WO2021084265A1 - Dérivés d'isoquinoléine en tant qu'inhibiteurs de sik2 - Google Patents

Dérivés d'isoquinoléine en tant qu'inhibiteurs de sik2 Download PDF

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Publication number
WO2021084265A1
WO2021084265A1 PCT/GB2020/052745 GB2020052745W WO2021084265A1 WO 2021084265 A1 WO2021084265 A1 WO 2021084265A1 GB 2020052745 W GB2020052745 W GB 2020052745W WO 2021084265 A1 WO2021084265 A1 WO 2021084265A1
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alkyl
cycloalkyl
halogen
alkoxy
haloalkyl
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PCT/GB2020/052745
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English (en)
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Mairi Sime
Justin Bower
Duncan Mcarthur
Angelo PUGLIESE
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Cancer Research Technology Limited
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Publication of WO2021084265A1 publication Critical patent/WO2021084265A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the compounds of Formula I and their salts and solvates inhibit salt-inducible kinases (SIK), in particular SIK2, and may be used to treat diseases or conditions mediated, at least in part, by aberrant SIK activity.
  • SIK salt-inducible kinases
  • compositions comprising at least one compound of Formula I and/or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient.
  • the present application also provides methods of treating a disease or condition mediated, at least in part, by aberrant SIK activity (for instance, a proliferative disorder, a benign neoplasm, pathological angiogenesis, an inflammatory disease or condition, a musculoskeletal disease or condition, an autoimmune disease, a haematological disease or condition, a neurological disease or condition, a psychiatric disorder, or a metabolic disorder) comprising administering to a subject in need a compound of Formula I and/or a pharmaceutically acceptable salt or solvate thereof.
  • SIK activity for instance, a proliferative disorder, a benign neoplasm, pathological angiogenesis, an inflammatory disease or condition, a musculoskeletal disease or condition, an autoimmune disease, a haematological disease or condition, a neurological disease or condition, a psychiatric disorder, or a metabolic disorder
  • Protein kinases play a central role in cellular activation processes. Aberrant kinase activity has been observed in many diseases states including benign and malignant proliferative disorders as well as diseases resulting from inappropriate activation of the immune or nervous system.
  • Salt-inducible kinase is a serine/threonine protein kinase that belongs to the sucrose non-fermenting 1 /AMP-activated protein kinase (SNF1/AMPK) family.
  • the SIK family comprises three isoforms, namely, SIK1, SIK2, and SIK3, all of which may act as metabolic transmitters.
  • SIK2 modulates various biological functions and acts as a signal transmitter in various pathways.
  • SIK2 has been shown to function in diverse biological processes, including gluconeogenesis, neuronal survival, melanogenesis, hepatic steatosis, and centrosome splitting (1-5).
  • SIK2 is also implicated in the progression of cancer (1, 6-8) and the expression of SIK2 has been found to be significantly higher in multiple types of tumors.
  • SIK expression is significantly different from that in adjacent tissues in cancers such as breast cancer, lung cancer, melanoma, primary liver cancer, and ovarian cancer, (1, 3, 5, 9 -11).
  • WO 2018/009544 describes small molecule inhibitors of SIK2 in vitro. Furthermore, other small molecule inhibitors have shown promise in anticancer models (12-14).
  • SIK small molecule inhibitors of SIK, and in particular SIK2, in order to realise a therapeutically effective drug for treatment of diseases caused by aberrant activity of SIK, in particular SIK2.
  • the present invention provides alternative and/or improved compounds which inhibit SIK2.
  • the present invention provides a compound of Formula I as defined herein, and/or a salt or solvate thereof.
  • the present invention provides a pharmaceutical composition which comprises a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients.
  • the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in therapy.
  • the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a disease or condition associated with aberrant activity of salt-inducible kinase (SIK).
  • SIK salt-inducible kinase
  • the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a proliferative disorder, a benign neoplasm, pathological angiogenesis, an inflammatory disease or condition, a musculoskeletal disease or condition, an autoimmune disease, a haematological disease or condition, a neurological disease or condition, a psychiatric disorder, or a metabolic disorder.
  • the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a cancer.
  • the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of a disease or condition associated with aberrant activity of salt-inducible kinase (SIK).
  • SIK salt-inducible kinase
  • the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of a proliferative disorder, a benign neoplasm, pathological angiogenesis, an inflammatory disease or condition, a musculoskeletal disease or condition, an autoimmune disease, a haematological disease or condition, a neurological disease or condition, a psychiatric disorder, or a metabolic disorder.
  • the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of a cancer.
  • the present invention provides a method of treating a disease or condition associated with aberrant activity of salt-inducible kinase (SIK), said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof.
  • SIK salt-inducible kinase
  • the present invention provides a method of treating a proliferative disorder, a benign neoplasm, pathological angiogenesis, an inflammatory disease or condition, a musculoskeletal disease or condition, an autoimmune disease, a haematological disease or condition, a neurological disease or condition, a psychiatric disorder, or a metabolic disorder, said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a method of treating a cancer, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.
  • the present invention provides a combination comprising a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, as defined herein, with one or more additional therapeutic agents.
  • references to the various sub formulae of formula I encompass isomers of the described compounds as listed above, unless specifically described to the contrary.
  • C a-b alkyl indicates an alkyl moiety having the integer “a” to the integer “b” number of carbon atoms, inclusive.
  • Certain moieties may also be described according to the minimum and maximum number of members with or without specific reference to a particular atom or overall structure.
  • the terms “a to b membered ring” or “having between a to b members” refer to a moiety having the integer “a” to the integer “b” number of atoms, inclusive.
  • alkyl and alkyl group refer to a branched or unbranched saturated hydrocarbon chain. Unless specified otherwise, alkyl groups typically contain 1-10 carbon atoms, such as 1-6 carbon atoms or 1-4 carbon atoms or 1-3 carbon atoms, and can be substituted or unsubstituted.
  • Representative examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n- butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, tert-butyl, isobutyl, etc.
  • alkylene and “alkylene group” refer to a divalent branched or unbranched saturated hydrocarbon chain, i.e. which has two points of attachment to the remainder of the molecule. Unless specified otherwise, alkylene groups typically contain 1-10 carbon atoms, such as 1-6 carbon atoms or
  • 1-3 carbon atoms and can be substituted or unsubstituted.
  • Representative examples include, but are not limited to, methylene (-CH 2 -), the ethylene isomers (-CH(CH 3 )- and -CH 2 CH 2 -), the propylene isomers (-CH(CH 3 )CH 2 -, -CH(CH 2 CH 3 )-, -C(CH 3 ) 3 -, and -CH 2 CH 2 CH 2 -), etc.
  • alkenyl and alkenyl group refer to a branched or unbranched hydrocarbon chain containing at least one double bond. Unless specified otherwise, alkenyl groups typically contain 2-10 carbon atoms, such as 2-6 carbon atoms or 2-4 carbon atoms, and can be substituted or unsubstituted. Representative examples include, but are not limited to, ethenyl, 3-buten-1-yl,
  • alkynyl and alkynyl group refer to a branched or unbranched hydrocarbon chain containing at least one triple bond. Unless specified otherwise, alkynyl groups typically contain 2-10 carbon atoms, such as 2-6 carbon atoms or 2-4 carbon atoms, and can be substituted or unsubstituted. Representative examples include, but are not limited to, ethynyl, 3-butyn-1-yl, propynyl, 2-butyn-1-yl, and 3-pentyn-1-yl.
  • aromatic refers to monocyclic and polycyclic ring systems containing 4n+2 pi electrons, where n is an integer.
  • Aromatic should be understood as referring to and including ring systems that contain only carbon atoms (i.e. “aryl”) as well as ring systems that contain at least one heteroatom selected from N, O or S (i.e. “heteroaromatic” or “heteroaryl”).
  • An aromatic ring system can be substituted or unsubstituted.
  • non-aromatic refers to a monocyclic or polycyclic ring system having at least one double bond that is not part of an extended conjugated pi system.
  • non-aromatic refers to and includes ring systems that contain only carbon atoms as well as ring systems that contain at least one heteroatom selected from N, O or S.
  • a non-aromatic ring system can be substituted or unsubstituted.
  • aryl and aryl group refer to phenyl and 7-15 membered bicyclic or tricyclic hydrocarbon ring systems, including bridged, spiro, and/or fused ring systems, in which at least one of the rings is aromatic.
  • Aryl groups can be substituted or unsubstituted. Unless specified otherwise, an aryl group may contain 6 ring atoms (i.e., phenyl) or a ring system containing 9 to 15 atoms, such as 9 to 11 ring atoms, or 9 or 10 ring atoms.
  • Representative examples include, but are not limited to, naphthyl, indanyl, 1 ,2,3,4-tetrahydronaphthalenyl, 6,7,8,9-tetrahydro-5H- benzocycloheptenyl, and 6,7,8,9-tetrahydro-5H-benzocycloheptenyl.
  • an aryl group is phenyl and naphthyl, suitably phenyl.
  • arylene and arylene group refer to a phenylene (-C 6 H 4 -) or to 7 to 15 membered bicyclic or tricyclic hydrocarbon ring systems, including bridged, spiro, and/or fused ring systems, in which at least one of the rings is aromatic.
  • Arylene groups can be substituted or unsubstituted.
  • an arylene group may contain 6 (i.e., phenylene) ring atoms or be a ring system containing 9 to 15 atoms; such as 9 to 11 ring atoms; or 9 or 10 ring atoms.
  • Arylene groups can be substituted or unsubstituted.
  • alkylaryl and alkylaryl group refer to an alkyl group in which a hydrogen atom is replaced by an aryl group, wherein alkyl group and aryl group are as previously defined, such as, for example, benzyl (C 6 H 5 CH 2 -). Alkylaryl groups can be substituted or unsubstituted.
  • Carbocyclic group and “carbocycle” refer to monocyclic and polycyclic ring systems that contain only carbon atoms in the ring(s), i.e., hydrocarbon ring systems, without regard or reference to aromaticity or degree of unsaturation.
  • carbocyclic group should be understood as referring to and including ring systems that are fully saturated (such as, for example, a cyclohexyl group), ring systems that are aromatic (such as, for example, a phenyl group), as well as ring systems having fully saturated, aromatic and/or unsaturated portions (such as, for example, cyclohexenyl, 2,3-dihydro-indenyl, and 1,2,3,4-tetrahydro- naphthalenyl).
  • the terms carbocyclic and carbocycle further include bridged, fused, and spirocyclic ring systems.
  • cycloalkyl and cycloalkyl group refer to a non-aromatic carbocyclic ring system, that may be monocyclic, bicyclic, or tricyclic, saturated or unsaturated, and may be bridged, spiro, and/or fused.
  • a cycloalkyl group may be substituted or unsubstituted. Unless specified otherwise, a cycloalkyl group typically contains from 3 to 12 ring atoms.
  • a cycloalkyl group may contain 4 to 10 ring atoms (e.g., 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, etc.).
  • Representative examples include, but are not limited to, cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, norbornyl, norbornenyl, bicyclo[2.2.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.1]heptene, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[3.3.2]decane.
  • alkylcycloalkyl and “alkylcycloalkyl group” refer to an alkyl group in which a hydrogen atom is replaced by a cycloalkyl group, wherein alkyl group and cycloalkyl group are as previously defined, such as, for example, cyclohexylmethyl (C 6 H 11 CH 2 -). Alkylcycloalkyl groups can be substituted or unsubstituted.
  • haloalkyl and “haloalkyl group” refer to alkyl groups in which one or more hydrogen atoms are replaced by halogen atoms.
  • Haloalkyl includes both saturated alkyl groups as well as unsaturated alkenyl and alkynyl groups.
  • Haloalkyl groups can be substituted or unsubstituted.
  • a haloalkyl group is selected from CHF2 and CF 3 , suitably CF 3 .
  • haloalkoxy and haloalkoxy group refer to alkoxy groups (i.e. O-alkyl groups) in which one or more hydrogen atoms are replaced by halogen atoms.
  • Haloalkoxy includes both saturated alkoxy groups as well as unsaturated alkenyl and alkynyl groups.
  • Haloalkoxy groups can be substituted or unsubstituted.
  • a haloalkyoxy group is selected from -OCHF 2 and -OCF 3 , suitably - OCF 3 .
  • halo and halogen include fluorine, chlorine, bromine and iodine atoms and substituents.
  • heteroaryl and heteroaryl group refer to (a) 5 and 6 membered monocyclic aromatic rings, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen or sulfur, and (b) 7 to 15 membered bicyclic and tricyclic rings, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen or sulfur, and in which at least one of the rings is aromatic.
  • a heteroaryl group can contain two or more heteroatoms, which may be the same or different.
  • Heteroaryl groups can be substituted or unsubstituted, and may be bridged, spiro, and/or fused.
  • a heteroaryl group may contain 5, 6, or 8 to 15 ring atoms.
  • a heteroaryl group may contain 5 to 10 ring atoms, such as 5, 6, 9, or 10 ring atoms.
  • Representative examples include, but are not limited to, 2,3-dihydrobenzofuranyl, 1 ,2-dihydroquinolinyl, 3,4-dihydroisoquinolinyl, 1 ,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, benzoxazinyl, benzthiazinyl, chromanyl, furanyl, 2-furanyl, 3-furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, 2-, 3-, or 4-pyridinyl, pyrimidinyl, 2-, 4-, or 5-pyrimidinyl, pyrazolyl, pyrrolyl, 2- or 3-pyrrolyl, pyrazinyl, pyridazinyl, 3- or 4-pyridazinyl, 2-pyrazinyl, thien
  • alkylheteroaryl and alkylheteroaryl group refer to an alkyl group in which a hydrogen atom is replaced by a heteroaryl group, wherein alkyl group and heteroaryl group are as previously defined. Alkylheteroaryl groups can be substituted or unsubstituted. Where carbon numbers are provided, e.g. (C n-m )alkylheteroaryl, the range refers to the whole group. Suitably, the constituent alkyl group has 1-6 carbons, suitable 1-3 carbons.
  • heterocyclic group and “heterocycle” refer to monocyclic and polycyclic ring systems that contain carbon atoms and at least one heteroatom selected from nitrogen, oxygen, sulfur or phosphorus in the ring(s), without regard or reference to aromaticity or degree of unsaturation.
  • heterocyclic group should be understood as referring to and including ring systems that are fully saturated (such as, for example, a piperidinyl group), ring systems that are aromatic (such as, for example, a pyrindinyl group), as well as ring systems having fully saturated, aromatic and/or unsaturated portions (such as, for example, 1 , 2,3,6- tetrahydropyridinyl and 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrizinyl).
  • the terms heterocyclic and heterocycle further include bridged, fused, and spirocyclic ring systems.
  • heterocycloalkyl and “heterocycloalkyl group” refer to 3 to15 membered monocyclic, bicyclic, and tricyclic non-aromatic ring systems, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen, sulfur or phosphorus. Heterocycloalkyl groups may be fully saturated or contain unsaturated portions and may be bridged, spiro, and/or fused ring systems. In some instances a heterocycloalkyl group may contain at least two or heteroatoms, which may be the same or different. Heterocycloalkyl groups can be substituted or unsubstituted.
  • a heterocycloalkyl group may contain from 3 to 10 ring atoms or from 3 to 7 ring atoms or from 5 to 7 ring atoms, such as 5 ring atoms, 6 ring atoms, or 7 ring atoms.
  • Representative examples include, but are not limited to, tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, isoindolinyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidyl, homopiperazinyl, thiomorpholinyl-5-oxide, thiomorpholinyl-S,S-dioxide, pyrrolidinyl, tetrahydropyranyl, piperidinyl, tetrahydrothienyl, homopiperidinyl, homothiomorpholinyl-S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridin
  • a heterocyclylalkyl group as defined herein is a monocyclic, bicyclic or spiro heterocyclyl group comprising one, two or three heteroatoms selected from N, O or S.
  • heterocycloalkylene and “heterocycloalkylene group” refer to 3 to15 membered monocyclic, bicyclic, or tricyclic non-aromatic ring systems, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen, sulfur or phosphorus. Heterocycloalkylene groups may be fully saturated or contain unsaturated portions and may be bridged, spiro, and/or fused. Heterocycloalkylene groups can be substituted or unsubstituted.
  • a heterocycloalkylene group may contain from 3 to 10 ring atoms; such as from 3 to 7 ring atoms. In other instances a heterocycloalkylene group may contain from 5 to 7 ring atoms, such as 5 ring atoms, 6 ring atoms, or 7 ring atoms.
  • alkylheterocycloalkyl and “alkylheterocycloalkyl group” refer to an alkyl group in which a hydrogen atom is replaced by a heterocycloalkyl group, wherein alkyl group and heterocycloalkyl group are as previously defined, such as, for example, pyrrolidinylmethyl (C 4 H 8 NCH 2 -).
  • Alkylheteroycloalkyl groups can be substituted or unsubstituted. Where carbon numbers are provided, e.g. (C n-m )alkylheterocycloalkyl, the range refers to the whole group.
  • the constituent alkyl group has 1-6 carbons, suitable 1-3 carbons.
  • “pharmaceutically acceptable” refers to materials that are generally chemically and/or physically compatible with other ingredients (such as, for example, with reference to a formulation), and/or is generally physiologically compatible with the recipient (such as, for example, a subject) thereof.
  • composition refers to a composition that can be used to treat a disease, condition, or disorder in a subject, including a human.
  • pseudohalogen refers to -OCN, -SCN, -CF 3 , and -CN.
  • substituted indicates that a hydrogen atom on a molecule has been replaced with a different atom or group of atoms and the atom or group of atoms replacing the hydrogen atom is a “substituent.” It should be understood that the terms “substituent”, “substituents”, “moiety”, “moieties”, “group”, or “groups” refer to substituent(s).
  • terapéutica refers to an amount a compound, composition or medicament that (a) inhibits or causes an improvement in a particular disease, condition or disorder; (b) attenuates, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder; (c) or delays the onset of one or more symptoms of a particular disease, condition or disorder described herein. It should be understood that the terms “therapeutic” and “therapeutically effective” encompass any one of the aforementioned effects (a)-(c), either alone or in combination with any of the others (a)-(c).
  • a therapeutically effective amount in, for example, a human or other mammal, can be determined experimentally in a laboratory or clinical setting, or a therapeutically effective amount may be the amount required by the guidelines of the United States Food and Drug Administration (FDA) or equivalent foreign regulatory body, for the particular disease and subject being treated. It should be appreciated that determination of proper dosage forms, dosage amounts, and routes of administration is within the level of ordinary skill in the pharmaceutical and medical arts.
  • FDA United States Food and Drug Administration
  • treating refers to and include prophylactic, ameliorative, palliative, and curative uses and results.
  • the terms “treating”, “treated”, and “treatment” refer to curative uses and results as well as uses and results that diminish or reduce the severity of a particular condition, characteristic, symptom, disorder, or disease described herein.
  • treatment can include diminishment of several symptoms of a condition or disorder or complete eradication of said condition or disorder.
  • prophylactic as used herein is not absolute but rather refers to uses and results where the administration of a compound or composition diminishes the likelihood or seriousness of a condition, symptom, or disease state, and/or delays the onset of a condition, symptom, or disease state for a period of time.
  • a “therapeutically active agent”, whether used alone or in conjunction with another term or terms, refers to any compound, i.e. a drug, that has been found to be useful in the treatment of a disease, disorder or condition and is not described by Formula I. It should be understood that a therapeutically active agent may not be approved by the FDA or an equivalent foreign regulatory body.
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a subject or patient for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the subject or patient to be treated.
  • a wavy bond is used herein to show a point of attachment. For instance, to show how group L of L-A bonds to the remainder of the molecule.
  • a bond terminating inside a cyclic structure and not terminating at an atom of the ring structure represents that the bond may be connected to any of the atoms in the ring structure where allowed by valency.
  • stable and “chemically stable” refer to a compound that is sufficiently robust to be isolated from a reaction mixture with a useful degree of purity.
  • the present application is directed solely to the preparation of stable compounds.
  • substituents include members which, owing to valency requirements, chemical stability, or other reasons, cannot be used to substitute a particular group, the list is intended to be read in context to include only those members of the list that are suitable for substituting the particular group.
  • degree of optional substitution of a particular moiety it should be understood that the number of substituents does not exceed the valency appropriate for that moiety.
  • group R is a methyl group (-CH 3 ), it can be optionally substituted by 1 to 3 substituents.
  • the present invention relates to:
  • X 2 is selected from C-L-A and CR 5 ; where R 5 is selected from the group consisting of hydrogen, CN, C(O)NH 2 , C(O)NHR f , C(O)N(R f ) 2 and N(R p1 )C(O)R f , where each R f is independently selected from C 1 -6 alkyl which is optionally substituted with one or more groups selected from halogen, OH, NH 2 , NHMe, NMe 2 , and C 1-3 alkoxy, and R p1 is selected from hydrogen, C 1-3 alkyl and C 1-3 haloalkyl;
  • X 1 is selected from CR 4 and C-L-A; where R 4 is selected from the group consisting of hydrogen, halogen, CN, C(O)NH 2 , C(O)NHR m , C(O)N(R m ) 2 , N(R p2 )C(O)R m , where each R m is independently selected from C 1 -6 alkyl which is optionally substituted with one or more groups selected from halogen, OH, NH 2 , NHMe, NMe 2 , and C 1-3 alkoxy, and R p2 is selected from hydrogen, C 1-3 alkyl and C 1-3 haloalkyl; with the proviso that one of X 1 or X 2 must be C-L-A; and only one of X 1 and X 2 can be
  • R 1 is selected from the group consisting of hydrogen, C 1-3 alkyl, and halogen
  • R 2 is selected from the group consisting of hydrogen; C 1-3 alkyl and NH 2 ;
  • R 3 is selected from the group consisting of hydrogen, -NH 2 , -NHR a , -NR a R b , -NHC(O)R c , - NHC(O)OR d , -NHS(O) 2 OR d , -NHS(O) 2 R d -C(O)NHR a , -C(O)R c , C(O)OR d , -OC(O)R c , -OH, - OR d , where each of R a , R b , R c and R d are independently selected from C 1 -6 alkyl and C 3 -C 6 cycloalkyl wherein said C 1 -6 alkyl and C 3 -C 6 cycloalkyl are optionally substituted by one or more groups selected from OH, halogen, CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3
  • R 6 is selected from hydrogen, halogen, OH, CN, NH 2 and C 1-3 alkyl.
  • R 9 is selected from the group consisting of a hydrogen, methyl and ethyl.
  • a compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein A is selected from the group consisting of 4-11 membered heterocycloalkyl and C 3-7 -cycloalkyl wherein each 4-11 membered heterocycloalkyl and C 3-7 - cycloalkyl is optionally substituted by one or more substituents R e , where R e is selected from hydrogen, halogen, CN, O, (CH 2 ) y OH, C 1 -4 alkyl, (CH 2 ) y C 1 -4 alkoxy, (CH 2 ) y C 1 -4 haloalkyl, (CH 2 ) y C 1 -4 haloalkoxy, (CH 2 ) y NH 2 , (CH 2 ) y NHR q , (CH 2 ) y N(R q ) 2 , (CH 2 ) y NHCO(R q ), (CH 2 ) y CONH
  • a compound according to any one of paragraphs 1 to 17, or a salt or solvate thereof, wherein A is selected from the group consisting of 4-7 membered heterocycloalkyl and C 3-7 -cycloalkyl wherein each 4-7 membered heterocycloalkyl and C 3-7 -cycloalkyl is optionally substituted by one or more substituents R e , where R e is selected from hydrogen, halogen, CN, O, (CH 2 ) y OH, C 1 -4 alkyl, (CH 2 ) y C 1 -4 alkoxy, (CH 2 ) y C 1 -4 haloalkyl, (CH 2 ) y C 1 -4 haloalkoxy, (CH 2 ) y NH 2 , (CH 2 ) y NHR q , (CH 2 ) y N(R q ) 2 , (CH 2 ) y CONH 2 , (CH 2 ) y CONH(R q q
  • a compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein A is selected from azetidinyl, oxetanyl, cyclobutyl, pyrrolidinyl, cyclopentyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, cyclohexyl, tetrahydropyran, azepanyl, diazepanyl and cycloheptane, each of which is optionally substituted by one or more substituents R e , where R e is selected from hydrogen, halogen, CN, O, (CH 2 ) y OH, C 1 -4 alkyl, (CH 2 ) y C 1 -4 alkoxy, (CH 2 ) y C 1 -4 haloalkyl, (CH 2 ) y C 1 -4 haloalkoxy, (CH 2 ) y NH 2
  • a compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein A is selected from azetidinyl, cyclobutyl, pyrrolidinyl, cyclopentyl, piperidinyl, piperazinyl, morpholinyl, cyclohexyl, azepanyl, diazepanyl and cycloheptane, each of which is optionally substituted by one or more substituents R e , where R e is selected from hydrogen, halogen, CN, O, (CH 2 ) y OH, C 1-4 alkyl, (CH 2 ) y C 1 -4 alkoxy, (CH 2 ) y C 1 -4 haloalkyl, (CH 2 ) y C 1 -4 haloalkoxy, (CH 2 ) y NH 2 , (CH 2 ) y NHR q , (CH 2 ) y N(R q , (
  • a compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein A is selected from azetidinyl, cyclobutyl, pyrrolidinyl, cyclopentyl, piperidinyl, piperazinyl, morpholinyl, and cyclohexyl, each of which is optionally substituted by one or more substituents R e , where R e is selected from hydrogen, halogen, CN, O, (CH 2 ) y OH, C 1 -4 alkyl, (CH 2 ) y C 1 -4 alkoxy, (CH 2 ) y C 1 -4 haloalkyl, (CH 2 ) y C 1 -4 haloalkoxy, (CH 2 ) y NH 2 ,
  • each R q is independently selected from C 1-4 alkyl which is optionally substituted with one or more groups selected from halogen, OH, NH 2 , NHMe, NMe 2 , and C 1-3 alkoxy; and where y is a number between 0 and 3.
  • a compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein A is selected from azetidinyl, cyclobutyl, pyrrolidinyl, cyclopentyl, piperidinyl, piperazinyl, morpholinyl, and cyclohexyl, each of which is optionally substituted by one or more substituents R e , where R e is selected from hydrogen, halogen, CN, O, (CH 2 ) y OH, C 1 -4 alkyl, (CH 2 ) y C 1 -4 alkoxy, (CH 2 ) y C 1 -4 haloalkyl, (CH 2 ) y C 1 -4 haloalkoxy, (CH 2 ) y NH 2 ,
  • each R q is independently selected from C 1-4 alkyl which is optionally substituted with one or more groups selected from halogen, OH, NH 2 , NHMe, NMe 2 , and C 1-3 alkoxy; and where y is a number between 0 and 3.
  • a compound according to any one of paragraphs 1 to 21 , or a salt or solvate thereof, wherein A is selected from azetidinyl, cyclobutyl, pyrrolidinyl, cyclopentyl, piperidinyl, cyclohexyl and azepanyl each of which is optionally substituted by one or more substituents R e , where R e is selected from hydrogen, halogen, CN, O, (CH 2 ) y OH, C 1-4 alkyl, (CH 2 ) y C 1 -4 alkoxy, (CH 2 ) y C 1-4 haloalkyl, (CH 2 ) y C 1-4 haloalkoxy, (CH 2 ) y NH 2 , (CH 2 ) y NHR q , (CH 2 ) y N(R q ) 2 , (CH 2 ) y NHCO(R q ), (CH 2 ) y CONH
  • a compound according to paragraph 25, or a salt or solvate thereof, wherein L is a -NH- and A is selected from azetidinyl, cyclobutyl, pyrrolidinyl, cyclopentyl, piperidinyl, cyclohexyl and azepanyl each of which is optionally substituted by one or more substituents R e , where R e is selected from hydrogen, halogen, CN, O, (CH 2 ) y OH, C 1 -4 alkyl, (CH 2 ) y C 1 -4 alkoxy, (CH 2 ) y C 1-4 haloalkyl, (CH 2 ) y C 1-4 haloalkoxy, (CH 2 ) y NH 2 , (CH 2 ) y NHR q , (CH 2 ) y N(R q ) 2 , (CH 2 ) y CONH 2 , (CH 2 ) y CONH(R)
  • L-A is selected from the group consisting of:
  • L-A is selected from the group consisting of:
  • L-A is selected from the group consisting of:
  • L-A is selected from the group consisting of:
  • R 1 is selected from the group consisting of hydrogen, C 1-3 alkyl, and halogen
  • R 2 is selected from the group consisting of hydrogen; C 1-3 alkyl and NH 2 ;
  • R 3 is selected from the group consisting of hydrogen, -NH 2 , -NHR a , -NR a R b , -N(R a1 )C(O)R c , -
  • R 4 is selected from the group consisting of hydrogen, halogen, CN, C(O)NH 2 , C(O)NHR m , C(O)N(R m ) 2 , N(R p2 )C(O)R m , where each R m is independently selected from C 1 -4 alkyl which is optionally substituted with one or more groups selected from halogen, OH, NH 2 , NHMe, NMe 2 , and C 1-3 alkoxy, and R p2 is selected from hydrogen, C 1-3 alkyl and C 1-3 haloalkyl;
  • R 6 is selected from hydrogen, halogen, OH, CN, NH 2 and C 1-3 alkyl;
  • R 3 is selected from the group consisting of -NH 2 , -NHR a , -NR a R b , -NHC(O)R c , -N(R a1 )C(O)OR d , -N(R a1 )S(O) 2 OR d , -N(R a1 )S(O) 2 R d , -C(O)NHR a , -C(O)NR a R b , C(O)OR d , - OC(O)R c , -OH, and -OR d , where each of R a , R b , R c and R d are independently selected from C 1-4 alkyl and C 3 -C 6 cycloalkyl wherein said C 1-4 alkyl and C 3 -C 6 cycloalkyl
  • R 3 is selected from the group consisting of -NH 2 , -NHR a , -NR a R b , -NHC(O)R c , -N(R a1 )C(O)OR d , -N(R a1 )S(O) 2 OR d , -N(R a1 )S(O) 2 R d , -OC(O)R c , -OH, and -OR d , where each of R a , R b , R c and R d are independently selected from C 1-4 alkyl and C 3 -C 6 cycloalkyl wherein said C 1-4 alkyl and C 3 -C 6 cycloalkyl are optionally substituted by one or more groups selected from OH, halogen, CN, C 1-3 alkyl, C 1 -3 al
  • R 3 is selected from the group consisting of -NH 2 , -NHR a , -NR a R b , - N(R a1 )C(O)R c , -N(R a1 )C(O)OR d , -N(R a1 )S(O) 2 OR d , -N(R a1 )S(O) 2 R d , -C(O)NHR a , and - C(O)NR a R b , where each of R a , R b , R c and R d are independently selected from C 1-4 alkyl and C 3 -C 6 cycloalkyl wherein said C 1-4 alkyl and C 3 -C 6 cycloalkyl are optionally substituted by one or more groups selected from OH, halogen, CN, C
  • R 3 is selected from the group consisting of -NH 2 , -NHR a and -NR a R b , - N(R a1 )C(O)R c , where each of R a , R b , R c and R d are independently selected from C 1-4 alkyl and C 3 -C 6 cycloalkyl wherein said C 1.4 alkyl and C 3 -C 6 cycloalkyl are optionally substituted by one or more groups selected from OH, halogen, CN, C 1-3 alkyl, C 1-3 alkoxy, C 1.3 haloalkyl, C 1.3 haloalkoxy, NH 2 , NH(C 1-3 alkyl) and N(C 1-3 alkyl) 2 ; or R a and R b when attached to the same atom and together with the atom to which they are attached
  • R 3 is selected from the group consisting of -NH 2 , -NHR a and -NR a R b , where each of R a , R b , R c and R d are independently selected from C 1-4 alkyl and C 3 -C 6 cycloalkyl wherein said C 1-4 alkyl and C 3 -C 6 cycloalkyl are optionally substituted by one or more groups selected from OH, halogen, CN, C 1-3 alkyl, C 1-3 alkoxy, C 1.3 haloalkyl, C 1.3 haloalkoxy, NH 2 , NH(C 1-3 alkyl) and N(C 1 -3 alkyl) 2 ; or R a and R b when attached to the same atom and together with the atom to which they are attached combine to provide a 3-7 membered heterocycloalkyl which is
  • R 3 is selected from the group consisting of hydrogen, -NH 2 , -NHR a , -NR a R b , -N(R a1 )C(O)R c , -N(R a1 )C(O)OR d , -N(R a1 )S(O) 2 OR d , -N(R a1 )S(O) 2 R d , -C(O)NHR a , and - C(O)NR a R b , where each of R a , R b , R c and R d are independently selected from C 1-4 alkyl and C 3 -C 6 cycloalkyl wherein said C 1.4 alkyl and C 3 -C 6 cycloalkyl are optionally substituted by one or more groups selected from OH, halogen, CN,
  • R 3 is selected from the group consisting of hydrogen, -NH 2 , -NHR a , -NR a R b , and -N(R a1 )C(O)R c , where each of R a , R b , R c and R d are independently selected from C 1 -4 alkyl and C 3 -C 6 cycloalkyl wherein said C 1 -4 alkyl and C 3 -C 6 cycloalkyl are optionally substituted by one or more groups selected from OH, halogen, CN, C 1-3 alkyl, C 1-3 alkoxy, C1.3 haloalkyl, C1.3 haloalkoxy, NH 2 , NH(C 1-3 alkyl) and N(C 1 -3 alkyl) 2 ; or R a and R b when attached to the same atom and together with the atom
  • R 3 is selected from the group consisting of hydrogen, -NH 2 , -NHR a and - NR a R b , where each of R a , R b , R c and R d are independently selected from C 1-4 alkyl and C 3 -C 6 cycloalkyl wherein said C 1-4 alkyl and C 3 -C 6 cycloalkyl are optionally substituted by one or more groups selected from OH, halogen, CN, C 1-3 alkyl, C 1-3 alkoxy, C 1.3 haloalkyl, C 1.3 haloalkoxy, NH 2 , NH(C 1-3 alkyl) and N(C 1-3 alkyl) 2 ; or R a and R b when attached to the same atom and together with the atom to which they are attached combine to provide a 3-7 membered heterocycloalkyl
  • R a , R b , R c and R d are independently selected from C 1 -4 alkyl wherein said Ci. 4 alkyl is optionally substituted by one or more groups selected from OH, halogen, CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, NH 2 , NH(CI-3 alkyl) and N(CI-3 alkyl) 2 ; or R a and R b when attached to the same atom and together with the atom to which they are attached combine to provide a 3-7 membered heterocycloalkyl which is optionally substituted by one or more groups selected from OH, halogen, CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, NH 2 , NH(CI
  • R a , R b , R c and R d are independently selected from methyl or ethyl; or R a and R b when attached to the same atom and together with the atom to which they are attached combine to provide a 3-7 membered heterocycloalkyl which is optionally substituted by one or more groups selected from OH, halogen, CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, NH 2 , NH(C 1-3 alkyl) and N(C 1 - 3alkyl) 2 .
  • R a1 is independently selected from hydrogen, methyl and ethyl.
  • R a1 is independently selected from hydrogen and methyl.
  • R e is selected from hydrogen, C 1 -4 alkyl, NH 2 , NH(CI-4 alkyl), and N (C 1 -4 alkyl) 2 .
  • R e is selected from hydrogen, methyl, ethyl, NH 2 , NHMe, and NMe 2 .
  • R q is selected from methyl or ethyl which is optionally substituted with one or more groups selected from halogen, OH, NH 2 , NHMe, NMe 2 , and C 1-3 alkoxy.
  • a compound according to paragraph 106, or a salt or solvate thereof, wherein R x is selected from hydroxyl, halogen, CN, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkyl, C 1-6 alkoxy, C 3 - 6 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-11 aryl, heteroaryl; where said C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-11 aryl, and heteroaryl and are optionally substituted with one or more groups selected from hydroxyl, halogen, O, CN, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, NR j R k , C 1-6 alkyl, O-C 1-6 alkyl, and phenyl; where each R j and R K are
  • R x is selected from hydroxyl, halogen, CN, C 1 -6 haloalkyl, C 1 -6 haloalkoxy, C 1 -6 alkyl, C 1 -6 alkoxy, C 3 - 6 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-11 aryl, heteroaryl; where said C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-11 aryl, and heteroaryl and are optionally substituted with one or more groups selected from hydroxyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, NR j R k , C 1-6 alkyl, O-C 1-6 alkyl, and phenyl; where each R j and R K are independently selected from hydrogen, C
  • a compound according to any one of paragraphs 1 to 31 , 56 and 68-96, or a salt or solvate thereof, wherein R x is selected from hydroxyl, halogen, CN, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-11 aryl, heteroaryl; where said C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-11 aryl, and heteroaryl and are optionally substituted with one or more groups selected from hydroxyl, halogen, O, CN, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, NR j R k , C 1-6 alkyl, O- C 1-6 alkyl, and pheny
  • R x is selected from hydroxyl, halogen, CN, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkyl, C 1-6 alkoxy, C 3 - 6 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-11 aryl, heteroaryl; where said C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-11 aryl, and heteroaryl and are optionally substituted with one or more groups selected from hydroxyl, C 1 -6 haloalkyl, C 1 -6 haloalkoxy, C 3-6 cycloalkyl, NR j R k , C 1-6 alkyl, O-C 1-6 alkyl, and phenyl; where each R j and R K are independently selected from hydrogen, C 1-6 halogen, CN, C 1-6 haloalkyl, C 1-6 hal
  • a compound according to paragraph 110, or a salt or solvate thereof, wherein R x is selected from hydroxyl, halogen, CN, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkyl, and C 1 -6 alkoxy where said C 1-6 alkyl and C 1-6 alkoxy, are optionally substituted with one or more groups selected from hydroxyl, halogen, O, CN, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, NR j R k , C 1-6 alkyl, O-C 1-6 alkyl, and phenyl; where each R j and R K are independently selected from hydrogen, C 1-6 haloalkyl, C 3-6 cycloalkyl, phenyl, benzyl and C 1-6 alkyl wherein said C 1-6 haloalkyl, C 3-6 cycloalkyl, phenyl,
  • R x is selected from hydroxyl, halogen, CN, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkyl, and C 1-6 alkoxy where said C 1-6 alkyl and C 1-6 alkoxy, are optionally substituted with one or more groups selected from hydroxyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3 - 6 cycloalkyl, NR j R k , C 1-6 alkyl, O-C 1-6 alkyl, and phenyl; where each R j and R K are independently selected from hydrogen, C 1-6 haloalkyl, C 3-6 cycloalkyl, phenyl, benzyl and C 1-6 alkyl wherein said C 1-6 haloalkyl, C 3-6 cycloalkyl,
  • R x is selected from halogen, CN, C 1 -6 haloalkyl and C 1 -6 alkyl, and where said C 1 -6 alkyl is optionally substituted with one or more groups selected from hydroxyl, C 1 -6 haloalkyl, C 1 -6 haloalkoxy, C 3-6 cycloalkyl, NR j R k , C 1 -6 alkyl, O-C 1 -6 alkyl, and phenyl; where each R j and R K are independently selected from hydrogen, C 1 -6 haloalkyl, C 3-6 cycloalkyl, phenyl, benzyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, and C 1 -6 alkyl wherein said C 3-6 cycloalkyl, phenyl, benzyl
  • R h is independently selected from C 1-3 alkyl optionally substituted by one or more groups selected from halogen, C 1 -6 alkoxy, NH 2 , NH(C 1-3 alkyl) and N(C 1 -3 alkyl) 2 .
  • R h is independently selected from C 1-3 alkyl optionally substituted by one or more groups selected from halogen, OMe, NH 2 , NH(Me) and N(Me) 2 .
  • R h is independently selected from methyl and ethyl optionally substituted by one or more groups selected from halogen, OMe, NH 2 , NH(Me) and N(Me)2.
  • a compound according to any one of the preceding paragraphs, or a salt or solvate thereof, wherein R j and R K are independently selected from hydrogen, methyl and ethyl; or R j and R K when attached to the same atom and together with the atom to which they are attached combine to provide a 3-6 membered heterocycloalkyl which is optionally substituted by one or more groups selected from halogen, hydroxy, methyl, ethyl, OMe, O and CN.
  • R 1 is selected from the group consisting of hydrogen, methyl, ethyl and halogen.
  • R 4 is selected from the group consisting of hydrogen, halogen, CN.
  • R 4 is selected from the group consisting of hydrogen, fluoro, chloro, and CN.
  • R m is independently selected from methyl and ethyl each of which is optionally substituted with one or more groups selected from halogen, OH, NH 2 , NHMe, NMe 2 , and OMe.
  • R 5 is selected from the group consisting of hydrogen, halogen, CN, C(O)NH 2 , C(O)NHR f , C(O)N(R f ) 2 , where each R f is independently selected from C 1 -4 alkyl which is optionally substituted with one or more groups selected from halogen, OH, NH 2 , NHMe, NMe 2 , and C 1-3 alkoxy.
  • R 5 is selected from the group consisting of hydrogen, fluoro, chloro, and CN.
  • R f is independently selected from methyl and ethyl each of which is optionally substituted with one or more groups selected from halogen, OH, NH 2 , NHMe, NMe 2 , and OMe.
  • R 1 is selected from the group consisting of hydrogen, C 1-3 alkyl, and halogen
  • R 2 is selected from the group consisting of hydrogen; C 1-3 alkyl and NH 2 ;
  • R 3 is selected from the group consisting of hydrogen, -NH 2 , -NHR a , -NR a R b , -N(R a1 )C(O)R c , - N(R a1 )C(O)OR d , -N(R a1 )S(O) 2 OR d , -N(R a1 )S(O) 2 R d -C(O)NHR a , -C(O)NR a R b , -C(O)R c , C(O)OR d , -OC(O)R c , -OH, -OR d , where each of R a , R b , R c and R d are independently selected from C 1 -6 alkyl and C 3 -C 6 cycloalkyl wherein said C 1 -6 alkyl and C 3 -C 6 cycloalkyl are optionally substituted by one
  • R 4 is selected from the group consisting of hydrogen, halogen, CN, C(O)NH 2 , C(O)NHR m , C(O)N(R m ) 2 , N(R p2 )C(O)R m , where each R m is independently selected from C 1-4 alkyl which is optionally substituted with one or more groups selected from halogen, OH, NH 2 , NHMe, NMe 2 , and C 1 -3 alkoxy, and R p2 is selected from hydrogen, C 1-3 alkyl and C 1.3 haloalkyl;
  • R 6 is selected from hydrogen, halogen, OH, CN, NH 2 and C 1-3 alkyl;
  • R 3 is selected from the group consisting of hydrogen, -NH 2 , -NHR a , -NR a R b , -N(R a1 )C(O)R c , - N(R a1 )C(O)OR d , -N(R a1 )S(O) 2 OR d , -N(R a1 )S(O) 2 R d -C(O)NHR a , -C(O)NR a R b , -C(O)R c , C(O)OR d , -OC(O)R c , -OH, -OR d , where each of R a , R b , R c and R d are independently selected from C 1 -6 alkyl and C 3 -C 6 cycloalkyl wherein said C 1 -6 alkyl and C 3 -C 6 cycloalkyl are optionally substituted by one
  • R 3 is selected from the group consisting of -NH 2 , -NHR a , -NR a R b , -NHC(O)R c , -N(R a1 )C(O)OR d , -N(R a1 )S(O) 2 OR d , -N(R a1 )S(O) 2 R d , -C(O)NHR a , -C(O)NR a R b , C(O)OR d , - OC(O)R c , -OH, and -OR d , where each of R a , R b , R c and R d are independently selected from C 1 -4 alkyl and C 3 -C 6 cycloalkyl wherein said C 1 -4 alkyl and C 3 -C 6 cycloalkyl wherein said C 1 -4 alkyl and C 3 -C 6 cycloalkyl
  • R 3 is selected from the group consisting of -NH 2 , -NHR a , -NR a R b , -NHC(O)R c , -N(R a1 )C(O)OR d , -N(R a1 )S(O) 2 OR d , -N(R a1 )S(O) 2 R d , OC(O)R c , -OH, and -OR d , where each of R a , R b , R c and R d are independently selected from C 1-4 alkyl and C 3 -C 6 cycloalkyl wherein said C 1-4 alkyl and C 3 -C 6 cycloalkyl are optionally substituted by one or more groups selected from OH, halogen, CN, C 1-3 alkyl, C 1 -3 al
  • R 3 is selected from the group consisting of -NH 2 , -NHR a , -NR a R b , - N(R a1 )C(O)R c , -N(R a1 )C(O)OR d , -N(R a1 )S(O) 2 OR d , -N(R a1 )S(O) 2 R d , -C(O)NHR a , and - C(O)NR a R b , where each of R a , R b , R c and R d are independently selected from C 1-4 alkyl and C 3 -C 6 cycloalkyl wherein said C 1-4 alkyl and C 3 -C 6 cycloalkyl are optionally substituted by one or more groups selected from OH, halogen, CN,
  • R 3 is selected from the group consisting of -NH 2 , -NHR a , -NR a R b and - N(R a1 )C(O)R c , where each of R a , R b , and R c are independently selected from C 1-4 alkyl and C 3 -C 6 cycloalkyl wherein said C 1-4 alkyl and C 3 -C 6 cycloalkyl are optionally substituted by one or more groups selected from OH, halogen, CN, C 1-3 alkyl, C 1-3 alkoxy, C 1.3 haloalkyl, C 1.3 haloalkoxy, NH 2 , NH(C 1-3 alkyl) and N(C 1-3 alkyl) 2 ; or R a and R b when attached to the same atom and together with the atom to which they are attached combine to
  • R 3 is selected from the group consisting of hydrogen, -NH 2 , -NHR a , -NR a R b , -N(R a1 )C(O)R c , -N(R a1 )C(O)OR d , -N(R a1 )S(O) 2 OR d , -N(R a1 )S(O) 2 R d , -C(O)NHR a , and - C(O)NR a R b , where each of R a , R b , R c and R d are independently selected from C 1-4 alkyl and C 3 -C 6 cycloalkyl wherein said C 1.4 alkyl and C 3 -C 6 cycloalkyl are optionally substituted by one or more groups selected from OH, halogen,
  • R 3 is selected from the group consisting of hydrogen, -NH 2 , -NHR a , -NR a R b , -N(R a1 )C(O)R c , where each of R a , R b and R c are independently selected from C 1-4 alkyl and C 3 -C 6 cycloalkyl wherein said C 1.4 alkyl and C 3 -C 6 cycloalkyl are optionally substituted by one or more groups selected from OH, halogen, CN, C 1-3 alkyl, C 1-3 alkoxy, C 1.3 haloalkyl, C 1.3 haloalkoxy, NH 2 , NH(C 1-3 alkyl) and N(C 1-3 alkyl) 2 ; or R a and R b when attached to the same atom and together with the atom to which they are attached combine to
  • R 3 is selected from the group consisting of hydrogen, -NH 2 , -NHR a , and - NR a R b , where each of R a and R b , are independently selected from C 1 -4 alkyl and C 3 -C 6 cycloalkyl wherein said C 1 -4 alkyl and C 3 -C 6 cycloalkyl are optionally substituted by one or more groups selected from OH, halogen, CN, C 1-3 alkyl, C 1-3 alkoxy, C1.3 haloalkyl, C1.3 haloalkoxy, NH 2 , NH(C 1-3 alkyl) and N(C 1-3 alkyl) 2 ; or R a and R b when attached to the same atom and together with the atom to which they are attached combine to provide a 3-7 membered heterocycloalkyl which is optionally substitute
  • R a , R b , R c and R d are independently selected from C 1 -4 alkyl wherein said C 1 - 4 alkyl is optionally substituted by one or more groups selected from OH, halogen, CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, NH 2 , NH(C 1-3 alkyl) and N(C 1-3 alkyl) 2 ; or R a and R b when attached to the same atom and together with the atom to which they are attached combine to provide a 3-7 membered heterocycloalkyl which is optionally substituted by one or more groups selected from OH, halogen, CN, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, NH 2 ,
  • X 4 is selected from nitrogen and CH; ml and m2 are numbers independently selected from 1 , 2, 3 and 4; q is a number independently selected from 1 , 2 and 3;
  • X 4 is selected from nitrogen and CH; ml and m2 are numbers independently selected from 1 , 2, 3 and 4; q is a number independently selected from 1 , 2 and 3;
  • R x1 and R x5 are independently selected from hydroxyl, halogen, CN, C 1 -6 haloalkyl, C 1 -6 haloalkoxy, C 1 -6 alkyl and C 1 -6 alkoxy.
  • R x1 and R x5 are independently selected from halogen, CN, C 1 -6 haloalkyl, C 1 - 6 haloalkoxy, C 1 -6 alkyl and C 1 -6 alkoxy.
  • the present invention may relate to any compound or particular group of compounds defined herein by way of optional, preferred or suitable features or otherwise in terms of particular embodiments, the present invention may also relate to any compound or particular group of compounds that specifically excludes said optional, preferred or suitable features or particular embodiments. [0066] Suitably, the present invention excludes any individual compounds not possessing the biological activity defined herein.
  • the compounds (including final products and intermediates) described herein may be isolated and used per se or may be isolated in the form of a salt, suitably pharmaceutically acceptable salts.
  • salt(s) and salt form(s) used by themselves or in conjunction with another term or terms encompasses all inorganic and organic salts, including industrially acceptable salts, as defined herein, and pharmaceutically acceptable salts, as defined herein, unless otherwise specified.
  • industrially acceptable salts are salts that are generally suitable for manufacturing and/or processing (including purification) as well as for shipping and storage, but may not be salts that are typically administered for clinical or therapeutic use.
  • Industrially acceptable salts may be prepared on a laboratory scale, i.e. multi-gram or smaller, or on a larger scale, i.e. up to and including a kilogram or more.
  • Pharmaceutically acceptable salts are salts that are generally chemically and/or physically compatible with the other ingredients comprising a formulation, and/or are generally physiologically compatible with the recipient thereof.
  • Pharmaceutically acceptable salts may be prepared on a laboratory scale, i.e. multi-gram or smaller, or on a larger scale, i.e. up to and including a kilogram or more. It should be understood that pharmaceutically acceptable salts are not limited to salts that are typically administered or approved by the FDA or equivalent foreign regulatory body for clinical or therapeutic use in humans. A practitioner of ordinary skill will readily appreciate that some salts are both industrially acceptable as well as pharmaceutically acceptable salts. It should be understood that all such salts, including mixed salt forms, are within the scope of the application.
  • the compounds of Formula I and sub-formulae thereof are isolated as pharmaceutically acceptable salts.
  • a suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, 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
  • salts of the present application can be prepared in situ during the isolation and/or purification of a compound (including intermediates), or by separately reacting the compound (or intermediate) with a suitable organic or inorganic acid or base (as appropriate) and isolating the salt thus formed.
  • the degree of ionisation in the salt may vary from completely ionised to almost non-ionised.
  • the various salts may be precipitated (with or without the addition of one or more co-solvents and/or anti-solvents) and collected by filtration or the salts may be recovered by evaporation of solvent(s).
  • Salts of the present application may also be formed via a “salt switch” or ion exchange/double displacement reaction, i.e. reaction in which one ion is replaced (wholly or in part) with another ion having the same charge.
  • salts may be prepared and/or isolated using a single method or a combination of methods.
  • Representative salts include, but are not limited to, acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate, trifluoroacetate and the like.
  • salts include alkali or alkaline earth metal cations such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, lysine, arginine, benzathine, choline, tromethamine, diolamine, glycine, meglumine, olamine and the like.
  • Certain compounds of the Formula I and sub-formulae thereof may 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 that possess the biological activity described herein.
  • N-oxides Compounds of the Formula I and sub-formulae thereof containing an amine function may also form N-oxides.
  • a reference herein to a compound of the Formula I and sub-formulae thereof that contains an amine function also includes the N-oxide.
  • one or more than one nitrogen atom may be oxidised to form an N-oxide.
  • Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.
  • N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g.
  • N-oxides can be made by the procedure of L. W. Deady ( Syn . Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.
  • mCPBA m-chloroperoxybenzoic acid
  • keto-, enol-, and enolate-forms examples include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), pyrimidone/hydroxypyrimidine, imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.
  • keto enol enolate examples include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), pyrimidone/hydroxypyrimidine, imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.
  • isomers Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
  • Certain compounds of Formula I and sub-formulae thereof may have one or more asymmetric centres and therefore can exist in a number of stereoisomeric configurations. Consequently, such compounds can be synthesized and/or isolated as mixtures of enantiomers and/or as individual (pure) enantiomers, and, in the case of two or more asymmetric centres, single diastereomers and/or mixtures of diastereomers. It should be understood that the present application includes all such enantiomers and diastereomers and mixtures thereof in all ratios.
  • the compounds of the present invention are described herein using structural formulas that do not specifically recite the mass numbers or the isotope ratios of the constituent atoms. As such it is intended that the present application includes compounds in which the constituent atoms are present in any ratio of isotope forms. For example, carbon atoms may be present in any ratio of 12 C, 13 C, and 14 C; hydrogen atoms may be present in any ratio of 1 H, 2 H, and 3 H; etc.
  • the constituent atoms in the compounds of the present invention are present in their naturally occurring ratios of isotope forms.
  • the compounds of Formula I and sub-formulae thereof may be administered in the form of a pro-drug which is broken down in the human or animal body to release a compound of the invention.
  • a pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the invention.
  • a pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a propertymodifying group can be attached.
  • pro-drugs include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the Formula I and in-vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the Formula I and sub-formulae thereof.
  • the present invention includes those compounds of the Formula I and sub-formulae thereof as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the Formula I that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the Formula I and sub-formulae thereof may be a synthetically-produced compound or a metabolically-produced compound.
  • a suitable pharmaceutically acceptable pro-drug of a compound of the Formula I and sub-formulae thereof is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
  • pro-drug Various forms of pro-drug have been described, for example in the following documents :- a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, etal. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H.
  • a suitable pharmaceutically acceptable pro-drug of a compound of the Formula I and sub-formulae thereof that possesses a carboxy group is, for example, an in vivo cleavable ester thereof.
  • An in vivo cleavable ester of a compound of the Formula I containing a carboxy group is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid.
  • Suitable pharmaceutically acceptable esters for carboxy include C 1 -6 alkyl esters such as methyl, ethyl and tert- butyl, C 1 -6 alkoxymethyl esters such as methoxymethyl esters, C 1 -6 alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, C 3-8 cycloalkylcarbonyloxy- C 1 -6 alkyl esters such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters, 2-oxo-1,3- dioxolenylmethyl esters such as 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl esters and
  • a suitable pharmaceutically acceptable pro-drug of a compound of the Formula I and sub-formulae thereof that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof.
  • An in vivo cleavable ester or ether of a compound of the Formula I and sub-formulae thereof containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound.
  • Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters).
  • ester forming groups for a hydroxy group include C 1 -10 alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C 1 -10 alkoxycarbonyl groups such as ethoxycarbonyl, N,N- (C 1 -6 )2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups.
  • Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include a-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.
  • a suitable pharmaceutically acceptable pro-drug of a compound of the Formula I and sub-formulae thereof that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C 1 -4 alkylamine such as methylamine, a (C 1 -4 alkyl) 2 amine such as dimethylamine, N-ethyl- N-methylamine or diethylamine, a C 1 -4 alkoxy- C 2-4 alkylamine such as 2-methoxyethylamine, a phenyl-C 1 - 4alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.
  • an amine such as ammonia
  • a C 1 -4 alkylamine such as methylamine
  • a (C 1 -4 alkyl) 2 amine such as dimethylamine, N-ethyl- N-methylamine or diethyl
  • a suitable pharmaceutically acceptable pro-drug of a compound of the Formula I and sub-formulae thereof that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof.
  • Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C 1 -10 alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups.
  • ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C 1 -4 alkyl)piperazin-1- ylmethyl.
  • the in vivo effects of a compound of the Formula I and sub-formulae thereof may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the Formula I and sub-formulae thereof.
  • the in vivo effects of a compound of the Formula I and sub-formulae thereof may also be exerted by way of metabolism of a precursor compound (a pro-drug).
  • a pharmaceutical composition which comprises a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or
  • compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • An effective amount of a compound of the present invention for use in therapy is an amount sufficient to treat or prevent a proliferative condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
  • dosages and dosing regimens may vary with the type and severity of the condition to be alleviated, and may include the administration of single or multiple doses, i.e. QD (once daily), BID (twice daily), etc., over a particular period of time (days or hours). It is to be further understood that for any particular subject or patient, specific dosage regimens may need to be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the pharmaceutical compositions. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and/or laboratory values.
  • the present application encompasses intra-patient dose-escalation as determined by the person skilled in the art.
  • Procedures and processes for determining the appropriate dosage(s) and dosing regimen(s) are well-known in the relevant art and would readily be ascertained by the skilled artisan.
  • dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the pharmaceutical compositions described herein.
  • a daily dose in the range for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses.
  • a parenteral route is employed.
  • a dose in the range for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used.
  • a dose in the range for example, 0.05 mg/kg to 25 mg/kg body weight will be used.
  • Oral administration may also be suitable, particularly in tablet form.
  • unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.
  • the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in therapy.
  • the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of treatment of a disease or condition associated with aberrant activity of salt-inducible kinase (SIK).
  • SIK salt-inducible kinase
  • the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of a disease or condition associated with aberrant activity of salt-inducible kinase (SIK).
  • SIK salt-inducible kinase
  • the present invention provides a method of treating a disease or condition associated with aberrant activity of salt-inducible kinase (SIK), said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof.
  • SIK salt-inducible kinase
  • SIK salt-inducible kinase
  • the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a proliferative disorder, a benign neoplasm, pathological angiogenesis, an inflammatory disease or condition, a musculoskeletal disease or condition, an autoimmune disease, a haematological disease or condition, a neurological disease or condition, a psychiatric disorder, or a metabolic disorder.
  • a proliferative disorder a benign neoplasm, pathological angiogenesis, an inflammatory disease or condition, a musculoskeletal disease or condition, an autoimmune disease, a haematological disease or condition, a neurological disease or condition, a psychiatric disorder, or a metabolic disorder.
  • the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of a proliferative disorder, a benign neoplasm, pathological angiogenesis, an inflammatory disease or condition, a musculoskeletal disease or condition, an autoimmune disease, a haematological disease or condition, a neurological disease or condition, a psychiatric disorder, or a metabolic disorder.
  • the present invention provides a method of treating a proliferative disorder, a benign neoplasm, pathological angiogenesis, an inflammatory disease or condition, a musculoskeletal disease or condition, an autoimmune disease, a haematological disease or condition, a neurological disease or condition, a psychiatric disorder, or a metabolic disorder, said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof.
  • proliferative disorder and “proliferative condition” are used interchangeably herein and pertain to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro or in vivo.
  • proliferative conditions include, but are not limited to, pre-malignant and malignant cellular proliferation, including but not limited to, malignant neoplasms and tumours, cancers, leukemias, psoriasis, bone diseases, fibroproliferative disorders (e.g. of connective tissues), and atherosclerosis. Any type of cell may be treated, including but not limited to, lung, colon, breast, ovarian, prostate, liver, pancreas, brain, blood and skin.
  • the proliferative disorder is cancer, suitably a cancer selected from lung, colon, breast, ovarian, prostate, liver, pancreas, brain, blood and skin cancer.
  • the proliferative disorder is cancer, suitably a cancer selected from breast, brain, blood and ovarian cancer.
  • the proliferative disorder is cancer, suitably a cancer selected from blood and ovarian cancer.
  • the proliferative disorder is hematopoietic tumour, including: myelogenous and granulocytic leukemia (malignancy of the myeloid and granulocytic white blood cell series); lymphatic, lymphocytic, and lymphoblastic leukemia (malignancy of the lymphoid and lymphocytic blood cell series); polycythemia vera and erythremia (malignancy of various blood cell products, but with red cells predominating); and myelofibrosis.
  • myelogenous and granulocytic leukemia malignancy of the myeloid and granulocytic white blood cell series
  • lymphatic, lymphocytic, and lymphoblastic leukemia malignancy of the lymphoid and lymphocytic blood cell series
  • polycythemia vera and erythremia malignancy of various blood cell products,
  • the benign neoplasm may be, for example, hemangiomas, hepatocellular adenoma, cavernous haemangioma, focal nodular hyperplasia, acoustic neuromas, neurofibroma, bile duct adenoma, bile duct cystanoma, fibroma, lipomas, leiomyomas, mesotheliomas, teratomas, myxomas, nodular regenerative hyperplasia, trachomas, pyogenic granulomas, moles, uterine fibroids, thyroid adenomas, adrenocortical adenomas or pituitary adenomas.
  • the benign neoplasm may be endometrial implants or a keratocystic odontogenic tumor.
  • the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a cancer.
  • the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of a cancer.
  • the present invention provides a method of treating a cancer, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein.
  • the cancer may be non-metastatic or metastatic and which may be a solid tumour or a haematological (“liquid”) cancer.
  • the cancer may, for example, be selected from:
  • Carcinoma including for example tumours derived from stratified squamous epithelia (squamous cell carcinomas) and tumours arising within organs or glands (adenocarcinomas).
  • squamous cell carcinomas stratified squamous epithelia
  • adenocarcinomas derived from stratified squamous epithelia (squamous cell carcinomas) and tumours arising within organs or glands.
  • squamous cell carcinomas include breast, colon, lung, prostate, ovary esophageal carcinoma (including, but not limited to, esophageal adenocarcinoma and squamous cell carcinoma), basal-like breast carcinoma, basal cell carcinoma (a form of skin cancer), squamous cell carcinoma (various tissues), head and neck carcinoma (including, but not limited to, squamous cell carcinomas), stomach carcinoma (including, but not limited to, stomach adenocarcinoma, gastrointestinal stromal tumor), signet
  • Sarcomas including: osteosarcoma and osteogenic sarcoma (bone); chondrosarcoma (cartilage); leiomyosarcoma (smooth muscle); rhabdomyosarcoma (skeletal muscle); mesothelial sarcoma and mesothelioma (membranous lining of body cavities); fibrosarcoma (fibrous tissue); angiosarcoma and hemangioendothelioma (blood vessels); liposarcoma (adipose tissue); glioma and astrocytoma (neurogenic connective tissue found in the brain); myxosarcoma (primitive embryonic connective tissue); chordoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, Ewing's sarcoma, mesenchymous and mixed mesodermal tumor (mixed connective
  • Myeloma and multiple myeloma (4) Hematopoietic tumours, including: myelogenous and granulocytic leukemia (malignancy of the myeloid and granulocytic white blood cell series); lymphatic, lymphocytic, and lymphoblastic leukemia (malignancy of the lymphoid and lymphocytic blood cell series); polycythemia vera and erythremia (malignancy of various blood cell products, but with red cells predominating); myelofibrosis.
  • myelogenous and granulocytic leukemia malignancy of the myeloid and granulocytic white blood cell series
  • lymphatic, lymphocytic, and lymphoblastic leukemia malignancy of the lymphoid and lymphocytic blood cell series
  • polycythemia vera and erythremia malignancy of various blood cell products, but with red cells predominating
  • Lymphomas including: Hodgkin and Non-Hodgkin lymphomas;
  • Solid tumors of the nervous system including medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma and schwannoma;
  • Mixed Types including, e.g., adenosquamous carcinoma, mixed mesodermal tumor, carcinosarcoma or teratocarcinoma.
  • a compound of the invention, or a pharmaceutically acceptable salt thereof may be for use in the treatment of a cancer selected from cancer selected from lung, colon, breast, ovarian, prostate, liver, pancreas, brain, blood and skin cancer.
  • the cancer is selected from breast, brain, blood and ovarian cancer.
  • the cancer is selected from blood and ovarian cancer.
  • the blood cancer is leukemia.
  • the leukemia is selected from chronic myeloid leukaemia (CML), acute myeloid leukaemia (AML), chronic lymphocytic leukaemia (CLL) and acute lymphoblastic leukaemia (ALL).
  • CML chronic myeloid leukaemia
  • AML acute myeloid leukaemia
  • CLL chronic lymphocytic leukaemia
  • ALL acute lymphoblastic leukaemia
  • the anti-cancer effect may arise through one or more mechanisms, including but not limited to, the regulation of cell proliferation, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumour from its origin), the inhibition of invasion (the spread of tumour cells into neighbouring normal structures), or the promotion of apoptosis (programmed cell death).
  • the compounds described herein are for use in treating an acute or chronic autoimmune and/or inflammatory condition.
  • the compounds described herein are for use in treating one or more of the following: rheumatoid arthritis, osteoarthritis, acute gout, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease (Crohn's disease and Ulcerative colitis), asthma, chronic obstructive airways disease, pneumonitis, myocarditis, pericarditis, myositis, eczema, dermatitis (including atopic dermatitis), alopecia, vitiligo, bullous skin diseases, nephritis, vasculitis, hypercholesterolemia, atherosclerosis, Alzheimer's disease, depression, Sjogren'' syndrome, sialoadenitis, central retinal vein occlusion, branched retinal vein occlusion,
  • the compounds described herein are for use in the treatment a inflammatory disorder such as rheumatoid arthritis, osteoarthritis, acute gout, psoriasis, systemic lupus erythematosus, multiple sclerosis or inflammatory bowel disease (Crohn's disease and Ulcerative colitis).
  • a inflammatory disorder such as rheumatoid arthritis, osteoarthritis, acute gout, psoriasis, systemic lupus erythematosus, multiple sclerosis or inflammatory bowel disease (Crohn's disease and Ulcerative colitis).
  • the compounds of the invention or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically/ peripherally or topically (i.e. , at the site of desired action).
  • Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, infraorbital, intraperitoneal, intratrache
  • the compounds of the invention and salts, solvates thereof defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, one or more additional therapeutic agents, e.g. an anti-tumour agent.
  • additional therapeutic agents e.g. an anti-tumour agent.
  • cancer treatment in addition to the compound of the invention therapy may involve conventional surgery or radiotherapy or chemotherapy.
  • chemotherapy may include one or more of the 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, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and 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
  • cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), 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 5a-reductase such as finasteride;
  • antioestrogens for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene
  • antiandrogens for example
  • anti-invasion agents for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4- yloxyquinazoline (AZD0530; International Patent Application WO 01/94341), N-(2-chloro-6- methylphenyl)-2- ⁇ 6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino ⁇ thiazole- 5-carboxamide (dasatinib, BMS-354825; J. Med.
  • inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [HerceptinTM], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. (Critical reviews in oncology/haematology, 2005, Vol.
  • inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the 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 (gefitinib, ZD1839), 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 (Cl 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor
  • vascular endothelial growth factor for example the anti-vascular endothelial cell growth factor antibody bevacizumab (AvastinTM) and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034) and 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1- ylpropoxy)quinazoline (AZD2171; Example 240 within WO 00/47212), compounds such as those disclosed in International Patent Applications W097/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms (for example linomide, inhibitor
  • 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;
  • an endothelin receptor antagonist for example zibotentan (ZD4054) or atrasentan
  • - antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • 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
  • the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
  • a combination for use in the treatment of a cancer comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and another anti-tumour agent.
  • a combination for use in the treatment of a proliferative condition such as cancer (for example a cancer involving a solid tumour), comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and any one of the anti-tumour agents listed herein above.
  • a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate thereof for use in the treatment of cancer in combination with another anti-tumour agent, optionally selected from one listed herein above.
  • a combination refers to simultaneous, separate or sequential administration.
  • “combination” refers to simultaneous administration.
  • “combination” refers to separate administration.
  • “combination” refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.
  • a combination refers to a combination product.
  • a pharmaceutical composition which comprises a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in combination with an anti-tumour agent (optionally selected from one listed herein above), in association with a pharmaceutically acceptable diluent or carrier.
  • the compounds of the invention may be prepared using synthetic techniques that are known in the art (as illustrated by the examples herein).
  • Reagents were purchased from commercial sources and used as received. All solvents were of reagent grade unless otherwise stated, with anhydrous equivalents being sourced from external suppliers. All reactions were performed under an inert atmosphere of nitrogen unless otherwise stated. Brine refers to a saturated aqueous solution of sodium chloride.
  • HPLC High Performance Liquid Chromatography
  • MS Mass Spectrometer
  • Table 1 LCMS Method codes (Flow expressed in mL/min; column temperature (T) in °C; Run time in minutes).
  • N-[(3-Bromo-5-chloro-phenyl)methyl]-2,2-diethoxy-acetamidine (P6) (44. Og, 0.125mol) was added to cone.
  • H2SO4 150mL
  • the mixture was stirred at 80°C for 2 hours.
  • the mixture was added to ice-water slowly and the pH adjusted to 8 by addition of NaOH aq. solution (12M).
  • a precipitate formed which was filtered, washed with water and Pet. ether, and dried.
  • the reaction was heated in a microwave at 110°C for 4 hours in a sealed tube. After this time, the mixture was allowed to cool to room temperature. The organics were extracted into EtOAc, washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure.
  • tert-butyl 4-[[7-(2-fluoro-6-methyl-phenyl)-3-(methylamino)-5- isoquinolyl]amino]piperidine-1-carboxylate and tert-butyl 4-[[5-(2-fluoro-6-methyl-phenyl)-3- (methylamino)-7-isoquinolyl]amino]piperidine-1-carboxylate as a mixture of regioisomers (P64) (0.054g), LCMS ES + 465 [M+H] + , Rt 1.05, 1.37 mins (Method 2).
  • the mixture was degassed by bubbling a stream of argon through.
  • the reaction was heated at 110°C for 2 hours in a sealed tube. After this time, the mixture was allowed to cool to room temperature.
  • the organics were extracted into EtOAc, washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was chromatographed [Si0 2 , Pet.
  • SIK2, SIK1, SIK3, Abl, Src and EPHA2 assays were performed using an IMAP fluorescence polarization assay format (Molecular Devices Inc.). 0.6-13 nM of each kinase (Life T echnologies) was incubated for 60 min at room temperature with 100 nM of either FAM- Abltide, FAM-Srctide or FAM-HDAC protein derived peptide (synthesized by Alta Biosciences, Birmingham UK).
  • Assays were carried out in the presence of 50 or 100 mM ATP in either 20 mM Tris buffer (pH 7.2) containing 4 mM MgCI 2 , 0.2% BSA and 2 mM DTT (SIK2, SIK1, SIK3, Abl, Src); or 20 mM Tris buffer (pH 8.5) containing 20 mM MgCL, 0.5% BSA, 0.2% Triton and 5 mM DTT (EPHA2). Typically, dose response analyses were performed over concentration ranges from 0.00005 - 1 pM.
  • Reactions were stopped by adding 2 assay volumes of 0.25% (v/v) IMAP binding reagent in either an 85:15 ratio (SIK2, SIK1 , SIK3, Abl, EPHA2) or 30:70 ratio (Src) of IMAP binding buffers A and B (Molecular Devices). After incubation to allow the detection reagents to bind to the phosphorylated peptide, fluorescence polarization was measured on a Tecan Infinite plate reader at excitation (470 nm) and emission (530 nm) wavelengths. Inhibition was calculated using no inhibitor and no enzyme controls as 0 and 100% inhibition, respectively.
  • Table 3 provides details of the inhibitory constant (nM) of compounds of the invention at SIK1, SIK2 and SIK3 and other kinases.
  • SIK2 is a centrosome kinase required for bipolar mitotic spindle formation that provides a potential target for therapy in ovarian cancer. Cancer Cell 2010;18:109-21.

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Abstract

L'invention concerne des composés de formule I, et des sels et des solvates de ceux-ci : (I) dans laquelle R1, R2, R3, R6, X1, X2 et Z ont la signification indiquée dans la description. Les composés sont des inhibiteurs de kinase inductible par un sel (SIK), en particulier SIK2, et sont utiles en thérapie, en particulier dans le traitement des troubles et maladies suivants : trouble prolifératif, néoplasme bénin, angiogenèse pathologique, maladie ou état inflammatoire, maladie ou état musculo-squelettique, maladie auto-immune, maladie ou état hématologique, maladie ou état neurologique, trouble psychiatrique ou trouble métabolique.
PCT/GB2020/052745 2019-10-31 2020-10-30 Dérivés d'isoquinoléine en tant qu'inhibiteurs de sik2 WO2021084265A1 (fr)

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