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WO2010056758A1 - Quinazoline derivatives as kinase inhibitors - Google Patents

Quinazoline derivatives as kinase inhibitors Download PDF

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Publication number
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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kinase
compound
alkyl
scheme
procedures
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French (fr)
Inventor
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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    • 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

The invention is directed to quinazoline compounds that can inhibit the bioactivity of one or more kinase enzymes, including 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; to methods of use of those compounds; and to methods of preparation of those compounds. The inventive compounds can be used in the treatment of malconditions including cardiovascular disease, neurogenic pain, hypertension, atherosclerosis, angina, stroke, arterial obstruction, peripheral arterial disease, 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, open angle glaucoma, multiple sclerosis, pulmonary hypertension, acute respiratory distress syndrome, inflammation, diabetes, urinary organ diseases and benign prostatic hypertrophy (BPH), metastasis, cancer, glaucoma, ocular hypertension, retinopathy, autoimmune disease, viral infection, or myocardial pathology.

Description

QUINAZOLINE DERIVATIVES AS KINASE INHIBITORS
CROSS REFERENCE TO RELATED APPLICATIONS This application claims the priority of U.S. provisional patent application serial number 61/113,833, filed Nov. 12, 2008, the disclosure of which is incorporated by reference herein in its entirety.
BACKGROUND There are believed to be in excess of 500 distinct kinase enzymes coded in the human genome. Kinases 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. Among these many different kinase enzymes are subclasses known as Rho kinases,
Protein Kinase B (also known as AKT), kinase p70S6K that acts on a ribosomal protein, LIM kinases, IKK kinases, an Fit kinases, Aurora kinases, and Src kinases. 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. Two Rho kinase isoforms, ROCK I and ROCK II, have been identified. 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. Satoh, et al, Jpn. J. Pharmacol, 1999, 79, Suppl I, 211 , K. Kuwahara, et al. , FEBS Lett., 1999, 452, 314-18; N. Sawada, et al, Circulation, 2000, 101, 2030- 33; C. Kataoka, et al, Hypertension, 2002, 39(2), 245-50; F. Imamura, et al, Jpn. J. Cancer Res., 2000, 91, 811-16, K. Itoh et al, Nature Medicine, 1999, 5, 221-5, M. Nakajima, et al, Clin. Exp. Pharmacol. Physiol, 2003; 30(7): 457-63;
W. Guoyan, et al, J. Biol. Chem., 2004, 279(13), 13205-14; S. Tatsumi,
Neuroscience, 2005, 131(2) 491-98.
Various compounds have been described in the literature as Rho kinase inhibitors. See, e.g. WO98/06433; WO00/09162; WO00/78351; WO01/17562;
WO02/076976; EP1256574; WO02/100833; WO03/082808; WO2004/009555;
WO2004/024717; WO2004/041813; WO2004/108724; WO2005/003101;
WO2005/035501; WO2005/035503; WO2005/035506; WO2005/037198;
WO2005/058891; WO2005/074642; WO2005/074643; WO2005/080934; WO2005/082367; WO2005/082890; WO2005/097790; WO2005/100342;
WO2005/103050; WO2005/105780; WO2005/108397; WO2006/044753;
WO2006/051311; WO2006/057270; WO2006/058120; WO2006/065946;
WO2006/099268; WO2006/072792; WO2007/026920; WO2008/011557;
WO2008/011560; WO2008/036458; US2008/153813A; WO2009079008; WO2009079009; WO2009079011; Takami, et al, Bioorg. Med. Chem., 2004,
12, 2115-37; M. Iwakubo, et al, Bioorg. Med. Chem., 2007, 15, 350-64; M.
Iwakubo, et al, Bioorg. Med. Chem., 2007, 15, 1022-33.
Protein Kinase B (PKB) is a group of enzymes, also referred to as the
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 (LIMK) including LIMKl and LIMK2, are 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 IKKα (IKKl), IKKβ (IKK2), IKKi (IKKε), and TKBl, are regulatory signaling molecules that interact with NK-κB, a transcription factor that regulates the expression of many genes. NK-κB 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-κB 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:
10.1021/jm9007533, "Identification of N-5-?er?-Butyl-isoxazol-3-yl)-N'-({4-[7- (2-morpholin-4-yl-ethoxy)imidazo-[2,l-έ][l,3]benzothiazol-2-yl]phenyl}urea Dihydrochloride (AC220), a Uniquely Potent, Selective, and Efficacious FMS- Like Tyrosine Kinase-3 (FLT3) Inhibitor". Aurora kinases are a family of homologous serine/threonine protein kinases, include Aurora-A, Aurora-B, and Aurora-C. They are involved in processes controlling cell mitosis, including chromosome condensation, centrosome maturation, and spindle formation, and perhaps cell meiosis include spermatogenesis. See for example D. Bebbington et al. (2009), "The Discovery of Potent Aurora Inhibitor MK 0457 (VX-680)", Biochem. Med. Chem. Lett. , 19, 3856-3592; L. Garuti, et al. (2009), "Small Molecule Aurora Kinases Inhibitors," Curr. Med. Chem., 16, 1949-1963; M. Zhong et al. (2009), "2- Aminobenzimidazoles as Potent Aurora Kinase Inhibitors," Biochem. Med. Chem. Lett., 19, 5158-5161; WO2009114703; and WO2009111028. 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. Among other effects, 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),
"Structure-based Virtual Screening of Src Kinase Inhibitors," Bioorg. Med. Chem., 17, 3152-3161; H. Mukaiyama, et al. (2008), "Novel Pyrazolo[l,5- a]pyrimidines as c-SRc Kinase Inhibitors that Reduce Ikr Channel Blockade," Bioorg. Med. Chem., 16, 909-921; N. Rucci et al. (2008), Anti-Cancer Agents in Medicinal Chemistry, 8, 342-349; and WO2008058341.
Thus, 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.
SUMMARY 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. In various embodiments, the invention provides a compound of formula (I):
Figure imgf000006_0001
(I), wherein a dashed line indicates a bond that can be present or absent;
RN is absent or present; when RN is absent, there is a double bond between the carbon atom bearing R2 and the adjacent nitrogen atom; and when RN is present, there is a single bond between the carbon atom bearing R2 and the adjacent nitrogen atom; RN comprises aralkyl wherein any carbon atom of the aralkyl is optionally substituted with J;
R1 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 of NR', O, S, S(O) and S(0)2, wherein the heterocyclic ring formed thereby is substituted with 0-3 substituents selected independently from J;
J is independently at each occurrence halogen, R, (CH2)o-2θR', (CH2V 2CN, CF3, OCF3, O, S, C(O), S(O), methylenedioxy, ethylenedioxy, (CH2V 2N(R)2, (CH2V2SR, (CH2V2S(O)R, (CH2V2S(O)2R, (CH2)0-2S(O)2N(R')2, (CH2V2SO3R', (CH2V2C(O)R, (CH2V2C(O)C(O)R', (CH2V2C(O)CH2C(O)R, (CH2V2C(S)R', (CH2V2C(O)OR', (CH2V2OC(O)R, (CH2)0-2C(O)N(R')2, (CH2V2OC(O)N(R)2, (CH2V2C(S)N(R)2, (CH2V2N(R)N(R)C(O)R, (CH2V 2N(R)N(R)C(0)OR, (CH2)o-2N(R)N(R)CON(R)2, (CH2V2N(R)SO2R, (CH2)o-2N(R')S02N(R')2, (CH2)0-2N(R')C(O)OR', (CH2)0-2N(R)C(O)R, (CH2V 2N(R)C(S)R', (CH2)o-2N(R')C(0)N(R)2, (CH2)0-2N(R)C(S)N(R)2, (CH2V 2N(COR')COR, (CH2)o-2 N(OR')R, (CH2)0-2C(=NH)N(R)2, (CH2V 2C(O)N(OR')R, or (CH2)0-2C(=NOR)R, or J is (CH2)0-2-(cycloalkyl), (CH2V2- (aryl), (CH2)0-2-(heterocyclyl), or (CH2)0-2-(heteroaryl), wherein the cycloalkyl, aryl, heterocyclyl or heteroaryl can be mono- or independently pluri-substituted with J; each R is independently at each occurrence hydrogen, (Ci-Ci2)-alkyl, (C2-Ci2)-alkenyl, (C2-Ci2)-alkynyl, (C3-Ci0)-cycloalkyl, (C3-Ci0)-cycloalkenyl, [(C3-Cio)cycloalkyl or (C3-Cio)-cycloalkenyl]-[(Ci-Ci2)-alkyl or (C2-C12)- alkenyl or (C2-C12)-alkynyl], (C6-C10)-aryl, (C6-Ci0)-aryl-[(Ci-Ci2)-alkyl or (C2- Ci2)-alkenyl or (C2-C i2)-alkynyl], (3-10 membered)-heterocyclyl, (3-10 membered)-heterocyclyl-[(Ci-Ci2)-alkyl or (C2-Ci2)-alkenyl or (C2-C12)- alkynyl], (5-10 membered)-heteroaryl, or (5-10 membered)-heteroaryl-[(Ci-Ci2)- alkyl or (C2-Ci2)-alkenyl or (C2-Ci2)-alkynyl], wherein R' is substituted with 0-3 substituents selected independently from J; or, when two R' are bound to a nitrogen atom or to two adjacent nitrogen atoms, the two R groups together with the nitrogen atom or atoms to which they are bound can form a 3- to 8-membered monocyclic heterocyclic ring, or an 8- to 20-membered, bicyclic or tricyclic, heterocyclic ring system, wherein any ring or ring system can further contain 1 -3 additional heteroatoms selected from the group consisting of N, NR, O, S, S(O) and S(O)2, and wherein each ring is substituted with 0-3 substituents selected independently from J; wherein, in any bicyclic or tricyclic ring system, each ring can be linearly fused, bridged, or spirocyclic, wherein each ring can be aromatic or non-aromatic, wherein each ring can be fused to a (Ce-Cio)aryl, (5-10 membered)-heteroaryl, (C3- Cio)cycloalkyl or (3-10 membered)-heterocyclyl ring; when RN is absent, R2 comprises OR', SR, or NR2, and when RN is present, R2 is oxo; R3 comprises a nitrogen-containing monocyclic or polycyclic heteroaryl group which can be mono- or independently plurisubstituted with J;
R4 comprises H, aryl optionally substituted with J, OR, SR, N(R)2, NR'(CH2)mNR2, NR(CH2)mOH, OCH2CH(OH)CH2NR'2, O(CH2CH2O)PCH2CH2OR', O(CH2)mNR'2, O(CH2)mNR2, O(CH2)mC(O)NR'2, S(CH2)mNR'2, O(CH2)p-heterocyclyl, N(R')(CH2)p-heterocyclyl, O(CH2)P- heteroaryl, N(R')(CH2)p-heteroaryl, wherein p is 0 to about 3, and wherein any heterocyclyl or heteroaryl can be mono- or independently plurisubstituted with J;
Q1 is N, CR3, or CR5; Q2 is N, CR3 or CR5; and
R5 comprises H, F, Cl, Me, CN, C(O)R', C(O)OR', C(O)NR2, CF3, OR, OCF3, 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.
In various embodiments, pharmaceutical compositions comprising an effective amount of a compound of the invention and a suitable excipient are provided.
In various embodiments, pharmaceutical combinations comprising an effective amount of a compound of the invention and an effective amount of a second medicament are provided.
In various embodiments, pharmaceutical 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.
Various embodiments of the invention provide methods of inhibiting a kinase, comprising contacting the kinase with an effective amount of a compound of the invention. For example, 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.
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 duration of time sufficient to provide a beneficial effect to the patient.
Various embodiments of the invention provide uses of 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.
Various embodiments of the invention provide compounds, compositions, and combinations of the invention for treatment of 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 DESCRIPTION
As used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. As used herein, "individual" (as in the subject of the treatment) means both mammals and non-mammals. 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. The term "disease" or "disorder" or "malcondition" are used interchangeably, and are used to refer to diseases or conditions wherein a 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.
The expression "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.
"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. Similarly, as used herein, 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. In particular, 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.
By "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.
When a substituent is specified to be an atom or atoms of specified identity, "or a bond", a configuration is referred to when the substituent is "a bond" that the groups that are immediately adjacent to the specified substituent are directly connected to each other in a chemically feasible bonding configuration.
All chiral, diastereomeric, racemic forms of a structure are intended, unless a particular stereochemistry or isomeric form is specifically indicated. Compounds used in the present invention can include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions, at any degree of enrichment. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of the invention. The inclusion of 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. For example, any hydrogen atom or set thereof in a molecule can be any of the isotopic forms of hydrogen, i.e., protium (1H), deuterium (2H), or tritium (3H) in any combination. Similarly, any carbon atom or set thereof in a molecule can be any of the isotopic form of carbons, such as 11C, 12C, 13C, or 14C, or any nitrogen atom or set thereof in a molecule can be any of the isotopic forms of nitrogen, such as 13N, 14N, or 15N. 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. For example, a sample of a compound can include molecules containing various different isotopic compositions, such as in a tritium or 14C 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 14N and 15N, 32S and 34S, 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, radiolabeled or stable, 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. For example, 14C and 3H can be prepared using neutrons generated in a nuclear reactor. Following nuclear transformation, 14C and 3H are incorporated into precursor molecules, followed by further elaboration as needed.
The term "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, α- 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-nitrobenzyloxycarbonyl, 2- nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4- dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4- dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5- dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, l-(p- biphenylyl)- 1 -methylethoxycarbonyl, α,α-dimethyl-3,5- dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl, 2- trimethylsilylethyloxycarbonyl (Teoc), phenoxycarbonyl, 4- nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; aralkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Amine protecting groups also include cyclic amino protecting groups such as phthaloyl and dithiosuccinimidyl, which incorporate the amino nitrogen into a heterocycle. Typically, 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.
The term "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, α-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-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4- dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5- dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, l-(p- biphenylyl)- 1 -methylethoxycarbonyl, α,α-dimethyl-3,5- dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl, 2- trimethylsilylethyloxycarbonyl (Teoc), phenoxycarbonyl, 4- nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; aralkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. It is well within the skill of the ordinary artisan to select and use the appropriate hydroxyl protecting group for the synthetic task at hand. In general, "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, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups. 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, CF3, OCF3, R', O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR', SO2R', SO2N(R')2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(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, (CH2V2N(R)C(O)R, (CH2)0-2N(R)N(R)2, N(R)N(R')C(0)R', N(R)N(R)C(O)OR', N(R)N(R')C0N(R)2, N(R')S02R', N(R')SO2N(R')2, N(R')C(0)0R, N(R)C(O)R, N(R')C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(C0R')C0R, N(0R')R, C(=NH)N(R')2, C(0)N(0R')R, or C(=N0R)R' wherein R' can be hydrogen or a carbon-based moiety, and wherein the carbon- based moiety can itself be further substituted.
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. When a substituent is more than monovalent, such as O, which is divalent, it can be bonded to the atom it is substituting by more than one bond, i.e., a divalent substituent is bonded by a double bond; for example, a C substituted with O forms a carbonyl group, C=O, which can also be written as "CO", "C(O)", or "C(=0)", wherein the C and the O are double bonded. When a carbon atom is substituted with a double-bonded oxygen (=0) group, the oxygen substituent is termed an "oxo" group. Alternatively, 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. For example, O, a divalent substituent, can be bonded to each of two adjacent carbon atoms to provide an epoxide group, or the O can form a bridging ether group, termed an "oxy" group, between adjacent or non-adjacent carbon atoms, for example bridging the 1,4-carbons of a cyclohexyl group to form a [2.2.1]- oxabicyclo system. Further, any substituent can be bonded to a carbon or other atom by a linker, such as (CH2)n or (CR2)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.
By a "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. By "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. Examples of 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. Examples of 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. In some embodiments, 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. The term "cycloalkenyl" alone or in combination denotes a cyclic alkenyl group.
The terms "carbocyclic," "carbocyclyl," and "carbocycle" denote a ring structure wherein the atoms of the ring are carbon, such as a cycloalkyl group or an aryl group. In some embodiments, the carbocycle has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms is 4, 5, 6, or 7. Unless specifically indicated to the contrary, 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, also denoted cycloalkylalkyl, 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.
Alkenyl groups include straight and branched chain and cyclic alkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Thus, alkenyl 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 vinyl, -CH=CH(CHs), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3),
-C(CH2CHs)=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others.
Cycloalkenyl groups include cycloalkyl groups having at least one double bond between 2 carbons. Thus for example, 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. Thus, 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(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH2CH3) among others. The term "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. Examples include: -0-CH2-CH2-CH3, -CH2-CH2CH2-OH, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, -CH2CH2-S(=O)-CH3, and -CH2CH2-O-CH2CH2-O-CH3. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3, or - CH2-CH2-S-S-CH3.
A "cycloheteroalkyl" ring is a cycloalkyl ring containing at least one heteroatom. A cycloheteroalkyl ring can also be termed a "heterocyclyl," described below.
The term "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. Examples include -CH=CH-O-CH3, -CH=CH-CH2-OH, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -CH2-CH=CH-CH2-SH, and and -CH=CH-O-CH2CH2- 0-CH3.
Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms. Thus aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, 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. Thus a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if poly cyclic, any combination thereof. In some embodiments, 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 C2-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. Likewise a C4-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. For example, a dioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenyl 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, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. 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 C2- 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. Likewise a C4- heteroaryl 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. 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, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups can be unsubstituted, or can be substituted with groups as is discussed above. Representative substituted heteroaryl groups can be substituted one or more times with groups such as those listed above.
Additional examples of 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-imidazolyl, 4-imidazolyl, 5- imidazolyl), triazolyl (1,2,3-triazol-l-yl, l,2,3-triazol-2-yl l,2,3-triazol-4-yl, l,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2- thiazolyl, 4-thiazolyl, 5 -thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3- pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl (2- quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6- isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7- benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro- benzo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro- benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro- benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl (2- benzo[b] thiophenyl, 3 -benzo[b] thiophenyl, 4-benzo[b]thiophenyl, 5 -benzo [b] thiophenyl, 6-benzo [b] thiophenyl, 7-benzo [b] thiophenyl), 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3-dihydro-benzo[b]thiophenyl), 3-(2,3- dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl), 5-(2,3- dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro-benzo[b]thiophenyl), 7-(2,3- dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2- benzoxazolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4- benzothiazolyl, 5 -benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-l-yl, 5H-dibenz[b,f]azepine-2-yl, 5H-dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine- 5-yl), 10,l l-dihydro-5H-dibenz[b,f]azepine (10,l l-dihydro-5H- dibenz[b,f]azepine-l-yl, 10,1 l-dihydro-5H-dibenz[b,f]azepine-2-yl, 10,11- dihydro-5H-dibenz[b,f]azepine-3-yl, 10,l l-dihydro-5H-dibenz[b,f]azepine-4-yl, 10,1 l-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like.
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.
The term "alkoxy" refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined above. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of 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. For example, an allyloxy group is an alkoxy group within the meaning herein. A methoxyethoxy group is also an alkoxy group within the meaning herein.
The terms "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. Examples of haloalkyl 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. Examples of haloalkoxy include trifluoromethoxy, 1,1- dichloroethoxy, 1,2-dichloroethoxy, l,3-dibromo-3,3-difluoropropoxy, perfluorobutoxy, and the like.
The term "(Cx-Cy )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. Preferred is -(Ci-C6)perfluoroalkyl, more preferred is -(Ci-C3)perfluoroalkyl, most preferred is -CF3.
The term "(Cx-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. Preferred is -(Ci-C6)perfluoroalkylene, more preferred is -(Ci-C3)perfluoroalkylene, most preferred is -CF2-.
The terms "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.
An "acyl" group as the term is used herein 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. In the special case wherein the carbonyl carbon atom is bonded to a hydrogen, 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. When the group containing the carbon atom that is bonded to the carbonyl carbon atom contains a halogen, the group is termed a
"haloacyl" group. An example is a trifluoroacetyl group.
The term "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-NH2, for example, alkylamines, arylamines, alkylarylamines; R2NH 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. The term "amine" also includes ammonium ions as used herein.
An "amino" group is a substituent of the form -NH2, -NHR, -NR2, -NR3 +, wherein each R is independently selected, and protonated forms of each.
Accordingly, 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.
An "ammonium" ion includes the unsubstituted ammonium ion NH4 +, 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.
The term "amide" (or "amido") includes C- and N-amide groups, i.e.,
-C(O)NR2, and -NRC(O)R groups, respectively. Amide groups therefore include but are not limited to carbamoyl groups (-C(O)NH2) and formamide groups (-NHC(O)H). A "carboxamido" group is a group of the formula
C(O)NR2, wherein R can be H, alkyl, aryl, etc.
The term "urethane" (or "carbamyl") includes N- and O-urethane groups, i.e., -NRC(O)OR and -OC(O)NR2 groups, respectively. The term "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 (- SO2NH2). An 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.
The term "amidine" or "amidino" includes groups of the formula -C(NR)NR2. Typically, an amidino group is -C(NH)NH2.
The term "guanidine" or "guanidino" includes groups of the formula -NRC(NR)NR2. Typically, a guanidino group is -NHC(NH)NH2.
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. For example, 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 NH4 + 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." The term "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. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids. Appropriate 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, β-hydroxybutyric, salicylic, galactaric and galacturonic acid. Examples of pharmaceutically unacceptable acid addition salts include, for example, perchlorates and tetrafluoroborates.
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 (Ν-methylglucamine) and procaine. Examples of pharmaceutically unacceptable base addition salts include lithium salts and cyanate salts. Although pharmaceutically unacceptable salts are not generally useful as medicaments, such 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). The term "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. As the term is used herein 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. For example, methanol or ethanol can form an "alcoholate", which can again be stoichiometic or non-stoichiometric. As the term is used herein 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.
A "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.
In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group. For example, if X is described as selected from the group consisting of bromine, chlorine, and iodine, claims for X being bromine and claims for X being bromine and chlorine are fully described. Moreover, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any combination of individual members or subgroups of members of Markush groups. Thus, for example, if X is described as selected from the group consisting of bromine, chlorine, and iodine, and Y is described as selected from the group consisting of methyl, ethyl, and propyl, claims for X being bromine and Y being methyl are fully described.
The present invention further embraces isolated compounds according to formula (I). The expression "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. Preferably 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. Preferably 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
Within the present invention it is to be understood that 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. The formulae drawings within this specification can represent only one of the possible tautomeric forms and it is to be understood that the specification encompasses all possible tautomeric forms of the compounds drawn not just those forms which it has been convenient to show graphically herein. For example, tautomerism may be exhibited by a pyrazolyl group bonded as indicated by the wavy line. While both substituents would be termed a 4-pyrazolyl group, it is evident that a different nitrogen atom bears the hydrogen atom in each structure.
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. For example, the equilibrium:
Figure imgf000029_0002
is an example oi tautomerism.
Accordingly, a structure depicted herein as one tautomer is intended to also include the other tautomer. Optical Isomerism
It will be understood that when compounds of the present invention contain one or more chiral centers, the compounds 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. Once the priority ranking of the four groups is determined, the molecule is oriented so that the lowest ranking group is pointed away from the viewer. Then, if the descending rank order of the other groups proceeds clockwise, the molecule is designated (R) and if the descending rank of the other groups proceeds counterclockwise, the molecule is designated (S). In the example in Scheme 14, the Cahn-Ingold-Prelog ranking is A > B > C > D. The lowest ranking atom, D is oriented away from the viewer.
Figure imgf000030_0001
(R) configuration (S) configuration
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. Preferably, 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
It is understood that due to chemical properties {i.e., resonance lending some double bond character to the C-N bond) of restricted rotation about the amide bond linkage (as illustrated below) it is possible to observe separate rotamer species and even, under some circumstances, to isolate such species (see below). It is further understood that certain structural elements, including steric bulk or substituents on the amide nitrogen, may enhance the stability of a rotamer to the extent that a compound may be isolated as, and exist indefinitely, as a single stable rotamer. The present invention therefore includes any possible stable rotamers of formula (I) which are biologically active in the treatment of cancer or other proliferative disease states. hindered rotation
Figure imgf000031_0002
Figure imgf000031_0001
Regioisomerism
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.
Figure imgf000031_0003
"para-" "meta-" "ortho-"
In various embodiments, 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.
In various 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.
In various embodiments, a compound as shown in any of the Examples, or among the exemplary compounds, is provided.
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. In various embodiments, the invention provides a compound of formula (I):
Figure imgf000032_0001
(I), wherein a dashed line indicates a bond that can be present or absent;
RN is absent or present; when RN is absent, there is a double bond between the carbon atom bearing R2 and the adjacent nitrogen atom; and when RN is present, there is a single bond between the carbon atom bearing R2 and the adjacent nitrogen atom; RN comprises aralkyl wherein any carbon atom of the aralkyl is optionally substituted with J;
R1 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 of NR', O, S, S(O) and S(0)2, wherein the heterocyclic ring formed thereby is substituted with 0-3 substituents selected independently from J;
J is independently at each occurrence halogen, R, (CH2)o-2θR', (CH2V 2CN, CF3, OCF3, O, S, C(O), S(O), methylenedioxy, ethylenedioxy, (CH2V 2N(R)2, (CH2V2SR, (CH2V2S(O)R, (CH2V2S(O)2R, (CH2)0-2S(O)2N(R')2, (CH2V2SO3R', (CH2V2C(O)R, (CH2V2C(O)C(O)R', (CH2V2C(O)CH2C(O)R, (CH2V2C(S)R', (CH2V2C(O)OR', (CH2V2OC(O)R, (CH2)0-2C(O)N(R')2, (CH2V2OC(O)N(R)2, (CH2V2C(S)N(R)2, (CH2V2N(R)N(R)C(O)R, (CH2V 2N(R)N(R)C(0)OR, (CH2)o-2N(R)N(R)CON(R)2, (CH2V2N(R)SO2R, (CH2)o-2N(R')S02N(R')2, (CH2)0-2N(R')C(O)OR', (CH2)0-2N(R)C(O)R, (CH2V 2N(R)C(S)R', (CH2)o-2N(R')C(0)N(R)2, (CH2)0-2N(R)C(S)N(R)2, (CH2V 2N(COR')COR, (CH2)o-2 N(OR')R, (CH2)0-2C(=NH)N(R)2, (CH2V 2C(O)N(OR')R, or (CH2)0-2C(=NOR)R, or J is (CH2)0-2-(cycloalkyl), (CH2V2- (aryl), (CH2)0-2-(heterocyclyl), or (CH2)0-2-(heteroaryl), wherein the cycloalkyl, aryl, heterocyclyl or heteroaryl can be mono- or independently pluri-substituted with J; each R is independently at each occurrence hydrogen, (Ci-Ci2)-alkyl, (C2-Ci2)-alkenyl, (C2-Ci2)-alkynyl, (C3-Ci0)-cycloalkyl, (C3-Ci0)-cycloalkenyl, [(C3-Cio)cycloalkyl or (C3-Cio)-cycloalkenyl]-[(Ci-Ci2)-alkyl or (C2-C12)- alkenyl or (C2-C12)-alkynyl], (C6-C10)-aryl, (C6-Ci0)-aryl-[(Ci-Ci2)-alkyl or (C2- Ci2)-alkenyl or (C2-C i2)-alkynyl], (3-10 membered)-heterocyclyl, (3-10 membered)-heterocyclyl-[(Ci-Ci2)-alkyl or (C2-Ci2)-alkenyl or (C2-C12)- alkynyl], (5-10 membered)-heteroaryl, or (5-10 membered)-heteroaryl-[(Ci-Ci2)- alkyl or (C2-Ci2)-alkenyl or (C2-Ci2)-alkynyl], wherein R' is substituted with 0-3 substituents selected independently from J; or, when two R' are bound to a nitrogen atom or to two adjacent nitrogen atoms, the two R groups together with the nitrogen atom or atoms to which they are bound can form a 3- to 8-membered monocyclic heterocyclic ring, or an 8- to 20-membered, bicyclic or tricyclic, heterocyclic ring system, wherein any ring or ring system can further contain 1 -3 additional heteroatoms selected from the group consisting of N, NR, O, S, S(O) and S(O)2, and wherein each ring is substituted with 0-3 substituents selected independently from J; wherein, in any bicyclic or tricyclic ring system, each ring can be linearly fused, bridged, or spirocyclic, wherein each ring can be aromatic or non-aromatic, wherein each ring can be fused to a (Ce-Cio)aryl, (5-10 membered)-heteroaryl, (C3- Cio)cycloalkyl or (3-10 membered)-heterocyclyl ring; when RN is absent, R2 comprises OR', SR, or NR2, and when RN is present, R2 is oxo; R3 comprises a nitrogen-containing monocyclic or polycyclic heteroaryl group which can be mono- or independently plurisubstituted with J;
R4 comprises H, aryl optionally substituted with J, OR, SR, N(R)2, NR'(CH2)mNR2, NR(CH2)mOH, OCH2CH(OH)CH2NR'2, O(CH2CH2O)PCH2CH2OR', O(CH2)mNR'2, O(CH2)mNR2, O(CH2)mC(O)NR'2, S(CH2)mNR'2, O(CH2)p-heterocyclyl, N(R')(CH2)p-heterocyclyl, O(CH2)P- heteroaryl, N(R')(CH2)p-heteroaryl, wherein p is 0 to about 3, and wherein any heterocyclyl or heteroaryl can be mono- or independently plurisubstituted with J;
Q1 is N, CR3, or CR5; Q2 is N, CR3 or CR5; and
R5 comprises H, F, Cl, Me, CN, C(O)R', C(O)OR', C(O)NR2, CF3, OR, OCF3, 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.
In various embodiments, the invention provides a compound of formula (I) wherein R1 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.
In various embodiments, the invention provides a compound of formula (I) wherein R1 comprises any of the following: a) an aryl-fused heterocyclyl moiety of the formula
Figure imgf000034_0001
X is O, CH, CHR5, N, NR5, when X is O, CHR5, or NR5 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 Jn 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
Figure imgf000034_0002
signifies mono- or independent plurisubstitution by J, wherein a wavy line signifies a point of attachment; c) an aralkyl moiety of the formula
Figure imgf000035_0001
, wherein n is 0, 1, or 2, R independently comprises H or alkyl wherein the alkyl can be mono- or independently plurisubstituted with J, and Jn signifies mono- or independent plurisubstitution by J, wherein a wavy line signifies a point of attachment; d) an aralkyl moiety of the formula
Figure imgf000035_0002
, wherein n is 0, 1, or 2, R comprises H or alkyl wherein the alkyl can be mono- or independently plurisubstituted with J, and Jn signifies mono- or independent plurisubstitution by J, Rc 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
Figure imgf000035_0003
, wherein R comprises H or alkyl wherein the alkyl can be mono- or independently plurisubstituted with J, and Jn 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
O
Figure imgf000036_0001
, wherein R comprises H or alkyl wherein the alkyl can be mono- or independently plurisubstituted with J, X is O, CH, or NR5, respectively, and R7 comprises (Ci-4)alkyl mono- or independently plurisubstituted with J, wherein a wavy line signifies a point of attachment.
In various embodiments, the invention provides a compound of formula (I) wherein R1 comprises a group of formula
Figure imgf000036_0002
R6 comprises H, (Ci-C6)alkyl, or (C3-Cs)cycloalkyl, wherein the alkyl or cycloalkyl can be mono- or independently plurisubstituted with J; or, a group of formula
Figure imgf000037_0001
a group of formula
Figure imgf000037_0002
Figure imgf000038_0001
wherein R independently at each occurrence comprises H, alkyl wherein the alkyl can be mono- or independently plurisubstituted with J, or C(O)R8, wherein R8 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, R7 comprises (Ci_4)alkyl-NR'2;
or, a group of the formula
Figure imgf000038_0002
or, a group of formula
Figure imgf000038_0003
wherein a wavy line signifies a point of attachment.
More specifically, R1 can comprise a moiety of formula
Figure imgf000038_0004
, wherein R comprises a group of the formula (C1-4 alkyl)OCH3, (C1-4 alkyl)NH2, (C1-4 alkyl)NHMe, (C1-4 alkyl)NMe2, (Ci_4 alkyl)SCH3, cyclopropyl, (Ci-4 alkyl)-2-thiazolyl, (Ci-4 alkyl)-4-imidazolyl, (Ci-4 alkyl)-2-pyridyl, (C1-4 alkyl)-3-pyridyl, (C1-4 alkyl)-4-pyridyl, (C1-4 alkyl)-4- morpholinyl, or (C1-4 alkyl)-4-N-methylpyridazinyl, wherein a wavy line signifies a point of attachment.
In various embodiments, the invention provides a compound of formula (I) wherein R comprises hydroxy, NH2, alkylamino, aminoalkylthio, hydroxyalkylamino, aminoalkylamino, amidoalkylamino, carboxyalkylamino, heterocyclyl, heterocyclylalkylamino, heteroarylamino, or heteroarylalkylamino, any of which can be mono- or independently plurisubstituted with J.
More specifically, in various embodiments, the invention provides a compound of formula (I) wherein R2 comprises a group of the formula
Figure imgf000039_0001
-S-(CH2)mNR2, -NR(CH2)mNR2, -NR(CH2)mOH, -NRCH2CH(OH)CH2NR2, NR(CH2)mC(O)OH, NR(CH2)mC(O)NR2, NR-pyrrolidinyl, NR(CH2)m- morpholinyl, NR(CH2)m-pyridinyl, or NR(CH2)mC(O)morpholinyl, wherein m is 1-4, and R comprises H or alkyl wherein the alkyl can be mono- or independently plurisubstituted with J, wherein a wavy line signifies a point of attachment. For example, m can be 2, R can be H or methyl, or both.
In various embodiments, 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 NR2, wherein R comprises H or alkyl wherein the alkyl can be mono- or independently plurisubstituted with J. More specifically, R3 can comprise a group of formula
Figure imgf000040_0001
wherein a wavy line signifies a point of attachment.
In various embodiments, the invention provides a compound of formula (I) wherein R4 comprises H, OH, OMe, NR(CH2)mNR2, NR(CH2)mOH, OCH2CH(OH)CH2NR2, O(CH2CH2O)PCH2CH2OR, O(CH2)mNR2, O(CH2)mNR2, O(CH2)mC(O)NR2, S(CH2)mNR2, O-(CH2)p-heterocyclyl, NR- (CH2)p-heterocyclyl, O-(CH2)p-heteroaryl, or NR-(CH2)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 0-3.
More specifically, R4 can comprise N(Me)(CH2)2NMe2,
N(Me)(CH2)3NMe2, O(CH2)2NMe2, O(CH2)3NMe2, O(CH2)2OH, O(CH2)3OH, OCH2C(O)-morpholinyl, O(CH2)2C(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, pyridin-2-yloxy, pyridin-3-yloxy, pyridin-4-yloxy, 2- picolinoxy, 3-picolinoxy, or 4-picolinoxy.
In various embodiments, both Q1 and Q2 can be N.
In various embodiments, both Q1 and Q2 can be CR3 or CR5, wherein each R and R is independently selected thus including CH. In various embodiments, one of Q1 or Q2 can be N, and the other can be
CH, or can be a C substituted with an R3 or an R5 other than H. R3 can be a pyrazolinyl, pyridinyl, or pyrimidinyl ring, which can be unsubstituted or substituted with alkyl or NR2, wherein R comprises H or alkyl wherein the alkyl can be mono- or independently plurisubstituted with J. R5 can be H, F, Cl, Me, CN, C(O)R', C(O)OR', C(O)NR2, CF3, OR, OCF3, NR'2, or (Ci-Cs)alkyl, wherein any (Ci-Cs)alkyl is mono- or independently plurisubstituted with J.
In various embodiments, 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.
Another aspect of an embodiment of the invention provides compositions of the compounds of the invention, alone or in combination with another medicament. As set forth herein, 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. For example, 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. When the active compound is mixed with 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. Some examples of 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. Similarly, 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.
If a solid carrier is used for oral administration, 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. Alternatively, sterile oils can be employed as solvents or suspending agents. Preferably, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides. For injection, the formulation can also be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates. For injection, 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).
For nasal administration, the preparation can contain a compound of the invention, dissolved or suspended in a liquid carrier, preferably an aqueous carrier, for aerosol application. 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.
For parenteral application, particularly suitable are 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 (as free compound or salt thereof) 250 mg Colloidal silicon dioxide (Aerosil)® 1.5 mg Cellulose, microcryst. (Avicel)® 70 mg
Modified cellulose gum (Ac-Di-Sol)® 7.5 mg Magnesium stearate Ad. Coating:
HPMC approx. 9 mg *Mywacett 9-40 T approx. 0.9 mg
*Acylated monoglyceride used as plasticizer for film coating.
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.
For example, in the treatment of adult humans, 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. In choosing a regimen for patients it can frequently be necessary to begin with a higher dosage and when the condition is under control to reduce the dosage. 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.
Generally, 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.
Usually, dosage forms suitable for oral, nasal, pulmonal or transdermal administration include from about 125 μg to about 1250 mg, preferably from about 250 μg 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.
Pharmaceutical Combinations
In various embodiments, a pharmaceutical combination comprising a compound of the invention in a therapeutically effective dose and a second medicament in a therapeutically effective dose is provided. More specifically, 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. For example, 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. For example, 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. For example, 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. For example, the anti-atherosclerotic agent can comprise a 3-HMG-coA-reductase inhibitor, a statin, atorvastatin, simvastatin, niacin, or a combination drug such as vytorin. For example, the anti-multiple sclerosis agent can comprise beta-inteferon, tysabri, or glatirimar acetate. For example, the anti-angina agent can comprise a beta receptor-blocker, a calcium channel blocker, nitroglycerin, isosorbide mononitrate, nicorandil, or ranolanzine. For example, the anti-erectile dysfunction agent can comprise a phosphodiesterase-5 inhibitor. For example, the anti-stroke agent can comprise tissue plasminogen activator. For example, the anti-asthma agent can comprise a bronchodilator, an inhaled corticosteroid, a leukotrine blockers, cromolyn, nedocromil, or theophylline. In various embodiments, a pharmaceutical combination of the invention can further comprise a suitable excipient as outlined above to provide a pharmaceutical composition comprising both medicaments.
In various embodiments, a method of treatment of a malcondition is provided 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 combination thereof.
In various embodiments, 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. By "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. For example, 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. For example, 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. For example, 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. For example, the anti-atherosclerotic agent can comprise a 3 -HMG- coA-reductase inhibitor, a statin, atorvastatin, simvastatin, niacin, or a combination drug such as vytorin. For example, the anti-multiple sclerosis agent can comprise beta-inteferon, tysaberai, or glatirimar acetate. For example, the anti-angina agent can comprise a beta receptor-blocker, a calcium channel blocker, nitroglycerin, isosorbide mononitrate, nicorandil, or ranolanzine. For example, the anti-erectile dysfunction agent can comprise a phosphodiesterase-5 inhibitor. For example, the anti-stroke agent can comprise tissue plasminogen activator. For example, the anti-asthma agent can comprise a bronchodilator, an inhaled corticosteroid, a leukotrine blockers, cromolyn, nedocromil, or theophylline.
Methods of Use Various embodiments of the invention provide a method of inhibiting a kinase, comprising contacting the kinase with an effective amount of a compound of the invention. For example, 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. 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. For example, 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. 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. For example, 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. In various embodiments, 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.
In various embodiment, 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. For example, 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. More specifically, 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. More specifically, 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. More specifically, the anti-atherosclerotic agent can comprise a 3-HMG-coA- reductase inhibitor, a statin, atorvastatin, simvastatin, niacin, or a combination drug such as vytorin. More specifically, the anti-multiple sclerosis agent can comprise a beta-inteferon, tysabri, or glatirimar acetate. More specifically, the anti-angina agent can comprise a beta receptor-blocker, a calcium channel blocker, nitroglycerin, isosoribide mononitrate, nicorandil, or ranolanzine. More specifically, the anti-erectile dysfunction agent can comprise a phosphodiesterase-5 inhibitor. More specifically, 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. More specifically, 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. In various embodiments, 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 are described above.
Examples
The following abbreviations are used throughout the
Bn Benzyl
DCM Dichloromethane
DMF N,N-Dimethylformamide
DMSO Dimethylsulfoxide eq Equivalents
Et2O Diethyl ether
EtOAc Ethyl acetate h Hours mg Milligrams min Minutes mL Milliliters μL Microliters mmole Millimoles
MS Mass spectroscopy
MeOH Methanol rb Round-bottom
RT Room temperature sat. Saturated
THF Tetrahydrofuran to (range, e.g., X-Y = X to Y) The following numbered Examples disclose compounds that have been prepared and characterized. Many have been evaluated as inhibitors of kinases. These compounds are examples only and in no way are limiting to the claims herein.
Figure imgf000051_0001
Scheme 1
To a solution of 2, 3-dihydrobenzo[b][l,4]dioxine-2-carboxylic acid (1 equiv) and oxalyl dichloride (2 equiv) in dry DCM was added 4 drops dry DMF. After the mixture was stirred at room temperature for 4 h, the solvent was removed under reduced pressure to give 2,3-dihydrobenzo[b][l,4]dioxine-2- carbonyl chloride in quantity yield. The acid chloride (1.5 equiv) was then dissolved in DCM and was added to a solution of 2-amino-5-bromobenzo nitrile (1 equiv) and pyridine (3 equiv) in DCM at O 0C. The 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). The 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). 1H-NMR (DMSO-dδ, 400 MHz) δ 10.4 (s, IH), 8.16 (s, IH), 7.92 (dd, J=8.8, 2.4 Hz, IH), 7.60 (d, J=8.8 Hz, IH), 7.04-7.01 (m, IH), 6.93-6.85 (m, 3H), 5.11 (dd, 7=6.0, 2.8 Hz, IH), 4.45 (dd, J=I 1.6, 2.8 Hz, IH), 4.36 (dd, J=I 1.6, 6.0 Hz, IH).
To prepare compound 1-2, a mixture of 1-1 (1 equiv) and R-YH (3 equiv, Y= NR', S) was stirred at 95 0C until 1-1 disappeared as monitored by LC-MS. After removing the excess R-YH under reduce pressure, the crude bromide 1-2 (45%-89% yield) was used in the next step without further purification.
A Suzuki reaction was applied to prepare compound 1-3. In one route, the crude bromide 1-2 (1 equiv) and a boronic acid ester (1.5 equiv) were dissolved in degassed dioxane/H2θ (5: 1 by volume) in a sealed tube. Pd(PPIi3)4 (0.03 equiv) and 2M solution of K2CO3 (3 equiv) were added sequentially. The mixture was then heated at 95 0C for 2h. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated in vacuo. The residue was then subjected to preparative HPLC to give product 1-3 as a white solid.
In another route, bromide 1-2 was first transferred to a boronic acid ester and then coupled with an aryl halide to provide compound 1-3. Thus, to a solution of 1-2 (1 equiv.) and the bispinacolatotoboronic ester (2.5 equiv.) in dioxane were added PdCl2(dppf) (0.1 equiv.) and KOAc (3 equiv). The resulting mixture was stirred at 80 0C 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.
Example 1. 2-(2, 3-dihvdrobenzorbiri,41dioxin-2-yl)-N-methyl-6-(lH-pyrazol- 4-yl)quinazolin-4-amine
Figure imgf000052_0001
Procedures in Scheme 1 were utilized to synthesize this compound. LC/MS:
C20Hi7N5O2 (M+ 1) 360. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 2. 2-(2, 3-dihvdrobenzorbiri,41dioxin-2-yl)-6-(lH-pyrazol-4- yl)quinazolin-4-amine
Figure imgf000053_0001
Procedures in Scheme 1 were utilized to synthesize this compound. 1H-NMR (DMSOd6, 400MHz) δ: 9.74 (s, IH), 9.15 (s, IH), 8.17 (s, 2H), 7.99-7.97 (m, IH), 7.44-7.30 (m, 7H), 4.55-4.53 (m, IH), 3.69-3.68 (m, IH), 2.85-2.82 (m, IH). LC/MS: Ci9Hi5N5O2 (M+ 1) 346. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 3. 2-(2, 3-dihvdrobenzorbiri,41dioxin-2-yl)-4-(4-methylpiperazin-l- yl)-6-(lH-pyrazol-4-yl)quinazoline
Figure imgf000053_0002
Procedures in Scheme 1 were utilized to synthesize this compound. 1H-NMR (DMSO-dδ, 400 MHz) δ 9.93 (s, IH), 8.29 (s, 2H), 8.19 (dd, J=8.8, 1.6 Hz, IH), 8.08 (d, 7=1.6 Hz, IH), 7.88 (d, J=8.8 Hz, IH), 7.02-6.99 (m, IH), 6.92-6.83 (m, 3H), 5.37 (dd, J=5.6, 2.8 Hz, IH), 4.61 (dd, J=I 1.6, 2.8 Hz, IH), 4.52 (dd, J=I 1.6, 5.6 Hz, IH), 4.39-4.31 (m, 2H), 3.51-3.44 (m, 4H), 3.20-3.15 (m, 2H), 2.85 (s, 3H). LC/MS: C24H24N6O2 (M+ 1) 429. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 4. 2-(2-(2, 3-dihvdrobenzorbirL41dioxin-2-yl)-6-(lH-pyrazol-4- yl)quinazolin-4-ylthio)-N,N-dimethylethanamine
Figure imgf000054_0001
Procedures in Scheme 1 were utilized to synthesize this compound. 1H-NMR (DMSOd6, 400 MHz) δ 9.51 (s, IH), 9.35-8.33 (m, IH), 8.16 (s, IH), 8.00-7.97 (m, IH), 7.06-7.04 (m, IH), 6.94-6.88 (m, 4H), 5.54 (dd, J=6.4, 2.4 Hz, IH), 4.71 (dd, J=I 1.2. 2.4 Hz, IH), 4.57 (dd, J=I 1.2, 6.4 Hz, IH), 3.70-3.64 (m, 2H), 2.86 (s, 6H), 2.81-2.79 (m, 2H). LC/MS: C23H23N5O2S (M+ 1) 434. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 5. 4-(2-(2, 3-dihydrobenzorbirL41dioxin-2-yl)-6-(lH-pyrazol-4- yl)quinazolin-4-yl)morpholine
Figure imgf000054_0002
Procedures in Scheme 1 were utilized to synthesize this compound. 1H-NMR (DMSOd6, 400 MHz) δ 8.25-8.24 (m, 2H), 8.15-8.11 (m, 2H), 7.86-7.84 (m, IH), 7.03-7.01 (m, IH), 6.90-6.83 (m, 4H), 5.41-5.40 (m, IH), 4.63-4.59 (m, 2H), 4.54-4.42 (m, 4H), 3.70-3.68 (m, 4H). LC/MS: C23H2iN5O3 (M+ 1) 416. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 6. N1-(2-(2, 3-dihvdrobenzorbiri,41dioxin-2-yl)-6-qH-pyrazol-4- vDquinazolin-4-vD-N1 ,N2,N2-trimethyl ethane- 1 ,2-diamine
Figure imgf000054_0003
Procedures in Scheme 1 were utilized to synthesize this compound; 1H-NMR (DMSOd6, 400 MHz) δ 9.41 (s, IH), 8.34 (s, IH), 8.25 (s, 2H), 8.20-8.17 (m, IH), 7.87-7.85 (m, IH), 7.06-7.04 (m, IH), 6.94-6.88 (m, 3H), 5.41 (dd, ./=6.4, 2.4 Hz, IH), 4.65 (dd, J=I 1.6, 2.4 Hz, IH), 4.50 (dd, J=I 1.6, 6.4 Hz, IH), 4.12 (t, J=6.4 Hz, 2H), 3.63 (s, 3H), 3.25-3.19 (m, 2H), 2.90-2.86 (m, 6H). LC/MS: C24H26N6O2 (M+ 1) 431. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 7. Nl-(2-(2, 3-dihvdrobenzorbiri,41dioxin-2-yl)-6-(lH-pyrazol-4- yl)quinazolin-4-yl)-N2,N2-dimethylethane- 1 ,2-diamine
Figure imgf000055_0001
Procedures in Scheme 1 were utilized to synthesize this compound; 1H-NMR (DMSO-dδ, 400 MHz) δ 9.44-9.38 (m, 2H), 8.51 (s, IH), 8.22-8.19 (m, 3H), 7.86-7.84 (m, IH), 7.08-7.05 (m, IH), 6.94-6.84 (m, 3H), 5.44 (dd, 7=6.4, 2.4 Hz, IH), 4.66 (dd, J=I 1.6, 2.4 Hz, IH), 4.52 (dd, J=I 1.6, 6.4 Hz, IH), 3.93-3.91 (m, 2H), 3.30-3.28 (m, 2H), 2.86 (s, 3H), 2.84 (s, 3H). LC/MS: C23H24N6O2 (M+ 1) 417. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 8. N1 -f 2-f 2. 3 -dihvdrobenzo FbI I" 1.41 dioxin-2-ylV6-f 1 H-pyrazol-4- yl)quinazolin-4-yl)-N3.N3-dimethylpropane- 1 ,3-diamine
Procedures in Scheme 1 were utilized to synthesize this compound. LC/MS: C24H26N6O2 (M+ 1) 431. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 9. N1-(6-(2-aminopyrimidin-4-yl)-2-(2, 3-dihydrobenzorbiri,41dioxin- 2-yl)quinazolin-4-yl)-N1,N2,N2-trimethylethane-l,2-diamine
Figure imgf000056_0001
Procedures in Scheme 1 were utilized to synthesize this compound; H-ΝMR (DMSOd6, 400 MHz) δ 9.41 (s, IH), 8.99 (s, IH), 8.54-8.51 (m, IH), 8.43-8.41 (m, IH), 7.92-7.90 (m, IH), 7.39-7.37 (m, IH), 7.05-7.02 (m, IH), 6.93-6.85 (m, 4H), 5.39 (dd, J=6.4, 2.4 Hz, IH), 4.63 (dd, J=I 1.6, 2.4, IH), 4.45 (dd, J=I 1.6, 6.4 Hz, IH), 4.13 (t, J=6.4 Hz, 2H), 3.64 (s, 3H), 3.20-3.15 (m, 2H), 2.89 (s, 3H), 2.86 (s, 3H). LC/MS: C25H27N7O2 (M+ 1) 458. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 10. 2-C2-C2 , 3 -dihydrobenzo [bl 11 ,41 dioxin-2-yl)-6-(3-methyl- 1 H- Pyrazol-4-yl)quinazolin-4-ylthio)-N,N-dimethylethanamine
Figure imgf000056_0002
Procedures in Scheme 1 were utilized to synthesize this compound. 1H-NMR (DMSO-dδ, 400 MHz) δ 9.57 (s, IH), 8.21 (dd, 7=8.8, 2.4 Hz, IH), 8.07 (s, IH), 8.02-7.99 (m, 2H), 7.05 (dd, 7=8.8, 2.4 Hz, IH), 6.94-6.86 (m, 3H), 6.56 (dd, 7=6.4, 2.4 Hz, IH), 4.70 (dd, J=I 1.2, 2.4 Hz, IH), 4.57 (dd, J=I 1.2, 6.4 Hz, IH), 3.69-3.64 (m, 2H), 3.40-3.35 (m, 2H), 2.88-2.85 (m, 6H). LC/MS: C24H25N5O2S (M+ 1) 448. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 11. Nl-(2-(2,3-dihvdrobenzofblfl,41dioxin-2-yl)-8-methoxy-6-(lH- vyrazol-4-yl)auinazolin-4-yl)-Nl,N3,N3-trimethylyrovane-l,3-diamine
Figure imgf000057_0001
Procedures in Scheme 1 were utilized to synthesize this compound. LC/MS: C26H30N6O3 (M+l) 475. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 12. 2-(2,3-dihydrobenzo[bl [1 ,41dioxin-2-yl)-8-methoxy-6-(lH- pyrazol-4-yl)quinazolin-4-amine
Figure imgf000057_0002
Procedures in Scheme 1 were utilized to synthesize this compound. LC/MS: C20H17N5O3 (M+l) 376. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 13. 2-(2,3-dihvdrobenzo[b][l,4]dioxin-2-yl)-8-methoxy-N,N-dimethyl- 6-(lH-pyrazol-4-yl)quinazolin-4-amine
Figure imgf000057_0003
Procedures in Scheme 1 were utilized to synthesize this compound. LC/MS: C22H21N5O3 (M+l) 404. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Figure imgf000058_0001
Scheme 2 5-bromoisatoic anhydride (5.0 g, 1 equiv) was dissolved in aqueous ammonia and stirred at room temperature for 2 hours, during which time a precipitate forms. The product 2-1 is then filtered off and washed with water and dried under vacuum (1.2 g). The aniline 2-1 (1 equiv) and DIPEA (1 equiv) were then 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
CH2CI2) in the presence of catalytic DMF for 1 hour. After aniline 2-1 has been added, the solution is stirred for 18 h during which time the quinazoline ring forms. The solution is then diluted with 1 : 1 THF:EtOAc and washed with aqueous NH4Cl solution. The organic portion is dried over MgSO4 and concentrated in vacuo. The product 2-2 can be purified on Siθ2 (Hexane/EtOAc) to give clean product (85 %-99 % yield).
BOP (1.3eq) was added to the suspension of 2-2, DBU (1.5eq) and a nucleophile (2eq) in acetonitrile. The reaction mixture was stirred for 2 h until LC-MS suggested the consumption of all starting material 2-2. The reaction mixture was diluted with EtOAc and the solution was washed with IM NaOH, brine, sated. NaHCθ3 solution, and brine consequently and dried over anhydrous Na2SO4. After filtration, the solvents were removed to provide crude 2-3. The crude 2-3 was dissolved in 4: 1 dioxane/water and potassium carbonate (4 equiv), boronic ester (1.5 equiv) and Pd(PPli3)4(10%) were added. The reaction mixture was sealed in a microwave cube and degassed. The reaction mixture was then heated by microwave for 30min at 140 0C. After the solvents were removed, the residue was subjected to preparative HPLC to provide product 2-4.
Example 14. Nl-(6-(lH-pyrazol-4-yl)-2-(o-tolyloxymethyl)quinazolin-4-yl)- Nl ,N2,N2-trimethylethane- 1 ,2-diamine
Figure imgf000059_0001
Procedures in Scheme 2 were utilized to synthesize this compound. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.56 (s, IH), 8.33 (dd, J = 8.8, 1.1 Hz, IH), 8.22 (s, 2H), 7.95 (d, J = 8.7 Hz, IH), 7.28-7.17 (m, 2H), 7.00 (dd, J = 15.0, 7.7 Hz, 2H), 5.40 (s, 2H), 4.47 (t, J = 6.3 Hz, 2H), 3.92 (s, 3H), 3.60 (t, J = 6.3 Hz, 2H), 3.00 (s, 6H), 2.37 (s, 3H). LC/MS: C24H28N6O (M+ 1) 417. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 15. N 1 -(2-((2-methoxyphenoxy)methyl)-6-( 1 H-pyrazol-4- yl)quinazolin-4-yl)-N 1 ,N2,N2-trimethylethane- 1 ,2-diamine
Figure imgf000059_0002
Procedures in Scheme 2 were utilized to synthesize this compound. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.56 (d, J = 1.3 Hz, IH), 8.33 (dd, J = 8.8, 1.2 Hz, IH), 8.22 (d, J = 0.5 Hz, 2H), 7.99 (d, J = 8.7 Hz, IH), 7.20-7.17 (m, IH), 7.14- 7.10 (m, 2H), 7.01-6.95 (m, IH), 5.35 (s, 2H), 4.45 (t, J = 6.2 Hz, 2H), 3.92-3.86 (m, 6H), 3.62 (t, J = 6.2 Hz, 2H), 3.03 (s, 6H). LC/MS: C24H28N6O2 (M+l) 433. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 16. Nl-(6-(lH-pyrazol-4-yl)-2-(m-tolyloxymethyl)quinazolin-4-yl)- Nl ,N2,N2-trimethylethane- 1 ,2-diamine
Figure imgf000060_0001
Procedures in Scheme 2 were utilized to synthesize this compound. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.54 (d, J = 1.6 Hz, IH), 8.32 (dd, J = 8.8, 1.8 Hz, IH), 8.20 (s, 2H), 8.01 (d, J = 8.8 Hz, IH), 7.24 (t, J = 7.9 Hz, IH), 6.99 (s, IH), 6.96-6.87 (m, 2H), 5.36 (s, 2H), 4.46 (t, J = 6.4 Hz, 2H), 3.90 (s, 3H), 3.61 (t, J = 6.4 Hz, 2H), 3.03 (s, 6H), 2.36 (s, 3H). LC/MS: C24H28N6O (M+l) 417. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 17. Nl-(2-((3-methoxyphenoxy)methyl)-6-(lH-pyrazol-4- yl)quinazolin-4-yl)-N 1 ,N2,N2-trimethylethane- 1 ,2-diamine
Figure imgf000060_0002
Procedures in Scheme 2 were utilized to synthesize this compound. LC/MS: C24H28N6O2 (M+l) 433. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 18. (R)-(l-(2-((3-methoxyphenoxy)methyl)-6-(lH-pyrazol-4- yl)quinazolin-4-yl)pyrrolidin-2-yl)methanol
Figure imgf000061_0001
Procedures in Scheme 2 were utilized to synthesize this compound. LC/MS: C24H25N5O3 (M+ 1) 432. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 19. 3-((2-((3-methoxyphenoxy)methyl)-6-('lH-pyrazol-4- yl)quinazolin-4-yl)(methyl)amino)propanamide
Figure imgf000061_0002
Procedures in Scheme 2 were utilized to synthesize this compound. LC/MS: C23H24N6O3 (M+ 1) 433. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 20. 2-((3-methoxyphenoxy)methyl)-N-methyl-6-(lH-pyrazol-4-yl)-N- (2-(pyrrolidin- 1 -yl)ethyl)quinazolin-4-amine
Figure imgf000061_0003
Procedures in Scheme 2 were utilized to synthesize this compound. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.39 (d, J = 0.9 Hz, IH), 8.16 (dd, J = 8.8, 1.3 Hz, IH), 8.08 (s, 2H), 7.87 (d, J = 8.8 Hz, IH), 7.13 (t, J = 8.5 Hz, IH), 6.61- 6.58 (m, 2H), 6.54-6.50 (m, IH), 5.24 (s, 2H), 4.35 (t, J = 6.2 Hz, 2H), 3.78 (s, 3H), 3.68 (s, 3H), 3.54 (t, J = 6.2 Hz, 2H), 2.58 (s, 4H),, 2.54-2.50 (m, 4H). LC/MS: C26H30N6O2 (M+ 1) 459. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 21. 2-((3-methoxyphenoxy)methyl)-N-methyl-N-(2-morpholinoethyl)- 6-(lH-pyrazol-4-yl)quinazolin-4-amine
Figure imgf000062_0001
Procedures in Scheme 2 were utilized to synthesize this compound. LC/MS: C26H3ON6O3 (M+ 1) 475. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 22. 2-((3-methoxyphenoxy)methyl)-N-methyl-6-(lH-pyrazol-4-yl)-N- (2-(pyridin-4-yl)ethyl)quinazolin-4-amine
Figure imgf000062_0002
Procedures in Scheme 2 were utilized to synthesize this compound. LC/MS: C27H26N6O2 (M+ 1) 467. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 23. 2-((3-methoxyphenoxy)methyl)-N-methyl-6-(lH-pyrazol-4-yl)-N- (pyridin-3-ylmethyl)quinazolin-4-amine
Figure imgf000063_0001
Procedures in Scheme 2 were utilized to synthesize this compound. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.86 (s, IH), 8.74 (d, J = 5.6 Hz, IH), 8.55-8.47 (m, 2H), 8.28 (dd, J = 8.7, 1.5 Hz, IH), 8.14 (s, 2H), 8.00-7.89 (m, 2H), 7.13 (t, J = 8.1 Hz, IH), 6.60-6.49 (m, 3H), 5.40 (s, 2H), 5.26 (s, 2H), 3.85 (s, 3H), 3.71 (s, 3H). LC/MS: C26H24N6O2 (M+ 1) 453. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 24. 2-((3-methoxyphenoxy)methyl)-N-methyl-6-(lH-pyrazol-4-yl)-N- (pyridin-4-ylmethyl)quinazolin-4-amine
Figure imgf000063_0002
Procedures in Scheme 2 were utilized to synthesize this compound. LC/MS: C26H24N6O2 (M+ 1) 453. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 25. 2-(6-methoxychroman-3-yl)-N-methyl-7-(lH-pyrazol-4-yl)-N-(2- (pyrrolidin- 1 -yl)ethyl)quinazolin-4-amine
Figure imgf000064_0001
Procedures in Scheme 2 were utilized to synthesize this compound. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.40 (d, J = 9.0 Hz, IH), 8.26 (s, 2H), 7.98 (dd, J = 8.9, 1.6 Hz, IH), 7.93 (s, IH), 6.82-6.74 (m, 3H), 4.55-4.42 (m, 2H), 4.41-4.30 (m, IH), 4.27-4.17 (m, IH), 3.83-3.75 (m, 5H), 3.68-3.59 (m, IH), 3.52-3.43 (m, IH), 3.38-3.33 (m, IH), 2.71 (m, 4H), 2.65-2.61 (m, 4H). LC/MS: C28H32N6O2 (M+ 1) 485. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 26. 2-(6-methoxychroman-3-yl)-N-methyl-7-(lH-pyrazol-4-yl)-N-(2- (pyridin-4-yl)ethyl)quinazolin-4-amine
Figure imgf000064_0002
Procedures in Scheme 2 were utilized to synthesize this compound. H-NMR (400 MHz, MeOH-d4) δ ppm 8.65 (d, J = 5.9 Hz, 2H), 8.38 (d, J = 8.8 Hz, IH), 8.27 (s, 2H), 7.98 (d, J = 8.5 Hz, IH), 7.88 (s, IH), 7.70 (d, J = 5.8 Hz, 2H), 6.77-6.70 (m, 2H), 6.69-6.63 (m, IH), 4.53-4.39 (m, 2H), 4.35-4.24 (m, IH), 4.23-4.12 (m, IH), 3.70 (m, 5H), 3.64-3.56 (m, IH), 3.25-3.14 (m, 2H), 2.75- 2.70 (m, IH), 2.69-2.66 (m, IH). LC/MS: C29H28N6O2 (M+l) 493. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 27. 2-((2-(6-methoxychroman-3-yl)-7-(lH-pyrazol-4-yl)quinazolin-4- yl)(methyl)amino)ethanol
Figure imgf000065_0001
Procedures in Scheme 2 were utilized to synthesize this compound. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.47 (d, J = 8.8 Hz, IH), 8.25 (s, 2H), 7.95 (dd, J = 8.9, 1.7 Hz, IH), 7.86 (d, J = 1.4 Hz, IH), 6.79-6.72 (m, 3H), 4.52 (dd, J = 10.9, 2.1 Hz, IH), 4.39 (dd, J = 11.0, 7.1 Hz, IH), 4.12 (q, J = 7.1 Hz, 4H), 4.07-3.95 (m, 3H), 3.85-3.79 (m, IH), 3.77 (s, 3H), 3.67-3.59 (m, IH), 3.58-3.50 (m, IH), 3.37 (s, IH). LC/MS: C24H25N5O3 (M+l) 432. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 28. 3-((2-(6-methoxychroman-3-yl)-7-(lH-pyrazol-4-yl)quinazolin-4- yl)(methyl)amino)propan- 1 -ol
Figure imgf000065_0002
Procedures in Scheme 2 were utilized to synthesize this compound. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.39 (d, J = 8.9 Hz, IH), 8.24 (s, 2H), 7.94 (dd, J = 8.9, 1.6 Hz, IH), 7.86 (d, J = 1.3 Hz, IH), 6.79-6.70 (m, 3H), 4.52 (dd, J = 10.9, 2.0 Hz, IH), 4.40 (dd, J = 10.9, 7.2 Hz, IH), 4.04-3.89 (m, 2H), 3.77 (s, 3H), 3.66-3.59 (m, 2H), 3.58-3.50 (m, IH), 3.23 (dd, J = 16.6, 5.8 Hz, IH), 2.05-1.82 (m, 2H). LC/MS: C25H27N5O3 (M+l) 446. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 29. 4-(azetidin-l-yl)-8-methoxy-2-(6-methoxychroman-3-yl)-6-(lH- vyrazol-4-yl)auinazoline
Figure imgf000066_0001
Procedures in Scheme 1 were utilized to synthesize this compound. LC/MS: C25H25N5O3 (M+l) 444. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 30. 2-(6-methoxychroman-3-yl)-6-(lH-pyrazol-4-yl)-N-(pyridin-3- ylmethyl)quinazolin-4-amine
Figure imgf000066_0002
Procedures in Scheme 2 were utilized to synthesize this compound. 1H-NMR (MeOD-d4, 400 MHz) δ 8.67 (m, 2H), 8.61 (s, IH), 8.34 (m, IH), 8.18 (m, 3H), 7.82 (m, IH), 7.75 (m, IH), 6.61 (m, 3H), 4.95 (m, 2H), 4.38 (m, 2H), 3.70 (s, 3H), 3.56 (m, IH), 3.22 (m, 2H). LC/MS: C27H24N6O2 (M+l) 465. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 31. 2-(6-methoxychroman-3-yl)-6-(lH-pyrazol-4-yl)-N-(2-(pyridin-3- yl)ethyl)quinazolin-4-amine
Figure imgf000066_0003
Procedures in Scheme 2 were utilized to synthesize this compound. 1H-NMR (MeOD-d4, 400 MHz) δ 8.75 (s, 2H), 8.53 (s, IH), 8.45 (m, IH), 8.32 (m, IH), 8.16 (s, 2H), 8.01 (m, IH), 7.80 (m, IH), 6.72 (m, 3H), 4.48 (m, 2H), 4.00 (m, 2H), 3.72 (s, 3H), 3.61 (m, IH), 3.32 (m, 2H), 3.15 (m, 2H). LC/MS: C28H26N6O2 (M+ 1) 479. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 32. 2-((2-(6-methoxychroman-3-yl)-6-(lH-pyrazol-4-yl)quinazolin-4- yl)(methyl)amino)acetic acid
Figure imgf000067_0001
Procedures in Scheme 2 were utilized to synthesize this compound. LC/MS: C24H23N5O4 (M+ 1) 446. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 33. 2-(2-(6-methoxychroman-3-yl)-6-(lH-pyrazol-4-yl)quinazolin-4- ylthio)-N,N-dimethylethanamine
Figure imgf000067_0002
Procedures in Scheme 2 were utilized to synthesize this compound. 1H-NMR (MeOD-d4, 400 MHz) δ 8.24 (m, 2H), 8.18 (s, 2H), 7.97 (d, J = 8.8 Hz, IH), 6.75 (m, 3H), 4.60 (m, IH), 4.42 (m, IH), 3.76 (m, 5H), 3.67 (m, IH), 3.48 (m, 3H), 3.26 (dd, J = 5.8 Hz, 16.2 Hz), 3.00 (s, 6H). LC/MS: C25H27N5O2S (M+l) 462. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 34. 2-((2-(6-methoxychroman-3-yl)-6-(lH-pyrazol-4-yl)quinazolin-4- yl)(methyl)amino)ethanol
Figure imgf000067_0003
Procedures in Scheme 2 were utilized to synthesize this compound. LC/MS: C24H25N5O3 (M+ 1) 432. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 35. Nl-(2-(6-methoxychroman-3-yl)-6-(lH-pyrazol-4-yl)quinazolin- 4-yl)-N 1 ,N2,N2-trimethylethane- 1 ,2-diamine
Figure imgf000068_0001
Procedures in Scheme 2 were utilized to synthesize this compound. 1H-NMR (THF-d8, 400 MHz) δ 8.43 (s, IH), 8.17 (m, 2H), 8.08 (s, 2H), 6.73 (m, 3H), 4.49 (m, 2H), 4.22 (m, 2H), 3.91 (m, IH), 3.79 (s, 3H), 3.75 (s, 3H), 3.29 (m, 4H), 2.83 (s, 6H). LC/MS: C26H30N6O2 (M+ 1) 459. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 36. 2-((2-(6-methoxychroman-3-yl)-6-(lH-pyrazol-4-yl)quinazolin-4- yl)(methyl)amino)- 1 -morpholinoethanone
Figure imgf000068_0002
Procedures in Scheme 2 were utilized to synthesize this compound. LC/MS: C28H30N6O4 (M+ 1) 515. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 37. 2-((2-(6-methoxychroman-3-yl)-6-(lH-pyrazol-4-yl)quinazolin-4- yl)(methyl)amino)acetamide
Figure imgf000068_0003
Procedures in Scheme 2 were utilized to synthesize this compound. LC/MS: C24H24N6O3 (M+ 1) 445. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 38. 2-((2-(6-methoxychroman-3-yl)-6-(lH-pyrazol-4-yl)quinazolin-4- yl)(methyl)amino)-N,N-dimethylacetamide
Figure imgf000069_0001
Procedures in Scheme 2 were utilized to synthesize this compound. 1H-NMR (MeOD-d4, 400 MHz) δ 8.50 (s, IH), 8.32 (m, IH), 8.20 (s, 2H), 7.71 (m, IH), 6.75 (m, 3H), 4.79 (m, 2H), 4.45 (m, IH), 4.23 (m, IH), 3.77 (s, 3H), 3.50 (m, IH), 3.20 (m, 3H), 3.04 (m, 6H). LC/MS: C26H28N6O3 (M+ 1) 473. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 39. 2-(3-methoxyphenethyl)-6-(lH-pyrazol-4-yl)quinazolin-4-ol
Figure imgf000069_0002
Procedures in Scheme 2 were utilized to synthesize this compound. LC/MS: (M+ 1) 347. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 40. 3-((2-(3-methoxyphenethyl)-6-(lH-pyrazol-4-yl)quinazolin-4- yl)(methyl)amino)propan- 1 -ol
Figure imgf000069_0003
Procedures in Scheme 2 were utilized to synthesize this compound. LC/MS: C24H28N5O2 (M+ 1) 418. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 41. 2-((2-(3-methoxyphenethyl)-6-(lH-pyrazol-4-yl)quinazolin-4- yl)(methyl)amino)ethanol
Figure imgf000070_0001
Procedures in Scheme 2 were utilized to synthesize this compound. LC/MS: C23H26N5O2 (M+ 1) 404. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 42. 2-((3-methoxyphenoxy)methyl)-N,N-dimethyl-6-(lH-pyrazol-4- yl)quinazolin-4-amine
Figure imgf000070_0002
Procedures in Scheme 2 were utilized to synthesize this compound. H NMR (400 MHz, MeOH-d4) δ ppm 8.30 (d, J = 1.9 Hz, IH), 8.03 (s, 2H), 8.10-8.05 (m, 2H), 7.62 (d, J = 8.5 Hz, IH), 7.14 (d, J = 7.8 Hz, IH), 7.08-7.05 (m, 2H), 6.97-6.90 (m, IH), 5.07 (s, 2H), 3.76 (s, 3H). 3.18 (s, 3H), 3.14 (s, 3H) LC/MS: C2iH2iN5O2 (M+ 1) 376. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 43. 2-((3-methoxyphenoxy)methyl)-6-(lH-pyrazol-4-yl)quinazolin-4- amine
Figure imgf000070_0003
Procedures in Scheme 2 were utilized to synthesize this compound. 2,4- dimethoxybenzylamine was used in the BOP coupling and the protecting group was removed by TFA in the last step. LC/MS: Ci9Hi7N5O2 (M+ 1) 348. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 44. 4-(2-(6-methoxychroman-3-yl)-7-(3-methyl-lH-pyrazol-4- yl)quinazolin-4-yl)morpholine
Figure imgf000071_0001
Procedures in Scheme 2 were utilized to synthesize this compound. LC/MS: C26H27N5O3 (M+ 1) 458. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 45. 4-(2-(6-methoxychroman-3-yl)-7-(pyridin-4-yl)quinazolin-4- vDmorpholine
Figure imgf000071_0002
Procedures in Scheme 2 were utilized to synthesize this compound. LC/MS: C27H26N4O3 (M+ 1) 455. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 46. 2-(6-methoxychroman-3-yl)-N,N-dimethyl-6-(lH-pyrazol-4- yl)quinazolin-4-amine
Figure imgf000071_0003
Procedures in Scheme 2 were utilized to synthesize this compound. LC/MS: C23H23N5O2 (M+ 1) 402. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Figure imgf000072_0001
Scheme 3 To a solution of the carboxylic acid (1 equiv) and 2-amino-5- bromobenzamide (prepared according to the procedure in Scheme 2. 1 equiv) in DMF (0.3 mL) was added HATU (1.2 equiv) and N-methylmorpholine (2 equiv). The resulting mixture was stirred at room temperature overnight. After removal of solvent by rotary evaporation, the residue was dissolved in ethyl acetate (15 mL) and washed with an aqueous 1 Ν HCl solution (2 x 10 mL), a saturated aqueous Νa2C03 solution (2 x 10 mL), and brine (10 mL), dried over Na2SO4, and filtered. The solvent was removed in vacuo and the crude amide product was taken to the next reaction without further purification.
To a solution of this amide in a 3:2 mixture of ethanol:toluene was added the boronic acid or boronic acid pinacol ester derivate (1.5 equiv), K2CO3 (2 M aqueous solution, 3 equiv), and tetrakis(triphenylphosphine)palladium (0) (0.05 equiv). The reaction mixture was degassed, purged with argon, and heated to 140 0C for 1 h by microwave irradiation. After cooling to room temperature, the mixture was treated with an aqueous 10% solution of TFA (1 mL) and the solvent was removed by rotary evaporation. The residue was purified by preparative HPLC to afford the desired final product.
Example 47. 2-(2,3-dihydrobenzorbirL41dioxin-2-yl)-6-(lH-pyrazol-4- yl)quinazolin-4-ol
Figure imgf000072_0002
Procedures in Scheme 3 were utilized to synthesize this compound. LC/MS: C19H14N4O3 (M+ 1) 347. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 48. 2-(2,3-dihydrobenzorbl [ 1.41dioxin-2-yl)-6-(pyridin-4- yl)quinazolin-4-ol
Figure imgf000073_0001
Procedures in Scheme 3 were utilized to synthesize this compound. LC/MS: C21H15N3O3 (M+ 1) 358. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 49. Synthesis of 2-(chroman-3-yl)-6-(lH-pyrazol-4-yl)quinazolin-4-ol
Figure imgf000073_0002
Procedures in Scheme 3 were used to synthesize this compound. LC/MS: C20H17N4O2 (M+H) 345. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 50. Synthesis of 2-(2H-chromen-3-yl)-6-(lH-pyrazol-4-yl)quinazolin- 4-ol
Figure imgf000073_0003
Procedures in Scheme 3 were used to synthesize this compound. 1H-NMR (DMSOd6, 400 MHz) δ 13.06 (s, 1 H), 12.29 (s, 1 H), 8.40 (br s, 1 H), 8.30 (d, J = 2.0 Hz, 1 H), 8.09 (m, 2 H), 7.83 (s, 1 H), 7.66 (d, J= 8.4 Hz, 1 H), 7.28 (td, J = 7.6, 2.0 Hz, 1 H), 7.23 (t, J= 7.6 Hz, 1 H), 6.91 (d, J= 8.0 Hz, 1 H), 5.23 (s, 2 H). LC/MS: C20Hi5N4O2 (M+H) 343. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 51. Synthesis of 2-(6-methoxychroman-3-yl)-6-(lH-pyrazol-4- yl)quinazolin-4-ol
Figure imgf000074_0001
Procedures in Scheme 3 were used to synthesize this compound. LC/MS: C21H19N4O3 (M+H) 375. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 52. Synthesis of 2-(chroman-3-yl)-6-(3-methyl-lH-pyrazol-4- yl)quinazolin-4-ol
Figure imgf000074_0002
Procedures in Scheme 3 were used to synthesize this compound. LC/MS: C21H19N4O2 (M+H) 359. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 53. Synthesis of 2-(chroman-3-yl)-6-('pyridin-4-yl)quinazolin-4-ol
Figure imgf000074_0003
Procedures in Scheme 3 were used to synthesize this compound. LC/MS: C22Hi8N3O2 (M+H) 356. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 54. Synthesis of 2-(6-methylchroman-3-yl)-6-(lH-pyrazol-4- yl)quinazolin-4-ol
Figure imgf000075_0001
Procedures in Scheme 3 were used to synthesize this compound. LC/MS: C2IHi9N4O2 (M+H) 359. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 55. Synthesis of 2-(chroman-2-yl)-6-(lH-pyrazol-4-yl)quinazolin-4-ol
Figure imgf000075_0002
Procedures in Scheme 3 were used to synthesize this compound. LC/MS:
C20HnN4O2 (M+H) 345. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 56. Synthesis of 2-(6-fluorochroman-3-yl)-6-(lH-pyrazol-4- yl)quinazolin-4-ol
Figure imgf000075_0003
Procedures in Scheme 3 were used to synthesize this compound. LC/MS: C2oHi6FN402 (M+H) 363. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 57. Synthesis of 2-(6-chlorochroman-3-yl)-6-(lH-pyrazol-4- yl)quinazolin-4-ol
Figure imgf000076_0001
Procedures in Scheme 3 were used to synthesize this compound. LC/MS: C20Hi6ClN4O2 (M+H) 379. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 58. Synthesis of 2-(8-methoxychroman-3-yl)-6-(lH-pyrazol-4- yl)quinazolin-4-ol
Figure imgf000076_0002
Procedures in Scheme 3 were used to synthesize this compound. LC/MS: C2iHi9N4O3 (M+H) 375. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 59. 6-(lH-pyrazol-4-yl)-2-(o-tolyloxymethyl)quinazolin-4-ol
Figure imgf000076_0003
Procedures in Scheme 3 were utilized to synthesize this compound. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.29 (d, J = 2.0 Hz, IH), 8.10 (dd, J = 8.5, 2.2 Hz, IH), 7.67 (d, J = 8.5 Hz, IH), 7.20-7.12 (m, 2H), 7.01 (d, J = 7.8 Hz, IH), 6.89 (s, IH), 5.01 (s, 2H), 2.24 (s, 3H). LC/MS: Ci9Hi6N4O2 (M+l) 333. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 60. 6-(5-methyl-lH-pyrazol-4-yl)-2-(o-tolyloxymethyr)quinazolin-4-ol
Figure imgf000077_0001
Procedures in Scheme 3 were utilized to synthesize this compound. H-NMR (400 MHz, DMSO-d6) δ ppm 8.26 (d, J = 2.0 Hz, IH), 8.14-8.09 (m, IH), 7.65 (d, J = 8.5 Hz, IH), 7.20-7.12 (m, 2H), 7.05 (d, J = 7.8 Hz, IH), 6.86 (s, IH), 5.00 (s, 2H), 2.45 (s, 3H), 2.21 (s, 3H). LC/MS: C20Hi8N4O2 (M+l) 347. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 61. 2-((2-methoxyphenoxy)methyl)-6-(lH-pyrazol-4-yl)quinazolin-4- ol
Figure imgf000077_0002
Procedures in Scheme 3 were utilized to synthesize this compound. H-NMR (400 MHz, MeOH-d4) δ ppm 8.41 (d, J = 1.9 Hz, IH), 8.13-8.08 (m, 3H), 7.72 (d, J = 8.5 Hz, IH), 7.14 (d, J = 7.8 Hz, IH), 7.08-7.05 (m, 2H), 6.97-6.90 (m, IH), 5.10 (s, 2H), 3.91 (s, 3H). LC/MS: Ci9Hi6N4O3 (M+l) 349. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 62. 2-((2-methoxyphenoxy)methyl)-6-(5 -methyl- lH-pyrazol-4- yl)quinazolin-4-ol
Figure imgf000077_0003
Procedures in Scheme 3 were utilized to synthesize this compound. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.13 (d, J = 2.0 Hz, IH), 7.92 (s, IH), 7.85 (dd, J = 8.5, 2.0 Hz, IH), 7.62 (d, J = 8.5 Hz, IH), 7.00 (d, J = 7.6 Hz, IH), 6.95-6.91 (m, 2H), 6.83-6.77 (m, IH), 4.98 (d, J = 7.4 Hz, 2H), 3.75 (s, 3H), 2.41 (s, 3H). LC/MS: C20Hi8N4O3 (M+ 1) 363. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 63. 2-((3-methoxyphenoxy)methyl)-6-(lH-pyrazol-4-yl)quinazolin-4- ol
Figure imgf000078_0001
Procedures in Scheme 3 were utilized to synthesize this compound. 1H-NMR
(400 MHz, MeOH-d4) δ ppm 8.40 (d, J = 1.9 Hz, IH), 8.13 (s, 2H), 8.10-8.08 (m, 2H), 7.72 (d, J = 8.5 Hz, IH), 7.14 (d, J = 7.8 Hz, IH), 7.08-7.05 (m, 2H), 6.97-6.90 (m, IH), 5.07 (s, 2H), 3.86 (s, 3H). LC/MS: Ci9Hi6N4O3 (M+l) 349. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 64. 2-((3-methoxyphenoxy)methyl)-6-(pyridin-4-yl)quinazolin-4-ol
Figure imgf000078_0002
Procedures in Scheme 3 were utilized to synthesize this compound. LC/MS: C2IHnN3O3 (M+l) 360. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 65. 6-(lH-pyrazol-4-yl)-2-(m-tolyloxymethyl)quinazolin-4-ol
Figure imgf000079_0001
Procedures in Scheme 3 were utilized to synthesize this compound. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.28 (d, J = 2.0 Hz, IH), 8.08 (dd, J = 8.5, 2.2 Hz, IH), 7.60 (d, J = 8.5 Hz, IH), 7.20-7.12 (m, 2H), 7.01 (d, J = 7.8 Hz, IH), 6.89 (s, IH), 5.03 (s, 2H), 2.20 (s, 3H). LC/MS: Ci9Hi6N4O2 (M+ 1) 333. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 66. 6-(5-methyl-lH-pyrazol-4-yl)-2-(6-methylchroman-3- yl)quinazolin-4-ol
Figure imgf000079_0002
Procedures in Scheme 3 were utilized to synthesize this compound. LC/MS: C22H20N4O2 (M+ 1) 373. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 67. 2-(6-methylchroman-3-yl)-6-(pyridin-4-yl)quinazolin-4-ol
Figure imgf000079_0003
Procedures in Scheme 3 were utilized to synthesize this compound. LC/MS: C23Hi9N3θ2 (M+ 1) 370. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 68. methyl 3-(4-hvdroxy-6-(lH-pyrazol-4-yl)quinazolin-2- yl)chroman-6-carboxylate
Figure imgf000080_0001
Procedures in Scheme 3 were utilized to synthesize this compound. 1H-NMR (MeOD-d4, 400 MHz) δ 8.39 (d, J = 2.0 Hz, IH), 8.12 (bs, 2H), 8.07 (dd, J = 2.1 Hz, 8.6 Hz, IH), 7.90 (m, IH), 7.81 (m, IH), 7.71 (d, J = 8.4 Hz, IH), 6.92 (d, J = 8.7 Hz, IH), 4.68 (m, IH), 4.33 (m, IH), 3.89 (s, 3H), 3.36 (m, 2H), 3.23 (m, IH). LC/MS: C22Hi8N4O4 (M+l) 403. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 69. 2-(5-methoxychroman-3-yl)-6-(lH-pyrazol-4-yl)quinazolin-4-ol
Figure imgf000080_0002
Procedures in Scheme 3 were utilized to synthesize this compound. LC/MS: C2iHisN4O3 (M+l) 375. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 70. 2-(5-methoxychroman-3-yl)-6-(5-methyl-lH-pyrazol-4- yl)quinazolin-4-ol
Figure imgf000080_0003
Procedures in Scheme 3 were utilized to synthesize this compound. LC/MS: C22H20N4O3 (M+l) 389. Single peak at both 215 nm and 254 nm in analytical HPLC traces Example 71. 2-(6-methoxychroman-3-yl)-6-(pyridin-4-yl)quinazolin-4-ol
Figure imgf000081_0001
Procedures in Scheme 3 were utilized to synthesize this compound. 1H-NMR (MeOD-d4, 400 MHz) δ 8.82 (d, J = 5.5 Hz, 2H), 8.74 (d, J = 2.2 Hz, IH), 8.34 (dd, J = 2.4 Hz, 8.7 Hz, IH), 8.26 (d, J = 6.2 Hz, 2H), 7.89 (d, J = 8.5 Hz, IH), 6.75 (m, 3H), 4.56 (m, IH), 4.20 (m, IH), 3.77 (s, 3H), 3.39 (m, 3H). LC/MS: C23H19N3O3 (M+ 1) 386. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 72. 2-(6-methoxychroman-3-yl)-6-(5-methyl-lH-pyrazol-4- yl)quinazolin-4-ol
Figure imgf000081_0002
Procedures in Scheme 3 were utilized to synthesize this compound. LC/MS: C22H20N4O3 (M+ 1) 389. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 73. ό-dH-pyrazol^-vD^-^-Cpyrrolidin-l-vDethyDquinazolin^CSH)- one
Figure imgf000081_0003
Procedures in Scheme 3 were utilized to synthesize this compound. LC/MS: Ci7Hi9N5O (M+ 1) 310. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Figure imgf000082_0001
Scheme 4
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 Et3N (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 (H2θ/MeCN) to give quinazoline 4-2 (20 %- 50% yield).
Example 74. 3-(4-hvdroxy-6-(lH-pyrazol-4-yl)quinazolin-2-yl)chroman-6- carboxylic acid
Figure imgf000082_0002
Procedures in Scheme 4 were utilized to synthesize this compound. LC/MS: C2IHi6N4O4 (M+l) 389. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 75. 3-(4-hvdroxy-6-(lH-pyrazol-4-yl)quinazolin-2-yl)-N-(2- methoxyethyl)chroman-6-carboxamide
Figure imgf000082_0003
Procedures in Scheme 4 were utilized to synthesize this compound. LC/MS: C24H23N5O4 (M+ 1) 446. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 76. N-(2-(dimethylamino)ethyl)-3-(4-hvdroxy-6-(lH-pyrazol-4- yl)quinazolin-2-yl)chroman-6-carboxamide
Figure imgf000083_0001
Procedures in Scheme 4 were utilized to synthesize this compound. LC/MS: C25H26N6O3 (M+ 1) 459. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 77. N-cvclopropyl-3-(4-hvdroxy-6-(lH-pyrazol-4-yl)quinazolin-2- yl)chroman-6-carboxamide
Figure imgf000083_0002
Procedures in Scheme 4 were utilized to synthesize this compound. LC/MS: C24H2IN5O3 (M+ 1) 428. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 78. 3-(4-hvdroxy-6-(lH-pyrazol-4-yl)quinazolin-2-yl)-N-(2- (thiophen-2-yl)ethyl)chroman-6-carboxamide
Figure imgf000083_0003
Procedures in Scheme 4 were utilized to synthesize this compound. LC/MS: C27H23N5O3S (M+ 1) 498. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 79. N-(2-(lH-imidazol-5-yl)ethyl)-3-(4-hvdroxy-6-(lH-pyrazol-4- yl)quinazolin-2-yl)chroman-6-carboxamide
Figure imgf000084_0001
Procedures in Scheme 4 were utilized to synthesize this compound. LC/MS: C26H23N7O3 (M+l) 482. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 80. 3-(4-hvdroxy-6-(lH-pyrazol-4-yl)quinazolin-2-yl)-N-(2-(pyridin- 2-yl)ethyl)chroman-6-carboxamide
Figure imgf000084_0002
Procedures in Scheme 4 were utilized to synthesize this compound. LC/MS: C28H24N6O3 (M+l) 493. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 81. 3-(4-hvdroxy-6-(lH-pyrazol-4-yl)quinazolin-2-yl)-N-(2-(pyridin- 3-yl)ethyl)chroman-6-carboxamide
Figure imgf000084_0003
Procedures in Scheme 4 were utilized to synthesize this compound. 1H-NMR (MeOD-d4, 400 MHz) δ 8.70 (d, J = 1.8 Hz, IH), 8.61 (d, J = 5.6 Hz, IH), 8.43 (d, J = 8.1 Hz, IH), 8.27 (d, J = 2.1 Hz, IH), 7.99 (s, 2H), 7.95 (dd, J = 2.1 Hz, 8.5 Hz, IH), 7.89 (dd, J = 5.8 Hz, 8.0 Hz, IH), 7.57 (d, J = 8.5 Hz, IH), 7.52 (s, IH), 7.44 (dd, J = 2.3 Hz, 8.6 Hz, IH), 6.78 (d, J = 8.6 Hz, IH), 4.54 (m, IH), 4.18 (m, IH), 3.62 (t, J = 6.7 Hz, 2H), 3.18 (m, 2H), 3.06 (m, 3H). LC/MS: C28H24N6O3 (M+ 1) 493. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 82. 3-(4-hvdroxy-6-(lH-pyrazol-4-yl)quinazolin-2-yl)-N-(2-(pyridin- 4-yl)ethyl)chroman-6-carboxamide
Figure imgf000085_0001
Procedures in Scheme 4 were utilized to synthesize this compound. LC/MS: C28H24N6O3 (M+ 1) 493. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 83. 3-(4-hvdroxy-6-(lH-pyrazol-4-yl)quinazolin-2-yl)-N-(2- morpholinoethyl)chroman-6-carboxamide
Figure imgf000085_0002
Procedures in Scheme 4 were utilized to synthesize this compound. 1H-NMR (MeOD-d4, 400 MHz) δ 8.37 (d, J = 2.0 Hz, IH), 8.10 (s, 2H), 8.05 (dd, J = 2.2 Hz, 8.5 Hz, IH), 7.76 (d, J = 2.2 Hz, IH), 7.68 (d, J = 8.3 Hz, 2H), 6.93 (d, J = 8.6 Hz, 2H), 4.66 (m, IH), 4.31 (dd, J = 9.9 Hz, 10.6 Hz, IH), 4.10 (m, 2H), 3.78 (m, 3H), 3.69 (m, 2H), 3.40 (m, 4H), 3.22 (m, 3H). LC/MS: C27H28N6O4 (M+l) 501. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 84. 3-(4-((2-(dimethylamino)ethyl)(methyl)amino)-6-(lH-pyrazol-4- vDquinazolin^-vDchroman-ό-carboxylic acid
Figure imgf000085_0003
Procedures in Scheme 4 were utilized to synthesize this compound. LC/MS: C2OH28N6O3 (M+ 1) 473. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 85. 3-(4-((2-(dimethylamino)ethyl)(methyl)amino)-6-(lH-pyrazol-4- yl)quinazolin-2-yl)chroman-6-carboxamide
Figure imgf000086_0001
Procedures in Scheme 4 were utilized to synthesize this compound. 1H-NMR (MeOD-d4, 400 MHz) δ 8.49 (s, IH), 8.33 (d, J = 8.7 Hz, IH), 8.20 (s, 2H), 7.85 (d, J = 8.7 Hz, IH), 7.80 (s, IH), 7.70 (d, J = 8.5 Hz, IH), 6.93 (d, J = 8.5 Hz, IH), 4.67 (d, J = 10.1 Hz, IH), 4.58 (dd, J = 6.9 Hz, 11.2 Hz, IH), 4.26 (t, J = 6.7 Hz, 2H), 3.86 (s, 3H), 3.66 (m, IH), 3.47 (m, 2H), 3.40 (m, 2H), 2.97 (s, 6H). LC/MS: C26H29N7O2 (M+ 1) 472. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 86. N-cvclopropyl-3-('4-('('2-('dimethylamino)ethyl)('methyl)amino)-6- (lH-pyrazol-4-yl)quinazolin-2-yl)chroman-6-carboxamide
Figure imgf000086_0002
Procedures in Scheme 4 were utilized to synthesize this compound. H-NMR (MeOD-d4, 400 MHz) δ 8.47 (s, IH), 8.31 (d, J = 8.8 Hz, IH), 8.18 (s, 2H), 7.82 (d, J = 8.7 Hz, IH), 7.71 (s, IH), 7.59 (d, J = 8.5 Hz, IH), 6.90 (d, J = 8.5 Hz, IH), 4.64 (m, IH), 4.55 (dd, J = 10.8 Hz, 11.0 Hz, IH), 4.24 (t, J = 6.4 Hz, 2H), 3.84 (s, 3H), 3.66 (m, IH), 3.42 (m, 4H), 2.96 (s, 6H), 2.84 (m, IH), 0.81 (m, 2H), 0.62 (m, 2H). LC/MS: C29H33N7O2 (M+l) 512. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 87. 3-(4-((2-(dimethylamino)ethyl)(methyl)amino)-6-(lH-pyrazol-4- yl)quinazolin-2-yl)-N-('2-morpholinoethyl)chroman-6-carboxamide
Figure imgf000087_0001
Procedures in Scheme 4 were utilized to synthesize this compound. 1H-NMR (MeOD-d4, 400 MHz) δ 8.48 (s, IH), 8.31 (d, J = 8.7 Hz, IH), 8.19 (s, 2H), 7.84 (d, J = 8.8 Hz, IH), 7.77 (s, IH), 7.68 (d, J = 8.6 Hz, IH), 6.95 (d, J = 8.6 Hz, IH), 4.67 (d, J = 9.8 Hz, IH), 4.54 (dd, J = 8.2 Hz, 10.5 Hz, IH), 4.35 (m, 2H), 4.07 (m, 2H), 3.86 (s, 3H), 3.79 (m, 4H), 3.66 (m, 3H), 3.52 (t, J = 6.5 Hz, 2H), 3.39 (m, 4H), 3.22 (m, 2H), 2.98 (s, 6H). LC/MS: C32H40N8O3 (M+l) 585. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 88. 3-(4-(2-(dimethylamino)ethylthio)-6-(lH-pyrazol-4-yl)quinazolin- 2-yl)chroman-6-carboxylic acid
Figure imgf000087_0002
Procedures in Scheme 4 were utilized to synthesize this compound. LC/MS: C25H25N5O3S (M+l) 476. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 89. N-cvclopropyl-3-('4-('2-('dimethylamino)ethylthio)-6-('lH-pyrazol- 4-yl)quinazolin-2-yl)chroman-6-carboxamide
Figure imgf000087_0003
Procedures in Scheme 4 were utilized to synthesize this compound. 1H-NMR (MeOD-d4, 400 MHz) δ 8.22 (dd, J = 1.9 Hz, 8.8 Hz, IH), 8.18 (m, IH), 8.15 (s, 2H), 7.93 (d, J = 8.7 Hz, IH), 7.70 (s, IH), 7.56 (dd, J = 2.3 Hz, 8.6 Hz, IH), 6.85 (d, J = 8.6 Hz, IH), 4.70 (m, IH), 4.54 (dd, J = 8.3 Hz, 10.7 Hz, IH), 3.70 (m, 3H), 3.48 (m, 3H), 3.33 (m, IH), 2.99 (s, 6H), 2.83 (m, IH), 0.80 (m, 2H), 0.63 (m, 2H). LC/MS: C28H30N6O2S (M+l) 515. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 90. 3-(4-(2-(dimethylamino)ethylthio)-6-(lH-pyrazol-4-yl)quinazolin- 2-yl)-N-(2-methoxyethyl)chroman-6-carboxamide
Figure imgf000088_0001
Procedures in Scheme 4 were utilized to synthesize this compound. 1H-NMR (MeOD-Cl4, 400 MHz) δ 8.23 (dd, J = 2.0 Hz, 8.7 Hz, IH), 8.19 (d, J = 1.4 Hz, IH), 8.16 (s, 2H), 7.95 (d, J = 8.8 Hz, IH), 7.73 (s, IH), 7.60 (dd, J = 2.3 Hz, 8.5 Hz, IH), 6.86 (d, J = 8.6 Hz, IH), 4.70 (m, IH), 4.56 (dd, J = 8.1 Hz, 10.8 Hz, IH), 3.70 (m, 3H), 3.56 (m, 4H), 3.49 (m, 3H), 3.38 (m, 4H), 2.99 (s, 6H). LC/MS: C28H32N6O3S (M+l) 533. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 91. 3-(4-(2-(dimethylamino)ethylthio)-6-(lH-pyrazol-4-yl)quinazolin- 2-yl)-N-(2-morpholinoethyl)chroman-6-carboxamide
Figure imgf000088_0002
Procedures in Scheme 4 were utilized to synthesize this compound. LC/MS: C3IH37N7O3S (M+l) 588. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Figure imgf000089_0001
Scheme 5
To a solution of the carboxylic acid (1 equiv) and 2-amino-5- bromobenzamide (1 equiv) in DMF (0.3 mL) was added HATU (1.2 equiv) and N-methylmorpholine (2 equiv). The resulting mixture was stirred at room temperature overnight. After removal of solvent by rotary evaporation, the residue was dissolved in ethyl acetate (15 mL) and washed with an aqueous 1 Ν HCl solution (2 x 10 mL), a saturated aqueous Na2CCh solution (2 x 10 mL), and brine (20 mL), dried over Na2SO4, and filtered. The solvent was removed in vacuo and the crude amide product was taken to the next reaction without further purification.
The residue was dissolved in dioxane and to this solution was added bis(pinacolato)diboron (2.5 equiv), potassium acetate (5 equiv), and PdCl2(dppf) (0.1 equiv). The reaction mixture was degassed, purged with argon, and heated to 100 0C for 2 h by microwave irradiation. After the reaction was determined to be complete by LC-MS, the mixture was diluted with ethyl acetate (20 mL) and washed with brine (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to yield the crude aryl boronic ester. The residue was dissolved in a 3:2 mixture of ethanol:toluene and to this mixture was added 2- amino-4-chloro-pyrimidine (1.2 equiv), K2Cθ3 (2 M aqueous solution, 3 equiv), and tetrakis(triphenylphosphine)palladium (0) (0.05 equiv). The reaction mixture was degassed, purged with argon, and heated to 140 0C for 1 h by microwave irradiation. After cooling to room temperature, the mixture was treated with an aqueous 10% solution of TFA (1 mL) and the solvent was removed by rotary evaporation. The residue was purified by preparative HPLC to afford the desired final product. Example 92. Synthesis of 6-(2-ammopyrimidin-4-yl)-2-(chroman-3- yl)quinazolin-4-ol
Figure imgf000090_0001
Procedures in Scheme 5 were used to synthesize this compound. LC/MS: C2IHi8N5O2 (M+H) 372. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 93. 6-(2-aminopyrimidin-4-yl)-2-(6-methoxychroman-3- yl)quinazolin-4-ol
Figure imgf000090_0002
Procedures in Scheme 5 were utilized to synthesize this compound. LC/MS: C22Hi9N5O3 (M+ 1) 402. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 94. 6-(2-aminopyridin-4-yl)-2-(6-methoxychroman-3-yl)quinazolin-4- ol
Figure imgf000090_0003
Procedures in Scheme 5 were utilized to synthesize this compound. LC/MS: C23H20N4O3 (M+ 1) 401. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 95. 6-(2-aminopyrimidin-4-yl)-2-(2-(dimethylamino)ethyl)-8- methoxyquinazolin-4(3H)-one
Figure imgf000091_0001
Procedures in Scheme 5 were utilized to synthesize this compound. LC/MS: Ci7H2ON6O2 (M+l) 341. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 96. 6-(2-aminopyrimidin-4-yl)-2-('2-('pyrrolidin-l-yl)ethyl)quinazolin- 4(3H)-one
Figure imgf000091_0002
Procedures in Scheme 5 were utilized to synthesize this compound. LC/MS: Ci8H20N6O (M+l) 337. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 97. 6-(5-chloro-7H-pyrrolor2,3-dlpyrimidin-4-yl)-2-(6- methoxychroman-3-yl)quinazolin-4-ol
Figure imgf000091_0003
Procedures in Scheme 5 were utilized to synthesize this compound. LC/MS: C24Hi8N5O3Cl (M+l) 460. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 98. 7-ethyl-6-(4-hvdroxy-2-(6-methoxychroman-3-yl)quinazolin-6-yl)- 7H-purin-8(9H)-one
Figure imgf000092_0001
Procedures in Scheme 5 were utilized to synthesize this compound. LC/MS: C25H22N6O4 (M+ 1) 471. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 99. 7-ethyl-6-(4-hvdroxy-8-methoxy-2-(6-methoxychroman-3- yl)quinazolin-6-yl)-7H-purin-8(9H)-one
Figure imgf000092_0002
Procedures in Scheme 5 were utilized to synthesize this compound. LC/MS: C26H24N6O5 (M+ 1) 501. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 100. 7-(7-ethyl-8-oxo-8,9-dihvdro-7H-purin-6-yl)-2-(6- methoxychroman-3-yl)quinazolin-4(3H)-one
Figure imgf000092_0003
Procedures in Scheme 5 were utilized to synthesize this compound. LC/MS: C25H22N6O4 (M+ 1) 471. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Figure imgf000093_0001
Scheme 6
To a solution of the amino acid (1.2 equiv) and 2-amino-5- bromobenzamide (1 equiv) in DMF (1 mL) was added HATU (1.3 equiv) and N- methylmorpholine (2 equiv). The resulting mixture was stirred at room temperature overnight. After removal of solvent by rotary evaporation, the residue was dissolved in ethyl acetate (15 mL) and washed with an aqueous 0.5 Ν HCl solution (2 x 10 mL), a saturated aqueous Νa2C03 solution (2 x 10 mL), and brine (10 mL), dried over Na2SO4, and filtered. The solvent was removed in vacuo and the crude amide product was taken to the next reaction without further purification.
To a solution of this methyl amide in a 3:2 mixture of ethanol: toluene was added the boronic acid or boronic acid pinacol ester derivate (1.5 equiv), K2CO3 (2 M aqueous solution, 3 equiv), and tetrakis(triphenylphosphine)palladium (0) (0.05 equiv). The reaction mixture was degassed, purged with argon, and heated to 140 0C for 1 h by microwave irradiation. After cooling to room temperature, the solvent was removed in vacuo and the residue was treated with a 1:2 (TFA:CH2C12) solution, and the mixture was stirred for 1 h. The solvent was removed by rotary evaporation and the residue was purified by preparative HPLC to afford the desired final product. Example 101. Synthesis of (S)-2-(l-amino-2-phenylethyl)-6-(lH-pyrazol-4- yl)quinazolin-4-ol
Figure imgf000094_0001
Procedures in Scheme 6 were used to synthesize this compound. LC/MS: Ci9Hi8N5O (M+H) 332. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 102. Synthesis of (S)-2-(l-amino-2-phenylethyl)-6-(pyridin-4- yl)quinazolin-4-ol
Figure imgf000094_0002
Procedures in Scheme 6 were used to synthesize this compound. LC/MS: C21H19N4O (M+H) 343. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 103. Synthesis of fSy2-α-amino-2-(4-chlorophenyl)ethyr)-6-('lH- pyrazol-4-yl)quinazolin-4-ol
Figure imgf000094_0003
Procedures in Scheme 6 were used to synthesize this compound. LC/MS: Ci9Hi7ClN5O (M+H) 366. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 104. Synthesis of (R)-2-(l-amino-2-(4-chlorophenyl)ethyl)-6-(lH- pyrazol-4-yl)quinazolin-4-ol
Figure imgf000095_0001
Procedures in Scheme 6 were used to synthesize this compound. LC/MS: Ci9Hi7ClN5O (M+H) 366. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 105. Synthesis of (R)-2-(l-amino-2-(3-fluorophenyl)ethyl)-6-(lH- pyrazol-4-yl)quinazolin-4-ol
Figure imgf000095_0002
Procedures in Scheme 6 were used to synthesize this compound. LC/MS: Ci9Hi7FN5O (M+H) 350. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 106. Synthesis of (R)-2-(l-amino-2-(3-chlorophenyl)ethyl)-6-(lH- pyrazol-4-yl)quinazolin-4-ol
Figure imgf000095_0003
Procedures in Scheme 6 were used to synthesize this compound. LC/MS: Ci9Hi7ClN5O (M+H) 366. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 107. Synthesis of (R)-2-(l-amino-2-(3,4-dimethoxyphenyl)ethyl)-6- (lH-pyrazol-4-yl)quinazolin-4-ol
Figure imgf000096_0001
Procedures in Scheme 6 were used to synthesize this compound. 1H-NMR (DMSO-dδ, 400 MHz) δ 12.58 (br s, 1 H), 8.46 (br s, 3 H), 8.31 (d, J = 2.0 Hz, 1 H), 8.24 (br s, 1 H), 8.12 (dd, J= 8.4, 2.4 Hz, 1 H), 7.69 (d, J= 8.4 Hz, 1 H), 6.89 (d, J= 8.4 Hz, 1 H), 6.85 (d, J= 1.6 Hz, 1 H), 6.74 (d, J= 8.4, 2.0 Hz, I H), 4.35 (m, 1 H), 3.71 (s, 3 H), 3.66 (s, 3 H), 3.25 (dd, J= 14.0, 5.6 Hz, 1 H), 3.06 (dd, J= 13.6, 8.0 Hz, 1 H). LC/MS: C2IH22N5O3 (M+H) 392. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 108. Synthesis of (R)-2-(l-amino-3-phenylpropyl)-6-(lH-pyrazol-4- yl)quinazolin-4-ol
Figure imgf000096_0002
Procedures in Scheme 6 were used to synthesize this compound. LC/MS:
C20H20N5O (M+H) 346. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 109. Synthesis of (R)-2-(l-amino-2-(3-(trifluoromethyl)phenyl)ethyl)- 6-(lH-pyrazol-4-yl)quinazolin-4-ol
Figure imgf000096_0003
Procedures in Scheme 6 were used to synthesize this compound. LC/MS: C20HnF3N5O (M+H) 400. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 110. Synthesis of (R)-2-(l-amino-2-(3,4-difluorophenyl)ethyl)-6-(lH- pyrazol-4-yl)quinazolin-4-ol
Figure imgf000097_0001
Procedures in Scheme 6 were used to synthesize this compound. LC/MS: Ci9Hi6F2N5O (M+H) 368. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 111. Synthesis of (R)-2-(l-amino-2-(4-methoxyphenyl)ethyl)-6-(lH- pyrazol-4-yl)quinazolin-4-ol
Figure imgf000097_0002
Procedures in Scheme 6 were used to synthesize this compound. LC/MS: C20H20N5O2 (M+H) 362. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 112. Synthesis of (R)-2-( l-amino-2-(4-ethoxyphenyl)ethyl)-6-( IH- pyrazol-4-yl)quinazolin-4-ol
Figure imgf000097_0003
Procedures in Scheme 6 were used to synthesize this compound. LC/MS: C2IH23N5O2 (M+H) 376. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 113. Synthesis of (S)-2-(l-amino-2-(3-fluorophenyl)ethyl)-6-(lH- pyrazol-4-yl)quinazolin-4-ol
Figure imgf000098_0001
Procedures in Scheme 6 were used to synthesize this compound. 1H-NMR (DMSO-dδ, 400 MHz) δ 12.51 (br s, 1 H), 8.46 (br s, 3 H), 8.23 (d, J = 2.0 Hz, 1 H), 8.17 (br s, 2 H), 8.06 (dd, J = 8.4, 2.4 Hz, 1 H), 7.63 (d, J = 8.8 Hz, 1 H), 7.22 (dd, J = 8.8, 5.6 Hz, 2 H), 7.10 (t, J= 8.8 Hz, 2 H), 4.32 (m, 1 H), 3.25 (dd, J= 14.4, 6.0 Hz, 1 H), 3.07 (dd, J = 14.0, 8.4 Hz, 1 H). LC/MS: Ci9Hi7FN5O (M+H) 350. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 114. Synthesis of (R)-2-(l-amino-2-(4-fluorophenyl)ethyl)-6-(lH- pyrazol-4-yl)quinazolin-4-ol
Figure imgf000098_0002
Procedures in Scheme 6 were used to synthesize this compound. LC/MS: Ci9Hi7FN5O (M+H) 350. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 115. Synthesis of (Rl-N-q-^-chlorophenvD-l-^-hvdroxy-ό-dH- pyrazol-4-yl)quinazolin-2-yl)ethyl)-2-(pyridin-3-yl)acetamide
Figure imgf000098_0003
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: C26H22ClN6O2 (M+H) 485. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 116. (R)-2-(6-methoxy-L2,3,4-tetrahydroisoquinolin-3-yl)-6-(lH- pyrazol-4-yl)quinazolin-4-ol
Figure imgf000099_0001
Procedures in Scheme 6 were utilized to synthesize this compound. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.45 (d, J = 2.1 Hz, IH), 8.16-8.11 (m, 3H), 7.82 (d, J = 8.5 Hz, IH), 7.24 (d, J = 8.6 Hz, IH), 6.96 (dd, J = 8.6, 2.5 Hz, IH), 6.89 (d, J = 2.3 Hz, IH), 4.60 (dd, J = 12.1, 4.7 Hz, IH), 4.52 (d, J = 4.1 Hz, IH), 3.81 (s, 3H), 3.60 (dd, J = 17.1, 4.7 Hz, IH), 2.70 (m, 2H). LC/MS: C2IHi9N5O2 (M+ 1) 374. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 117. (S)-2-(6-methoxy-L2,3,4-tetrahydroisoquinolin-3-yl)-6-(lH- pyrazol-4-yl)quinazolin-4-ol
Figure imgf000099_0002
Procedures in Scheme 6 were utilized to synthesize this compound. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.44 (d, J = 2.1 Hz, IH), 8.16-8.11 (m, 3H), 7.82 (d, J = 8.5 Hz, IH), 7.26 (d, J = 8.6 Hz, IH), 6.96 (dd, J = 8.6, 2.5 Hz, IH), 6.91 (d, J = 2.3 Hz, IH), 4.63 (dd, J = 12.1, 4.7 Hz, IH), 4.54 (d, J = 4.1 Hz, IH), 3.83 (s, 3H), 3.60 (dd, J = 17.1, 4.7 Hz, IH), 2.70 (m, 2H). LC/MS: C2iHi9N5O2 (M+ 1) 374. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 118. 2-(amino(4-chlorophenyl)methyl)-6-(lH-pyrazol-4-yl)quinazolin- 4-ol
Figure imgf000100_0001
Procedures in Scheme 6 were utilized to synthesize this compound. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.43 (d, J = 2.1 Hz, IH), 8.16-8.13 (m, 3H), 7.86 (d, J = 8.5 Hz, IH), 7.59-7.54 (m, 2H), 7.51-7.45 (m, 2H), 6.05 (s, IH). LC/MS: Ci8Hi4N5OCl (M+l) 352. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 119. 2-(amino(3-chlorophenyl)methyl)-6-(lH-pyrazol-4-yl)quinazolin- 4-ol
Figure imgf000100_0002
Procedures in Scheme 6 were utilized to synthesize this compound. H-NMR (400 MHz, MeOH-d4) 8.41 (d, J = 2.1 Hz, IH), 8.17 (dd, J = 8.5, 2.1 Hz, IH), 8.14 (s, 2H), 7.92 (d, J = 8.5 Hz, IH), 7.66-7.63 (m, IH), 7.59-7.53 (m, IH), 7.53-7.48 (m, 2H), 5.48 (s, IH). LC/MS: Ci8Hi4N5OCl (M+l) 352. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 120. 2-(amino(4-methoxyphenyl)methyl)-6-( 1 H-pyrazol-4- yl)quinazolin-4-ol
Figure imgf000100_0003
Procedures in Scheme 6 were utilized to synthesize this compound. H-NMR (400 MHz, MeOH-d4) δ ppm 8.43 (d, J = 2.0 Hz, IH), 8.21-8.15 (m, 3H), 7.94 (d, J = 8.5 Hz, IH), 7.53-7.49 (m, 2H), 7.11-7.07 (m, 2H), 5.44 (s, IH), 3.87 (s, 3H). LC/MS: Ci9Hi7N5O2 (M+ 1) 348. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 121. 2-(amino(4-methoxyphenyl)methyl)-6-(3-methyl-lH-pyrazol-4- yl)quinazolin-4-ol
Figure imgf000101_0001
Procedures in Scheme 6 were utilized to synthesize this compound. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.28 (d, J = 2.1 Hz, IH), 8.04 (dd, J = 8.5, 1.9 Hz, IH), 7.95-7.89 (m, 2H), 7.50-7.45 (m, 2H), 7.08-7.03 (m, 2H), 5.41 (s, IH), 3.84 (s, 3H), 2.52 (s, 3H). LC/MS: C20Hi9N5O2 (M+ 1) 362. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 122. N-((4-chlorophenyl)(4-hvdroxy-6-(lH-pyrazol-4-yl)quinazolin-2- yl)methyl)-2-(dimethylamino)acetamide
Figure imgf000101_0002
Compound of Example 111 was coupled to the corresponding carboxylic acid using HATU as the coupling reagent to provide this compound. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.43 (d, J = 2.1 Hz, IH), 8.18-8.14 (m, IH), 7.83 (d, J = 8.5 Hz, IH), 7.59-7.54 (m, IH), 7.52-7.47 (m, IH), 6.07 (s, IH), 4.16 (d, J = 3.5 Hz, 2H), 3.02 (s, 6H). LC/MS: C22H2iClN6O2Cl (M+ 1) 437. 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
Figure imgf000102_0001
Compound of Example 111 was coupled to the corresponding carboxylic acid using HATU as the coupling reagent to provide this compound. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.43 (d, J = 2.0 Hz, IH), 8.19-8.14 (m, 3H), 7.83 (d, J = 8.4 Hz, IH), 7.59-7.52 (m, 2H), 7.51-7.46 (m, 2H), 6.05 (s, IH), 3.33-3.24 (m, 2H), 2.96-2.73 (m, 2H). LC/MS: C2IHi9ClN6O2Cl (M+ 1) 423. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 124. N-((4-chlorophenyl)(4-hvdroxy-6-(lH-pyrazol-4-yl)quinazolin-2- yl)methyl)pyrrolidine-2-carboxamide
Figure imgf000102_0002
Compound of Example 111 was coupled to the corresponding carboxylic acid using HATU as the coupling reagent to provide this compound. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.37 (d, J = 2.1 Hz, IH), 8.13-8.08 (m, 3H), 7.77 (d, J = 8.5 Hz, IH), 7.52-7.47 (m, IH), 7.46-7.40 (m, 2H), 5.96-5.91 (m, IH), 3.61- 3.52 (m, 2H), 3.48-3.37 (m, 3H), 2.46-2.36 (m, 2H). LC/MS: C23H21ClN6O2Cl (M+ 1) 449. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 125. 4-(aminomethyl)-N-((4-chlorophenyl)(4-hvdroxy-6-(lH-pyrazol- 4-yl)quinazolin-2-yl)methyl)benzamide
Figure imgf000103_0001
Compound of Example 111 was coupled to the corresponding carboxylic acid using HATU as the coupling reagent to provide this compound. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.27 (d, J = 1.8 Hz, IH), 7.99 (s, 3H), 7.92 (d, J = 8.1 Hz, 2H), 7.66 (d, J = 8.4 Hz, IH), 7.46 (dd, J = 17.5, 8.3 Hz, 4H), 7.32 (d, J = 8.3 Hz, 2H), 6.10 (s, IH), 4.10 (s, 2H). LC/MS: C26H2IClN6O2Cl (M+ 1) 485. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 126. 3-(aminomethyl)-N-((4-chlorophenyl)(4-hvdroxy-6-(lH-pyrazol- 4-yl)quinazolin-2-yl)methyl)benzamide
Figure imgf000103_0002
Compound of Example 111 was coupled to the corresponding carboxylic acid using HATU as the coupling reagent to provide this compound. LC/MS: C26H2IClN6O2Cl (M+ 1) 485. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Figure imgf000104_0001
Scheme 7
To a stirred solution of £>-2-fluorophenyl alanine 7-1 (0.50 g, 2.7 mmol) in a mixture of water:dioxane:NaOH (1 M) (1: 1: 1) at room temperature was added a solution of Boc-anhydride (3.0 mmol) in dioxane at room temperature. The mixture was stirred at room temperature for 0.5 h whereupon the solvent was removed in vacuo. The residue was purified by using combiflash® (by employing gradient elution from 2% MeOH in DCM to 20% MeOH in DCM) to afford 7-2 as a colorless oil (0.43 g, 86% yield).
A solution of 7-2 (0.43 g, 2.34 mmol), 2-amino-5-bromobenzamide (0.55 g, 2.57 mmol, 1.1 equiv), HATU (0.98 g, 2.57 mmol, 1.1 equiv) and Et3N (0.66 mL, 5.14 mmol, 2.2 equiv) in DMF (7 mL) was allowed to react for 14 h at room temperature. Upon completion, the reaction mixture was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc (x2) and the combined organic layer was washed with water, dried (Na2SO4) and concentrated under vacuo. 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 K2CO3 (3.6 mL, 5.0 equiv) were added sequentially. The mixture was heated at 100 0C 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.
A 0.1 M solution of 7-4, BOP (3.0 equiv) and triethylamine (2.0 equiv) in DMF was treated with, N-methylamine (3.0 equiv) at room temperature and the reaction mixture stirred for 1.0 h. The reaction was quenched by addition of water. The aqueous layer was extracted with EtOAc (x3) and the combined organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was then purified by preparative HPLC to give the Boc-protected compound. The product was taken up in a mixture of DCM:TFA (1: 1) and stirred for 3 h at room temperature to afford the target compounds.
Example 127. (R)-N 1 -(2-( 1 -amino-2-(3-fluorophenyl)ethyl)-6-( 1 H-pyrazol-4- yl)quinolin-4-yl)-N,N,Nr-trimethylethane-l,2-diamine
Figure imgf000105_0001
Procedures in Scheme 7 were utilized to synthesize this compound. LC/MS: C24H29FN7 (M+ 1) 434. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 128. (Ry3-((2-α-amino-2-β-fluorophenyl)ethyl)-6-αH-pyrazol-4- yl)quinazolin-4-yl)(methyl)amino)propan- 1 -ol
Figure imgf000105_0002
Procedures in Scheme 7 were utilized to synthesize this compound. 1H-NMR (DMSO-dδ, 400 MHz) δ 8.40 (s, IH), 8.29 (d, J = 1.6 Hz, IH), 8.20 (s, IH), 8.09 (dd, J= 1.6, 8.4 Hz, IH), 7.72 (d, J= 8.8 Hz, IH), 7.30 (q, J= 7.2 Hz, IH), 7.15- 7.03 (m, 3H), 6.99 (d, J = 7.6 Hz, IH), 4.57 (s, IH), 3.84 (t, J = 7.6 Hz, 2H), 3.54 (t, J = 6.0 Hz, 2H), 3.41 (s, 3H), 3.31 (ddd, J = 6.8, 13.6, 35.2 Hz), 3.11 (ddd, J = 5.9, 14.2, 24.5 Hz, IH), 1.91 (ddd, J = 0.7, 6.0, 12.8 Hz, 2H); LC/MS: C23H26FN6O (M+ 1) 421. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 129. (R)-2-((2-(l-amino-2-(3-fluorophenyl)ethyl)-6-(lH-pyrazol-4- yl)quinazolin-4-yl)(methyl)amino)ethanol
Figure imgf000106_0001
Procedures in Scheme 7 were utilized to synthesize this compound. LC/MS: C22H23FN6O (M+ 1) 407. Single peak at 254 nm in analytical HPLC traces.
Example 130. (5VNl-(2-α-amino-2-β-fluorophenyl)ethyl)-6-αH-pyrazol-4- yl)quinazolin-4-yl)-N 1 ,N2,N2-trimethylethane- 1 ,2-diamine
Figure imgf000106_0002
Procedures in Scheme 7 were utilized to synthesize this compound. IH NMR (400 MHz, dmso-d6) δ ppm 8.78-8.40 (bs, 2H), 8.33 (s, IH), 8.24 (s, 2H), 8.13(d, J = 9 Hz, IH), 7.75 (d, J =9 Hz, IH), 7.30 (q, J = 7 Hz, 1 H), 7.09-7.02 (m, 2H), 6.99 (d, J = 8 Hz, 1 H), 4.67-4.59 (m, IH), 4.21-4.04 (m, 2H), 3.61 (s, 3H), 3.57-3.45 (m, 2H), 3.32 (ddd, J = 35, 14, 7 Hz, 2H), 2.90 (s, 6H). LC/MS: Ci9Hi8N5O2 (M+ 1) 348. LC/MS: C24H29FN7 (M+ 1) 434. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 131. (51-2-((2-(l-amino-2-(3-fluorophenyl)ethyl)-6-(lH-pyrazol-4- yl)quinazolin-4-yl)(methyl)amino)ethanol
Figure imgf000107_0001
Procedures in Scheme 7 were utilized to synthesize this compound. LC/MS: C22H24FN6O (M+ 1) 407. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 132. (S)-2-(l-amino-2-(3-fluorophenyl)ethyl)-6-(lH-pyrazol-4- yl)quinazolin-4-ol
Figure imgf000107_0002
Procedures in Scheme 7 were utilized to synthesize this compound. LC/MS: Ci9HnFN5O (M+ 1) 350. Single peak at 254 nm in analytical HPLC traces.
Example 133. (5)-2-(l -amino-2-(3-fluorophenyl)ethyl)-N,N-dimethyl-6-( IH- pyrazol-4-yl)quinazolin-4-amine
Figure imgf000107_0003
Procedures in Scheme 7 were utilized to synthesize this compound. LC/MS: C2iH22FN6 (M+ 1) 377. Single peak at 254 and 230 nm in analytical HPLC traces.
Figure imgf000108_0001
Scheme 8
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 NH4OH 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 H2 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 00C. The reaction was stirred for Ih. The solvent was removed under reduced pressure. The residue was suspended in EtOAc and washed with saturated NaHCθ3 and brine. After drying over anhydrous Na2SO4, the solvent was removed and the residue was subjected to flash column chromatograph to give 8-3.
Similar procedures for the transformation from 2-1 to 2-4 in Scheme 2 were applied to prepare compounds 8-4 and 8-6. Standard Suzuki coupling procedures as described in Scheme 2 and Scheme 3 were used to provide 8-5. To synthesize compound 8-7, 50% TFA in DCM was used to transform 8-6 to the corresponding 4- amino quinazoline derivative which was then subjected to Standard Suzuki coupling to give the 6-pyrazole quinazoline products.
Example 134. 8-methoxy-2-(6-methoxychroman-3-yl)-6-(lH-pyrazol-4- yl)quinazolin-4-ol
Figure imgf000109_0001
Procedures in Scheme 8 were utilized to synthesize this compound. LC/MS: C22H20N4O4 (M+ 1) 405. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 135. 2-(6-fluorochroman-3-yl)-8-methoxy-6-(lH-pyrazol-4- yl)quinazolin-4-ol
Figure imgf000109_0002
Procedures in Scheme 8 were utilized to synthesize this compound. LC/MS: C21H17N4O3F (M+ 1) 393. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 136. 8-methoxy-2-(6-methylchroman-3-yl)-6-('lH-pyrazol-4- yl)quinazolin-4-ol
Figure imgf000109_0003
Procedures in Scheme 8 were utilized to synthesize this compound. LC/MS:
C22H20N4O3 (M+ 1) 389. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 137. 2-(6-chlorochroman-3-yl)-8-methoxy-6-(lH-pyrazol-4- yl)quinazolin-4-ol
Figure imgf000110_0001
Procedures in Scheme 8 were utilized to synthesize this compound. LC/MS: C21H17N4O3CI (M+ 1) 409. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 138. 2-((8-methoxy-2-(6-methoxychroman-3-yl)-6-(lH-pyrazol-4- yl)quinazolin-4-yl)(methyl)amino)ethanol
Figure imgf000110_0002
Procedures in Scheme 8 were utilized to synthesize this compound. LC/MS: C25H27N5O4 (M+ 1) 462. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 139. 8-methoxy-2-(3-methoxyphenethyl)-6-(lH-pyrazol-4- yl)quinazolin-4-ol
Figure imgf000110_0003
Procedures in Scheme 8 were utilized to synthesize this compound. LC/MS: C21H20N4O3 (M+ 1) 377. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 140. 2-(23-dihvdrobenzorbiri,41dioxin-2-yl)-8-methoxy-6-(lH- pyrazol-4-yl)quinazolin-4-ol
Figure imgf000111_0001
Procedures in Scheme 8 were utilized to synthesize this compound. LC/MS: C20Hi6N4O4 (M+l) 377. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 141. 8-methoxy-2-(4-methoxybenzyl)-6-(lH-pyrazol-4-yl)quinazolin- 4-ol
Figure imgf000111_0002
Procedures in Scheme 8 were utilized to synthesize this compound. LC/MS: C20Hi8N4O3 (M+l) 363. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 142. 8-methoxy-2-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)quinazolin- 4-ol
Figure imgf000111_0003
Procedures in Scheme 8 were utilized to synthesize this compound. LC/MS: C20HiSN4O3 (M+l) 363. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 143. 8-methoxy-2-(7-methoxy- 1,2,3, 4-tetrahydronaphthalen-2-yl)-6- (lH-pyrazol-4-yl)quinazolin-4-ol
Figure imgf000112_0001
Procedures in Scheme 8 were utilized to synthesize this compound. LC/MS: C23H22N4O3 (M+ 1) 403. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 144. 8-methoxy-2-((3-methoxyphenoxy)methyl)-6-(lH-pyrazol-4- yl)quinazolin-4-ol
Figure imgf000112_0002
Procedures in Scheme 8 were utilized to synthesize this compound. 1H NMR
(400 MHz, MeOH-d4) δ ppm 8.45 (d, J = 1.9 Hz, IH), 8.13 (s, 2H), 8.11-8.08 (m, 2H), 7.72 (d, J = 8.5 Hz, IH), 7.14 (d, J = 7.8 Hz, IH), 7.08-7.05 (m, 2H), 6.92-6.87 (m, IH), 5.07 (s, 2H), 4.03 (s, 3H), 3.76 (s, 3H). LC/MS: C20Hi8N4O4 (M+ 1) 379. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 145. (R)-2-d-amino-2-(3-fluorophenyl)ethyl)-8-methoxy-6-('lH- pyrazol-4-yl)quinazolin-4-ol
Figure imgf000112_0003
Starting from the FMOC protected phenylalanine, procedures in Scheme 8 were utilized to synthesize this compound. FMOC group was deprotected by treatment with morpholine. LC/MS: C20Hi8N5O2F (M+ 1) 380. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
I l l Example 146. (S)-2-(l-amino-2-(3-fluorophenyl)ethyl)-8-methoxy-6-(lH- pyrazol-4-yl)quinazolin-4-ol
Figure imgf000113_0001
Starting from the FMOC protected phenylalanine, procedures in Scheme 8 were utilized to synthesize this compound. FMOC group was deprotected by treatment with morpholine. LC/MS: C20Hi8N5O2F (M+ 1) 380. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 147. 2-(amino(4-chlorophenyl)methyl)-8-methoxy-6-(lH-pyrazol-4- yl)quinazolin-4-ol
Figure imgf000113_0002
Starting from the FMOC protected phenylalanine, procedures in Scheme 8 were utilized to synthesize this compound. FMOC group was deprotected by treatment with morpholine. LC/MS: Ci9Hi6N5O2Cl (M+ 1) 382. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 148. 2-(amino(3-chlorophenyl)methyl)-8-methoxy-6-(lH-pyrazol-4- yl)quinazolin-4-ol
Figure imgf000113_0003
Starting from the FMOC protected phenylalanine, procedures in Scheme 8 were utilized to synthesize this compound. FMOC group was deprotected by treatment with morpholine. LC/MS: Ci9Hi6N5O2Cl (M+ 1) 382. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 149. N-(3-((4-hvdroxy-8-methoxy-6-(lH-pyrazol-4-yl)quinazolin-2- vDmethvDphenvDisobutyramide
Figure imgf000114_0001
Procedures in Scheme 8 were utilized to synthesize this compound. 1H NMR (400 MHz, CD3CN-d3) δ ppm 8.38 (s, IH), 8.23 (s, IH), 8.00-7.89 (m, 2H), 7.75 (s, IH), 7.64 (d, J= 1.4 Hz, IH), 7.37-7.25 (m, 2H), 7.06-7.00 (m, IH), 4.09 (s, 3H), 3.31 (s, IH), 3.23-3.11 (m, 4H), 3.04 (s, 2H), 2.60-2.50 (m, IH), 1.19 (s, 3H), 1.14 (s, 3H) LC/MS: C23H23N5O3 (M+ 1) 418. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 150. N-(3-((4-hvdroxy-8-methoxy-6-(lH-pyrazol-4-yl)quinazolin-2- vDmethvDphenvDbutyramide
Figure imgf000114_0002
Procedures in Scheme 8 were utilized to synthesize this compound. LC/MS: C23H23N5O3 (M+ 1) 418. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 151. N-(3-(2-(4-hvdroxy-8-methoxy-6-(lH-pyrazol-4-yl)quinazolin-2- vDethvDphenvDisobutyramide
Figure imgf000114_0003
Procedures in Scheme 8 were utilized to synthesize this compound. 1H NMR (400 MHz, CD3CN-d3) δ ppm 8.28 (s, IH), 8.13 (s, IH), 8.01-7.89 (m, 2H), 7.75 (s, IH), 7.64 (d, J= 1.34 Hz, IH), 7.37-7.25 (m, 2H), 7.06-7.00 (m, IH), 4.09 (s, 3H), 3.31 (s, IH), 3.23-3.11 (m, 4H), 2.94 (s, 2H), 2.82 (s, 2H), 2.60- 2.50 (m, IH), 1.18 (s, 3H), 1.14 (s, 3H) LC/MS: C24H25N5O3 (M+ 1) 432. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 152. N-(3-(2-(4-hvdroxy-8-methoxy-6-(lH-pyrazol-4-yl)quinazolin-2- vDethyDphenvDbutyramide
Figure imgf000115_0001
Procedures in Scheme 8 were utilized to synthesize this compound. LC/MS: C24H25N5O3 (M+ 1) 432. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 153. 2-(6-(2-(dimethylamino)ethoxy)chroman-3-yl)-8-methoxy-6-('lH- pyrazol-4-yl)quinazolin-4(3H)-one
Figure imgf000115_0002
Procedures in Scheme 8 were utilized to synthesize this compound. LC/MS: C25H27N5O4 (M+ 1) 462. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 154. 2-(5-(2-(dimethylamino)ethoxy)chroman-3-yl)-8-methoxy-6-(lH- pyrazol-4-yl)quinazolin-4(3H)-one
Figure imgf000115_0003
Procedures in Scheme 8 were utilized to synthesize this compound. LC/MS: C25H27N5O4 (M+ 1) 462. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 155. 2-(6-(cvclopropanecarbonyl)chroman-3-yl)-8-methoxy-6-(lH- pyrazol-4-yl)quinazolin-4(3H)-one
Figure imgf000116_0001
Procedures in Scheme 9 were utilized to synthesize this compound. LC/MS: C25H22N4O4 (M+ 1) 443.
Figure imgf000116_0002
Scheme 9
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 Et3N (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. The organic portion was dried over MgSO4, concentrated and chromatographed on SiO2 (DCM/MeOH + 0.1 % NH4OH) to give the Weinreb amide 9-2. This amide (1 equiv) was then dissolved in dry THF and stirred at room temperature under argon. To this solution was added cyclopropylmagnesium bromide (6 equiv). The solution was then stirred at room temperature for 6 hours, then at O 0C for 16 hours. The solution was then purified via preparatory HPLC (MeCN/water) to give the ketone 9-3. 1H-NMR (MeOD-d4, 400 MHz) δ 8.38 (d, J = 2.1 Hz, IH), 8.10 (s, 2H), 8.06 (dd, J = 2.2 Hz, 8.5 Hz, IH), 7.95 (s, IH), 7.88 (dd, J = 2.1 Hz, 8.8 Hz, IH), 7.69 (d, J = 8.5 Hz, IH), 6.95 (d, J = 8.6 Hz, IH), 4.68 (m, IH), 4.34 (m, IH), 3.41 (m, IH), 3.22 (m, 2H), 2.81 (m, IH), 1.11 (m, 2H), 1.06 (m, 2H). LC/MS: C24H20N4O3 (M+ 1) 413. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
DMF
Figure imgf000117_0001
Figure imgf000117_0002
Figure imgf000117_0003
Scheme 10
A stirred solution of the methyl ester of 4-methoxy-?rα«s-cinnamic acid 10-1 (0.53 g, 2.0 mmol) and N-benzyl-1-methoxy-N-
((trimethylsilyl)methyl)methanamine (0.58 g, 1.0 mmol) in DCM (5 mL) was treated with a solution of TFA (15.4 μL , 10 mol%) in DCM (0.2 mL) at room temperature under Argon. The mixture was stirred at room temperature for 14 h whereupon the solvent was removed in vacuo. The residue was diluted with EtOAc and washed with water, NaHCO3 and brine, dried over Na2SO4 and concentrated to afford a yellow oil. The crude product was subsequently dissolved in EtOH (4 mL) and treated with 4 M NaOH (4 mL) and the reaction mixture was stirred at room temperature for 3 h. Upon completion, the reaction mixture was concentrated to remove EtOH and the residue diluted with water and extracted with EtOAc (x5). The combined organics dried (Na2SO4) and concentrated under vacuo to afford acid 10-2 (38% yield, two steps, single trans diastereomer in racemic form).
A solution of 2-amino-5-bromobenzamide (0.050 g, 0.23 mmol), acid 10- 2 (1.0 equiv), HATU (0.057 g, 0.305 mmol, 1.3 equiv.) and Et3N (0.09 mL, 0.703 mmol, 3.0 equiv) in DMF (2 mL) was allowed to react at room temperature for 14 h. Upon completion, the reaction mixture was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc (x2) and the combined organic layer was dried (Na2SO4) and concentrated under vacuo. The crude product was forwarded to the next step without further purification. The bromide 10-3 (0.4686 mmol) and the boronic acid ester (0.100 g, 1.2 equiv) were dissolved in degassed EtOH/toluene (3.0 mL, 3:2 by volume) in a sealed tube. Tetrakis(triphenylphosphine)palladium (0) (48.8 mg, 9 mol%) and 2 M solution of K2CO3 (1.2 mL, 5 equiv) were added sequentially. The mixture was heated at 125 0C for 1 h in a microwave reactor. 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 in vacuo and the residue was then purified by preparative HPLC to give the product 10-4 (85% yield).
Example 156. (±)-2-((3S,4R)-l-benzyl-4-(4-methoxyphenyl)pyrrolidin-3-yl)-6- (lH-pyrazol-4-yl)quinazolin-4-ol
Figure imgf000118_0001
Procedures in Scheme 10 were utilized to synthesize this compound. LC/MS: C29H28N5O2 (M+ 1) 478. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 157. (±)-2-((3R,4S)-l-benzyl-4-(3-methoxyphenyl)pyrrolidin-3-yl)-6- ( 1 H-pyrazol-4-yl)quinazolin-4-ol
Figure imgf000118_0002
Procedures in Scheme 10 were utilized to synthesize this compound. LC/MS: C29H28N5O2 (M+ 1) 478. Single peak at 254 and 230 nm in analytical HPLC traces.
Figure imgf000119_0001
Microwave 14O0C 11-3
Scheme 11
2-Amino-4-bromobenzonitrile was dissolved in 4: 1 AcOHZH2SO4 to form a suspension. The mixture was stirred for 4 h until it became clear and all starting material was consumed as monitored by LC-MS. The solution was poured into ice water and extracted by EtOAc three times. The combined organic layer was washed with brine and dried over Na2SO4. After filtration, the solvent was removed to provide 11-1. Substituted benzyloxy acetic acid (1.1 equiv) was treated with 2 M oxalyl chloride in DCM for 3 h and concentrated to give the corresponding acid chloride, which was then added to a stirred solution of 11-1 and pyridine (5 equiv) in DCM. The reaction mixture was stirred for 3 h until 11-1 was consumed as monitored by LC-MS. The precipitate was collected by filtration and was dried under vacuum to provide 11-2 as white solid. 11-2, potassium carbonate (4 equiv), boronic ester (1.5 equiv) and Pd(PPh3 )4( 10%) were dissolved in 4: 1 dioxane/water and sealed in a microwave tube. The reaction mixture was degassed and heated by microwave for 30min at 140 0C. The solvent was removed and the residue was subjected to preparative HPLC to provide product 11-3 as a TFA salt. Example 158. 2-((3-methoxyphenoxy)methyl)-7-(lH-pyrazol-4-yl)quinazolin-4- ol
Figure imgf000120_0001
Procedures in Scheme 11 were utilized to synthesize this compound. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.30 (s, 2H), 8.07 (d, J = 8.3 Hz, IH), 7.92 (d, J = 1.5 Hz, IH), 7.80 (dd, J = 8.3, 1.70 Hz, IH), 7.24-7.19 (m, IH), 6.65-6.62 (m, 2H), 6.59-6.55 (m, IH), 4.99 (s, 2H), 3.73 (s, 3H). LC/MS: Ci9Hi6N4O3 (M+ 1) 349. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 159. 2-((3-methoxyphenoxy)methyl)-7-(5-methyl-lH-pyrazol-4- yl)quinazolin-4-ol
Figure imgf000120_0002
Procedures in Scheme 11 were utilized to synthesize this compound. H-NMR (400 MHz, DMSO-d6) δ ppm 8.09 (d, J = 8.3 Hz, IH), 8.01 (s, IH), 7.71-7.64 (m, IH), 7.21 (t, J = 8.1 Hz, IH), 6.67-6.54 (m, IH), 4.98 (s, 2H), 3.73 (s, 3H), 2.45 (s, 3H). LC/MS: C20Hi8N4O3 (M+ 1) 363. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 160. 2-((3-methoxyphenoxy)methyl)-7-(pyridin-4-yl)quinazolin-4-ol
Figure imgf000120_0003
Procedures in Scheme 11 were utilized to synthesize this compound. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.84-8.80 (m, 2H), 8.27 (d, J = 8.3 Hz, IH), 8.18- 8.17 (m, IH), 8.12-8.08 (m, 2H), 8.01 (dd, J = 8.3, 1.69 Hz, 2H), 7.22 (t, J = 8.5 Hz, IH), 6.67-6.63 (m, 2H), 6.60-6.56 (m, IH), 5.04 (s, 2H), 3.74 (s, 3H). LC/MS: C21H17N3O3 (M+ 1) 360. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 161. 2-(6-methoxychroman-3-yl)-7-(lH-pyrazol-4-yl)quinazolin-4-ol
Figure imgf000121_0001
Procedures in Scheme 11 were utilized to synthesize this compound. 1H-NMR (400 MHz, DMSO-d6) δ ppm 12.29 (s, IH), 8.28 (s, 2H), 8.03 (d, J = 8.24 Hz, IH), 7.83 (d, J = 1.42 Hz, IH), 7.75 (dd, J = 8.27, 1.70 Hz, IH), 6.75-6.66 (m, 3H), 4.52-4.47 (m, IH), 4.03-3.97 (m, IH), 3.68 (s, 3H), 3.25-3.15 (m, 2H), 3.09-3.01 (m, IH). LC/MS: C2IHi8N4O3 (M+ 1) 375. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 162. 2-(6-methoxychroman-3-yl)-7-(5-methyl-lH-pyrazol-4- yl)quinazolin-4-ol
Figure imgf000121_0002
Procedures in Scheme 11 were utilized to synthesize this compound. 1H-NMR (400 MHz,DMSO-d6) δ ppm 12.36 (s, IH), 8.09 (dd, J = 7.6, 1.3 Hz, IH), 8.03 (s, IH), 7.64 (dd, J = 7.8, 1.50 Hz, 2H), 6.74 (m, 3H), 4.55-4.47 (m, IH), 4.07- 3.96 (m, IH), 3.69 (s, 3H), 3.26-21 (m, 2H), 3.11-2.99 (m, IH), 2.45 (s, 3H). LC/MS: C22H20N4O3 (M+ 1) 389. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 163. 2-(6-methoxychroman-3-yl)-7-(pyridin-4-yl)quinazolin-4-ol
Figure imgf000121_0003
Procedures in Scheme 11 were utilized to synthesize this compound. 1H-NMR (400 MHz, DMSO-d6) δ ppm 12.54 (s, IH), 8.79 (d, J = 5.4 Hz, 2H), 8.26 (d, J = 8.3 Hz, IH), 8.09-8.04 (m, 2H), 7.99-7.95 (m, IH), 6.79-6.69 (m, 2H), 4.56- 4.51 (m, IH), 4.09-4.01 (m, IH), 3.69 (m, 3H), 3.32-3.19 (m, 2H), 3.14-3.05 (m, IH). LC/MS: C23Hi9N3O3 (M+ 1) 386. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Figure imgf000122_0001
Scheme 12
To a stirred suspension of nitrobenzene 12-1 (0.272 g, 1.14 mmol) and Cs2CO3 (0.44 g, 1.3 mmol, 1.2 equiv.) in 8 mL of anhydrous DMF at room temperature was added 148 μL of the amine at room temperature. The mixture was heated at 40 0C for 2 h whereupon the toluene was added and the solvent was removed in vacuo. The residue was taken up in CH3CN (2.5 mL) and tetraethylammonium cyanide (TEACN) (0.20 g, 1.3 mmol, 1.1 equiv.) was added and the reaction was heated at 55 0C for 2 h and stirred at room temperature for 14 h. The reaction was monitored by LC-MS and another 0.07 g of TEACN was added and heated the reaction at 55 0C for additional 2 h whereupon the reaction was concentrated under reduced pressure and the residue forwarded to the next reduction step without further purification.
Compound 12-2 (1.14 mmol) was dissolved in 36 mL of EtOH/water (4: 1 by volume) in a reaction flask and 1.4 mL of 1 M aqueous NH4Cl solution was added followed by the addition of iron powder (1.0 g). The reaction was refluxed for 4 h and after cooling to room temperature, the reaction mixture filtered through a pad of Celite. The filtrate was concentrated and treated with 6- methoxychroman-3-carbonyl chloride (1.24 mmol) in DMF (5 mL) at 40 0C for 24 h. Upon completion, the reaction mixture was diluted with EtOAc and washed sequentially with water and brine, dried (Na2SO4) and concentrated under reduced pressure. The product was purified by flash chromatograph using Combiflash® and employing a gradient of 0-20% MeOH in DCM to afford 0.12 g (0.24 mmol) of 12-4 in 21% yield over 4 steps.
The bromide 12-4 (0.32 mmol) and the boronic acid ester (0.31 g, 1.2 equiv) were dissolved in degassed 0.63 mL of EtOH/toluene (3:2 by volume) in a sealed tube. Tetrakis(triphenylphosphine)palladium (0) (0.13 g, 10 mol%) and 2 M solution of K2CO3 (0.4mL, 3.0 equiv.) were added sequentially. The mixture was heated at 140 0C for 2.0 h in a microwave reactor. After cooling to room temperature, the reaction was quenched with 10% TFA in water until to evolution of gas was complete. The reaction mixture was concentrated and the residue was purified by preparative HPLC to give the target compound 12-5 (4.4 mg, 7% yield).
Example 164. 8-((2-(dimethylamino)ethyl)(methyl)amino)-2-(6- methoxychroman-3-yl)-6-(3-methyl-lH-pyrazol-4-yl)quinazolin-4-ol
Figure imgf000123_0001
Procedures in Scheme 12 were utilized to synthesize this compound. LC/MS: C27H33N6O3 (M+ 1) 489. Single peak at 254 nm in analytical HPLC traces.
Example 165. 8-((2-(dimethylamino)ethyl)(methyl)amino)-2-(6- methoxychroman-3-yl)-6-(lH-pyrazol-4-yl)quinazolin-4-ol
Figure imgf000123_0002
Procedures in Scheme 12 were utilized to synthesize this compound. LC/MS: C2OH30N6O3 (M+ 1) 475. Single peak at 254 nm in analytical HPLC traces.
Example 166. (±)-2-(chroman-3-yl)-8-((2- (dimethylamino)ethyl)(methyl)amino)-6-(pyridin-4-yl)quinazolin-4-ol
Figure imgf000124_0001
Procedures in Scheme 12 were utilized to synthesize this compound. LC/MS: C27H30N5O2 (M+ 1) 456. Single peak at 254 and 230 nm in analytical HPLC traces.
Figure imgf000124_0002
Figure imgf000124_0003
Suzuki
Figure imgf000124_0004
Scheme 13A
Figure imgf000124_0005
Scheme 13B General procedures for Scheme 13A: A stirred suspension of the quinazoline 13-1 (prepared using procedures described in Scheme 8) in DCM was added 1 M solution of BBr3 (4 equiv) in DCM at -78°C under argon atmosphere. The reaction mixture was stirred for 1 h, gradually warmed to room temperature and continued the stirring until LC-MS suggested the consumption of all starting material. The reaction was quenched by the slow addition of EtOH at 0 0C. Saturated NaHCCh and EtOAc were added and layers were separated. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to provide the crude 13-2 which was then purified by flash chromatography. A halide (1.1 equiv) and
NaHCO3 (1.5 equiv) were added to a solution of 13-2 in dry DMF. The reaction mixture was heated at 60 0C for 6 h. Upon completion of the reaction as monitored by LC-MS, the solvent was evaporated and the residue was suspended in EtOAc. This suspension was washed with saturated NaHCθ3 (2x) and brine (2x), dried over anhydrous Na2SO4, and evaporated to provide crude 13-3. After flash chromatography, 13-3 was subjected to the standard Suzuki coupling conditions as described in Scheme 2 to provide crude 13-4 which was then subjected to preparative reverse phase HPLC to give pure product 13-4 as a TFA salt. General procedures for Scheme 13B: HATU (1.1 equiv) was added to a solution of 13-5 (1.0 equiv), ammonium (4 M in methanol, excess), and DIEA (1.5 equiv) in DMF. After gentle stirring of the solution for 4 h, the solvents were removed under reduced pressure, and the residue was suspended in ethyl acetate. The suspension was washed using saturated NaHCθ3 (3x) and brine (3x), dried over Na2SO4, and evaporated to give 13-6 which was used directly in the next step without further purification. Thus, 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. After the quinazoline ring formation was complete (monitored by LC-MS, normally 2-4 days), 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. Thus, R1YH (1.2 equiv, Y = NR, O, and S) was added to a solution of 13-7 (1.0 equiv) and K2CO3 (Y = NR, S) or KO1Bu (Y = O) (2 quiv) in DMF under argon. The resulting suspension was heated at 80-110 0C until the reaction was finished as monitored by LC-MS. The solvents were removed under reduced pressure, the residue was suspended in ethyl acetate, washed using saturated NaHCCh (3x) and brine (3x), dried over Na2SO4, and evaporated to give a residue which was then subjected to flash chromatography to produce 13-8. Finally, a standard Suzuki procedure as described in Scheme 2 was applied to prepare the pyrazole derivative which was then subjected to preparative reverse-phase HPLC to give 13-9 as a TFA salt.
Figure imgf000126_0001
To a stirring suspension of 8-3 in DCM was added IM solution of BBr3 (4eq) in DCM at -78°C under argon. The reaction mixture was stirred for Ih, then gradually warmed to room temperature and continued the stirring until LC- MS suggested the consumption of all starting material. The reaction was quenched by the slow addition of EtOH at O 0C. Saturated NaHCO3 and EtOAc were added and layers were separated. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to provide the crude 14-1 which was then purified by flash chromatography. 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 CH2CI2) 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 MgSO4 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. To prepare compound 14-6, BOP (1.3 equiv) was added to a suspension of 14-4, DBU (1.5 equiv) and 2,4-dimethoxybenzylamine (2 equiv) in acetonitrile. The reaction mixture was stirred for 2 h until LC-MS suggested the consumption of all starting material. The reaction mixture was diluted with EtOAc and the solution was washed with IM NaOH, brine, saturated NaHCθ3 solution, and brine consequently and dried over anhydrous Na2SO4. The solvents were removed under reduced pressure to provide crude 14-5 which was then purified by flash chromatography. Finally, 14-5 was subjected to standard Suzuki procedures as described in Scheme 2 to provide crude 14-6, which was then purified by reverse phase preparative HPLC.
Example 167. 8-(2-(dimethylamino)ethoxy)-2-(6-methoxychroman-3-yl)-6-(lH- pyrazol-4-yl)quinazolin-4-ol
Figure imgf000127_0001
Procedures in Scheme 13 or 14 were utilized to synthesize this compound. LC/MS: C25H27N5O4 (M+ 1) 462. Single peak at 254 nm in analytical HPLC traces. Example 168. 8-((2-(dimethylamino)ethyl)(methyl)amino)-2-(6- methoxychroman-3-yl)-6-(lH-pyrazol-4-yl)quinazolin-4-ol
Figure imgf000128_0001
Procedures in Scheme 13 or 14 were utilized to synthesize this compound. LC/MS: C26H29N6O3 (M+l) 476. Single peak at 254 nm in analytical HPLC traces.
Example 169. 2-(2,3-dihvdrobenzorbiri,41dioxin-2-yl)-8-(3- (dimethylamino)propoxy)-6-(lH-pyrazol-4-yl)quinazolin-4-amine
Figure imgf000128_0002
Procedures in Scheme 13 or 14 were utilized to synthesize this compound. LC/MS: C24H26N6O3 (M+l) 447. Single peak at 254 nm in analytical HPLC traces.
Example 170. 8-(2-(dimethylamino)ethoxy)-2-(6-methoxychroman-3-yl)-6-(lH- pyrazol-4-yl)quinazolin-4-amine
Figure imgf000128_0003
Procedures in Scheme 13 or 14 were utilized to synthesize this compound. LC/MS: C25H28N6O3 (M+l) 461. Single peak at 254 nm in analytical HPLC traces. Example 171. 8-(2-(dimethylamino)ethoxy)-2-(6-methoxychroman-3-yl)-6-(lH- pyrazol-4-yl)quinazolin-4('3H)-one
Figure imgf000129_0001
Procedures in Scheme 13 were utilized to synthesize this compound. LC/MS: C25H27N5O4 (M+ 1) 462. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Figure imgf000129_0002
Scheme 15
To a solution of compound 15-1 (1 equiv), DIEA (4 equiv) in DCM was added a solution of RCOCl (1.02 equiv) in DCM at room temperature. The stirring was continued until LC-MS showed the reaction was complete. The solvent was removed under reduced pressure, and the residue was suspended in ethyl acetate. After standard aqueous washing and removal of the organic solvent, the residue was subjected to flash chromatography to give compound 15-2. A few drops of dry DMF was added to solution of 15-2 (1 equiv) and oxalyl chloride (5 equiv) in dry DCM. After stirring the solution at room temperature overnight, the solvents were removed under reduced pressure. The residue was suspended in ethyl acetate, washed by saturated NaHCθ3 and brine, dried over anhydrous sodium sulfate, and evaporated to give compound 15-3. An aromatic amine (1.05 equiv) was added to a solution of 15-3 (1.0 equiv) in dioxane and the resulting suspension was heated at 90 0C for 6h under argon at which the reaction was complete as monitored by LC-MS. Removal of solvents by evaporation in vacuo provided crude 15-4 which was then subjected to preparative reverse phase HPLC to give the final compound 15-4 as a TFA salt.
Example 172. N-(lH-indazol-5-yl)-2-(6-methoxychroman-3-yl)quinazolin-4- amine
Figure imgf000130_0001
Procedures in Scheme 15 were utilized to synthesize this compound. LC/MS: C25H21N5O2 (M+ 1) 424. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 173. 2-(6-Methoxychroman-3-yl)-N-(pyridin-4-yl)quinazolin-4-amine
Figure imgf000130_0002
Procedures in Scheme 15 were utilized to synthesize this compound. LC/MS: C23H20N4O2 (M+ 1) 425. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 174. 2-(6-Methoxychroman-3-yl)-N-(pyridin-3-yl)quinazolin-4-amine
Figure imgf000130_0003
Procedures in Scheme 15 were utilized to synthesize this compound. LC/MS: C23H20N4O2 (M+ 1) 425. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 175. N-(isoquinolin-6-yl)-2-(6-methoxychroman-3-yl)quinazolin-4- amine
Figure imgf000131_0001
Procedures in Scheme 15 were utilized to synthesize this compound. LC/MS: C27H22N4O2 (M+ 1) 435. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 176. N-(lH-indazol-6-yl)-2-(6-methoxychroman-3-yl)quinazolin-4- amine
Figure imgf000131_0002
Procedures in Scheme 15 were utilized to synthesize this compound. LC/MS: C25H21N5O2 (M+ 1) 424. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 177. N-(Isoquinolin-5-yl)-2-(6-methoxychroman-3-yl)quinazolin-4- amine
Figure imgf000131_0003
Procedures in Scheme 15 were utilized to synthesize this compound. LC/MS: C27H22N4O2 (M+ 1) 435. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Figure imgf000132_0001
Scheme 16
The bromoaniline, acid (1. leq) and HOAt (0.5eq) were dissolved in dry
DCM and EDC (1.2eq) was added. The reaction mixture was stirred overnight to 5 days until LC-MS suggested the complete consumption of starting aniline and formation of product. The reaction mixture was diluted with EtOAc and the resulting organic layer was washed with IM HCl, brine, sated. NaHCθ3, and brine consequently. It was concentrated to provide crude product for next step. The crude amide was dissolved in 4: 1 1,4-dioxane/water and pyrazole-4-boronic acid pinacol ester (1.4eq), sodium bicarbonate (4eq) and tetrakis(triphenylphosphene) palladium (O) (10%) was added. The 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 178 (R)-2-(6-methoxychroman-3-yl)-6-(lH-pyrazol-4-yl)quinazolin- 4(3H)-one
Figure imgf000132_0002
Procedures in Scheme 16 were utilized to synthesize this compound. LC/MS: C2IHi8N4O3 (M+ 1) 375. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 179. (S)-2-(6-methoxychroman-3-yl)-6-(lH-pyrazol-4-yl)quinazolin- 4(3H)-one
Figure imgf000133_0001
Procedures in Scheme 16 were utilized to synthesize this compound. LC/MS: C2IHi8N4O3 (M+ 1) 375. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 180. (S)-2-(6-fluorochroman-3-yl)-6-(lH-pyrazol-4-yl)quinazolin- 4(3H)-one
Figure imgf000133_0002
Procedures in Scheme 16 were utilized to synthesize this compound. LC/MS: C20H15N4O2F (M+l) 363. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 181. (R)-2-(2.3-dihvdrobenzorbiri.41dioxin-2-yl)-6-(lH-pyrazol-4- yl)quinazolin-4(3H)-one
Figure imgf000133_0003
Procedures in Scheme 16 were utilized to synthesize this compound. LC/MS: Ci9Hi4N4O3 (M+l) 345. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 182. (S)-2-(2 ,3 -dihydrobenzo [bl T 1 ,41 dioxin-2-yl)-6-(' 1 H-pyrazol-4- yl)quinazolin-4(3H)-one
Figure imgf000134_0001
Procedures in Scheme 16 were utilized to synthesize this compound. LC/MS: C19H14N4O3 (M+ 1) 345. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
(aq), 3/2
Figure imgf000134_0002
Figure imgf000134_0003
Scheme 17 In a typical example, acid (0.26 mmol) was dissolved in 1.0 mL of anhydrous DMF and the reaction mixture was treated with HATU (1.2 equiv., 0.32 mmol), aniline 17-1 (1.2 equiv., 0.32 mmol) and triethyl amine (TEA) (5.0 equiv., 1.30 mmol). The reaction mixture was stirred overnight at room temperature and was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc (x3) and the combined organics were dried and concentrated under vacuo. The crude product was forwarded to the next step without further purification.
In a typical example, a solution of 17-2 (0.26 mmol) and boronic acid ester (1.5 equiv.) in 1.70 mL of EtOH/toluene (3:2 by volume) was treated with 2 M solution of K2CO3 (3.0 equiv.). Tetrakis (10 mol%) was added, the tube sealed and the solution degassed by a flow of argon. The mixture was heated at 145 0C for 1.0 h in a microwave reactor. After cooling to room temperature, the reaction was quenched with 10% TFA in water until evolution of gas was complete. The reaction mixture was concentrated and the residue purified by preparative HPLC. The boc-protected product was then treated with 1 mL of (CH2C^iTFA 1/1) and the mixture stirred at room temperature for 1-2 h. Concentration of the solution afforded the target compounds.
Example 183. (±)-2-((3R,4S)-4-(4-fluorophenyl)pyrrolidin-3-yl)-6-(lH-pyrazol- 4-yl)quinazolin-4-ol
Figure imgf000135_0001
Procedures in Scheme 17 were utilized to synthesize this compound. LC/MS: C21H19FN5O (M+ 1) 376. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 184. (±)-2-((3R,4S)-4-(4-chlorophenyl)pyrrolidin-3-yl)-6-(lH-pyrazol- 4-yl)quinazolin-4-ol
Figure imgf000135_0002
Procedures in Scheme 17 were utilized to synthesize this compound. LC/MS: C21H19CIN5O (M+ 1) 392. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 185. (±)-6-(lH-pyrazol-4-yl)-2-((3R,4S)-4-(4-
(trifluoromethyl)phenyl)pyrrolidin-3-yl)quinazolin-4-ol
Figure imgf000135_0003
Procedures in Scheme 17 were utilized to synthesize this compound. LC/MS: C22Hi9FSN5O (M+ 1) 426. Single peak at 230 and 254 nm in analytical HPLC traces.
Example 186. (±)-2-((3R,4S)-4-phenylpyrrolidin-3-yl)-6-(lH-pyrazol-4- yl)quinazolin-4-ol
Figure imgf000136_0001
Procedures in Scheme 17 were utilized to synthesize this compound. IH NMR (400 MHz, dmso-d6) δ ppm 12.35 (s, IH), 9.35-9.18 (bs, IH), 8.34-8.13 (m,
3H), 8.08 (dd, J = 9, 6 Hz, IH), 7.65 (d, J = 8 Hz, IH), 7.42-7.32 (m, 3 H), 7.32- 7.25 (m, IH), 7.18-7.08 (m, IH), 3.99 (dd, J= 10, 8 Hz, IH), 3.90-3.78 (m, 2H), 3.66-3.54 (m, 2H). LC/MS: C23Hi9N3O3 (M+ 1) 386. LC/MS: Ci9Hi8N5O2 (M+ 1) 348. LC/MS: Ci9H20N5O (M+ 1) 358. Single peak at 254 and 230 nm in analytical HPLC traces.
Example 187. (±)-6-(3-methyl-lH-pyrazol-4-yl)-2-('(3R,4S)-4-phenylpyrrolidin- 3-yl)quinazolin-4-ol
Figure imgf000136_0002
Procedures in Scheme 17 were utilized to synthesize this compound. LC/MS: C22H22N5O (M+ 1) 372. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 188. (±)-2-((3R,4S)-4-phenylpyrrolidin-3-yl)-6-(pyridin-4- yl)quinazolin-4-ol
Figure imgf000137_0001
Procedures in Scheme 17 were utilized to synthesize this compound. IH NMR (400 MHz, dmso-d6) δ ppm 12.42-12.70 (bs, IH), 9.45-9.22 (bs, IH), 8.78 (d, J
= 5 Hz, 2H), 8.91 (d, J = 2 Hz, IH), 8.32 (dd, J = 9, 2 Hz, IH), 8.03 (d, J = 6
Hz, 2H), 7.82 (d, J = 8 Hz, IH), 7.40-7.32 (m, 3 H), 7.29 (tt, J = 6, 2 Hz, IH),
7.20-7.10 (m, IH), 4.12-3.85 (m, 3H), 3.51-3.39 (m, 2H). LC/MS: C23Hi9N3O3
(M+ 1) 386. LC/MS: Ci9Hi8N5O2 (M+ 1) 348. LC/MS: C23H2iN4O (M+l) 369. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 189. 2-(l-aminocyclopropyl)-6-(2-aminopyrimidin-5-yl)quinazolin-4- ol
Figure imgf000137_0002
Procedures in Scheme 17 were utilized to synthesize this compound. IH NMR (400 MHz, dmso-d6) δ ppm 8.10-8.60 (bs, 2H), 8.71 (s, 2H), 8.30 (d, J = 2 Hz, IH), 8.15 (dd, J = 9, 2 Hz, IH), 7.73 (d, J = 8 Hz, IH), 7.08-6.80 (bs, 2 H), 1.76 (t, J = 6 Hz, 2H), 1.47 (t, J = 7 Hz, 2H). LC/MS: C23Hi9N3O3 (M+l) 386. LC/MS: Ci9Hi8N5O2 (M+l) 348. LC/MS: Ci5Hi5N6O (M+l) 295. Single peak at 254 and 230 nm in analytical HPLC traces.
Example 190. (±)-6-(2-aminopyrimidin-5-yl)-2-((3S,4R)-4-phenylpyrrolidin-3- yl)quinazolin-4-ol
Figure imgf000137_0003
Procedures in Scheme 17 were utilized to synthesize this compound. LC/MS: C22H20N6O (M+l) 385. Single peak at 254 nm in analytical HPLC traces. on
Figure imgf000138_0001
Scheme 18
Example 191. (±)-6-(2-aminopyrimidin-4^)-2-((3S^Ry4-phenylpyrrolidin-3- yl)quinazolin-4-ol
Figure imgf000138_0002
Procedures in Scheme 18 were utilized to synthesize this compound. LC/MS: C22H21N6O (M+ 1) 385. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 192. (±)-2-(('3S,4R)-4-phenylpyrrolidin-3-yl)-6-('lH-pyrrolor2,3- blpyridin-4-yl)quinazolin-4-ol
Procedures in Scheme 18 were utilized to synthesize this compound. LC/MS: C25H22N5O (M+ 1) 408. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Figure imgf000139_0001
Scheme 19
Example 193. (±)-2-((3S.4R)-4-(4-methoxyphenvnpyrrolidin-3-yl)-6-(lH- pyrazol-4-yl)quinazolin-4-ol
Figure imgf000139_0002
Procedures in Scheme 19 were utilized to synthesize this compound. Benzyl protected starting material was accessed via routes shown in Scheme 10. LC/MS: C22H22N5O2 (M+l) 388. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 194. (±)-2-((3S.4R)-4-(3-methoxyphenvnpyrrolidin-3-yl)-6-(lH- pyrazol-4-yl)quinazolin-4-ol
Figure imgf000139_0003
Procedures in Scheme 19 were utilized to synthesize this compound. Benzyl protected starting material was accessed via routes shown in Scheme 10. LC/MS: C22H22N5O2 (M+l) 388. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 195. (±^^-CCSSΛ^^-β-fluorophenvDpyrrolidin-S-vD-ό-dH-pyrazol- 4-yl)quinazolin-4-ol
Figure imgf000140_0001
Procedures in Scheme 19 were utilized to synthesize this compound. Benzyl protected starting material was accessed via routes shown in Scheme 10. LC/MS: C21H19FN5O (M+ 1) 376. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 196. (±)-2-rr3S.4R)-4-r2-fluorophenyl)pyrrolidin-3-yl)-6-riH-pyrazol- 4-yl)quinazolin-4-ol
Figure imgf000140_0002
Procedures in Scheme 19 were utilized to synthesize this compound. Benzyl protected starting material was accessed via routes shown in Scheme 10. LC/MS: C21H19FN5O (M+ 1) 376. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 197. (±)-2-((3S,4R)-4-(2-chlorophenyl)pyrrolidin-3-yl)-6-(lH-pyrazol- 4-yl)quinazolin-4-ol
Figure imgf000140_0003
Procedures in Scheme 19 were utilized to synthesize this compound. Benzyl protected starting material was accessed via routes shown in Scheme 10. LC/MS: C21H19CIN5O (M+l) 392. Single peak at 254 nm in analytical HPLC traces. Example 198. (±)-2-((3S,4R)-4-(2-methoxyphenyl)pyrrolidin-3-yl)-6-(lH- pyrazol-4-yl)quinazolin-4-ol
Figure imgf000141_0001
Procedures in Scheme 19 were utilized to synthesize this compound. Benzyl protected starting material was accessed via routes shown in Scheme 10. LC/MS: C22H22N5O2 (M+ 1) 388. Single peak at 254 and 230 nm in analytical HPLC traces.
Figure imgf000141_0002
Scheme 20
Example 199. (±)-(3S,4R)-N-cyclopropyl-3-(4-hydroxy-6-(lH-pyrazol-4- yl)quinazolin-2-yl)-4-phenylpyrrolidine- 1 -carboxamide
Figure imgf000141_0003
Procedures in Scheme 20 were utilized to synthesize this compound. LC/MS: C25H25N6O2 (M+ 1) 441. Single peak at 254 nm in analytical HPLC traces. Example 200. (±)-2,6-dimethylmorpholino)((3S,4R)-3-(4-hydroxy-6-(lH- pyrazol-4-yl)quinazolin-2-yl)-4-phenylpyrrolidin-l-yl)methanone
Figure imgf000142_0001
Procedures in Scheme 20 were utilized to synthesize this compound. LC/MS: C28H3IN6 O3(TVH-I) 499. Single peak at 254 and 230 nm in analytical HPLC traces.
Figure imgf000142_0002
Scheme 21
Example 201. (±)-2-((3S,4R)-l-ethyl-4-phenylpyrrolidin-3-yl)-6-(lH-pyrazol-4- yl)quinazolin-4-ol
Figure imgf000142_0003
Procedures in Scheme 21 were utilized to synthesize this compound. LC/MS: C23H24N5O (M+ 1) 386. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 202. (±)-2-(OSΛRH-(methylsulfonyl)-4-phenylpyrrolidin-3-yl)-6- (lH-pyrazol-4-yl)quinazolin-4-ol
Figure imgf000143_0001
Procedures in Scheme 21 were utilized to synthesize this compound. LC/MS: C22H22N5O3S (M+ 1) 436. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 203. (±)-(3S,4R)-methyl 3-(4-hydroxy-6-(lH-pyrazol-4-yl)quinazolin- 2-yl)-4-phenylpyrrolidine- 1 -carboxylate
Figure imgf000143_0002
Procedures in Scheme 21 were utilized to synthesize this compound. LC/MS: C23H22N5O3 (M+ 1) 416. Single peak at 254 and 230 nm in analytical HPLC traces.
Et3N ), rt
Figure imgf000143_0004
Figure imgf000143_0003
Scheme 22 Example 204. (±)-Nl,Nl,N2-trimethyl-N2-(2-((3S,4R)-4-phenylpyrrolidin-3- yl)-6-(lH-pyrazol-4-yl)quinazolin-4-yl)ethane-l,2-diamine
Figure imgf000144_0001
Procedures in Scheme 22 were utilized to synthesize this compound. LC/MS: C26H32N7 (M+ 1) 442. Single peak at 254 nm in analytical HPLC traces.
Example 205. (±)-N,N-dimethyl-2-((3S,4R)-4-phenylpyrrolidin-3-yl)-6-(lH- pyrazol-4-yl)quinazolin-4-amine
Figure imgf000144_0002
Procedures in Scheme 22 were utilized to synthesize this compound. LC/MS: C23H25N6 (M+ 1) 385. Single peak at 254 and 230 nm in analytical HPLC traces.
Example 206. (±)-Nl,Nl,N3-trimethyl-N3-(2-((3S,4R)-4-phenylpyrrolidin-3- yl)-6-(lH-pyrazol-4-yl)quinazolin-4-yl)propane-l,3-diamine
Figure imgf000144_0003
Procedures in Scheme 22 were utilized to synthesize this compound. LC/MS: C27H34N7 (M+ 1) 456. Single peak at 254 and 230 nm in analytical HPLC traces.
Figure imgf000145_0001
2. NaOH/MeOH
Scheme 23
To a solution of the carboxylic acid (0.2 mmol) and 2-amino-5- bromobenzamide (0.2 mmol) in DMF (1 mL) was added HATU (0.2 mmol) and DIEA (0.6 mmol). The resulting mixture was stirred at room temperature until started material completely disappeared. Saturated NaHCθ3 was added and EtOAc was used to extract the organic phase. The combined organic phase was washed with brine and dried over anhydrous Na2SO4. The solvent was removed in vacuo and the crude amide product was dissolved in dioxane and to this solution was added bis(pinacolato)diboron (0.4 mmol), potassium acetate (0.6 mmol), and PdCl2(dppf) (0.02 mmol). The reaction mixture was degassed, purged with argon, and heated to 80 0C for 2 h in oil bath. After the reaction was determined to be complete by LC-MS, the mixture was diluted with ethyl acetate (50 mL) and washed with brine (5 mL). The organic layer was dried over Na2SO4, and concentrated in vacuo to yield the crude aryl boronic ester. The residue was dissolved in a 1 : 1 mixture of dioxane: H2O and to this mixture was added 5-bromo-l-tosyl-lH-pyrrolo [2,3-b]pyridine-3-carbonitrile (0.24 mmol), Na2Cθ3 (0.6 mmol), and PdCl2dppf (0.02 mmol). The reaction mixture was degassed, purged with argon, and heated to 140 0C for 15 min. by microwave. After cooling to room temperature, the mixture was concentrated in vacuo and dissolved in a solution of NaOH (2 mmol) in MeOH (2 mL). After stirred in room temperature Ih, the mixture was treated with an aqueous 10% solution of TFA (1 mL) and the solvent was removed by rotary evaporation. The residue was purified by preparative HPLC to afford the desired final product. Example 207: 5 -(2-( 1 -aminocvclopropyl)-4-hvdroxyquinazolin-6-yl)- 1 H- pyrrolor2,3-blpyridine-3-carbonitrile
Figure imgf000146_0001
Procedures in Scheme 23 were utilized to synthesize this compound; LC/MS: Ci9Hi4N6O (M+ 1) 343. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 208: 2-(l-aminocvclopropyl)-6-(lH-pyrrolor2,3-blpyridin-5- yl)quinazolin-4-ol
Figure imgf000146_0002
Procedures in Scheme 23 were utilized to synthesize this compound; LC/MS: Ci8Hi5N6O (M+ 1) 318. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 209: 2-(l-aminocvclopropyl)-6-(lH-pyrrolor2,3-blpyridin-4- yl)quinazolin-4-ol
Figure imgf000146_0003
Procedures in Scheme 23 were utilized to synthesize this compound; LC/MS: Ci8Hi5N6O (M+ 1) 318. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 210: 5-(2-( 1 -aminocvclopropyl)-4-hvdroxyquinazolin-7-yl)- 1 H- pyrrolor2,3-blpyridine-3-carbonitrile
Figure imgf000147_0001
Procedures in Scheme 23 were utilized to synthesize this compound; LC/MS: Ci9Hi4N6O (M+l) 343. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 211: 5-(2-('l-aminocvclopropyl)-4-hvdroxy-8-methoxyquinazolin-6- yl)-lH-pyrrolor2,3-blpyridine-3-carbonitrile
Figure imgf000147_0002
Procedures in Scheme 23 were utilized to synthesize this compound; LC/MS: C20HiN6O (M+l) 373. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Figure imgf000148_0001
Scheme 24 An amine (leq), HOBt (0.5eq), DIPEA (2eq) and EDC (1.2eq) was added to a solution of 2-amino-4(or 5)-bromobenzoic acid 1 in DCM, and the reaction was stirred overnight. EtOAc was added and the organic layer was washed with IM NaOH, brine, sated. NaHCθ3 and brine. It was concentrated and the crude 2 was dried under vacuum and dissolved in DCM. Pyridine (2eq) and acid chloride was added consequently and the reaction mixture was stirred overnight. It was diluted with EtOAc and washed with IM HCl, brine, IM NaOH, brine, sated. NaHCθ3 and brine. It was concentrated and the crude 3 was heated in acetyl anhydride or IM NaOH solution to cyclized. The intermediate 4 was purified by column. The compound 4 was dissolved in 4: 1 dioxane/water and 1.4eq boronic ester, 10% Pd(PPh3 )4 and 4eq K2CO3 was added. It was heated by microwave condition for 30 mins. It was diluted with EtOAc and washed with sodium bicarbonate and brine. It was concentrated and purified with preparative HPLC to provide final product 5 (Ar = pyrazole, pyridine), which was purified by preparative HPLC. When Ar equals aminopyrimidine or pyrolopyrimidines, it was dissolved in dioxane and pinacol diborane (2eq) in presence of 10%
PdCl2(dppf) DCM complex and 4eq of KOAc was added. The reaction mixture was degassed and heated by microwave to 120 0C for 20 mins. It was diluted with EtOAc and washed with sated. NaHCO3 and brine. After concentration, the crude 6 was dissolved in 4: 1 dioxane/water and 1.5eq aryl chloride, 10% Pd(PPIi3)4 and 4eq K2CO3 were added and the reaction was degassed heated by microwave to 140 oC for 30mins. It was diluted with EtOAc and washed with sodium bicarbonate and brine. It was concentrated and purified with preparative HPLC to provide final product 5.
Example 212. 2-((dimethylamino)methyl)-3-(3-methoxybenzyl)-6-(lH-pyrazol- 4-yl)quinazolin-4(3H)-one
Figure imgf000149_0001
Procedures in Scheme 24 were utilized to synthesize this compound. LC/MS: C22H23N5O2 (M+ 1) 390. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 213 2-((dimethylamino)methyl)-3-(3-methoxybenzyl)-6-(lH-pyrazol- 4-yl)quinazolin-4('3H)-one
Figure imgf000149_0002
Procedures in Scheme 24 were utilized to synthesize this compound. LC/MS: C23H25N5O2 (M+ 1) 404. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 214. 3-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)-2-(2-(pyrrolidin-l- yl)ethyl)quinazolin-4(3H)-one
Figure imgf000149_0003
Procedures in Scheme 24 were utilized to synthesize this compound. LC/MS: C25H27N5O2 (M+ 1) 430. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 215 6-(2-aminopyrimidin-4-yl)-2-(2-(dimethylamino)ethyl)-3-(3- methoxybenzyl)quinazolin-4(3H)-one
Figure imgf000150_0001
Procedures in Scheme 24 were utilized to synthesize this compound. LC/MS: C24H26N6O2 (M+ 1) 431. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 216 6-(2-aminopyrimidin-4-yl)-2-(2-(dimethylamino)ethyl)-3-(3- fluorobenzyl)quinazolin-4(3H)-one
Figure imgf000150_0002
Procedures in Scheme 24 were utilized to synthesize this compound. LC/MS: C23H23FN6O (M+ 1) 419. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 217. 6-(2-aminopyrimidin-4-yl)-3-(3-chlorobenzyl)-2-(2-(pyrrolidin-l- yl)ethyl)quinazolin-4(3H)-one
Figure imgf000150_0003
Procedures in Scheme 24 were utilized to synthesize this compound. LC/MS: C2SH25ClN6O (M+ 1) 461. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 218. 6-(2-aminopyrimidin-4-yl)-3-(2-(3-chlorophenyl)propan-2-yl)-2- (2-(pyrrolidin-l-yl)ethyl)quinazolin-4(3H)-one
Figure imgf000151_0001
Procedures in Scheme 24 were utilized to synthesize this compound. LC/MS: C27H29ClN6O (M+ 1) 489. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 219. 6-(2-aminopyrimidin-4-yl)-3-('3-methoxybenzyl)-2-('2- (pyrrolidin- 1 -yl)ethyl)quinazolin-4(3H)-one
Figure imgf000151_0002
Procedures in Scheme 24 were utilized to synthesize this compound. LC/MS: C26H2SN6O2 (M+ 1) 457. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 220. 6-(2-aminopyrimidin-4-yl)-2-(2-(dimethylamino)ethyl)-8- methoxy-3-(3-methoxybenzyl)quinazolin-4(3H)-one
Figure imgf000151_0003
Procedures in Scheme 24 were utilized to synthesize this compound. LC/MS: C25H28N6O3 (M+ 1) 461. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 221. 2-(2-(dimethylamino)ethyl)-8-methoxy-3-(3-methoxybenzyl)-6- (7H-pyrrolor2,3-dlpyrimidin-4-yl)quinazolin-4(3H)-one
Figure imgf000152_0001
Procedures in Scheme 24 were utilized to synthesize this compound. LC/MS: C27H28N6O3 (M+ 1) 485. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 222. 3-(2-(3-chlorophenyl)propan-2-yl)-8-methoxy-2-methyl-6-(lH- Pyrazolor3,4-dlpyrimidin-4-yl)quinazolin-4('3H)-one
Figure imgf000152_0002
Procedures in Scheme 24 were utilized to synthesize this compound. LC/MS: C24H2IClN6O2 (M+ 1) 461. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Pd(PPh3J4, K2CO3
Figure imgf000153_0001
Pd(PPh3J4, K2CO3
Scheme 25
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. NaHCθ3 and brine consequently. This reaction provided two products that led to two serious of compounds 4 and 8. The first product: bromo-3N-substituted quinazolin-4- one 2 was dissolved in 4: 1 dioxane/water and 1.4eq boronic ester, 10% Pd(PPIi3)4 and 4eq K2CO3 was added. It was heated by microwave condition for 30 mins. It was diluted with EtOAc and washed with sodium bicarbonate and brine. It was concentrated and purified with preparative HPLC to provide final product 4 (Ar = pyrazole, pyridine), which was purified by preparative HPLC. When Ar equals aminopyrimidine or pyrolopyrimidines, it was dissolved in dioxane and pinacol diborane (2eq) in presence of 10% PdCl2(dppf) DCM complex and 4eq of KOAc was added. The reaction mixture was degassed and heated by microwave to 120 0C for 20 mins. It was diluted with EtOAc and washed with sated. NaHCθ3 and brine. After concentration, the crude 3 was dissolved in 4: 1 dioxane/water and 1.5eq aryl chloride, 10% Pd(PPl^)4 and 4eq K2CO3 were added and the reaction was degassed heated by microwave to 140 oC for 30mins. It was diluted with EtOAc and washed with sodium bicarbonate and brine. It was concentrated and purified with preparative HPLC to provide final product 4. The second product: 4-oxo-4H-benzo[d][l,3]oxazine 5 was refluxed in formamide to provide quinazoline intermediate 6 with carboxamido substitution on 2-positon. The desired product 7 was synthesized from 6 in similar fashion to the procedure describe above to synthesize compound 4 from intermediate 2.
Example 223. 4-hvdroxy-N-(3-methoxybenzyl)-6-(lH-pyrazol-4- yl)quinazoline-2-carboxamide
Figure imgf000154_0001
Procedures in Scheme 25 were utilized to synthesize this compound. LC/MS: C20Hi7N5O3 (M+ 1) 376. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 224. 4-hvdroxy-N-(3-methoxyphenethyl)-6-(lH-pyrazol-4- yl)quinazoline-2-carboxamide
Figure imgf000154_0002
Procedures in Scheme 25 were utilized to synthesize this compound. LC/MS: C21H19N5O3 (M+ 1) 390. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 225. 4-hvdroxy-N-(4-methoxyphenethyl)-6-(lH-pyrazol-4- yl)quinazoline-2-carboxamide
Figure imgf000155_0001
Procedures in Scheme 25 were utilized to synthesize this compound. LC/MS: C21H19N5O3 (M+l) 390. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 226. 4-hvdroxy-N-(3-methoxybenzyl)-6-(7H-pyrrolor2,3-dlpyrimidin- 4-yl)quinazoline-2-carboxamide
Figure imgf000155_0002
Procedures in Scheme 25 were utilized to synthesize this compound. LC/MS: C23Hi8N6O3 (M+l) 427. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 227. 4-hvdroxy-N-(3-methoxybenzyl)-6-(5-methyl-7H-pyrrolor2,3- dlpyrimidin-4-yl)quinazoline-2-carboxamide
Figure imgf000155_0003
Procedures in Scheme 25 were utilized to synthesize this compound. LC/MS: C24H2ON6O3 (M+l) 441. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 228. N-(3 -methoxyphenethyl)-4-oxo-7-( 1 H-pyrazol-4-yl)-3 A- dihvdroquinazoline-2-carboxamide
Figure imgf000156_0001
Procedures in Scheme 25 were utilized to synthesize this compound. LC/MS: C21H19N5O3 (M+l) 390. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 229. N-(4-methoxyphenethyl)-4-oxo-7-(lH-pyrazol-4-yl)-3,4- dihvdroquinazoline-2-carboxamide
Figure imgf000156_0002
Procedures in Scheme 25 were utilized to synthesize this compound. LC/MS: C21H19N5O3 (M+l) 390. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 230. 7-(7,7a-dihvdro-4aH-pyrrolor2,3-dlpyrimidin-4-yl)-N-('3- methoxyphenethyl)-4-oxo-3,4-dihvdroquinazoline-2-carboxamide
Figure imgf000156_0003
Procedures in Scheme 25 were utilized to synthesize this compound. LC/MS: C24H22N6O3 (M+l) 443. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 231. 3-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)quinazolin-4(3H)-one
Figure imgf000157_0001
Procedures in Scheme 25 were utilized to synthesize this compound. LC/MS: C19H16N4O2 (M+ 1) 333. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 232. 3-(3-methoxyphenethyl)-6-(lH-pyrazol-4-yl)quinazolin-4(3H)- one
Figure imgf000157_0002
Procedures in Scheme 25 were utilized to synthesize this compound. LC/MS: C20H18N4O2 (M+ 1) 347. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 233. 3-(3-methoxyphenethyl)-6-(lH-pyrazol-4-yl)quinazolin-4(3H)- one
Figure imgf000157_0003
Procedures in Scheme 25 were utilized to synthesize this compound. LC/MS: C20H18N4O2 (M+ 1) 347. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 234. 3-(3-methoxybenzyl)-6-(7H-pyrrolor2,3-dlpyrimidin-4- yl)quinazolin-4(3H)-one
Figure imgf000157_0004
Procedures in Scheme 25 were utilized to synthesize this compound. LC/MS: C22H17N5O2 (M+ 1) 384. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 235. 3 -(3 -methoxybenzyl)-6-(5-methyl-7H-pyrrolo \2 ,3 -dlpyrimidin-4- yl)quinazolin-4(3H)-one
Figure imgf000158_0001
Procedures in Scheme 25 were utilized to synthesize this compound. LC/MS: C23Hi9N5O2 (M+ 1) 398. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 236. 3-(4-methoxyphenethyl)-7-(lH-pyrazol-4-yl)quinazolin-4(3H)- one
Figure imgf000158_0002
Procedures in Scheme 25 were utilized to synthesize this compound. LC/MS: C20H18N4O2 (M+ 1) 347. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 237. 3-(3-methoxyphenethyl)-7-(7H-pyrrolor2,3-dlpyrimidin-4- yl)quinazolin-4(3H)-one
Figure imgf000158_0003
Procedures in Scheme 25 were utilized to synthesize this compound. LC/MS: C23H19N5O2 (M+ 1) 398. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Figure imgf000159_0001
Scheme 26
An amine (leq), HOBt (0.5eq), DIPEA (2eq) and EDC (1.2eq) was added to a solution of 2-amino-4-bromo-3-chlorobenzoic acid 1 in DCM, and the reaction was stirred overnight. EtOAc was added and the organic layer was washed with IM NaOH, brine, sated. NaHCθ3 and brine. It was concentrated and the crude 2 was dried under vacuum and dissolved in DCM. Pyridine (2eq) and acid chloride was added consequently and the reaction mixture was stirred overnight. It was diluted with EtOAc and washed with IM HCl, brine, IM NaOH, brine, sated. NaHCθ3 and brine. It was concentrated and the crude 3 was heated in acetyl anhydride to cyclize. The resulting intermediate 4 was purified by column. Compound 4 was dissolved in 4: 1 dioxane/water and 1.4eq pyrazol-4-ylboronic acid pinacol ester, 10% Pd(PPlIs)4 and 4eq K2CO3 was added. It was heated by microwave condition for 30 mins. It was diluted with EtOAc and washed with sodium bicarbonate and brine. It was concentrated and purified by column to provide the intermediate 5. 5 was dissolved in 4: 1 dioxane/water and 1.4eq boronic ester, 10% Pd(PPh3)4 and 4eq K2CO3 was added. It was heated by microwave condition for 30 mins. It was diluted with EtOAc and washed with sodium bicarbonate and brine. It was concentrated to provide 6. PMB group was deprotected by CAN and the final product 7 was purified by preparative HPLC. Example 238. 2-(6-methoxychroman-3-yl)-8-phenyl-6-(lH-pyrazol-4- yl)quinazolin-4-ol
Figure imgf000160_0001
Procedures in Scheme 26 were utilized to synthesize this compound. LC/MS: C27H22N4O3 (M+l) 451. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 239. 2-(6-methoxychroman-3-yl)-8-(3-methoxyphenyl)-6-(lH- pyrazol-4-yl)quinazolin-4-ol
Figure imgf000160_0002
Procedures in Scheme 26 were utilized to synthesize this compound. LC/MS: C28H24N4O4 (M+l) 481. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 240. 22-((3S,4R)-4-(4-methoxyphenyl)-l-methylpyrrolidin-3-yl)-6-
(lH-pyrazol-4-yl)quinazolin-4-ol
Figure imgf000160_0003
Procedures in Scheme 21 were utilized to synthesize this compound. LC/MS: C23H23N5O2 (M+l) 402. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 241. 5-(2-cvclopropyl-4-hvdroxyquinazolin-6-yl)-lH-pyrrolor2,3- blpyridine-3-carbonitrile
Figure imgf000161_0001
Procedures in Scheme 23 were utilized to synthesize this compound; LC/MS: Ci9Hi3N5O (M+ 1) 328. Single peak at both 215 nm and 254 nm in analytical HPLC traces..
Example 242. 6-(2-aminopyrimidin-4-yl)-2-cvclopropylquinazolin-4-ol
Figure imgf000161_0002
Procedures in Scheme 23 were utilized to synthesize this compound; LC/MS: Ci5Hi3N5O (M+ 1) 280. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 243. 2-cvclopropyl-6-(2-fluoropyridin-4-yl)quinazolin-4-ol
Figure imgf000161_0003
Procedures in Scheme 23 were utilized to synthesize this compound; LC/MS: Ci6Hi2FN3O (M+ 1) 282. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 244. 2-cyclopropyl-6-('lH-pyrrolor2,3-blpyridin-4-yl)quinazolin-4-ol
Figure imgf000162_0001
Procedures in Scheme 23 were utilized to synthesize this compound; LC/MS: Ci8Hi4N4O (M+l) 303. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 245. 2-cyclopropyl-6-('7H-pyrrolor2,3-dlpyrimidin-4-yl)quinazolin-4- ol
Figure imgf000162_0002
Procedures in Scheme 23 were utilized to synthesize this compound; LC/MS: Ci7Hi3N5O (M+l) 304. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 246. 2-cvclopropyl-6-(lH-pyrazol-4-yl)quinazolin-4-ol
Figure imgf000162_0003
Procedures in Scheme 23 were utilized to synthesize this compound; LC/MS: Ci4Hi2N4O (M+l) 253. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 247. 2-cvclopropyl-8-methoxy-6-(lH-pyrazol-4-yl)quinazolin-4-ol
Figure imgf000162_0004
Procedures in Scheme 23 were utilized to synthesize this compound; LC/MS: Ci5Hi4N4O2 (M+ 1) 283. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 248. 2-(cvclopropylmethyl)-8-methoxy-6-(lH-pyrazol-4- yl)quinazolin-4-ol
Figure imgf000163_0001
Procedures in Scheme 23 were utilized to synthesize this compound; LC/MS: Ci6Hi6N4O2 (M+ 1) 297. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 249. 2-isopropyl-8-methoxy-6-(3-methyl-lH-pyrazol-4-yl)quinazolin- 4-ol
Figure imgf000163_0002
Procedures in Scheme 23 were utilized to synthesize this compound; LC/MS: Ci6Hi8N4O2 (M+ 1) 299. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 250. 2-cvclopentyl-8-methoxy-6-(3-methyl-lH-pyrazol-4- yl)quinazolin-4-ol
Figure imgf000163_0003
Procedures in Scheme 23 were utilized to synthesize this compound; LC/MS: Ci8H2ON4O2 (M+ 1) 325. Single peak at both 215 nm and 254 nm in analytical HPLC traces. Example 251. (S)-2-(l-amino-2-methylpropyl)-8-methoxy-6-(3-methyl-lH- pyrazol-4-yl)quinazolin-4-ol
Figure imgf000164_0001
Procedures in Scheme 23 were utilized to synthesize this compound; LC/MS: Ci7H2IN5O2 (M+ 1) 328. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 252. ROCK-I/II enzymatic assays:
Assays were performed using the STK2 kinase system from Cisbio. 5 μl mixture of a 1 μM STK2 substrate and ATP (ROCK-I: 4 μM; ROCK-II: 20 μM) in STK-buffer was added to the wells using a BioRAPTR FRD™ Workstation (Aurora Discovery). 20nl of test compounds was dispensed. Reaction was started by addition of 5 μl of 2.5 nM ROCK-I (Upstate #14-601) or 0.5 nM ROCK-II in STK-buffer. After 4 h at RT the reaction was stopped by addition of 10 μl of Ix antibody and 62.5 nM Sa-XL in detection buffer. After 1 h at RT the plates were read on the Viewlux in HTRF mode. Typical IC50 values of ROCK-II for our compounds tested are between 0.05 nM and 1000 nM with most of them below 100 nM, and significant amount of them below 20 nM. Typical IC50 values for ROCK-I are between 1 nM and 20 uM.
Example 253. Myosin light chain bisphosphorylation assays (cell based assays, ppMLC)
A7r5 cells were plated at 5000 cells/well in a 96-well Packard View Plate (Perkin Elmer) in DMEM +10 % FBS. After allowing attachment overnight, cells were serum starved for 4 h and treated with inhibitor in 0.25 % DMSO final concentration for 1 h at 37 0C. Cells were then treated with 10 μM LPA for 10 min. Following treatment, cells were immediately fixed with 4 % paraformaldehyde for 30 minutes. After a brief wash in 0.1 M glycine, cells were permiabilized in 0.2 % Triton X for 10 minutes. Cells were then washed once in PBS and blocked in LI-COR blocking buffer (LI-COR Biosciences) for 1 h at 25 0C. Cells were probed for either phosphorylated myosin light chain 20 using 55 ng/ml primary rabbit antibody, total myosin light chain using 525 ng/ml primary rabbit antibody or for α-tubulin using 1 mg/ml primary mouse antibody, and incubated overnight at 4 0C. Following three washes, cells were probed with goat-anti-rabbit or goat-anti-mouse IR800 antibody (2 mg/ml in LI-COR block + 0.025 % Tween-20) for 1 h at 25 0C. Nuclei were stained with TO- PRO-3 iodide (642/661) (1 :4000) for 20 minutes, washed twice in PBS/0.05 % Tween-20 and read with an Odyssey Infrared Imaging System (LI-COR Biosciences). Typical IC50 values for our compounds tested are between 1 nM and 10 uM, with significant amount of them below 200 nM.
Example 254. Inhibitory Potency of Exemplary compounds.
IC50 < 10O nM: *
100 nM < IC50 < 1000 nM: **
IC50 > 100OnM: ***
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
It is within ordinary skill to evaluate any compound disclosed and claimed herein for effectiveness in inhibition of a kinase and in the various cellular assays using the procedures described above or found in the scientific literature. Accordingly, the person of ordinary skill can prepare and evaluate any of the claimed compounds without undue experimentation.
Any compound found to be an effective inhibitor of a kinase can likewise be tested in animal models and in human clinical studies using the skill and experience of the investigator to guide the selection of dosages and treatment regimens.
While the invention has been described and exemplified in sufficient detail for those skilled in this art to make and use it, various alternatives, modifications, and improvements will be apparent to those skilled in the art without departing from the spirit and scope of the claims. All patents and publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.
The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.

Claims

CLAIMSWhat is claimed is:
1. A compound of formula (I):
Figure imgf000170_0001
(I), wherein a dashed line indicates a bond that can be present or absent;
RN is absent or present; when RN is absent, there is a double bond between the carbon atom bearing R2 and the adjacent nitrogen atom; and when RN is present, there is a single bond between the carbon atom bearing R2 and the adjacent nitrogen atom;
RN comprises aralkyl wherein any carbon atom of the aralkyl is optionally substituted with J;
R1 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 of NR', O, S, S(O) and S(0)2, wherein the heterocyclic ring formed thereby is substituted with 0-3 substituents selected independently from J;
J is independently at each occurrence halogen, R, (CH2)o-2θR', (CH2V 2CN, CF3, OCF3, O, S, C(O), S(O), methylenedioxy, ethylenedioxy, (CH2)0- 2N(R)2, (CH2)O-2SR', (CH2)O-2S(O)R', (CH2)O-2S(O)2R', (CH2)0-2S(O)2N(R')2, (CH2V2SO3R', (CH2)O-2C(O)R', (CH2)O-2C(O)C(O)R', (CH2V2C(O)CH2C(O)R', (CH2)O-2C(S)R', (CH2V2C(O)OR', (CH2)O-2OC(O)R', (CH2)0-2C(O)N(R')2, (CH2V2OC(O)N(R)2, (CH2V2C(S)N(R)2, (CH2V2N(R)N(R)C(O)R, (CH2V 2N(R)N(R)C(0)0R, (CH2V2N(R)N(R)CON(R)2, (CH2)(^N(R)SO2R, (CH2)o-2N(R')S02N(R)2, (CH2)0-2N(R)C(O)OR, (CH2V2N(R)C(O)R, (CH2V 2N(R)C(S)R', (CH2)o-2N(R')C(0)N(R)2, (CH2)0-2N(R)C(S)N(R)2, (CH2V 2N(C0R')C0R, (CH2)o-2 N(0R')R, (CH2)0-2C(=NH)N(R)2, (CH2V 2C(0)N(0R')R, or (CH2)0-2C(=NOR')R, or J is (CH2)0-2-(cycloalkyl), (CH2)O-2- (aryl), (CH2)0-2-(heterocyclyl), or (CH2)0-2-(heteroaryl), wherein the cycloalkyl, aryl, heterocyclyl or heteroaryl can be mono- or independently pluri-substituted with J; each R is independently at each occurrence hydrogen, (Ci-Ci2)-alkyl, (C2-Ci2)-alkenyl, (C2-Ci2)-alkynyl, (C3-Ci0)-cycloalkyl, (C3-Ci0)-cycloalkenyl, [(C3-Cio)cycloalkyl or (C3-Ci0)-cycloalkenyl]-[(Ci-Ci2)-alkyl or (C2-C12)- alkenyl or (C2-C12)-alkynyl], (C6-C10)-aryl, (C6-Ci0)-aryl-[(Ci-Ci2)-alkyl or (C2- Ci2)-alkenyl or (C2-C i2)-alkynyl], (3-10 membered)-heterocyclyl, (3-10 membered)-heterocyclyl-[(Ci-Ci2)-alkyl or (C2-Ci2)-alkenyl or (C2-Ci2)- alkynyl], (5-10 membered)-heteroaryl, or (5-10 membered)-heteroaryl-[(Ci-Ci2)- alkyl or (C2-Ci2)-alkenyl or (C2-Ci2)-alkynyl], wherein R' is substituted with 0-3 substituents selected independently from J; or, when two R' are bound to a nitrogen atom or to two adjacent nitrogen atoms, the two R groups together with the nitrogen atom or atoms to which they are bound can form a 3- to 8-membered monocyclic heterocyclic ring, or an 8- to 20-membered, bicyclic or tricyclic, heterocyclic ring system, wherein any ring or ring system can further contain 1 -3 additional heteroatoms selected from the group consisting of N, NR, O, S, S(O) and S(O)2, and wherein each ring is substituted with 0-3 substituents selected independently from J; wherein, in any bicyclic or tricyclic ring system, each ring can be linearly fused, bridged, or spirocyclic, wherein each ring can be aromatic or non-aromatic, wherein each ring can be fused to a (Ce-Cio)aryl, (5-10 membered)-heteroaryl, (C3- Cio)cycloalkyl or (3-10 membered)-heterocyclyl ring; when RN is absent, R2 comprises OR', SR, or NR2, and when RN is present, R2 is oxo; R3 comprises a nitrogen-containing monocyclic or polycyclic heteroaryl group which can be mono- or independently plurisubstituted with J;
R4 comprises H, aryl optionally substituted with J, OR, SR, N(R)2, NR'(CH2)mNR2, NR(CH2)mOH, OCH2CH(OH)CH2NR'2, O(CH2CH2O)PCH2CH2OR', O(CH2)mNR'2, O(CH2)mNR2, O(CH2)mC(O)NR'2, S(CH2)mNR'2, O(CH2)p-heterocyclyl, N(R')(CH2)p-heterocyclyl, O(CH2)P- heteroaryl, N(R')(CH2)p-heteroaryl, wherein p is 0 to about 3, and wherein any heterocyclyl or heteroaryl can be mono- or independently plurisubstituted with J;
Q1 is N, CR3, or CR5;
Q2 is N, CR3 or CR5; and
R5 comprises H, F, Cl, Me, CN, C(O)R', C(O)OR', C(O)NR2, CF3, OR, OCF3, 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.
2. The compound of formula (I) of claim 1 wherein R1 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.
3. The compound of formula (I) of claim 1 wherein R1 comprises any of the following: a) an aryl-fused heterocyclyl moiety of the formula
Figure imgf000172_0001
is O, CH, CHR5, N, NR5, when X is O,
CHR5, or NR5 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 Jn 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
Figure imgf000173_0001
signifies mono- or independent plurisubstitution by J, wherein a wavy line signifies a point of attachment; c) an aralkyl moiety of the formula
Figure imgf000173_0002
, wherein n is 0, 1, or 2, R independently comprises H or alkyl wherein the alkyl can be mono- or independently plurisubstituted with J, and Jn signifies mono- or independent plurisubstitution by J, wherein a wavy line signifies a point of attachment; d) an aralkyl moiety of the formula
Figure imgf000173_0003
, wherein n is 0, 1, or 2, R comprises H or alkyl wherein the alkyl can be mono- or independently plurisubstituted with J, and Jn signifies mono- or independent plurisubstitution by J, Rc 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
Figure imgf000174_0001
, wherein R comprises H or alkyl wherein the alkyl can be mono- or independently plurisubstituted with J, and Jn 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
Figure imgf000174_0002
, wherein R comprises H or alkyl wherein the alkyl can be mono- or independently plurisubstituted with J, X is O, CH, or NR , respectively, and R7 comprises (Ci_4)alkyl mono- or independently plurisubstituted with J, wherein a wavy line signifies a point of attachment.
4. The compound of formula (I) of claim 1 wherein R1 comprises a group of formula
Figure imgf000174_0003
Figure imgf000175_0001
R6 comprises H, (Ci-C6)alkyl, or (C3-Cs)cycloalkyl, wherein the alkyl or cycloalkyl can be mono- or independently plurisubstituted with J;
or, a group of formula
Figure imgf000175_0002
or, a group of formula
Figure imgf000175_0003
Figure imgf000176_0001
wherein R independently at each occurrence comprises H, alkyl wherein the alkyl can be mono- or independently plurisubstituted with J, or C(O)R8, wherein R8 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, R7 comprises (Ci_4)alkyl-NR'2;
or, a group of the formula
Figure imgf000176_0002
or, a group of formula
Figure imgf000177_0001
wherein a wavy line signifies a point of attachment.
5. The compound of formula (I) of claim 4 wherein R1 comprises a moiety of formula
Figure imgf000177_0002
, wherein R comprises a group of the formula (C1-4 alkyl)OCH3, (C1-4 alkyl)NH2, (C1-4 alkyl)NHMe, (C1-4 alkyl)NMe2, (C1-4 alkyl)SCH3, cyclopropyl, (Ci-4 alkyl)-2-thiazolyl, (Ci-4 alkyl)-4-imidazolyl, (Ci-4 alkyl)-2-pyridyl, (C1-4 alkyl)-3-pyridyl, (Ci_4 alkyl)-4-pyridyl, (Ci_4 alkyl)-4- morpholinyl, or (C1-4 alkyl)-4-N-methylpyridazinyl, wherein a wavy line signifies a point of attachment.
6. The compound of formula (I) of claim 1 wherein R2 comprises hydroxy, NH2, alkylamino, aminoalkylthio, hydroxyalkylamino, aminoalkylamino, amidoalkylamino, carboxyalkylamino, heterocyclyl, heterocyclylalkylamino, heteroarylamino, or heteroarylalkylamino, any of which can be mono- or independently plurisubstituted with J.
7. The compound of formula (I) of claim 1 wherein R comprises a group of the formula
Figure imgf000178_0001
-S-(CH2)mNR2, -NR(CH2)mNR2, -NR(CH2)mOH, -NRCH2CH(OH)CH2NR2, NR(CH2)mC(O)OH, NR(CH2)mC(O)NR2, NR-pyrrolidinyl, NR(CH2)m- morpholinyl, NR(CH2)m-pyridinyl, or NR(CH2)mC(O)morpholinyl, wherein m is 1-4, and R comprises H or alkyl wherein the alkyl can be mono- or independently plurisubstituted with J, wherein a wavy line signifies a point of attachment.
8. The compound of formula (I) of claim 7 wherein m is 2, R is H or methyl, or both.
9. The compound of formula (I) of claim 1 wherein R comprises a pyrazolinyl, pyridinyl, or pyrimidinyl ring, which can be unsubstituted or substituted with alkyl or NR2, wherein R comprises H or alkyl wherein the alkyl can be mono- or independently plurisubstituted with J.
10. The compound of formula (I) of claim 1 wherein R comprises a group of formula
Figure imgf000178_0002
Figure imgf000179_0001
wherein a wavy line signifies a point of attachment.
11. The compound of formula (I) of claim 1 wherein R4 comprises H, OH, OMe, NR(CH2)mNR2, NR(CH2)mOH, OCH2CH(OH)CH2NR2, O(CH2CH2O)PCH2CH2OR, O(CH2)mNR2, O(CH2)mNR2, O(CH2)mC(O)NR2, S(CH2)mNR2, O-(CH2)p-heterocyclyl, NR-(CH2)p-heterocyclyl, O-(CH2)P- heteroaryl, or NR-(CH2)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 0-3.
12. The compound of formula (I) of claim 1 wherein R4 comprises N(Me)(CH2)2NMe2, N(Me)(CH2)3NMe2, O(CH2)2NMe2, O(CH2)3NMe2, O(CH2)2OH, O(CH2)3OH, OCH2C(O)-morpholinyl, O(CH2)2C(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, pyridin-2-yloxy, pyridin-3 -yloxy, pyridin-4-yloxy, 2-picolinoxy, 3-picolinoxy, or 4-picolinoxy.
13. The compound of formula (I) of claim 1 wherein Q1 and Q2 each is CH.
14. The compound of formula (I) of claim 1, comprising:
Figure imgf000179_0002
Figure imgf000180_0001

Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
ı82
Figure imgf000184_0001
ı83
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
ı88
Figure imgf000190_0001
Figure imgf000190_0002
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000192_0002
Figure imgf000193_0001
ı92
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000197_0002
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
ı99
Figure imgf000201_0001
Figure imgf000202_0001
201
Figure imgf000203_0001
202
Figure imgf000204_0001
Figure imgf000204_0003
Figure imgf000204_0002
or any salt, hydrate, solvate, isotopically labeled form, stereoisomer, tautomer, or prodrug thereof.
15. A pharmaceutical composition comprising a compound of any one of claims 1-14 and a suitable excipient.
16. A pharmaceutical combination comprising a compound of any one of claims 1-14 in a therapeutically effective dose and a second medicament in a therapeutically effective dose wherein the compound and the second medicament can be administered concurrently, sequentially, or intermittently.
17. The combination of claim 16 wherein the second medicament comprises 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, or any combination thereof.
18. The combination of claim 17 wherein the anti-proliferative agent comprises 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.
19. The combination of claim 17 wherein the anti-glaucoma agent comprises a beta receptor-blocker, a prostaglandin, an alpha-adrenergic agonist, a parasympathomimetic (cholinergic agonist), or a carbonic anhydrase inhibitor.
20. The combination of claim 17 wherein the anti-hypertensive agent comprises a beta receptor-blocker, a calcium channel blocker, a diueretic, an angiotensin converting enzyme (ACE) inhibitor, a renin inhibitor, or an angiotensin receptor antagonist.
21. The combination of claim 17 wherein the anti-atherosclerotic agent comprises a 3-HMG-coA-reductase inhibitor, a statin, atorvastatin, simvastatin, niacin, or a combination drug such as vytorin.
22. The combination of claim 17 wherein the anti-multiple sclerosis agent comprises beta-inteferon, tysabri, or glatirimar acetate.
23. The combination of claim 17 wherein the anti-angina agent comprises a beta receptor-blocker, a calcium channel blocker, nitroglycerin, isosorbide mononitrate, nicorandil, or ranolanzine.
24. The combination of claim 17 wherein the anti-erectile dysfunction agent comprises a phosphodiesterase-5 inhibitor.
25. The combination of claim 17 wherein the anti-stroke agent comprises tissue plasminogen activator.
26. The combination of claim 17 wherein the anti-asthma agent comprises a bronchodilator, an inhaled corticosteroid, a leukotrine blockers, cromolyn, nedocromil, or theophylline.
27. A pharmaceutical composition comprising the combination of claim 16 and a suitable excipient.
28. A method of inhibiting a kinase, comprising contacting the kinase with an effective amount of a compound of any one of claims 1-14.
29. The method of claim 28, wherein the kinase is 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.
30. A method of treatment of a malcondition in a patient in need thereof, comprising administering a therapeutically effective amount of the compound of any one of claims 1-14 to the patient at a frequency of administration and for a duration of time sufficient to provide a beneficial effect to the patient.
31. The method of claim 30 wherein the malcondition comprises 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.
32. The method of claim 30 for which binding of a ligand to a kinase or inhibition of a bioactivity of a kinase, or both, is medically indicated.
33. The method of claim 32 wherein the kinase is 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.
34. A method of treatment of a malcondition in a patient, comprising administering to the patient the pharmaceutical combination of claim 16 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.
35. The method of claim 34 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
36. The method of claim 30 further comprising administration of an effective amount of an additional medicament.
37. The method of claim 36 wherein the additional medicament comprises 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.
38. The method of claim 37 wherein the anti-proliferative agent comprises 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.
39. The method of claim 37 wherein the anti-glaucoma agent comprises a beta receptor-blocker, a prostaglandin, an alpha-adrenergic agonist, a parasympathomimetic (cholinergic agonist), or a carbonic anhydrase inhibitor.
40. The method of claim 37 wherein the anti-hypertensive agent comprises a beta receptor-blocker, a calcium channel blocker, a diueretic, an angiotensin converting enzyme (ACE) inhibitor, a renin inhibitor, or an angiotensin receptor antagonist.
41. The method of claim 37 wherein the anti-atherosclerotic agent comprises a 3-HMG-coA-reductase inhibitor, a statin, atorvastatin, simvastatin, niacin, or a combination drug such as vytorin.
42. The method of claim 37 wherein the anti-multiple sclerosis agent comprises beta-inteferon, tysabri, or glatirimar acetate.
43. The method of claim 37 wherein the anti-angina agent comprises a beta receptor-blocker, a calcium channel blocker, nitroglycerin, isosoribide mononitrate, nicorandil, or ranolanzine.
44. The method of claim 37 wherein the anti-erectile dysfunction agent comprises a phosphodiesterase-5 inhibitor.
45. The method of claim 37 wherein the anti-stroke agent comprises tissue plasminogen activator.
46. The method of claim 37 wherein the anti-asthma agent comprises a bronchodilator, an inhaled corticosteroid, a leukotrine blockers, cromolyn, nedocromil, or theophylline.
47. The use of the compound of any one of claims 1-14 in the preparation of a medicament for treatment of a malcondition.
48. The use of claim 47 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 for treatment of the malcondition.
49. The use of claim 47 wherein the malcondition comprises 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.
50. A compound of any one of claims 1 - 14 for use in medical therapy.
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