WO2010056758A1 - Dérivés de quinazoline en tant qu’inhibiteurs de kinase - Google Patents

Dérivés de quinazoline en tant qu’inhibiteurs de kinase Download PDF

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WO2010056758A1
WO2010056758A1 PCT/US2009/064048 US2009064048W WO2010056758A1 WO 2010056758 A1 WO2010056758 A1 WO 2010056758A1 US 2009064048 W US2009064048 W US 2009064048W WO 2010056758 A1 WO2010056758 A1 WO 2010056758A1
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Prior art keywords
kinase
compound
alkyl
scheme
procedures
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PCT/US2009/064048
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English (en)
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Yangbo Feng
Philip Lograsso
Thomas Bannister
Thomas Schroeter
Xingang Fang
Yan Yin
Yen Ting Chen
Hampton Sessions
Sarwat Chowdhury
Jun-Li Luo
Tomas Vojkovsky
Original Assignee
Yangbo Feng
Philip Lograsso
Thomas Bannister
Thomas Schroeter
Xingang Fang
Yan Yin
Yen Ting Chen
Hampton Sessions
Sarwat Chowdhury
Jun-Li Luo
Tomas Vojkovsky
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Publication of WO2010056758A1 publication Critical patent/WO2010056758A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/217—IFN-gamma
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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
    • C07D405/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • kinase enzymes catalyze the phosphorylation of specific amino acid residues in specific protein substrates, and by doing so are believed to be key components of regulatory systems controlling cell proliferation, cell differentiation, cell death (apoptosis), and tissue/organ organization.
  • Rho kinases subclasses known as Rho kinases
  • Protein Kinase B also known as AKT
  • AKT Protein Kinase B
  • kinase p70S6K that acts on a ribosomal protein
  • LIM kinases kinase p70S6K that acts on a ribosomal protein
  • IKK kinases kinase p70S6K that acts on a ribosomal protein
  • IKK kinases kinase p70S6K that acts on a ribosomal protein
  • LIM kinases IKK kinases
  • Fit kinases an Aurora kinases
  • Src kinases Protein Kinase B
  • Each of these subclasses can contain multiple forms, isozymes, protein sequences, and the like, and are characterized by structural and functional homologies.
  • Rho kinases also known as Rho-associated kinases, are serine/threonine kinases that function downstream of Rho which is a low molecular GTP-binding protein.
  • Rho kinase isoforms ROCK I and ROCK II.
  • the enzymes are believed to be involved in a variety of biological events such as smooth muscle contraction, apoptosis, cell growth, cell migration, cell proliferation, cytokinesis, cytoskeletal control, and inflammation, and to be involved in pathology of various diseases including cardiovascular disease, tumor infiltration, osteogenesis, elevation of intraocular pressure, retinal neurodegeneration, chondrocyte differentiation and neurogenic pain. See, e.g., H.
  • Rho kinase inhibitors See, e.g. WO98/06433; WO00/09162; WO00/78351; WO01/17562;
  • PKA Protein Kinase B
  • AKT protein family which are known to play a role in cellular signaling in mammals. In humans, there are at least three genes in the PCB/Akt family:
  • Aktl Akt2, and Akt3. These genes code for enzymes that are serine/threonine- specific protein kinases. Aktl is involved in cellular survival pathways, by inhibiting apoptotic processes. Aktl is also able to induce protein synthesis pathways, and is therefore a key signaling protein in the cellular pathways that lead to skeletal muscle hypertrophy, and general tissue growth. Since it can block apoptosis, and thereby promote cell survival, Aktl has been implicated as a major factor in many types of cancer. See, for example, published PCT patent application Pub. No. WO2008/110846 and documents cited therein.
  • the protein kinase known as p70S6K a 70 kDa ribosomal protein kinase is a serine/threonine-specific protein kinase that is known to control or modulate protein synthesis on the ribosome through phosphorylation of a ribosomal protein S6.
  • p70S6K is believed to be involved in cell cycle control, cell differentiation and motility, in the immune response, and in tissue repair.
  • This kinase may block apoptosis in tumor cells and thus plays a role in cancer proliferation. See, for example, published PCT patent application Pub. No. WO2008/110846 and documents cited therein.
  • LIM kinase including LIMKl and LIMK2
  • LIMK LIM kinase
  • LIMKl actin-binding kinases that may be involved in reorganization of the actin cytoskeleton, possibly by regulating Rho kinase dependent cytoskeletal rearrangement. See, for example, published patent application Pub. No. US2009/0042893 and documents cited therein.
  • IKK kinases including IKK ⁇ (IKKl), IKK ⁇ (IKK2), IKKi (IKK ⁇ ), and TKBl, are regulatory signaling molecules that interact with NK- ⁇ B, a transcription factor that regulates the expression of many genes.
  • NK- ⁇ B is believed to be involved in cellular and organismic processes including angiogenesis, inflammatory diseases, and ischemic/reperfusion injury.
  • the IKK kinases are believed to activate NK- ⁇ B by phosphorylation in response to a variety of different biochemical signals. See, for example, published PCT patent application WO2009/089042; R. Agami (2007), Cell, 129, 1043; and J.S. Boehm, et al. (2007), Cell, 129, 1065.
  • Fit kinases include Flt3, also known as FMS-like tyrosine kinase 3, is a membrane-spanning cytokine-binding kinase, involved in proliferation, differentiation, and apoptosis of cells in hematopoiesis. See for example US2006281788; Qi Chao, et al. (2009), J. Med. Chem., DOI:
  • Src kinases are members of the cytoplasmic protein tyrosine kinase family, and the Src family includes members such as BLK, FGR, FYN, HCK, LCK, LYN, YES, SRC, AND YRK.
  • Src is believed to be responsible for stimulation of VEGF, and is also involved in regulation of cell growth, migration, and survival. See for example K. Lee et al. (2009),
  • inhibition of one or more of these protein kinases could be therapeutically effective in the treatment of any of hypertension, atherosclerosis, angina, stroke, arterial obstruction, peripheral arterial disease, peripheral circulation disorder, erectile dysfunction, acute and chronic pain, dementia, Alzheimer's disease, Parkinson's disease, neuronal degeneration, asthma, amyotrophic lateral sclerosis, spinal cord injury, rheumatoid arthritis, osteoarthritis, osteoporosis, psoriasis, cerebral vasospasm, glaucoma, spinal cord injury, multiple sclerosis, pulmonary hypertension, acute respiratory distress syndrome, inflammation, diabetes, urinary organ diseases such as overactive bladder (OAB) and benign prostatic hypertrophy (BPH), metastasis, cancer, open angle glaucoma, ocular hypertension, retinopathy, autoimmune disease and viral infection, or in providing myocardial protection.
  • OAB overactive bladder
  • BPH benign prostatic hypertrophy
  • the present invention is directed to compounds that inhibit the bioactivity of one or more isoforms of Rho kinase, to methods of use of those compounds, and to methods of preparation of those compounds.
  • the invention provides a compound of formula (I):
  • R N is absent or present; when R N is absent, there is a double bond between the carbon atom bearing R 2 and the adjacent nitrogen atom; and when R N is present, there is a single bond between the carbon atom bearing R 2 and the adjacent nitrogen atom; R N comprises aralkyl wherein any carbon atom of the aralkyl is optionally substituted with J;
  • R 1 comprises alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryloxyalkyl, aminoalkyl, aminocycloalkyl, arylaminoalkyl, heterocyclyl or heterocyclyl alkyl wherein any heterocyclyl is optionally aryl-fused, and wherein any alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryloxyalkyl, aminoalkyl, aminocycloalkyl, arylaminoalkyl, heterocyclyl, heterocyclylalkyl, or aryl, is mono- or independently plurisubstituted with independently selected J; and wherein any amino group can be substituted with independently selected R, or two R can be bound to the nitrogen atom of the amino group that together with the nitrogen atom form a 3- to 8-membered monocyclic heterocyclic ring that can further contain 1-3 additional heteroatoms selected from the group consisting
  • J is independently at each occurrence halogen, R, (CH 2 )o- 2 ⁇ R', (CH 2 V 2 CN, CF 3 , OCF 3 , O, S, C(O), S(O), methylenedioxy, ethylenedioxy, (CH 2 V 2 N(R) 2 , (CH 2 V 2 SR, (CH 2 V 2 S(O)R, (CH 2 V 2 S(O) 2 R, (CH 2 ) 0 - 2 S(O) 2 N(R') 2 , (CH 2 V 2 SO 3 R', (CH 2 V 2 C(O)R, (CH 2 V 2 C(O)C(O)R', (CH 2 V 2 C(O)CH 2 C(O)R, (CH 2 V 2 C(S)R', (CH 2 V 2 C(O)OR', (CH 2 V 2 OC(O)R, (CH 2 ) 0 - 2 C(O)N(R') 2 , (CH 2 V 2 OC(
  • R 4 comprises H, aryl optionally substituted with J, OR, SR, N(R) 2 , NR'(CH 2 ) m NR 2 , NR(CH 2 ) m OH, OCH 2 CH(OH)CH 2 NR' 2 , O(CH 2 CH 2 O) P CH 2 CH 2 OR', O(CH 2 ) m NR' 2 , O(CH 2 ) m NR 2 , O(CH 2 ) m C(O)NR' 2 , S(CH 2 ) m NR' 2 , O(CH 2 ) p -heterocyclyl, N(R')(CH 2 ) p -heterocyclyl, O(CH2) P - heteroaryl, N(R')(CH 2 ) p -heteroaryl, wherein p is 0 to about 3, and wherein any heterocyclyl or heteroaryl can be mono- or independently plurisubstituted with J;
  • Q 1 is N, CR 3 , or CR 5
  • Q 2 is N, CR 3 or CR 5 ;
  • R 5 comprises H, F, Cl, Me, CN, C(O)R', C(O)OR', C(O)NR 2 , CF 3 , OR, OCF 3 , NR' 2 , or (Ci-Cs)alkyl, wherein any (Ci-Cs)alkyl is mono- or independently plurisubstituted with J; or any salt, hydrate, solvate, isotopically labeled form, stereoisomer, tautomer, or prodrug thereof.
  • compositions comprising an effective amount of a compound of the invention and a suitable excipient are provided.
  • pharmaceutical combinations comprising an effective amount of a compound of the invention and an effective amount of a second medicament are provided.
  • compositions comprising an effective amount of a compound of the invention, an effective amount of a second medicament, and a suitable excipient are provided.
  • Various embodiments of the invention provide methods of synthesis of compounds of the invention.
  • kinase can be a Rho kinase, an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Fit kinase, an Aurora kinase, or a Src kinase, or any combination thereof.
  • Various embodiments provide methods of using a compound, composition, or combination of the invention, the methods comprising identifying a patient with a malcondition for which administration of an effective amount of a compound, composition, or combination of the invention is medically indicated, and administering an effective amount of the compound, composition, or combination to the patient at a frequency of administration and for a duration of time sufficient to provide a beneficial effect to the patient.
  • Various embodiments provide methods of using a compound, composition or combination of the invention, comprising identifying a patient with a malcondition for which binding of a ligand to a Rho kinase, an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Fit kinase, an Aurora kinase, or a Src kinase, or any combination thereof; or inhibition of a bioactivity of a Rho kinase, an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Fit kinase, an Aurora kinase, or a Src kinase, or any combination thereof; or both, is medically indicated, and administering an effective amount of the compound, composition, or combination to the patient at a frequency of administration and for
  • a compound, composition, or combination of the invention in preparing a medicament for the treatment of a malcondition in a human patient.
  • the malcondition can be one wherein inhibition of the bioactivity of a kinase is medically indicated.
  • the kinase can be a Rho kinase, an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Fit kinase, an Aurora kinase, or a Src kinase, or any combination thereof.
  • a malcondition in a human patient such as cardiovascular disease, neurogenic pain, hypertension, atherosclerosis, angina, stroke, arterial obstruction, peripheral arterial disease, peripheral circulation disorder, erectile dysfunction, acute or chronic pain, dementia, Alzheimer's disease, Parkinson's disease, neuronal degeneration, asthma, amyotrophic lateral sclerosis, spinal cord injury, rheumatoid arthritis, osteoarthritis, osteoporosis, elevation of intraocular pressure, retinal neurodegeneration, psoriasis, cerebral vasospasm, open angle glaucoma, multiple sclerosis, pulmonary hypertension, acute respiratory distress syndrome, inflammation, diabetes, urinary organ diseases such as overactive bladder (OAB) and benign prostatic hypertrophy (BPH), metastasis, cancer, glaucoma, ocular hypertension, retinopathy, autoimmune disease and viral infection, or myocardial pathology.
  • DETAILED D overactive bladder
  • BPH benign prostatic hypertrophy
  • mammals include, for example, humans; non-human primates, e.g. apes and monkeys; and non-primates, e.g. dogs, cats, cattle, horses, sheep, and goats.
  • Non-mammals include, for example, fish and birds.
  • kinase enzyme such as a Rho kinase, an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Fit kinase, an Aurora kinase, or a Src kinase, or any combination thereof, plays a role in the biochemical mechanisms involved in the disease or malcondition such that a therapeutically beneficial effect can be achieved by acting on the kinase.
  • Acting on” the kinase can include binding to the kinase and/or inhibiting the bioactivity of the kinase.
  • an effective amount when used to describe therapy to an individual suffering from a disorder, refers to the amount of a compound of the invention that is effective to inhibit or otherwise act on a kinase enzyme such as a Rho kinase, an an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Fit kinase, an Aurora kinase, or a Src kinase, or any combination thereof in the individual's tissues wherein the kinase involved in the disorder is active, wherein such inhibition or other action occurs to an extent sufficient to produce a beneficial therapeutic effect.
  • a kinase enzyme such as a Rho kinase, an an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Fit kinase, an Aurora kina
  • substantially as the term is used herein means completely or almost completely; for example, a composition that is "substantially free” of a component either has none of the component or contains such a trace amount that any relevant functional property of the composition is unaffected by the presence of the trace amount, or a compound is "substantially pure” is there are only negligible traces of impurities present.
  • Treating” or “treatment” within the meaning herein refers to an alleviation of symptoms associated with a disorder or disease, or inhibition of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder, or curing the disease or disorder.
  • an "effective amount” or a “therapeutically effective amount” of a compound of the invention refers to an amount of the compound that alleviates, in whole or in part, symptoms associated with the disorder or condition, or halts or slows further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disorder or condition.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of compounds of the invention are outweighed by the therapeutically beneficial effects.
  • chemically feasible is meant a bonding arrangement or a compound where the generally understood rules of organic structure are not violated; for example a structure within a definition of a claim that would contain in certain situations a pentavalent carbon atom that would not exist in nature would be understood to not be within the claim.
  • the structures disclosed herein, in all of their embodiments are intended to include only “chemically feasible” structures, and any recited structures that are not chemically feasible, for example in a structure shown with variable atoms or groups, are not intended to be disclosed or claimed herein.
  • an isotopic form of one or more atoms in a molecule that is different from the naturally occurring isotopic distribution of the atom in nature is referred to as an "isotopically labeled form" of the molecule.
  • All isotopic forms of atoms are included as options in the composition of any molecule, unless a specific isotopic form of an atom is indicated.
  • any hydrogen atom or set thereof in a molecule can be any of the isotopic forms of hydrogen, i.e., protium ( 1 H), deuterium ( 2 H), or tritium ( 3 H) in any combination.
  • any carbon atom or set thereof in a molecule can be any of the isotopic form of carbons, such as 11 C, 12 C, 13 C, or 14 C, or any nitrogen atom or set thereof in a molecule can be any of the isotopic forms of nitrogen, such as 13 N, 14 N, or 15 N.
  • a molecule can include any combination of isotopic forms in the component atoms making up the molecule, the isotopic form of every atom forming the molecule being independently selected. In a multi- molecular sample of a compound, not every individual molecule necessarily has the same isotopic composition.
  • a sample of a compound can include molecules containing various different isotopic compositions, such as in a tritium or 14 C radiolabeled sample where only some fraction of the set of molecules making up the macroscopic sample contains a radioactive atom. It is also understood that many elements that are not artificially isotopically enriched themselves are mixtures of naturally occurring isotopic forms, such as 14 N and 15 N, 32 S and 34 S, and so forth. A molecule as recited herein is defined as including isotopic forms of all its constituent elements at each position in the molecule. As is well known in the art, isotopically labeled compounds can be prepared by the usual methods of chemical synthesis, except substituting an isotopically labeled precursor molecule.
  • the isotopes can be obtained by any method known in the art, such as generation by neutron absorption of a precursor nuclide in a nuclear reactor, by cyclotron reactions, or by isotopic separation such as by mass spectrometry.
  • the isotopic forms are incorporated into precursors as required for use in any particular synthetic route.
  • 14 C and 3 H can be prepared using neutrons generated in a nuclear reactor. Following nuclear transformation, 14 C and 3 H are incorporated into precursor molecules, followed by further elaboration as needed.
  • amino protecting group or "N-protected” as used herein refers to those groups intended to protect an amino group against undesirable reactions during synthetic procedures and which can later be removed to reveal the amine. Commonly used amino protecting groups are disclosed in Protective Groups in Organic Synthesis, Greene, T. W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999).
  • Amino protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2- bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, ⁇ - chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; alkoxy- or aryloxy-carbonyl groups (which form urethanes with the protected amine) such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbony
  • Amine protecting groups also include cyclic amino protecting groups such as phthaloyl and dithiosuccinimidyl, which incorporate the amino nitrogen into a heterocycle.
  • amino protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, Alloc, Teoc, benzyl, Fmoc, Boc and Cbz. It is well within the skill of the ordinary artisan to select and use the appropriate amino protecting group for the synthetic task at hand.
  • hydroxyl protecting group or "O-protected” as used herein refers to those groups intended to protect an OH group against undesirable reactions during synthetic procedures and which can later be removed to reveal the amine. Commonly used hydroxyl protecting groups are disclosed in Protective Groups in Organic Synthesis, Greene, T. W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999).
  • Hydroxyl protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2- chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, ⁇ -chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4- bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; acyloxy groups (which form urethanes with the protected amine) such as benzyloxycarbonyl (Cbz), p- chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbon
  • substituted refers to an organic group as defined herein in which one or more bonds to a hydrogen atom contained therein are replaced by one or more bonds to a non-hydrogen atom such as, but not limited to, a halogen (i.e., F, Cl, Br, and I); an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxylamines, n
  • Non-limiting examples of substituents that can be bonded to a substituted carbon (or other) atom include F, Cl, Br, I, OR', OC(O)N(R') 2 , CN, CF 3 , OCF 3 , R', O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R) 2 , SR, SOR', SO 2 R', SO 2 N(R') 2 , SO 3 R, C(O)R, C(O)C(O)R, C(O)CH 2 C(O)R, C(S)R, C(O)OR, OC(O)R, C(0)N(R') 2 , 0C(0)N(R') 2 , C(S)N(R) 2 , (CH 2 V 2 N(R)C(O)R, (CH 2 ) 0 - 2 N(R)N(R) 2 , N(R)N(R
  • a substituent When a substituent is monovalent, such as, for example, F or Cl, it is bonded to the atom it is substituting by a single bond.
  • a divalent substituent such as O, S, C(O), S(O), or
  • S(O) 2 can be connected by two single bonds to two different carbon atoms.
  • O a divalent substituent
  • any substituent can be bonded to a carbon or other atom by a linker, such as (CH 2 ) n or (CR 2 ) n wherein n is 1, 2, 3, or more, and each R is independently selected.
  • Substituted alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groups as well as other substituted groups also include groups in which one or more bonds to a hydrogen atom are replaced by one or more bonds, including double or triple bonds, to a carbon atom, or to a heteroatom such as, but not limited to, oxygen in carbonyl (oxo), carboxyl, ester, amide, imide, urethane, and urea groups; and nitrogen in imines, hydroxyimines, oximes, hydrazones, amidines, guanidines, and nitriles.
  • Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups also include rings and fused ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups can also be substituted with alkyl, alkenyl, and alkynyl groups as defined herein.
  • ring system as the term is used herein is meant a moiety comprising one, two, three or more rings, which can be substituted with non-ring groups or with other ring systems, or both, which can be fully saturated, partially unsaturated, fully unsaturated, or aromatic, and when the ring system includes more than a single ring, the rings can be fused, bridging, or spirocyclic.
  • spirocyclic is meant the class of structures wherein two rings are fused at a single tetrahedral carbon atom, as is well known in the art.
  • Alkyl groups include straight chain and branched alkyl groups and cycloalkyl groups having from 1 to about 20 carbon atoms, and typically from 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms.
  • straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups.
  • branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec -butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.
  • Representative substituted alkyl groups can be substituted one or more times with any of the groups listed above, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
  • Cycloalkyl groups are cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
  • the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 6, or 7.
  • Cycloalkyl groups further include poly cyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above.
  • Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbornyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
  • cycloalkenyl alone or in combination denotes a cyclic alkenyl group.
  • carbocyclic denotes a ring structure wherein the atoms of the ring are carbon, such as a cycloalkyl group or an aryl group.
  • the carbocycle has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms is 4, 5, 6, or 7.
  • the carbocyclic ring can be substituted with as many as N-I substituents wherein N is the size of the carbocyclic ring with, for example, alkyl, alkenyl, alkynyl, amino, aryl, hydroxy, cyano, carboxy, heteroaryl, heterocyclyl, nitro, thio, alkoxy, and halogen groups, or other groups as are listed above.
  • a carbocyclyl ring can be a cycloalkyl ring, a cycloalkenyl ring, or an aryl ring.
  • a carbocyclyl can be monocyclic or poly cyclic, and if poly cyclic each ring can be independently be a cycloalkyl ring, a cycloalkenyl ring, or an aryl ring.
  • (Cycloalkyl)alkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkyl group as defined above.
  • -C(CH 2 CHs) CH 2 , cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others.
  • Cycloalkenyl groups include cycloalkyl groups having at least one double bond between 2 carbons.
  • cycloalkenyl groups include but are not limited to cyclohexenyl, cyclopentenyl, and cyclohexadienyl groups.
  • Cycloalkenyl groups can have from 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 6, or 7.
  • Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bomyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like, provided they include at least one double bond within a ring.
  • Cycloalkenyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above.
  • (Cycloalkenyl)alkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkenyl group as defined above.
  • Alkynyl groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms.
  • alkynyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to -C ⁇ CH, -OC(CH 3 ), -C ⁇ C(CH 2 CH 3 ), -CH 2 C ⁇ CH, -CH 2 C ⁇ C(CH 3 ), and -CH 2 C ⁇ C(CH 2 CH 3 ) among others.
  • heteroalkyl by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized.
  • the heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group.
  • Up to two heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH 3 , or - CH 2 -CH 2 -S-S-CH 3 .
  • a “cycloheteroalkyl” ring is a cycloalkyl ring containing at least one heteroatom.
  • a cycloheteroalkyl ring can also be termed a “heterocyclyl,” described below.
  • heteroalkenyl by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain monounsaturated or di-unsaturated hydrocarbon group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Up to two heteroatoms may be placed consecutively.
  • Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms.
  • aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups.
  • aryl groups contain about 6 to about 14 carbons in the ring portions of the groups.
  • Aryl groups can be unsubstituted or substituted, as defined above.
  • Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or 2-8 substituted naphthyl groups, which can be substituted with carbon or non-carbon groups such as those listed above.
  • Aralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above.
  • Representative aralkyl groups include benzyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl.
  • Aralkenyl group are alkenyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above.
  • Heterocyclyl groups or the term "heterocyclyl” includes aromatic and non-aromatic ring compounds containing 3 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S.
  • a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if poly cyclic, any combination thereof.
  • heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members.
  • a heterocyclyl group designated as a C 2 -heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth.
  • a C 4 -heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth.
  • the number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms.
  • a heterocyclyl ring can also include one or more double bonds.
  • a heteroaryl ring is an embodiment of a heterocyclyl group.
  • the phrase "heterocyclyl group" includes fused ring species including those comprising fused aromatic and non-aromatic groups.
  • a dioxolanyl ring and a benzdioxolanyl ring system are both heterocyclyl groups within the meaning herein.
  • the phrase also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl.
  • Heterocyclyl groups can be unsubstituted, or can be substituted as discussed above.
  • Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquino
  • Representative substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with groups such as those listed above.
  • Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12 ring members.
  • a heteroaryl group is a variety of a heterocyclyl group that possesses an aromatic electronic structure.
  • a heteroaryl group designated as a C 2 - heteroaryl can be a 5 -ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth.
  • a C 4 - heteroaryl can be a 5 -ring with one heteroatom, a 6-ring with two heteroatoms, and so forth.
  • Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolin
  • aryl and heteroaryl groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N- hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1- anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl) , indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-
  • Heterocyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group as defined above is replaced with a bond to a heterocyclyl group as defined above.
  • Representative heterocyclyl alkyl groups include, but are not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydro furan-2-yl ethyl, and indol-2-yl propyl.
  • Heteroarylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined above.
  • alkoxy refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined above.
  • linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like.
  • branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like.
  • cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • An alkoxy group can include one to about 12-20 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms.
  • an allyloxy group is an alkoxy group within the meaning herein.
  • a methoxyethoxy group is also an alkoxy group within the meaning herein.
  • halo or “halogen” or “halide” by themselves or as part of another substituent mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine.
  • a "haloalkyl” group includes mono-halo alkyl groups, poly-halo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro.
  • haloalkyl examples include trifluoromethyl, 1,1-dichloroethyl, 1,2- dichloroethyl, l,3-dibromo-3,3-difluoropropyl, perfluorobutyl, and the like.
  • a "haloalkoxy" group includes mono-halo alkoxy groups, poly-halo alkoxy groups wherein all halo atoms can be the same or different, and per-halo alkoxy groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro.
  • haloalkoxy examples include trifluoromethoxy, 1,1- dichloroethoxy, 1,2-dichloroethoxy, l,3-dibromo-3,3-difluoropropoxy, perfluorobutoxy, and the like.
  • (C x -C y )perfluoroalkyl wherein x ⁇ y, means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine atoms.
  • x ⁇ y means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine atoms.
  • Preferred is -(Ci-C 6 )perfluoroalkyl, more preferred is -(Ci-C 3 )perfluoroalkyl, most preferred is -CF 3 .
  • (C x -Cy )perfluoroalkylene wherein x ⁇ y, means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine atoms.
  • x ⁇ y means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine atoms.
  • Preferred is -(Ci-C6)perfluoroalkylene, more preferred is -(Ci-C3)perfluoroalkylene, most preferred is -CF 2 -.
  • aryloxy and arylalkoxy refer to, respectively, an aryl group bonded to an oxygen atom and an aralkyl group bonded to the oxygen atom at the alkyl moiety. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy.
  • acyl group refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom.
  • the carbonyl carbon atom is also bonded to another carbon atom, which can be part of an alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like.
  • the group is a "formyl” group, an acyl group as the term is defined herein.
  • An acyl group can include 0 to about 12-20 additional carbon atoms bonded to the carbonyl group.
  • An acyl group can include double or triple bonds within the meaning herein.
  • An acryloyl group is an example of an acyl group.
  • An acyl group can also include heteroatoms within the meaning here.
  • a nicotinoyl group (pyridyl-3-carbonyl) group is an example of an acyl group within the meaning herein.
  • Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and the like.
  • haloacyl group.
  • An example is a trifluoroacetyl group.
  • amine includes primary, secondary, and tertiary amines having, e.g., the formula N(group) 3 wherein each group can independently be H or non-H, such as alkyl, aryl, and the like.
  • Amines include but are not limited to
  • R-NH 2 for example, alkylamines, arylamines, alkylarylamines; R 2 NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R3N wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like.
  • amine also includes ammonium ions as used herein.
  • amino group is a substituent of the form -NH 2 , -NHR, -NR 2 , -NR 3 + , wherein each R is independently selected, and protonated forms of each.
  • any compound substituted with an amino group can be viewed as an amine.
  • An "amino group” within the meaning herein can be a primary, secondary, tertriary or quaternary amino group.
  • An "alkylamino” group includes a monoalkylamino, dialkylamino, and trialkylamino group.
  • ammonium ion includes the unsubstituted ammonium ion NH 4 + , but unless otherwise specified, it also includes any protonated or quaternarized forms of amines. Thus, trimethylammonium hydrochloride and tetramethylammonium chloride are both ammonium ions, and amines, within the meaning herein.
  • amide (or “amido”) includes C- and N-amide groups, i.e.,
  • Amide groups therefore include but are not limited to carbamoyl groups (-C(O)NH 2 ) and formamide groups (-NHC(O)H).
  • a "carboxamido” group is a group of the formula
  • R can be H, alkyl, aryl, etc.
  • urethane (or “carbamyl”) includes N- and O-urethane groups, i.e., -NRC(O)OR and -OC(O)NR 2 groups, respectively.
  • sulfonamide (or “sulfonamido”) includes S- and N- sulfonamide groups, i.e., -SO2NR2 and -NRSO2R groups, respectively. Sulfonamide groups therefore include but are not limited to sulfamoyl groups (- SO 2 NH 2 ).
  • organosulfur structure represented by the formula -S(O)(NR)- is understood to refer to a sulfoximine, wherein both the oxygen and the nitrogen atoms are bonded to the sulfur atom, which is also bonded to two carbon atoms.
  • amidine or “amidino” includes groups of the formula -C(NR)NR 2 .
  • an amidino group is -C(NH)NH 2 .
  • guanidine or "guanidino” includes groups of the formula -NRC(NR)NR 2 .
  • a guanidino group is -NHC(NH)NH 2 .
  • a “salt” as is well known in the art includes an organic compound such as a carboxylic acid, a sulfonic acid, or an amine, in ionic form, in combination with a counterion.
  • acids in their anionic form can form salts with cations such as metal cations, for example sodium, potassium, and the like; with ammonium salts such as NH 4 + or the cations of various amines, including tetraalkyl ammonium salts such as tetramethylammonium, or other cations such as trimethylsulfonium, and the like.
  • a “pharmaceutically acceptable” or “pharmacologically acceptable” salt is a salt formed from an ion that has been approved for human consumption and is generally non-toxic, such as a chloride salt or a sodium salt.
  • a “zwitterion” is an internal salt such as can be formed in a molecule that has at least two ionizable groups, one forming an anion and the other a cation, which serve to balance each other. For example, amino acids such as glycine can exist in a zwitterionic form.
  • a “zwitterion” is a salt within the meaning herein.
  • the compounds of the present invention may take the form of salts.
  • the term “salts" embraces addition salts of free acids or free bases which are compounds of the invention.
  • Salts can be "pharmaceutically- acceptable salts.”
  • pharmaceutically-acceptable salt refers to salts which possess toxicity profiles within a range that affords utility in pharmaceutical applications. Pharmaceutically unacceptable salts may nonetheless possess properties such as high crystallinity, which have utility in the practice of the present invention, such as for example utility in process of synthesis, purification or formulation of compounds of the invention.
  • Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid.
  • inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids.
  • organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, ⁇ -hydroxybutyric, sal
  • Suitable pharmaceutically acceptable base addition salts of compounds of the invention include, for example, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts.
  • Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N ⁇ -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine ( ⁇ -methylglucamine) and procaine.
  • Examples of pharmaceutically unacceptable base addition salts include lithium salts and cyanate salts.
  • salts may be useful, for example as intermediates in the synthesis of Formula (I) compounds, for example in their purification by recrystallization.
  • All of these salts may be prepared by conventional means from the corresponding compound according to Formula (I) by reacting, for example, the appropriate acid or base with the compound according to Formula (I).
  • pharmaceutically acceptable salts refers to nontoxic inorganic or organic acid and/or base addition salts, see, for example, Lit et al., Salt Selection for Basic Drugs (1986), IntJ. Pharm., 33, 201-217, incorporated by reference herein.
  • a “hydrate” is a compound that exists in a composition with water molecules.
  • the composition can include water in stoichiometic quantities, such as a monohydrate or a dihydrate, or can include water in random amounts.
  • a "hydrate” refers to a solid form, i.e., a compound in water solution, while it may be hydrated, is not a hydrate as the term is used herein.
  • a “solvate” is a similar composition except that a solvent other that water replaces the water.
  • a solvent other that water replaces the water.
  • methanol or ethanol can form an "alcoholate", which can again be stoichiometic or non-stoichiometric.
  • a “solvate” refers to a solid form, i.e., a compound in solution in a solvent, while it may be solvated, is not a solvate as the term is used herein.
  • prodrug as is well known in the art is a substance that can be administered to a patient where the substance is converted in vivo by the action of biochemicals within the patients body, such as enzymes, to the active pharmaceutical ingredient.
  • examples of prodrugs include esters of carboxylic acid groups, which can be hydrolyzed by endogenous esterases as are found in the bloodstream of humans and other mammals. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • the present invention further embraces isolated compounds according to formula (I).
  • isolated compound refers to a preparation of a compound of formula (I), or a mixture of compounds according to formula (I), wherein the isolated compound has been separated from the reagents used, and/or byproducts formed, in the synthesis of the compound or compounds. "Isolated” does not mean that the preparation is technically pure (homogeneous), but it is sufficiently pure to compound in a form in which it can be used therapeutically.
  • an “isolated compound” refers to a preparation of a compound of formula (I) or a mixture of compounds according to formula (I), which contains the named compound or mixture of compounds according to formula (I) in an amount of at least 10 percent by weight of the total weight.
  • the preparation contains the named compound or mixture of compounds in an amount of at least 50 percent by weight of the total weight; more preferably at least 80 percent by weight of the total weight; and most preferably at least 90 percent, at least 95 percent or at least 98 percent by weight of the total weight of the preparation.
  • the compounds of the invention and intermediates may be isolated from their reaction mixtures and purified by standard techniques such as filtration, liquid-liquid extraction, solid phase extraction, distillation, recrystallization or chromatography, including flash column chromatography, or HPLC.
  • Isomerism and Tautomerism in Compounds of the Invention Tautomerism
  • a compound of the formula (I) or a salt thereof may exhibit the phenomenon of tautomerism whereby two chemical compounds that are capable of facile interconversion by exchanging a hydrogen atom between two atoms, to either of which it forms a covalent bond. Since the tautomeric compounds exist in mobile equilibrium with each other they may be regarded as different isomeric forms of the same compound. It is to be understood that the formulae drawings within this specification can represent only one of the possible tautomeric forms. However, it is also to be understood that the invention encompasses any tautomeric form, and is not to be limited merely to any one tautomeric form utilized within the formulae drawings.
  • Such tautomerism can also occur with substituted pyrazoles such as 3- methyl, 5-methyl, or 3,5-dimethylpyrazoles, and the like.
  • Another example of tautomerism is amido-imido (lactam-lactim when cyclic) tautomerism, such as is seen in heterocyclic compounds bearing a ring oxygen atom adjacent to a ring nitrogen atom.
  • the compounds of the present invention may exist in, and may be isolated as pure enantiomeric or diastereomeric forms or as racemic mixtures.
  • the present invention therefore includes any possible enantiomers, diastereomers, racemates or mixtures thereof of the compounds of the invention.
  • the isomers resulting from the presence of a chiral center comprise a pair of non-superimposable isomers that are called "enantiomers.”
  • Single enantiomers of a pure compound are optically active, i.e., they are capable of rotating the plane of plane polarized light.
  • Single enantiomers are designated according to the Cahn-Ingold-Prelog system.
  • the priority of substituents is ranked based on atomic weights, a higher atomic weight, as determined by the systematic procedure, having a higher priority ranking.
  • the present invention is meant to encompass diastereomers as well as their racemic and resolved, diastereomerically and enantiomerically pure forms and salts thereof. Diastereomeric pairs may be resolved by known separation techniques including normal and reverse phase chromatography, and crystallization.
  • isolated optical isomer means a compound which has been substantially purified from the corresponding optical isomer(s) of the same formula.
  • the isolated isomer is at least about 80%, more preferably at least 90% pure, even more preferably at least 98% pure, most preferably at least about 99% pure, by weight.
  • Isolated optical isomers may be purified from racemic mixtures by well-known chiral separation techniques. According to one such method, a racemic mixture of a compound of the invention, or a chiral intermediate thereof, is separated into 99% wt.% pure optical isomers by HPLC using a suitable chiral column, such as a member of the series of DAICEL ® CHIRALP AK ® family of columns (Daicel Chemical Industries, Ltd., Tokyo, Japan). The column is operated according to the manufacturer's instructions. Rotational Isomerism
  • the preferred compounds of the present invention have a particular spatial arrangement of substituents on the aromatic rings, which is related to the structure activity relationship demonstrated by the compound class. Often such substitution arrangement is denoted by a numbering system; however, numbering systems are often not consistent between different ring systems. In six-membered aromatic systems, the spatial arrangements are specified by the common nomenclature "para" for 1,4-substitution, "meta” for 1,3-substitution and "ortho" for 1 ,2-substitution as shown below.
  • the compound or set of compounds such as are among the inventive compounds or are used in the inventive methods, can be any one of any of the combinations and/or sub-combinations of the above-listed embodiments.
  • the compound or set of compounds such as are among the inventive compounds or used in the inventive methods, can be any one of any of the combinations and/or sub-combinations of the above-listed embodiments.
  • Provisos may apply to any of the disclosed categories or embodiments wherein any one or more of the other above disclosed embodiments or species may be excluded from such categories or embodiments.
  • the invention provides a compound of formula (I):
  • R N is absent or present; when R N is absent, there is a double bond between the carbon atom bearing R 2 and the adjacent nitrogen atom; and when R N is present, there is a single bond between the carbon atom bearing R 2 and the adjacent nitrogen atom; R N comprises aralkyl wherein any carbon atom of the aralkyl is optionally substituted with J;
  • R 1 comprises alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryloxyalkyl, aminoalkyl, aminocycloalkyl, arylaminoalkyl, heterocyclyl or heterocyclyl alkyl wherein any heterocyclyl is optionally aryl-fused, and wherein any alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryloxyalkyl, aminoalkyl, aminocycloalkyl, arylaminoalkyl, heterocyclyl, heterocyclylalkyl, or aryl, is mono- or independently plurisubstituted with independently selected J; and wherein any amino group can be substituted with independently selected R, or two R can be bound to the nitrogen atom of the amino group that together with the nitrogen atom form a 3- to 8-membered monocyclic heterocyclic ring that can further contain 1-3 additional heteroatoms selected from the group consisting
  • J is independently at each occurrence halogen, R, (CH 2 )o- 2 ⁇ R', (CH 2 V 2 CN, CF 3 , OCF 3 , O, S, C(O), S(O), methylenedioxy, ethylenedioxy, (CH 2 V 2 N(R) 2 , (CH 2 V 2 SR, (CH 2 V 2 S(O)R, (CH 2 V 2 S(O) 2 R, (CH 2 ) 0 - 2 S(O) 2 N(R') 2 , (CH 2 V 2 SO 3 R', (CH 2 V 2 C(O)R, (CH 2 V 2 C(O)C(O)R', (CH 2 V 2 C(O)CH 2 C(O)R, (CH 2 V 2 C(S)R', (CH 2 V 2 C(O)OR', (CH 2 V 2 OC(O)R, (CH 2 ) 0 - 2 C(O)N(R') 2 , (CH 2 V 2 OC(
  • R 4 comprises H, aryl optionally substituted with J, OR, SR, N(R) 2 , NR'(CH 2 ) m NR 2 , NR(CH 2 ) m OH, OCH 2 CH(OH)CH 2 NR' 2 , O(CH 2 CH 2 O) P CH 2 CH 2 OR', O(CH 2 ) m NR' 2 , O(CH 2 ) m NR 2 , O(CH 2 ) m C(O)NR' 2 , S(CH 2 ) m NR' 2 , O(CH 2 ) p -heterocyclyl, N(R')(CH 2 ) p -heterocyclyl, O(CH2) P - heteroaryl, N(R')(CH 2 ) p -heteroaryl, wherein p is 0 to about 3, and wherein any heterocyclyl or heteroaryl can be mono- or independently plurisubstituted with J;
  • Q 1 is N, CR 3 , or CR 5
  • Q 2 is N, CR 3 or CR 5 ;
  • R 5 comprises H, F, Cl, Me, CN, C(O)R', C(O)OR', C(O)NR 2 , CF 3 , OR, OCF 3 , NR' 2 , or (Ci-Cs)alkyl, wherein any (Ci-Cs)alkyl is mono- or independently plurisubstituted with J; or any salt, hydrate, solvate, isotopically labeled form, stereoisomer, tautomer, or prodrug thereof.
  • the invention provides a compound of formula (I) wherein R 1 comprises a cyclopropyl, cyclopropylcarbinyl, cyclopentyl, isopropyl, phenoxyalkyl, phenylaminoalkyl, phenylalkyl, amino-substituted phenylalkyl, amido-substituted phenylalkyl, or aryl-fused heterocyclyl wherein any cyclopropyl, cyclopropylcarbinyl, cyclopentyl, isopropyl, phenoxyalkyl, phenylaminoalkyl, phenylalkyl, amino-substituted phenylalkyl, amido- substituted phenylalkyl, or aryl-fused heterocyclyl is optionally mono- or independently plurisubstituted with J.
  • R 1 comprises a cyclopropyl, cyclopropylcarbiny
  • the invention provides a compound of formula (I) wherein R 1 comprises any of the following: a) an aryl-fused heterocyclyl moiety of the formula
  • X is O, CH, CHR 5 , N, NR 5 , when X is O, CHR 5 , or NR 5 a double bond indicated by the dashed line is absent, when X is N or CH a double bond indicated by the dashed line is present, and J n signifies mono- or independent plurisubstitution by J, wherein a wavy line signifies a point of attachment; b) an aryloxyalkyl, aralkyl, or arylaminoalkyl moiety of the formula
  • R independently comprises H or alkyl wherein the alkyl can be mono- or independently plurisubstituted with J, and J n signifies mono- or independent plurisubstitution by J, wherein a wavy line signifies a point of attachment; d) an aralkyl moiety of the formula
  • R comprises H or alkyl wherein the alkyl can be mono- or independently plurisubstituted with J, and J n signifies mono- or independent plurisubstitution by J
  • R c comprises alkyl, aryl, cycloalkyl, cycloalkylalkyl, aralkyl, heterocyclyl, heterocyclyl alkyl, heteroaryl, or heteroaryl alkyl, wherein any alkyl, aryl, cycloalkyl, cycloalkylalkyl, aralkyl, heterocyclyl, heterocyclyl alkyl, heteroaryl, or heteroaryl alkyl, is optionally mono- or independently plurisubstituted with J, wherein a wavy line signifies a point of attachment; e) an aryl-fused heterocyclyl moiety of the formula
  • R comprises H or alkyl wherein the alkyl can be mono- or independently plurisubstituted with J, and J n signifies mono- or independent plurisubstitution by J, wherein a wavy line signifies a point of attachment; or, f) an aryloxyalkyl, aralkyl, or arylaminoalkyl moiety of formula
  • R comprises H or alkyl wherein the alkyl can be mono- or independently plurisubstituted with J
  • X is O, CH, or NR 5 , respectively
  • R 7 comprises (Ci-4)alkyl mono- or independently plurisubstituted with J, wherein a wavy line signifies a point of attachment.
  • the invention provides a compound of formula (I) wherein R 1 comprises a group of formula
  • R 6 comprises H, (Ci-C 6 )alkyl, or (C 3 -Cs)cycloalkyl, wherein the alkyl or cycloalkyl can be mono- or independently plurisubstituted with J; or, a group of formula a group of formula
  • R independently at each occurrence comprises H, alkyl wherein the alkyl can be mono- or independently plurisubstituted with J, or C(O)R 8 , wherein R 8 comprises (Ci_4)alkylNR'2, (5-7 membered)heterocyclyl, (5-7 membered)heterocyclyl-(Ci- 4 )alkyl, (5-7 membered)heteroaryl, (5-7 membered)heteroaryl-(Ci_ 4 )alkyl, phenylamino, phenyl(Ci_ 4 )alkylamino; and, R 7 comprises (Ci_4)alkyl-NR'2;
  • R 1 can comprise a moiety of formula
  • R comprises a group of the formula (C 1-4 alkyl)OCH 3 , (C 1-4 alkyl)NH 2 , (C 1-4 alkyl)NHMe, (C 1-4 alkyl)NMe 2 , (Ci_ 4 alkyl)SCH 3 , cyclopropyl, (Ci- 4 alkyl)-2-thiazolyl, (Ci- 4 alkyl)-4-imidazolyl, (Ci- 4 alkyl)-2-pyridyl, (C 1-4 alkyl)-3-pyridyl, (C 1-4 alkyl)-4-pyridyl, (C 1-4 alkyl)-4- morpholinyl, or (C 1-4 alkyl)-4-N-methylpyridazinyl, wherein a wavy line signifies a point of attachment.
  • the invention provides a compound of formula (I) wherein R comprises hydroxy, NH 2 , alkylamino, aminoalkylthio, hydroxyalkylamino, aminoalkylamino, amidoalkylamino, carboxyalkylamino, heterocyclyl, heterocyclylalkylamino, heteroarylamino, or heteroarylalkylamino, any of which can be mono- or independently plurisubstituted with J.
  • the invention provides a compound of formula (I) wherein R 2 comprises a group of the formula
  • the invention provides a compound of formula (I) wherein R comprises a pyrazolinyl, pyridinyl, or pyrimidinyl ring, which can be unsubstituted or substituted with alkyl or NR 2 , wherein R comprises H or alkyl wherein the alkyl can be mono- or independently plurisubstituted with J. More specifically, R 3 can comprise a group of formula (I) wherein R comprises a pyrazolinyl, pyridinyl, or pyrimidinyl ring, which can be unsubstituted or substituted with alkyl or NR 2 , wherein R comprises H or alkyl wherein the alkyl can be mono- or independently plurisubstituted with J. More specifically, R 3 can comprise a group of formula (I) wherein R comprises a pyrazolinyl, pyridinyl, or pyrimidinyl ring, which can be unsubstituted or substituted with al
  • the invention provides a compound of formula (I) wherein R 4 comprises H, OH, OMe, NR(CH 2 ) m NR 2 , NR(CH 2 ) m OH, OCH 2 CH(OH)CH 2 NR 2 , O(CH 2 CH 2 O) P CH 2 CH 2 OR, O(CH 2 ) m NR 2 , O(CH 2 ) m NR 2 , O(CH 2 ) m C(O)NR 2 , S(CH 2 ) m NR 2 , O-(CH 2 ) p -heterocyclyl, NR- (CH 2 ) p -heterocyclyl, O-(CH 2 ) p -heteroaryl, or NR-(CH 2 ) p -heteroaryl, wherein R comprises H or alkyl wherein the alkyl can be mono- or independently plurisubstituted with J, wherein m is 1-4 and p is
  • R 4 can comprise N(Me)(CH 2 ) 2 NMe 2 ,
  • N(Me)(CH2)3NMe2 O(CH 2 ) 2 NMe 2 , O(CH 2 ) 3 NMe 2 , O(CH 2 ) 2 OH, O(CH 2 ) 3 OH, OCH 2 C(O)-morpholinyl, O(CH 2 ) 2 C(O)-morpholinyl, tetrahydrofuran-3-yloxy, N-pyrrolidinylethoxy, N-methylpyrrolidin-3-yloxy, methyldiethyleneglycoloxy, 2-hydroxy-3-(N,N-dimethylamino)propoxy, dimethylaminoethylthio, hexahydropyran-3-yloxy, hexahydropyran-3-yloxy, hexahydropyran-4-yloxy, piperidin-3-yloxy, N-methylpiperidin-3-yloxy, piperidin-4-yloxy, N- methylpiperidin-4-yloxy, pyr
  • both Q 1 and Q 2 can be N.
  • both Q 1 and Q 2 can be CR 3 or CR 5 , wherein each R and R is independently selected thus including CH.
  • one of Q 1 or Q 2 can be N, and the other can be
  • R 3 can be a pyrazolinyl, pyridinyl, or pyrimidinyl ring, which can be unsubstituted or substituted with alkyl or NR 2 , wherein R comprises H or alkyl wherein the alkyl can be mono- or independently plurisubstituted with J.
  • R 5 can be H, F, Cl, Me, CN, C(O)R', C(O)OR', C(O)NR 2 , CF 3 , OR, OCF 3 , NR' 2 , or (Ci-Cs)alkyl, wherein any (Ci-Cs)alkyl is mono- or independently plurisubstituted with J.
  • the compounds provides compounds of any of Examples 1-251, shown below, or any salt, hydrate, solvate, isotopically labeled form, stereoisomer, tautomer, or prodrug thereof.
  • compositions of the compounds of the invention alone or in combination with another medicament.
  • compounds of the invention include stereoisomers, tautomers, solvates, prodrugs, pharmaceutically acceptable salts and mixtures thereof.
  • Compositions containing a compound of the invention can be prepared by conventional techniques, e.g. as described in Remington: The Science and Practice of Pharmacy, 19th Ed., 1995, incorporated by reference herein.
  • the compositions can appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
  • Typical compositions include a compound of the invention and a pharmaceutically acceptable excipient which can be a carrier or a diluent.
  • the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which can be in the form of an ampoule, capsule, sachet, paper, or other container.
  • a carrier or when the carrier serves as a diluent, it can be solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid carrier, for example contained in a sachet.
  • suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the carrier or diluent can include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the formulations can be mixed with auxiliary agents which do not deleteriously react with the active compounds.
  • Such additives can include wetting agents, emulsifying and suspending agents, salt for influencing osmotic pressure, buffers and/or coloring substances preserving agents, sweetening agents or flavoring agents.
  • the compositions can also be sterilized if desired.
  • the route of administration can be any route which effectively transports the active compound of the invention to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal or parenteral, e.g., rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment, the oral route being preferred.
  • the preparation can be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. If a liquid carrier is used, the preparation can be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • Injectable dosage forms generally include aqueous suspensions or oil suspensions which can be prepared using a suitable dispersant or wetting agent and a suspending agent Injectable forms can be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent.
  • Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution.
  • sterile oils can be employed as solvents or suspending agents.
  • the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.
  • the formulation can also be a powder suitable for reconstitution with an appropriate solution as described above.
  • the formulations can optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
  • the compounds can be formulated for parenteral administration by injection such as by bolus injection or continuous infusion.
  • a unit dosage form for injection can be in ampoules or in multi-dose containers.
  • the formulations of the invention can be designed to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art. Thus, the formulations can also be formulated for controlled release or for slow release.
  • compositions contemplated by the present invention can include, for example, micelles or liposomes, or some other encapsulated form, or can be administered in an extended release form to provide a prolonged storage and/or delivery effect. Therefore, the formulations can be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections. Such implants can employ known inert materials such as silicones and biodegradable polymers, e.g., polylactide-polyglycolide. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • the preparation can contain a compound of the invention, dissolved or suspended in a liquid carrier, preferably an aqueous carrier, for aerosol application.
  • a liquid carrier preferably an aqueous carrier
  • the carrier can contain additives such as solubilizing agents, e.g., propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabens.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
  • Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • a typical tablet that can be prepared by conventional tabletting techniques can contain: Core:
  • Active compound 250 mg Colloidal silicon dioxide (Aerosil)® 1.5 mg Cellulose, microcryst. (Avicel)® 70 mg
  • a typical capsule for oral administration contains compounds of the invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin capsule.
  • a typical injectable preparation is produced by aseptically placing 250 mg of compounds of the invention into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of sterile physiological saline, to produce an injectable preparation.
  • the compounds of the invention can be administered to a mammal, especially a human in need of such treatment, prevention, elimination, alleviation or amelioration of a malcondition. Such mammals include also animals, both domestic animals, e.g. household pets, farm animals, and non- domestic animals such as wildlife.
  • the compounds of the invention are effective over a wide dosage range.
  • dosages from about 0.05 to about 5000 mg, preferably from about 1 to about 2000 mg, and more preferably between about 2 and about 2000 mg per day can be used.
  • a typical dosage is about 10 mg to about 1000 mg per day.
  • the exact dosage will depend upon the activity of the compound, mode of administration, on the therapy desired, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
  • the compounds of the invention are dispensed in unit dosage form including from about 0.05 mg to about 1000 mg of active ingredient together with a pharmaceutically acceptable carrier per unit dosage.
  • dosage forms suitable for oral, nasal, pulmonal or transdermal administration include from about 125 ⁇ g to about 1250 mg, preferably from about 250 ⁇ g to about 500 mg, and more preferably from about 2.5 mg to about 250 mg, of the compounds admixed with a pharmaceutically acceptable carrier or diluent.
  • Dosage forms can be administered daily, or more than once a day, such as twice or thrice daily. Alternatively dosage forms can be administered less frequently than daily, such as every other day, or weekly, if found to be advisable by a prescribing physician.
  • a pharmaceutical combination comprising a compound of the invention in a therapeutically effective dose and a second medicament in a therapeutically effective dose
  • the second medicament can comprise an anti-proliferative agent, an anti-glaucoma agent, an anti-hypertensive agent, an anti-atherosclerotic agent, an anti-multiple sclerosis agent, an anti-angina agent, an anti-erectile dysfunction agent, an anti-stroke agent, or an anti-asthma agent.
  • the anti-proliferative agent can comprise an alkylating agent, an anti-metabolite, a vinca alkaloid, a terpenoid, a topoisomerase inhibitor, a monoclonal antibody, a kinase inhibitor, carboplatin, cisplatin, taxol, leucovorin, 5-flurouracil, eloxatin, cyclophosphamide, chlorambucil, avastin, or imatinib mesylate.
  • an alkylating agent an anti-metabolite, a vinca alkaloid, a terpenoid, a topoisomerase inhibitor, a monoclonal antibody, a kinase inhibitor, carboplatin, cisplatin, taxol, leucovorin, 5-flurouracil, eloxatin, cyclophosphamide, chlorambucil, avastin, or imatinib mesylate.
  • the anti-glaucoma agent can comprise a beta receptor-blocker, a prostaglandin, an alpha-adrenergic agonist, a parasympathomimetic (cholinergic agonist), or a carbonic anhydrase inhibitor.
  • the anti-hypertensive agent can comprise a beta receptor-blocker, a calcium channel blocker, a diueretic, an angiotensin converting enzyme (ACE) inhibitor, a renin inhibitor, or an angiotensin receptor antagonist.
  • ACE angiotensin converting enzyme
  • the anti-atherosclerotic agent can comprise a 3-HMG-coA-reductase inhibitor, a statin, atorvastatin, simvastatin, niacin, or a combination drug such as vytorin.
  • the anti-multiple sclerosis agent can comprise beta-inteferon, tysabri, or glatirimar acetate.
  • the anti-angina agent can comprise a beta receptor-blocker, a calcium channel blocker, nitroglycerin, isosorbide mononitrate, nicorandil, or ranolanzine.
  • the anti-erectile dysfunction agent can comprise a phosphodiesterase-5 inhibitor.
  • the anti-stroke agent can comprise tissue plasminogen activator.
  • the anti-asthma agent can comprise a bronchodilator, an inhaled corticosteroid, a leukotrine blockers, cromolyn, nedocromil, or theophylline.
  • a pharmaceutical combination of the invention can further comprise a suitable excipient as outlined above to provide a pharmaceutical composition comprising both medicaments.
  • a method of treatment of a malcondition comprising administering an effective amount of a compound of the invention and co-administering an effective amount of an additional medicament.
  • the malcondition can comprise cardiovascular disease, neurogenic pain, hypertension, atherosclerosis, angina, stroke, arterial obstruction, peripheral arterial disease, peripheral circulation disorder, erectile dysfunction, acute and chronic pain, dementia, Alzheimer's disease, Parkinson's disease, neuronal degeneration, asthma, amyotrophic lateral sclerosis, spinal cord injury, rheumatoid arthritis, osteoarthritis, osteoporosis, psoriasis, cerebral vasospasm, glaucoma, multiple sclerosis, pulmonary hypertension, acute respiratory distress syndrome, inflammation, diabetes, urinary organ diseases such as overactive bladder (OAB) and benign prostatic hypertrophy (BPH), metastasis, cancer, glaucoma, ocular hypertension, retinopathy, autoimmune disease and viral infection, or myocardial pathology, or any
  • the additional medicament that can be coadministered can comprise an anti-proliferative agent, an anti-glaucoma agent, an anti-hypertensive agent, an anti-atherosclerotic agent, an anti-multiple sclerosis agent, an anti-angina agent, an anti-erectile dysfunction agent, an anti- stroke agent, or an anti-asthma agent.
  • co-administered is meant that the patient is provided with an effective dose of an inventive compound and with an effective dose of the second medicament during the course of treatment, such as concurrently, consecutively, intermittently, or in other regimens.
  • the compound of the invention and the second medicament can be administered in separate dosage forms.
  • the anti-proliferative agent can comprise an alkylating agent, an anti-metabolite, a vinca alkaloid, a terpenoid, a topoisomerase inhibitor, a monoclonal antibody, a kinase inhibitor, carboplatin, cisplatin, taxol, leucovorin, 5-flurouracil, eloxatin, cyclophosphamide, chlorambucil, avastin, or imatinib mesylate.
  • an alkylating agent an anti-metabolite, a vinca alkaloid, a terpenoid, a topoisomerase inhibitor, a monoclonal antibody, a kinase inhibitor, carboplatin, cisplatin, taxol, leucovorin, 5-flurouracil, eloxatin, cyclophosphamide, chlorambucil, avastin, or imatinib mesylate.
  • the anti-glaucoma agent can comprise a beta receptor-blocker, a prostaglandin, an alpha-adrenergic agonist, a parasympathomimetic (cholinergic agonist), or a carbonic anhydrase inhibitor.
  • the anti-hypertensive agent can comprise a beta receptor-blocker, a calcium channel blocker, a diueretic, an angiotensin converting enzyme (ACE) inhibitor, a renin inhibitor, or an angiotensin receptor antagonist.
  • ACE angiotensin converting enzyme
  • the anti-atherosclerotic agent can comprise a 3 -HMG- coA-reductase inhibitor, a statin, atorvastatin, simvastatin, niacin, or a combination drug such as vytorin.
  • the anti-multiple sclerosis agent can comprise beta-inteferon, tysaberai, or glatirimar acetate.
  • the anti-angina agent can comprise a beta receptor-blocker, a calcium channel blocker, nitroglycerin, isosorbide mononitrate, nicorandil, or ranolanzine.
  • the anti-erectile dysfunction agent can comprise a phosphodiesterase-5 inhibitor.
  • the anti-stroke agent can comprise tissue plasminogen activator.
  • the anti-asthma agent can comprise a bronchodilator, an inhaled corticosteroid, a leukotrine blockers, cromolyn, nedocromil, or theophylline.
  • kinase can be a Rho kinase, an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Fit kinase, an Aurora kinase, or a Src kinase, or any combination thereof.
  • Various embodiments of the invention provide a method of treatment of a malcondition in a patient in need thereof, comprising administering a therapeutically effective amount of the compound of the invention to the patient at a frequency of administration and for a duration of time sufficient to provide a beneficial effect to the patient.
  • the malcondition can comprise cardiovascular disease, neurogenic pain, hypertension, atherosclerosis, angina, stroke, arterial obstruction, peripheral arterial disease, peripheral circulation disorder, erectile dysfunction, acute or chronic pain, dementia, Alzheimer's disease, Parkinson's disease, neuronal degeneration, asthma, amyotrophic lateral sclerosis, spinal cord injury, rheumatoid arthritis, osteoarthritis, osteoporosis, elevation of intraocular pressure, retinal neurodegeneration, psoriasis, cerebral vasospasm, glaucoma, multiple sclerosis, pulmonary hypertension, acute respiratory distress syndrome, inflammation, diabetes, urinary organ diseases such as overactive bladder (OAB) and benign prostatic hypertrophy (BPH), metastasis, cancer, glaucoma, ocular hypertension, retinopathy, autoimmune disease and viral infection, or myocardial pathology, or any combination thereof.
  • OAB overactive bladder
  • BPH benign prostatic hypertrophy
  • the malcondition can be such that binding of a ligand to a kinase or inhibition of a bioactivity of a kinase, or both, is medically indicated.
  • the kinase that is modulated or inhibited by a compound of the invention can be a Rho kinase, an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Fit kinase, an Aurora kinase, or a Src kinase, or any combination thereof.
  • Various embodiments of the invention provide a method of treatment of a malcondition in a patient, comprising administering to the patient the pharmaceutical combination or composition of the invention in a therapeutically effective amount at a frequency of administration and for a duration of time sufficient to provide a beneficial effect to the patient.
  • the method can be for treatment of a malcondition for which binding of a ligand to a Rho kinase, an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Fit kinase, an Aurora kinase, or a Src kinase, or any combination thereof; or inhibition of a bioactivity of a Rho kinase, an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Fit kinase, an Aurora kinase, or a Src kinase, or any combination thereof; or both, is medically indicated.
  • the method of treatment of a malcondition in a patient can further comprise administration of an effective amount of an additional medicament.
  • the additional medicament can comprise an antiproliferative agent, an anti-glaucoma agent, an anti-hypertensive agent, an anti- atherosclerotic agent, an anti-multiple sclerosis agent, an anti-angina agent, an anti-erectile dysfunction agent, an anti-stroke agent, or an anti-asthma agent.
  • the anti-proliferative agent can comprise an alkylating agent, an anti-metabolite, a vinca alkaloid, a terpenoid, a topoisomerase inhibitor, a monoclonal antibody, a kinase inhibitor, carboplatin, cisplatin, taxol, leucovorin, 5-flurouracil, eloxatin, cyclophosphamide, chlorambucil, avastin, or imatinib mesylate.
  • an alkylating agent an anti-metabolite, a vinca alkaloid, a terpenoid, a topoisomerase inhibitor, a monoclonal antibody, a kinase inhibitor, carboplatin, cisplatin, taxol, leucovorin, 5-flurouracil, eloxatin, cyclophosphamide, chlorambucil, avastin, or imatinib mesylate.
  • the anti-glaucoma agent can comprise a beta receptor-blocker, a prostaglandin, an alpha-adrenergic agonist, a parasympathomimetic (cholinergic agonist), or a carbonic anhydrase inhibitor.
  • the anti-hypertensive agent can comprise a beta receptor- blocker, a calcium channel blocker, a diueretic, an angiotensin converting enzyme (ACE) inhibitor, a renin inhibitor, or an angiotensin receptor antagonist.
  • ACE angiotensin converting enzyme
  • the anti-atherosclerotic agent can comprise a 3-HMG-coA- reductase inhibitor, a statin, atorvastatin, simvastatin, niacin, or a combination drug such as vytorin.
  • the anti-multiple sclerosis agent can comprise a beta-inteferon, tysabri, or glatirimar acetate.
  • the anti-angina agent can comprise a beta receptor-blocker, a calcium channel blocker, nitroglycerin, isosoribide mononitrate, nicorandil, or ranolanzine.
  • the anti-erectile dysfunction agent can comprise a phosphodiesterase-5 inhibitor.
  • the anti-stroke agent can comprise tissue plasminogen activator. More specifically, the anti-asthma agent can comprise a bronchodilator, an inhaled corticosteroid, a leukotrine blockers, cromolyn, nedocromil, or theophylline.
  • Various embodiments of the invention provide a use of the compound of the invention, or of a composition or combination of the invention in the preparation of a medicament for treatment of a malcondition.
  • the medicament can be adapted to treat a malcondition wherein binding of a ligand to a Rho kinase, an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Fit kinase, an Aurora kinase, or a Src kinase, or any combination thereof; or inhibition of a bioactivity of a Rho kinase, an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Fit kinase, an Aurora kinase, or a Src kinase, or any combination thereof; or both, is medically indicated
  • the malcondition can comprise cardiovascular disease, neurogenic pain, hypertension, atherosclerosis, angina, stroke, arterial obstruction, peripheral arterial disease, peripheral circulation disorder, erectile dysfunction, acute or chronic pain, dementia, Alzheimer's disease, Parkinson's disease, neuronal degeneration, asthma, amyotrophic lateral sclerosis, spinal cord injury, rheumatoid arthritis, osteoarthritis, osteoporosis, psoriasis, cerebral vasospasm, glaucoma, multiple sclerosis, pulmonary hypertension, acute respiratory distress syndrome, inflammation, diabetes, urinary organ diseases such as overactive bladder (OAB) and benign prostatic hypertrophy (BPH), metastasis, cancer, glaucoma, ocular hypertension, retinopathy, autoimmune disease and viral infection, or myocardial pathology, or any combination thereof.
  • the medicament can further comprise an additional bioactive agent or a plurality of additional bioactive agents for preparation of a medicament for the treatment of the malcondition such as
  • reaction mixture was allowed to stir at room temperature until the starting material disappeared as monitored by TLC.
  • the reaction was quenched by addition of saturated aqueous NaHCCh and extracted with EtOAc (3 X).
  • EtOAc extracts were washed with brine and dried over sodium sulfate to give crude 1-1 which was then purified by chromatography over silica gel (92% yield).
  • bromide 1-2 was first transferred to a boronic acid ester and then coupled with an aryl halide to provide compound 1-3.
  • a boronic acid ester 2,5-bispinacolatotoboronic ester
  • PdCl 2 0.1 equiv.
  • KOAc 3 equiv.
  • the resulting mixture was stirred at 80 0 C for 4h. Water was added and extracted with EtOAc. The organic layers were combined, dried over sodium sulfate and concentrated in vacuo to give 1-4.
  • This crude 1-4 was then subjected to standard Suzuki coupling as described above and the product was purified by preparative HPLC to give 1-3 as a white solid.
  • Ester 4-1 (1 equiv), which was prepared based on procedures in Scheme 2 or Scheme 3, was dissolved in dioxane/water (1 : 1) and LiOH (5 equiv) was added and stirred until saponification was complete (typically 2-4 hours). Upon completion, the solution was quenched with HCl (4N in dioxane, 5 equiv) and concentrated in vacuo. This carboxylic acid (1 equiv) was then dissolved in DMF. To this solution is added Et 3 N (5 equiv), a primary or secondary amine (3 equiv) and lastly HATU (2 equiv). This solution was stirred at room temperature for 60 min and then purified via preparatory HPLC (H 2 ⁇ /MeCN) to give quinazoline 4-2 (20 %- 50% yield).
  • Example 100 7-(7-ethyl-8-oxo-8,9-dihvdro-7H-purin-6-yl)-2-(6- methoxychroman-3-yl)quinazolin-4(3H)-one
  • Example 15 To a solution of Example 15 in DMF (0.3 mL) was added 2-(pyridin-3-yl)acetic acid (1.2 equiv), HOBT (1.0 equiv), N-methylmorpholine (2.0 equiv), and EDC (1.2 equiv). The resulting mixture was stirred at room temperature overnight. After removal of solvent by rotary evaporation, the residue was purified by preparative HPLC to afford the title compound. LC/MS: C 26 H 22 ClN 6 O 2 (M+H) 485. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
  • Example 123 3-amino-N-((4-chlorophenyl)(4-hydroxy-6-(lH-pyrazol-4- yl)quinazolin-2-yl)methyl)propanamide
  • Example 125 4-(aminomethyl)-N-((4-chlorophenyl)(4-hvdroxy-6-(lH-pyrazol- 4-yl)quinazolin-2-yl)methyl)benzamide
  • the crude product 7-3 was forwarded to the next step without further purification.
  • the bromide 7-3 (1.17 mmol) and the boronic acid ester (0.27 g, 1.2 equiv) were dissolved in degassed 6.5 mL of EtOH/toluene (3:2 by volume) in a sealed tube.
  • Tetrakis(triphenlphosphine)palladium (0) (0.10 g, 8 mol%) and 2 M solution Of K 2 CO 3 (3.6 mL, 5.0 equiv) were added sequentially.
  • the mixture was heated at 100 0 C for 2.5 h. After cooling to room temperature, the reaction was quenched with 10% TFA in water until evolution of gas was complete. The reaction mixture was then concentrated and the precipitate filtered off.
  • the crude product was judged 80% pure by LC-MS.
  • Example 130 (5VNl-(2- ⁇ -amino-2- ⁇ -fluorophenyl)ethyl)-6- ⁇ H-pyrazol-4- yl)quinazolin-4-yl)-N 1 ,N2,N2-trimethylethane- 1 ,2-diamine
  • the 3-methoxy-2-nitrobenzoic acid was treated with excess of 2 M oxalyl chloride in DCM for 2 h at room temperature and concentrated to provide the acid chloride, which was then suspended in DCM and slowly added to a large amount of concentrated NH 4 OH solution.
  • the solid formed during the reaction was collected by filtration and washed with water to provide the carboxamide 8-1 as white solid.
  • 8-1 was dissolved in dry MeOH and 10% wt of Pd/C catalyst was added. The reaction was stirred under H 2 atmosphere overnight. After filtration, the solution was concentrated to give the crude aniline 8-2.
  • 8-2 was dissolved in dry DMF and a solution of NBS (1.2eq) in DMF was added at 0 0 C. The reaction was stirred for Ih.
  • Ester 9-1 (1 equiv) was dissolved in dioxane/water (1: 1) and LiOH (5 equiv) is added and stirred until saponification is complete (typically 2-4 hours). Upon completion, the solution was quenched with HCl (4N in dioxane, 5 equiv) and concentrated in vacuo. This carboxylic acid (1 equiv) was then dissolved in DMF. To this solution was added Et 3 N (5 equiv), N, O-dimethylhydroxylamine (3 equiv) and lastly HATU (2 equiv). This solution was stirred at room temperature for 60 min and then partitioned between EtOAc and Brine.
  • Example 164 8-((2-(dimethylamino)ethyl)(methyl)amino)-2-(6- methoxychroman-3-yl)-6-(3-methyl-lH-pyrazol-4-yl)quinazolin-4-ol
  • Example 165 8-((2-(dimethylamino)ethyl)(methyl)amino)-2-(6- methoxychroman-3-yl)-6-(lH-pyrazol-4-yl)quinazolin-4-ol
  • the crude 13-6 (1.0 equiv) was added to a suspension of RCOCl (1.1 equiv, preformed from the corresponding acid and oxaly chloride using standard literature procedures) and DIEA (5 equiv) in DCM at room temperature.
  • RCOCl 1.1 equiv, preformed from the corresponding acid and oxaly chloride using standard literature procedures
  • DIEA 5 equiv
  • the solvents were evaporated in vacuo, and the residue was subjected to flash chromatography to give quinazoline 13-7.
  • a SNAr reaction was used to form 13-8 from 13-7.
  • the aniline 14-1 (1 equiv) and DIPEA (1 equiv) were added to a methylene chloride solution of an acid chloride prepared by mixing the acid (1 equiv) with oxalyl chloride (1.2 equiv, 2.0 M solution in CH 2 CI 2 ) in the presence of catalytic DMF for 1 hour. After 14-1 has been added, the solution was stirred until the quinazoline ring formation was complete as monitored by LC-MS. The solution was then diluted with EtOAc and washed with brine, dried over MgSO 4 and concentrated in vacuo to give crude 14-2. After flash chromatography, 14-2 was subjected to procedures described in Scheme 13 for the transformation from 13-2 to 13-4 to prepare compounds 14-3 and 14-4.
  • Example 170 8-(2-(dimethylamino)ethoxy)-2-(6-methoxychroman-3-yl)-6-(lH- pyrazol-4-yl)quinazolin-4-amine
  • reaction mixture was sealed in a microwave vial and degassed under vacuum and filled with argon. It was heated with microwave to 120 degree for Ih until completion of reaction as indicated by LC-MS. The reaction mixture was then concentrated and diluted with EtOAc. The resulting organic layer was washed with water and brine. It was concentrated and purified by preparative HPLC.
  • Example 207 5 -(2-( 1 -aminocvclopropyl)-4-hvdroxyquinazolin-6-yl)- 1 H- pyrrolor2,3-blpyridine-3-carbonitrile
  • 2-Amino-4(or 5)-bromobenzoic acid 1 was disolved in 2M oxalyl chloride solution in DCM with catalytic amount of DMF and the solution was stirred for 3 h. After the reaction was complete, the solution was concentrated and the residue was dissovled in dry DCM. This solution was then added to the solution of amine (leq) in DCM in presence of pyridine (4eq) as base. EtOAc was added and the organic layer was washed with IM NaOH, brine, sated. NaHC ⁇ 3 and brine consequently. This reaction provided two products that led to two serious of compounds 4 and 8.
  • Example 240 22-((3S,4R)-4-(4-methoxyphenyl)-l-methylpyrrolidin-3-yl)-6-

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Abstract

La présente invention concerne des composés de quinazoline qui peuvent inhiber la bioactivité d’une ou plusieurs enzymes kinases, comprenant une kinase Rho, une kinase AKT, une kinase p70S6K, une kinase LIM, une kinase IKK, une kinase Fit, une kinase Aurora, ou une kinase Src, ou une combinaison quelconque de celles-ci ; des procédés d’utilisation de ces composés ; et des procédés de préparation de ces composés. Les composés de l’invention peuvent être utilisés dans le traitement d’affections comprenant une maladie cardiovasculaire, une douleur neurogène, l’hypertension, l’athérosclérose, l’angine de poitrine, un accident cérébrovasculaire, une obstruction artérielle, une maladie artérielle périphérique, un trouble de l’érection, une douleur aiguë et chronique, la démence, la maladie d’Alzheimer, la maladie de Parkinson, la dégénérescence neuronale, l’asthme, la sclérose latérale amyotrophique, une lésion de la moelle épinière, la polyarthrite rhumatoïde, l’arthrose, l’ostéoporose, le psoriasis, un angiospasme cérébral, un glaucome à angle ouvert, la sclérose en plaques, l’hypertension pulmonaire, le syndrome de détresse respiratoire aigu, l’inflammation, le diabète, des maladies d’organe urinaire et une hypertrophie bénigne de la prostate (BPH), des métastases, le cancer, le glaucome, l’hypertension oculaire, la rétinopathie, une maladie auto-immune, une infection virale, ou une pathologie myocardique.
PCT/US2009/064048 2008-11-12 2009-11-11 Dérivés de quinazoline en tant qu’inhibiteurs de kinase WO2010056758A1 (fr)

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WO2019131798A1 (fr) * 2017-12-27 2019-07-04 国立研究開発法人理化学研究所 Nouveau composé dihydro-quinazolinone ou sel pharmacologiquement acceptable de ce dernier, et inhibiteur de la croissance cellulaire
WO2020021064A1 (fr) 2018-07-26 2020-01-30 Domain Therapeutics Dérivés de quinazolinone substitués et leur utilisation en tant que modulateurs allostériques positifs de mglur4
CN113891711A (zh) * 2019-03-11 2022-01-04 复旦大学 用于治疗神经退行性疾病的化合物
WO2020182144A1 (fr) * 2019-03-11 2020-09-17 复旦大学 Composé pour le traitement de troubles neurodégénératifs
WO2021018948A1 (fr) 2019-07-30 2021-02-04 Janssen Pharmaceutica Nv Dérivés de quinazolin-4-one utiles en tant qu'inhibiteurs de grk2
WO2021018951A1 (fr) * 2019-07-30 2021-02-04 Janssen Pharmaceutica Nv Dérivés de phtalazin-1-one utiles en tant qu'inhibiteurs de grk2
WO2021056072A1 (fr) * 2019-09-25 2021-04-01 Macquarie University Traitement d'états associés à l'excitotoxicité
CN113416181A (zh) * 2021-08-02 2021-09-21 四川大学 喹唑啉类衍生物及其用途
CN113416181B (zh) * 2021-08-02 2022-05-03 四川大学 喹唑啉类衍生物及其用途

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