carbamoyl, N,N-(Ci-6alkyl)2carbamoyl, Cι-6alkylS(O)a wherein a is 0 to 2, Cι-6alkoxycarbonyl, N-(Cι-6alkyl)sulphamoyl, N,N-(C1-6alkyl)2sulphamoyl, Cι-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R19 and R21 independently of each other may be optionally substituted on carbon by one or more R23; and wherein if said heterocyclyl contains an -ΝH- moiety that nitrogen may be optionally substituted by a group selected from R ; R23 is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,
N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl, N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl or N-methyl-N-ethylsulphamoyl; and R24 is selected from Ci-βalkyl, Cι-6alkanoyl, Cι-6alkylsulphonyl, Cι-6alkoxycarbonyl, carbamoyl, N-(Cι-6alkyl)carbamoyl, N,N-(Cι-6alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl; or a pharmaceutically acceptable salt thereof.
2. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 wherein A is a direct bond.
3. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in either of claims 1 or 2 wherein Ring C is carbocyclyl.
4. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-3 wherein R1 and R4 are independently selected from hydrogen, Cι-6alkyl, -βalkoxy and carbocyclyl.
5. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-4 wherein R2 is selected from hydrogen or Cι-6alkyl; wherein R2 may be optionally substituted on carbon by one or more R10; wherein R10 is hydroxy.
6. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-5 wherein R3 is halo.
7. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-6 wherein R6 is independently selected from halo, nitro, cyano, amino and N-(Cι-6alkyl)amino; wherein R6 independently of each other may be optionally substituted on carbon by one or more R15; wherein R15 is selected from hydroxy.
8. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-7 wherein n is 1.
9. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-8 wherein m is 0-3; wherein the values of R6 may be the same or different.
10. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-9 wherein R5 is hydrogen.
11. A compound of formula (I) :
Figure imgf000051_0001
(I) wherein: A is a direct bond; Ring C is phenyl; R1 is selected from t-butyl, isopropoxy and cyclopropyl; R2 is selected from hydrogen, methyl or hydroxymethyl; R3 is fluoro; R4 is hydrogen; R5 is hydrogen; R6 is independently selected from fluoro, chloro, nitro, cyano, amino and 2-hydroxy ethylamino ; n is 1; m is 0-3; wherein the values of R6 may be the same or different; or a pharmaceutically acceptable salt thereof.
11. A compound of formula (I) :
Figure imgf000052_0001
(I) selected from:
N1-(3-Cyclopropylpyrazol-5-yl)-N3-(α-(R)-hydroxymethyl-4-fluorobenzyl)-6-chlorobenzene-
1,3 -diamine;
(R)-2-(5-(5-Cyclopropyl-lH-pyrazol-3-ylamino)-2-fluoro-4-nitrophenylamino)-2-(4- fluorophenyl)ethanol;
(S)-N;-(5-Cyclopropyl-lH-pyrazol-3-yl)-4-fluoro-N5-(l-(4-fluorophenyl)ethyl)-6- nitrobenzene- 1 ,3-diamine;
(R)-4-(5-Cyclopropyl-lΗ-pyrazol-3-ylamino)-2-(l-(4-fluorophenyl)-2-hydroxyethylamino)-
5-nitrobenzonitrile;
(S)-4-(5-Cyclopropyl-lH-pyrazol-3-ylamino)-2-(l-(4-fluorophenyl)ethylamino)-5- nitrobenzonitrile;
(S)-2-(3-(5-Cyclopropyl-lH-pyrazol-3-ylamino)-5-(l-(4-fluorophenyl)ethylamino)-2- nitrophenylamino)ethanol; or a pharmaceutically acceptable salt thereof.
12. A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim 1, which process comprises of: Process a) reaction of a compound of formula (II) :
Figure imgf000052_0002
(II) wherein Pg is a nitrogen protecting group; with a compound of formula (HI):
Figure imgf000053_0001
(III) wherein L is a displaceable group;
Process b) for compounds of formula (I) wherein R2 is hydroxymethyl; reaction of a compound of formula (II) with an epoxide of formula (IV):
Figure imgf000053_0002
(IV)
Process c) reacting a compound of formula (V):
Figure imgf000053_0003
(V) with hydrazine;
Process d) reacting a compound of formula (VI):
Figure imgf000054_0001
(VI) wherein Pg is a nitrogen protecting group and L is a displaceable group; with a compound of formula (VII):
Figure imgf000054_0002
(VII)
Process e) reacting a compound of formula (Vffl):
Figure imgf000054_0003
(VIII) wherein L is a displaceable group; with a compound of formula (IX):
Figure imgf000054_0004
(IX) wherein Pg is a nitrogen protecting group; Process j reacting a compound of formula (X):
Figure imgf000055_0001
(X) with a compound of formula (XI):
Figure imgf000055_0002
(XI) wherein L is a displaceable group and Pg is a nitrogen protecting group; and thereafter if necessary: i) converting a compound ofthe formula (I) into another compound ofthe formula (I); ii) removing any protecting groups; iii) forming a pharmaceutically acceptable salt.
13. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-11, together with at least one pharmaceutically acceptable carrier, diluent or excipient.
14. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-11, for use as a medicament.
15. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 - 11 , for use in the manufacture of a medicament for use in the inhibition of Trk activity. - 33 -
16. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-11, for use in the manufacture of a medicament for use in the treatment or prophylaxis of cancer.
17. The use according to claim 16 wherein said cancer is selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, ewings tumour, neuroblastoma, kaposis sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer, and small cell lung cancer, gastric cancer, head and neck cancer, renal cancer, lymphoma, leukaemia, tumours ofthe central and peripheral nervous system, melanoma, fibrosarcoma and osteosarcoma.
18. A compound ofthe formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 - 11 , for use in the manufacture of a medicament for use in the treatment or prophylaxis of cancers, fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation in a warm-blooded animal such as man.
19. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-11 , for use in the manufacture of a medicament for use in the production of an anti-proliferative effect.
20. A method of inhibiting Trk activity comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-11.
21. A method for the treatment or prophylaxis of cancer comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-11.
22. The method according to claim 21 wherein said cancer is selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, ewings tumour, neuroblastoma, _ _
kaposis sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer, and small cell lung cancer, gastric cancer, head and neck cancer, renal cancer, lymphoma, leukaemia, tumours ofthe central and peripheral nervous system, melanoma, fibrosarcoma and osteosarcoma.
23. A method for the treatment or prophylaxis of cancers, fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation in a warm-blooded animal such as man comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-11.
24. A method of producing an anti-proliferative effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-11.
25. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-11, together with at least one pharmaceutically acceptable carrier, diluent or excipient for use in the inhibition of Trk activity.
26. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-11, together with at least one pharmaceutically acceptable carrier, diluent or excipient for use in the treatment or prophylaxis of cancer.
27. The use according to claim 26 wherein said cancer is selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, ewings tumour, neuroblastoma, kaposis sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer, and small cell lung cancer, gastric cancer, head and neck cancer, renal cancer, lymphoma, leukaemia, tumours ofthe central and peripheral nervous system, melanoma, fibrosarcoma and osteosarcoma.
28. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-11, together with at least one pharmaceutically acceptable carrier, diluent or excipient for use in the treatment or prophylaxis of cancers, fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation.
29. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-11, together with at least one pharmaceutically acceptable carrier, diluent or excipient for use in the production of an anti-proliferative effect in a warm-blooded animal such as man.
30. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-11, for use in the inhibition of Trk activity.
31. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-11, for use in the treatment or prophylaxis of cancer.
32. The use according to claim 31 wherein said cancer is selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, ewings tumour, neuroblastoma, kaposis sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer, and small cell lung cancer, gastric cancer, head and neck cancer, renal cancer, lymphoma, leukaemia, tumours ofthe central and peripheral nervous system, melanoma, fibrosarcoma and osteosarcoma.
33. A compound ofthe formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-11, for use in the treatment or prophylaxis of cancers, fibroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acute and chronic inflammation, bone diseases and ocular diseases with retinal vessel proliferation in a warm-blooded animal such as man.
34. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 - 11 , for use in the production of an anti-proliferative effect.
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