WO2010129802A1 - Inhibitors of jak - Google Patents

Inhibitors of jak Download PDF

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Publication number
WO2010129802A1
WO2010129802A1 PCT/US2010/033921 US2010033921W WO2010129802A1 WO 2010129802 A1 WO2010129802 A1 WO 2010129802A1 US 2010033921 W US2010033921 W US 2010033921W WO 2010129802 A1 WO2010129802 A1 WO 2010129802A1
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Prior art keywords
carboxamide
pyrimidine
phenylamino
acetamidophenylamino
carboxamido
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PCT/US2010/033921
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French (fr)
Inventor
Shawn M. Bauer
Jack W. Rose
Yonghong Song
Qing Xu
Mukund Mehrotra
Wolin Huang
Anjali Pandey
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Portola Pharmaceuticals, Inc.
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Publication of WO2010129802A1 publication Critical patent/WO2010129802A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention is directed to pyrimidine and pyridine-based compounds which act as inhibitors of JAK.
  • This invention is also directed to pharmaceutical compositions containing the pyrimidine and pyridine-based compounds and methods of using the compounds or compositions to treat a condition mediated at least in part by JAK activity.
  • the invention is also directed to methods of making the compounds described herein.
  • Janus tyrosine kinases are a small family of structurally and functionally related non-receptor, cytoplasmic protein tyrosine kinases, including JAKl, JAK2, JAK3, and tyrosine kinase 2 (TYK2). JAKs play pivotal roles in the initiation of cytokine- triggered signaling events by signal transducers and activators of transcriptions (STATs) via tyrosine phosphorylation. JAK-mediated tyrosine phosphorylations of cytokine receptors and STATs are the important signal transduction pathways used by many cytokines, growth factors, and interferons.
  • the STATs Upon phosphorylation, the STATs dimerize and translocate to the nucleus where they can then induce transcription of the corresponding cytokine- responsive genes.
  • This association with relevant cytokine signaling pathways makes JAK3 an important target for therapeutic intervention in the treatment of autoimmune disorders, inflammatory diseases, cell proliferative disorder and organ transplant rejection such as rheumatoid arthritis, psoriasis, Crohn's disease, multiple sclerosis, asthma and acute myeloid leukemias (AML).
  • JAK-3 in particular plays an essential role in the function of lymphocytes, macrophages and mast cells.
  • the compounds that inhibit JAK-3 can be therapeutically useful in treatment of, leukemia, lymphoma where JAK3 is hyperactivated.
  • JAK3 inhibition will be useful as immunosuppressive agent for treatment of chronic and/or acute organ transplant and autoimmune diseases such as rheumatoid arthritis , Type 1 diabetes, systemic lupus, multiple sclerosis, Crohn's disease and inflammatory diseases such as, asthma, psoriasis, chronic obstructive pulmonary disease.
  • JAK3 cytokine receptor gamma chain
  • ⁇ cytokine receptor gamma chain
  • JAK3 expression seems to be mainly limited to the endoplasmic membranes of hematopoietic cells.
  • JAK3 The pivotal roles in signaling through the gamma chain of ⁇ c containing cytokine receptors cytokine receptors and its limited expression and unique tissue distribution make JAK3 an attractive therapeutic target relative to the other JAK family members to manage the abnormal cytokine activities implicated in many cancer cells and inflammatory lymphocytes.
  • JAK3 inhibitors have been reported, such as the non-selective (within JAK family) but very potent tetracyclic pyridone 2, reported by Merck.
  • Aventis has published an oxindole JAK3 inhibitor that shows good enzymatic selectivity vs JAK2.
  • this oxindole inhibitor also shows very strong inhibition vs a panel of CDK kinases.
  • Vertex has described aza indoles as JAK inhibitors (WO2005/95400).
  • AstraZeneca has published quinoline 3-carboxamides as JAK 3 inhibitors (WO2002/92571) and other compounds for inhibition of all JAKs for the treatment of cancer (WO2008/135786).
  • JAK2 JAK2 kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kina
  • Bcr-JAK2 PCMl -J AK2
  • PCMl -J AK2 PCMl -J AK2
  • STAT3 and STAT5 have been detected in a wide range of cancers and hyperproliferative diseases (Haura et al, Oncology, 2005, 2(6), 315-324). Further, aberrant activation of the JAK/STAT pathway provides an important proliferative and/or anti-apoptotic drive downstream of many kinases (e.g. Flt3, EGFR) whose constitutive activation have been implicated as key drivers in a variety of cancers and hyperproliferative disorders.
  • many kinases e.g. Flt3, EGFR
  • JAKl and JAK2 will be useful in the treatment of cancers including multiple myeloma, prostate, breat and lung cancer, B-cell Chronic Lymphocytic Leukemia, metastatic melanoma, multiple myeloma, and hepatoma.
  • the present invention provides novel compounds having activity as inhibitors of JAK kinase activity (also referred to herein as "JAK inhibitors”), as well as to methods for their preparation and use, and to pharmaceutical compositions containing the same.
  • JAK inhibitors also referred to herein as "JAK inhibitors”
  • Such compounds have the following structure (I):
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutical acceptable salt thereof, and a pharmaceutically acceptable carrier and/or diluent.
  • the compounds of the present invention have utility over a wide range of therapeutic applications, and may be used to treat a variety of conditions, mediated at least in part by JAK activity, in both men and women, as well as a mammal in general (also referred to herein as a "subject").
  • such conditions include, but are not limited to, those associated with cardiovascular disease, inflammatory disease or autoimmune disease.
  • the compounds of the present invention have utility for treating conditions or disorders including, but not limited to: allergy, asthma, rheumatoid arthritis, Crohn's disease, anti-phospholipid syndrome, lupus, psoriasis, multiple sclerosis, and chronic lymphocytic leukemia .
  • methods are disclosed which include the administration of an effective amount of a compound of formula (I), typically in the form of a pharmaceutical composition, to a subject in need thereof.
  • the present invention also provides a method for inhibiting the JAK activity of a blood sample comprising contacting said sample with a compound of the present invention.
  • the present invention further provides compounds in purified forms, as well as chemical intermediates.
  • Boc t-butylcarboxy
  • BOP benzotriazol-l-yloxytris(dimethylamino)-phosphonium hexafluorophosphate
  • BPO benzoyl peroxide
  • nBuOH n-butanol
  • CBr4 tetrabromomethane
  • mCPBA m- chloroperoxybenzoic acid
  • CH2CI2 or DCM dichloromethane
  • CS2CO3 cesium carbonate
  • CuCl2 copper chloride
  • DIBAL diisobutylaluminum hydride
  • DIEA Hunig's base or diisopropyl ethylamine
  • DME dimethoxy ethane
  • DMF dimethyl formamide
  • DMSO dimethyl sulfoxide
  • Et3N triethylamine
  • EtOAc ethyl acetate
  • g g.
  • Alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, fully saturated aliphatic hydrocarbon radical having the number of carbon atoms designated.
  • Q-salkyl refers to a hydrocarbon radical straight or branched, containing from 1 to 8 carbon atoms that is derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane.
  • unsubstituted alkyl refers to alkyl groups that do not contain groups other than fully saturated aliphatic hydrocarbon radicals.
  • the phrase includes straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like.
  • the phrase also includes branched chain isomers of straight chain alkyl groups such as isopropyl, t-butyl, isobutyl, sec-butyl, and the like.
  • Representative alkyl groups include straight and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms.
  • Further representative alkyl groups include straight and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms.
  • alkenyl by itself or as part of another substituent refers to a straight or branched chain, which may be mono- or polyunsaturated, having the number of carbon atoms designated.
  • C 2 -C 8 alkenyl means an alkenyl radical having from 2, 3, 4, 5, 6, 7 or 8 atoms that is derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene. Examples include, but are not limited to vinyl, 2-propenyl i.e.
  • a "substituted" alkenyl group includes alkenyl groups in which a non-carbon or non-hydrogen atom is bonded to a carbon double bonded to another carbon and those in which one of the non- carbon or non-hydrogen atoms is bonded to a carbon not involved in a double bond to another carbon.
  • Each site of unsaturation may be either cis or trans configuration about the double bond(s).
  • alkynyl by itself or as part of another substituent, means a straight or branched chain hydrocarbon radical, which may be mono- or polyunsaturated, having the number of carbon atoms designated.
  • C 2 -C 8 alkynyl means an alkynyl radical having from 2 to 8 carbon atoms that is derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne.
  • Unsubstituted alkynyl refers to straight and branched chain groups such as those described with respect to unsubstituted alkyl groups as defined above, except that at least one triple bond exists between two carbon atoms.
  • a "substituted" alkynyl group includes alkynyl groups in which a non-carbon or non-hydrogen atom is bonded to a carbon triple bonded to another carbon and those in which a non-carbon or non-hydrogen atom is bonded to a carbon not involved in a triple bond to another carbon.
  • Alkylene by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified by -CH 2 CH 2 CH 2 CH 2 -.
  • an alkylene group will have from 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms that is derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyl.
  • Cycloalkyl or “carbocycle”, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of “alkyl”, “alkenyl” and “alkynyl” in which all ring atoms are carbon. "Cycloalkyl” or “carbocycle” refers to a mono- or polycyclic group. When used in connection with cycloalkyl substituents, the term
  • polycyclic refers herein to fused and non-fused alkyl cyclic structures.
  • Cycloalkyl or “carbocycle” may form a bridged ring or a spiro ring.
  • the cycloalkyl group may have one or more double or triple bond(s).
  • cycloalkenyl refers to a cycloalkyl group that has at least one site of alkenyl unsaturation between the ring vertices.
  • cycloalkynyl refers to a cycloalkyl group that has at least one site of alkynyl unsaturation between the ring vertices.
  • cycloalkyl When “cycloalkyl” is used in combination with “alkyl”, as in C 3-8 cycloalkylC 3 - 8 alkylene-, the cycloalkyl portion is meant to have the stated number of carbon atoms (e.g., from three to eight carbon atoms), while the alkylene portion has from one to eight carbon atoms. Typical cycloalkyl substituents have from 3 to 8 ring atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclpentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • Aryl by itself or as part of another substituent refers to a polyunsaturated, aromatic, hydrocarbon group containing from 6 to 14 carbon atoms, which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently.
  • the phrase includes, but is not limited to, groups such as phenyl, biphenyl, anthracenyl, naphthyl by way of example.
  • unsubstituted aryl groups include phenyl, 1 -naphthyl, 2-naphthyl and 4-biphenyl.
  • “Substituted aryl group” includes, for example, -CH2OH (one carbon atom and one heteroatom replacing a carbon atom) and
  • heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified by -CH2-CH2-S-CH2CH2- - and -CH2-S-CH2-CH2-NH-CH2-
  • heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied.
  • heterocycle refers to a saturated or unsaturated non-aromatic cyclic group containing at least one heteroatom.
  • heteroatom is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).
  • Each heterocycle can be attached at any available ring carbon or heteroatom.
  • Each heterocycle may have one or more rings. When multiple rings are present, they can be fused together or linked covalently.
  • Each heterocycle typically contains 1, 2, 3, 4 or 5, independently selected heteroatoms.
  • these groups contain 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, 0, 1, 2, 3, 4 or 5 nitrogen atoms, 0, 1 or 2 sulfur atoms and 0, 1 or 2 oxygen atoms. More preferably, these groups contain 1, 2 or 3 nitrogen atoms, 0-1 sulfur atoms and 0-1 oxygen atoms.
  • heterocycle groups include morpholin-3-one, piperazine-2-one, piperazin-1 -oxide, pyridine-2-one, piperidine, morpholine, piperazine, isoxazoline, pyrazoline, imidazoline, pyrazol-5-one, pyrrolidine-2,5- dione, imidazolidine-2,4-dione, pyrrolidine, tetrahydroquinolinyl, decahydroquinolinyl, tetrahydrobenzooxazepinyl dihydrodibenzooxepin and the like.
  • Heteroaryl refers to a cyclic or polycyclic aromatic radical that contain from one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom or through a carbon atom and can contain 5 to 10 carbon atoms.
  • heteroaryl groups include 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 2-imidazolyl, A- imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5- isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2- pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl and 4-pyrimidyl.
  • substituted heteroaryl refers to a unsubstituted heteroaryl group as defined above in which one or more of the ring members is bonded to a non-hydrogen atom such as described above with respect to substituted alkyl groups and substituted aryl groups.
  • each of the terms herein is meant to include both “unsubstituted” and optionally “substituted” forms of the indicated radical, unless otherwise indicated.
  • each radical is substituted with 0, 1, 2 3 4 or 5 substituents, unless otherwise indicated. Examples of substituents for each type of radical are provided below.
  • Substituted refers to a group as defined herein in which one or more bonds to a carbon(s) or hydrogen(s) are replaced by a bond to non-hydrogen and non-carbon atom "substituents" such as, but not limited to, a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy, and acyloxy groups; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amino, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, alkoxyamino, hydroxyamino, acylamino, sulfonylamino, N-oxides, imides, and en
  • Substituents also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom is replaced by a higher-order bond (e.g., a double- or triple- bond) to a heteroatom such as oxygen in oxo, acyl, amido, alkoxycarbonyl, aminocarbonyl, carboxyl, and ester groups; nitrogen in groups such as imines, oximes, hydrazones, and nitriles. "Substituents” further include groups in which one or more bonds to a carbon(s) or hydrogen(s) atoms is replaced by a bond to a cycloalkyl, heterocyclyl, aryl, and heteroaryl groups.
  • substituted alkyl groups include, among others, groups in which one or more bonds to a carbon or hydrogen atom is/are replaced by one or more bonds to fluoro, chloro, or bromo group. Another representative “substituent” is the trifluoromethyl group and other groups that contain the trifluoromethyl group. Other representative “substituents” include those in which one or more bonds to a carbon or hydrogen atom is replaced by a bond to an oxygen atom such that the substituted alkyl group contains a hydroxyl, alkoxy, or aryloxy group.
  • substituted or unsubstituted alkylamine dialkylamine, arylamine, (alkyl)(aryl)amine, diarylamine, heterocyclylamine, diheterocyclylamine, (alkyl)(heterocyclyl)amine, or (aryl)(heterocyclyl)amine group.
  • Still other representative "substituents” include those in which one or more bonds to a carbon(s) or hydrogen(s) atoms is replaced by a bond to an alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl group.
  • alkylamino refers to a group of the formula -NR a R b .
  • R a , and R b are each independently selected from H, alkyl, alkoxy, thioalkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl or are optionally joined together with the atom(s) to which they are attached to form a cyclic group.
  • R a and R b are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6- or 7-membered ring.
  • -NR a R b is meant to include 1-pyrrolidinyl and 4-morpholinyl.
  • R c , R d , R e and R f are each independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl or alkylenearyl as defined herein.
  • a particular radical will have 0, 1, 2 or 3 substituents, with those groups having two or fewer substituents being preferred in the present invention. More preferably, a radical will be unsubstituted or monosubstituted. Most preferably, a radical will be unsubstituted.
  • substituted aryl and heteroaryl groups are varied and are selected from: -halogen, -0R ⁇ -OC(O) R a , -NR a R b , -SR a , -R a , -CN, -NO 2 , -C0 2 R a ,
  • Two of the "substituents'On adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(0)-(CH 2 )q-U-, wherein T and U are independently -NH-, -0-, -CH 2- . or a single bond, and q is O, 1 or 2.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 ) r _B-, wherein A and B are independently -CH 2 _,
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CH 2 ) S _X-(CH 2 )(_ -, where s and t are independently integers of from O to 3, and X is -0-, -NR a -, -S- , -S(O)-, -S(O) 2 ., or -S(O) 2 NR a -.
  • the substituent R a in -NR a - and -S(O) 2 NR 3 - is selected from hydrogen or unsubstituted C ⁇ .galkyl. Otherwise, R' is as defined above.
  • Alkoxy refers to -OR d wherein R d is alkyl as defined herein.
  • Representative examples of alkoxy groups include methoxy, ethoxy, r-butoxy, trifluoromethoxy, and the like.
  • Amino refers to the group -NR a R b where R a and R b are independently H, alkyl, aryl, heterocyclyl and the like; or can also be combined to form a 3-7 membered ring with the nitrogen atom to which each is attached.
  • alkylamino refers to the group -NR a R b where R a is alkyl and R b is H or alkyl.
  • arylamino refers to the group -NR a R b where R a is aryl and R b is hydrogen, alkyl, aryl, or heterocyclyl.
  • (alkyl)(aryl)amino refers to the group -NR a R b where R a is alkyl and R b is aryl. Additionally, for dialkylamino groups, the alkyl portions can be the same or different and can also be combined to form a 3-7 membered ring with the nitrogen atom to which each is attached. Accordingly, a group represented as -NR a R b is meant to include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl and the like.
  • Representative aminocarbonyl groups include, for example, those shown below. These aminocarbonyl group can be further substituted as will be apparent to those having skill in the organic and medicinal chemistry arts in conjunction with the disclosure herein.
  • Carboxy or “carboxyl” refers to the group -CO 2 H.
  • (Carboxyl ester)amino refers to the groups -NR a -C(O)OR c , where R a is alkyl or hydrogen.
  • Cyano refers to -CN.
  • Halo or "halogen” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl”, are meant to include alkyl in which one or more hydrogen is substituted with halogen atoms which can be the same or different, in a number ranging from one up to the maximum number of halogens permitted e.g. for alkyl, (2m'+l), where m' is the total number of carbon atoms in the alkyl group.
  • haloCi_galkyl is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • perhaloalkyl means, unless otherwise stated, alkyl substituted with (2m'+l) halogen atoms, where m' is the total number of carbon atoms in the alkyl group.
  • perhaloCi_galkyl is meant to include trifluoromethyl, pentachloroethyl, l,l,l-trifluoro-2-bromo-2-chloroethyl, and the like.
  • haloalkoxy refers to an alkoxy radical substituted with one or more halogen atoms.
  • Heteroalkyl means an alkyl radical as defined herein with one, two or three components independently selected from cyano, oxo, -O-, -OR W , -NR X -, -NR X RY, -S(O) n - and -S(O) n R 2 (where n is an integer from 0 to 2 ), with the understanding that the point of attachment of the heteroalkyl radical is through a carbon, nitrogen, oxygen or sulfur atom of the heteroalkyl radical.
  • R w is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, araalkyl, alkoxycarbonyl, aryloxycarbonyl, carboxamido, or mono- or di-alkylcarbamoyl.
  • R x is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl or araalkyl.
  • Ry is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, araalkyl, alkoxycarbonyl, aryloxycarbonyl, carboxamido, mono- or di-alkylcarbamoyl or alkylsulfonyl.
  • R z is hydrogen (provided that n is 0), alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, araalkyl, amino, mono-alkylamino, di-alkylamino, or hydroxyalkyl.
  • R w , R x ,RY, and R z can be further substituted by amino, fluorine, alkylamino, di-alkylamino, OH or alkoxy.
  • the prefix indicating the number of carbon atoms refers to the total number of carbon atoms in the portion of the heteroalkyl group exclusive of the cyano, oxo, -O-, -OR W , -NR X -, -NR X RY, - S(O) n - and -S(O) n R z portions.
  • Examples include alkoxy, alkoxyalkylene, amino, aminoalkylene, aminocarbonyl, alkylcarbonylamino, and the like.
  • heterocyclo group optionally mono- or di- substituted with an alkyl group means that the alkyl may but need not be present, and the description includes situations where the heterocyclo group is mono- or disubstituted with an alkyl group and situations where the heterocyclo group is not substituted with the alkyl group.
  • Optionally substituted means a ring which is optionally substituted independently with substituents.
  • a site of a group that is unsubstituted may be substituted with hydrogen.
  • stereoisomers Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. "Stereoisomer” and “stereoisomers” refer to compounds that exist in different stereoisomeric forms if they possess one or more asymmetric centers or a double bond with asymmetric substitution and, therefore, can be produced as individual stereoisomers or as mixtures. Stereoisomers include enantiomers and diastereomers.
  • stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”.
  • enantiomers When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof.
  • a mixture containing equal proportions of the enantiomers is called a "racemic mixture".
  • the description is intended to include individual stereoisomers as well as mixtures.
  • the methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art ⁇ see discussion in Chapter 4 of ADVANCED ORGANIC CHEMISTRY, 4th edition J. March, John Wiley and Sons, New York, 1992) differ in the chirality of one or more stereocenters.
  • a proton such as enol-keto and imine-enamine tautomers
  • Protecting group refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group.
  • a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3 rd Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, VoIs. 1-8, 1971-1996, John Wiley & Sons, NY.
  • Representative amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl (“TES”), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”), nitro- veratryloxycarbonyl (“NVOC”) and the like.
  • hydroxy protecting groups include, but are not limited to, those where the hydroxy group is either acylated or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPPS groups) and allyl ethers.
  • salts are meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like.
  • Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally- occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N'- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge, S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19, 1977).
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
  • the present invention provides compounds which are in a prodrug ester form. "Prodrug"s of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment.
  • prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • Prodrugs are frequently, but not necessarily, pharmacologically inactive until converted into the active drug.
  • Prodrugs are typically obtained by masking a functional group in the drug believed to be in part required for activity with a progroup (defined below) to form a promoiety which undergoes a transformation, such as cleavage, under the specified conditions of use to release the functional group, and hence the active drug.
  • the cleavage of the promoiety may proceed spontaneously, such as by way of a hydrolysis reaction, or it may be catalyzed or induced by another agent, such as by an enzyme, by light, by acid or base, or by a change of or exposure to a physical or environmental parameter, such as a change of temperature.
  • the agent may be endogenous to the conditions of use, such as an enzyme present in the cells to which the prodrug is administered or the acidic conditions of the stomach, or it may be supplied exogenously.
  • Progroup refers to a type of protecting group that, when used to mask a functional group within an active drug to form a promoiety, converts the drug into a prodrug.
  • Progroups are typically attached to the functional group of the drug via bonds that are cleavable under specified conditions of use.
  • a progroup is that portion of a promoiety that cleaves to release the functional group under the specified conditions of use.
  • an amide promoiety of the formula -NH-C(O)CH 3 comprises the progroup -C(O)CH 3 .
  • progroups as well as the resultant promoieties, suitable for masking functional groups in the active JAK selective inhibitory compounds to yield prodrugs are well-known in the art.
  • a hydroxyl functional group may be masked as a sulfonate, ester (such as acetate or maleate) or carbonate promoiety, which may be hydrolyzed in vivo to provide the hydroxyl group.
  • An amino functional group may be masked as an amide, carbamate, imine, urea, phosphenyl, phosphoryl or sulfenyl promoiety, which may be hydrolyzed in vivo to provide the amino group.
  • a carboxyl group may be masked as an ester (including methyl, ethyl, pivaloyloxymethyl, silyl esters and thioesters), amide or hydrazide promoiety, which may be hydrolyzed in vivo to provide the carboxyl group.
  • the invention includes those esters and acyl groups known in the art for modifying the solubility or hydrolysis characteristics for use as sustained-release or prodrug formulations. Other specific examples of suitable progroups and their respective promoieties will be apparent to those of skill in the art.
  • Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms.
  • “Solvate” refers to a complex formed by combination of solvent molecules with molecules or ions of the solute.
  • the solvent can be an organic compound, an inorganic compound, or a mixture of both.
  • Some examples of solvents include, but are not limited to, methanol, N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water.
  • the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
  • Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
  • Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present invention. These isomers can be resolved or asymmetrically synthesized using conventional methods to render the isomers "optically pure", i.e., substantially free of its other isomers.
  • a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chrial auxilliary, where the resulting diastereomeric mixture is separated and the auxilliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diasteromers thus formed by fractional crystallization or chromatagraphic means well known in the art, and subsequent recovery of the pure enantiomers.
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
  • administering refers to oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, or the implantation of a slow-release device e.g., a mini-osmotic pump, to a subject.
  • Adminsitration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal).
  • Parenteral administration includes, e.g., intravenous, intramuscular, intra- arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial.
  • Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.
  • An "agonist” or “activator” refers to an agent or molecule that binds to a receptor of the invention, stimulates, increases, opens, activates, facilitates, enhances activation or enzymatic activity, sensitizes or up regulates the activity of a receptor of the invention.
  • an "antagonist” or “inhibitor” refers to an agent or molecule that inhibits or binds to, partially or totally blocks stimulation or activity, decreases, closes, prevents, delays activation or enzymatic activity, inactivates, desensitizes, or down regulates the activity of a receptor of the invention.
  • antagonist also includes a reverse or inverse agonist.
  • condition or disorder responsive to modulation of JAK refers to a condition or disorder associated with inappropriate, e.g., less than or greater than normal, activity of JAK and at least partially responsive to or affected by modulation of JAK (e.g., JAK antagonist or agonist results in some improvement in patient well-being in at least some patients).
  • Inappropriate functional activity of JAK might arise as the result of expression of JAK in cells which normally do not express the receptor, greater than normal production of JAK, or slower than normal metabolic inactivation or elimination of JAK or its active metabolites, increased expression of JAK or degree of intracellular activation (leading to, e.g., inflammatory and immune-related disorders and conditions) or decreased expression of JAK.
  • a condition or disorder associated with JAK may include a "JAK -mediated condition or disorder”.
  • a condition or disorder mediated at least in part by JAK activity refers to a condition or disorder characterized by inappropriate, e.g., greater than normal, JAK activity. Inappropriate JAK functional activity might arise as the result of JAK expression in cells which normally do not express JAK or increased JAK expression or degree of intracellular activation (leading to, e.g., inflammatory and immune-related disorders and conditions).
  • a condition or disorder mediated at least in part by JAK activity may be completely or partially mediated by inappropriate JAK functional activity.
  • a condition or disorder mediated at least in part by JAK activity is one in which modulation of JAK results in some effect on the underlying condition or disorder (e.g., an JAK antagonist results in some improvement in patient well-being in at least some patients).
  • inflammation refers to infiltration of white blood cells (e.g., leukocytes, monocytes, etc.) into the area being treated for restenosis.
  • white blood cells e.g., leukocytes, monocytes, etc.
  • intervention refers to an action that produces an effect or that is intended to alter the course of a disease process.
  • vascular intervention refers to the use of an intravascular procedure such as angioplasty or a stent to open an obstructed blood vessel.
  • intravascular device refers to a device useful for a vascular recanalization procedure to restore blood flow through an obstructed blood vessel.
  • intravascular devices include, without limitation, stents, balloon catheters, autologous venous/arterial grafts, prosthetic venous/arterial grafts, vascular catheters, and vascular shunts.
  • JAK refers to a Janus kinase (RefSeq Accession No. P- 43408) or a variant thereof that is capable of mediating gene expression in vitro or in vivo.
  • JAK variants include proteins substantially homologous to native JAK, i.e., proteins having one or more naturally or non-naturally occurring amino acid deletions, insertions or substitutions (e.g., JAK derivatives, homologs and fragments).
  • the amino acid sequence of JAK variant preferably is at least about 80% identical to a native JAK, more preferably at least about 90% identical, and most preferably at least about 95% identical.
  • leukocyte refers to any of the various blood cells that have a nucleus and cytoplasm, separate into a thin white layer when whole blood is centrifuged, and help protect the body from infection and disease.
  • leukocytes include, without limitation, neutrophils, eosinophils, basophils, lymphocytes, and monocytes.
  • mamal includes, without limitation, humans, domestic animals (e.g., dogs or cats), farm animals (cows, horses, or pigs), monkeys, rabbits, mice, and laboratory animals.
  • modulate refers to the ability of a compound to increase or decrease the function and/or expression of JAK, where such function may include transcription regulatory activity and/or protein-binding. Modulation may occur in vitro or in vivo. Modulation, as described herein, includes the inhibition, antagonism, partial antagonism, activation, agonism or partial agonism of a function or characteristic associated with JAK, either directly or indirectly, and/or the upregulation or downregulation of the expression of JAK, either directly or indirectly. In a preferred embodiment, the modulation is direct.
  • Inhibitors or antagonists are compounds that, e.g., bind to, partially or totally block stimulation, decrease, prevent, inhibit, delay activation, inactivate, desensitize, or downregulate signal transduction.
  • Activators or agonists are compounds that, e.g., bind to, stimulate, increase, open, activate, facilitate, enhance activation, activate, sensitize or upregulate signal transduction.
  • the ability of a compound to inhibit the function of JAK can be demonstrated in a biochemical assay, e.g., binding assay, or a cell-based assay, e.g., a transient transfection assay.
  • Modulators of activity are used to refer to "ligands", “antagonists” and “agonists” identified using in vitro and in vivo assays for activity and their homologs and mimetics. Modulators include naturally occurring and synthetic ligands, antagonists, agonists, molecules and the like. Assays to identify antagonists and agonists include, e.g., applying putative modulator compounds to cells, in the presence or absence of a receptor of the invention and then determining the functional effects on a receptor of the invention activity. Samples or assays comprising a receptor of the invention that are treated with a potential activator, inhibitor, or modulator are compared to control samples without the inhibitor, activator, or modulator to examine the extent of effect.
  • Control samples (untreated with modulators) are assigned a relative activity value of 100%. Inhibition is achieved when the activity value of a receptor of the invention relative to the control is about 80%, optionally 50% or 25-1%. Activation is achieved when the activity value of a receptor of the invention relative to the control is 110%, optionally 150%, optionally 200-500%, or 1000-3000% higher.
  • "Patient” refers to human and non-human animals, especially mammals. Examples of patients include, but are not limited to, humans, cows, dogs, cats, goats, sheep, pigs and rabbits.
  • the term "pharmaceutically acceptable carrier or excipient” means a carrier or excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a “pharmaceutically acceptable carrier or excipient” as used in the specification and claims includes both one and more than one such carrier or excipient.
  • pharmaceutically effective amount refers to the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • therapeutically effective amount includes that amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the condition or disorder being treated. The therapeutically effective amount will vary depending on the compound, the disorder or condition and its severity and the age, weight, etc., of the mammal to be treated.
  • prevent refers to a method of partially or completely delaying or precluding the onset or recurrence of a disorder or condition and/or one or more of its attendant symptoms or barring a subject from acquiring or reacquiring a disorder or condition or reducing a subject's risk of acquiring or reaquiring a disorder or condition or one or more of its attendant symptoms.
  • the phrase "selectively" or “specifically” when referring to binding to a receptor refers to a binding reaction that is determinative of the presence of the receptor, often in a heterogeneous population of receptors and other biologies.
  • the compounds bind to a particular receptor at least two times the background and more typically more than 10 to 100 times background.
  • Specific binding of a compound under such conditions requires a compound that is selected for its specificity for a particular receptor.
  • small organic molecules can be screened to obtain only those compounds that specifically or selectively bind to a selected receptor and not with other receptors or proteins.
  • a variety of assay formats may be used to select compounds that are selective for a particular receptor. For example, High-throughput screening assays are routinely used to select compounds that are selective for a particular a receptor.
  • the "subject” is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In preferred embodiments, the subject is a human.
  • treat includes partially or completely delaying, alleviating , mitigating or reducing the intensity of one or more attendant symptoms of a disorder or condition and/or alleviating, mitigating or impeding one or more causes of a disorder or condition.
  • Treatments according to the invention may be applied preventively, prophylactically, pallatively or remedially.
  • a blood vessel refers to any of the vessels through which blood circulates in the body.
  • the lumen of a blood vessel refers to the inner open space or cavity of the blood vessel.
  • the present invention provides one group of embodiments, a compound having the formula I:
  • R Ia is (a) C 3 . 8 cycloalkyl, optionally substituted with from 1 to 3 substituents R ld wherein each R ld is independently selected from the group consisting of C].
  • 8 alkyl, C 2 . 8alkenyl, C 2 - 8 alkynyl, hydroxyl, halogen, Ci -8 heteroalkyl, cyano, aryl, heteroaryl, heterocyclyl and heterocyclylcarbonyl; or if on adjacent carbon atoms of the C 3 . 8 cycloalkyl, may be combined with the atoms to which each are attached to form an aryl group;
  • Ci_ 8 alkyl optionally substituted with from 1 to 3 substituents selected from the group consisting of C 2 . 8 alkenyl, C 2 . 8 alkynyl, amino, hydroxyl, halogen, Q.sheteroalkyl, cyano, C 3 _ 8 cycloalkyl, aryl, haloaryl, Ci_ 8 alkylaryl, Q-galkoxyaryl, heteroaryl, C 3 .
  • heterocyclyl optionally substituted with from 1 to 3 substituents selected from the group consisting of Ci_ 8 alkyl, C 2 - 8 alkenyl, C 2 - 8 alkynyl, hydroxyl, halogen, C 1- 8 heteroalkyl, cyano, aryl, heteroaryl, heterocyclyl and heterocyclylcarbonyl;
  • aryl optionally substituted with from 1 to 3 substituents selected from the group consisting of Ci_ 8 alkyl, C 2 - 8 alkenyl, C 2 - 8 alkynyl, hydroxyl, halogen, Q.sheteroalkyl, cyano, aryl, heteroaryl, heterocyclyl and heterocyclylcarbonyl, amino and alkylsulfonyl; and
  • heteroaryl optionally substituted with from 1 to 3 substituents selected from the group consisting of Ci_ 8 alkyl, C 2 - 8 alkenyl, C 2 - 8 alkynyl, hydroxyl, halogen, C 1 . 8heteroalkyl, cyano, aryl, heteroaryl, heterocyclyl and heterocyclylcarbonyl;
  • R lb is H or C,. 8 alkyl
  • R lc is H, Ci -8 alkyl or halogen
  • R 2 is H, Ci. 8 alkyl, Cj.sheteroalkyl, heterocyclylCi.salkoxy, halogen or heterocyclyl;
  • R 3 is H or Ci -8 alkyl or C 3 . 8 cycloalkyl
  • R 4 is selected from the group consisting amino, Ci -8 alkyl, aminoCi_ 8 alkyl, C 2 . 8alkenyl, C 2 . 8 alkynyl, Ci_ 8 heteroalkyl, C 3-8 cycloalkyl, aryl, heteroaryl and C 3 . 8 heterocyclyl; and m is O, 1, 2 or 3.
  • R la is (a) C 3-8 cycloalkyl, optionally substituted with from 1 to 3 substituents R ld wherein each R ld is independently selected from the group consisting of Ci_ 8 alkyl, C 2 - 8 alkenyl, C 2-8 alkynyl, hydroxyl, halogen, Q.gheteroalkyl, cyano, aryl, heteroaryl, heterocyclyl and heterocyclylcarbonyl; or if on adjacent carbon atoms of the C 3-8 cycloalkyl, may be combined with the atoms to which each are attached to form an aryl group;
  • Ci_ 8 alkyl optionally substituted with from 1 to 3 substituents selected from the group consisting of C 2-8 alkenyl, C 2 _ 8 alkynyl, amino, hydroxyl, halogen, Q-sheteroalkyl, cyano, C ⁇ scycloalkyl, aryl, haloaryl, Ci_ 8 alkylaryl, C 1-8 alkoxyaryl, heteroaryl, C 3 . 8heterocyclyl and Q.sheterocyclylcarbonyl; R lb is H or d-galkyl;
  • R lc is H, Ci -8 alkyl or halogen
  • R 2 is H, Ci-galkyl, Ci -8 alkoxy or halogen
  • R 3 is H or Ci -8 alkyl
  • R 4 is selected from the group consisting amino, Ci -8 alkyl, C 2 . 8 alkenyl, C 2 _ 8 alkynyl, Ci -8 heteroalkyl, C 3 _ 8 cycloalkyl, aryl, heteroaryl and C 3 . 8 heterocyclyl; and m is 0, 1, 2 or 3.
  • the present invention provides another group of embodiments, a compound wherein Y 1 is N. In another group of embodiments, Y 1 is CH.
  • the present invention provides one group of embodiments, a compound having the formula Ia:
  • R la is (a) optionally substituted with from 1 to 3 substituents R ld wherein each R ld is independently selected from the group consisting of C 1-8 alkyl, C 2- 8 alkenyl, C 2-8 alkynyl, hydroxyl, halogen, Q.sheteroalkyl, cyano, aryl, heteroaryl, heterocyclyl and heterocyclylcarbonyl; or if on adjacent carbon atoms of the C 3-8 cycloalkyl, may be combined with the atoms to which each are attached to form an aryl group; (b) C] -8 alkyl, optionally substituted with from 1 to 3 substituents selected from the group consisting of C 2 - 8 alkenyl, C 2 - 8 alkynyl, amino, hydroxyl, halogen, Ci -8 heteroalkyl, cyano, C 3 _ 8 cycloalkyl, aryl, hal
  • R lb is H or Ci_ 8 alkyl
  • R 2 is H, Ci_ 8 alkyl, Ci -8 alkoxy or halogen
  • R 3 is H or Ci- ⁇ alkyl
  • R 4 is selected from the group consisting Ci- 8 alkyl, Ci- 8 heteroalkyl, C 3-8 cycloalkyl, and amino; and m is 0, 1, 2 or 3.
  • the present invention provides another group of embodiments, a compound wherein R 3 is H.
  • the present invention provides another group of embodiments, a compound having the formula (Ib):
  • R 1 is (a) C 3-8 cycloalkyl, optionally substituted with hydroxyl and aryl;
  • Ci_ 8 alkyl optionally substituted with from 1 to 3 substituents selected from the group consisting of C 2-8 alkynyl, hydroxyl, halogen, Ci_ 8 alkoxy, cyano, aminocarbonyl, C ⁇ scyclopropyl, aryl, haloaryl, Q.galkylaryl, C 1-8 alkoxyaryl, heteroaryl, and heterocyclyl, heterocyclylcarbonyl;
  • R 2a is H, d-salkyl, Ci- 8 alkoxy or halogen;
  • R 2b is H, Ci -8 alkyl, Q-galkoxy or halogen
  • R 4 is selected from the group consisting Ci_ 8 alkyl, Ci -8 alkoxyCi_ 8 alkylene, C 3- 8 cycloalkyl, Ci -8 alkoxy, and amino.
  • R 1 is C 3 . 8 cycloalkyl, optionally substituted with hydroxy.
  • R 1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, optionally substituted with hydroxy.
  • R 1 is Ci- salkyl, optionally substituted with from 1 to 3 substituents selected from the group consisting of C 2 _galkynyl, hydroxy, halogen, Ci_ 8 alkoxy, cyano, aminocarbonyl, C 3 - 8 cycloalkyl, aryl, haloaryl, heteroaryl, heterocyclyl and heterocyclylcarbonyl.
  • R 1 is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 or -CH 2 CH 2 CH(CH 3 ) 2 .
  • R 1 is Ci_ 8 alkyl, optionally substituted with from 1 to 3 substituents selected from the group consisting of C 2-8 alkynyl, hydroxy, halogen, Ci- 8 alkoxy, cyano, aminocarbonyl and C 3 _ 8 cycloalkyl.
  • R 1 is - CH 2 C ⁇ CH, -CH 2 CF 3 , -CH 2 -CPr, -CH 2 CH 2 OCH 3 or CH 2 CH 2 CH 2 OCH 3 .
  • R 1 is Ci_ 8 alkyl, substituted with from 1 to 3 substituents selected from the group consisting of aryl, haloaryl, Ci -8 alkylaryl, Ci_ 8 alkoxyaryl, heteroaryl, heterocyclyl and heterocyclylcarbonyl.
  • R 2a is H, methyl, methoxy, fluoro or chloro and R 2b is H, methyl, methoxy, fluoro or chloro.
  • R 2a is chloro and R 2b is H.
  • Y 2 is -CH or -CH-CH-;
  • R 5 is H, Ci-salkyl or hydroxyCi.salkylene
  • R 6 is C 2-8 alkynyl, hydroxyl, halogen, Ci_ 8 alkoxy, cyano, aminocarbonyl, C 3- scyclopropyl, aryl, haloaryl, heteroaryl, heterocyclyl and heterocyclylcarbonyl or Q-galkyl, optionally substituted with from 1 to 3 substituents selected from the group consisting of C 2 - 8 alkynyl, hydroxyl, halogen, Q.salkoxy, cyano, aminocarbonyl, C 3-8 cyclopropyl, aryl, haloaryl, Ci- 8 alkylaryl, Ci.galkoxyaryl, heteroaryl, heterocyclyl and heterocyclylcarbonyl.
  • R 4 is Ci.gheteroalkyl, selected from the group consisting of Ci_ 8 alkoxy and Ci-salkoxyCi-salkylene.
  • R 5 is CH 3 ;
  • R 6 is Ph or
  • R 8 is selected from the group consisting of Cj-salkyl, halogen, C]. 8 alkoxy, or may be taken together to form a heterocyclic ring; and q is 0, 1 , 2 or 3; the wavy line indicates the point of attachment to the rest of the molecule.
  • R 5 is Ci-salkyl or hydroxyCi-salkylene; or may be taken together with R 8 to form a cyclic ring;
  • R 7 is Ci-salkyl, hydroxyl or d-galkoxy
  • R 8 is selected from the group consisting of Ci -8 alkyl, halogen and Ci-salkoxy, or may be taken together to form a heterocyclic ring; and p is 0, 1, 2, or 3; and q is 0, 1, 2 or 3.
  • R 5 is Ci_galkyl or hydroxyCi.salkylene; or may be taken together with R 8a or R 8b to form a cyclic ring;
  • R 8a is H, halogen, or may be taken together with R 5 to form 5-6 membered carbocyclic ring;
  • R 8b is H, halogen or, or may be taken together with R 8a to form a heterocyclic ring;
  • R 8c is H, Q-galkyl, halogen or Ci -8 alkoxy, or may be taken together with R 8b to form a heterocyclic ring;
  • R 8d is H
  • R 8e is H, halogen or may be taken together with R 5 to form 5-6 membered carbocyclic ring.
  • R 9 is heteroCi -8 alkyl.
  • the present invention provides another group of embodiments, a compound having the formula Ig:
  • R 10 is H or C 1-8 alkyl; or may be taken together with R 11 and the nitrogen atom to which each is attached to form a heterocyclic ring;
  • R 1 ' is H or Ci_salkyl; or may be taken together with R 10 and the nitrogen atom to which each is attached to form a heterocyclic ring.
  • the compound has the formula Ih:
  • R 1 and R 4 are C 3-8 cycloalkyl.
  • the compound has the formula (Ii):
  • R 4 is Ci_galkyl or heterocyclyl
  • R 4 is selected from the group consisting of -CH 3 , -CH 2 CH 3 , -NH 2 , -NHCH 3 , -NCH 2 CH 3 , -N(CH 3 ) 2 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , - CH 2 OCH 3 , -CH 2 CONH 2 , cPr and cBu.
  • R 4 has the formula:
  • R 12 is selected from the group consisting of H and OH, r is 0 or 1 ; and the wavy line indicates the point of attachment to the rest of the molecule.
  • R 4 has the formula:
  • R 12 is selected from the group consisting of H and OH; and the wavy line indicates the point of attachment to the rest of the molecule.
  • the present invention provides another group of embodiments, a compound selected from the group consisting of: Methyl 3-(5-carbamoyl-4-(2,2,2- trifluoroethylamino)pyrimidin-2-ylamino)phenylcarbamate; 2-(3-
  • the present invention provides another group of embodiments, a compound selected from the group consisting of: 2-(3-acetamidophenylamino)-4-(piperidin-3- ylmethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-((l- carbamoylpiperidin-3-yl)methylamino)pyrimidine-5-carboxamide; 2-(3- acetamidophenylamino)-4-(( 1 -(4-fluorophenylcarbamoyl)piperidin-3- yl)methylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-((l- acetylpiperidin-3-yl)methylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)- 4-((l-(methylsulfonyl)piperidamide; 2-
  • the present invention provides that the compound is not a compound selected from the group consisting of:
  • any of the above embodiments may also be combined with other embodiments listed herein, to form other embodiments of the invention.
  • listing of groups includes embodiments wherein one or more of the elements of those groups is not included.
  • the compounds of the present invention may be prepared by known organic synthesis techniques, including the methods described in more detail in the Examples.
  • the compounds of formula (I) above may be made by the following Figure 1 , wherein all substituents are as defined above unless indicated otherwise.
  • Dihydroxy compound, A is dichlorinated with a chlorinating agent, such as phosphorous oxychloride.
  • a chlorinating agent such as phosphorous oxychloride.
  • Selective displacement of the one of the activated groups by an appropriate amine, such as R or R (available commercially or synthesized using methods known to those skilled in the art), under basic conditions, such as with diisopropylamine (DIA), provides compounds of formula D or E.
  • Displacement of the other activated group with an appropriate amine, such as R (available commercially or synthesized using methods known to those skilled in the art), gives the desired product F, wherein R 1 and R 2 are represented herein in Formula I.
  • W 1 or W 2 comprises a terminal heteroatom
  • the protecting group can be removed using methods known to those skilled in the art to yield compounds of structure F.
  • the compounds of the present invention may generally be utilized as the free base. Alternatively, the compounds of this invention may be used in the form of acid addition salts as described below.
  • the activity of a specified compound as an inhibitor of a JAK may be assessed in vitro or in vivo.
  • the activity of a specified compound can be tested in a cellular assay. Selectivity could also be ascertained in biochemical assays with isolated kinases.
  • Similar types of assays can be used to assess JAK inhibitory activity and to determine the degree of selectivity of the particular compound as compared to syk.
  • One means of assaying for such inhibition is detection of the effect of the compounds of the present invention on the upregulation of downstream gene products.
  • B-cells are stimulated with the cytokine Interleukin-4 (IL-4) leading to the activation of the JAK/Stat pathway through phosphorylation of the JAK family kinases, JAKl and JAK3, which in turn phosphorylate and activate the transcription factor Stat-6.
  • IL-4 cytokine Interleukin-4
  • One of the genes upregulated by activated Stat-6 is the low affinity IgE receptor, CD23.
  • IL-6 stimulation of Ramos B-cells induces JAKs 1, 2, and Tyk2, leading to Stat-3 and Erk phosphorylation.
  • JAKs 1, 2, and Tyk2 leading to Stat-3 and Erk phosphorylation.
  • cells are subjected to intracellular flow cytometry to measure the ability of compound to inhibit these phosphorylation events.
  • the CellSensor irfl-bla HEL cell line expressing the beta-lactamase reporter gene controlled by Stat5 will be used (Invitrogen, Carlsbad, CA).
  • JAK2 inhibitory activity of compounds [0118] Stimulation with IL- l ⁇ through the IL-I ⁇ receptor activates the TRAF6/NF ⁇ B pathway resulting in up-regulation of ICAM-I. IFN ⁇ induces ICAM-I up-regulation through activation of the JAK1/JAK2 pathway.
  • the up-regulation of ICAM-I can be quantified by flow cytometry across a compound dose curve and EC 50 values are calculated. Exemplary assays of this type are described in greater detail in the Examples.
  • Active compounds as described herein generally inhibit the JAK pathway with an IC 50 in the range of about 1 mM or less, as measured in the assays described herein.
  • IC 50 in the range of about 1 mM or less, as measured in the assays described herein.
  • compounds which exhibit lower IC 50 S (on the order, for example, of 100 ⁇ M, 75 ⁇ M, 50 ⁇ M, 40 ⁇ M, 30 ⁇ M, 20 ⁇ M, 15 ⁇ M, 10 ⁇ M, 5 ⁇ M, 1 ⁇ M, 500 nM, 100 nM, 10 nM, 1 nM, or even lower) can be particularly useful in therapeutic applications.
  • the compound can be assayed for activity with the desired cell type and counter- screened for a lack of activity against other cell types.
  • the desired degree of "inactivity" in such counter screens, or the desired ratio of activity vs. inactivity, may vary for different situations and can be selected by the user.
  • the active compounds also typically inhibit IL-4 stimulated expression of CD23 in B-cells with an IC 5O in the range of about 20 ⁇ M or less, typically in the range of about 10 ⁇ M, 1 ⁇ M, 500 nM, 100 nM, 10 nM, 1 nM, or even lower.
  • a suitable assay that can be used is the assay described in the Examples, "Assay for Ramos B-cell Line Stimulated with IL-4.”
  • the active compounds of the present invention have an IC 5O of less than or equal to 5 ⁇ M, greater than 5 ⁇ M but less than 20 ⁇ M, greater than 20 ⁇ M, or greater than 20 ⁇ M but less than 50 ⁇ M in the assay described in the Examples.
  • the active compounds also typically inhibit expression of ICAMl (CD54) induced by IFN ⁇ exposure in A549 cells with an IC 50 in the range of about 20 ⁇ M or less, typically in the range of about 10 ⁇ M, 1 ⁇ M, 500 nM, 100 nM, 10 nM, 1 nM, or even lower.
  • the IC 50 against expression of ICAM (CD54) in IFN ⁇ stimulated cells can be determined in a functional cellular assay with an isolated A549 cell line. Suitable assays that can be used are the assays described in the Examples, "A549 Epithelial Line Stimulated with IFN ⁇ ".
  • the active compounds of the present invention have an IC 50 of less than or equal to 20 ⁇ M, greater than 20 ⁇ M, or greater than 20 ⁇ M but less than 50 ⁇ M in the assays described in the Examples.
  • compositions and Methods of Administration [0122] The present invention further provides compositions comprising one or more compounds of formula (I) or a pharmaceutically acceptable salt, ester or prodrug thereof, and a pharmaceutically acceptable carrier or diluent. It will be appreciated that the compounds of formula (I)) in this invention may be derivatized at functional groups to provide prodrug derivatives which are capable of conversion back to the parent compounds in vivo.
  • prodrugs examples include the physiologically acceptable and metabolically labile ester derivatives, such as methoxymethyl esters, methylthiomethyl esters, or pivaloyloxymethyl esters derived from a hydroxyl group of the compound or a carbamoyl moiety derived from an amino group of the compound. Additionally, any physiologically acceptable equivalents of the compounds of formula (I), similar to metabolically labile esters or carbamates, which are capable of producing the parent compounds of formula (I) in vivo, are within the scope of this invention.
  • salts refers to any acid or base addition salt whose counter-ions are non-toxic to the patient in pharmaceutical doses of the salts.
  • a host of pharmaceutically acceptable salts are well known in the pharmaceutical field. If pharmaceutically acceptable salts of the compounds of this invention are utilized in these compositions, those salts are preferably derived from inorganic or organic acids and bases.
  • acid salts include the following: acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, lucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenyl- propionate, picrate, pivalate, propionate, succinate, tartrate,
  • Pharmaceutically acceptable base addition salts include, without limitation, those derived from alkali or alkaline earth metal bases or conventional organic bases, such as triethylamine, pyridine, piperidine, morpholine, N-methylmorpholine, ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
  • alkali or alkaline earth metal bases or conventional organic bases such as triethylamine, pyridine, piperidine, morpholine, N-methylmorpholine, ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamine salts, N-methyl-D
  • the basic nitrogen-containing groups may be quaternized with agents like lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides, such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides, such as benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.
  • lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides
  • dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides, such as de
  • compositions and methods of this invention may also be modified by appending appropriate functionalities to enhance selective biological properties.
  • modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system, etc.), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
  • compositions of the invention can be manufactured by methods well known in the art such as conventional granulating, mixing, dissolving, encapsulating, lyophilizing, or emulsifying processes, among others.
  • Compositions may be produced in various forms, including granules, precipitates, or particulates, powders, including freeze dried, rotary dried or spray dried powders, amorphous powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions.
  • Formulations may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of drug calculated to produce the desired onset, tolerability, and/or therapeutic effects, in association with a suitable pharmaceutical excipient (e.g., an ampoule).
  • a suitable pharmaceutical excipient e.g., an ampoule
  • more concentrated compositions may be prepared, from which the more dilute unit dosage compositions may then be produced.
  • the more concentrated compositions thus will contain substantially more than, e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more times the amount of one or more JAK inhibitors.
  • compositions typically include a conventional pharmaceutical carrier or excipient and may additionally include other medicinal agents, carriers, adjuvants, diluents, tissue permeation enhancers, solubilizers, and the like.
  • the composition will contain about 0.01% to about 90%, preferably about 0.1% to about 75%, more preferably about 0.1% to 50%, still more preferably about 0.1% to 10% by weight of one or more JAK inhibitors, with the remainder consisting of suitable pharmaceutical carrier and/or excipients.
  • Appropriate excipients can be tailored to the particular composition and route of administration by methods well known in the art, e.g., REMINGTON'S PHARMACEUTICAL SCIENCES, supra.
  • compositions include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances, such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen
  • excipients include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, saline, syrup, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, and polyacrylic acids such as Carbopols.
  • compositions can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying agents; suspending agents; preserving agents such as methyl-, ethyl-, and propyl-hydroxy-benzoates; pH adjusting agents such as inorganic and organic acids and bases; sweetening agents; and flavoring agents.
  • lubricating agents such as talc, magnesium stearate, and mineral oil
  • wetting agents such as talc, magnesium stearate, and mineral oil
  • emulsifying agents such as methyl-, ethyl-, and propyl-hydroxy-benzoates
  • pH adjusting agents such as inorganic and organic acids and bases
  • sweetening agents and flavoring agents.
  • administration can be, for example, oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intra-joint, parenteral, intra-arteriole, intradermal, intraventricular, intracranial, intraperitoneal, intralesional, intranasal, rectal, vaginal, by inhalation or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra- synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally or intravenously.
  • the formulations of the invention may be designed as short- acting, fast-releasing, or long- acting.
  • compositions of this invention are formulated for pharmaceutical administration to a mammal, preferably a human being.
  • compositions of the present invention containing one or more JAK inhibitors can be administered repeatedly, e.g., at least 2, 3, 4, 5, 6, 7, 8, or more times, or the composition may be administered by continuous infusion.
  • Suitable sites of administration include, but are not limited to, skin, bronchial, gastrointestinal, anal, vaginal, eye, and ear.
  • the formulations may take the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as, for example, tablets, pills, capsules, powders, solutions, suspensions, emulsions, suppositories, retention enemas, creams, ointments, lotions, gels, aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.
  • compositions of this invention may be in any orally acceptable dosage form, including tablets, capsules, cachets, emulsions, suspensions, solutions, syrups, elixirs, sprays, boluses, lozenges, powders, granules, and sustained-release formulations.
  • Suitable excipients for oral administration include pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, gelatin, sucrose, magnesium carbonate, and the like.
  • carriers that are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • the compositions take the form of a pill, tablet, or capsule, and thus, the composition can contain, along with one or more JAK inhibitors, a diluent such as lactose, sucrose, dicalcium phosphate, and the like; a disintegrant such as starch or derivatives thereof; a lubricant such as magnesium stearate and the like; and/or a binder such a starch, gum acacia, polyvinylpyrrolidone, gelatin, cellulose and derivatives thereof.
  • a tablet can be made by any compression or molding process known to those of skill in the art.
  • Compressed tablets may be prepared by compressing in a suitable machine the JAK inhibitors in a free-flowing form, e.g., a powder or granules, optionally mixed with accessory ingredients, e.g., binders, lubricants, diluents, disintegrants, or dispersing agents. Molded tablets can be made by molding in a suitable machine a mixture of the powdered JAK inhibitors with any suitable carrier.
  • compositions of this invention may be in the form of suppositories for rectal administration. These may be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax, polyethylene glycol (PEG), hard fat, and/or hydrogenated cocoglyceride.
  • a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • Such materials include cocoa butter, beeswax, polyethylene glycol (PEG), hard fat, and/or hydrogenated cocoglyceride.
  • Compositions suitable for rectal administration may also comprise a rectal enema unit containing one or more JAK inhibitors and pharmaceutically-acceptable vehicles (e.g., 50% aqueous ethanol or an aqueous salt solution) that are physiologically compatible with the rectum and/or
  • the rectal enema unit contains an applicator tip protected by an inert cover, preferably comprised of polyethylene, lubricated with a lubricant such as white petrolatum, and preferably protected by a one-way valve to prevent back-flow of the dispensed formula.
  • the rectal enema unit is also of sufficient length, preferably two inches, to be inserted into the colon via the anus.
  • Liquid compositions can be prepared by dissolving or dispersing one or more JAK inhibitors and optionally one or more pharmaceutically acceptable adjuvants in a carrier such as, for example, aqueous saline, aqueous dextrose, glycerol, ethanol, and the like, to form a solution or suspension, e.g., for oral, topical, or intravenous administration.
  • a carrier such as, for example, aqueous saline, aqueous dextrose, glycerol, ethanol, and the like
  • Pharmaceutical formulations may be prepared as liquid suspensions or solutions using a sterile liquid, such as oil, water, alcohol, and combinations thereof.
  • Pharmaceutically suitable surfactants, suspending agents or emulsifying agents may be added for oral or parenteral administration.
  • Suspensions may include oils, such as peanut oil, sesame oil, cottonseed oil, corn oil and olive oil.
  • Suspension preparation may also contain esters of fatty acids, such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides.
  • Suspension formulations may include alcohols, such as ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol.
  • Ethers such as poly(ethyleneglycol), petroleum hydrocarbons, such as mineral oil and petrolatum, and water may also be used in suspension formulations.
  • compositions of this invention may also be in a topical form, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • the composition containing one or more JAK inhibitors can be in the form of emulsions, lotions, gels, foams, creams, jellies, solutions, suspensions, ointments, and transdermal patches.
  • Topical application for the lower intestinal tract may be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically- transdermal patches may also be used.
  • the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutical compositions may be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters, wax, cetyl alcohol, 2- octyldodecanol, benzyl alcohol and water.
  • compositions of this invention may also be administered by nasal aerosol or inhalation.
  • the compositions can be delivered as a dry powder or in liquid form via a nebulizer.
  • Such compositions are prepared according to techniques known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons and/or other conventional solubilizing or dispersing agents.
  • the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative, such as benzylalkonium chloride.
  • the pharmaceutical compositions may be formulated in an ointment, such as petrolatum.
  • compositions can be in the form of sterile injectable solutions and sterile packaged powders.
  • injectable solutions are formulated at a pH of about 4.5 to about 7.5.
  • Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • Compounds may be formulated for parenteral administration by injection such as by bolus injection or continuous infusion.
  • a unit dosage form for injection may be in ampoules or in multi- dose containers.
  • compositions of the present invention can also be provided in a lyophilized form.
  • Such compositions may include a buffer, e.g., bicarbonate, for reconstitution prior to administration, or the buffer may be included in the lyophilized composition for reconstitution with, e.g., water.
  • the lyophilized composition may further comprise a suitable vasoconstrictor, e.g., epinephrine.
  • the lyophilized composition can be provided in a syringe, optionally packaged in combination with the buffer for reconstitution, such that the reconstituted composition can be immediately administered to a patient.
  • a therapeutically effective dose may vary depending upon the route of administration and dosage form.
  • the representative compound or compounds of the invention is a formulation that exhibits a high therapeutic index.
  • the therapeutic index is the dose ratio between toxic and therapeutic effects which can be expressed as the ratio between LD5 0 and ED 50 .
  • the LD 50 is the dose lethal to 50% of the population and the ED 50 is the dose therapeutically effective in 50% of the population.
  • the LD 50 and ED 50 are determined by standard pharmaceutical procedures in animal cell cultures or experimental animals.
  • compositions are generally known to those skilled in the art and are included in the invention. It should be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex and diet of the patient, and the time of administration, rate of excretion, drug combination, judgment of the treating physician and severity of the particular disease being treated. The amount of active ingredient(s) will also depend upon the particular compound and other therapeutic agent, if present, in the composition.
  • the invention provides methods of inhibiting or decreasing JAK activity as well as treating or ameliorating a JAK associated state, symptom, condition, disorder or disease in a patient in need thereof ⁇ e.g., human or non-human).
  • the JAK associated state, symptom, condition, disorder or disease is mediated, at least in part by JAK activity.
  • the present invention provides a method for treating a condition or disorder mediated at least in part by JAK activity is cardiovascular disease, inflammatory disease or autoimmune disease.
  • the compounds described herein are also potent and/or selective inhibitors of JAKs.
  • the compounds can be used in a variety of in vitro, in vivo, and ex vivo contexts to regulate or inhibit JAK activity, signaling cascades in which JAKs play a role, and the biological responses effected by such signaling cascades.
  • the compounds can be used to inhibit JAK, either in vitro or in vivo, in virtually any cell type expressing the JAK, such as in hematopoietic cells in which, for example, JAK3 is predominantly expressed. They may also be used to regulate signal transduction cascades in which JAKs, particularly JAK3, play a role.
  • Such JAK-dependent signal transduction cascades include, but are not limited to, the signaling cascades of cytokine receptors that involve the common gamma chain, such as, for example, the IL-4, IL-7, IL-5, IL-9, IL-15 and IL-21, or EL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 receptor signaling cascades.
  • the compounds may also be used in vitro or in vivo to regulate, and in particular to inhibit, cellular or biological responses affected by such JAK-dependent signal transduction cascades.
  • Such cellular or biological responses include, but are not limited to, IL-4/Ramos CD23 upregulation and IL-2 mediated T-cell proliferation.
  • JAK mediated diseases include, but are not limited to, the following: allergies; asthma; autoimmune diseases such as transplant rejection (e.g., kidney, heart, lung, liver, pancreas, skin, small intestine, large intestine, host versus graft reaction (HVGR), and graft versus host reaction (GVHR)), rheumatoid arthritis, and amyotrophic lateral sclerosis; T-cell mediated autoimmune diseases such as multiple sclerosis, psoraiasis, and Sjogren's syndrome; Type II inflammatory diseases such as vascular inflammation (including vasculitis, arteritis, atherosclerosis, and coronary artery disease); diseases of the central nervous system such as stroke;
  • Examples of diseases that are mediated, at least in part, by JAKs that can be treated or prevented according to the methods include, but are not limited to, allergies, asthma, autoimmune diseases such as transplant rejection (e.g., kidney, heart, lung, liver, pancreas, skin, host versus graft reaction (HVGR), etc.), rheumatoid arthritis, and amyotrophic lateral sclerosis, multiple sclerosis, psoraiasis and Sjogren's syndrome, Type II inflammatory disease such as vascular inflammation (including vasculitis, ateritis, atherosclerosis and coronary artery disease) or other inflammatory diseases such as osteoarthritis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, idiopathic inflammatory bowel disease, irritable bowel syndrome, spastic colon, low grade scarring (e.g., scleroderma, increased fibrosis, keloids, post-surgical scars, pulmonary fibrosis,
  • this invention provides a method of inhibiting an activity of a JAK, comprising contacting the JAK with an amount of a compound effective to inhibit an activity of the JAK, wherein the compound is selected from the compounds of this invention.
  • the method is carried out in vivo.
  • this invention provides a method of inhibiting an activity of a JAK, comprising contacting in vitro a JAK3 with an amount of a compound effective to inhibit an activity of the JAK, wherein the compound is selected from the compounds of this invention.
  • the compounds can be used to treat and/or prevent rejection in organ and/or tissue transplant recipients (i.e., treat and/or prevent allorgraft rejection). Allografts can be rejected through either a cell-mediated or humoral immune reaction of the recipient against transplant (histocompability) antigens present on the membranes of the donor's cells. The strongest antigens are governed by a complex of genetic loci termed human leukocyte group A (HLA) antigens. Together with the ABO blood groups antigens, they are the chief transplantation antigens detectable in humans.
  • HLA human leukocyte group A
  • Rejection following transplantation can generally be broken into three categories: hyperacute, occurring hours to days following transplantation; acute, occurring days to months following transplantation; and chronic, occurring months to years following transplantation.
  • Hyperacute rejection is caused mainly by the production of host antibodies that attack the graft tissue.
  • antibodies are observed in the transplant vascular very soon after transplantation. Shortly thereafter, vascular clotting occurs, leading to ischemia, eventual necrosis and death.
  • the graft infarction is unresponsive to known immunosuppressive therapies.
  • pre-transplant screening is used to significantly reduce hyperacute rejection. As a consequence of this screening, hyperacute rejection is relatively uncommon today.
  • Acute rejection is thought to be mediated by the accumulation of antigen specific cells in the graft tissue.
  • the T-cell-mediated immune reaction against these antigens is the principle mechanism of acute rejection. Accumulation of these cells leads to damage of the graft tissue. It is believed that both CD4+ helper T-cells and CD8+ cytotoxic T-cells are involved in the process and that the antigen is presented by donor and host dendritic cells. The CD4+ helper T-cells help recruit other effector cells, such as macrophapges and eosinophils, to the graft. Accessing T-cell activation signal transduction cascades (for example, CD28, CD40L, and CD2 cascades) are also involved.
  • T-cell activation signal transduction cascades for example, CD28, CD40L, and CD2 cascades
  • the cell-mediated acute rejection can be reversed in many cases by intensifying immunotherapy. After successful reversal, severely damaged elements of the graft heal by fibrosis and the remainder of the graft appears normal. After resolution of acute rejection, dosages of immunosuppressive drugs can be reduced to very low levels.
  • Chronic rejection which is a particular problem in renal transplants, often progresses insidiously despite increased immunosuppressive therapy. It is thought to be due, in large part, to cell-mediated Type IV hypersensitivity. The pathologic profile differs from that of acute rejection.
  • the arterial endothelium is primarily involved with extensive proliferation that may gradually occlude the vessel lumen, leading to ischemia, fibrosis, a thickened intima, and atherosclerotic changes.
  • Chronic rejection is mainly due to a progressive obliteration of graft vasculature and resembles a slow, vasculitic process.
  • CD8 cytotoxic T-cells and CD4 helper T cells recognize either intracellular or extracellular synthesized antigen when it is complexed, respectively, with either Class I or Class II MHC molecules. Macrophages function as antigen-presenting cells and release IL-I, which promotes proliferation of helper T-cells. Helper T-cells release interferon gamma and IL-2, which together regulate delayed hyperactivity reactions mediated by macrophage activation and immunity mediated by T cells. In the case of organ transplant, the cytotoxic T-cells destroy the graft cells on contact.
  • the compounds described herein can be used to treat and/or prevent many aspects of transplant rejection, and are particularly useful in the treatment and/or prevention of rejection reactions that are mediated, at least in part, by T-cells, such as HVGR or GVHR.
  • the compounds can also be used to treat and/or prevent chronic rejection in transplant recipients and, in particular, in renal transplant recipients.
  • the compound can also be administered to a tissue or an organ prior to transplanting the tissue or organ in the transplant recipient.
  • this invention provides a method of treating a T-cell mediated autoimmune disease, comprising administering to a patient suffering from such an autoimmune disease an amount of a compound effective to treat the autoimmune disease wherein the compound is selected from the compounds of the invention.
  • the autoimmune disease is multiple sclerosis (MS), psoraisis, or Sjogran's syndrome.
  • MS multiple sclerosis
  • psoraisis psoraisis
  • Sjogran's syndrome Such autoimmune disease include, but are not limited to, those autoimmune diseases that are frequently designated as single organ or single cell-type autoimmune disorders and those autoimmune disease that are frequently designated as involving systemic autoimmune disorder.
  • Non-limiting examples of diseases frequently designated as single organ or single cell-type autoimmune disorders include: Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Graves' disease, primary biliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis and membranous glomerulopathy.
  • Non-limiting examples of diseases often designated as involving systemic autoimmune disorder include: systemic lupus erythematosis, rheumatoid arthritis, Sjogren's syndrome, Reiter's syndrome, polymyositis-dermatomyositis, systemic sclerosis, polyarteritis nodosa, multiple sclerosis and bullous pemphigoid.
  • Additional autoimmune diseases which can be .beta.-cell (humoral) based or T-cell based, include Cogan's syndrome, ankylosing spondylitis, Wegener's granulomatosis, autoimmune alopecia, Type I or juvenile onset diabetes, and thyroiditis.
  • the types of autoimmune diseases that may be treated or prevented with such prodrugs generally include those disorders involving tissue injury that occurs as a result of a humoral and/or cell-mediated response to immunogens or antigens of endogenous and/or exogenous origin. Such diseases are frequently referred to as diseases involving the nonanaphylactic (i.e., Type II, Type III and/or Type IV) hypersensitivity reactions.
  • Type I hypersensitivity reactions generally result from the release of pharmacologically active substances, such as histamine, from mast and/or basophil cells following contact with a specific exogenous antigen. As mentioned above, such Type I reactions play a role in numerous diseases, including allergic asthma, allergic rhinitis, etc.
  • Type II hypersensitivity reactions also referred to as cytotoxic, cytolytic complement-dependent or cell-stimulating hypersensitivity reactions
  • Diseases that are commonly associated with Type II hypersensitivity reactions include, but are not limited, to autoimmune hemolytic anemia, erythroblastosis fetalis and Goodpasture's disease.
  • Type III hypersensitivity reactions (also referred to as toxic complex, soluble complex, or immune complex hypersensitivity reactions) result from the deposition of soluble circulating antigen-immunoglobulin complexes in vessels or in tissues, with accompanying acute inflammatory reactions at the site of immune complex deposition.
  • Type III reaction diseases include the Arthus reaction, rheumatoid arthritis, serum sickness, systemic lupus erythematosis, certain types of glomerulonephritis, multiple sclerosis and bullous pemphingoid.
  • Type IV hypersensitivity reactions (frequently called cellular, cell-mediated, delayed, or tuberculin-type hypersensitivity reactions) are caused by sensitized T- lymphocytes which result from contact with a specific antigen.
  • diseases cited as involving Type IV reactions are contact dermatitis and allograft rejection.
  • Autoimmune diseases associated with any of the above nonanaphylactic hypersensitivity reactions may be treated or prevented with the prodrugs according to structural formula (I).
  • the methods may be used to treat or prevent those autoimmune diseases frequently characterized as single organ or single cell-type autoimmune disorders including, but not limited to: Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Graves' disease, primary biliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis and membranous glomerulopathy, as well as those autoimmune diseases frequently characterized as involving systemic autoimmune disorder, which include but are not limited to: systemic lupus erythematosis (SLE), rheumatoid arthritis, Sjogren
  • Treatment using the compounds described herein can be applied alone, or it can be applied in combination with or adjunctive to other common immunosuppressive therapies, such as, for example, the following: mercaptopurine; corticosteroids such as prednisone; methylprednisolone and prednisolone; alkylating agents such as cyclophosphamide; calcineurin inhibitors such as cyclosporine, sirolimus, and tacrolimus; inhibitors of inosine monophosphate dehydrogenase (IMPDH) such as mycophenolate, mycophenolate mofetil, and azathioprine; and agents designed to suppress cellular immunity while leaving the recipient's humoral immunologic response intact, including various antibodies (for example, antilymphocyte globulin (ALG), antithymocyte globulin (ATG), monoclonal anti-T-cell antibodies (OKT3)) and irradiation.
  • ALG antilymphocyte globulin
  • ATG anti
  • Azathioprine is currently available from Salix Pharmaceuticals, Inc., under the brand name AZASAN; mercaptopurine is currently available from Gate Pharmaceuticals, Inc., under the brand name PURINETHOL; prednisone and prednisolone are currently available from Roxane Laboratories, Inc.; Methyl prednisolone is currently available from Pfizer; sirolimus (rapamycin) is currently available from Wyeth under the brand name RAPAMUNE; tacrolimus is currently available from Fujisawa under the brand name PROGRAF; cyclosporine is current available from Novartis under the brand name SANDIMMUNE and from Abbott under the brand name GENGRAF; IMPDH inhibitors such as mycophenolate mofetil and mycophenolic acid are currently available from Roche under the brand name CELLCEPT and from Novartis under the brand name MYFORTIC; azathioprine is currently available from Glaxo Smith Kline under the brand name IMURAN; and antibodies are currently available from Ortho Biotech under
  • the compounds could be administered either in combination or adjunctively with an inhibitor of a syk.
  • Syk is a tyrosine kinase known to play a critical role in Fey receptor signaling, as well as in other signaling cascades, such as those involving B-cell receptor signaling (Turner et al., (2000), Immunology Today 21: 148-154) and integrins beta(l), beta (2), and beta (3) in neutrophils (Mocsai et al., (2002), Immunity 16:547-558).
  • syk plays a pivotal role in high affinity IgE receptor signaling in mast cells that leads to activation and subsequent release of multiple chemical mediators that trigger allergic attacks.
  • syk helps regulate the pathways involved in immediate IgE-mediated, Type I hypersensitivity reactions. Certain compounds that affect the syk pathway may or may not also affect the JAK pathways.
  • Suitable syk inhibitory compounds are described, for example, in Ser. No.
  • the compounds can be used to treat or prevent these diseases in patients that are either initially non-responsive (resistant) to or that become non- responsive to treatment with a JAK inhibitory compound or one of the other current treatments for the particular disease.
  • the compounds could also be used in combination with syk inhibitory compounds in patients that are JAK -compound resistant or non-responsive.
  • Suitable JAK -inhibitory compounds with which the compounds can be administered are provided infra.
  • this invention provides a method of treating a T-cell mediated autoimmune disease, comprising administering to a patient suffering from such an autoimmune disease an amount of a compound effective to treat the autoimmune disease wherein the compound is selected from the compounds of the invention, as described herein, and the compound is administered in combination with or adjunctively to a compound that inhibits JAK with an IC 50 in the range of at least 10 ⁇ M.
  • this invention provides a method of treating or preventing allograft transplant rejection in a transplant recipient, comprising administering to the transplant recipient an amount of a compound effective to treat or prevent the rejection wherein the compound is selected from the compounds of the invention, as described herein.
  • the compound is administered to a tissue or an organ prior to transplanting the tissue or organ in the transplant recipient.
  • this invention provides a method of treating or preventing allograft transplant rejection in a transplant recipient, in which the rejection is acute rejection, comprising administering to the transplant recipient an amount of a compound effective to treat or prevent the rejection, wherein the compound is selected from the compounds of the invention.
  • this invention provides a method of treating or preventing allograft transplant rejection in a transplant recipient, in which the rejection is chronic rejection, comprising administering to the transplant recipient an amount of a compound effective to treat or prevent the rejection, wherein the compound is selected from the compounds of the invention.
  • this invention provides a method of treating or preventing allograft transplant rejection in a transplant recipient, in which the rejection is mediated by HVGR or GVHR, comprising administering to the transplant recipient an amount of a compound effective to treat or prevent the rejection, wherein the compound is selected from the compounds of this invention, as described herein.
  • this invention provides a method of treating or preventing allograft transplant rejection in a transplant recipient, in which the allograft transplant is selected from a kidney, a heart, a liver, and a lung, comprising administering to the transplant recipient an amount of a compound effective to treat or prevent the rejection, wherein the compound is selected from the compounds of this invention, as described herein.
  • this invention provides a method of treating or preventing allograft transplant rejection in a transplant recipient, in which the allograft transplant is selected from a kidney, a heart, a liver, and a lung, comprising administering to the transplant recipient an amount of a compound effective to treat or prevent the rejection wherein the compound is selected from the compounds of the invention, as described herein, in which the compound is administered in combination with or adjunctively to another immunosuppressant.
  • this invention provides a method of treating or preventing allograft transplant rejection in a transplant recipient, in which the allograft transplant is selected from a kidney, a heart, a liver, and a lung, comprising administering to the transplant recipient an amount of a compound effective to treat or prevent the rejection, wherein the compound is selected from the compounds of the invention, as described herein, in which the compound is administered in combination with or adjunctively to another immunosuppressant, in which the immunosuppressant is selected from cyclosporine, tacrolimus, sirolimus, an inhibitor of EVIPDH, mycophenolate, mycophanolate mofetil, an anti-T-Cell antibody, and OKT3.
  • the compounds described herein are cytokine moderators of IL-4 signaling. As a consequence, the compounds could slow the response of Type I hypersensitivity reactions. Thus, in a specific embodiment, the compounds could be used to treat such reactions and, therefore, the diseases associated with, mediated by, or caused by such hypersensitivity reactions (for example, allergies), prophylactically. For example, an allergy sufferer could take one or more of the JAK selective compounds described herein prior to expected exposure to allergens to delay the onset or progress of, or eliminate altogether, an allergic response.
  • the compounds can be administered singly, as mixtures of one or more compounds, or in mixture or combination with other agents useful for treating such diseases and/or the symptoms associated with such diseases.
  • the compounds may also be administered in mixture or in combination with agents useful to treat other disorders or maladies, such as steroids, membrane stabilizers, 5-lipoxygenase (5LO) inhibitors, leukotriene synthesis and receptor inhibitors, inhibitors of IgE isotype switching or IgE synthesis, IgG isotype switching or IgG synthesis, beta.-agonists, tryptase inhibitors, aspirin, cyclooxygenase (COX) inhibitors, methotrexate, anti-TNF drugs, anti
  • CD20 antibody CD20 antibody, PD4 inhibitors, p38 inhibitors, PDE4 inhibitors, and antihistamines, to name a few.
  • the compounds can be administered per se in the form of prodrugs or as pharmaceutical compositions, comprising an active compound or prodrug.
  • this invention provides a method of treating or preventing a Type IV hypersensitivity reaction, comprising administering to a subject an amount of a compound effective to treat or prevent the hypersensitivity reaction, wherein the compound is selected from the compounds of this invention, as described herein.
  • this invention provides a method of treating or preventing a Type IV hypersensitivity reaction, which is practical prophylactically, comprising administering to a subject an amount of a compound effective to treat or prevent the hypersensitivity reaction, wherein the compound is selected from the compounds of this invention, as described herein, and is administered prior to exposure to an allergen.
  • this invention provides a method of inhibiting a signal transduction cascade in which JAK3 plays a role, comprising contacting a cell expressing a receptor involved in such a signaling cascade with a compound wherein the compound is selected from the compounds of this invention, as described herein.
  • this invention provides a method of treating or preventing a JAK-mediated disease, comprising administering to a subject an amount of compound effective to treat or prevent the JAK-mediated disease, wherein the compound is selected from the compounds of this invention, as described herein.
  • this invention provides a method of treating or preventing a JAK-mediated disease, in which the JAK-disease is HVGR or GVHR, comprising administering to a subject an amount of compound effective to treat or prevent the JAK- mediated disease, wherein the compound is selected from the compounds of the invention, as described herein.
  • this invention provides a method of treating or preventing a JAK-mediated disease, in which the JAK-disease is acute allograft rejection, comprising administering to a subject an amount of compound effective to treat or prevent the JAK- mediated disease, wherein the compound is selected from the compounds of the invention, as described herein.
  • this invention provides a method of treating or preventing a JAK-mediated disease, in which the JAK-mediated disease is chronic allograft rejection, comprising administering to a subject an amount of compound effective to treat or prevent the JAK-mediated disease, wherein the compound is selected from the compounds of the invention, as described herein.
  • Active compounds of the invention typically inhibit theJAK/Stat pathway.
  • the activity of a specified compound as an inhibitor of a JAK can be assessed in vitro or in vivo. In some embodiments, the activity of a specified compound can be tested in a cellular assay.
  • Cell proliferative disorder refers to a disorder characterized by abnormal proliferation of cells. A proliferative disorder does not imply any limitation with respect to the rate of cell growth, but merely indicates loss of normal controls that affect growth and cell division. Thus, in some embodiments, cells of a proliferative disorder can have the same cell division rates as normal cells but do not respond to signals that limit such growth.
  • neoplasm or tumor which is an abnormal growth of tissue.
  • Cancer refers to any of various malignant neoplasms characterized by the proliferation of cells that have the capability to invade surrounding tissue and/or metastasize to new colonization sites.
  • cell proliferative disorders treatable with the compounds disclosed herein relate to any disorder characterized by aberrant cell proliferation. These include various tumors and cancers, benign or malignant, metastatic or non-metastatic. Specific properties of cancers, such as tissue invasiveness or metastasis, can be targeted using the methods described herein.
  • Cell proliferative disorders include a variety of cancers, including, among others, ovarian cancer, renal cancer, gastrointestinal cancer, kidney cancer, bladder cancer, pancreatic cancer, lung squamous carcinoma, and adenocarcinoma.
  • the cell proliferative disorder treated is a hematopoietic neoplasm, which is aberrant growth of cells of the hematopoietic system.
  • Hematopoietic malignancies can have its origins in pluripotent stem cells, multipotent progenitor cells, oligopotent committed progenitor cells, precursor cells, and terminally differentiated cells involved in hematopoiesis. Some hematological malignancies are believed to arise from hematopoietic stem cells, which have the ability for self renewal.
  • Blast cells that do not have a cell marker characteristic of hematopoietic stem cells appear to be incapable of establishing tumors upon transplantation (Blaire et al., 1997, Blood 89:3104-3112).
  • the stem cell origin of certain hematological malignancies also finds support in the observation that specific chromosomal abnormalities associated with particular types of leukemia can be found in normal cells of hematopoietic lineage as well as leukemic blast cells.
  • the reciprocal translocation t(9q34;22ql 1) associated with approximately 95% of chronic myelogenous leukemia appears to be present in cells of the myeloid, erythroid, and lymphoid lineage, suggesting that the chromosomal aberration originates in hematopoietic stem cells.
  • a subgroup of cells in certain types of CML displays the cell marker phenotype of hematopoietic stem cells.
  • fusion protein Bcr/Abl associated with chronic myelogenous leukemia
  • common myeloid progenitor or granulocyte/macrophage progenitor cells produces a leukemic-like condition.
  • some chromosomal aberrations associated with subtypes of leukemia are not found in the cell population with a marker phenotype of hematopoietic stem cells, but are found in a cell population displaying markers of a more differentiated state of the hematopoietic pathway (Turhan et al., 1995, Blood 85:2154-2161).
  • leukemic cells may have acquired the ability to grow unregulated, in some instances mimicking the self-renewal characteristics of hematopoietic stem cells (Passegue et al., Proc. Natl. Acad. Sci. USA, 2003, 100:11842-9).
  • the hematopoietic neoplasm treated is a lymphoid neoplasm, where the abnormal cells are derived from and/or display the characteristic phenotype of cells of the lymphoid lineage.
  • Lymphoid neoplasms can be subdivided into B-cell neoplasms, T and NK-cell neoplasms, and Hodgkin's lymphoma.
  • B-cell neoplasms can be further subdivided into precursor B-cell neoplasm and mature/peripheral B-cell neoplasm.
  • Exemplary B-cell neoplasms are precursor B-lymphoblastic leukemia/lymphoma (precursor B-cell acute lymphoblastic leukemia) while exemplary mature/peripheral B-cell neoplasms are B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone B-cell lymphoma, hairy cell leukemia, plasma cell myeloma/plasmacytoma, extranodal marginal zone B-cell lymphoma of MALT type, nodal marginal zone B-cell lymphoma, follicular lymphoma, mantle-cell lymphoma, diffuse large B-cell lymphoma, mediastinal large B-cell lymphoma, primary effusion lymphoma, and Burkitt's lymphoma/Burkitt cell leukemia.
  • T- cell and Nk-cell neoplasms are further subdivided into precursor T-cell neoplasm and mature (peripheral) T-cell neoplasms.
  • Exemplary precursor T-cell neoplasm is precursor T- lymphoblastic lymphoma/leukemia (precursor T-cell acute lymphoblastic leukemia) while exemplary mature (peripheral) T-cell neoplasms are T-cell prolymphocytic leukemia T-cell granular lymphocytic leukemia, aggressive NK-cell leukemia, adult T-cell lymphoma/leukemia (HTLV-I), extranodal NK/T-cell lymphoma, nasal type, enteropathy- type T-cell lymphoma, hepatosplenic gamma-delta T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, Mycosis fungoides/Sezary syndrome, Anaplastic large- cell
  • the third member of lymphoid neoplasms is Hodgkin's lymphoma, also referred to as Hodgkin's disease.
  • Exemplary diagnosis of this class that can be treated with the compounds include, among others, nodular lymphocyte- predominant Hodgkin's lymphoma, and various classical forms of Hodgkin's disease, exemplary members of which are Nodular sclerosis Hodgkin's lymphoma (grades 1 and 2), Lymphocyte-rich classical Hodgkin's lymphoma, Mixed cellularity Hodgkin's lymphoma, and Lymphocyte depletion Hodgkin's lymphoma.
  • any of the lymphoid neoplasms that are associated with aberrant JAK activity can be treated with the JAK inhibitory compounds.
  • the hematopoietic neoplasm treated is a myeloid neoplasm.
  • This group comprises a large class of cell proliferative disorders involving or displaying the characteristic phenotype of the cells of the myeloid lineage.
  • Myeloid neoplasms can be subdivided into myeloproliferative diseases, myelodysplastic/myeloproliferative diseases, myelodysplastic syndromes, and acute myeloid leukemias.
  • Exemplary myeloproliferative diseases are chronic myelogenous leukemia (e.g., Philadelphia chromosome positive (t(9;22)(qq34;ql l)), chronic neutrophilic leukemia, chronic eosinophilic leukemia/hypereosinophilic syndrome, chronic idiopathic myelofibrosis, polycythemia vera, and essential thrombocythemia.
  • Exemplary myelodysplastic/myeloproliferative diseases are chronic myelomonocytic leukemia, atypical chronic myelogenous leukemia, and juvenile myelomonocytic leukemia.
  • Exemplary myelodysplastic syndromes are refractory anemia, with ringed sideroblasts and without ringed sideroblasts, refractory cytopenia (myelodysplastic syndrome) with multilineage dysplasia, refractory anemia (myelodysplastic syndrome) with excess blasts, 5q-syndrome, and myelodysplastic syndrome.
  • any of the myeloid neoplasms that are associated with aberrant JAK activity can be treated with the JAK inhibitory compounds.
  • the compounds can be used to treat Acute myeloid leukemias (AML), which represent a large class of myeloid neoplasms having its own subdivision of disorders. These subdivisions include, among others, AMLs with recurrent cytogenetic translocations, AML with multilineage dysplasia, and other AML not otherwise categorized.
  • AML Acute myeloid leukemias
  • Exemplary AMLs with recurrent cytogenetic translocations include, among others, AML with t(8;21)(q22;q22), AMLl(CBF-alpha)/ETO, Acute promyelocytic leukemia (AML with t(15;17)(q22;ql 1-12) and variants, PML/RAR-alpha), AML with abnormal bone marrow eosinophils (inv(16)(pl3q22) or t(16;16)(pl3;ql 1), CBFb/MYHl IX), and AML with 1 Iq23 (MLL) abnormalities.
  • AML with t(8;21)(q22;q22) AMLl(CBF-alpha)/ETO
  • Acute promyelocytic leukemia AML with t(15;17)(q22;ql 1-12
  • PML/RAR-alpha Acute promyelocytic leukemia
  • Exemplary AML with multilineage dysplasia are those that are associated with or without prior myelodysplastic syndrome.
  • Other acute myeloid leukemias not classified within any definable group include, AML minimally differentiated, AML without maturation, AML with maturation, Acute myelomonocytic leukemia, Acute monocytic leukemia, Acute erythroid leukemia, Acute megakaryocytic leukemia, Acute basophilic leukemia, and Acute panmyelosis with myelofibrosis.
  • Treating within the context of the invention means an alleviation of symptoms associated with a disorder or disease, or halt of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder.
  • mammal includes organisms which express JAK. Examples of mammals include mice, rats, cows, sheep, pigs, goats, horses, bears, monkeys, dogs, cats and, preferably, humans. Transgenic organisms which express JAK are also included in this definition.
  • inventive methods comprise administering an effective amount of a compound or composition described herein to a mammal or non-human animal.
  • effective amount of a compound or composition of the invention includes those amounts that antagonize or inhibit JAK.
  • An amount which antagonizes or inhibits JAK is detectable, for example, by any assay capable of determining JAK activity, including the one described below as an illustrative testing method.
  • Effective amounts may also include those amounts which alleviate symptoms of a JAK associated disorder treatable by inhibiting JAK.
  • JAK binding compounds include compounds which interact with the JAK, respectively, and modulate, e.g., inhibit or decrease, the ability of a second compound, e.g., another JAK ligand, to interact with the JAK, respectively.
  • the JAK binding compounds are preferably antagonists of JAK, respectively.
  • the language "JAK-binding compound” (e.g., exhibits binding affinity to the receptor) includes those compounds which interact with JAK resulting in modulation of the activity of JAK, respectively.
  • JAK binding compounds may be identified using an in vitro (e.g., cell and non-cell based) or in vivo method. A description of in vitro methods are provided below.
  • compositions of this invention may further comprise another therapeutic agent.
  • the second agent may be administered either as a separate dosage form or as part of a single dosage form with the compounds or compositions of this invention.
  • inventive compounds can be used in an application of monotherapy to treat a disorder, disease or symptom, they also may be used in combination therapy, in which the use of an inventive compound or composition (therapeutic agent) is combined with the use of one or more other therapeutic agents for treating the same and/or other types of disorders, symptoms and diseases.
  • Combination therapy includes administration of the two or more therapeutic agents concurrently or sequentially. The agents may be administered in any order. Alternatively, the multiple therapeutic agents can be combined into a single composition that can be administered to the patient.
  • a single pharmaceutical composition could comprise the compound or pharmaceutically acceptable salt, ester or prodrug thereof according to the formula (I), another therapeutic agent (e.g., methotrexate) or a pharmaceutically acceptable salt, ester or prodrug thereof, and a pharmaceutically acceptable excipient or carrier.
  • another therapeutic agent e.g., methotrexate
  • a pharmaceutically acceptable salt, ester or prodrug thereof e.g., methotrexate
  • the invention comprises a compound having the formula (I), a method for making an inventive compound, a method for making a pharmaceutical composition from at least one inventive compound and at least one pharmaceutically acceptable carrier or excipient, and a method of using one or more inventive compounds to treat a variety of disorders, symptoms and diseases (e.g., inflammatory, autoimmune, neurological, neurodegenerative, oncology and cardiovascular), such as RA, osteoarthritis, irritable bowel disease IBD, asthma, chronic obstructive pulmonary disease COPD and MS.
  • disorders, symptoms and diseases e.g., inflammatory, autoimmune, neurological, neurodegenerative, oncology and cardiovascular
  • RA inflammatory, autoimmune, neurological, neurodegenerative, oncology and cardiovascular
  • RA e.g., osteoarthritis, irritable bowel disease IBD, asthma, chronic obstructive pulmonary disease COPD and MS.
  • inventive compounds and their pharmaceutically acceptable salts and/or neutral compositions may be formulated together with a pharmaceutically acceptable excipient or carrier and the resulting composition may be administered in vivo to mammals, such as men, women and animals, to treat a variety of disorders, symptoms and diseases. Furthermore, the inventive compounds can be used to prepare a medicament that is useful for treating a variety of disorders, symptoms and diseases.
  • AU of the compounds of the present invention are either potent inhibitors of JAK kinases, exhibiting ⁇ C 50 S in the respective assay in the range of less than 5 ⁇ M, with most being in the nanomolar, and several in the sub-nanomolar, range.
  • the compounds of the present invention may be "dual" syk/JAK inhibitors in that they inhibit both syk and JAK kinase to some degree. In other embodiments, the compounds of the present invention may selectively inhibit JAK kinase, but not appreciably inhibit one or more syk kinases.
  • kits comprising separate containers in a single package, wherein the inventive pharmaceutical compounds, compositions and/or salts thereof are used in combination with pharmaceutically acceptable carriers to treat states, disorders, symptoms and diseases where JAK plays a role.
  • the starting materials and reagents used in preparing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, 1967-2004, Volumes 1-22; Rodd's Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and Supplemental; and Organic Reactions, Wiley & Sons: New York, 2005, Volumes 1-65.
  • the starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.
  • the reactions described herein preferably are conducted under an inert atmosphere at atmospheric pressure at a reaction temperature range of from about -78°C to about 150°C, more preferably from about 0 0 C to about 125°C, and most preferably and conveniently at about room (or ambient) temperature, e.g., about 20°C to about 75°C.
  • a reaction temperature range of from about -78°C to about 150°C, more preferably from about 0 0 C to about 125°C, and most preferably and conveniently at about room (or ambient) temperature, e.g., about 20°C to about 75°C.
  • the compounds and/or intermediates may be characterized by high performance liquid chromatography (HPLC) using a Waters Alliance chromatography system with a 2695 Separation Module (Milford, Mass.).
  • the analytical columns may be C-18 SpeedROD RP- 18E Columns from Merck KGaA (Darmstadt, Germany).
  • characterization may be performed using a Waters Unity (UPLC) system with Waters Acquity UPLC BEH C-18 2.1 mm x 15 mm columns.
  • a gradient elution may be used, typically starting with 5 % acetonitrile/95% water and progressing to 95% acetonitrile over a period of 5 minutes for the Alliance system and 1 minute for the Acquity system.
  • All solvents may contain 0.1% trifluoroacetic acid (TFA).
  • TFA trifluoroacetic acid
  • Compounds may be detected by ultraviolet light (UV) absorption at either 220 nm or 254 nm or by mass spectrometry in the case of the Acuity system by using a Waters SQD detector.
  • HPLC solvents may be from EMD Chemicals, Inc. (Gibbstown, NJ).
  • purity may be assessed by thin layer chromatography (TLC) using glass backed silica gel plates, such as, for example, EMD Silica Gel 60 2.5cm x 7.5cm plates. TLC results may be readily detected visually under ultraviolet light, or by employing well known iodine vapor and other various staining techniques.
  • Nuclear magnetic resonance (NMR) analysis may be performed on some of the compounds with a Varian 400 MHz NMR (Palo Alto, Calif.).
  • the spectral reference may be either TMS or the known chemical shift of the solvent.
  • Melting points may be determined on a Laboratory Devices Mel-Temp apparatus (Holliston, Mass.).
  • Preparative separations may be carried out as needed, using either a SqI 6x or a SgIOOc or a CombiPrep Rf chromatography system and prepackaged silica gel columns all purchased from Teledyne Isco, (Lincoln, NE).
  • compounds and intermediates may be purified by flash column chromatography using silica gel (230-400 mesh) packing material, or by HPLC using a C-18 reversed phase column.
  • Typical solvents employed for the Isco systems and flash column chromatography may be dichloromethane, methanol, ethyl acetate, hexane, acetone, aqueous hydroxyamine and triethyl amine.
  • Typical solvents employed for the reverse phase HPLC may be varying concentrations of acetonitrile and water with 0.1% trifluoroacetic acid.
  • Step 1 To a stirring solution of carboxylic acid 1.1 (85g, 540mmol) in thionyl chloride (425mL) was added pyridine (8.5mL, 0.1 lmmol), slowly. The reaction was stirred at 75 0 C overnight at which time it was concentrated and dried under vacuum to a light yellow powder which was used immediately for the next step.
  • Step 2 The yellow solid from the previous page was slowly diluted with 750 niL of ethanol and refluxed overnight.
  • Step 3 Ester 1.3 (22g, 120 mmol) was dissolved in phosphorous oxychloride (60 niL, 600 mmol) and the mixture treated with N,N-diethylaniline (27 mL, 167 mmol) and the mixture heated to 105 0 C until the reaction was determined to be complete by HPLC. It was then cooled to it and slowly added to 1 L of crushed ice resulting in the formation of a beige precipitate which was collected by filtration and dried under vacuum affording the desired dichloride (1.4) as a light yellow powder (22.5g, 85%).
  • Step 4 Dichloropyrimidine 1.4 (5.9g, 27 mmol) was dissolved in acetonitrile (50 mL) and treated sequentially with diisopropylamine (5.2 mL, 30 mmol) followed by cyclobutyl amine (1.9g, 27 mmol) and stirred at rt until all starting material had been consumed. The reaction mixture was then diluted with water to a total volume of 150 mL and the precipitate collected by filtration affording the desired product as a light yellow solid (6.02g, 87%).
  • Step 6 Carboxylic acid 1.6 (3.15g, 15 mmol) was dissolved in N,N- dimethylformamide (70 mL) and treated with HOBt (3.13g, 23 mmol) and EDC (4.4g, 23 mmol). After stirring ca. 25 min ammonia (0.5 M in 1,4-dioxane, 72 mL, 36 mmol) was added and the reaction stirred overnight. The following morning the reaction was diluted with water to a total volume of 500 mL and the desired product collected by filtration affording 3.62g (74%) of a light-beige solid.
  • Step 3 Sulfide 2.4 (3.87 g, 14 mmol) was suspended in 40 mL of dioxane and treated with peroxyacetic acid in acetic acid (5.9 M, 2.9 mL, 17 mmol) and stirred at rt for 1 hr at which time the reaction was found to be incomplete. It was treated with 1 mL of peroxyacetic acid/acetic acid and stirred at rt. Later, the reaction was checked and found to contain sulfoxide with small amounts of 2.4 and sulfone.
  • Step 1 Dichloropyrimidine 1.4 (3.39 g, 15 mmol) was diluted with toluene (8 mL) and treated with benzyltriethylammonium chloride (0.68 g, 3 mmol) then sodium thiomethoxide (1.2 g, 17 mmol). The resulting suspension was then diluted with 8 mL of water and stirred vigorously for one hr at which time the starting material was found to be consumed by UPLC. The mixture was then diluted with water and ethyl acetate and the layers separated. The organic phase was extracted once with ethyl acetate and the combined organic layers concentrated in vacuo. The resulting solid was then triturated with ca.
  • Step 3 Carboxylic acid 3.2 (0.50 g, 2.5 mmol) was dissolved in 10 mL of DMF, then treated with hydroxybenzotriazole - hydrate (0.44 g, 2.9 mmol) and EDC (0.56 g, 2.9 mmol) and stirred at rt. After stirring 10 min the reaction was checked by UPLC which showed complete conversion to the activated species. The reaction was then treated with ammonia / dioxane (0.5 M, 10 mL, 10 mmol) and stirred overnight. The following morning the reaction was checked by UPLC which showed the desired product (MS found for Ci 2 Hi O N 6 O 2 S as (M+H) + 303.2).
  • Step 4 Amide 3.3 (1.4 gm 4.6 mmol) was diluted with 10 rnL of NMP, then treated with 3-aminoacetanilide (0.83 g, 5.6 mmol) and TsOH (1.1 g, 5.6 mmol). The reaction was heated to 100 0 C and stirred until only a trace of 3.3 remained. The reaction was then cooled to rt and diluted with water to 100 rnL total volume. After stirring vigorously for 30 min the desired product (3.4) was isolated by filtration as a light beige solid (MS found for Ci 4 Hi 5 N 5 O 2 S as (M+H) + 318.2).
  • Step 5 Sulfide 3.4 (0.35 g, 1.1 mmol) was dissolved in NMP (10 mL) then treated with mCPBA (65%, 0.35 g, 1.3 mmol) and stirred at rt until all starting material had been oxidized to the sulfoxide (MS found for Ci 4 Hi 5 N 5 O 3 S as (MH-H) + 334.2). DIEA (1.0 mL, 5.5 mmol) was then added and then 1/10 th of the solution aliquotted into a scintillation vial and treated with 100 microliters of (S)-2-phenyl-l -propylamine. The reaction was then heated to 100 0 C until complete, then purified by preparative HPLC affording the desired product as a fluffy solid after lyophilization. MS found for C 22 H 24 N 6 O 2 as (M+H) + 405.4.
  • Example 88 4-(isopropylamino)-2-(3-(2-methoxy-N- methylacetamido)phenylamino)py ⁇ midine-5-carboxamide
  • Example 104 4-(4-fluorobenzylamino)-2-(3-(2-methoxyacetamido)phenylamino)pyrimidine- 5-carboxamide
  • Step IV (R)-2-(3-(2,5-dihydro-lH-pyrrole-l-carboxamido)phenylamino)-4-(l- phenylethylamino) pyrimidine-5-carboxamide (4)
  • Step 1 To a solution of ethyl 2,4-dichloropyrimidine-5-carboxylate (328 mg, 1.48 mmol) and 1 -methyl- lH-indol-4-amine (260 mg, 1.78 mmol) in CH 3 CN (6 mL) at room temperature, DIEA (0.4 mL, 2.22 mmol) was added. The mixture was stirred at room temperature for 24 h. Water (15 mL) was added to induce precipitation. The precipitate was collected, dried on vacuum to give ethyl 2-chloro-4-(l -methyl- lH-indol-4-ylamino) pyrimidine-5-carboxylate as a solid.
  • Step 2 To a solution of ethyl 2-chloro-4-(l -methyl- lH-indol-4-ylamino) pyrimidine-5-carboxylate (crude from step 1) in T ⁇ F (4 mL), aq. IN LiOH (2.25 mL, 2.25 mmol) was added. The mixture was stirred at room temperature overnight. Upon acidification of the mixture with IN HCl, white solids precipitated out, which were collected, and dried on vacuum to give 2-chloro-4-(l -methyl- lH-indol-4-ylamino) pyrimidine- 5-carboxylic acid (325 mg). MS 303.3, 305.3 (M+ ⁇ , Cl pattern)
  • Step 3 To a solution of 2-chloro-4-(l -methyl- lH-indol-4-ylamino)pyrimidine-5- carboxylic acid (325 mg, 1.08 mmol) and HOBtH 2 O (198 mg, 1.29 mmol) in DMF (4 mL), EDC (248 mg, 1.29 mmol) was added. The mixture was stirred at room temperature for 1.5 h. Ammonia (0.5 M in dioxane, 8.00 mL, and 4.00 mmol) was added. It was stirred at room temperature overnight. Water and EtOAc were added.
  • Step 4 To a solution of 2-(lH-benzo[(fI[7,2,5]triazol-l-yloxy)-4-(l-methyl-lH- indol-4-ylamino)pyrimidine-5-carboxamide (60 mg, 0.15 mmol) in NMP (0.6 mL) was added 3-acetamidoaniline (25 mg, 0.165 mmol) and pTsO ⁇ 2 O (28 mg, 0.15 mmol).

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Abstract

The present invention is directed to compounds of formula (I) and tautomers and pharmaceutically acceptable salts thereof which are selective inhibitors of JAK. The present invention is also directed to intermediates used in making such compounds, the preparation of such a compound, pharmaceutical compositions containing such a compound, methods of inhibition JAK activity, and methods to prevent or treat a number of conditions mediated at least in part by JAK activity.

Description

INHIBITORS OF JAK
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority under 35 U.S. C. 119(e) to U.S. Provisional Application No. 61/176,077 filed on May 6, 2009 and U.S. Provisional Application No. 61/256,239 filed on October 29, 2009 which are herein incorporated in their entirety by reference.
BACKGROUND OF THE INVENTION
[0002] This invention is directed to pyrimidine and pyridine-based compounds which act as inhibitors of JAK. This invention is also directed to pharmaceutical compositions containing the pyrimidine and pyridine-based compounds and methods of using the compounds or compositions to treat a condition mediated at least in part by JAK activity. The invention is also directed to methods of making the compounds described herein.
[0003] Janus tyrosine kinases (JAKs) are a small family of structurally and functionally related non-receptor, cytoplasmic protein tyrosine kinases, including JAKl, JAK2, JAK3, and tyrosine kinase 2 (TYK2). JAKs play pivotal roles in the initiation of cytokine- triggered signaling events by signal transducers and activators of transcriptions (STATs) via tyrosine phosphorylation. JAK-mediated tyrosine phosphorylations of cytokine receptors and STATs are the important signal transduction pathways used by many cytokines, growth factors, and interferons. Upon phosphorylation, the STATs dimerize and translocate to the nucleus where they can then induce transcription of the corresponding cytokine- responsive genes. This association with relevant cytokine signaling pathways makes JAK3 an important target for therapeutic intervention in the treatment of autoimmune disorders, inflammatory diseases, cell proliferative disorder and organ transplant rejection such as rheumatoid arthritis, psoriasis, Crohn's disease, multiple sclerosis, asthma and acute myeloid leukemias (AML).
[0004] JAK-3 in particular plays an essential role in the function of lymphocytes, macrophages and mast cells. The compounds that inhibit JAK-3 can be therapeutically useful in treatment of, leukemia, lymphoma where JAK3 is hyperactivated. JAK3 inhibition will be useful as immunosuppressive agent for treatment of chronic and/or acute organ transplant and autoimmune diseases such as rheumatoid arthritis , Type 1 diabetes, systemic lupus, multiple sclerosis, Crohn's disease and inflammatory diseases such as, asthma, psoriasis, chronic obstructive pulmonary disease. [0005] An important feature of JAK3 is that it specifically associates with the common cytokine receptor gamma (γ) chain (cc) which is a shared component of the receptors for IL- 2, IL-4, IL-7, IL-9, and IL-15. Unlike the other JAK family members, that are more widely expressed in many mammalian tissues, JAK3 expression seems to be mainly limited to the endoplasmic membranes of hematopoietic cells.
[0006] The pivotal roles in signaling through the gamma chain of γc containing cytokine receptors cytokine receptors and its limited expression and unique tissue distribution make JAK3 an attractive therapeutic target relative to the other JAK family members to manage the abnormal cytokine activities implicated in many cancer cells and inflammatory lymphocytes.
[0007] In the relatively young field of Janus kinase inhibition, Pfizer has already progressed their JAK3 inhibitor, Tasocitinib (CP-690,550), into Phase III clinical trials for acute rejection in kidney transplant patients. Other JAK3 inhibitors have been reported, such as the non-selective (within JAK family) but very potent tetracyclic pyridone 2, reported by Merck. Aventis has published an oxindole JAK3 inhibitor that shows good enzymatic selectivity vs JAK2. However, this oxindole inhibitor also shows very strong inhibition vs a panel of CDK kinases. Vertex has described aza indoles as JAK inhibitors (WO2005/95400). AstraZeneca has published quinoline 3-carboxamides as JAK 3 inhibitors (WO2002/92571) and other compounds for inhibition of all JAKs for the treatment of cancer (WO2008/135786).
[0008] Several mutated forms of JAK2 have been identified in a variety of disease settings, for example translocations resulting in the fusion of the JAK2 kianse domain with an oligomeriaztiondomain, TEL- J AK2, Bcr-JAK2 and PCMl -J AK2 have been implicated in the pathogenesis of various hematological malignancies (SD Turner and Alesander DR, Leukemia, 2006, 20, 572-582).Recently a unique mutation encoding a valine to phenylalanine substitution in JAK2 was detected in a significant number of myleoproliferative diseases such as polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis patients.
[0009] Constitutive activation of the STAT family, in particular STAT3 and STAT5 have been detected in a wide range of cancers and hyperproliferative diseases (Haura et al, Oncology, 2005, 2(6), 315-324). Further, aberrant activation of the JAK/STAT pathway provides an important proliferative and/or anti-apoptotic drive downstream of many kinases (e.g. Flt3, EGFR) whose constitutive activation have been implicated as key drivers in a variety of cancers and hyperproliferative disorders. Potent and specific inhibitors of JAKl and JAK2 will be useful in the treatment of cancers including multiple myeloma, prostate, breat and lung cancer, B-cell Chronic Lymphocytic Leukemia, metastatic melanoma, multiple myeloma, and hepatoma.
[0010] While progress has been made in this field, there remains a need in the art for compounds that inhibit JAK kinase, as well as for methods for treating conditions in a patient, such as rheumatoid arthritis, psoriasis, Crohn's disease, multiple sclerosis, asthma, acute myeloid leukemias (AML) and/or inflammation that can benefit from such inhibition. Moreover, the availability of compounds that selectively inhibit one of these kinases as compared to other kinases would also be desirable. The present invention satisfies this and other needs.
BRIEF SUMMARY OF THE INVENTION
[0011] The present invention provides novel compounds having activity as inhibitors of JAK kinase activity (also referred to herein as "JAK inhibitors"), as well as to methods for their preparation and use, and to pharmaceutical compositions containing the same. Such compounds have the following structure (I):
Figure imgf000005_0001
(D or a pharmaceutically acceptable salt thereof, wherein each Rla, Rlb, R2, R3, R4 , Y1 and m are as defined below.
[0012] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutical acceptable salt thereof, and a pharmaceutically acceptable carrier and/or diluent.
[0013] The compounds of the present invention have utility over a wide range of therapeutic applications, and may be used to treat a variety of conditions, mediated at least in part by JAK activity, in both men and women, as well as a mammal in general (also referred to herein as a "subject"). For example, such conditions include, but are not limited to, those associated with cardiovascular disease, inflammatory disease or autoimmune disease. More specifically, the compounds of the present invention have utility for treating conditions or disorders including, but not limited to: allergy, asthma, rheumatoid arthritis, Crohn's disease, anti-phospholipid syndrome, lupus, psoriasis, multiple sclerosis, and chronic lymphocytic leukemia . Thus, in one embodiment, methods are disclosed which include the administration of an effective amount of a compound of formula (I), typically in the form of a pharmaceutical composition, to a subject in need thereof.
[0014] The present invention also provides a method for inhibiting the JAK activity of a blood sample comprising contacting said sample with a compound of the present invention.
[0015] The present invention further provides compounds in purified forms, as well as chemical intermediates.
[0016] These and other aspects, objects, features and advantages of the invention will be apparent upon reference to the following detailed description. To this end, various references are set forth herein which describe in more detail certain background information, procedures, compounds and/or compositions, and are each hereby incorporated by reference in their entirety.
DETAILED DESCRIPTION OF THE INVENTION
[0017] As used herein, the below terms have the following meanings unless specified otherwise:
1. Abbreviations and Definitions
[0018] The abbreviations used herein are conventional, unless otherwise defined. The following abbreviations are used: AcOH = acetic acid, AIBN = azobisisobutyronitrile (also azobisisobutylonitrile), aq. = aqueous, Boc = t-butylcarboxy, Bz - benzyl, BOP = benzotriazol-l-yloxytris(dimethylamino)-phosphonium hexafluorophosphate, BPO = benzoyl peroxide, nBuOH = n-butanol, CBr4 = tetrabromomethane, mCPBA = m- chloroperoxybenzoic acid, CH2CI2 or DCM = dichloromethane, CS2CO3 = cesium carbonate, CuCl2 = copper chloride; DIBAL = diisobutylaluminum hydride, DIEA = Hunig's base or diisopropyl ethylamine, DME = dimethoxy ethane, DMF = dimethyl formamide, DMSO = dimethyl sulfoxide, Et3N = triethylamine, EtOAc = ethyl acetate, g = gram, HATU
= 2-(1H 7-Azabenzotriazol-l-yl)-l,l,3,3-tetramethyl uronium hexafluorophosphate, H2 = hydrogen; H2O = water; HBr = hydrogen bromide; HCl = hydrogen chloride, HIV = human immunodeficiency virus, HPLC = high pressure liquid chromatography, h = hour, IgE = immunoglobulin E, IC50 = The concentration of an inhibitor that is required for 50% inhibition of an enzyme in vitro, IPA = isopropyl alcohol, kg = kilogram, KCN = potassium cyanide, KOH = potassium hydroxide, K2PO4 = potassium phosphate, LDA = lithium diisopropylamide, LiAlH4 = lithium aluminum hydride = LiOH: lithium hydroxide; MeCN = acetonitrile; MS = Mass Spec, m/z = mass to charge ratio, MHz = Mega Hertz, MeOH = methanol, μM = micromolar, μL = microliter, mg = milligram, mm = millimeter, mM = millimolar, mmol = millimole, mL = milliliter, mOD/min = millioptical density units per minute, min = minute, M = molar, Na2CO3 = sodium carbonate, ng = nanogram, NaHCθ3 = sodium bicarbonate; NaNθ2 = sodium nitrite; NaOH = sodium hydroxide; Na2S2θ3 = sodium thiosulfate; Na2SO4 = sodium sulfate; NBS = N-bromosuccinimide; NH4CI = ammonium chloride; NH4OAC = ammonium acetate; NaSMe = sodium methylthiolate, NBS
= N-bromosuccinamide, n-BuLi = n-butyl lithium, nm = nanometer, nM = nanomolar, N = Normal, NMP = N-methyl-2-pyrrolidone, NMR = nuclear magnetic resonance, Pd/C = palladium on carbon, Pd(PPh3)4 = Tetrakis-(triphenyl-phosphihe)-palladium, pM = picomolar, Pin = pinacolato, PEG = polyethylene glycol, PPh3 or Ph3P = triphenyl phosphine, RLV = Raucher leukemia virus, Ra-Ni = Rainey Nickel, SOCI2 = thionyl chloride, RT = room temperature, TEA = triethylamine, THF = tetrahydrofuran, TFA = trifluoroacetic acid, TLC = thin layer chromatography, TMS = trimethylsilyl, Tf = trifluoromethylsulfonyl and TSC = trisodium citrate.
[0019] It is noted here that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural reference unless the context clearly dictates otherwise.
[0020] "Alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, fully saturated aliphatic hydrocarbon radical having the number of carbon atoms designated. For example, "Q-salkyl" refers to a hydrocarbon radical straight or branched, containing from 1 to 8 carbon atoms that is derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. The phrase "unsubstituted alkyl" refers to alkyl groups that do not contain groups other than fully saturated aliphatic hydrocarbon radicals. Thus the phrase includes straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. The phrase also includes branched chain isomers of straight chain alkyl groups such as isopropyl, t-butyl, isobutyl, sec-butyl, and the like. Representative alkyl groups include straight and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. Further representative alkyl groups include straight and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms.
[0021] "Alkenyl" by itself or as part of another substituent refers to a straight or branched chain, which may be mono- or polyunsaturated, having the number of carbon atoms designated. For example, "C2-C8 alkenyl" means an alkenyl radical having from 2, 3, 4, 5, 6, 7 or 8 atoms that is derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene. Examples include, but are not limited to vinyl, 2-propenyl i.e. - CH=C(H)(CH3), -CH=C(CH3)2, -C(CH3)=C(H)2, -C(CH3)=C(H)(CH3), -C(CH2CH3)=CH2, butadienyl e.g. 2-(butadienyl), pentadienyl e.g. 2,4-pentadienyl and 3-(l,4-pentadienyl), and hexadienyl, among others, and higher homologs and stereoisomers thereof. A "substituted" alkenyl group includes alkenyl groups in which a non-carbon or non-hydrogen atom is bonded to a carbon double bonded to another carbon and those in which one of the non- carbon or non-hydrogen atoms is bonded to a carbon not involved in a double bond to another carbon. Each site of unsaturation may be either cis or trans configuration about the double bond(s).
[0022] The term "alkynyl", by itself or as part of another substituent, means a straight or branched chain hydrocarbon radical, which may be mono- or polyunsaturated, having the number of carbon atoms designated. For example, "C2-C8 alkynyl" means an alkynyl radical having from 2 to 8 carbon atoms that is derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne. "Unsubstituted alkynyl" refers to straight and branched chain groups such as those described with respect to unsubstituted alkyl groups as defined above, except that at least one triple bond exists between two carbon atoms. Examples include, but are not limited to ethynyl e.g. -C=C(H), 1- propynyl e.g. -C≡C(CH3), -C≡C(CH2CH3), -C(H2)C=C(H), -C(H)2C=C(CH3), and -C(H)2C=C(CH2CH3) among others, and higher homologs and isomers thereof. A "substituted" alkynyl group includes alkynyl groups in which a non-carbon or non-hydrogen atom is bonded to a carbon triple bonded to another carbon and those in which a non-carbon or non-hydrogen atom is bonded to a carbon not involved in a triple bond to another carbon.
[0023] "Alkylene" by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified by -CH2CH2CH2CH2-. Typically, an alkylene group will have from 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms that is derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyl.
[0024] "Cycloalkyl" or "carbocycle", by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkyl", "alkenyl" and "alkynyl" in which all ring atoms are carbon. "Cycloalkyl" or "carbocycle" refers to a mono- or polycyclic group. When used in connection with cycloalkyl substituents, the term
"polycyclic" refers herein to fused and non-fused alkyl cyclic structures. "Cycloalkyl" or "carbocycle" may form a bridged ring or a spiro ring. The cycloalkyl group may have one or more double or triple bond(s). The term "cycloalkenyl" refers to a cycloalkyl group that has at least one site of alkenyl unsaturation between the ring vertices. The term "cycloalkynyl" refers to a cycloalkyl group that has at least one site of alkynyl unsaturation between the ring vertices. When "cycloalkyl" is used in combination with "alkyl", as in C3-8cycloalkylC3-8alkylene-, the cycloalkyl portion is meant to have the stated number of carbon atoms (e.g., from three to eight carbon atoms), while the alkylene portion has from one to eight carbon atoms. Typical cycloalkyl substituents have from 3 to 8 ring atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclpentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
[0025] "Aryl" by itself or as part of another substituent refers to a polyunsaturated, aromatic, hydrocarbon group containing from 6 to 14 carbon atoms, which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently. Thus the phrase includes, but is not limited to, groups such as phenyl, biphenyl, anthracenyl, naphthyl by way of example. Non-limiting examples of unsubstituted aryl groups include phenyl, 1 -naphthyl, 2-naphthyl and 4-biphenyl. "Substituted aryl group" includes, for example, -CH2OH (one carbon atom and one heteroatom replacing a carbon atom) and
-CH2SH. The term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified by -CH2-CH2-S-CH2CH2- - and -CH2-S-CH2-CH2-NH-CH2- For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied.
[0026] The terms "heterocycle", "heterocyclyl" or "heterocyclic" refer to a saturated or unsaturated non-aromatic cyclic group containing at least one heteroatom. As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si). Each heterocycle can be attached at any available ring carbon or heteroatom. Each heterocycle may have one or more rings. When multiple rings are present, they can be fused together or linked covalently. Each heterocycle typically contains 1, 2, 3, 4 or 5, independently selected heteroatoms. Preferably, these groups contain 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, 0, 1, 2, 3, 4 or 5 nitrogen atoms, 0, 1 or 2 sulfur atoms and 0, 1 or 2 oxygen atoms. More preferably, these groups contain 1, 2 or 3 nitrogen atoms, 0-1 sulfur atoms and 0-1 oxygen atoms. Non-limiting examples of heterocycle groups include morpholin-3-one, piperazine-2-one, piperazin-1 -oxide, pyridine-2-one, piperidine, morpholine, piperazine, isoxazoline, pyrazoline, imidazoline, pyrazol-5-one, pyrrolidine-2,5- dione, imidazolidine-2,4-dione, pyrrolidine, tetrahydroquinolinyl, decahydroquinolinyl, tetrahydrobenzooxazepinyl dihydrodibenzooxepin and the like.
[0027] "Heteroaryl" refers to a cyclic or polycyclic aromatic radical that contain from one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom or through a carbon atom and can contain 5 to 10 carbon atoms. Non-limiting examples of heteroaryl groups include 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 2-imidazolyl, A- imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5- isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2- pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl and 4-pyrimidyl. If not specifically stated, substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described herein. "Substituted heteroaryl" refers to a unsubstituted heteroaryl group as defined above in which one or more of the ring members is bonded to a non-hydrogen atom such as described above with respect to substituted alkyl groups and substituted aryl groups. Representative substituents include straight and branched chain alkyl groups-CH3, -C2H5, -CH2OH, -OH, -OCH3, -OC2H5, -OCF3, -OC(=O)CH3, - OQ=O)NH2, -OC(=O)N(CH3)2, -CN, -NO2, -C(=O)CH3, -CO2H, -CO2CH3, -CONH2, - NH2,-N(CH3)2, -NHSO2CH3, -NHCOCH3, -NHC(=O)OCH3, -NHSO2CH3, -SO2CH3, - SO2NH2 and halo.
[0028] In each of the above embodiments designating a number of atoms e.g. "C^8" is meant to include all possible embodiments that have one fewer atom. Non-limiting examples include Cj-7, C2-8, C2-7, C3-8, C3-7 and the like.
[0029] Each of the terms herein (e.g., "alkyl," "heteroalkyl," "aryl" and "heteroaryl") is meant to include both "unsubstituted" and optionally "substituted" forms of the indicated radical, unless otherwise indicated. Typically each radical is substituted with 0, 1, 2 3 4 or 5 substituents, unless otherwise indicated. Examples of substituents for each type of radical are provided below.
[0030] "Substituted" refers to a group as defined herein in which one or more bonds to a carbon(s) or hydrogen(s) are replaced by a bond to non-hydrogen and non-carbon atom "substituents" such as, but not limited to, a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy, and acyloxy groups; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amino, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, alkoxyamino, hydroxyamino, acylamino, sulfonylamino, N-oxides, imides, and enamines; and other heteroatoms in various other groups. "Substituents" also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom is replaced by a higher-order bond (e.g., a double- or triple- bond) to a heteroatom such as oxygen in oxo, acyl, amido, alkoxycarbonyl, aminocarbonyl, carboxyl, and ester groups; nitrogen in groups such as imines, oximes, hydrazones, and nitriles. "Substituents" further include groups in which one or more bonds to a carbon(s) or hydrogen(s) atoms is replaced by a bond to a cycloalkyl, heterocyclyl, aryl, and heteroaryl groups. Representative "substituents" include, among others, groups in which one or more bonds to a carbon or hydrogen atom is/are replaced by one or more bonds to fluoro, chloro, or bromo group. Another representative "substituent" is the trifluoromethyl group and other groups that contain the trifluoromethyl group. Other representative "substituents" include those in which one or more bonds to a carbon or hydrogen atom is replaced by a bond to an oxygen atom such that the substituted alkyl group contains a hydroxyl, alkoxy, or aryloxy group. Other representative "substituents" include alkyl groups that have an amine, or a substituted or unsubstituted alkylamine, dialkylamine, arylamine, (alkyl)(aryl)amine, diarylamine, heterocyclylamine, diheterocyclylamine, (alkyl)(heterocyclyl)amine, or (aryl)(heterocyclyl)amine group. Still other representative "substituents" include those in which one or more bonds to a carbon(s) or hydrogen(s) atoms is replaced by a bond to an alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl group.
[0031] The herein-defined groups may include prefixes and/or suffixes that are commonly used in the art to create additional well-recognized substituent groups. As examples, "alkylamino" refers to a group of the formula -NRaRb. Unless stated otherwise, for the following groups containing Ra, Rb, Rc, Rd and Re: Ra, and Rb are each independently selected from H, alkyl, alkoxy, thioalkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl or are optionally joined together with the atom(s) to which they are attached to form a cyclic group. When Ra and Rb are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6- or 7-membered ring. For example, -NRaRb is meant to include 1-pyrrolidinyl and 4-morpholinyl.
[0032] Rc, Rd, Re and Rf are each independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl or alkylenearyl as defined herein.
[0033] Typically, a particular radical will have 0, 1, 2 or 3 substituents, with those groups having two or fewer substituents being preferred in the present invention. More preferably, a radical will be unsubstituted or monosubstituted. Most preferably, a radical will be unsubstituted.
[0034] "Substituents"for the alkyl and heteroalkyl radicals (as well as those groups referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocyclyl) can be a variety of groups selected from: -ORa, =0, =NRa, =N-ORa, -NRaRb, -SRa, halogen, -SiRaRb Rc, -OC(O)R3, -C(O)R3, -CO2Ra, -CONRaRb, -OC(O)NRaRb, -NRbC(O)Ra, -NRa-
C(O)NRbRc, -NR3-SO2NRbRc, -NRbCO2 Ra, -NH-C(NH2)=NH, -NR3C(NH2)=NH, -NH-C(NH2)=NRa, -S(O) Ra, -SO2R3, -SO2NRaRb, -NRbSO2R, -CN and -NO2, in a number ranging from zero to three, with those groups having zero, one or two substituents being particularly preferred.
[0035] In some embodiments, "substituents'Tor the alkyl and heteroalkyl radicals are selected from: -OR\ =0, - NR3Rb, -SRa, halogen, -SiRaRbRc, -OC(O)R3, -C(O)Ra, -CO2R3, -CONRaRb, -0C(0)NRaRb, -NRbC(0)R3, -NRbCO2Ra, -NRa-SO2NRbRc, -S(O) Ra, -SO2R3, -SO2NRaRb, -NR0SO2R, -CN and -NO2, where R3 and Rb are as defined above. In some embodiments, substituents are selected from: -ORa, =O, - NRaRb, halogen, -OC(O) Ra, -CO2R3, -CONRaRb, -OC(O)NRaRb, -NRbC(O)Ra, -NRbCO2Ra, -NRa-SO2NRbRc, -SO2Ra,
-SO2NRaRb, -NR11SO2R, -CN and -NO2.
[0036] Examples of substituted alkyl are: -(CH2)3NH2, -(CH2)3NH(CH3), -(CH2)3NH(CH3)2, -CH2CC=CH2)CH2NH2, -CH2Q=O)CH2NH2, -CH2S C=O)2CH3, -
CH2OCH2NH2, -CO2H. Examples of substituents of substituted alkyl are: CH2OH, -OH, - OCH3, -OC2H5, -OCF3, -OCC=O)CH3, -OC(=O)NH2, -OC(=O)N(CH3)2, -CN, -NO2, - CC=O)CH3, -CO2H, -CO2CH3, -CONH2, -NH2,-N(CH3)2, -NHSO2CH3, -NHCOCH3, -NHCC=O)OCH3, -NHSO2CH3, -SO2CH3, -SO2NH2, and halo.
[0037] Similarly, "substituents" for the aryl and heteroaryl groups are varied and are selected from: -halogen, -0R\ -OC(O) Ra, -NRaRb, -SRa, -Ra, -CN, -NO2, -C02Ra,
-C0NRaRb, -C(O) Ra, -0C(0)NRaRb, -NRbC(O) Ra, -NRbC(0)2Ra, -NRa-C(0)NRbRc,
-NH-C(NH2)=NH, -NRaC(NH2)=NH, -NH-C(NH2)=NRa, -S(O) Ra, -S(O) 2 Ra, -S(O) 2NRa'Rb, -N3, -CH(Ph)2, perfluoroCi_galkoxy, and perfluoroC^.galkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where Ra, R and Rc are independently selected from hydrogen, C^alkyl and heteroalkyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-Ci_galkyl, and (unsubstituted aryl)oxy-Ci _galkyl.
[0038] Two of the "substituents'On adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(0)-(CH2)q-U-, wherein T and U are independently -NH-, -0-, -CH2-. or a single bond, and q is O, 1 or 2. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r_B-, wherein A and B are independently -CH2_,
-0-, -NH-, -S-, -S(O)-, -S(O)2., -S(O) 2NRa- or a single bond, and r is 1, 2 or 3. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CH2)S_X-(CH2)(_ -, where s and t are independently integers of from O to 3, and X is -0-, -NRa-, -S- , -S(O)-, -S(O)2., or -S(O) 2NRa-. The substituent Ra in -NRa- and -S(O)2NR3- is selected from hydrogen or unsubstituted C^.galkyl. Otherwise, R' is as defined above. [0039] Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent "arylalkyloxycarbonyl" refers to the group (aryl)-(alkyl)-O-C(O)-.
[0040] "Alkoxy" refers to -ORd wherein Rd is alkyl as defined herein. Representative examples of alkoxy groups include methoxy, ethoxy, r-butoxy, trifluoromethoxy, and the like.
[0041] "Amino" refers to the group -NRaRb where Ra and Rb are independently H, alkyl, aryl, heterocyclyl and the like; or can also be combined to form a 3-7 membered ring with the nitrogen atom to which each is attached. The term "alkylamino" refers to the group -NRaRb where Ra is alkyl and Rb is H or alkyl. The term "arylamino" refers to the group -NRaRb where Ra is aryl and Rb is hydrogen, alkyl, aryl, or heterocyclyl. The term "(alkyl)(aryl)amino" refers to the group -NRaRb where Ra is alkyl and Rb is aryl. Additionally, for dialkylamino groups, the alkyl portions can be the same or different and can also be combined to form a 3-7 membered ring with the nitrogen atom to which each is attached. Accordingly, a group represented as -NRaRb is meant to include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl and the like.
[0042] "Aminocarbonyl" or "aminoacyl" refers to the amide -C(=O)-NRaRb where Ra is H and Rb is H. The term "alkylaminocarbonyl" refers herein to the group -C(=O)-NRaRb where Ra is alkyl and Rb is H or alkyl. The term "arylaminocarbonyl" refers herein to the group -C(=O)-NRaRb where Ra or Rb is aryl. Representative aminocarbonyl groups include, for example, those shown below. These aminocarbonyl group can be further substituted as will be apparent to those having skill in the organic and medicinal chemistry arts in conjunction with the disclosure herein.
[0043] "Bond" when used a element in a Markush group means that the corresponding group does not exist, and the groups of both sides are directly linked.
[0044] "Carbonyl" refers to the divalent group -C(=O)-.
[0045] "Carboxy" or "carboxyl" refers to the group -CO2H.
[0046] "Carboxyl ester" or "carboxy ester" refers to the groups -C(=O)ORC. [0047] "(Carboxyl ester)amino" refers to the groups -NRa-C(O)ORc, where Ra is alkyl or hydrogen. [0048] "Cyano" refers to -CN.
[0049] "Ester" refers to -C(=O)ORd wherein Rd is alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl.
[0050] "Halo" or "halogen" by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl", are meant to include alkyl in which one or more hydrogen is substituted with halogen atoms which can be the same or different, in a number ranging from one up to the maximum number of halogens permitted e.g. for alkyl, (2m'+l), where m' is the total number of carbon atoms in the alkyl group. For example, the term "haloCi_galkyl" is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. The term "perhaloalkyl" means, unless otherwise stated, alkyl substituted with (2m'+l) halogen atoms, where m' is the total number of carbon atoms in the alkyl group. For example, the term "perhaloCi_galkyl", is meant to include trifluoromethyl, pentachloroethyl, l,l,l-trifluoro-2-bromo-2-chloroethyl, and the like. Additionally, term "haloalkoxy" refers to an alkoxy radical substituted with one or more halogen atoms.
[0051] "Heteroalkyl" means an alkyl radical as defined herein with one, two or three components independently selected from cyano, oxo, -O-, -ORW, -NRX-, -NRXRY, -S(O)n- and -S(O)nR2 (where n is an integer from 0 to 2 ), with the understanding that the point of attachment of the heteroalkyl radical is through a carbon, nitrogen, oxygen or sulfur atom of the heteroalkyl radical. Rw is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, araalkyl, alkoxycarbonyl, aryloxycarbonyl, carboxamido, or mono- or di-alkylcarbamoyl. Rx is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl or araalkyl. Ry is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, araalkyl, alkoxycarbonyl, aryloxycarbonyl, carboxamido, mono- or di-alkylcarbamoyl or alkylsulfonyl. Rz is hydrogen (provided that n is 0), alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, araalkyl, amino, mono-alkylamino, di-alkylamino, or hydroxyalkyl. Representative examples include, for example, 2-hydroxyethyl, 2,3- dihydroxypropyl, 2-methoxyethyl, benzyloxymethyl, 2-cyanoethyl, and 2-methylsulfonyl- ethyl. For each of the above, Rw, Rx ,RY, and Rz can be further substituted by amino, fluorine, alkylamino, di-alkylamino, OH or alkoxy. Additionally, the prefix indicating the number of carbon atoms (e.g., C^ -C ^Q) refers to the total number of carbon atoms in the portion of the heteroalkyl group exclusive of the cyano, oxo, -O-, -ORW, -NRX-, -NRXRY, - S(O)n- and -S(O)nRz portions. Examples include alkoxy, alkoxyalkylene, amino, aminoalkylene, aminocarbonyl, alkylcarbonylamino, and the like.
[0052] "Heterocyclylcarbonyl" refers to the -C(=O)RC where Rc is heterocyclyl.
[0053] "Hydroxy" or "hydroxyl" refers to the group -OH.
[0054] The terms "optional" or "optionally" as used throughout the specification means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "heterocyclo group optionally mono- or di- substituted with an alkyl group means that the alkyl may but need not be present, and the description includes situations where the heterocyclo group is mono- or disubstituted with an alkyl group and situations where the heterocyclo group is not substituted with the alkyl group.
[0055] "Optionally substituted " means a ring which is optionally substituted independently with substituents. A site of a group that is unsubstituted may be substituted with hydrogen.
[0056] "Oxo" refers to the divalent group =O.
[0057] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers". Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers". "Stereoisomer" and "stereoisomers" refer to compounds that exist in different stereoisomeric forms if they possess one or more asymmetric centers or a double bond with asymmetric substitution and, therefore, can be produced as individual stereoisomers or as mixtures. Stereoisomers include enantiomers and diastereomers. Stereoisomers that are not mirror images of one another are termed "diastereomers" and those that are non-superimposable mirror images of each other are termed "enantiomers". When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture". Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art {see discussion in Chapter 4 of ADVANCED ORGANIC CHEMISTRY, 4th edition J. March, John Wiley and Sons, New York, 1992) differ in the chirality of one or more stereocenters.
[0058] "Tautomer" refers to alternate forms of a molecule that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a -N=C(H)-NH- ring atom arrangement, such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles. A person of ordinary skill in the art would recognize that other tautomeric ring atom arrangements are possible.
[0059] It is understood that in all substituted groups defined above, polymers arrived at by defining substituents with further substituents to themselves (e.g., substituted aryl having a substituted aryl group as a substituent which is itself substituted with a substituted aryl group, which is further substituted by a substituted aryl group, etc.) are not intended for inclusion herein. In such cases, the maximum number of such substitutions is three. For example, serial substitutions of substituted aryl groups are limited to -substituted aryl- (substituted aryl)- substituted aryl.
[0060] "Protecting group" refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group. Typically, a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3rd Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, VoIs. 1-8, 1971-1996, John Wiley & Sons, NY. Representative amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("TES"), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), nitro- veratryloxycarbonyl ("NVOC") and the like. Representative hydroxy protecting groups include, but are not limited to, those where the hydroxy group is either acylated or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPPS groups) and allyl ethers.
[0061] The term "pharmaceutically acceptable salts" is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally- occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N'- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, e.g., Berge, S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19, 1977). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
[0062] The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention. [0063] In addition to salt forms, the present invention provides compounds which are in a prodrug ester form. "Prodrug"s of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are frequently, but not necessarily, pharmacologically inactive until converted into the active drug. Prodrugs are typically obtained by masking a functional group in the drug believed to be in part required for activity with a progroup (defined below) to form a promoiety which undergoes a transformation, such as cleavage, under the specified conditions of use to release the functional group, and hence the active drug. The cleavage of the promoiety may proceed spontaneously, such as by way of a hydrolysis reaction, or it may be catalyzed or induced by another agent, such as by an enzyme, by light, by acid or base, or by a change of or exposure to a physical or environmental parameter, such as a change of temperature. The agent may be endogenous to the conditions of use, such as an enzyme present in the cells to which the prodrug is administered or the acidic conditions of the stomach, or it may be supplied exogenously.
[0064] "Progroup" refers to a type of protecting group that, when used to mask a functional group within an active drug to form a promoiety, converts the drug into a prodrug. Progroups are typically attached to the functional group of the drug via bonds that are cleavable under specified conditions of use. Thus, a progroup is that portion of a promoiety that cleaves to release the functional group under the specified conditions of use. As a specific example, an amide promoiety of the formula -NH-C(O)CH3 comprises the progroup -C(O)CH3.
[0065] A wide variety of progroups, as well as the resultant promoieties, suitable for masking functional groups in the active JAK selective inhibitory compounds to yield prodrugs are well-known in the art. For example, a hydroxyl functional group may be masked as a sulfonate, ester (such as acetate or maleate) or carbonate promoiety, which may be hydrolyzed in vivo to provide the hydroxyl group. An amino functional group may be masked as an amide, carbamate, imine, urea, phosphenyl, phosphoryl or sulfenyl promoiety, which may be hydrolyzed in vivo to provide the amino group. A carboxyl group may be masked as an ester (including methyl, ethyl, pivaloyloxymethyl, silyl esters and thioesters), amide or hydrazide promoiety, which may be hydrolyzed in vivo to provide the carboxyl group. The invention includes those esters and acyl groups known in the art for modifying the solubility or hydrolysis characteristics for use as sustained-release or prodrug formulations. Other specific examples of suitable progroups and their respective promoieties will be apparent to those of skill in the art.
[0066] Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. "Solvate" refers to a complex formed by combination of solvent molecules with molecules or ions of the solute. The solvent can be an organic compound, an inorganic compound, or a mixture of both. Some examples of solvents include, but are not limited to, methanol, N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
[0067] Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present invention. These isomers can be resolved or asymmetrically synthesized using conventional methods to render the isomers "optically pure", i.e., substantially free of its other isomers. If, for instance, a particular enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chrial auxilliary, where the resulting diastereomeric mixture is separated and the auxilliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diasteromers thus formed by fractional crystallization or chromatagraphic means well known in the art, and subsequent recovery of the pure enantiomers.
[0068] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
[0069] The term "administering" refers to oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, or the implantation of a slow-release device e.g., a mini-osmotic pump, to a subject. Adminsitration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra- arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.
[0070] An "agonist" or "activator" refers to an agent or molecule that binds to a receptor of the invention, stimulates, increases, opens, activates, facilitates, enhances activation or enzymatic activity, sensitizes or up regulates the activity of a receptor of the invention.
[0071] An "antagonist" or "inhibitor" refers to an agent or molecule that inhibits or binds to, partially or totally blocks stimulation or activity, decreases, closes, prevents, delays activation or enzymatic activity, inactivates, desensitizes, or down regulates the activity of a receptor of the invention. As used herein, "antagonist" also includes a reverse or inverse agonist.
[0072] As used herein, the term "condition or disorder responsive to modulation of JAK " and related terms and phrases refer to a condition or disorder associated with inappropriate, e.g., less than or greater than normal, activity of JAK and at least partially responsive to or affected by modulation of JAK (e.g., JAK antagonist or agonist results in some improvement in patient well-being in at least some patients). Inappropriate functional activity of JAK might arise as the result of expression of JAK in cells which normally do not express the receptor, greater than normal production of JAK, or slower than normal metabolic inactivation or elimination of JAK or its active metabolites, increased expression of JAK or degree of intracellular activation (leading to, e.g., inflammatory and immune-related disorders and conditions) or decreased expression of JAK. A condition or disorder associated with JAK may include a "JAK -mediated condition or disorder".
[0073] As used herein, the phrases "a condition or disorder mediated at least in part by JAK activity", and related phrases and terms refer to a condition or disorder characterized by inappropriate, e.g., greater than normal, JAK activity. Inappropriate JAK functional activity might arise as the result of JAK expression in cells which normally do not express JAK or increased JAK expression or degree of intracellular activation (leading to, e.g., inflammatory and immune-related disorders and conditions). A condition or disorder mediated at least in part by JAK activity may be completely or partially mediated by inappropriate JAK functional activity. However, a condition or disorder mediated at least in part by JAK activity is one in which modulation of JAK results in some effect on the underlying condition or disorder (e.g., an JAK antagonist results in some improvement in patient well-being in at least some patients).
[0074] The term "inflammation" as used herein refers to infiltration of white blood cells (e.g., leukocytes, monocytes, etc.) into the area being treated for restenosis.
[0075] The term "intervention" refers to an action that produces an effect or that is intended to alter the course of a disease process. For example, "vascular intervention" refers to the use of an intravascular procedure such as angioplasty or a stent to open an obstructed blood vessel.
[0076] The term "intravascular device" refers to a device useful for a vascular recanalization procedure to restore blood flow through an obstructed blood vessel. Examples of intravascular devices include, without limitation, stents, balloon catheters, autologous venous/arterial grafts, prosthetic venous/arterial grafts, vascular catheters, and vascular shunts.
[0077] As used herein, the term "JAK" refers to a Janus kinase (RefSeq Accession No. P- 43408) or a variant thereof that is capable of mediating gene expression in vitro or in vivo. JAK variants include proteins substantially homologous to native JAK, i.e., proteins having one or more naturally or non-naturally occurring amino acid deletions, insertions or substitutions (e.g., JAK derivatives, homologs and fragments). The amino acid sequence of JAK variant preferably is at least about 80% identical to a native JAK, more preferably at least about 90% identical, and most preferably at least about 95% identical.
[0078] The term "leukocyte" refers to any of the various blood cells that have a nucleus and cytoplasm, separate into a thin white layer when whole blood is centrifuged, and help protect the body from infection and disease. Examples of leukocytes include, without limitation, neutrophils, eosinophils, basophils, lymphocytes, and monocytes. [0079] The term "mammal" includes, without limitation, humans, domestic animals (e.g., dogs or cats), farm animals (cows, horses, or pigs), monkeys, rabbits, mice, and laboratory animals.
[0080] The terms "modulate", "modulation" and the like refer to the ability of a compound to increase or decrease the function and/or expression of JAK, where such function may include transcription regulatory activity and/or protein-binding. Modulation may occur in vitro or in vivo. Modulation, as described herein, includes the inhibition, antagonism, partial antagonism, activation, agonism or partial agonism of a function or characteristic associated with JAK, either directly or indirectly, and/or the upregulation or downregulation of the expression of JAK, either directly or indirectly. In a preferred embodiment, the modulation is direct. Inhibitors or antagonists are compounds that, e.g., bind to, partially or totally block stimulation, decrease, prevent, inhibit, delay activation, inactivate, desensitize, or downregulate signal transduction. Activators or agonists are compounds that, e.g., bind to, stimulate, increase, open, activate, facilitate, enhance activation, activate, sensitize or upregulate signal transduction. The ability of a compound to inhibit the function of JAK can be demonstrated in a biochemical assay, e.g., binding assay, or a cell-based assay, e.g., a transient transfection assay.
[0081] "Modulators" of activity are used to refer to "ligands", "antagonists" and "agonists" identified using in vitro and in vivo assays for activity and their homologs and mimetics. Modulators include naturally occurring and synthetic ligands, antagonists, agonists, molecules and the like. Assays to identify antagonists and agonists include, e.g., applying putative modulator compounds to cells, in the presence or absence of a receptor of the invention and then determining the functional effects on a receptor of the invention activity. Samples or assays comprising a receptor of the invention that are treated with a potential activator, inhibitor, or modulator are compared to control samples without the inhibitor, activator, or modulator to examine the extent of effect. Control samples (untreated with modulators) are assigned a relative activity value of 100%. Inhibition is achieved when the activity value of a receptor of the invention relative to the control is about 80%, optionally 50% or 25-1%. Activation is achieved when the activity value of a receptor of the invention relative to the control is 110%, optionally 150%, optionally 200-500%, or 1000-3000% higher. [0082] "Patient" refers to human and non-human animals, especially mammals. Examples of patients include, but are not limited to, humans, cows, dogs, cats, goats, sheep, pigs and rabbits.
[0083] Turning next to the compositions of the invention, the term "pharmaceutically acceptable carrier or excipient" means a carrier or excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or excipient that is acceptable for veterinary use as well as human pharmaceutical use. A "pharmaceutically acceptable carrier or excipient" as used in the specification and claims includes both one and more than one such carrier or excipient.
[0084] The terms "pharmaceutically effective amount", "therapeutically effective amount" or "therapeutically effective dose" refers to the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. The term "therapeutically effective amount" includes that amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the condition or disorder being treated. The therapeutically effective amount will vary depending on the compound, the disorder or condition and its severity and the age, weight, etc., of the mammal to be treated.
[0085] The terms "prevent", "preventing", "prevention" and grammatical variations thereof as used herein, refers to a method of partially or completely delaying or precluding the onset or recurrence of a disorder or condition and/or one or more of its attendant symptoms or barring a subject from acquiring or reacquiring a disorder or condition or reducing a subject's risk of acquiring or reaquiring a disorder or condition or one or more of its attendant symptoms.
[0086] The phrase "selectively" or "specifically" when referring to binding to a receptor, refers to a binding reaction that is determinative of the presence of the receptor, often in a heterogeneous population of receptors and other biologies. Thus, under designated conditions, the compounds bind to a particular receptor at least two times the background and more typically more than 10 to 100 times background. Specific binding of a compound under such conditions requires a compound that is selected for its specificity for a particular receptor. For example, small organic molecules can be screened to obtain only those compounds that specifically or selectively bind to a selected receptor and not with other receptors or proteins. A variety of assay formats may be used to select compounds that are selective for a particular receptor. For example, High-throughput screening assays are routinely used to select compounds that are selective for a particular a receptor.
[0087] The "subject" is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In preferred embodiments, the subject is a human.
[0088] The terms "treat", "treating", "treatment" and grammatical variations thereof as used herein, includes partially or completely delaying, alleviating , mitigating or reducing the intensity of one or more attendant symptoms of a disorder or condition and/or alleviating, mitigating or impeding one or more causes of a disorder or condition. Treatments according to the invention may be applied preventively, prophylactically, pallatively or remedially.
[0089] The term "vessel" refers to any channel for carrying a fluid, such as an artery or vein. For example, a "blood vessel" refers to any of the vessels through which blood circulates in the body. The lumen of a blood vessel refers to the inner open space or cavity of the blood vessel.
2. Embodiments of the Invention
a. Compounds
[0090] The present invention provides one group of embodiments, a compound having the formula I:
Figure imgf000025_0001
(D or a tautomer or pharmaceutically acceptable salt thereof, wherein: Y1 is N or CRlc; RIa is (a) C3.8cycloalkyl, optionally substituted with from 1 to 3 substituents Rld wherein each Rld is independently selected from the group consisting of C].8alkyl, C2. 8alkenyl, C2-8alkynyl, hydroxyl, halogen, Ci-8heteroalkyl, cyano, aryl, heteroaryl, heterocyclyl and heterocyclylcarbonyl; or if on adjacent carbon atoms of the C3.8cycloalkyl, may be combined with the atoms to which each are attached to form an aryl group;
(b) Ci_8alkyl, optionally substituted with from 1 to 3 substituents selected from the group consisting of C2.8alkenyl, C2.8alkynyl, amino, hydroxyl, halogen, Q.sheteroalkyl, cyano, C3_8cycloalkyl, aryl, haloaryl, Ci_8alkylaryl, Q-galkoxyaryl, heteroaryl, C3. 8heterocyclyl and C3-8heterocyclylcarbonyl; (c) heterocyclyl, optionally substituted with from 1 to 3 substituents selected from the group consisting of Ci_8alkyl, C2-8alkenyl, C2-8alkynyl, hydroxyl, halogen, C1- 8heteroalkyl, cyano, aryl, heteroaryl, heterocyclyl and heterocyclylcarbonyl;
(d) aryl, optionally substituted with from 1 to 3 substituents selected from the group consisting of Ci_8alkyl, C2-8alkenyl, C2-8alkynyl, hydroxyl, halogen, Q.sheteroalkyl, cyano, aryl, heteroaryl, heterocyclyl and heterocyclylcarbonyl, amino and alkylsulfonyl; and
(e) heteroaryl, optionally substituted with from 1 to 3 substituents selected from the group consisting of Ci_8alkyl, C2-8alkenyl, C2-8alkynyl, hydroxyl, halogen, C1. 8heteroalkyl, cyano, aryl, heteroaryl, heterocyclyl and heterocyclylcarbonyl;
Rlb is H or C,.8alkyl; Rlc is H, Ci-8alkyl or halogen;
R2 is H, Ci.8alkyl, Cj.sheteroalkyl, heterocyclylCi.salkoxy, halogen or heterocyclyl;
R3 is H or Ci-8alkyl or C3.8cycloalkyl;
R4 is selected from the group consisting amino, Ci-8alkyl, aminoCi_8alkyl, C2. 8alkenyl, C2.8alkynyl, Ci_8heteroalkyl, C3-8cycloalkyl, aryl, heteroaryl and C3.8heterocyclyl; and m is O, 1, 2 or 3.
[0091] The present invention provides another group of embodiments, a compound having the formula I:
Figure imgf000027_0001
(D or a tautomer or pharmaceutically acceptable salt thereof, wherein: Y1 is N or CRlc;
Rla is (a) C3-8cycloalkyl, optionally substituted with from 1 to 3 substituents Rld wherein each Rld is independently selected from the group consisting of Ci_8alkyl, C2- 8alkenyl, C2-8alkynyl, hydroxyl, halogen, Q.gheteroalkyl, cyano, aryl, heteroaryl, heterocyclyl and heterocyclylcarbonyl; or if on adjacent carbon atoms of the C3-8cycloalkyl, may be combined with the atoms to which each are attached to form an aryl group;
(b) Ci_8alkyl, optionally substituted with from 1 to 3 substituents selected from the group consisting of C2-8alkenyl, C2_8alkynyl, amino, hydroxyl, halogen, Q-sheteroalkyl, cyano, C^scycloalkyl, aryl, haloaryl, Ci_8alkylaryl, C1-8alkoxyaryl, heteroaryl, C3. 8heterocyclyl and Q.sheterocyclylcarbonyl; Rlb is H or d-galkyl;
Rlc is H, Ci-8alkyl or halogen; R2 is H, Ci-galkyl, Ci-8alkoxy or halogen; R3 is H or Ci-8alkyl;
R4 is selected from the group consisting amino, Ci-8alkyl, C2.8alkenyl, C2_8alkynyl, Ci-8heteroalkyl, C3_8cycloalkyl, aryl, heteroaryl and C3.8heterocyclyl; and m is 0, 1, 2 or 3.
[0092] The present invention provides another group of embodiments, a compound wherein Y1 is N. In another group of embodiments, Y1 is CH.
[0093] The present invention provides one group of embodiments, a compound having the formula Ia:
Figure imgf000028_0001
(Ia)
or a tautomer or pharmaceutically acceptable salt thereof, wherein: Rla is (a)
Figure imgf000028_0002
optionally substituted with from 1 to 3 substituents Rld wherein each Rld is independently selected from the group consisting of C1-8alkyl, C2- 8alkenyl, C2-8alkynyl, hydroxyl, halogen, Q.sheteroalkyl, cyano, aryl, heteroaryl, heterocyclyl and heterocyclylcarbonyl; or if on adjacent carbon atoms of the C3-8cycloalkyl, may be combined with the atoms to which each are attached to form an aryl group; (b) C]-8alkyl, optionally substituted with from 1 to 3 substituents selected from the group consisting of C2-8alkenyl, C2-8alkynyl, amino, hydroxyl, halogen, Ci-8heteroalkyl, cyano, C3_8cycloalkyl, aryl, haloaryl, Q-salkylaryl, Ci-8alkoxyaryl, heteroaryl, C3. 8heterocyclyl and C3.8heterocyclylcarbonyl;
Rlb is H or Ci_8alkyl; R2 is H, Ci_8alkyl, Ci-8alkoxy or halogen;
R3 is H or Ci-βalkyl;
R4 is selected from the group consisting Ci-8alkyl, Ci-8heteroalkyl, C3-8cycloalkyl, and amino; and m is 0, 1, 2 or 3.
[0094] The present invention provides another group of embodiments, a compound wherein R3 is H.
[0095] The present invention provides another group of embodiments, a compound having the formula (Ib):
Figure imgf000029_0001
(Ib)
or a tautomer or pharmaceutically acceptable salt thereof, wherein: R1 is (a) C3-8cycloalkyl, optionally substituted with hydroxyl and aryl;
(b) Ci_8alkyl, optionally substituted with from 1 to 3 substituents selected from the group consisting of C2-8alkynyl, hydroxyl, halogen, Ci_8alkoxy, cyano, aminocarbonyl, C^scyclopropyl, aryl, haloaryl, Q.galkylaryl, C1-8alkoxyaryl, heteroaryl, and heterocyclyl, heterocyclylcarbonyl; R2a is H, d-salkyl, Ci-8alkoxy or halogen;
R2b is H, Ci-8alkyl, Q-galkoxy or halogen;
R4 is selected from the group consisting Ci_8alkyl, Ci-8alkoxyCi_8alkylene, C3- 8cycloalkyl, Ci-8alkoxy, and amino.
[0096] In another group of embodiments, R1 is C3.8cycloalkyl, optionally substituted with hydroxy. In another group of embodiments, R1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, optionally substituted with hydroxy. In another group of embodiments, R1 is Ci- salkyl, optionally substituted with from 1 to 3 substituents selected from the group consisting of C2_galkynyl, hydroxy, halogen, Ci_8alkoxy, cyano, aminocarbonyl, C3-8cycloalkyl, aryl, haloaryl, heteroaryl, heterocyclyl and heterocyclylcarbonyl. In another group of embodiments, R1 is -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3 or -CH2CH2CH(CH3)2. In another group of embodiments, R1 is Ci_8alkyl, optionally substituted with from 1 to 3 substituents selected from the group consisting of C2-8alkynyl, hydroxy, halogen, Ci-8alkoxy, cyano, aminocarbonyl and C3_8cycloalkyl. In another group of embodiments, R1 is - CH2C≡CH, -CH2CF3, -CH2-CPr, -CH2CH2OCH3 or CH2CH2CH2OCH3. In another group of embodiments, R1 is Ci_8alkyl, substituted with from 1 to 3 substituents selected from the group consisting of aryl, haloaryl, Ci-8alkylaryl, Ci_8alkoxyaryl, heteroaryl, heterocyclyl and heterocyclylcarbonyl. [0097] In another group of embodiments, R2a is H, methyl, methoxy, fluoro or chloro and R2b is H, methyl, methoxy, fluoro or chloro. In another group of embodiments, R2a is chloro and R2b is H.
[0098] The present invention provides another group of embodiments, a compound having the formula (Ic):
Figure imgf000030_0001
(Ic)
or a tautomer or pharmaceutically acceptable salt thereof, wherein: Y2 is -CH or -CH-CH-;
R5 is H, Ci-salkyl or hydroxyCi.salkylene; and
R6 is C2-8alkynyl, hydroxyl, halogen, Ci_8alkoxy, cyano, aminocarbonyl, C3- scyclopropyl, aryl, haloaryl, heteroaryl, heterocyclyl and heterocyclylcarbonyl or Q-galkyl, optionally substituted with from 1 to 3 substituents selected from the group consisting of C2- 8alkynyl, hydroxyl, halogen, Q.salkoxy, cyano, aminocarbonyl, C3-8cyclopropyl, aryl, haloaryl, Ci-8alkylaryl, Ci.galkoxyaryl, heteroaryl, heterocyclyl and heterocyclylcarbonyl.
[0099] In another group of embodiments, R4 is Ci.gheteroalkyl, selected from the group consisting of Ci_8alkoxy and Ci-salkoxyCi-salkylene. In another group of embodiments, R5 is CH3; and
R6 is Ph or
Figure imgf000030_0002
R8 is selected from the group consisting of Cj-salkyl, halogen, C].8alkoxy, or may be taken together to form a heterocyclic ring; and q is 0, 1 , 2 or 3; the wavy line indicates the point of attachment to the rest of the molecule.
[0100] The present invention provides another group of embodiments, a compound having the formula (Id):
Figure imgf000031_0001
(Id)
or a tautomer or pharmaceutically acceptable salt thereof,
wherein:
R5 is Ci-salkyl or hydroxyCi-salkylene; or may be taken together with R8 to form a cyclic ring;
R7 is Ci-salkyl, hydroxyl or d-galkoxy;
R8 is selected from the group consisting of Ci-8alkyl, halogen and Ci-salkoxy, or may be taken together to form a heterocyclic ring; and p is 0, 1, 2, or 3; and q is 0, 1, 2 or 3.
[0101] The present invention provides another group of embodiments, a compound having the formula (Ie):
Figure imgf000031_0002
(Ie)
or a tautomer or pharmaceutically acceptable salt thereof,
wherein:
R5 is Ci_galkyl or hydroxyCi.salkylene; or may be taken together with R8a or R8b to form a cyclic ring;
R8a is H, halogen, or may be taken together with R5 to form 5-6 membered carbocyclic ring;
R8b is H, halogen or, or may be taken together with R8a to form a heterocyclic ring;
R8c is H, Q-galkyl, halogen or Ci-8alkoxy, or may be taken together with R8b to form a heterocyclic ring;
R8d is H; and
R8e is H, halogen or may be taken together with R5 to form 5-6 membered carbocyclic ring.
[0102] The present invention provides another group of embodiments, a compound having the formula If:
(If)
or a tautomer or pharmaceutically acceptable salt thereof,
wherein:
R9 is heteroCi-8alkyl.
[0103] The present invention provides another group of embodiments, a compound having the formula Ig:
Figure imgf000033_0001
(Ig) or a tautomer or pharmaceutically acceptable salt thereof,
wherein:
R10 is H or C1-8alkyl; or may be taken together with R11 and the nitrogen atom to which each is attached to form a heterocyclic ring; and
R1 ' is H or Ci_salkyl; or may be taken together with R10 and the nitrogen atom to which each is attached to form a heterocyclic ring.
[0104] In another group of embodiments, the compound has the formula Ih:
Figure imgf000033_0002
(Ih)
or a tautomer or pharmaceutically acceptable salt thereof, wherein:
R1 and R4 are C3-8cycloalkyl. [0105] In another group of embodiments, the compound has the formula (Ii):
Figure imgf000034_0001
(Ii) or a tautomer or pharmaceutically acceptable salt thereof, wherein: R5 is H or Ci.8alkyl;
R4 is Ci_galkyl or heterocyclyl
[0106] In another group of embodiments, R4 is selected from the group consisting of -CH3, -CH2CH3, -NH2, -NHCH3, -NCH2CH3, -N(CH3)2, -OCH3, -OCH2CH3, -OCH(CH3)2, - CH2OCH3, -CH2CONH2, cPr and cBu. In another group of embodiments, R4 has the formula:
R12 ^
; wherein R12 is selected from the group consisting of H and OH, r is 0 or 1 ; and the wavy line indicates the point of attachment to the rest of the molecule. In another group of embodiments, R4 has the formula:
X N i
^ ; wherein R12 is selected from the group consisting of H and OH; and the wavy line indicates the point of attachment to the rest of the molecule.
[0107] The present invention provides another group of embodiments, a compound selected from the group consisting of: Methyl 3-(5-carbamoyl-4-(2,2,2- trifluoroethylamino)pyrimidin-2-ylamino)phenylcarbamate; 2-(3-
(cyclopropanecarboxamido)phenylamino)-4-(2,2,2-trifluoroethylamino)pyrimidine-5- carboxamide; 2-(3-(2-methoxyacetamido)phenylamino)-4-(2,2,2- trifluoroethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(2,2,2- trifluoroethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4- (methylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4- (ethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(prop-2- ynylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4- (isopropylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4- (cyclopropylmethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(tert- butylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(2- methoxyethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4- (cyclopentylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(3- methoxypropylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4- (benzylamino)pyrimidine-5-carboxamide; methyl 5-(5-carbamoyl-4-(2,2,2- trifluoroethylamino)pyrimidin-2-ylamino)-2-chlorophenylcarbamate; 4-(cyclopentylamino)- 2-(3-(cyclopropanecarboxamido)phenylamino)pyrimidine-5-carboxamide; 2-(3-
(cyclobutanecarboxamido)phenylamino)-4-(cyclopentylamino)pyrimidine-5-carboxamide; 4- (cyclopentylamino)-2-(3-propionamidophenylamino)pyrimidine-5-carboxamide; 4- (cyclopentylamino)-2-(3-(2-methoxyacetamido)phenylamino)pyrimidine-5-carboxamide; methyl 3-(5-carbamoyl-4-(cyclopentylamino)pyrimidin-2-ylamino)phenylcarbamate; ethyl 3- (5-carbamoyl-4-(cyclopentylamino)pyrimidin-2-ylamino)phenylcarbamate; methyl 5-(5- carbamoyl-4-(cyclopentylamino)pyrimidin-2-ylamino)-2-chlorophenylcarbamate; 4- (benzylamino)-2-(3-(cyclopropanecarboxamido)phenylamino)pyrimidine-5-carboxamide; 4- (benzylamino)-2-(3-(cyclobutanecarboxamido)phenylamino)pyrimidine-5-carboxamide; 4- (benzylamino)-2-(3-propionamidophenylamino)pyrimidine-5-carboxamide; 4-(benzylamino)- 2-(3-(2-methoxyacetamido)phenylamino)pyrimidine-5-carboxamide; methyl 3-(4- (benzylamino)-5-carbamoylpyrimidin-2-ylamino)phenylcarbamate; ethyl 3-(4- (benzylamino)-5-carbamoylpyrimidin-2-ylamino)phenylcarbamate; methyl 5-(4- (benzylamino)-5-carbamoylpyrimidin-2-ylamino)-2-chlorophenylcarbamate; 4- (cyclopentylamino)-2-(3-ureidophenylamino)pyrimidine-5-carboxamide; 4- (cyclopentylamino)-2-(3-(3-methylureido)phenylamino)pyrimidine-5-carboxamide; 4-
(cyclopentylamino)-2-(3-(3,3-dimethylureido)phenylamino)pyrimidine-5-carboxamide; 4- (cyclopentylamino)-2-(3-(3-ethylureido)phenylamino)pyrimidine-5-carboxamide; 4- (cyclopentylamino)-2-(3-(pyrrolidine-l-carboxamido)phenylamino)pyrimidine-5- carboxamide; 4-(benzylamino)-2-(3-ureidophenylamino)pyrimidine-5-carboxamide; 4- (benzylamino)-2-(3-(3-methylureido)phenylamino)pyrimidine-5-carboxamide; 4- (benzylamino)-2-(3-(pyrrolidine-l-carboxamido)phenylamino)pyrimidine-5-carboxamide; isopropyl 3-(4-(benzylamino)-5-carbamoylpyrimidin-2-ylamino)phenylcarbamate; (S)-2-(3- (2-methoxyacetamido)phenylamino)-4-( 1 -phenylethylamino)pyrimidine-5-carboxamide; 2- (3-(2-methoxyacetamido)phenylamino)-4-(4-methylbenzylamino)pyrimidine-5- carboxamide ; 2-(3-(2-methoxyacetamido)phenylamino)-4-(4- methoxybenzylamino)pyrimidine-5-carboxamide; 4-(4-chlorobenzylamino)-2-(3-(2- methoxyacetamido)phenylamino)pyrimidine-5 -carboxamide; 4-(3 ,4-dichlorobenzylamino)-2- (3-(2-methoxyacetamido)phenylamino)pyrimidine-5-carboxamide; (R)-2-(3-(2- methoxyacetamido)phenylamino)-4-(l-phenylethylamino)pyrirnidine-5-carboxarnide; (S)-2- (3-acetamidophenylamino)-4-(2-hydroxy-2-phenylethylamino)pyrimidine-5-carboxamide; (R)-2-(3-acetamidophenylamino)-4-(2-hydroxy-2-phenylethylamino)pyrimidine-5- carboxamide; 2-(3-acetamidophenylamino)-4-(2-amino-2-oxoethylamino)pyrimidine-5- carboxamide; 2-(3-acetamidophenylamino)-4-(2-phenylcyclopropylamino)pyrimidine-5- carboxamide; 2-(3-acetamidophenylamino)-4-(cyclohexylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-((trans)-2-hydroxycyclopentylamino)pyrimidine-5- carboxamide; 2-(3-acetamidophenylamino)-4-(benzyl(methyl)amino)pyrimidine-5- carboxamide; 4-(cyclobutylamino)-2-(3-(2-methoxyacetamido)phenylamino)pyrimidine-5- carboxamide; 2-(3-acetamidophenylamino)-4-(cyclobutylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(phenethylamino)pyrimidine-5-carboxamide; 4-
(isopropylamino)-2-(3-(2-methoxyacetamido)phenylamino)pyrimidine-5-carboxamide; 2-(3- (2-methoxyacetamido)phenylamino)-4-(2,3,6-trifluorobenzylamino)pyrimidine-5- carboxamide; 2-(3-acetamidophenylamino)-4-(2,3,6-trifluorobenzylamino)pyrimidine-5- carboxamide; (S)-2-(3-acetamidophenylamino)-4-(2-phenylpropylamino)pyrimidine-5- carboxamide; (S)-2-(3-acetamidophenylamino)-4-(l-hydroxy-3-(lH-imidazol-5-yl)propan-2- ylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(3-amino-3- oxopropylamino)pyrimidine-5-carboxamide; (R)-2-(3-acetamidophenylamino)-4-(l-hydroxy- 4-methylpentan-2-ylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(2- (pyrrolidin-l-yl)ethylamino)pyrimidine-5 -carboxamide; (S)-2-(3-acetamidophenylamino)-4- (l-phenylethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(2-oxo-2- (pyrrolidin-l-yl)ethylamino)pyrimidine-5-carboxamide; (R)-2-(3-acetamidophenylamino)-4- (piperidin-3-ylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(4- methylbenzylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(4- methoxybenzylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(4- chlorobenzylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(3,4- dichlorobenzylamino)pyrimidine-5-carboxamide; (R)-2-(3-acetamidophenylamino)-4-(l- phenylethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(2- (methylamino)-2-oxoethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4- ((2S,3S)-l-hydroxy-3-methylpentan-2-ylamino)pyrimidine-5-carboxamide; 2-(3- acetamidophenylamino)-4-(cyanomethylamino)pyrimidine-5-carboxamide; 2-(3- acetamidophenylamino)-4-(tetrahydro-2H-pyran-4-ylamino)pyrimidine-5-carboxamide; (S)- 2-(3-acetamidophenylamino)-4-(l-hydroxy-3-phenylpropan-2-ylamino)pyrimidine-5- carboxamide; 4-(isopropylamino)-2-(3-(N-methylacetamido)phenylamino)pyrimidine-5- carboxamide; 4-(cyclopentylamino)-2-(3-(N-methylacetamido)phenylamino)pyrimidine-5- carboxamide; 4-(benzylamino)-2-(3-(N-methylacetamido)phenylamino)pyrimidine-5- carboxamide; 2-(3-acetamidophenylamino)-4-(2-morpholinoethylamino)pyrimidine-5- carboxamide; (R)-2-(3-acetamidophenylamino)-4-(2-phenylpropylamino)pyrimidine-5- carboxamide; (S)-2-(3-acetamidophenylamino)-4-(2-hydroxypropylamino)pyrimidine-5- carboxamide; (R)-2-(3-acetamidophenylamino)-4-(2,3-dihydroxypropylamino)pyrimidine-5- carboxamide; 2-(3-acetamidophenylamino)-4-(2-methoxy-2-phenylethylamino)pyrimidine-5- carboxamide; (S)-2-(3-acetamidophenylamino)-4-(l -amino- 1 -oxopropan-2- ylamino)pyrimidine-5 -carboxamide; (R)-2-(3-(2-methoxy-N- methylacetamido)phenylamino)-4-(l-phenylethylamino)pyrimidine-5-carboxamide; (R)-2-(3- (N-methylacetamido)phenylamino)-4-( 1 -phenylethylamino)pyrimidine-5-carboxamide; 4- (isopropylamino)-2-(3-(2-methoxy-N-methylacetamido)phenylamino)pyrimidine-5- carboxamide; 4-(cyclopentylamino)-2-(3-(2-methoxy-N- methylacetamido)phenylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(3-(2- methoxy-N-methylacetamido)phenylamino)pyrimidine-5-carboxamide; (R)-2-(3- acetamidophenylamino)-4-(l-amino-l-oxopropan-2-ylamino)pyrimidine-5-carboxamide; 2- (3-acetamidophenylamino)-4-(2,3-dihydro-lH-inden-2-ylamino)pyrimidine-5-carboxamide; (S)-2-(3-acetamidophenylamino)-4-(2-hydroxy-l-phenylethylamino)pyrimidine-5- carboxamide; 2-(3-acetamidophenylamino)-4-(3-fluorobenzylamino)pyrimidine-5- carboxamide; 2-(3-acetamidophenylamino)-4-(2,3-difluorobenzylamino)pyrimidine-5- carboxamide; (S)-2-(3-acetamidophenylamino)-4-(2,3-dihydro-lH-inden-l- ylamino)pyrimidine-5-carboxamide; (R)-2-(3-acetamidophenylamino)-4-(2,3-dihydro-lH- inden-l-ylamino)pyrimidine-5-carboxamide; (R)-2-(3-acetamidophenylamino)-4-(2-hydroxy- l-phenylethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4- (benzofd] [ 1 ,3]dioxol-5-ylmethylamino)pyrimidine-5-carboxamide; 2-(3- acetamidophenylamino)-4-(2-fluorobenzylamino)pyrimidine-5-carboxamide; 2-(3- acetamidophenylamino)-4-(3-chlorobenzylamino)pyrimidine-5-carboxamide; 2-(3- acetamidophenylamino)-4-(2,5-difluorobenzylamino)pyrimidine-5-carboxamide; 2-(3- acetamidophenylamino)-4-(4-fluorobenzylamino)pyrimidine-5-carboxamide; 4-(4- fluorobenzylamino)-2-(3-(2-methoxyacetamido)phenylamino)pyrimidine-5-carboxamide; (R)-4-( 1 -phenylethylamino)-2-(3-(pyrrolidine- 1 -carboxamido)phenylamino)pyrimidine-5- carboxamide; 2-(3-acetamido-4-chlorophenylamino)-4-(benzylamino)pyrimidine-5- carboxamide; 4-(benzylamino)-2-(4-chloro-3-(2- methoxyacetamido)phenylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(4-chloro-3- (3-cyclobutylureido)phenylamino)pyrimidine-5-carboxamide; (R)-2-(3-acetamido-4- chlorophenylamino)-4-( 1 -phenylethylamino)pyrimidine-5-carboxamide; (R)-2-(4-chloro-3- (2-methoxyacetamido)phenylamino)-4-( 1 -phenylethylamino)pyrimidine-5-carboxamide; (R)- 2-(4-chloro-3-(cyclopropanecarboxamido)phenylamino)-4-(l-phenylethylamino)pyrimidine- 5-carboxamide; (R)-2-(4-cmoro-3-(3-cyclobutylureido)phenylamino)-4-(l- phenylethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4- (benzylamino)-N-methylpyrimidine-5-carboxamide; 4-(benzylamino)-2-(3-(2- methoxyacetamido)phenylamino)-N-methylpyrimidine-5-carboxamide ; methoxyacetamido)phenylamino)-N-methylpyrimidine-5-carboxamide ; benzyl 3-((2-(3- acetamidophenylamino)-5-carbamoylpyrimidin-4-ylamino)methyl)piperidine-l-carboxylate ; and 6-(3-acetamidophenylamino)-4-(benzylamino)nicotinamide.
[0108] The present invention provides another group of embodiments, a compound selected from the group consisting of: 2-(3-acetamidophenylamino)-4-(piperidin-3- ylmethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-((l- carbamoylpiperidin-3-yl)methylamino)pyrimidine-5-carboxamide; 2-(3- acetamidophenylamino)-4-(( 1 -(4-fluorophenylcarbamoyl)piperidin-3- yl)methylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-((l- acetylpiperidin-3-yl)methylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)- 4-((l-(methylsulfonyl)piperidin-3-yl)methylamino)pyrimidine-5-carboxamide; (R)-2-(3-(2,5- dihydro- 1 H-pyrrole- 1 -carboxamido)phenylamino)-4-( 1 -phenylethylamino) pyrimidine-5- carboxamide; (R)-2-(3-(N-methylpyrrolidine-l-carboxamido)phenylamino)-4-(l- phenylethylamino) pyrimidine-5-carboxamide; 4-(cyclopropylmethylamino)-2-(3- (pyrrolidine- 1 -carboxamido)phenylamino) pyrimidine-5-carboxamide; 4- (cyclopropylmethylamino)-2-(3-(2-methoxyacetamido)phenylamino) pyrimidine-5- carboxamide; 4-(cyclopropylmethylamino)-2-(3-(2-methoxy-N- methylacetamido)phenylamino) pyrimidine-5-carboxamide; 4-(cyclopropylmethylamino)-2- (3-(N-methylacetamido)phenylamino) pyrimidine-5-carboxamide; 4- (cyclopropylmethylamino)-2-(3-(N-methylpyrrolidine-l-carboxamido) phenylamino)pyrimidine-5-carboxamide; 2-(3-((S)-3-hydroxypyrrolidine-l- carboxamido)phenylamino)-4-((R)-l-phenylethylamino) pyrimidine-5-carboxamide; (R)- methyl 5-(5-carbamoyl-4-(l-phenylethylamino)pyrimidin-2-ylamino)-2- chlorophenylcarbamate; 4-(benzylamino)-2-(4-chloro-3-(pyrrolidine- 1 - carboxamido)phenylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(4-chloro-3-(3- methylureido)phenylamino)pyrimidine-5-carboxamide; (R)-2-(4-chloro-3-(3- methylureido)phenylamino)-4-( 1 -phenylethylamino) pyrimidine-5-carboxamide;
4-(methylamino)-2-(3-(pyrrolidine-l-carboxamido)phenylamino)pyrimidine-5-carboxamide; 4-(ethylamino)-2-(3-(pyrrolidine- 1 -carboxamido)phenylamino)pyrimidine-5-carboxamide; A- (butylamino)-2-(3-(pyrrolidine- 1 -carboxamido)phenylamino)pyrimidine-5-carboxamide; 2- (3-(pyrrolidine-l-carboxamido)phenylamino)-4-(2,2,2-trifluoroethylamino)pyrimidine-5- carboxamide; 2-(3-((S)-2-methylpyrrolidine-l-carboxamido)phenylamino)-4-((R)-l- phenylethylamino) pyrimidine-5-carboxamide; 2-(3-((S)-2-(methoxymethyl)pyrrolidine-l- carboxamido) phenylamino)-4-((R)-l -phenylethylamino) pyrimidine-5-carboxamide; (S)-4- (benzylamino)-2-(3-(2-methylpyrrolidine-l-carboxamido)phenylamino) pyrimidine-5- carboxamide; (S)-4-(benzylamino)-2-(3-(2-(methoxymethyl)pyrrolidine-l-carboxamido) phenylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(3-(N-methylpyrrolidine-l- carboxamido) phenylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(3-(2,5-dihydro- lH-pyrrole-l-carboxamido)phenylamino) pyrimidine-5-carboxamide; (S)-4-(benzylamino)-2- (3-(3-hydroxypyrrolidine- 1 -carboxamido)phenylamino) pyrimidine-5-carboxamide; (S)-4- (sec-butylamino)-2-(3-(2-methoxyacetamido)phenylamino)pyrimidine-5-carboxamide; (R)-4- (benzylamino)-2-(3-(2-methylpyrrolidine- 1 -carboxamido) phenylamino)pyrimidine-5- carboxamide; (R)-4-(benzylamino)-2-(3-(2-(methoxymethyl)pyrrolidine-l-carboxamido) phenylamino)pyrimidine-5-carboxamide; 2-(3-((R)-2-methylpyrrolidine- 1 - carboxamido)phenylamino)-4-((R)-l-phenylethylamino)pyrimidine-5-carboxamide; 2-(3- ((R)-2-(methoxymethyl)pyrrolidine- 1 -carboxamido) phenylamino)-4-((R)- 1 - phenylethylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(3-(N-cyclopropyl-2- methoxyacetamido) phenylamino)pyrimidine-5 -carboxamide; 4-(benzylamino)-2-(3-(N- cyclopropylcyclopropanecarboxamido) phenylamino)pyrimidine-5-carboxamide; (R)-2-(3- acetamidophenylamino)-4-(cyclopropyl(phenyl)methylamino)pyrimidine-5-carboxamide; 4- (benzylamino)-2-(4-chloro-3-(3-cyclopropylureido)phenylamino)pyrimidine-5-carboxamide; 2-(3-acetamido-4-methylphenylamino)-4-(benzylamino)pyrimidine-5-carboxamide; 2-(3- acetamido-4-fluorophenylamino)-4-(benzylamino)pyrimidine-5-carboxamide; 4- (benzylamino)-2-(4-methyl-3-(3-methylureido)phenylamino)pyrimidine-5-carboxamide; (R)- 2-(3-(N-cyclopropylacetamido)phenylamino)-4-( 1 -phenylethylamino) pyrimidine-5- carboxamide; (R)-2-(3-(N-cyclopropyl-2-methoxyacetamido)phenylamino)-4-(l- phenylethylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(4-methoxy-3-(pyrrolidine- l-carboxamido)phenylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(4-methoxy-3- (3-methylureido)phenylamino)pyrimidine-5-carboxamide; 2-(4-chloro-3-(3- methylureido)phenylamino)-4-(3-chlorobenzylamino)pyrimidine-5-carboxarnide; 2-(4- chloro-3-(3-methylureido)phenylamino)-4-(cyclopentylamino)pyrimidine-5-carboxamide; 2- (4-chloro-3-(pyrrolidine-l-carboxamido)phenylamino)-4-(cyclopentylamino)pyrimidine-5- carboxamide; 2-(4-chloro-3-(pyrrolidine-l-carboxamido)phenylamino)-4-(3- chlorobenzylamino)pyrimidine-5-carboxamide; 2-(4-chloro-3-(pyrrolidine-l- carboxamido)phenylamino)-4-(cyclopropylmethylamino)pyrimidine-5-carboxamide; (S)-4- (sec-butylamino)-2-(4-chloro-3-(3-methylureido)phenylamino)pyrimidine-5-carboxamide; (S)-4-(sec-butylamino)-2-(4-chloro-3-(pyrrolidine-l-carboxamido)phenylamino)pyrimidine- 5-carboxamide; 2-(4-chloro-3-(pyrrolidine- 1 -carboxamido)phenylamino)-4-(3- fluorobenzylamino)pyrimidine-5-carboxamide; 2-(4-chloro-3-(3- methylureido)phenylamino)-4-(cyclopropylmethylamino)pyrimidine-5-carboxamide; 4-(3- fluorobenzylamino)-2-(3-(pyrrolidine-l-carboxamido)phenylamino)pyrimidine-5- carboxamide; 4-(3-chlorobenzylamino)-2-(3-(pyrrolidine- 1- carboxamido)phenylamino)pyrimidine-5-carboxamide; 4-(2-fluorobenzylamino)-2-(3-(3- methylureido)phenylamino)pyrimidine-5-carboxamide; N-(5-(4-(benzylamino)-5- carbamoylpyrimidin-2-ylamino)-2-chlorophenyl)morpholine-4-carboxamide; (R)-N-(5-(5- carbamoyl-4-(l-phenylethylamino)pyrimidin-2-ylamino)-2-chlorophenyl)morpholine-4- carboxamide; 2-(3-acetamidophenylamino)-4-( 1 -methyl- lH-indol-4-ylamino)pyrimidine-5- carboxamide; 2-(3-acetamidophenylamino)-4-( 1 -ethyl- lH-indol-4-ylamino)pyrimidine-5- carboxamide; 2-(3-acetamidophenylamino)-4-(2-methyl-2H-indazol-4-ylamino)pyrimidine- 5-carboxamide; 2-(3-acetamidophenylamino)-4-(piperidin-4-ylmethylamino)pyrimidine-5- carboxamide; 2-(3-acetamidophenylamino)-4-( 1 -methyl- lH-indazol-4-ylamino)pyrimidine- 5-carboxamide; 2-(3-acetamidophenylamino)-4-(benzo[c][7,2,5]thiadiazo-4- ylamino)pyrimidine-5-carboxamide; (R)-2-(4-chloro-3-ureidophenylamino)-4-( 1 - phenylethylamino) pyrimidine-5-carboxamide; 4-(benzylamino)-2-(4-chloro-3- ureidophenylamino)pyrimidine-5-carboxamide; (R)-2-(4-chloro-3-(3,3- dimethylureido)phenylamino)-4-( 1 -phenylethylamino) pyrimidine-5-carboxamide; 4- (benzylamino)-2-(4-chloro-3-(3,3-dimethylureido)phenylamino) pyrimidine-5-carboxamide; 4-(benzylamino)-2-(2-fluoro-5-(3-methylureido)phenylamino)pyrimidine-5-carboxamide; 4- (benzylamino)-2-(5-(3,3-dimethylureido)-2-fluorophenylamino)pyrimidine-5-carboxamide; (R)-4-(benzylamino)-2-(3-(tetrahydrofuran-2-carboxamido)phenylamino)pyrimidine-5- carboxamide; 4-(benzylamino)-2-(3-(tetrahydrofuran-3- carboxamido)phenylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(2-fluoro-5- (pyrrolidine-l-carboxamido)phenylamino)pyrimidine-5-carboxamide; (R)-2-(4-chloro-3-
(piperidine- 1 -carboxamido)phenylamino)-4-( 1 -phenylethylamino)pyrimidine-5-carboxamide; (S)-4-(benzylamino)-2-(3-(tetrahydrofuran-2-carboxamido) phenylamino)pyrimidine-5- carboxamide; 4-((R)- 1 -phenylethylamino)-2-(3-((S)-tetrahydrofuran-2-carboxamido) phenylamino)pyrimidine-5-carboxamide; (S)-4-(3-fluorobenzylamino)-2-(3-(tetrahydrofuran- 2-carboxamido) phenylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(4-chloro-3- (piperidine-1-carboxamido) phenylamino) pyrimidine-5-carboxamide; (R)-4-(benzylamino)- 2-(3-(3-(dimethylamino)pyrrolidine-l-carboxamido)phenylamino)pyrimidine-5-carboxamide; (R)-4-(benzylamino)-2-(3-(3-hydroxypiperidine-l-carboxamido)phenylamino)pyrimidine-5- carboxamide; (R)-2-(3-(4-hydroxypiperidine- 1 -carboxamido)phenylamino)-4-( 1 - phenylethylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(3-(4-methylpiperazine- 1 - carboxamido) phenylamino) pyrimidine-5-carboxamide; N-(3-(4-(benzylamino)-5- carbamoylpyrimidin-2-ylamino) phenyl)morpholine-4-carboxamide; 4-(benzylamino)-2-(3- (piperidine-1 -carboxamido) phenylamino)pyrimidine-5-carboxamide; 2-(3-(azetidine-l- carboxamido)phenylamino)-4-(benzylamino) pyrimidine-5-carboxamide; (R)-4-( 1 - phenylethylamino)-2-(3-(piperidine- 1 -carboxamido) phenylamino)pyrimidine-5- carboxamide; (R)-2-(4-chloro-3-(pyrrolidine-l-carboxamido)phenylamino)-4-(l- phenylethylamino) pyrimidine-5-carboxamide; 2-(3-(azetidine- 1 -carboxamido)phenylamino)- 4-(benzylamino) pyrimidine-5-carboxamide; 2-(3-acetamido-4-(2-(pyrrolidin-l- yl)ethoxy)phenylamino)-4-(3-fluorobenzylamino)pyrimidine-5-carboxamide; 2-(3- acetamido~4-(2-(pyrrolidin- 1 -yl)ethoxy)phenylamino)-4-(2-methyl-2H-indazol-4- ylamino)pyrimidine-5-carboxamide; tert-butyl 3-((2-(3-acetamidophenylamino)-5- carbamoylpyrimidin-4-ylamino)methyl)pyrrolidine- 1 -carboxylate; 2-(3- acetamidophenylamino)-4-(pyrrolidin-3-ylmethylamino)pyrimidine-5-carboxylic acid; 2-(3- acetamido-4-(2-(pyrrolidin- l-yl)ethoxy)phen ylamino)-4-(benzo[c] [1, 2,5] thiadiazo-4- ylamino)pyrimidine-5-carboxamide; 2-(3-acetamido-4-(2-
(dimethylamino)ethoxy)phenylamino)-4-(3-fluorobenylamino)pyrimidine-5-carboxamide; 2- (3-acetamido-4-(2-(dimethylamino)ethoxy)phenylamino)-4-(2-methyl-2H-indazol-4- ylamino)pyrimidine-5-carboxamide; 2-(3-acetamido-4-(2- (dimethylamino)ethoxy)phenylamino)-4-(benzo[c][i,2,5]thiadiazo-4-ylamino)pyrimidine-5- carboxamide; 2-(3-acetamido-4-(2-(piperidin-l-yl)propoxy)phenylamino)-4-(3- fluorobenzylamino)pyrimidine-5-carboxamide; 2-(3-acetamido-4-(2-(piperidin-l- yl)propoxy)phenylamino)-4-(2-methyl-2H-indazol-4-ylamino)pyrimidine-5-carboxamide; 2- (3-(azetidine- 1 -carboxamido)-4-chlorophenylamino)-4-(benzylamino) pyrimidine-5- carboxamide; 2-(3-(azetidine-l-carboxamido)-4-fluorophenylamino)-4-(benzylamino) pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(isobutylamino)pyrimidine-5- carboxamide; 2-(4-chloro-3-(pyrrolidine-l-carboxamido)phenylamino)-4- (isobutylamino)pyrimidine-5-carboxamide; (R)-4-(sec-butylamino)-2-(4-chloro-3- (pyrrolidine- 1 -carboxamido)phenylamino)pyrimidine-5-carboxamide; (R)-2-(3- acetamidophenylamino)-4-(sec-butylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2- (4-methoxy-3-(N-methylpyrrolidine-l-carboxamido)phenylamino)pyrimidine-5- carboxamide; 4-(3-fluorobenzylamino)-2-(4-methoxy-3-(N-methylpyrrolidine- 1 - carboxamido)phenylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(4-chloro-3-(N- methylpyrrolidine-l-carboxamido)phenylamino)pyrimidine-5-carboxamide; 2-(4-chloro-3- (N-methylpyrrolidine- 1 -carboxamido)phenylamino)-4-(3-fluorobenzylamino)pyrimidine-5- carboxamide; 2-(3-acetamido-4-(2-(piperidin-l-yl)propoxy)phenylamino)-4-( benzo[c][i,2,5]thiadiazo-4-ylamino)pyrimidine-5-carboxamide; 2-(3-acetamido-4-(2- (pyrrolidin- 1 -yl)ethoxy)phenylamino)-4-(benzylamino)pyrimidine-5-carboxamide; 2-(3- acetamido-4-(2-(piperidin-l-yl)propoxy)phenylamino)-4-(benzylamino)pyrimidine-5- carboxamide; 2-(3-acetamido-4-(2-(piperidin-l-yl)propoxy)phenylamino)-4-(l -methyl- IH- indazol-4-ylamino)pyrimidine-5-carboxamide; (S)-2-(3-acetamidophenylamino)-4-(3- methylbutan-2-ylamino)pyrimidine-5-carboxamide; (S)-2-(4-chloro-3-(pyrrolidine- 1 - carboxamido)phenylamino)-4-(3-methylbutan-2-ylamino)pyrimidine-5-carboxamide; 2-(3- acetamidophenylamino)-4-(2-methylbutylamino)pyrimidine-5-carboxamide; 2-(4-chloro-3- (pyrrolidine- 1 -carboxamido)phenylamino)-4-(2-methylbutylamino)pyrimidine-5- carboxamide; 2-(3-acetamidophenylamino)-4-(isopentylamino)pyrimidine-5-carboxamide; (R)-2-(3-acetamidophenylamino)-4-(3-methylbutan-2-ylamino)pyrimidine-5-carboxamide; (R)-2-(4-chloro-3-(pyrrolidine-l-carboxamido)phenylamino)-4-(3-methylbutan-2- ylamino)pyrimidine-5-carboxamide; (R)-2-(3-(4-methylpiperazine- 1 - carboxamido)phenylamino)-4-( 1 -phenylethylamino) pyrimidine-5-carboxamide; (R)-N-(3- (5-carbamoyl-4-( 1 -phenylethylamino)pyrimidin-2-ylamino) phenyl)morpholine-4- carboxamide; 4-(3-fluorobenzylamino)-2-(3-(4-methylpiperazine- 1 -carboxamido) phenylamino)pyriniidine-5-carboxamide; 2-(3-(2-cyanoacetamido)phenylamino)-4-(3- fluorobenzylamino)-pyrimidine-5-carboxamide ; N-(3-(5-carbamoyl-4-(3- fluorobenzylamino)pyrimidin-2-ylamino) phenyl)morpholine-4-carboxamide ; 2-(3- acetamido-5-chlorophenylamino)-4-(benzylamino)pyrimidine-5-carboxamide ; 2-(3- acetamido-5-chlorophenylamino)-4-(3-fluorobenzylamino)pyrimidine-5-carboxamide ; 2-(3- acetamidophenylamino)-4-(cyclobutylmethylamino)pyrimidine-5-carboxamide; 2-(4-chloro- 3-(pyrrolidine-l-carboxamido)phenylamino)-4-(cyclobutylmethylamino)pyrimidine-5- carboxamide; 2-(3-acetamidophenylamino)-4-(4-aminophenylamino) pyrimidine-5- carboxamide ; 4-(benzylamino)-2-(4-fluoro-3-(3-methylureido)phenylamino)pyrimidine-5- carboxamide; 4-(3-fluorobenzylamino)-2-(3-(3,3,3-trifluoropropanamido) phenylamino)- pyrimidine-5-carboxamide; benzyl 3-(5-carbarnoyl-4-(3-fluorobenzylarnino)pyrimidin-2- ylamino)phenylcarbamate ; 2-(3-(l-cyanocyclopropanecarboxamido)phenylamino)-4-(3- fluorobenzylamino)pyrimidine-5-carboxamide ; 4-(2-fluorobenzylamino)-2-(3- (isonicotinamido)-phenylamino)pyrimidine-5-carboxamide ; 4-(2-fluorobenzylamino)-2-(3- (picolinamido)-phenylamino)pyrimidine-5-carboxamide; 4-(2-fluorobenzylamino)-2-(3- (nicotinamido)-phenylamino)pyrimidine-5-carboxamide; 4-(2-fluorobenzylamino)-2-(3-(2- (pyridin-3-yl)acetamido)-phenylamino)pyrimidine-5-carboxamide; 4-(2-fluorobenzylamino)- 2-(3-(6-hydroxypicolinamido)-phenylamino)pyrimidine-5-carboxamide; 4-(2- fluorobenzylamino)-2-(3-(2-(pyridin-4-yl)acetamido)-phenylamino)pyrimidine-5- carboxamide; 4-(2-fluorobenzylamino)-2-(3-(2-(pyridin-2-yl)acetamido)- phenylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(4-(2- cyanoacetamido)-phenylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4- (4-(l-cyanocyclopropane-carboxamido) phenylamino)pyrimidine-5-carboxamide; 2-(3- acetamidophenylamino)-4-(4-(3,3,3-tπfluoro-propanamido) phenylamino)pyrimidine-5- carboxamide; 2-(3-acetamido-4-(2-(pyrrolidin-l-yl)ethoxy)phenylamino)-4-(l -methyl- IH- indazol-4-ylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(3-(2- (dimethylamino)acetamido)phenylamino)pyrimidine-5-carboxamide; 2-(3-(2-
(dimethylamino)acetamido)phenylamino)-4-(l-methyl-lH-indazol-4-ylamino)pyrimidine-5- carboxamide; 2-(3-acetamidophenylamino)-4-( 1 -phenylcyclopropylamino)pyrimidine-5- carboxamide; 2-(3-(2-(dimethylamino)acetamido)phenylamino)-4-( 1 - phenylcyclopropylamino)pyrimidine-5-carboxamide; 2-(3-acetamido-4-methylphenylamino)- 4-( 1 -phenylcyclopropylamino)pyrimidine-5-carboxamide; 4-(benylamino)-2-(2,2-dimethyl-3- oxo-3,4-dihydro-2H-benzo[έ>][i,4]oxazin-6-ylamino)- pyrimidine-5-carboxamide; 2-(2,2- dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][i,4]oxazin-6-ylamino)-4-(l- phenylcyclopropylamino)pyrimidine-5-carboxamide; 4-(benylamino)-2-(3- isobutyraminophenylamino)pyrimidine-5-carboxamide; 4-(benylamino)-2-(3- pivalaminophenylamino)pyrimidine-5-carboxamide; (S)-4-(benylamino)-2-(3-( 1 - methylpyrrolidine-2-carboxamido)phenylamino)pyrimidine-5-carboxamide; 2-(3- acetamidophenylamino)-4-(( 1 -methyl- lH-pyrazol-4-yl)methylamino)pyrimidine-5- carboxamide; 4-(( 1 -methyl- lH-pyrazol-4-yl)methylamino)-2-(2-oxo-2,3- dihydrobenzo[d]oxazol-5-ylamino)- pyrimidine-5-carboxamide; 2-(2,2-dimethyl-3-oxo-3,4- dihydro-2H-benzo[b] [i,4]oxazin-6-ylamino)- 4-(( 1-methyl- lH-pyrazol-4- yl)methylamino)pyrimidine-5-carboxamide; 2-(2,2-dimethyl-3-oxo-3,4-dihydro-2H- benzo[&][/,4]oxazin-6-ylamino)- 4-(pyridine-2-ylmethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(cyclopentylmethylamino)pyrimidine-5-carboxamide; A- (cyclopentylmethylamino)-2-(3 -(pyrrolidine- l-carboxamido)phenylamino)pyrimidine-5- carboxamide; (R)-4-(benzylamino)-2-(3-(3-hydroxypyrrolidine-l- carboxamido)phenylamino)pyrimidine-5-carboxamide; (R)-4-(benzylamino)-2-(3-(3- fluoropyrrolidine-l-carboxamido)phenylamino)pyrimidine-5-carboxamide; (S)-4- (benzylamino)-2-(3-(3-fluoropyrrolidine-l-carboxamido)phenylamino) pyrimidine-5- carboxamide ; and6-(4-fluoro-3-(pyrrolidine-l-carboxamido)phenylamino)-4-(pyridin-3- ylmethylamino)nicotinamide; 6-(3-(azetidine-l-carboxamido)-4-fluorophenylamino)-4-(3- fluorobenzylamino)nicotinamide; (R)-6-(3-(3-(dimethylamino)pyrrolidine-l- carboxamido)phenylamino)-4-(3-fluorobenzylamino)nicotinamide; (6-(4-fluoro-3- (pyrrolidine- 1 -carboxamido)phenylamino)-4-(3-fluorobenzylamino)nicotinamide; N-(3-(5- carbamoyl-4-(3-fluorobenzylamino)pyridin-2-ylamino)phenyl)moφholine-4-carboxamide; 4- (3-fluorobenzylamino)-6-(3-(pyrrolidine-l-carboxamido)phenylamino)nicotinamide; 6-(3- acetamidophenylamino)-4-(3-fluorobenzylamino)nicotinamide; (S)-6-(3-(azetidine-l- carboxamido)-4-fluorophenylamino)-4-(2-hydroxy-l-phenylethylamino)nicotinamide; 6-(3- ((R)-3-(dimethylamino)pyrrolidine-l-carboxamido)phenylamino)-4-((S)-2-hydroxy-l- phenylethylamino)nicotinamide; (S)-6-(4-fluoro-3-(pyrrolidine- 1 - carboxamido)phenylamino)-4-(2-hydroxy-l-phenylethylamino)nicotinamide; (S)-N-(3-(5- carbamoyl-4-(2-hydroxy-l-phenylethylamino)pyridin-2-ylamino)phenyl)morpholine-4- carboxamide; (S)-4-(2-hydroxy- 1 -phenyl ethylamino)-6-(3 -(pyrrolidine- 1- carboxamido)phenylamino)nicotinamide; (S)-6-(3-acetamidophenylamino)-4-(2-hydroxy-l- phenylethylamino)nicotinamide; 6-(3-(azetidine- 1 -carboxamido)-4-fluorophenylamino)-4- (pyridin-3-ylmethylamino)nicotinamide; (R)-6-(3-(3-(dimethylamino)pyrrolidine-l- carboxamido)phenylamino)-4-(pyridin-3-ylmethylamino)nicotinamide; N-(3-(5-carbamoyl-4- (pyridin-3-ylmethylamino)pyridin-2-ylamino)phenyl)moφholine-4-carboxamide; 4-(pyridin- 3-ylmethylamino)-6-(3-(pyrrolidine-l-carboxamido)phenylamino)nicotinamide; 6-(3- acetamidophenylamino)-4-(pyridin-3-ylmethylamino)nicotinamide; (R)-6-(3- acetamidophenylamino)-4-(l-phenylethylamino)nicotinamide; 6-(3-acetamidophenylamino)- 4-(isobutylamino)nicotinamide; 4-(isobutylamino)-6-(3-(pyrrolidine-l- carboxamido)phenylamino)nicotinamide; (R)-4-( 1 -phenylethylamino)-6-(3-(pyrrolidine- 1 - carboxamido)phenylamino)nicotinamide; 4-(benzylamino)-6-(3-(pyrrolidine-l- carboxamido)phenylamino)nicotinamide; 6-(3-acetamidophenylamino)-4- (isopentylamino)nicotinamide; 4-(isopentylamino)-6-(3-(pyrrolidine- 1 - carboxamido)phenylamino)nicotinamide; 6-(3-acetamidophenylamino)-4- (cyclopropylmethylamino)nicotinamide; 6-(3-acetamidophenylamino)-4- (cyclopentylamino)nicotinamide; 6-(3-acetamidophenylamino)-4-
(cyclobutylmethylamino)nicotinamide; 6-(3-acetamidophenylamino)-4-(4- fluorobenzylamino)nicotinamide; 6-(3-acetamidophenylamino)-4-(2,3-dihydro-lH-inden-2- ylamino)nicotinamide; 6-(3-acetamidophenylamino)-4-(benzo[d] [ 1 ,3]dioxol-5- ylmethylamino)nicotinamide; (S)-6-(3-acetamidophenylamino)-4-(2,3-dihydro-lH-inden-l- ylamino)nicotinamide.; 6-(3-acetamidophenylamino)-4-(2,3- difluorobenzylamino)nicotinamide; 6-(3-acetamidophenylamino)-4-(3- chlorobenzylamino)nicotinamide; 6-(3-acetamidophenylamino)-4- (phenethylamino)nicotinamide; 6-(3-acetamidophenylamino)-4-(benzylamino)-N- methylnicotinamide; 6-(3-acetamidophenylamino)-4-(2-fluorobenzylamino)nicotinamide; and 4-(3,5-difluorobenzylamino)-6-(3-(pyrrolidine-l- carboxamido)phenylamino)nicotinamide
[0109] In any of the embodiments, the present invention provides that the compound is not a compound selected from the group consisting of:
Figure imgf000046_0001
and
Figure imgf000046_0002
[0110] It is understood that in another group of embodiments, any of the above embodiments may also be combined with other embodiments listed herein, to form other embodiments of the invention. Similarly, it is understood that in other embodiments, listing of groups includes embodiments wherein one or more of the elements of those groups is not included.
b. Methods of Synthesis [0111] The compounds of the present invention may be prepared by known organic synthesis techniques, including the methods described in more detail in the Examples. In general, the compounds of formula (I) above may be made by the following Figure 1 , wherein all substituents are as defined above unless indicated otherwise.
[0112] Compounds having formula I may be prepared according to Figure 1:
Figure 1:
Figure imgf000047_0001
Figure imgf000047_0002
Dihydroxy compound, A, is dichlorinated with a chlorinating agent, such as phosphorous oxychloride. Other activated compounds, B or C, wherein one of Z or Z is e.g. a -S-alkyl or a benzotriazolyl ether, may also be prepared through a linear route. Selective displacement of the one of the activated groups by an appropriate amine, such as R or R , (available commercially or synthesized using methods known to those skilled in the art), under basic conditions, such as with diisopropylamine (DIA), provides compounds of formula D or E. Displacement of the other activated group with an appropriate amine, such as R (available commercially or synthesized using methods known to those skilled in the art), gives the desired product F, wherein R1 and R2 are represented herein in Formula I.
[0113] One skilled in the art will recognize that in certain embodiments of formulas (I) when W1 or W2 comprises a terminal heteroatom, it may be advantageous to use a protecting group strategy. The protecting group can be removed using methods known to those skilled in the art to yield compounds of structure F. [0114] The compounds of the present invention may generally be utilized as the free base. Alternatively, the compounds of this invention may be used in the form of acid addition salts as described below.
c. Inhibition of Kinases
[0115] The activity of a specified compound as an inhibitor of a JAK may be assessed in vitro or in vivo. In some embodiments, the activity of a specified compound can be tested in a cellular assay. Selectivity could also be ascertained in biochemical assays with isolated kinases.
[0116] Similar types of assays can be used to assess JAK inhibitory activity and to determine the degree of selectivity of the particular compound as compared to syk. One means of assaying for such inhibition is detection of the effect of the compounds of the present invention on the upregulation of downstream gene products. In the Ramos/IL4 assay, B-cells are stimulated with the cytokine Interleukin-4 (IL-4) leading to the activation of the JAK/Stat pathway through phosphorylation of the JAK family kinases, JAKl and JAK3, which in turn phosphorylate and activate the transcription factor Stat-6. One of the genes upregulated by activated Stat-6 is the low affinity IgE receptor, CD23. To study the effect of inhibitors (e.g., the 2,4-substituted pyrimindinediamine compounds described herein) on the JAKl and JAK3, human Ramos B-cells are stimulated with human IL-4. 10' post- stimulation, cells are subjected to intracellular flow cytometry to measure the extent of STAT-6 phosphorylation. 20 to 24 hours post-stimulation, cells are stained for upregulation of CD23 and analyzed using flow cytometry. A reduction of the amount of phospohorylated STAT-6 and/or cell surface CD23 present compared to control conditions indicates that the test compound actively inhibits the JAK pathway.
[0117] Additionally, IL-6 stimulation of Ramos B-cells induces JAKs 1, 2, and Tyk2, leading to Stat-3 and Erk phosphorylation. 10' post-stimulation, cells are subjected to intracellular flow cytometry to measure the ability of compound to inhibit these phosphorylation events. To specifically measure the activity of JAK2, the CellSensor irfl-bla HEL cell line expressing the beta-lactamase reporter gene controlled by Stat5 will be used (Invitrogen, Carlsbad, CA). These cells express a constituitively active JAK2 mutant (JAK2V617F), found naturally in myeloproliferative neoplasms (Constantinescu, S., et.al, Trends Biochem ScL, 2008; 33:122-31). A reduction in the amount of beta-lactamase reporter gene expression is used a measure of the JAK2 inhibitory activity of compounds. [0118] Stimulation with IL- lβ through the IL-I β receptor activates the TRAF6/NFκB pathway resulting in up-regulation of ICAM-I. IFNγ induces ICAM-I up-regulation through activation of the JAK1/JAK2 pathway. The up-regulation of ICAM-I can be quantified by flow cytometry across a compound dose curve and EC50 values are calculated. Exemplary assays of this type are described in greater detail in the Examples.
[0119] Active compounds as described herein generally inhibit the JAK pathway with an IC50 in the range of about 1 mM or less, as measured in the assays described herein. Of course, skilled artisans will appreciate that compounds which exhibit lower IC50S, (on the order, for example, of 100 μM, 75 μM, 50 μM, 40 μM, 30 μM, 20 μM, 15 μM, 10 μM, 5 μM, 1 μM, 500 nM, 100 nM, 10 nM, 1 nM, or even lower) can be particularly useful in therapeutic applications. In instances where activity specific to a particular cell type is desired, the compound can be assayed for activity with the desired cell type and counter- screened for a lack of activity against other cell types. The desired degree of "inactivity" in such counter screens, or the desired ratio of activity vs. inactivity, may vary for different situations and can be selected by the user.
[0120] The active compounds also typically inhibit IL-4 stimulated expression of CD23 in B-cells with an IC5O in the range of about 20 μM or less, typically in the range of about 10 μM, 1 μM, 500 nM, 100 nM, 10 nM, 1 nM, or even lower. A suitable assay that can be used is the assay described in the Examples, "Assay for Ramos B-cell Line Stimulated with IL-4." In certain embodiments, the active compounds of the present invention have an IC5O of less than or equal to 5 μM, greater than 5 μM but less than 20 μM, greater than 20 μM, or greater than 20 μM but less than 50 μM in the assay described in the Examples.
[0121] The active compounds also typically inhibit expression of ICAMl (CD54) induced by IFNγ exposure in A549 cells with an IC50 in the range of about 20 μM or less, typically in the range of about 10 μM, 1 μM, 500 nM, 100 nM, 10 nM, 1 nM, or even lower. The IC50 against expression of ICAM (CD54) in IFNγ stimulated cells can be determined in a functional cellular assay with an isolated A549 cell line. Suitable assays that can be used are the assays described in the Examples, "A549 Epithelial Line Stimulated with IFNγ". In certain embodiments, the active compounds of the present invention have an IC50 of less than or equal to 20 μM, greater than 20 μM, or greater than 20μM but less than 50 μM in the assays described in the Examples. d. Compositions and Methods of Administration [0122] The present invention further provides compositions comprising one or more compounds of formula (I) or a pharmaceutically acceptable salt, ester or prodrug thereof, and a pharmaceutically acceptable carrier or diluent. It will be appreciated that the compounds of formula (I)) in this invention may be derivatized at functional groups to provide prodrug derivatives which are capable of conversion back to the parent compounds in vivo. Examples of such prodrugs include the physiologically acceptable and metabolically labile ester derivatives, such as methoxymethyl esters, methylthiomethyl esters, or pivaloyloxymethyl esters derived from a hydroxyl group of the compound or a carbamoyl moiety derived from an amino group of the compound. Additionally, any physiologically acceptable equivalents of the compounds of formula (I), similar to metabolically labile esters or carbamates, which are capable of producing the parent compounds of formula (I) in vivo, are within the scope of this invention.
[0123] As used herein, the term "pharmaceutically acceptable salts" refers to any acid or base addition salt whose counter-ions are non-toxic to the patient in pharmaceutical doses of the salts. A host of pharmaceutically acceptable salts are well known in the pharmaceutical field. If pharmaceutically acceptable salts of the compounds of this invention are utilized in these compositions, those salts are preferably derived from inorganic or organic acids and bases. Included among such acid salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, lucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenyl- propionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, hydrohalides (e.g., hydrochlorides and hydrobromides), sulphates, phosphates, nitrates, sulphamates, malonates, salicylates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, ethanesulphonates, cyclohexylsulphamates, quinates, and the like. Pharmaceutically acceptable base addition salts include, without limitation, those derived from alkali or alkaline earth metal bases or conventional organic bases, such as triethylamine, pyridine, piperidine, morpholine, N-methylmorpholine, ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
[0124] Furthermore, the basic nitrogen-containing groups may be quaternized with agents like lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides, such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides, such as benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.
[0125] The compounds utilized in the compositions and methods of this invention may also be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system, etc.), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
[0126] The pharmaceutical compositions of the invention can be manufactured by methods well known in the art such as conventional granulating, mixing, dissolving, encapsulating, lyophilizing, or emulsifying processes, among others. Compositions may be produced in various forms, including granules, precipitates, or particulates, powders, including freeze dried, rotary dried or spray dried powders, amorphous powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions. Formulations may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
[0127] The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of drug calculated to produce the desired onset, tolerability, and/or therapeutic effects, in association with a suitable pharmaceutical excipient (e.g., an ampoule). In addition, more concentrated compositions may be prepared, from which the more dilute unit dosage compositions may then be produced. The more concentrated compositions thus will contain substantially more than, e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more times the amount of one or more JAK inhibitors.
[0128] Methods for preparing such dosage forms are known to those skilled in the art (see, for example, REMINGTON'S PHARMACEUTICAL SCIENCES, 18TH ED., Mack Publishing Co., Easton, PA (1990)). In addition, pharmaceutically acceptable salts of the JAK inhibitors of the present invention (e.g., acid addition salts) may be prepared and included in the compositions using standard procedures known to those skilled in the art of synthetic organic chemistry and described, e.g., by J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed. (New York: Wiley-Interscience, 1992).
[0129] The compositions typically include a conventional pharmaceutical carrier or excipient and may additionally include other medicinal agents, carriers, adjuvants, diluents, tissue permeation enhancers, solubilizers, and the like. Preferably, the composition will contain about 0.01% to about 90%, preferably about 0.1% to about 75%, more preferably about 0.1% to 50%, still more preferably about 0.1% to 10% by weight of one or more JAK inhibitors, with the remainder consisting of suitable pharmaceutical carrier and/or excipients. Appropriate excipients can be tailored to the particular composition and route of administration by methods well known in the art, e.g., REMINGTON'S PHARMACEUTICAL SCIENCES, supra.
[0130] Pharmaceutically acceptable carriers that may be used in these compositions include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances, such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
[0131] Examples of suitable excipients include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, saline, syrup, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, and polyacrylic acids such as Carbopols. The compositions can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying agents; suspending agents; preserving agents such as methyl-, ethyl-, and propyl-hydroxy-benzoates; pH adjusting agents such as inorganic and organic acids and bases; sweetening agents; and flavoring agents. [0132] Administration of a composition comprising one or more JAK inhibitors with one or more suitable pharmaceutical excipients as advantageous can be carried out via any of the accepted modes of administration. Thus, administration can be, for example, oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intra-joint, parenteral, intra-arteriole, intradermal, intraventricular, intracranial, intraperitoneal, intralesional, intranasal, rectal, vaginal, by inhalation or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra- synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally or intravenously. The formulations of the invention may be designed as short- acting, fast-releasing, or long- acting. Still further, compounds can be administered in a local rather than systemic means, such as administration (e.g., injection) as a sustained release formulation. According to a representative embodiment, the compositions of this invention are formulated for pharmaceutical administration to a mammal, preferably a human being.
[0133] The compositions of the present invention containing one or more JAK inhibitors can be administered repeatedly, e.g., at least 2, 3, 4, 5, 6, 7, 8, or more times, or the composition may be administered by continuous infusion. Suitable sites of administration include, but are not limited to, skin, bronchial, gastrointestinal, anal, vaginal, eye, and ear. The formulations may take the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as, for example, tablets, pills, capsules, powders, solutions, suspensions, emulsions, suppositories, retention enemas, creams, ointments, lotions, gels, aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.
[0134] The pharmaceutical compositions of this invention may be in any orally acceptable dosage form, including tablets, capsules, cachets, emulsions, suspensions, solutions, syrups, elixirs, sprays, boluses, lozenges, powders, granules, and sustained-release formulations. Suitable excipients for oral administration include pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, gelatin, sucrose, magnesium carbonate, and the like. In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. [0135] In some embodiments, the compositions take the form of a pill, tablet, or capsule, and thus, the composition can contain, along with one or more JAK inhibitors, a diluent such as lactose, sucrose, dicalcium phosphate, and the like; a disintegrant such as starch or derivatives thereof; a lubricant such as magnesium stearate and the like; and/or a binder such a starch, gum acacia, polyvinylpyrrolidone, gelatin, cellulose and derivatives thereof. A tablet can be made by any compression or molding process known to those of skill in the art. Compressed tablets may be prepared by compressing in a suitable machine the JAK inhibitors in a free-flowing form, e.g., a powder or granules, optionally mixed with accessory ingredients, e.g., binders, lubricants, diluents, disintegrants, or dispersing agents. Molded tablets can be made by molding in a suitable machine a mixture of the powdered JAK inhibitors with any suitable carrier.
[0136] Alternatively, the pharmaceutical compositions of this invention may be in the form of suppositories for rectal administration. These may be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax, polyethylene glycol (PEG), hard fat, and/or hydrogenated cocoglyceride. Compositions suitable for rectal administration may also comprise a rectal enema unit containing one or more JAK inhibitors and pharmaceutically-acceptable vehicles (e.g., 50% aqueous ethanol or an aqueous salt solution) that are physiologically compatible with the rectum and/or colon. The rectal enema unit contains an applicator tip protected by an inert cover, preferably comprised of polyethylene, lubricated with a lubricant such as white petrolatum, and preferably protected by a one-way valve to prevent back-flow of the dispensed formula. The rectal enema unit is also of sufficient length, preferably two inches, to be inserted into the colon via the anus.
[0137] Liquid compositions can be prepared by dissolving or dispersing one or more JAK inhibitors and optionally one or more pharmaceutically acceptable adjuvants in a carrier such as, for example, aqueous saline, aqueous dextrose, glycerol, ethanol, and the like, to form a solution or suspension, e.g., for oral, topical, or intravenous administration. Pharmaceutical formulations may be prepared as liquid suspensions or solutions using a sterile liquid, such as oil, water, alcohol, and combinations thereof. Pharmaceutically suitable surfactants, suspending agents or emulsifying agents, may be added for oral or parenteral administration. Suspensions may include oils, such as peanut oil, sesame oil, cottonseed oil, corn oil and olive oil. Suspension preparation may also contain esters of fatty acids, such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. Suspension formulations may include alcohols, such as ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol. Ethers, such as poly(ethyleneglycol), petroleum hydrocarbons, such as mineral oil and petrolatum, and water may also be used in suspension formulations.
[0138] The pharmaceutical compositions of this invention may also be in a topical form, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. For topical administration, the composition containing one or more JAK inhibitors can be in the form of emulsions, lotions, gels, foams, creams, jellies, solutions, suspensions, ointments, and transdermal patches.
[0139] Topical application for the lower intestinal tract may be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically- transdermal patches may also be used. For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions may be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters, wax, cetyl alcohol, 2- octyldodecanol, benzyl alcohol and water.
[0140] The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation. For delivery by inhalation, the compositions can be delivered as a dry powder or in liquid form via a nebulizer. Such compositions are prepared according to techniques known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons and/or other conventional solubilizing or dispersing agents. [0141] For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative, such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment, such as petrolatum.
[0142] For parenteral administration, the compositions can be in the form of sterile injectable solutions and sterile packaged powders. Preferably, injectable solutions are formulated at a pH of about 4.5 to about 7.5.
[0143] Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation. Compounds may be formulated for parenteral administration by injection such as by bolus injection or continuous infusion. A unit dosage form for injection may be in ampoules or in multi- dose containers.
[0144] The compositions of the present invention can also be provided in a lyophilized form. Such compositions may include a buffer, e.g., bicarbonate, for reconstitution prior to administration, or the buffer may be included in the lyophilized composition for reconstitution with, e.g., water. The lyophilized composition may further comprise a suitable vasoconstrictor, e.g., epinephrine. The lyophilized composition can be provided in a syringe, optionally packaged in combination with the buffer for reconstitution, such that the reconstituted composition can be immediately administered to a patient.
[0145] Any of the above dosage forms containing effective amounts are within the bounds of routine experimentation and within the scope of the invention. A therapeutically effective dose may vary depending upon the route of administration and dosage form. The representative compound or compounds of the invention is a formulation that exhibits a high therapeutic index. The therapeutic index is the dose ratio between toxic and therapeutic effects which can be expressed as the ratio between LD50 and ED50. The LD50 is the dose lethal to 50% of the population and the ED50 is the dose therapeutically effective in 50% of the population. The LD50 and ED50 are determined by standard pharmaceutical procedures in animal cell cultures or experimental animals.
[0146] Besides those representative dosage forms described above, pharmaceutically acceptable excipients and carriers and dosage forms are generally known to those skilled in the art and are included in the invention. It should be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex and diet of the patient, and the time of administration, rate of excretion, drug combination, judgment of the treating physician and severity of the particular disease being treated. The amount of active ingredient(s) will also depend upon the particular compound and other therapeutic agent, if present, in the composition.
e. Methods of Use [0147] The invention provides methods of inhibiting or decreasing JAK activity as well as treating or ameliorating a JAK associated state, symptom, condition, disorder or disease in a patient in need thereof {e.g., human or non-human). In one embodiment, the JAK associated state, symptom, condition, disorder or disease is mediated, at least in part by JAK activity. In more specific embodiments, the present invention provides a method for treating a condition or disorder mediated at least in part by JAK activity is cardiovascular disease, inflammatory disease or autoimmune disease.
[0148] The compounds described herein are also potent and/or selective inhibitors of JAKs. As a consequence of this activity, the compounds can be used in a variety of in vitro, in vivo, and ex vivo contexts to regulate or inhibit JAK activity, signaling cascades in which JAKs play a role, and the biological responses effected by such signaling cascades. For example, in one embodiment, the compounds can be used to inhibit JAK, either in vitro or in vivo, in virtually any cell type expressing the JAK, such as in hematopoietic cells in which, for example, JAK3 is predominantly expressed. They may also be used to regulate signal transduction cascades in which JAKs, particularly JAK3, play a role. Such JAK-dependent signal transduction cascades include, but are not limited to, the signaling cascades of cytokine receptors that involve the common gamma chain, such as, for example, the IL-4, IL-7, IL-5, IL-9, IL-15 and IL-21, or EL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 receptor signaling cascades. The compounds may also be used in vitro or in vivo to regulate, and in particular to inhibit, cellular or biological responses affected by such JAK-dependent signal transduction cascades. Such cellular or biological responses include, but are not limited to, IL-4/Ramos CD23 upregulation and IL-2 mediated T-cell proliferation. Importantly, the compounds can be used to inhibit JAKs in vivo as a therapeutic approach towards the treatment or prevention of diseases mediated, either wholly or in part, by a JAK activity (referred to herein as "JAK mediated diseases"). Non-limiting examples of JAK mediated diseases that can be treated or prevented with the compounds include, but are not limited to, the following: allergies; asthma; autoimmune diseases such as transplant rejection (e.g., kidney, heart, lung, liver, pancreas, skin, small intestine, large intestine, host versus graft reaction (HVGR), and graft versus host reaction (GVHR)), rheumatoid arthritis, and amyotrophic lateral sclerosis; T-cell mediated autoimmune diseases such as multiple sclerosis, psoraiasis, and Sjogren's syndrome; Type II inflammatory diseases such as vascular inflammation (including vasculitis, arteritis, atherosclerosis, and coronary artery disease); diseases of the central nervous system such as stroke; pulmonary diseases such as bronchitis obliteraus and primary pulmonary hypertension; solid, delayed Type IV hypersensitivity reactions; and hematologic malignancies such as leukemia and lymphomas.
[0149] Examples of diseases that are mediated, at least in part, by JAKs that can be treated or prevented according to the methods include, but are not limited to, allergies, asthma, autoimmune diseases such as transplant rejection (e.g., kidney, heart, lung, liver, pancreas, skin, host versus graft reaction (HVGR), etc.), rheumatoid arthritis, and amyotrophic lateral sclerosis, multiple sclerosis, psoraiasis and Sjogren's syndrome, Type II inflammatory disease such as vascular inflammation (including vasculitis, ateritis, atherosclerosis and coronary artery disease) or other inflammatory diseases such as osteoarthritis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, idiopathic inflammatory bowel disease, irritable bowel syndrome, spastic colon, low grade scarring (e.g., scleroderma, increased fibrosis, keloids, post-surgical scars, pulmonary fibrosis, vascular spasms, migraine, reperfusion injury and post myocardial infarction), and sicca complex or syndrome, diseases of the central nervous system such as stroke, pulmonary diseases such as bronchitis obliterous and primary and primary pulmonary hypertension, delayed or cell-mediated, Type IV hypersensitivity and solid and hematologic malignancies such as leukemias and lyphomas.
[0150] In another embodiment, this invention provides a method of inhibiting an activity of a JAK, comprising contacting the JAK with an amount of a compound effective to inhibit an activity of the JAK, wherein the compound is selected from the compounds of this invention. In certain embodiments of the methods described herein, the method is carried out in vivo.
[0151] In another embodiment, this invention provides a method of inhibiting an activity of a JAK, comprising contacting in vitro a JAK3 with an amount of a compound effective to inhibit an activity of the JAK, wherein the compound is selected from the compounds of this invention.
[0152] In a specific embodiment, the compounds can be used to treat and/or prevent rejection in organ and/or tissue transplant recipients (i.e., treat and/or prevent allorgraft rejection). Allografts can be rejected through either a cell-mediated or humoral immune reaction of the recipient against transplant (histocompability) antigens present on the membranes of the donor's cells. The strongest antigens are governed by a complex of genetic loci termed human leukocyte group A (HLA) antigens. Together with the ABO blood groups antigens, they are the chief transplantation antigens detectable in humans.
[0153] Rejection following transplantation can generally be broken into three categories: hyperacute, occurring hours to days following transplantation; acute, occurring days to months following transplantation; and chronic, occurring months to years following transplantation.
[0154] Hyperacute rejection is caused mainly by the production of host antibodies that attack the graft tissue. In a hyperacute rejection reaction, antibodies are observed in the transplant vascular very soon after transplantation. Shortly thereafter, vascular clotting occurs, leading to ischemia, eventual necrosis and death. The graft infarction is unresponsive to known immunosuppressive therapies. Because HLA antigens can be identified in vitro, pre-transplant screening is used to significantly reduce hyperacute rejection. As a consequence of this screening, hyperacute rejection is relatively uncommon today. [0155] Acute rejection is thought to be mediated by the accumulation of antigen specific cells in the graft tissue. The T-cell-mediated immune reaction against these antigens (i.e., HVGR or GVHR) is the principle mechanism of acute rejection. Accumulation of these cells leads to damage of the graft tissue. It is believed that both CD4+ helper T-cells and CD8+ cytotoxic T-cells are involved in the process and that the antigen is presented by donor and host dendritic cells. The CD4+ helper T-cells help recruit other effector cells, such as macrophapges and eosinophils, to the graft. Accessing T-cell activation signal transduction cascades (for example, CD28, CD40L, and CD2 cascades) are also involved.
[0156] The cell-mediated acute rejection can be reversed in many cases by intensifying immunotherapy. After successful reversal, severely damaged elements of the graft heal by fibrosis and the remainder of the graft appears normal. After resolution of acute rejection, dosages of immunosuppressive drugs can be reduced to very low levels.
[0157] Chronic rejection, which is a particular problem in renal transplants, often progresses insidiously despite increased immunosuppressive therapy. It is thought to be due, in large part, to cell-mediated Type IV hypersensitivity. The pathologic profile differs from that of acute rejection. The arterial endothelium is primarily involved with extensive proliferation that may gradually occlude the vessel lumen, leading to ischemia, fibrosis, a thickened intima, and atherosclerotic changes. Chronic rejection is mainly due to a progressive obliteration of graft vasculature and resembles a slow, vasculitic process.
[0158] In Type IV hypersensitivity, CD8 cytotoxic T-cells and CD4 helper T cells recognize either intracellular or extracellular synthesized antigen when it is complexed, respectively, with either Class I or Class II MHC molecules. Macrophages function as antigen-presenting cells and release IL-I, which promotes proliferation of helper T-cells. Helper T-cells release interferon gamma and IL-2, which together regulate delayed hyperactivity reactions mediated by macrophage activation and immunity mediated by T cells. In the case of organ transplant, the cytotoxic T-cells destroy the graft cells on contact.
[0159] Since JAKs play a critical role in the activation of T-cells, the compounds described herein can be used to treat and/or prevent many aspects of transplant rejection, and are particularly useful in the treatment and/or prevention of rejection reactions that are mediated, at least in part, by T-cells, such as HVGR or GVHR. The compounds can also be used to treat and/or prevent chronic rejection in transplant recipients and, in particular, in renal transplant recipients. The compound can also be administered to a tissue or an organ prior to transplanting the tissue or organ in the transplant recipient.
[0160] In another embodiment, this invention provides a method of treating a T-cell mediated autoimmune disease, comprising administering to a patient suffering from such an autoimmune disease an amount of a compound effective to treat the autoimmune disease wherein the compound is selected from the compounds of the invention. In certain embodiments of the methods the autoimmune disease is multiple sclerosis (MS), psoraisis, or Sjogran's syndrome. Such autoimmune disease include, but are not limited to, those autoimmune diseases that are frequently designated as single organ or single cell-type autoimmune disorders and those autoimmune disease that are frequently designated as involving systemic autoimmune disorder. Non-limiting examples of diseases frequently designated as single organ or single cell-type autoimmune disorders include: Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Graves' disease, primary biliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis and membranous glomerulopathy. Non-limiting examples of diseases often designated as involving systemic autoimmune disorder include: systemic lupus erythematosis, rheumatoid arthritis, Sjogren's syndrome, Reiter's syndrome, polymyositis-dermatomyositis, systemic sclerosis, polyarteritis nodosa, multiple sclerosis and bullous pemphigoid. Additional autoimmune diseases, which can be .beta.-cell (humoral) based or T-cell based, include Cogan's syndrome, ankylosing spondylitis, Wegener's granulomatosis, autoimmune alopecia, Type I or juvenile onset diabetes, and thyroiditis.
[0161] The types of autoimmune diseases that may be treated or prevented with such prodrugs generally include those disorders involving tissue injury that occurs as a result of a humoral and/or cell-mediated response to immunogens or antigens of endogenous and/or exogenous origin. Such diseases are frequently referred to as diseases involving the nonanaphylactic (i.e., Type II, Type III and/or Type IV) hypersensitivity reactions.
[0162] Type I hypersensitivity reactions generally result from the release of pharmacologically active substances, such as histamine, from mast and/or basophil cells following contact with a specific exogenous antigen. As mentioned above, such Type I reactions play a role in numerous diseases, including allergic asthma, allergic rhinitis, etc. [0163] Type II hypersensitivity reactions (also referred to as cytotoxic, cytolytic complement-dependent or cell-stimulating hypersensitivity reactions) result when immunoglobulins react with antigenic components of cells or tissue, or with an antigen or hapten that has become intimately coupled to cells or tissue. Diseases that are commonly associated with Type II hypersensitivity reactions include, but are not limited, to autoimmune hemolytic anemia, erythroblastosis fetalis and Goodpasture's disease.
[0164] Type III hypersensitivity reactions, (also referred to as toxic complex, soluble complex, or immune complex hypersensitivity reactions) result from the deposition of soluble circulating antigen-immunoglobulin complexes in vessels or in tissues, with accompanying acute inflammatory reactions at the site of immune complex deposition. Non-limiting examples of prototypical Type III reaction diseases include the Arthus reaction, rheumatoid arthritis, serum sickness, systemic lupus erythematosis, certain types of glomerulonephritis, multiple sclerosis and bullous pemphingoid.
[0165] Type IV hypersensitivity reactions (frequently called cellular, cell-mediated, delayed, or tuberculin-type hypersensitivity reactions) are caused by sensitized T- lymphocytes which result from contact with a specific antigen. Non-limiting examples of diseases cited as involving Type IV reactions are contact dermatitis and allograft rejection.
[0166] Autoimmune diseases associated with any of the above nonanaphylactic hypersensitivity reactions may be treated or prevented with the prodrugs according to structural formula (I). In particular, the methods may be used to treat or prevent those autoimmune diseases frequently characterized as single organ or single cell-type autoimmune disorders including, but not limited to: Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Graves' disease, primary biliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis and membranous glomerulopathy, as well as those autoimmune diseases frequently characterized as involving systemic autoimmune disorder, which include but are not limited to: systemic lupus erythematosis (SLE), rheumatoid arthritis, Sjogren's syndrome, Reiter's syndrome, polymyositis-dermatomyositis, systemic sclerosis, polyarteritis nodosa, multiple sclerosis and bullous pemphigoid.
[0167] It will be appreciated by skilled artisans that many of the above-listed autoimmune diseases are associated with severe symptoms, the amelioration of which provides significant therapeutic benefit even in instances where the underlying autoimmune disease may not be ameliorated.
[0168] Therapy using the compounds described herein can be applied alone, or it can be applied in combination with or adjunctive to other common immunosuppressive therapies, such as, for example, the following: mercaptopurine; corticosteroids such as prednisone; methylprednisolone and prednisolone; alkylating agents such as cyclophosphamide; calcineurin inhibitors such as cyclosporine, sirolimus, and tacrolimus; inhibitors of inosine monophosphate dehydrogenase (IMPDH) such as mycophenolate, mycophenolate mofetil, and azathioprine; and agents designed to suppress cellular immunity while leaving the recipient's humoral immunologic response intact, including various antibodies (for example, antilymphocyte globulin (ALG), antithymocyte globulin (ATG), monoclonal anti-T-cell antibodies (OKT3)) and irradiation. These various agents can be used in accordance with their standard or common dosages, as specified in the prescribing information accompanying commercially available forms of the drugs (see also: the prescribing information in the 2006 Edition of The Physician's Desk Reference), the disclosures of which are incorporated herein by reference. Azathioprine is currently available from Salix Pharmaceuticals, Inc., under the brand name AZASAN; mercaptopurine is currently available from Gate Pharmaceuticals, Inc., under the brand name PURINETHOL; prednisone and prednisolone are currently available from Roxane Laboratories, Inc.; Methyl prednisolone is currently available from Pfizer; sirolimus (rapamycin) is currently available from Wyeth under the brand name RAPAMUNE; tacrolimus is currently available from Fujisawa under the brand name PROGRAF; cyclosporine is current available from Novartis under the brand name SANDIMMUNE and from Abbott under the brand name GENGRAF; IMPDH inhibitors such as mycophenolate mofetil and mycophenolic acid are currently available from Roche under the brand name CELLCEPT and from Novartis under the brand name MYFORTIC; azathioprine is currently available from Glaxo Smith Kline under the brand name IMURAN; and antibodies are currently available from Ortho Biotech under the brand name ORTHOCLONE, from Novartis under the brand name SEVIULECT (basiliximab), and from Roche under the brand name ZENAPAX (daclizumab). [0169] In another embodiment, the compounds could be administered either in combination or adjunctively with an inhibitor of a syk. Syk is a tyrosine kinase known to play a critical role in Fey receptor signaling, as well as in other signaling cascades, such as those involving B-cell receptor signaling (Turner et al., (2000), Immunology Today 21: 148-154) and integrins beta(l), beta (2), and beta (3) in neutrophils (Mocsai et al., (2002), Immunity 16:547-558). For example, syk plays a pivotal role in high affinity IgE receptor signaling in mast cells that leads to activation and subsequent release of multiple chemical mediators that trigger allergic attacks. However, unlike the JAKs, which help regulate the pathways involved in delayed or cell-mediated Type IV hypersensitivity reactions, syk helps regulate the pathways involved in immediate IgE-mediated, Type I hypersensitivity reactions. Certain compounds that affect the syk pathway may or may not also affect the JAK pathways.
[0170] Suitable syk inhibitory compounds are described, for example, in Ser. No.
10/355,543 filed Jan. 31, 2003 (publication no. 2004/0029902); WO 03/063794; Ser. No. 10/631,029 filed JuI. 29, 2003; WO 2004/014382; Ser. No. 10/903,263 filed JuL 30, 2004;
PCT/US2004/24716 filed JuL 30, 2004 (WO005/016893); Ser. No. 10/903,870 filed JuI. 30,
2004; PCT/US2004/24920 filed JuI. 30, 2004; Ser. No. 60/630,808 filed Nov. 24, 2004; Ser.
No. 60/645,424 filed Jan. 19, 2005; and Ser. No. 60/654,620, filed Feb. 18, 2005, the disclosures of which are incorporated herein by reference. The compounds described herein and syk inhibitory compounds could be used alone or in combination with one or more conventional transplant rejection treatments, as described above.
[0171] In a specific embodiment, the compounds can be used to treat or prevent these diseases in patients that are either initially non-responsive (resistant) to or that become non- responsive to treatment with a JAK inhibitory compound or one of the other current treatments for the particular disease. The compounds could also be used in combination with syk inhibitory compounds in patients that are JAK -compound resistant or non-responsive. Suitable JAK -inhibitory compounds with which the compounds can be administered are provided infra.
[0172] In another embodiment, this invention provides a method of treating a T-cell mediated autoimmune disease, comprising administering to a patient suffering from such an autoimmune disease an amount of a compound effective to treat the autoimmune disease wherein the compound is selected from the compounds of the invention, as described herein, and the compound is administered in combination with or adjunctively to a compound that inhibits JAK with an IC50 in the range of at least 10 μM. [0173] In another embodiment, this invention provides a method of treating or preventing allograft transplant rejection in a transplant recipient, comprising administering to the transplant recipient an amount of a compound effective to treat or prevent the rejection wherein the compound is selected from the compounds of the invention, as described herein. In a further embodiment, the compound is administered to a tissue or an organ prior to transplanting the tissue or organ in the transplant recipient.
[0174] In another embodiment, this invention provides a method of treating or preventing allograft transplant rejection in a transplant recipient, in which the rejection is acute rejection, comprising administering to the transplant recipient an amount of a compound effective to treat or prevent the rejection, wherein the compound is selected from the compounds of the invention.
[0175] In another embodiment, this invention provides a method of treating or preventing allograft transplant rejection in a transplant recipient, in which the rejection is chronic rejection, comprising administering to the transplant recipient an amount of a compound effective to treat or prevent the rejection, wherein the compound is selected from the compounds of the invention.
[0176] In another embodiment, this invention provides a method of treating or preventing allograft transplant rejection in a transplant recipient, in which the rejection is mediated by HVGR or GVHR, comprising administering to the transplant recipient an amount of a compound effective to treat or prevent the rejection, wherein the compound is selected from the compounds of this invention, as described herein.
[0177] In another embodiment, this invention provides a method of treating or preventing allograft transplant rejection in a transplant recipient, in which the allograft transplant is selected from a kidney, a heart, a liver, and a lung, comprising administering to the transplant recipient an amount of a compound effective to treat or prevent the rejection, wherein the compound is selected from the compounds of this invention, as described herein.
[0178] In another embodiment, this invention provides a method of treating or preventing allograft transplant rejection in a transplant recipient, in which the allograft transplant is selected from a kidney, a heart, a liver, and a lung, comprising administering to the transplant recipient an amount of a compound effective to treat or prevent the rejection wherein the compound is selected from the compounds of the invention, as described herein, in which the compound is administered in combination with or adjunctively to another immunosuppressant. [0179] In another embodiment, this invention provides a method of treating or preventing allograft transplant rejection in a transplant recipient, in which the allograft transplant is selected from a kidney, a heart, a liver, and a lung, comprising administering to the transplant recipient an amount of a compound effective to treat or prevent the rejection, wherein the compound is selected from the compounds of the invention, as described herein, in which the compound is administered in combination with or adjunctively to another immunosuppressant, in which the immunosuppressant is selected from cyclosporine, tacrolimus, sirolimus, an inhibitor of EVIPDH, mycophenolate, mycophanolate mofetil, an anti-T-Cell antibody, and OKT3.
[0180] The compounds described herein are cytokine moderators of IL-4 signaling. As a consequence, the compounds could slow the response of Type I hypersensitivity reactions. Thus, in a specific embodiment, the compounds could be used to treat such reactions and, therefore, the diseases associated with, mediated by, or caused by such hypersensitivity reactions (for example, allergies), prophylactically. For example, an allergy sufferer could take one or more of the JAK selective compounds described herein prior to expected exposure to allergens to delay the onset or progress of, or eliminate altogether, an allergic response.
[0181] When used to treat or prevent such diseases, the compounds can be administered singly, as mixtures of one or more compounds, or in mixture or combination with other agents useful for treating such diseases and/or the symptoms associated with such diseases. The compounds may also be administered in mixture or in combination with agents useful to treat other disorders or maladies, such as steroids, membrane stabilizers, 5-lipoxygenase (5LO) inhibitors, leukotriene synthesis and receptor inhibitors, inhibitors of IgE isotype switching or IgE synthesis, IgG isotype switching or IgG synthesis, beta.-agonists, tryptase inhibitors, aspirin, cyclooxygenase (COX) inhibitors, methotrexate, anti-TNF drugs, anti
CD20 antibody, PD4 inhibitors, p38 inhibitors, PDE4 inhibitors, and antihistamines, to name a few. The compounds can be administered per se in the form of prodrugs or as pharmaceutical compositions, comprising an active compound or prodrug.
[0182] In another embodiment, this invention provides a method of treating or preventing a Type IV hypersensitivity reaction, comprising administering to a subject an amount of a compound effective to treat or prevent the hypersensitivity reaction, wherein the compound is selected from the compounds of this invention, as described herein. [0183] In another embodiment, this invention provides a method of treating or preventing a Type IV hypersensitivity reaction, which is practical prophylactically, comprising administering to a subject an amount of a compound effective to treat or prevent the hypersensitivity reaction, wherein the compound is selected from the compounds of this invention, as described herein, and is administered prior to exposure to an allergen.
[0184] In another embodiment, this invention provides a method of inhibiting a signal transduction cascade in which JAK3 plays a role, comprising contacting a cell expressing a receptor involved in such a signaling cascade with a compound wherein the compound is selected from the compounds of this invention, as described herein.
[0185] In another embodiment, this invention provides a method of treating or preventing a JAK-mediated disease, comprising administering to a subject an amount of compound effective to treat or prevent the JAK-mediated disease, wherein the compound is selected from the compounds of this invention, as described herein.
[0186] In another embodiment, this invention provides a method of treating or preventing a JAK-mediated disease, in which the JAK-disease is HVGR or GVHR, comprising administering to a subject an amount of compound effective to treat or prevent the JAK- mediated disease, wherein the compound is selected from the compounds of the invention, as described herein.
[0187] In another embodiment, this invention provides a method of treating or preventing a JAK-mediated disease, in which the JAK-disease is acute allograft rejection, comprising administering to a subject an amount of compound effective to treat or prevent the JAK- mediated disease, wherein the compound is selected from the compounds of the invention, as described herein.
[0188] In another embodiment, this invention provides a method of treating or preventing a JAK-mediated disease, in which the JAK-mediated disease is chronic allograft rejection, comprising administering to a subject an amount of compound effective to treat or prevent the JAK-mediated disease, wherein the compound is selected from the compounds of the invention, as described herein.
[0189] Active compounds of the invention typically inhibit theJAK/Stat pathway. The activity of a specified compound as an inhibitor of a JAK can be assessed in vitro or in vivo. In some embodiments, the activity of a specified compound can be tested in a cellular assay. [0190] "Cell proliferative disorder" refers to a disorder characterized by abnormal proliferation of cells. A proliferative disorder does not imply any limitation with respect to the rate of cell growth, but merely indicates loss of normal controls that affect growth and cell division. Thus, in some embodiments, cells of a proliferative disorder can have the same cell division rates as normal cells but do not respond to signals that limit such growth. Within the ambit of "cell proliferative disorder" is neoplasm or tumor, which is an abnormal growth of tissue. Cancer refers to any of various malignant neoplasms characterized by the proliferation of cells that have the capability to invade surrounding tissue and/or metastasize to new colonization sites.
[0191] Generally, cell proliferative disorders treatable with the compounds disclosed herein relate to any disorder characterized by aberrant cell proliferation. These include various tumors and cancers, benign or malignant, metastatic or non-metastatic. Specific properties of cancers, such as tissue invasiveness or metastasis, can be targeted using the methods described herein. Cell proliferative disorders include a variety of cancers, including, among others, ovarian cancer, renal cancer, gastrointestinal cancer, kidney cancer, bladder cancer, pancreatic cancer, lung squamous carcinoma, and adenocarcinoma.
[0192] In some embodiments, the cell proliferative disorder treated is a hematopoietic neoplasm, which is aberrant growth of cells of the hematopoietic system. Hematopoietic malignancies can have its origins in pluripotent stem cells, multipotent progenitor cells, oligopotent committed progenitor cells, precursor cells, and terminally differentiated cells involved in hematopoiesis. Some hematological malignancies are believed to arise from hematopoietic stem cells, which have the ability for self renewal. Blast cells that do not have a cell marker characteristic of hematopoietic stem cells appear to be incapable of establishing tumors upon transplantation (Blaire et al., 1997, Blood 89:3104-3112). The stem cell origin of certain hematological malignancies also finds support in the observation that specific chromosomal abnormalities associated with particular types of leukemia can be found in normal cells of hematopoietic lineage as well as leukemic blast cells. For instance, the reciprocal translocation t(9q34;22ql 1) associated with approximately 95% of chronic myelogenous leukemia appears to be present in cells of the myeloid, erythroid, and lymphoid lineage, suggesting that the chromosomal aberration originates in hematopoietic stem cells. A subgroup of cells in certain types of CML displays the cell marker phenotype of hematopoietic stem cells. [0193] Although hematopoietic neoplasms often originate from stem cells, committed progenitor cells or more terminally differentiated cells of a developmental lineage can also be the source of some leukemias. For example, forced expression of the fusion protein Bcr/Abl (associated with chronic myelogenous leukemia) in common myeloid progenitor or granulocyte/macrophage progenitor cells produces a leukemic-like condition. Moreover, some chromosomal aberrations associated with subtypes of leukemia are not found in the cell population with a marker phenotype of hematopoietic stem cells, but are found in a cell population displaying markers of a more differentiated state of the hematopoietic pathway (Turhan et al., 1995, Blood 85:2154-2161). Thus, while committed progenitor cells and other differentiated cells may have only a limited potential for cell division, leukemic cells may have acquired the ability to grow unregulated, in some instances mimicking the self-renewal characteristics of hematopoietic stem cells (Passegue et al., Proc. Natl. Acad. Sci. USA, 2003, 100:11842-9).
[0194] In some embodiments, the hematopoietic neoplasm treated is a lymphoid neoplasm, where the abnormal cells are derived from and/or display the characteristic phenotype of cells of the lymphoid lineage. Lymphoid neoplasms can be subdivided into B-cell neoplasms, T and NK-cell neoplasms, and Hodgkin's lymphoma. B-cell neoplasms can be further subdivided into precursor B-cell neoplasm and mature/peripheral B-cell neoplasm. Exemplary B-cell neoplasms are precursor B-lymphoblastic leukemia/lymphoma (precursor B-cell acute lymphoblastic leukemia) while exemplary mature/peripheral B-cell neoplasms are B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone B-cell lymphoma, hairy cell leukemia, plasma cell myeloma/plasmacytoma, extranodal marginal zone B-cell lymphoma of MALT type, nodal marginal zone B-cell lymphoma, follicular lymphoma, mantle-cell lymphoma, diffuse large B-cell lymphoma, mediastinal large B-cell lymphoma, primary effusion lymphoma, and Burkitt's lymphoma/Burkitt cell leukemia. T- cell and Nk-cell neoplasms are further subdivided into precursor T-cell neoplasm and mature (peripheral) T-cell neoplasms. Exemplary precursor T-cell neoplasm is precursor T- lymphoblastic lymphoma/leukemia (precursor T-cell acute lymphoblastic leukemia) while exemplary mature (peripheral) T-cell neoplasms are T-cell prolymphocytic leukemia T-cell granular lymphocytic leukemia, aggressive NK-cell leukemia, adult T-cell lymphoma/leukemia (HTLV-I), extranodal NK/T-cell lymphoma, nasal type, enteropathy- type T-cell lymphoma, hepatosplenic gamma-delta T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, Mycosis fungoides/Sezary syndrome, Anaplastic large- cell lymphoma, T/null cell, primary cutaneous type, Peripheral T-cell lymphoma, not otherwise characterized, Angioimmunoblastic T-cell lymphoma, Anaplastic large-cell lymphoma, T/null cell, primary systemic type. The third member of lymphoid neoplasms is Hodgkin's lymphoma, also referred to as Hodgkin's disease. Exemplary diagnosis of this class that can be treated with the compounds include, among others, nodular lymphocyte- predominant Hodgkin's lymphoma, and various classical forms of Hodgkin's disease, exemplary members of which are Nodular sclerosis Hodgkin's lymphoma (grades 1 and 2), Lymphocyte-rich classical Hodgkin's lymphoma, Mixed cellularity Hodgkin's lymphoma, and Lymphocyte depletion Hodgkin's lymphoma. In various embodiments, any of the lymphoid neoplasms that are associated with aberrant JAK activity can be treated with the JAK inhibitory compounds.
[0195] In some embodiments, the hematopoietic neoplasm treated is a myeloid neoplasm. This group comprises a large class of cell proliferative disorders involving or displaying the characteristic phenotype of the cells of the myeloid lineage. Myeloid neoplasms can be subdivided into myeloproliferative diseases, myelodysplastic/myeloproliferative diseases, myelodysplastic syndromes, and acute myeloid leukemias. Exemplary myeloproliferative diseases are chronic myelogenous leukemia (e.g., Philadelphia chromosome positive (t(9;22)(qq34;ql l)), chronic neutrophilic leukemia, chronic eosinophilic leukemia/hypereosinophilic syndrome, chronic idiopathic myelofibrosis, polycythemia vera, and essential thrombocythemia. Exemplary myelodysplastic/myeloproliferative diseases are chronic myelomonocytic leukemia, atypical chronic myelogenous leukemia, and juvenile myelomonocytic leukemia. Exemplary myelodysplastic syndromes are refractory anemia, with ringed sideroblasts and without ringed sideroblasts, refractory cytopenia (myelodysplastic syndrome) with multilineage dysplasia, refractory anemia (myelodysplastic syndrome) with excess blasts, 5q-syndrome, and myelodysplastic syndrome. In various embodiments, any of the myeloid neoplasms that are associated with aberrant JAK activity can be treated with the JAK inhibitory compounds.
[0196] In some embodiments, the compounds can be used to treat Acute myeloid leukemias (AML), which represent a large class of myeloid neoplasms having its own subdivision of disorders. These subdivisions include, among others, AMLs with recurrent cytogenetic translocations, AML with multilineage dysplasia, and other AML not otherwise categorized. Exemplary AMLs with recurrent cytogenetic translocations include, among others, AML with t(8;21)(q22;q22), AMLl(CBF-alpha)/ETO, Acute promyelocytic leukemia (AML with t(15;17)(q22;ql 1-12) and variants, PML/RAR-alpha), AML with abnormal bone marrow eosinophils (inv(16)(pl3q22) or t(16;16)(pl3;ql 1), CBFb/MYHl IX), and AML with 1 Iq23 (MLL) abnormalities. Exemplary AML with multilineage dysplasia are those that are associated with or without prior myelodysplastic syndrome. Other acute myeloid leukemias not classified within any definable group include, AML minimally differentiated, AML without maturation, AML with maturation, Acute myelomonocytic leukemia, Acute monocytic leukemia, Acute erythroid leukemia, Acute megakaryocytic leukemia, Acute basophilic leukemia, and Acute panmyelosis with myelofibrosis.
[0197] "Treating" within the context of the invention means an alleviation of symptoms associated with a disorder or disease, or halt of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder.
[0198] The term "mammal" includes organisms which express JAK. Examples of mammals include mice, rats, cows, sheep, pigs, goats, horses, bears, monkeys, dogs, cats and, preferably, humans. Transgenic organisms which express JAK are also included in this definition.
[0199] The inventive methods comprise administering an effective amount of a compound or composition described herein to a mammal or non-human animal. As used herein, "effective amount" of a compound or composition of the invention includes those amounts that antagonize or inhibit JAK. An amount which antagonizes or inhibits JAK is detectable, for example, by any assay capable of determining JAK activity, including the one described below as an illustrative testing method. Effective amounts may also include those amounts which alleviate symptoms of a JAK associated disorder treatable by inhibiting JAK. Accordingly, "antagonists of JAK" include compounds which interact with the JAK, respectively, and modulate, e.g., inhibit or decrease, the ability of a second compound, e.g., another JAK ligand, to interact with the JAK, respectively. The JAK binding compounds are preferably antagonists of JAK, respectively. The language "JAK-binding compound" (e.g., exhibits binding affinity to the receptor) includes those compounds which interact with JAK resulting in modulation of the activity of JAK, respectively. JAK binding compounds may be identified using an in vitro (e.g., cell and non-cell based) or in vivo method. A description of in vitro methods are provided below. [0200] The amount of compound present in the methods and compositions described herein should be sufficient to cause a detectable decrease in the severity of the disorder, as measured by any of the assays described in the examples. The amount of JAK modulator needed will depend on the effectiveness of the modulator for the given cell type and the length of time required to treat the disorder. In certain embodiments, the compositions of this invention may further comprise another therapeutic agent. When a second agent is used, the second agent may be administered either as a separate dosage form or as part of a single dosage form with the compounds or compositions of this invention. While one or more of the inventive compounds can be used in an application of monotherapy to treat a disorder, disease or symptom, they also may be used in combination therapy, in which the use of an inventive compound or composition (therapeutic agent) is combined with the use of one or more other therapeutic agents for treating the same and/or other types of disorders, symptoms and diseases. Combination therapy includes administration of the two or more therapeutic agents concurrently or sequentially. The agents may be administered in any order. Alternatively, the multiple therapeutic agents can be combined into a single composition that can be administered to the patient. For instance, a single pharmaceutical composition could comprise the compound or pharmaceutically acceptable salt, ester or prodrug thereof according to the formula (I), another therapeutic agent (e.g., methotrexate) or a pharmaceutically acceptable salt, ester or prodrug thereof, and a pharmaceutically acceptable excipient or carrier.
[0201] The invention comprises a compound having the formula (I), a method for making an inventive compound, a method for making a pharmaceutical composition from at least one inventive compound and at least one pharmaceutically acceptable carrier or excipient, and a method of using one or more inventive compounds to treat a variety of disorders, symptoms and diseases (e.g., inflammatory, autoimmune, neurological, neurodegenerative, oncology and cardiovascular), such as RA, osteoarthritis, irritable bowel disease IBD, asthma, chronic obstructive pulmonary disease COPD and MS. The inventive compounds and their pharmaceutically acceptable salts and/or neutral compositions may be formulated together with a pharmaceutically acceptable excipient or carrier and the resulting composition may be administered in vivo to mammals, such as men, women and animals, to treat a variety of disorders, symptoms and diseases. Furthermore, the inventive compounds can be used to prepare a medicament that is useful for treating a variety of disorders, symptoms and diseases. [0202] AU of the compounds of the present invention are either potent inhibitors of JAK kinases, exhibiting ΪC50S in the respective assay in the range of less than 5 μM, with most being in the nanomolar, and several in the sub-nanomolar, range. In some embodiments, the compounds of the present invention may be "dual" syk/JAK inhibitors in that they inhibit both syk and JAK kinase to some degree. In other embodiments, the compounds of the present invention may selectively inhibit JAK kinase, but not appreciably inhibit one or more syk kinases.
f. Kits [0203] Still another aspect of this invention is to provide a kit comprising separate containers in a single package, wherein the inventive pharmaceutical compounds, compositions and/or salts thereof are used in combination with pharmaceutically acceptable carriers to treat states, disorders, symptoms and diseases where JAK plays a role.
EXAMPLES
[0204] The following examples are offered to illustrate, but not to limit, the claimed invention.
[0205] The starting materials and reagents used in preparing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, 1967-2004, Volumes 1-22; Rodd's Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and Supplemental; and Organic Reactions, Wiley & Sons: New York, 2005, Volumes 1-65.
[0206] The starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.
[0207] Unless specified to the contrary, the reactions described herein preferably are conducted under an inert atmosphere at atmospheric pressure at a reaction temperature range of from about -78°C to about 150°C, more preferably from about 00C to about 125°C, and most preferably and conveniently at about room (or ambient) temperature, e.g., about 20°C to about 75°C. [0208] Referring to the examples that follow, compounds of the present invention were synthesized using the methods described herein, or other methods, which are well known in the art.
[0209] The compounds and/or intermediates may be characterized by high performance liquid chromatography (HPLC) using a Waters Alliance chromatography system with a 2695 Separation Module (Milford, Mass.). The analytical columns may be C-18 SpeedROD RP- 18E Columns from Merck KGaA (Darmstadt, Germany). Alternately, characterization may be performed using a Waters Unity (UPLC) system with Waters Acquity UPLC BEH C-18 2.1 mm x 15 mm columns. A gradient elution may be used, typically starting with 5 % acetonitrile/95% water and progressing to 95% acetonitrile over a period of 5 minutes for the Alliance system and 1 minute for the Acquity system. All solvents may contain 0.1% trifluoroacetic acid (TFA). Compounds may be detected by ultraviolet light (UV) absorption at either 220 nm or 254 nm or by mass spectrometry in the case of the Acuity system by using a Waters SQD detector. HPLC solvents may be from EMD Chemicals, Inc. (Gibbstown, NJ). In some instances, purity may be assessed by thin layer chromatography (TLC) using glass backed silica gel plates, such as, for example, EMD Silica Gel 60 2.5cm x 7.5cm plates. TLC results may be readily detected visually under ultraviolet light, or by employing well known iodine vapor and other various staining techniques.
[0210] Nuclear magnetic resonance (NMR) analysis may be performed on some of the compounds with a Varian 400 MHz NMR (Palo Alto, Calif.). The spectral reference may be either TMS or the known chemical shift of the solvent.
[0211] The purity of some of the invention compounds may be assessed by elemental analysis (Robertson Microlit, Madison, NJ.).
[0212] Melting points may be determined on a Laboratory Devices Mel-Temp apparatus (Holliston, Mass.).
[0213] Preparative separations may be carried out as needed, using either a SqI 6x or a SgIOOc or a CombiPrep Rf chromatography system and prepackaged silica gel columns all purchased from Teledyne Isco, (Lincoln, NE). Alternately, compounds and intermediates may be purified by flash column chromatography using silica gel (230-400 mesh) packing material, or by HPLC using a C-18 reversed phase column. Typical solvents employed for the Isco systems and flash column chromatography may be dichloromethane, methanol, ethyl acetate, hexane, acetone, aqueous hydroxyamine and triethyl amine. Typical solvents employed for the reverse phase HPLC may be varying concentrations of acetonitrile and water with 0.1% trifluoroacetic acid.
General methods
[0214] The following synthetic reaction schemes are merely illustrative of some methods by which the compounds of the present invention can be synthesized, and various modifications to these synthetic reaction schemes can be made and will be suggested to one skilled in the art having referred to the disclosure contained in this application.
Example 1. 2-(3-acetamidophenylamino)-4-(cyclobutylamino)pyrimidine-5-carboxamide
Scheme 1.
Figure imgf000075_0001
1.1 1.2 1.3
Figure imgf000075_0002
1.4 1.5 1.6
Figure imgf000075_0003
1.7
[0215] Step 1: To a stirring solution of carboxylic acid 1.1 (85g, 540mmol) in thionyl chloride (425mL) was added pyridine (8.5mL, 0.1 lmmol), slowly. The reaction was stirred at 750C overnight at which time it was concentrated and dried under vacuum to a light yellow powder which was used immediately for the next step. [0216] Step 2: The yellow solid from the previous page was slowly diluted with 750 niL of ethanol and refluxed overnight. The next day the reaction was determined to be complete by HPLC and then cooled in an ice bath and the solid filtered and washed with diethyl ether affording the desired ethyl ester 1.3 as an off-white powder (9 Ig, 87% for two steps). MS found for C7H8N2O4 as (M+H)+ 185.0.
[0217] Step 3: Ester 1.3 (22g, 120 mmol) was dissolved in phosphorous oxychloride (60 niL, 600 mmol) and the mixture treated with N,N-diethylaniline (27 mL, 167 mmol) and the mixture heated to 1050C until the reaction was determined to be complete by HPLC. It was then cooled to it and slowly added to 1 L of crushed ice resulting in the formation of a beige precipitate which was collected by filtration and dried under vacuum affording the desired dichloride (1.4) as a light yellow powder (22.5g, 85%). 1H NMR (DMSOd6, 400 MHz): δ 9.13 (s, IH), 4.37 (q, 2H), 1.32 (t, 3H).
[0218] Step 4: Dichloropyrimidine 1.4 (5.9g, 27 mmol) was dissolved in acetonitrile (50 mL) and treated sequentially with diisopropylamine (5.2 mL, 30 mmol) followed by cyclobutyl amine (1.9g, 27 mmol) and stirred at rt until all starting material had been consumed. The reaction mixture was then diluted with water to a total volume of 150 mL and the precipitate collected by filtration affording the desired product as a light yellow solid (6.02g, 87%). 1H NMR (DMSOd6, 400 MHz): δ 8.60 (S, IH), 8.48 (d, IH), 4.52 (m, IH), 4.29 (q, 2H), 2.30 (m, 2H), 2.04 (m, 2H), 1.73 (m, 2H), 1.30 (t, 3H).
[0219] Step 5: Ethyl ester 1.5 (6.02g, 24 mmol) was diluted with 1,4-dioxane (26 mL) followed by aqueous lithium hydroxide (1.0 M, 26 mL, 26 mmol) and stirred at rt until all starting material had been converted to the carboxylic acid. The reaction was then diluted with water to a total volume of 100 mL and acidified to pH = 2 with 6 M HCl. The resulting suspension was then filtered and dried by aspiration giving 3.5 Ig of the carboxylic acid (64%). 1H NMR (DMSO-d6, 400 MHz): δ 8.64 (d, IH), 8.74 (s, IH), 4.50 (m, IH), 2.31 (m, 2H), 2.03 (m, 2H), 1.72 (m, 2H).
[0220] Step 6: Carboxylic acid 1.6 (3.15g, 15 mmol) was dissolved in N,N- dimethylformamide (70 mL) and treated with HOBt (3.13g, 23 mmol) and EDC (4.4g, 23 mmol). After stirring ca. 25 min ammonia (0.5 M in 1,4-dioxane, 72 mL, 36 mmol) was added and the reaction stirred overnight. The following morning the reaction was diluted with water to a total volume of 500 mL and the desired product collected by filtration affording 3.62g (74%) of a light-beige solid. 1H NMR (DMSO-d6, 400 MHz): δ 9.30 (d, IH), 8.54 (s, IH), 8.15 (d, IH), 8.09 (s, IH), 7.74 (d, IH), 7.64 (m, 2H), 7.51 (t, IH), 3.77 (m, IH), 1.79 (m, 2H), 1.74 (m, 2H), 1.53 (m, IH), 1.41 (m, IH).
[0221] Step 7: Benzotriazolyl ether 1.7 (50 mg, 0.17 mmol), 3-aminiacetanilide (40 mg) and p-toluenesulfonic acid ( 30 mg, 0.17 mmol) were diluted with 1,4-dioxane (5 niL) or NMP (5 mL) and stirred at 1000C until all starting material had been consumed. The reaction was cooled to rt, diluted with water and directly purified by preparative HPLC affording the desired product after lyophilization. The above compound was prepared using the procedure described in Scheme 1. MS found for CnH20N6O2 as (M+H)+ 341. UV: λ = 251.
Example 2 2-(3-acetamido-4-chlorophenylamino)-4-(benzylamino)pyrimidine-5- carboxamide
Scheme 2:
Figure imgf000077_0001
2.1 2.2 2.3
Figure imgf000077_0002
[0222] Step 1: Chloropyrimidine 2.1 (6.2 g, 27 mmol) was dissolved in dioxane (30 mL) and treated sequentially with diisopropylamine (5.0 mL, 29 mmol) followed by benzylamine (3.2 mL, 29 mmol) and stirred at rt until all starting material had been consumed and converted to the desired product (C15H17N3O2S as (M+H)+ 304.2; UV: λ = 203, 257). The reaction mixture was then diluted with 45 mL of 1.0 M aqueous LiOH and stirred overnight. The following morning the reaction had not gone to completion, and was treated with ca. 1.0 g of solid LiOH and stirred at rt overnight. The following day all material had been converted to the carboxylic acid (Ci3H13N3O2S as (Mn-H)+ 276.2; UV: λ = 202, 257). The reaction mixture was concentrated by rotary evaporation to remove a majority of the dioxane, then acidifed with 3M HCl to pH = 2 (250 mL total volume) resulting in the formation of a white precipitate. The solid was isolated by filtration and dried by aspiration, then used for the next step. (7.2 g, 97%)
[0223] Step 2: Carboxylic acid 2.3 (7.2 g, 26 mmol) was dissolved in N,N- dimethylformamide (30 mL) and treated with HOBt (4.8 g, 31 mmol) and EDC (6.0 31 mmol). After stirring ca. 40 min aq ammonia (17 M, 3.1 mL, 52mmol) was added and the reaction stirred at rt. After 30 min the reaction was determined to be complete by UPLC (Ci3Hi4N4OS as (M+H)+ 275.2; UV: λ = 200, 258. It was then diluted with water 150 mL total volume and stirred until a filterable precipitate formed. The solid was then isolated by filtration and dried by aspiration affording the desired amide as a white solid (3.87 g, 54%).
[0224] Step 3: Sulfide 2.4 (3.87 g, 14 mmol) was suspended in 40 mL of dioxane and treated with peroxyacetic acid in acetic acid (5.9 M, 2.9 mL, 17 mmol) and stirred at rt for 1 hr at which time the reaction was found to be incomplete. It was treated with 1 mL of peroxyacetic acid/acetic acid and stirred at rt. Later, the reaction was checked and found to contain sulfoxide with small amounts of 2.4 and sulfone. It was then diluted with water until precipitate formation ceased, filtered, and the solid dried by aspiration affording the desired product as a white solid Cj3Hi4N4O2S as (M+H)+ 291.2; UV: λ = 203, 254, 316.
[0225] Step 4: Sulfoxide 2.5 (50 mg, 0.14 mmol) and TsOH (30 mg, 0.16 mmol) was dissolved in 1 mL of NMP, then treated with approximately 40 mg of 2-chloro-5- aminoacetanilide and stirred at 1000C for 1 hr. The reaction was then checked by UPLC and found to be incomplete, but with some impurities present. The reaction solution was cooled, purified by preparative HPLC, and the desired product lyophilized affording a fluffy solid. MS found for C20Hi9ClN6O2 as (M+H)+ 411.3, 413.3. UV: λ = 206, 250.
Example 3 (S)-2-(3-acetamidophenylamino)-4-(2-phenylpropylamino)pyrimidine-5- carboxamide
Scheme 3:
Figure imgf000079_0001
1.4 3.1 3.2
Figure imgf000079_0002
[0226] Step 1: Dichloropyrimidine 1.4 (3.39 g, 15 mmol) was diluted with toluene (8 mL) and treated with benzyltriethylammonium chloride (0.68 g, 3 mmol) then sodium thiomethoxide (1.2 g, 17 mmol). The resulting suspension was then diluted with 8 mL of water and stirred vigorously for one hr at which time the starting material was found to be consumed by UPLC. The mixture was then diluted with water and ethyl acetate and the layers separated. The organic phase was extracted once with ethyl acetate and the combined organic layers concentrated in vacuo. The resulting solid was then triturated with ca. 15 mL of diethyl ether and the solid isolated by filtration and washed with a small amount of diethyl ether resulting in a light beige solid (0.66 g, 19%). MS found for C8H9ClN2O2S as (M+H)+ 233.0, 235.1.
[0227] Step 2: Ethyl ester 3.1 (0.66 g, 2.8 mmol) was diluted with dioxane (8 mL), then treated with aqueous LiOH (I M, 4.2 mL, 4.2 mmol) and stirred until all starting material had been consumed. The reaction mixture was then acidified to pH = 2 with 1 M HCl and stirred until a filterable solid formed. The solid was isolated by filtration, washed with water, then aspirated to dryness afording the desired carboxylic acid as a light pink solid (0.50 g, 88%). found for Ci2H10N6O2S as (M+H)+ 205.0, 207.0.3. UV: λ = 224, 277.
[0228] Step 3: Carboxylic acid 3.2 (0.50 g, 2.5 mmol) was dissolved in 10 mL of DMF, then treated with hydroxybenzotriazole - hydrate (0.44 g, 2.9 mmol) and EDC (0.56 g, 2.9 mmol) and stirred at rt. After stirring 10 min the reaction was checked by UPLC which showed complete conversion to the activated species. The reaction was then treated with ammonia / dioxane (0.5 M, 10 mL, 10 mmol) and stirred overnight. The following morning the reaction was checked by UPLC which showed the desired product (MS found for Ci2HiON6O2S as (M+H)+ 303.2). The reaction was concentrated by rotary evaporation to remove the dioxane, then diluted with water slowly until precipitation ceased. The solid was then isolated by filtration and aspirated to dryness affording amide 3.3 as a light pink solid (0.57 g, 75%).
[0229] Step 4: Amide 3.3 (1.4 gm 4.6 mmol) was diluted with 10 rnL of NMP, then treated with 3-aminoacetanilide (0.83 g, 5.6 mmol) and TsOH (1.1 g, 5.6 mmol). The reaction was heated to 1000C and stirred until only a trace of 3.3 remained. The reaction was then cooled to rt and diluted with water to 100 rnL total volume. After stirring vigorously for 30 min the desired product (3.4) was isolated by filtration as a light beige solid (MS found for Ci4Hi5N5O2S as (M+H)+ 318.2).
[0230] Step 5: Sulfide 3.4 (0.35 g, 1.1 mmol) was dissolved in NMP (10 mL) then treated with mCPBA (65%, 0.35 g, 1.3 mmol) and stirred at rt until all starting material had been oxidized to the sulfoxide (MS found for Ci4Hi5N5O3S as (MH-H)+ 334.2). DIEA (1.0 mL, 5.5 mmol) was then added and then 1/10th of the solution aliquotted into a scintillation vial and treated with 100 microliters of (S)-2-phenyl-l -propylamine. The reaction was then heated to 1000C until complete, then purified by preparative HPLC affording the desired product as a fluffy solid after lyophilization. MS found for C22H24N6O2 as (M+H)+ 405.4.
Example 4. Methyl 3-(5-carbamoyl-4-(2,2,2-trifluoroethylamino)pyrimidin-2- ylamino)phenylcarbamate
Figure imgf000080_0001
[0231] The above compound was prepared using a procedure similar to that described in Scheme 1 using trifluoroethylamine in place of cyclobutylamine and using an aniline prepared from 3-nitroaniline and methyl chloroformate followed by reduction using hydrogen gas and Pd/C. MS found for Ci5H15F3N6O3 as (M+H)+ 385.3.
Example 5. 2-(3-(cyclopropanecarboxamido)phenylamino)-4-(2,2,2- trifluoroethylamino)pyrimidine-5-carboxamide
Figure imgf000081_0001
[0232] The above compound was prepared using a procedure similar to that described in Scheme 1 using trifluoroethylamine in place of cyclobutylamine and an aniline prepared from 3-nitro aniline and cyclopropylcarbonyl chloride followed by reduction using hydrogen gas and Pd/C. MS found for C17H17F3N6O2 as (M+H)+ 395.3.
Example 6. 2-(3-(2-methoxyacetamido)phenylamino)-4-(2,2,2- trifluoroethylamino)pyrimidine-5-carboxamide
Figure imgf000081_0002
[0233] The above compound was prepared using a procedure similar to that described in Scheme 1 using trifluoroethylamine in place of cyclobutylamine and an aniline prepared from 3-nitro aniline and methoxyacetyl achloride chloride followed by reduction using hydrogen gas and Pd/C. MS found for C16HnF3N5O3 as (M+H)+ 399.3.
Example 7. 2-(3-acetamidophenylamino)-4-(2, 2,2-trifluoroethylamino)pyrimidine-5- carboxamide
Figure imgf000081_0003
[0234] The above compound was prepared using a procedure similar to that described in Scheme 1 using trifluoroethylamine in place of cyclobutylamine and 3-aminoacetanilide. MS found for C15Hi5F3N6O2 as (M+H)+ 369.2. UV: λ = 209, 246.
Example 8. 2-(3-acetamidophenylamino)-4-(methylamino)pyrimidine-5-carboxamide
Figure imgf000082_0001
[0235] The above compound was prepared using a procedure similar to that described in Scheme 1 using methylamine in place of cyclobutylamine and 3-aminoacetanilide. MS found for C14H]6N6O2 as (M+H)+ 301.3. UV: λ = 201, 249.
Example 9. 2-(3-acetamidophenylamino)-4-(ethylamino)pyrimidine-5-carboxamide
Figure imgf000082_0002
[0236] The above compound was prepared using a procedure similar to that described in Scheme 1 using ethylamine in place of cyclobutylamine and 3-aminoacetanilide. MS found for Ci5Hi8N6O2 as (M+H)+ 315.3.
Example 10. 2-(3-acetamidophenylamino)-4-(prop-2-ynylamino)pyrimidine-5-carboxamide
Figure imgf000082_0003
[0237] The above compound was prepared using a procedure similar to that described in Scheme 1 using propargylamine in place of cyclobutylamine and 3-aminoacetanilide. MS found for C16Hi6N6O2 as (M+H)+ 325.3.
Example 11. 2-(3-acetamidophenylamino)-4-(isopropylamino)pyrimidine-5-carboxamide
Figure imgf000082_0004
[0238] The above compound was prepared using a procedure similar to that described in Scheme 1 using isopropylamine in place of cyclobutylamine and 3-aminoacetanilide. MS found for Ci6H20N6O2 as (M+H)+ 329.3.
Example 12 2-(3-acetamidophenylamino)-4-(cyclopropylmethylamino)pyrimidine-5- carboxamide
Figure imgf000083_0001
[0239] The above compound was prepared using a procedure similar to that described in Scheme 1 using cyclopropylmethyl amine in place of cyclobutylamine and 3- aminoacetanilide. MS found for C17H20N6O2 as (M+H)+ 341.3.
Example 13. 2-(3-acetamidophenylamino)-4-(tert-butylamino)pyrimidine~5-carboxamide
Figure imgf000083_0002
[0240] The above compound was prepared using a procedure similar to that described in Scheme 1 using ter?-butylamine in place of cyclobutylamine and 3-aminoacetanilide. MS found for CnH20N6O2 as (M+H)+ 343.3. UV: λ = 200, 248.
Example 14. 2-(3-acetamidophenylamino)-4-(2-methoxyethylamino)pyrimidine-5- carboxamide
Figure imgf000083_0003
[0241] The above compound was prepared using a procedure similar to that described in Scheme 1 using methoxyethylamine in place of cyclobutylamine and 3-aminoacetanilide. MS found for Ci6H20N6O3 as (M+H)+ 345.3.
Example 15. 2-(3-acetamidophenylamino)-4-(cyclopentylamino)pyrimidine-5-carboxamide
Figure imgf000084_0001
[0242] The above compound was prepared using a procedure similar to that described in Scheme 1 using cyclopentylamine in place of cyclobutylamine and 3-aminoacetanilide. MS found for C18H22N6O2 as (M+H)+ 355.3.
Example 16. 2-(3-acetamidophenylamino)-4-(3-methoxypropylamino)pyrimidine-5- carboxamide
Figure imgf000084_0002
[0243] The above compound was prepared using a procedure similar to that described in Scheme 1 using 3-methoxypropylamine in place of cyclobutylamine and 3-aminoacetanilide. MS found for CnH22N6O3 as (M+H)+ 359.3.
Example 17. 2-(3-acetamidophenylamino)-4~(benzylamino)pyrimidine-5-carboxamide
Figure imgf000084_0003
[0244] The above compound was prepared using a procedure similar to that described in Scheme 1 using benzylamine in place of cyclobutylamine and 3-aminoacetanilide. MS found for C20H20N6O2 as (M+H)+ 377.3.
Example 18. methyl 5-(5-carbamoyl-4-(2,2,2-trifluoroethylamino)pyrimidin-2-ylamino)-2- chlorophenylcarbamate
Figure imgf000085_0001
[0245] The above compound was prepared using a procedure similar to that described Scheme 1 using trifluoroethylamine in place of cyclobutylamine and an aniline prepared from methylchloroformate and 2-chloro-5-nitroaniline. MS found for C15H14ClF3N6O3 as (M+H)+ 419.2, 421.2. UV: λ = 206, 241, 276.
Example 19. 4-(cyclopentylamino)-2-(3- (cyclopropanecarboxamido)phenylamino)pyrimidine-5-carboxamide
Figure imgf000085_0002
[0246] The above compound was prepared using a procedure similar to that described in Scheme 1, using cyclopentylamine in place of cyclobutylamine and an aniline prepared from 3-nitroaniline and cyclopropanecarbonyl chloride. MS found for C2OH24N6O2 as (M+H)+ 381.4. UV: λ = 202, 250.
Example 20. 2-(3-(cyclobutanecarboxamido)phenylamino)-4- (cyclopentylamino)pyrimidine-5-carboxamide
Figure imgf000085_0003
[0247] The above compound was prepared using a procedure similar to that described in Scheme 1, using cyclopentylamine in place of cyclobutylamine and an aniline prepared from 3-nitroaniline and cyclobutanecarbonyl chloride. MS found for C2IH26N6O2 as (M+H)+ 395.4. UV: λ = 205, 252.
Example 21. 4-(cyclopentylamino)-2-(3-propionamidophenylamino)pyrimidine-5- carboxamide
Figure imgf000086_0001
[0248] The above compound was prepared using a procedure similar to that described in Scheme 1, using cyclopentylamine in place of cyclobutylamine and an aniline prepared from 3-nitroaniline and propionyl chloride. MS found for Ci9H24N6O2 as (M+H)+ 369.4. UV: λ = 210, 249.
Example 22. 4-(cyclopentylamino)-2-(3-(2-methoxyacetamido)phenylamino)pyrimidine-5- carboxamide
Figure imgf000086_0002
[0249] The above compound was prepared using a procedure similar to that described in Scheme 1 , using cyclopentylamine in place of cyclobutylamine and an aniline prepared from 3-nitroaniline and methoxyacetyl chloride. MS found for Ci9H24N6O3 as (M+H)+ 385.3. UV: λ = 204, 251.
Example 23. methyl 3-(5-carbamoyl-4-(cyclopentylamino)pyrimidin-2- ylamino)phenylcarbamate
Figure imgf000087_0001
[0250] The above compound was prepared using a procedure similar to that described in Scheme 1, using cyclopentylamine in place of cyclobutylamine and an aniline prepared from 3-nitroaniline and methyl chloroformate. MS found for Ci8H22N6O3 as (M+H)+ 371.3. UV: λ = 204, 243.
Example 24. ethyl 3-(5-carbamoyl-4-(cyclopentylamino)pyrimidin-2- ylaminojphenylcarbamate
Figure imgf000087_0002
[0251] The above compound was prepared using a procedure similar to that described in Scheme 1, using cyclopentylamine in place of cyclobutylamine and an aniline prepared from 3-nitroaniline and ethyl chloroformate chloride. MS found for CIgH24N6O3 as (MH-H)+ 385.4. UV: λ = 203, 244.
Example 25. methyl 5-(5-carbamoylA-{cyclopentylamino)pyήmidin-2-ylarnino)-2- chlorophenylcarbamate
Figure imgf000087_0003
[0252] The above compound was prepared using a procedure similar to that described in Scheme 1, using cyclopentylamine in place of cyclobutylamine and an aniline prepared from 2-chloro-5-nitroaniline and methyl chloroformate. MS found for C18H2IClN6O3 as (M+H)+ 405.4, 407.4. UV: λ = 205, 244. Example 26. 4-(benzylamino)-2-(3-(cyclopropanecarboxamido)phenylamino)pyrimidine-5- carboxamide
Figure imgf000088_0001
[0253] The above compound was prepared using a procedure similar to that described in Scheme 1, using benzylamine in place of cyclobutylamine and an aniline prepared from 3- nitroaniline and cyclopropanecarbonyl chloride. MS found for C22H22N6O2 as (M+H)+ 403.4. UV: λ = 205, 250.
Example 27. 4-(benzylamino)-2-(3-(cyclobutanecarboxamido)phenylamino)pyrimidine-5- carboxamide
Figure imgf000088_0002
[0254] The above compound was prepared using a procedure similar to that described in Scheme 1, using benzylamine in place of cyclobutylamine and an aniline prepared from 3- nitroaniline and cyclobutanecarbonyl chloride. MS found for C23H24N6O2 as (M+H)+ 417.4. UV: λ = 250.
Example 28. 4-(benzylamino)-2-(3-propionamidophenylamino)pyrimidine-5-carboxamide
Figure imgf000088_0003
[0255] The above compound was prepared using a procedure similar to that described in Scheme 1, using benzylamine in place of cyclobutylamine and an aniline prepared from 3- nitroaniline and cyclopropanecarbonyl chloride. MS found for C2iH22N6O2 as (M+H)+ 391.3. UV: λ = 200, 249.
Example 29. 4-(benzylamino)-2-(3-(2-methoxyacetamido)phenylamino)pyrimidine-5- carboxamide
Figure imgf000089_0001
[0256] The above compound was prepared using a procedure similar to that described in Scheme 1, using benzylamine in place of cyclobutylamine and an aniline prepared from 3- nitroaniline and methoxyacetyl chloride. MS found for C2iH22N6O3 as (M+H)+ 407.3. UV: λ = 202, 249.
Example 30. methyl 3-(4-(benzylamino)-5-carbamoylpyrimidin-2- ylaminojphenylcarbamate
Figure imgf000089_0002
[0257] The above compound was prepared using a procedure similar to that described in Scheme 1, using benzylamine in place of cyclobutylamine and an aniline prepared from 3- nitroaniline and methyl chloroformate. MS found for C2OH2ON6O3 as (M+H)+ 393.4. UV: λ = 200, 244.
Example 31. ethyl 3-(4-(benzylamino)-5-carbamoylpyrimidin-2-ylamino)phenylcarbamate
Figure imgf000090_0001
[0258] The above compound was prepared using a procedure similar to that described in Scheme 1, using benzylamine in place of cyclobutylamine and an aniline prepared from 3- nitroaniline and ethyl chloroformate. MS found for C21H22N6O3 as (M+H)+ 407.3. UV: λ = 202, 249.
Example 32. methyl 5-(4-(benzylamino)-5-carbamoylpyrimidin-2-ylamino)-2- chlorophenylcarbamate
Figure imgf000090_0002
[0259] The above compound was prepared using a procedure similar to that described in Scheme 1 , using benzylamine in place of cyclobutylamine and an aniline prepared from 2- chloro-5-nitroaniline and methyl chloroformate. MS found for C2OHIgClN6O3 as (M+H)+ 427.3, 429.3. UV: λ = 201, 244.
Example 33. 4-(cyclopentylamino)-2-(3-ureidophenylamino)pyrimidine-5-carboxamide
Figure imgf000090_0003
[0260] The above compound was prepared using a procedure similar to that described in Scheme 1 , using cyclopentyl amine in place of cyclobutylamine and an aniline prepared from 3-nitroaniline and sodium isocyanate. MS found for Ci7H2iN7O2 as (M+H)+ 356.4. UV: λ = 205, 246.
Example 34. 4-(cyclopentylamino)-2-(3-(3-methylureido)phenylamino)pyrimidine-5- carboxamide
Figure imgf000091_0001
[0261] The above compound was prepared using a procedure similar to that described in Scheme 1, using cyclopentylamine in place of cyclobutylamine and an aniline prepared from 3-nitroaniline, phosgene, and methylamine. MS found for C18H23N7O2 as (M+H)+ 370.4. UV: λ = 208, 252.
Example 35. 4-(cyclopentylamino)-2-(3-(3,3-dimethylureido)phenylamino)pyήmidine-5- carboxamide
Figure imgf000091_0002
[0262] The above compound was prepared using a procedure similar to that described in Scheme 1, using cyclopentylamine in place of cyclobutylamine and an aniline prepared from 3-nitroaniline, phosgene, and dimethylamine. MS found for Ci9H2SN7O2 as (M+H)+ 384.4. UV: λ = 206, 248.
Example 36. 4-(cyclopentylamino)-2-(3-(3-ethylureido)phenylamino)pyrimidine-5- carboxamide
Figure imgf000091_0003
[0263] The above compound was prepared using a procedure similar to that described in Scheme 1 , using cyclopentylamine in place of cyclobutylamine and an aniline prepared from 3-nitroaniline, phosgene, and ethylamine. MS found for CIgH25N7O2 as (M+H)+ 384.4. UV: λ = 206, 247.
Example 37. 4-(cyclopentylamino)-2-(3-(pyrrolidine-l~ carboxamido)phenylamino)pyrimidine-5-carboxaπιide
Figure imgf000092_0001
[0264] The above compound was prepared using a procedure similar to that described in Scheme 1, using cyclopentylamine in place of cyclobutylamine and an aniline prepared from 3-nitroaniline, phosgene, and pyrrolidine. MS found for C2iH27N7O2 as (M+H)+ 410.5. UV: λ = 207, 249.
Example 38. 4-(benzylamino)-2-(3-ureidophenylamino)pyrimidine-5-carboxamide
Figure imgf000092_0002
[0265] The above compound was prepared using a procedure similar to that described in Scheme 1, using benzylamine in place of cyclobutylamine and an aniline prepared from 3- nitroanilineand sodium isocyanate. MS found for Ci9H19N7O2 as (M+H)+ 378.4. UV: λ = 205, 246.
Example 39. 4-(benzylamino)-2-(3-(3-methylureido)phenylamino)pyrimidine-5- carboxamide
Figure imgf000093_0001
[0266] The above compound was prepared using a procedure similar to that described in Scheme 1, using benzylamine in place of cyclobutylamine and an aniline prepared from 3- nitroaniline, phosgene, and methylamine. MS found for C2oH2jN702 as (M+H)+ 392.5. UV: λ = 207, 247.
Example 40. 4-(benzylamino)-2-(3-(pyrrolidine-l-carboxamido)phenylamino)pyrimidine-5- carboxamide
Figure imgf000093_0002
[0267] The above compound was prepared using a procedure similar to that described in Scheme 1, using benzylamine in place of cyclobutylamine and an aniline prepared from 3- nitroaniline, phosgene, and pyrrolidine. MS found for C23H25N7O2 as (M+H)+ 432.5. UV: λ = 206, 249.
Example 41. isopropyl 3-(4-(benzylamino)-5-carbamoylpyrimidin-2- ylamino)phenylcarbamate
Figure imgf000093_0003
[0268] The above compound was prepared using a procedure similar to that described in Scheme 1, using benzylamine in place of cyclobutylamine and an aniline prepared from 3- nitroaniline and isopropylchloroformate. MS found for C22H24N6O3 as (M+H)+ 421.5. UV: λ = 244.
Example 42. (S)-2-(3-(2-methoxyacetamido)phenylamino)-4-(l- phenylethylamino)pyrimidine-5-carboxamide
Figure imgf000094_0001
[0269] The above compound was prepared using a procedure similar to that described in Scheme 1, using (S)-l-phenylethylamine in place of cyclobutylamine and an aniline prepared from 3-nitroaniline and methoxyacetyl chloride. MS found for C22H24N6O3 as (M+H)+ 421.0. UV: λ == 250.
Example 43. 2-(3-(2-methoxyacetamido)phenylamino)-4-(4-methylbenzylamino)pyήmidine- 5-carboxamide.
Figure imgf000094_0002
[0270] The above compound was prepared using a procedure similar to that described in Scheme 1 , using 4-methylbenzylamine in place of cyclobutylamine and an aniline prepared from 3-nitroaniline and methoxyacetyl chloride. MS found for C22H24N6O3 as (M+H)+ 421.0. UV: λ = 247.
Example 44. 2-(3-(2-methoxyacetamido)phenylamino)-4-(4- methoxybenzylamino)pyrimidine-5-carboxamide
Figure imgf000095_0001
[0271] The above compound was prepared using a procedure similar to that described in Scheme 1 , using 4-methoxybenzylamine in place of cyclobutylamine and an aniline prepared from 3-nitroaniline and methoxyacetyl chloride. MS found for C22H24N6O4 as (M+H)+ 437.0. UV: λ = 246.
Example 45. 4-(4-chlorobenzylamino)-2-(3-(2-methoxyacetamido)phenylamino)pyήmidine- 5-carboxamide
Figure imgf000095_0002
[0272] The above compound was prepared using a procedure similar to that described in Scheme 1, using 4-chlorobenzylamine in place of cyclobutylamine and an aniline prepared from 3-nitroaniline and methoxyacetyl chloride. MS found for C2IH2JC1N6O3 as (M+H)+ 441. UV: λ = 250.
Example 46. 4-(3,4-dichlorobenzylamino)-2-(3-(2- methoxyacetamido)phenylamino)pyrimidine-5-carboxamide
Figure imgf000096_0001
[0273] The above compound was prepared using a procedure similar to that described in Scheme 1, using 3,4-dichlorobenzylamine in place of cyclobutylamine and an aniline prepared from 3-nitroaniline and methoxyacetyl chloride. MS found for C2iH2oQ2N6θ3 as (M+H)+ 475, 477. UV: λ = 249.
Example 47. (R)-2-(3-(2-methoxyacetamido)phenylamino)-4-( 1 - phenylethylamino)pyrimidine-5-carboxamide
Figure imgf000096_0002
[0274] The above compound was prepared using a procedure similar to that described in Scheme 1, using (R)-l-phenylethylamine in place of cyclobutylamine and an aniline prepared from 3-nitroaniline and methoxyacetyl chloride. MS found for C22H24N6O3 as (M+H)+ 421. UV: λ = 249.
Example 48. (S)-2-(3-acetamidophenylamino)-4-(2-hydroxy-2- phenylethylamino)pyrimidine-5-carboxamide
Figure imgf000097_0001
[0275] The above compound was prepared using a procedure similar to that described in Scheme 3, using (S)-2-hydroxy-2-phenylethylamine in place of (S)-2-phenyl-l -propylamine. MS found for C21H22N6O3 as (M+H)+ 407.4. UV: λ = 203, 250.
Example 49. (R)-2-(3-acetamidophenylamino)-4-(2-hydroxy-2- phenylethylamino)pyrimidine-5-carboxamide
Figure imgf000097_0002
[0276] The above compound was prepared using a procedure similar to that described in Scheme 3, using (R)-2-hydroxy-2-phenylethylamine in place of (S)-2-phenyl-l -propylamine. MS found for C2iH22N6O3 as (M+H)+ 407.4. UV: λ = 250.
Example 50. 2-(3-acetamidophenylamino)-4-(2-amino-2-oxoethylamino)pyrimidine-5- carboxamide
Figure imgf000097_0003
[0277] The above compound was prepared using a procedure similar to that described in Scheme 3, using glycinamide in place of (S)-2-phenyl-l -propylamine. MS found for C5H17N7O3 as (M+H)+ 344.3. Example 51. 2-(3-acetamidophenylamino)-4-(2-phenylcyclopropylamino)pyrimidine-5- carboxamide
Figure imgf000098_0001
[0278] The above compound was prepared using a procedure similar to that described in Scheme 3, using fr-αns-2-phenylcyclopropylamine in place of (S)-2-phenyl-l -propylamine. MS found for C22H22N6O2 as (M+H)+ 403.4.
Example 52. 2-(3-acetamidophenylamino)-4-(cyclohexylamino)pyrimidine-5-carboxamide
Figure imgf000098_0002
[0279] The above compound was prepared using a procedure similar to that described in Scheme 3, using cyclopentylamine in place of (S)-2-phenyl-l -propylamine. MS found for C9H24N6O2 as (M+H)+ 369.4.
Example 53. 2-(3-acetamidophenylamino)-4-((trans)-2- hydroxycyclopentylamino)pyrimidine-5-carboxamide
Figure imgf000098_0003
[0280] The above compound was prepared using a procedure similar to that described in Scheme 3, using rrα«s-2-aminopentanol in place of (S)-2-phenyl-l -propylamine. MS found for C8H22N6O3 as (M+H)+ 371.4. UV: λ = 250. Example 54. 2-(3-acetamidophenylamino)-4-(benzyl(methyl)amino)pyrimidine-5- carboxamide
Figure imgf000099_0001
[0281] The above compound was prepared using a procedure similar to that described in Scheme 3, using N-methylbenzylamine in place of (S)-2-phenyl-l -propylamine. MS found for C21H22N6O2 as (M+H)+ 391.4. UV: λ = 207, 252.
Example 55. 4-(cyclobutylamino)-2-(3-(2-methoxyacetamido)phenylamino)pyrimidine-5- carboxamide
Figure imgf000099_0002
[0282] The above compound was prepared using a procedure similar to that described in Scheme 1, using an aniline prepared from 3-nitroaniline and methoxyacetyl chloride. MS found for Ci8H22N6O3 as (M+H)+ 371. UV: λ = 252.
Example 56. 2-(3-acetamidophenylamino)-4-(phenethylamino)pyrimidine-5-carboxamide
Figure imgf000099_0003
[0283] The above compound was prepared using a procedure similar to that described in Scheme 3, using phenethylamine in place of (S)-2-phenyl-l -propylamine. MS found for C21H22N6O2 as (M+H)+ 391.4. Example 57. 4-(isopropylamino)-2-(3-(2-methoxyacetamido)phenylamino)pyrimidine-5- carboxamide
Figure imgf000100_0001
[0284] The above compound was prepared using a procedure similar to that described in Scheme 1, using isopropylamine in place of cyclobutylamine and an aniline prepared from 3- nitroaniline and methoxyacetyl chloride. MS found for C17H22N6O3 as (M+H)+ 359. UV: λ
= 247.
Example 58. 2-(3-(2-methoxyacetamido)phenylamino)-4-(2,3,6- trifluorobenzylamino)pyήmidine-5-carboxamide
Figure imgf000100_0002
[0285] The above compound was prepared using a procedure similar to that described in Scheme 1, using 2,3,6-trifluorobenzylamine in place of cyclobutylamine and an aniline prepared from 3-nitroaniline and methoxyacetyl chloride. MS found for C2]HIgF3N6O3 as (M+H)+ 461. UV: λ = 204, 247.
Example 59. 2-(3-acetamidophenylamino)-4-(2,3,6-trifluorobenzylamino)pyrimidine-5- carboxamide
Figure imgf000100_0003
[0286] The above compound was prepared using a procedure similar to that described in Scheme 1, using benzylamine in place of cyclobutylamine and 3-aminoacetanilide. MS found for C2IHi9F3N6O3 as (M+H)+ 461. UV: λ = 204, 247.
Example 60. (S)-2-(3-acetamidophenylamino)-4-(l -hydroxy-3-(lH-imidazol-5-yl)propan-2- ylamino)pyrimidine-5-carboxamide
Figure imgf000101_0001
[0287] The above compound was prepared using a procedure similar to that described in Scheme 3, using (S)-histidinol in place of (S)-2-phenyl-l -propylamine. MS found for C19H22N8O3 as (M+H)+ 411.3. UV: λ = 249.
Example 61. 2-(3-acetamidophenylamino)-4-(3-amino-3-oxopropylamino)pyrimidine-5- carboxamide
Figure imgf000101_0002
[0288] The above compound was prepared using a procedure similar to that described in Scheme 3, using 3-aminobutylamine in place of (S)-2-phenyl-l -propylamine.. MS found for Cj6Hi9N7O3 as (M+H)+ 358.3. UV: λ = 204, 277.
Example 62. (R)-2-(3-acetamidophenylamino)-4-(l-hydroxy-4-methylpentan-2- ylamino)pyrimidine-5-carboxamide
Figure imgf000102_0001
[0289] The above compound was prepared using a procedure similar to that described in Scheme 3, using (R)-leucinol in place of (S)-2-phenyl-l-propylamine.. MS found for Ci9H26N6O3 as (M+H)+ 387.4. UV: λ = 250.
Example 63. 2-(3-acetamidophenylamino)-4-(2-(pyrrolidin-l-yl)ethylamino)pyrimidine-5- carboxamide
Figure imgf000102_0002
[0290] The above compound was prepared using a procedure similar to that described in Scheme 3, using 2-(pyrrolidin-l-yl)ethylamine in place of (S)-2-phenyl-l -propylamine. MS found for C19H25N7O2 as (M+H)+ 384.4. UV: λ = 204, 246.
Example 64. (S)-2-(3-acetamidophenylamino)-4-(l-phenylethylamino)pyrimidine-5- carboxamide
Figure imgf000102_0003
[0291] The above compound was prepared using a procedure similar to that described in Scheme 1 , using (S)- 1 -phenylethylamine in place of cyclobutylamine and 3- aminoacetanilide. MS found for C22H24N6O2 as (MH-H)+ 405.4. UV: λ = 204, 250. Example 65. 2-(3-acetamidophenylamino)-4-(2-oxo-2-(pyrrolidin-l~ yl)ethylamino)pyrimidine-5-carboxamide
Figure imgf000103_0001
[0292] The above compound was prepared using a procedure similar to that described in Scheme 2, using 2-amino-l-(pyrrolidin-l-yl)ethanone in place of benzylamine and 3- aminoacetanilide. MS found for C19H23N7O3 as (M+H)+ 398.4.
Example 66. (R)-2-(3-acetamidophenylamino)-4-(piperidin-3-ylamino)pyrimidine-5- carboxamide
Figure imgf000103_0002
[0293] The above compound was prepared using a procedure similar to that described in Scheme 1, using (R)-tert-butyl 3-aminopiperidine-l-carboxylate in place of cyclobutylamine and acetanilide. MS found for Ci8H23N7O2 as (M+H)+ 370.3.
Example 67. 2-(3-acetamidophenylamino)-4-(4-methylbenzylamino)pyrimidine-5- carboxamide
Figure imgf000103_0003
[0294] The above compound was prepared using a procedure similar to that described in Scheme 1, using 4-methylbenzylamine in place of cyclobutyl amine and acetanilide. MS found for C2iH22N6O2 as (M+H)+ 391. UV: λ = 249.
Example 68. 2-(3-acetamidophenylamino)-4-(4-methoxybenzylamino)pyrimidine-5- carboxamide
Figure imgf000104_0001
[0295] The above compound was prepared using a procedure similar to that described in Scheme 1, using 4-methoxybenzylamine in place of cyclobutylamine and acetanilide. MS found for C21H22N6O3 as (M+H)+ 407. UV: λ = 249.
Example 69. 2-(3-acetamidophenylamino)-4-(4-chlorobenzylamino)pyrimidine-5- carboxamide
Figure imgf000104_0002
[0296] The above compound was prepared using a procedure similar to that described in Scheme 1, using 4-chlorobenzylamine in place of cyclobutylamine and acetanilide. MS found for C20H19ClN6O2 as (M+H)+ 411. UV: λ = 249.
Example 70. 2-(3-acetamidophenylamino)-4-(3,4-dichlorobenzylamino)pyrimidine-5- carboxamide
Figure imgf000105_0001
[0297] The above compound was prepared using a procedure similar to that described in Scheme 1, using 3,4-dichlorobenzylamine in place of cyclobutylamine and acetanilide. MS found for C20Hi8Cl2N6O2 as (M+H)+ 445, 447. UV: λ = 203, 243, 292.
Example 71. (R)-2-(3-acetamidophenylamino)-4-(l-phenylethylamino)pyrimidine-5- carboxamide
Figure imgf000105_0002
[0298] The above compound was prepared using a procedure similar to that described in Scheme 1, using 3,4-dichlorobenzylamine in place of cyclobutylamine and acetanilide. MS found for C21H22N6O2 as (M+H)+ 391. UV: λ = 213, 256.
Example 72. 2-(3-acetamidophenylamino)-4-(2-(methylamino)-2- oxoethylamino)pyrimidine-5-carboxamide
Figure imgf000105_0003
[0299] The above compound was prepared using a procedure similar to that described in Scheme 3, using 2-amino-N-methylacetamide in place of (S)-2-phenyl-l -propylamine. MS found for C16Hj9N7O3 as (M+H)+ 358.3. Example 73. 2-(3-acetamidophenylamino)-4-((2S, 3S)-I -hydroxy-3-methylpentan-2- ylamino)pyrimidine-5-carboxamide
Figure imgf000106_0001
[0300] The above compound was prepared using a procedure similar to that described in Scheme 3, using (2S,3S)-l-hydroxy-3-methylpentan-2-ylamine in place of (S)-2-phenyl-l- propylamine. MS found for Ci9H26N6O3 as (M+H)+ 387.4. UV: λ = 249.
Example 74. 2-(3-acetamidophenylamino)-4-(cyanomethylamino)pyrimidine-5- carboxamide
Figure imgf000106_0002
[0301] The above compound was prepared using a procedure similar to that described in Scheme 3, using aminoacetonitrile in place of (S)-2-phenyl-l -propylamine.. MS found for
C15Hi5N7O2 as (M+H)+ 326.2. UV: λ = 245.
Example 75. 2-(3-acetamidophenylamino)~4-(tetrahydro-2H-pyran-4-ylamino)pyrimidine- 5-carboxamide
Figure imgf000106_0003
[0302] The above compound was prepared using a procedure similar to that described in Scheme 3, using 4-aminotetrahydropyran in place of (S)-2-phenyl-l -propylamine.. MS found for Ci8H22N6O3 as (M+H)+ 371.3. Example 76. (S)-2-(3-acetamidophenylamino)-4-(l -hydroxy >-3 '-phenylpropan-2- ylamino)pyrimidine-5-carboxamide
Figure imgf000107_0001
[0303] The above compound was prepared using a procedure similar to that described in Scheme 3, using (S)-alaninol in place of (S)-2-phenyl-l-propylamine. MS found for C22H24N6O3 as (M+H)+ 421.4.
Example 77. 4-(isopropylamino)-2-(3-(N-methylacetamido)phenylamino)pyrimidine-5- carboxamide
Figure imgf000107_0002
[0304] The above compound was prepared using a procedure similar to that described in Scheme 1 using isopropylamine in place of cyclobutylamine and an aniline prepared from 3- nitroaniline, acetyl chloride, and iodomethane. MS found for Ci7H22N6O2 as (M+H)+ 343. UV: λ = 219, 255.
Example 78. 4-(cyclopentylamino)-2-(3-(N-methylacetamido)phenylamino)pyrimidine-5- carboxamide
Figure imgf000107_0003
[0305] The above compound was prepared using a procedure similar to that described in Scheme 1 using cyclopentylamine in place of cyclobutylamine and an aniline prepared from 3-nitroaniline, acetyl chloride, and iodomethane. MS found for C19H24N6O2 as (M+H)+ 369. UV: λ = 204, 259.
Example 79. 4-(benzylamino)-2-(3-(N-methylacetamido)phenylamino)pyrimidine-5- carboxamide
Figure imgf000108_0001
[0306] The above compound was prepared using a procedure similar to that described in Scheme 1 using benzylamine in place of cyclobutylamine and an aniline prepared from 3- nitroaniline, acetyl chloride, and iodomethane. MS found for C2]H22N6O2 as (M+H)+ 391. UV: λ = 255.
Example 80. 2-(3-acetamidophenylamino)-4-(2-morpholinoethylamino)pyrimidine-5- carboxamide
Figure imgf000108_0002
[0307] The above compound was prepared using a procedure similar to that described in Scheme 3, using 2-(l-morpholinyl)ethylamine in place of (S)-2-phenyl-l -propylamine. MS found for C9H25N7O3 as (M+H)+ 400.3.
Example 81. (R)-2-(3-acetamidophenylamino)-4-(2-phenylpropylamino)pyrimidine-5- carboxamide
Figure imgf000109_0001
[0308] The above compound was prepared using a procedure similar to that described in Scheme 3, using (R)-2-phenylpropylamine in place of (S)-2-phenyl-l-propylamine. MS found for C22H24N6O2 as (M+H)+ 405.3.
Example 82. (S)-2-(3-acetamidophenylamino)-4-(2-hydroxypropylamino)pyrimidine-5- carboxamide
Figure imgf000109_0002
[0309] The above compound was prepared using a procedure similar to that described in Scheme 3, using (S)-2-hydroxy-l -propylamine in place of (S)-2-phenyl-l -propylamine. MS found for Ci6H20N6O3 as (M+H)+ 405.3.
Example 83. (R)-2-(3-acetamidophenylamino)-4-(2, 3-dihydroxypropylamino)pyrimidine-5- carboxamide
Figure imgf000109_0003
[0310] The above compound was prepared using a procedure similar to that described in Scheme 3, using (R)- 2,3-dihydroxypropylamine in place of (S)-2-phenyl-l -propylamine. MS found for C16H20N6O3 as (M+H)+ 361.2.
Example 84. 2-(3-acetamidophenylamino)-4-(2-methoxy-2-phenylethylamino)pyrimidine-5- carboxamide
Figure imgf000110_0001
[0311] The above compound was prepared using a procedure similar to that described in Scheme 3, using 2-methoxy-2-phenylethylamine in place of (S)-2-phenyl-l -propylamine. MS found for C22H24N6O3 as (M+H)+ 421.3.
Example 85. (S )-2-( 3-acetamidophenylamino)-4-( 1 -amino- 1 -oxopropan-2- ylamino)pyrimidine-5-carboxamide
Figure imgf000110_0002
[0312] The above compound was prepared using a procedure similar to that described in Scheme 3, using (S)-alaninamide in place of (S)-2-phenyl-l -propylamine. MS found for Ci6Hi9N7O3 as (M+H)+ 358.3.
Example 86. (R)-2-(3-(2-methoxy-N-methylacetamido)phenylamino)-4-(l - phenylethylamino)pyrimidine-5-carboxamide
Figure imgf000110_0003
[0313] The above compound was prepared using a procedure similar to that described in Scheme 1, using (R)- 1-phenylethylamine in place of cyclobutylamine and an aniline prepared from 3-nitroaniline, methoxyacetyl chloride, and iodomethane. MS found for C23H26N6O3 as (M+H)+ 435. UV: λ = 208, 252, 292. Example 87. (R)-2-(3-(N-methylacetamido)phenylamino)-4-(l- phenylethylamino)pyrimidine-5-carboxamide
Figure imgf000111_0001
[0314] The above compound was prepared using a procedure similar to that described in Scheme 1, using (R)-l-phenylethylamine in place of cyclobutylamine and an aniline prepared from 3-nitroaniline, acetyl chloride, and iodomethane. MS found for C22H24N6O2 as (M+H)+ 405. UV: λ = 207, 246.
Example 88. 4-(isopropylamino)-2-(3-(2-methoxy-N- methylacetamido)phenylamino)pyήmidine-5-carboxamide
Figure imgf000111_0002
[0315] The above compound was prepared using a procedure similar to that described in Scheme 1, using isopropylamine in place of cyclobutylamine and an aniline prepared from 3- nitroaniline, methoxyacetyl chloride, and iodomethane. MS found for Ci8H24N6O3 as (M+H)+ 373. UV: λ = 217, 246.
Example 89. 4-(cyclopentylamino)-2-(3-(2-methoxy-N- methylacetamido)phenylamino)pyrimidine-5-carboxamide
Figure imgf000111_0003
[0316] The above compound was prepared using a procedure similar to that described in Scheme 1, using cyclopentylamine in place of cyclobutylamine and an aniline prepared from 3-nitroaniline, methoxyacetyl chloride, and iodomethane. MS found for C2OH26N6O3 as (M+H)+ 399. UV: λ = 204, 256.
Example 90. 4-(benzylamino)-2-(3-(2-methoxy-N- methylacetamido)phenylamino)pyrimidine-5-carboxamide
Figure imgf000112_0001
[0317] The above compound was prepared using a procedure similar to that described in Scheme 1, using benzylamine in place of cyclobutylamine and an aniline prepared from 3- nitroaniline, methoxyacetyl chloride, and iodomethane. MS found for C22H24N6O3 as (M+H)+ 421. UV: λ = 204, 255.
Example 91. (R)-2-(3-acetamidophenylamino)-4-(l -amino- l-oxopropan-2- ylamino)pyrimidine-5-carboxamide
Figure imgf000112_0002
[0318] The above compound was prepared using a procedure similar to that described in Scheme 3, using (R)-alaninamide in place of (S)-2-phenyl-l -propylamine. MS found for C16H19N7O3 as (M+H)+ 358.3.
Example 92. 2-(3-acetamidophenylamino)-4-(2,3-dihydro-lH-inden-2-ylamino)pyrimidine- 5-carboxamide
Figure imgf000113_0001
[0319] The above compound was prepared using a procedure similar to that described in Scheme 3, using 2-aminoindan in place of (S)-2-phenyl-l -propylamine. MS found for C22H22N6O2 as (M+H)+ 403.3. UV: λ = 204, 250.
Example 93. (S)-2-(3-acetamidophenylamino)-4-(2-hydroxy-l- phenylethylamino)pyrimidine-5-carboxamide
Figure imgf000113_0002
[0320] The above compound was prepared using a procedure similar to that described in Scheme 3, using (S)-phenylglycinol in place of (S)-2-phenyl-l -propylamine. MS found for
C2JH22N6O3 as (M+H)+ 407.3. UV: λ = 249.
Example 94. 2-(3-acetamidophenylamino)-4-(3-fluorobenzylamino)pyrimidine-5- carboxamide
Figure imgf000113_0003
[0321] The above compound was prepared using a procedure similar to that described in Scheme 3, using 3-fluorobenzylamine in place of (S)-2-phenyl-l -propylamine. MS found for C20H19FN6O2 as (M+H)+ 395.3. UV: λ = 204, 249.
I l l Example 95. 2-(3-acetamidophenylamino)-4-(2, 3-difluorobenzylamino)pyrimidine-5- carboxamide
Figure imgf000114_0001
[0322] The above compound was prepared using a procedure similar to that described in Scheme 3, using 2,3-difluorobenzylamine in place of (S)-2-phenyl-l -propylamine. MS found for C20H18F2N6O2 as (M+H)+ 413.3.
Example 96. (S)-2-(3-acetamidophenylamino)-4-(2,3-dihydro-lH-inden-l- ylamino)pyrimidine-5-carboxamide
Figure imgf000114_0002
[0323] The above compound was prepared using a procedure similar to that described in Scheme 3, using (S)-l-aminoindan in place of (S)-2-phenyl-l -propylamine. MS found for C22H22N6O2 as (M+H)+ 403.3.
Example 97. (R)-2-(3-acetamidophenylamino)-4-(2,3-dihydro-lH-inden-l- ylamino)pyήmidine-5-carboxamide
Figure imgf000114_0003
[0324] The above compound was prepared using a procedure similar to that described in Scheme 3, using (R)-l-aminoindan in place of (S)-2-phenyl-l -propylamine. MS found for C22H22N6O2 as (M+H)+ 403.3. UV: λ = 205, 250.
Example 98. (R)-2-(3-acetamidophenylamino)-4-(2-hydroxy-l- phenylethylamino)pyrimidine-5-carboxamide
Figure imgf000115_0001
[0325] The above compound was prepared using a procedure similar to that described in Scheme 3, using (R)-phenylglycinol in place of (S)-2-phenyl-l -propylamine. MS found for C21H22N6O3 as (M+H)+ 407.3. UV: λ = 205, 249.
Example 99. 2-(3-acetamidophenylamino)-4-(benzo[d] [ 1 ,3] dioxol-5- ylmethylamino)pyrimidine-5-carboxamide
Figure imgf000115_0002
[0326] The above compound was prepared using a procedure similar to that described in Scheme 3, using benzo[d][l,3]dioxol-5-ylmethylamine in place of (S)-2-phenyl-l- propylamine. MS found for C2]H20N6O4 as (M+H)+ 421.3. UV: λ = 205, 250.
Example 100. 2-(3-acetamidophenylamino)-4-(2-fluorobenzylamino)pyrimidine-5- carboxamide
Figure imgf000116_0001
[0327] The above compound was prepared using a procedure similar to that described in Scheme 3, using 2-fluorobenzylamine in place of (S)-2-phenyl-l -propylamine. MS found for C20Hi9FN6O2 as (M+H)+ 395.3.
Example 101. 2-(3-acetamidophenylamino)-4-(3-chlorobenzylamino)pyrimidine-5- carboxamide
Figure imgf000116_0002
[0328] The above compound was prepared using a procedure similar to that described in Scheme 3, using 3-chlorobenzylamine in place of (S)-2-phenyl-l -propylamine. MS found for C20H19ClN6O2 as (M+H)+ 411.3, 413.3.
Example 102. 2-(3-acetamidophenylamino)-4-(2, 5-difluorobenzylamino)pyrimidine-5- carboxamide
Figure imgf000116_0003
[0329] The above compound was prepared using a procedure similar to that described in Scheme 3, using 2,5-difluorobenzylamine in place of (S)-2-phenyl-l -propylamine. MS found for C20H18F2N6O2 as (M+H)+ 413.3. UV: λ = 204, 250. Example 103. 2-(3-acetamidophenylamino)-4-(4-fluorobenzylamino)pyrimidine-5- carboxamide
Figure imgf000117_0001
[0330] The above compound was prepared using a procedure similar to that described in Scheme 2, using 4-fluorobenzylamine in place of benzylamine and acetanilide. MS found for C20H19FN6O2 as (M+H)+ 395. UV: λ = 201, 249.
Example 104. 4-(4-fluorobenzylamino)-2-(3-(2-methoxyacetamido)phenylamino)pyrimidine- 5-carboxamide
Figure imgf000117_0002
[0331] The above compound was prepared using a procedure similar to that described in Scheme 2, using 4-fluorobenzylamine in place of benzylamine and an aniline prepared from 3-nitroaniline and methoxyacetyl chloride. MS found for C2iH2iFN6θ3 as (M+H)+ 425. UV: λ = 201, 250.
Example 105. (R)-4-(l -phenylethylamino)-2-(3 '-(pyrrolidine- 1- carboxamido)phenylamino)pyrimidine-5-carboxamide
Figure imgf000118_0001
[0332] The above compound was prepared using a procedure similar to that described in Scheme 1, using (R)- 1 -phenylethylamine in place of cyclobutylamine and an aniline prepared from 3-nitroaniline, phosgene, and pyrrolidine. MS found for C24H27N7O2 as (M+H)+ 446. UV: λ = 250.
Example 106. 4-(benzylamino)-2-(4-chloro-3-(2- methoxyacetamido)phenylamino)pyrimidine-5-carboxamide
Figure imgf000118_0002
[0333] The above compound was prepared using a procedure similar to that described in Scheme 2, using an aniline prepared from 2-chloro-5-nitroaniline and methoxyacetyl chloride. MS found for C2iH2iClN6O3 as (M+H)+ 441.4, 443.3. UV: λ = 207, 250.
Example 107. 4-(benzylamino)-2-(4-chloro-3-(3-cyclobutylureido)phenylamino)pyrimidine- 5-carboxamide
Figure imgf000118_0003
[0334] The above compound was prepared using a procedure similar to that described in Scheme 2, using an aniline prepared from 2-chloro-5-nitroaniline, phosgene, and cyclobutylamine. MS found for C23H24ClN7O2 as (M+H)+ 466.4, 468.4. UV: λ = 208, 249.
Example 108. (R)-2-(3-acetamido-4-chlorophenylamino)-4-(l -phenylethylamino)pyrimidine- 5-carboxamide
Figure imgf000119_0001
[0335] The above compound was prepared using a procedure similar to that described in Scheme 2, using (R)-l-phenylethylamine in place of benzylamine an aniline prepared from 2- chloro-5-nitroaniline and acetyl chloride. MS found for C21H21ClN6O2 as (M+H)+ 425.3, 427.4.
Example 109. (R)-2-(4-chloro-3-(2-methoxyacetamido)phenylamino)-4-(l- phenylethylamino)pyrimidine- 5-carboxamide
Figure imgf000119_0002
[0336] The above compound was prepared using a procedure similar to that described in Scheme 2, using (R)-I -phenyl ethylamine in place of benzylamine an aniline prepared from 2- chloro-5-nitroaniline and methoxyacetyl chloride. MS found for C22H23ClN6O3 as (M+H)+ 455.3, 457.3. UV: λ = 206, 250.
Example 110. (R)-2-(4-chloro-3-(cyclopropanecarboxamido)phenylamino)-4-(l - phenylethylamino)pyrimidine-5-carboxamide
Figure imgf000120_0001
[0337] The above compound was prepared using a procedure similar to that described in Scheme 2, using (R)-l-phenylethylamine in place of benzylamine an aniline prepared from 2- chloro-5-nitroaniline and cyclopropylcarbonyl chloride. MS found for C23H23ClN6O2 as (M+H)+ 451.3, 453.3. UV: λ = 206, 250.
Example 111. (R)-2-(4-chloro-3-(3-cyclobutylureido)phenylamino)-4-(l - phenylethylamino)pyrimidine-5-carboxamide
Figure imgf000120_0002
[0338] The above compound was prepared using a procedure similar to that described in Scheme 2, using (R)-l-phenylethylamine in place of benzylamine an aniline prepared from 2- chloro-5-nitroaniline, phosgene, and cyclobutylamine. MS found for C24H26ClN7O2 as (M+H)+ 480.4, 482.5. UV: λ = 208, 250.
Example 112. 2-(3-acetamidophenylamino)-4-(benzylamino)-N-methylpyrimidine-5- carboxamide
Figure imgf000120_0003
The above compound was prepared using a procedure similar to that described in Scheme 1, using benzylamine in place of cyclobutylamine, methylamine in place of ammonia, and acetanilide. MS found for C2JH22N6O2 as (M+H)+ 391. UV: λ = 203, 250.
Example 113. 4-(benzylamino)-2-(3-(2-methoxyacetamido)phenylamino)-N- πιethylpyrimidine-5-carboxamide
Figure imgf000121_0001
[0339] The above compound was prepared using a procedure similar to that described in Scheme 1 , using benzylamine in place of cyclobutylamine, methylamine in place of ammonia, and an aniline prepared from 3-nitroaniline and methoxyaceyl chloride. MS found for C22H24N6O3 as (M+H)+ 421. UV: λ = 250.
Example 114. 4-(2,3-dihydro-lH-inden-2-ylamino)-2-(3-(2- methoxyacetamido)phenylamino)-N-methylpyrimidine-5-carboxamide
Figure imgf000121_0002
[0340] The above compound was prepared using a procedure similar to that described in Scheme 1, using 2-aminoindane in place of cyclobutylamine and an aniline prepared from 2- chloro-5-nitroaniline and methoxyacetyl chloride. MS found for C23H24N6O3 as (M+H)+ 433. UV: λ = 201, 250.
Example 115. Benzyl 3-((2-(3-acetamidophenylamino)-5-carbamoylpyrimidin-4- ylamino)methyl)pipeήdine-l-carboxylate
Figure imgf000122_0001
Scheme 4
Figure imgf000122_0002
[0341] The mixture of ethyl 2,4-dichloropyrimidine-5-carboxylate (442 mg, 2.00 mmol), 3- aminomethyl-1-N-CBz-piperidine (496 mg, 2.00 mmol) and DEEA (0.700 mL, 4.02 mmol) in CH3CN (12 mL) was stirred at room temperature for 5 h. Water and EtOAc were added. The organic phase was separated, washed with IN HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give ethyl 4-((l-(benzyloxycarbonyl)piperidin-3- yl)methylamino)-2-chloropyrimidine-5-carboxylate (808 mg).
[0342] To a solution of ethyl 4-((l-(benzyloxycarbonyl)piperidin-3-yl)methylamino)-2- chloropyrimidine-5-carboxylate (808 mg, 1.86 mmol) in THF (10 mL), aq. IN NaOH (10 mL, 10.0 mmol) was added. The mixture was stirred at room temperature for 18 h. It was acidified to pH 1-2 with 6N HCl. Water and EtOAc were added. The organic phase was separated, washed with brine, dried over Na2SO4, concentrated in vacuo to give 4-((l- (benzyloxycarbonyl)piperidin-3-yl)methylamino)-2-chloropyrimidine-5-carboxylic acid (745 mg).
[0343] To a solution of 4-((l-(benzyloxycarbonyl)piperidin-3-yl)methylamino)-2- chloropyrimidine-5-carboxylic acid (745 mg, 1.84 mmol) and HOBt monohydrate (422 mg, 2.76 mmol) in DMF (10 mL), EDC (529 mg, 2.76 mmol) was added. After 1 h of stirring, NH3 (0.5 M in dioxane, 11.0 mL, 5.50 mmol) was added. The mixture was stirred at room temperature for 18 h. Water and EtOAc were added. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give benzyl 3-((2- (lH-benzo[d][l,2,3]triazol-l-yloxy)-5-carbamoylpyrimidin-4-ylamino)methyl)piperidine-l- carboxylate (779 mg).
[0344] A mixture of benzyl 3-((2-(lH-benzo[d][l,2,3]triazol-l-yloxy)-5- carbamoylpyrimidin-4-ylamino)methyl)piperidine-l -carboxylate (582 mg, 1.16 mmol), 3'- amino-acetanilide (210 mg, 1.40 mmol) and pTsOH (220 mg, 1.16 mmol) in dioxane (10 mL) was stirred at 100 C for 4 h. Water and EtOAc were added. The organic phase was separated, washed with IN HCl. During the washing white solids precipitated out, which were collected to give the titled compound (412 mg). MS 518.5 (M+H); UV 201.6, 249.8 nm.
Example 116 2-(3-acetamidophenylamino)-4-(piperidin-3-ylmethylamino)pyrimidine-5-carboxamide
Figure imgf000123_0001
Scheme 5
Figure imgf000123_0002
[0345] A mixture of benzyl 3-((2-(3-acetamidophenylamino)-5-carbamoylpyrimidin-4- ylamino)methyl)piperidine-l -carboxylate (340 mg, 0.657 mmol) and Pd-C (10%, 52 mg) in MeOH (10 mL) containing 5 drops of aq. 6N HCl was hydrogenated under balloon H2 for 18 h. It was then filtered through celite. The filtrate was concentrated in vacuo to give the titled compound (219 mg). MS 384.4 (M+H); UV 246.7 nm.
Example 117
2-(3-acetamidophenylamino)-4-((l-carbamoylpiperidin-3-yl)methylamino)pyrimidine-5- carboxamide
Figure imgf000124_0001
Scheme 6
Figure imgf000124_0002
[0346] To a mixture of 2-(3-acetamidophenylamino)-4-(piperidin-3- ylmethylamino)pyrimidine-5-carboxamide (40 mg, 0.104 mmol) in CH3CN (2 mL), a solution of KOCN (50 mg, 0.617 mmol) in H2O (1 mL) was added. The mixture was stirred at 70 C for 4 h. It was then purified by HPLC to give the titled compound (3 mg). MS 427.4 (M+H); UV 202.2, 248.6 nm.
Example 118
2-(3-acetamidophenylamino)-4-((l-(4-fluorophenylcarbamoyl)piperidin-3- yl)methylamino)pyrimidine-5-carboxamide
Figure imgf000124_0003
Scheme 7
Figure imgf000124_0004
[0347] To a mixture of 2-(3-acetamidophenylamino)-4-(piperidin-3- ylmethylamino)pyrimidine-5-carboxamide (40 mg, 0.104 mmol) and DIEA (0.100 mL, 0.575 mmol) in CH2Cl2 (2 mL), 4-fluorophenyl isocyanate (0.023 mL, 0.205 mmol) was added. The mixture was stirred at room temperature for 4 h. It was then purified by HPLC to give the titled compound (32 mg). MS 521.5 (M+H); UV 204.1, 243.1 nm.
Example 119
2-(3-acetamidophenylamino)-4-((l-acetylpiperidin-3-yl)methylamino)pyrimidine-5- carboxamide
Figure imgf000125_0001
Scheme 8
Figure imgf000125_0002
[0348] To a mixture of 2-(3-acetamidophenylamino)-4-(piperidin-3- ylmethylamino)pyrimidine-5-carboxamide (40 mg, 0.104 mmol) and DIEA (0.100 mL, 0.575 mmol) in CH2Cl2 (2 mL), acetic anhydride (0.040 mL, 0.423 mmol) was added. The mixture was stirred at room temperature for 4 h. It was then purified by HPLC to give the titled compound (5 mg). MS 426.5 (M+H); UV 248.6 nm.
Example 120
2-(3-acetamidophenylamino)-4-((l-(methylsulfonyl)piperidin-3-yl)methylamino)pyrimidine-
5-carboxamide
Figure imgf000126_0001
Scheme 9
Figure imgf000126_0002
[0349] To a mixture of 2-(3-acetamidophenylamino)-4-(piperidin-3- ylmethylamino)pyrimidine-5-carboxamide (40 mg, 0.104 mmol) and DEEA (0.100 mL, 0.575 mmol) in CH2Cl2 (2 mL), methanesulfonyl chloride (0.032 mL, 0.413 mmol) was added. The mixture was stirred at room temperature for 18 h. It was then purified by HPLC to give the titled compound (6 mg). MS 462.4 (M+H); UV 204.7, 248.6 nm.
Example 121
(R)-2-(3-(2,5-dihydro-lH-pyrrole-l-carboxamido)phenylamino)-4-(l-phenylethylamino) pyrimidine-5-carboxamide
Figure imgf000126_0003
[0350] The title compound was synthesized as in scheme 10 and as described in following procedures. Scheme 10
Figure imgf000127_0001
Figure imgf000127_0002
Figure imgf000127_0003
[0351] The title compound was synthesized as scheme 10 described in following procedures.
Step I, 2,4-dichloropyrimidine-5-carboxamide (1)
[0352] A suspension of 2,4-dihydroxypyrimidine-5-carboxylic acid (3.10 g, 20 mmoles) in phosphoryl trichloride (50 mL) was stirred at 100 0C for 4 hrs. After cooled to room temperature, the reaction solution was poured into a cold ammonium hydroxide solution (27- 30 %) in several portions and kept the mixture basic. The first portion of desired product as precipitate was collected by filtration. The second portion of desired product was obtained by extraction of mother aqueous liquid with DCM. The total amount of 2,4-dichloropyrimidine- 5-carboxamide (1) was 2.78 g. MS+: 191.0, UV: λ = 201.0; 269.2 nm, 1H NMR: (CDCl3) δ8.77(s,lH), δ7.45(s,lH), δ6.34(b,lH), 56.21(b,lH).
Step II, 2-chloro-4-(l-phenylethylamino)pyrimidine-5-carboxamide (2)
[0353] A mixture of 2,4-dichloropyrimidine-5-carboxamide (1, 950 mg, 5 mmoles), 3-1- phenylethanamine (756 mg, 7 mmoles) and DIEA (12 mmoles) in NMP (5 mL) was stirred at 60 0C for 20 hrs. The reaction mixture was concentrated under an oil pump. The residue was washed with water and dried under an oil pump. The desired 2-chloro-4-(l- phenylethylamino)pyrimidine-5-carboxamide (2, 1.085 g) was obtained. MS+: 263.1, UV: λ = 220.9; 260.9 nm. 1R NMR: (CDCl3) δ8.96(s,lH), δ8.60(s,lH), δ8.57(d,J=3.2 Hz,lH), δ8.30(s,lH), δ7.64(d,J=7.6Hz,lH), 57.31 (dd,Jl=7.6Hz,J2=3.2Hz,lH), 56.51(s,lH), δ5.80(b,2H), δ4.47(s, IH), 54.45(s, IH).
Step III, N-(3-aminophenyl)-2,5-dihydro-lH-pyrrole-l-carboxamide (3)
[0354] A mixture of l-isocyanato-3-nitrobenzene (1.125 g, 6.18 mmoles) and pyrrolidine (485 mg, 6.8 mmoles) in DCM (20 rnL) was stirred at r.t. for 14 hrs. After concentrated, the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous citric acid solution and dried over MgSO4, followed by hydrogenation with Pd/C (wet,10 %, 0.15 g) under a hydrogen balloon overnight. After filtration and concentration, the reasonable pure N-(3-aminophenyl)-2,5-dihydro-lH-pyrrole-l-carboxamide (3, 1.44 g) was used for the next reactions. MS+: 224.2, UV: λ = 271.6 nm. 1H NMR: (DMSO) δ7.44 (s, IH), δ6.78 (m, IH), δ6.20 (m, IH), δ3.32 (m, 4H), 51.83 (m, 4H).
Step IV, (R)-2-(3-(2,5-dihydro-lH-pyrrole-l-carboxamido)phenylamino)-4-(l- phenylethylamino) pyrimidine-5-carboxamide (4)
[0355] A mixture of 2-chloro-4-(l-phenylethylamino)pyrimidine-5-carboxamide (2, 27 mg, 0.1 mmoles), N-(3-aminophenyl)-2,5-dihydro-lH-pyrrole-l-carboxamide (3, 34 mg, 0.15 mmoles), Pd(OAc)2 (2 mg). BINAP (15 mg), Cs2CO3 (100 mg) in dioxane (1 mL) was heated at 120 0C under microwave for 60 min. Purification with reversed phase HPLC, (R)-2-(3- (2,5-dihydro-lH-pyrrole-l-carboxamido)phenylamino)-4-(l-phenylethylamino) pyrimidine- 5-carboxamide (4, 10 mg) was obtained. MS found for C24H25N7O2 as (M+H)+444. UV: λ = 248 nm. 1H NMR: (CD3OD) δ 8.35 (s, IH), 7.85 (s, IH), 7.3 (m, 4H), 7.2 (m, 3H), 7.05 (d, IH), 5.95 (s, 2H), 5.4 (dd, IH), 4.25 (s, 4H), 1.48 (d, 3H).
Example 122
(R)-2-(3-(N-methylpyrrolidine- 1 -carboxamido)phenylamino)-4-( 1 -phenylethylamino) pyrimidine-5-carboxamide.
Figure imgf000129_0001
[0356] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C25H29N7O2 as (M+H)+460. UV: λ = 206, 259 nm. 1H NMR: (CD3OD) δ 8.4 (s, IH), 7.38 (m, 6H), 7.25 (t, 2H), 7.05 (d, IH), 5.25 (dd, IH), 3.25 (s, 3H), 3.10 (t, 4H), 1.75 (t, 3H), 1.6 (d, 3H).
Example 123
4-(cyclopropylmethylamino)-2-(3-(pyrrolidine- 1 -carboxamido)phenylamino) pyrimidine-5- carboxamide.
Figure imgf000129_0002
[0357] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C20H25N7O2 as (M+H)+ 396.4. UV: λ = 206, 247 nm. 1H NMR: (D- DMSO) δ 8.2 (s, IH), 7.9 (s, IH), 7.8 (s, 2H), 6.9 (m, 3H), 3.15 (m, 4H), 1.65 (t, 4H), 0.85 (t, IH), 0.25 (d, 2H), 0.15 (d, 2H).
Example 124
4-(cyclopropylmethylamino)-2-(3-(2-methoxyacetamido)phenylamino) pyrimidine-5- carboxamide.
Figure imgf000129_0003
[0358] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C19H24N6O3 as (M+H)+ 371.3. UV: λ = 248 nm. 1H NMR: (CD3OD) δ 8.35 (s, IH), 8.15 (s, IH), 7.38 (t, IH), 7.35 (d, IH), 7.28 (s, IH), 4.05 (s, 2H), 3.5 (s, 3H), 3.05 (d, 2H), 1.15 (t, IH), 0.55 (d, 2H), 0.35 (d, 2H).
Example 125
4-(cyclopropylmethylamino)-2-(3-(2-methoxy-N-methylacetamido)phenylamino) pyrimidine-5-carboxamide.
Figure imgf000130_0001
[0359] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C19H24N6O3 as (M+H)+ 385.3. UV: λ = 257 nm. 1R NMR: (CD3OD) δ 8.4 (s, IH), 7.8 (s, IH), 7.5 (t, 2H), 7.15 (d, IH), 3.9 (s, 2H), 3.45 (d, 2H), 3.4 (t, IH), 1.2 (t, IH), 0.6 (d, 2H), 0.3 (d, 2H).
Example 126
4-(cyclopropylmethylamino)-2-(3-(N-methylacetamido)phenylamino) pyrimidine-5- carboxamide.
Figure imgf000130_0002
[0360] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C18H22N6O2 as (M+H)+ 355.3. UV: λ = 258 nm. 1H NMR: (CD3OD) δ 8.4 (s, IH), 7.8 (s, IH), 7.5 (d, 2H), 7.19 (t, IH), 3.45 (s, 3H), 1.9 (s, 3H), 1.15 (t, IH), 0.6 (d, 2H), 0.3 (d, 2H).
Example 127
4-(cyclopropylmethylamino)-2-(3-(N-methylpyrrolidine- 1 -carboxamido) phenylamino)pyrimidine-5-carboxamide.
Figure imgf000131_0001
[0361] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C2iH27N7O2 as (M+H)+410. UV: λ = 205, 248 nm. 1H NMR: (CD3OD) δ 8.35 (s, IH), 7.55 (s, IH), 7.4 (t, IH), 7.3 (d, IH), 7.0 (d, IH), 3.35 (t, 4H), 3.2 (s, 3H), 3.1 (d, 2H), 1.75 (t, 4H), 1.15 (t, IH), 0.6 (d, 2H), 0.3 (d, 2H).
Example 128
2-(3-((S)-3-hydroxypyrrolidine- 1 -carboxamido)phenylamino)-4-((R)- 1 -phenylethylamino) pyrimidine-5-carboxamide.
Figure imgf000131_0002
[0362] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C24H27N7O3 as (M+H)+ 462.4. UV: λ = 208, 250 nm.
Example 129
(R)-methyl 5-(5-carbamoyl-4-(l-phenylethylamino)pyrimidin-2-ylamino)-2- chlorophenylcarbamate.
Figure imgf000131_0003
[0363] The title compound was synthesized similar Example 121. MS found for C2]H21ClN6O3 as (M+H)+ UV: λ = 8.41 nm. 1H NMR: (CD3OD) δ 8.42 (s, IH), 8.26 (s, IH), 7.38 (d, IH), 7.30 (m, 5H), 7.22 (d, IH), 4.83 (s, 2H).5.42 (q, IH), 3.78 (s, 3H), 1.58 (d, 3H).
Example 130
4-(benzylamino)-2-(4-chloro-3-(pyrrolidine-l-carboxamido)phenylamino)pyrimidine-5- carboxamide.
Figure imgf000132_0001
[0364] The title compound was synthesized similar to Example 121. MS found for C23H24ClN7O2 as (M+H)+ 466.4, 468.2. UV: λ = 249 nm. 1H NMR: (CD3OD) δ 8.42 (s, IH), 8.23 (s, IH), 7.39 (d, IH), 7.35 (m, 6H), 7.20 (d, IH), 4.82 (s, 2H), 3.46 (m, 4H), 1.99 (m, 4H).
Example 131
4-(benzylamino)-2-(4-chloro-3-(3-methylureido)phenylamino)pyrimidine-5-carboxamide.
Figure imgf000132_0002
[0365] The title compound was synthesized similar to Example 121. MS found for C20H20ClN7O2 as (M+H)+ 426.2, 428.5. UV: λ = 248 nm. 1H NMR: (CD3OD) δ 8.49 (s, IH), 8.42 (s, IH), 7.38 (m, 5H), 7.29 (m, IH), 7.11 (d, IH), 4.82 (s, 2H), 2.77 (s, 3H).
Example 132
(R)-2-(4-chloro-3-(3-methylureido)phenylamino)-4-(l-phenylethylamino) pyrimidine-5- carboxamide
Figure imgf000133_0001
[0366] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C2iH22ClN7O2 as (M+H)+ 440.4. UV: λ = 206, 250 nm. 1H NMR: (D- DMSO) δ 8.4 (s, IH), 7.9 (s, IH), 7.1-7.3 (m,5H), 7.0 (d, IH), 6.8 (d, IH), 5.4 (t, IH), 2.6 (d, 3H), 1.4 (d, 3H).
Example 133
4-(methylaniino)-2-(3-(pyrrolidine-l-carboxamido)phenylamino)pyrimidine-5-carboxamide
Figure imgf000133_0002
[0367] The title compound was synthesized similar to Example 121. MS found for CnH2IN7O2 as (M+H)+ 356.3. UV: λ = 202, 250 nm. 1H NMR: (CD30D) δ 8.39 (s, IH), 7.94 (s, IH), 7.34 (m, 3H), 7.24 (d, IH), 3.51 (m, 4H), 3.14 (s, 3H), 2.01 (m, 4H). 3, 442, 3. UV: λ = 249 nm.
Example 134
4-(ethylamino)-2-(3-(pyrrolidine-l-carboxamido)phenylamino)pyrimidine-5-carboxamide.
Figure imgf000133_0003
[0368] The title compound was synthesized similar to Example 121. MS found for C18H23N7O2 as (M+H)+ 370.3. UV: λ = 247 nm. 1H NMR: (CD3OD) δ 8.33 (s, IH), 7.82 (s, IH), 7.33 (t, IH), 7.19 (m, 3H), 3.63 (q, 2H), 3.46 (m, 4H), 1.98 (m, 4H), 1.27 (t, 3H).
Example 135
4-(butylamino)-2-(3-(pyrrolidine-l-carboxamido)phenylamino)pyrimidine-5-carboxamide.
Figure imgf000134_0001
[0369] The title compound was synthesized Example 121. MS found for C2oH27N702 as (M+H)+ 398.3. UV: λ = 248 nm. 1H NMR: (CD3OD) δ 8.38 (s, IH), 7.91 (s, IH), 7.31 (t, IH), 7.22 (m, 2H), 3.61 (t, 2H), 3.49 (m, 4H), 1.99 (m, 4H), 1.64 (m, 2H), 1.42 (m, 2H), 0.98 (t, 3H).
Example 136
2-(3-(pyrrolidine-l-carboxamido)phenylamino)-4-(2,2,2-trifluoroethylamino)pyrimidine-5- carboxamide.
Figure imgf000134_0002
[0370] The title compound was synthesized similar to Example 121. MS found for
Ci8H20F3N7O2 as (M+H)+ 424.3. UV: λ = 246 nm. 1H NMR: (CD3OD) δ 8.52 (s, IH), 8.01 (s, IH), 7.29 (t, IH), 7.18 (m, 2H), 4.47 (q, 2H), 3.48 (m, 4H), 1.97 (m, 4H).
Example 137
2-(3-((S)-2-methylpyrrolidine-l-carboxamido)phenylamino)-4-((R)-l-phenylethylamino) pyrimidine-5-carboxamide.
Figure imgf000134_0003
[0371] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C25H29N7O2 as (M+H)+ 460.5. UV: λ = 205, 251 nm. 1H NMR: (D- DMSO) 6 8.1 (s, IH), 7.3 (m, 5H), 7.2 (d, IH), 7.1 (IH), 7.05 (d, IH), 5.4 (t, IH), 4.0 (t, IH), 3.5 (m, IH), 3.3 (d, IH), 2 (s, 3H), 1.9 (m, 4H), 1.5 (d, 4H), 1.1 (d, 3H).
Example 138
2-(3-((S)-2-(methoxymethyl)pyrrolidine-l-carboxamido) phenylamino)-4-((R)-l- phenylethylamino) pyrimidine-5-carboxamide.
Figure imgf000135_0001
[0372] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C26H3IN7O3 as (M+H)+ 490.5. UV: λ = 207, 251 nm. 1U NMR: (D- DMSO) δ 8.0 (s, IH), 7.0-7.4 (m, 8H), 5.4 (t, IH), 4.05 (d, IH), 3.4 (t, 2H), 3.35 (s, IH), 3.3 (s, 3H), 1.7-1.9 (m, 4H), 1.5 (d, 3H).
Example 139
(S)-4-(benzylamino)-2-(3-(2-methylpyrrolidine-l-carboxamido)phenylamino) pyrimidine-5- carboxamide.
Figure imgf000135_0002
[0373] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C24H27N7O2 as (M+H)+ 446.4. UV: λ = 248 nm. 1H NMR: (D-DMSO) δ 8.4 (s, IH), 8.0 (s, 2H), 7.3 (m, 4H), 7.2 (m, IH), 7.1 (t, 2H), 4.7 (d, 2H), 3.5 (t, IH), 3.3 (dd, 2H), 1.7-1.9 (m, 3H), 1.5 (d, IH), 1.1 (d, 3H).
Example 140
(S)-4-(benzylamino)-2-(3-(2-(methoxymethyl)pyrrolidine-l-carboxamido) phenylamino)pyrimidine-5-carboxamide.
Figure imgf000136_0001
[0374] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C25H29N7O3 as (M+H)+476. UV: λ = 250 nm. 1H NMR: (D-DMSO) δ 8.3 (s, IH), 7.1 (d, 2H), 6.9 (t, 2H), 6.7-6.85 (m, 5H), 4.5 (d, 2H), 3.7 (d, IH), 3.1 (m, 2H), 2.9 (s, 3H), 1.5 (m, 2H), 1.4 (m, 2H).
Example 141
4-(benzylamino)-2-(3-(N-methylpyrrolidine-l-carboxamido) phenylamino)pyrimidine-5- carboxamide.
Figure imgf000136_0002
[0375] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C24H27N7O2 as (M+H)+ 446.4. UV: λ = 207, 257 nm. 1H NMR: (D- DMSO) δ 8.25 (s, IH), 7.35 (t, IH), 7.1 (d, IH), 7.0 (d, 2H), 6.95 (t, 2H), 6.9 (t, 2H) 6.4 (d, IH), 4.4 (d, 2H), 2.7 (s, 3H), 2.65 (t, 2H), 1.3 (t, 2H).
Example 142
4-(benzylamino)-2-(3-(2,5-dihydro-lH-pyrrole-l-carboxamido)phenylamino) pyrimidine-5- carboxamide.
Figure imgf000136_0003
[0376] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C23H23N7O2 as (M+H)+ 430.4. UV: λ = 201, 248 nm. 1H NMR: (D- DMSO) δ 8.3 (s, IH), 7.0 (d, 2H), 6.95, (t, 2H), 6.9 (t, 2H), 6.8, (d, 2H), 5.5 (s, 2H), 4.5 (d, 2H)3.8 (s, 4H).
Example 143
(S)-4-(benzylamino)-2-(3-(3-hydroxypyrrolidine- 1 -carboxamido)phenylamino) pyrimidine-5- carboxamide.
Figure imgf000137_0001
[0377] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C23H25N7O3 as (M+H)+ 448.4. UV: λ = 206, 247 nm. 1H NMR: (D-
DMSO) δ 8.3 (s, IH), 7.1 (d, 2H), 6.95 (t, 2H), 6.9 (d, 3H), 6.8 (d, 2H), 4.45 (d, 2H), 3.15 (m, 2H), 3.05 (d, IH).
Example 144
(S)-4-(sec-butylamino)-2-(3-(2-methoxyacetamido)phenylamino)pyrimidine-5-carboxamide.
Figure imgf000137_0002
[0378] The title compound was synthesized similar to step Example 121. MS found for C18H24N6O3 as (M+H)+ 373.4. UV: λ = 204, 247 nm. 1U NMR: (CD3OD) δ 8.35 (s, IH), 8.08 (s, IH), 7.30 (m, 3H), 4.23 (m, IH), 4.03 (s, 2H), 3.48 (s, 3H), 1.63 (m, 2H), 1.26 (d, 3H), 0.97 (t, 3H).
Example 146 (R)-4-(benzylamino)-2-(3-(2-methylpyrrolidine- 1 -carboxamido) phenylamino)pyrimidine-5- carboxamide.
Figure imgf000138_0001
[0379] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C24H27N7O2 as (M+H)+ 446.4. UV: λ = 201, 247 nm. 1H NMR: (D- DMSO) δ 8.5 (s, IH), 7.3 (d, 5H), 7.2 (m, 2H), 7.1 (bs, 3H), 4.7 (d, 2H), 4.0 (t, IH), 3.45 (t, IH), 3.25 (d, IH), 1.9 (d, 2H), 1.8 (t, IH), 1.5 (IH).
Example 147
(R)-4-(benzylamino)-2-(3-(2-(methoxymethyl)pyrrolidine-l-carboxamido) phenylamino)pyrimidine-5-carboxamide.
Figure imgf000138_0002
[0380] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C25H29N7O3 as (M+H)+ 476.4. UV: λ =205, 245 nm. 1H NMR: (D- DMSO) δ 8.5 (s, IH), 7.3 (d, 4H), 7.2 (d, IH), 7.1 (d, 2H), 4.7 (d, 2H), 4.0 (d, 2H), 3.3 (m, 4H), 3.2 (t,3H), 1.7-2.9 (m, 4H).
Example 148
2-(3-((R)-2-methylpyrrolidine-l-carboxamido)phenylamino)-4-((R)-l- phenylethylamino)pyrimidine-5-carboxamide.
Figure imgf000138_0003
[0381] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C25H29N7O2 as (M+H)+ 460.5. UV: λ =208, 248 nm. 1H NMR: (D- DMSO) δ 8.4 (s, IH), 7.25 dd, 4H), 7.2 (t, IH), 7.0 (d, IH), 6.9 (m, 3H). 5.3 (t, IH), 4.0 (t, IH), 1.7-1.9 (m, 3H), 1.45 (d, IH), 1.4 (d, 3H), 1.1 (d, 3H).
Example 149
2-(3-((R)-2-(methoxymethyl)pyrrolidine-l-carboxamido) phenylamino)-4-((R)-l- phenylethylamino)pyrimidine-5-carboxamide.
Figure imgf000139_0001
[0382] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C26H31N7O3 as (M+H)+ 490.5. UV: λ =208, 250 nm. 1H NMR: (D-
DMSO) 6 8.5 (s, IH), 8.3 (s, IH), 7.3 (d, 5H), 7.25 (t, IH), 7.1 (d, IH), 7.05 (t, IH), 5.04 (t, IH), 4.05 (d, IH), 3.4 (t, 3H), 1.9 (t, 2H), 1.8 (d, IH), 1.5 (d, 3H).
Example 150
4-(benzylamino)-2-(3-(N-cyclopropyl-2-methoxyacetamido) phenylamino)pyrimidine-5- carboxamide.
Figure imgf000139_0002
[0383] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C24H26N6O3 as (M+H)+ 447.4. UV: λ = 247 nm. 1H NMR: (CD3OD) δ 8.5 (s, IH), 7.7 (s, IH), 7.3 (m, 7H). 7.0 (d, IH). 4.6 (s, 2H), 2.9 (s, IH), 0.8 (d, 2H), 0.6 (d, 2H).
Example 151
4-(benzylamino)-2-(3-(N-cyclopropylcyclopropanecarboxamido) phenylamino)pyrimidine-5- carboxamide.
Figure imgf000140_0001
[0384] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C25H26N6O2 as (M+H)+ 443.5. UV: λ = 247 nm. 1H NMR: (CD3OD) δ 8.5 (s, IH), 7.8 (s, IH), 7.4 (m, 7H), 7.0 (d, IH), 4.6 (s, 2H), 3.0 (s, IH), 0.9 (s, 3H), 0.8 (s, 4H), 0.5 (s, 2H).
Example 152
(R)-2-(3-acetamidophenylamino)-4-(cyclopropyl(phenyl)methylamino)pyrimidine-5- carboxamide
Figure imgf000140_0002
[0385] The title compound was synthesized similar to step Example 121 using the 2- methylsulfoxide and an amine synthesized using a procedure similar to that described in Eleveld, M.B.; Hogeveen, H.; Schudde, E.P. J. Org. Chem., 1986, 51 (19), pp 3635-3642. MS found for C23H24N6O2 as (M+H)+417.4. UV: λ = 205, 212 nm. 1H NMR: (CD3OD) δ 8.37 (s, IH), 8.00 (s, IH), 7.10 - 7.32 (m, 6H), 7.02 (d, IH), 4.67 (d, IH), 2.18 (s, 3H), 1.33 (m, IH), 0.61 (m, 2H), 0.43 (m, 2H).
Example 154
4-(benzylamino)-2-(4-chloro-3-(3-cyclopropylureido)phenylamino)pyrimidine-5- carboxamide.
Figure imgf000141_0001
[0386] The title compound was synthesized similar to Example 121. MS found for C22H22ClN7O2 as (M+H)+ 452.4, 454.2. UV: λ = 206, 246 nm. 1H NMR: (CD3OD) δ 8.57 (s, IH), 8.43 (s, IH), 7.34 (m, 6H), 7.18 (d, IH), 4.81 (s, 2H), 2.61 (m, IH), 0.73 (m, 2H), 0.52 (m, 2H).
Example 155
2-(3-acetamido-4-methylphenylamino)-4-(benzylamino)pyrimidine-5-carboxamide
Figure imgf000141_0002
[0387] The title compound was synthesized similar to Example 121. MS found for C2IH22N6O2 as (M+H)+ 391.4. UV: λ = 207, 248 nm. 1H NMR: (CD3OD) δ 8.49 (s, IH), 7.84 (s, IH), 7.21 - 7.40 (m, 7H), 4.82 (s, 2H), 2.28 (s, 3H), 2.13 (s, 3H).
Example 156 (
2-(3-acetamido-4-fluorophenylamino)-4-(benzylamino)pyrimidine-5-carboxamide
Figure imgf000141_0003
[0388] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C20H19FN6O2 as (M+H)+ 395.2. UV: λ = 208, 250 nm. Example 157 (
4-(benzylamino)-2-(4-methyl-3-(3-methylureido)phenylamino)pyrimidine-5-carboxamide.
Figure imgf000142_0001
[0389] The title compound was synthesized similar to Example 121. MS found for C21H23N7O2 as (M+H)+ 406.4. UV: λ = 209, 246 nm. 1H NMR: (CD3OD) δ 8.31 (s, IH), 7.88 (s, IH), 7.30 (m, 5H), 7.20 (d, IH), 7.03 (d, IH), 4.77 (s, 2H), 2.74 (s, 3H), 2.24 (s, 3H).
Example 158 (
4-(benzylamino)-2-(4-fluoro-3-(3-methylureido)phenylamino)pyrimidine-5-carboxamide.
Figure imgf000142_0002
[0390] The title compound was synthesized similar to Example 121. MS found for
C20H20FN7O2 as (M+H)+ 410.3. UV: λ = 206, 244 nm. 1H NMR: (CD3OD) δ 8.33 (s, IH), 8.28 (m, IH), 7.26 (m, 5H), 7.02 (m, 2H), 4.77 (s, 2H), 2.76 (s, 3H).
Example 159 (
4-(benzylamino)-2-(4-(pyrrolidin-l-yl)-3-(pyrrolidine-l- carboxamido)phenylamino)pyrimidine-5-carboxamide.
Figure imgf000143_0001
[0391] The title compound was synthesized similar to Example 121, using an aniline derived from 2-fluoro-5-nitroisocyanate and excess pyrrolidine. MS found for C27H32N8O2 as (M+H)+ 501.5 UV: λ = 202, 256 nm. 1H NMR: (CD3OD) δ 8.37 (s, IH), 7.79 (broad s, IH), 7.30 (m, 7H), 4.77 (s, 2H), 3.59 (m, 4H), 3.43 (m, 4H), 2.11 (m, 4H), 1.92 (m, 4H).
Example 161 (
(R)-2-(3-(N-cyclopropylacetamido)phenylamino)-4-(l-phenylethylamino) pyrimidine-5- carboxamide
Figure imgf000143_0002
[0392] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C24H26N6O2 as (M+H)+431.4. UV: λ = 252 nm. 1H NMR: (CD3OD) δ 8.4 (s, IH), 7.5 (s, IH), 7.4 (d, 2H), 7.3 (m, 4H), 7.2 (d, IH), 7.0 (s, IH), 5.3 (d, IH), 3.2 (d, IH), 1.6 (d, 3H), 0.9 (s, 2H), 0.6 (s, 2H).
Example 162 (
(R)-2-(3-(N-cyclopropyl-2-methoxyacetamido)phenylamino)-4-(l- phenylethylamino)pyrimidine-5-carboxamide.
Figure imgf000143_0003
[0393] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C25H28N6O3 as (M+H)+ 461.4. UV: λ = 254 nm. 1H NMR: (CD3OD) δ 8.4 (s, IH), 7.5 (s, IH), 7.4 (d, 2H), 7.3 (m, 4H), 7.2 (d, IH), 7.0 (d, IH), 5.4 (d, IH), 3.4 (s, 3H), 3.2 (d, 2H), 1.6 (s, 3H), 0.9 (s, 2H), 0.6 (s, 2H).
Example 163 (
4-(benzylamino)-2-(4-methoxy-3-(pyrrolidine-l-carboxamido)phenylamino)pyrimidine-5- carboxamide.
Figure imgf000144_0001
[0394] The title compound was synthesized similar to Example 121. MS found for
C24H27N7O3 as (M+H)+ 462.5. UV: λ = 213, 247 nm. 1H NMR: (DMSO) δ 8.42 (s, IH), 8.23 (broad s, IH), 7.51 (broad s, IH), 4.31 (m, 4H), 7.23 (m, IH), 7.13 (s, IH), 7.08 (dd, IH), 6.92 (d, IH), 4.70 (d, 2H), 3.81 (s, 3H), 3.32 (m, 4H), 1.82 (m, 4H).
Example 164 (
4-(benzylamino)-2-(4-methoxy-3-(3-methylureido)phenylamino)pyrimidine-5-carboxamide.
Figure imgf000144_0002
[0395] The title compound was synthesized similar to Example 121. MS found for C2JH23N7O3 as (M+H)+ 422.4. UV: λ = 245, 293 nm. 1H NMR: (DMSO) δ 8.42 (s, IH), 8.40 (s, IH), 8.07 (s, IH), 7.95 (s, IHO, 7.52 (s, IH), 7.30 (m, 4H), 7.23 (m, IH), 6.98 (dd, IH), 6.89 (d, IH), 6.73 (m, IH), 4.70 (d, 2H), 3.80 (s, 3H), 2.60 (d, 3H). Example 165 (
2-(4-chloro-3-(3-methylureido)phenylamino)-4-(3-chlorobenzylamino)pyrimidine-5- carboxamide.
Figure imgf000145_0001
[0396] The title compound was synthesized similar to Example 121. MS found for C20Hi9Cl2N7O2 as (M+H)+ 460.2, 462.3. UV: λ = 211, 247 nm. 1U NMR: (CD3OD) δ 8.54 (s, IHO, 8.46 (s, IH), 7.20 - 7.36 (m, 6H), 4.73 (s, 2H), 2.62 (s, 3H).
Example 166 (
2-(4-chloro-3-(3-methylureido)phenylamino)-4-(cyclopentylamino)pyrimidine-5- carboxamide.
Figure imgf000145_0002
[0397] The title compound was synthesized similar to Example 121. MS found for Ci8H22ClN7O2 as (M+H)+ 404.3. UV: λ = 258 nm. 1H NMR: (DMSO) δ 8.57 (s, IHO, 8.38 (s, IH), 7.90 (s, IH), 7.88 (s, IH), 7.24 (d, IH), 7.12 (dd, IH), 6.77 (m, IH), 4.41 (q, IH), 2.58 (d, 3H), 1.92 (m, IH), 1.59 (m, 2H), 1.52 (m, 2H), 1.39 (m, 2H). Example 167 (
2-(4-chloro-3-(pyrrolidine-l-carboxamido)phenylamino)-4-(cyclopentylamino)pyrimidine-5- carboxamide
Figure imgf000146_0001
[0398] The title compound was synthesized similar to Example 121. MS found for
C21H26ClN7O2 as (M+H)+ 444.5. UV: λ = 214, 253 nm. 1H NMR: (CD3OD) δ 8.42 (s, IHO, 8.79 (s, IHO, 7.33 (d, IH), 7.27 (d, IHO, 4.52 (m, IH), 3.38 (m, 4H), 1.99 (m, 2H), 1.89 (m, 4H), 1.58 (m, 2HO, 1.50 (m, 2HO, 1.39 (m, 2H).
Example 168 (
4-(2-fluorobenzylamino)-2-(3-(pyrrolidine-l-carboxamido)phenylamino)pyrimidine-5- carboxamide,
Figure imgf000146_0002
[0399] The title compound was synthesized similar to Example 121. MS found for C23H24FN7O2 as (M+H)+ 450.4. UV: λ = 207, 248 nm. 1H NMR: (CD3OD) δ 8.43 (s, IH), 7.92 (s, IH), 7.38 (m, 2H), 7.23 (m, IH), 7.18 (m, 5H), 4.7 (s, 2H), 3.45 (m, 4H), 1.97 (m, 4H).
Example 169 (
2-(4-chloro-3-(3-methylureido)phenylamino)-4-(2-fluorobenzylamino)pyrimidine-5- carboxamide
Figure imgf000147_0001
[0400] The title compound was synthesized similar to Example 121. MS found for C20Hi9ClFN7O2 as (MH-H)+ 444.4, 446.4. 1H NMR: (CD3OD) δ 8.45 (s, IH), 8.42 (s, IH), 7.37 (m, 3H), 7.13 (m, 3H), 4.87 (s, 2H), 2.78 (s, 3H).
Example 170 (
2-(4-chloro-3-(pyrrolidine- 1 -carboxamido)phenylamino)-4-(2- fluorobenzylamino)pyrimidine-5-carboxamide
Figure imgf000147_0002
[0401] The title compound was synthesized similar to Example 121. MS found for C23H23ClFN7O2 as (M+H)+ 484.5, 486.5. UV: λ = 207, 249 nm. 1H NMR: (CD3OD) δ 8.42 (s, IH), 8.22 (s, IH), 7.38 (d, IH), 7.35 (m, 2H), 7.20 (d, IH), 7.14 (m, 2H), 4.83 (s, 2H), 3.45 (m, 4H), 1.99 (m, 4H).
Example 171 (
2-(5-acetamido-2-fluorophenylamino)-4-(benzylamino)pyrimidine-5-carboxamide
Figure imgf000147_0003
[0402] The title compound was synthesized similar to Example 121. MS found for C20H19FN6O2 as (M+H)+ 395.4. UV: λ = 204, 246 nm. 1H NMR: (CD3OD) δ 8.51 (s, IH), 8.37 (s, IH), 7.68 (d, IH), 7.29 (m, 7H), 4.78 (s, 2H), 2.18 (s, 3H).
Example 172 (
4-(benzylamino)-2-(2-fluoro-5-(2-methoxyacetamido)phenylamino)pyrimidine-5- carboxamide.
Figure imgf000148_0001
[0403] The title compound was synthesized similar to Example 121. MS found for C2IH21FN6O3 as (M+H)+ 425.4. 1H NMR: (CD3OD) δ 8.47 (s, IH), 8.43 (s, IH), 7.41 (s, IH), 7.29 (6H), 4.77 (s, 2H), 4.05 (s, 2H), 3.48 (s, 3H).
Example 173 (
2-(4-chloro-3-(pyrrolidine- 1 -carboxamido)phenylamino)-4-(3- chlorobenzylamino)pyrimidine-5-carboxamide.
Figure imgf000148_0002
[0404] The title compound was synthesized similar to Example 121. MS found for
C23H23Cl2N7O2 as (M+H)+ 500.4. 1H NMR: (CD3OD) δ 8.43 (s, IH), 8.23 (d, IHO, 7.20 - 7.32 (m, 5H), 7.12 (dd, IH), 4.76 (s, 2HO, 3.37 (m, 4HO, 1.82 (m, 4H). Example 174 (
2-(4-chloro-3-(pyrrolidine- 1 -carboxamido)phenylamino)-4- (cyclopropylmethylamino)pyrimidine-5-carboxamide.
Figure imgf000149_0001
[0405] The title compound was synthesized similar to Example 121. MS found for C20H24ClN7O2 as (M+H)+ 430.4. UV: λ = 212, 246, 290 nm. 1H NMR: (CD3OD) δ 8.43 (s, IHO, 8.33 (s, IHO, 7.33 (d, IH), 7.29 (dd, IH), 3.38 (m, 6H), 1.84 (m, 4HO, 1.08 (m, IHO, 0.43 (m, 2HO, 0.22 (m, 2H).
Example 175 (
(S)-4-(sec-butylamino)-2-(4-chloro-3-(3-methylureido)phenylamino)pyrimidine-5- carboxamide.
Figure imgf000149_0002
[0406] The title compound was synthesized similar to Example 121. MS found for
CnH22ClN7O2 as (M+H)+ 292.3. UV: λ = 210, 246, 288 nm. 1H NMR: (CD3OD) δ 8.52 (s, IH), 8.38 (s, IHO, 7.28 (d, IH), 7.18 (dd, IHO, 4.21 (m, IH), 3.63 (s, 3H), 1.51 (m, 2H), 1.13 (d, 3H), 0.83 (t, 3H). Example 176 (
(S)-4-(sec-butylamino)-2-(4-chloro-3-(pyrrolidine-l-carboxamido)phenylamino)pyrimidine- 5-carboxamide.
Figure imgf000150_0001
[0407] The title compound was synthesized similar to Example 121. MS found for C20H26ClN7O2 as (M+H)+ 432.2. UV: λ = 214, 258 nm. 1H NMR: (CD3OD) 8 8.41 (s, IH), 8.26 (d, IHO, 7.32 (d, IH), 7.27 (dd, IH), 4.18 (m, IH), 3.38 (m, 4H), 1.85 (m, 4H), 1.52 (m, 2H), 1.17 (d, 3H), 0.84 (t, 3H).
Example 177 (
2-(4-chloro-3-(pyrrolidine-l-carboxamido)phenylamino)-4-(3- fluorobenzylamino)pyrimidine-5-carboxamide.
Figure imgf000150_0002
[0408] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C23H23ClFN7O2 as (M+H)+ 484.4. UV: λ = 250 nm.
Example 178 (
2-(4-chloro-3-(3-methylureido)phenylamino)-4-(cyclopropylmethylamino)pyrimidine-5- carboxamide.
Figure imgf000150_0003
[0409] The title compound was synthesized similar to Example 121. MS found for C,7H20ClN7O2 as (M+H)+ 390.4. UV: λ = 210, 249 nm. 1H NMR: (CD3OD) δ 8.57 (s, IH), 8.39 (s, IH), 7.29 (d, IH), 7.17 (d, IH), 3.37 (d, 2H), 3.63 (s, 3H), 1.07 (m, IH), 0.43 (m, 2H), 0.22 (m, 2H).
Example 179 (
4-(3-fluorobenzylamino)-2-(3-(pyrrolidine-l-carboxamido)phenylammo)pyrimidine-5- carboxamide.
Figure imgf000151_0001
[0410] The title compound was synthesized similar to Example 121. MS found for
C23H24FN7O2 as (M+H)+ 450.5. UV: λ = 256 nm. 1H NMR: (CD3OD) δ 8.41 (s, IH), 7.92 (s, IH), 7.27 (m, IH), 6.93 - 7.12 (m, 6H), 4.68 (s, 2H), 3.31 (m, 4H), 1.81 (m, 4H).
Example 180 (
4-(3-chlorobenzylamino)-2-(3-(pyrrolidine-l-carboxamido)phenylamino)pyrimidine-5- carboxamide
Figure imgf000151_0002
[0411] The title compound was synthesized similar to Example 121. MS found for C23H24ClN7O2 as (M+H)+ 466.5. UV: λ = 202, 249 nm. 1H NMR: (CD3OD) δ 8.40 (s, IH), 7.94 (s, IH), 7.30 (s, IH), 7.22 (m, 3H), 7.08 (m, 2H), 6.98 (dd, IH), 4.72 (s, 2H), 3.30 (m, 4H), 1.82 (m, 4H). Example 181 (
4-(2-fluorobenzylamino)-2-(3-(3-methylureido)phenylamino)pyrimidine-5-carboxamide
Figure imgf000152_0001
[0412] The title compound was synthesized similar to Example 121. MS found for C20H20FN7O2 as (M+H)+ 394.5. UV: λ = 205, 249 8.42 (s, IH), 7.97 (s, IH), 7.22 (m, 4H), 7.03 (m, 4H), nm. 1H NMR: (CD3OD) δ 8.42 (s, IH), 7.97 (s, IH), 7.22 (m, 4H), 7.03 (m, 4H), 4.76 (s, 2H).
Example 182 (
N-(5-(4-(benzylamino)-5-carbamoylpyrimidin-2-ylamino)-2-chlorophenyl)morpholine-4- carboxamide.
Figure imgf000152_0002
[0413] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C23H24ClN7O3 as (M+H)+ 482.4. UV: λ = 250 nm. 1H NMR: (D-DMSO) δ 8.5 (s, IH), 7.3 (m, 8H), 4.7 (d, 2H), 3.5 (d, 4H), 3.4 (d, 4H).
Example 183 (
(R)-N-(5-(5-carbamoyl-4-(l-phenylethylamino)pyrimidin-2-ylamino)-2- chlorophenyl)morpholine-4-carboxamide.
Figure imgf000153_0001
[0414] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C24H26ClN7O3 as (M+H)+ 496.5. UV: λ = 250 nm. 1H NMR: (D-DMSO) 6 8.5 (s, IH), 7.3 (m, 5H), 7.2 (dd, 2H), 5.4 (t, IH), 3.5 (t, 4H), 3.4 (t, 4H), 1.5 (d, 3H).
Example 184 (
Preparation of 2-(3-acetamidophenylamino)-4-( 1 -methyl- lH-indol-4-ylamino)pyrimidine-5- carboxamide
Scheme 11
Figure imgf000153_0002
[0415] Step 1: To a solution of ethyl 2,4-dichloropyrimidine-5-carboxylate (328 mg, 1.48 mmol) and 1 -methyl- lH-indol-4-amine (260 mg, 1.78 mmol) in CH3CN (6 mL) at room temperature, DIEA (0.4 mL, 2.22 mmol) was added. The mixture was stirred at room temperature for 24 h. Water (15 mL) was added to induce precipitation. The precipitate was collected, dried on vacuum to give ethyl 2-chloro-4-(l -methyl- lH-indol-4-ylamino) pyrimidine-5-carboxylate as a solid.
[0416] Step 2: To a solution of ethyl 2-chloro-4-(l -methyl- lH-indol-4-ylamino) pyrimidine-5-carboxylate (crude from step 1) in TΗF (4 mL), aq. IN LiOH (2.25 mL, 2.25 mmol) was added. The mixture was stirred at room temperature overnight. Upon acidification of the mixture with IN HCl, white solids precipitated out, which were collected, and dried on vacuum to give 2-chloro-4-(l -methyl- lH-indol-4-ylamino) pyrimidine- 5-carboxylic acid (325 mg). MS 303.3, 305.3 (M+Η, Cl pattern)
[0417] Step 3: To a solution of 2-chloro-4-(l -methyl- lH-indol-4-ylamino)pyrimidine-5- carboxylic acid (325 mg, 1.08 mmol) and HOBtH2O (198 mg, 1.29 mmol) in DMF (4 mL), EDC (248 mg, 1.29 mmol) was added. The mixture was stirred at room temperature for 1.5 h. Ammonia (0.5 M in dioxane, 8.00 mL, and 4.00 mmol) was added. It was stirred at room temperature overnight. Water and EtOAc were added. The organic phase was separated, washed with 1 N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give 2-( lH-benzo[<i][7,2, Jjtriazol- 1 -yloxy)-4-( 1 -methyl- lH-indol-4-ylamino)pyrimidine-5- carboxamide (378 mg). MS 401.4 (M+Η)
[0418] Step 4: To a solution of 2-(lH-benzo[(fI[7,2,5]triazol-l-yloxy)-4-(l-methyl-lH- indol-4-ylamino)pyrimidine-5-carboxamide (60 mg, 0.15 mmol) in NMP (0.6 mL) was added 3-acetamidoaniline (25 mg, 0.165 mmol) and pTsOΗΗ2O (28 mg, 0.15 mmol). The mixture was heated at 100 °C for 2 h, cooled to room temperature, purified by preparative HPLC to give 2-(3-acetamidophenylamino)-4-(l -methyl- lH-indol-4-ylamino)pyrimidine-5- carboxamide (20 mg). MS found for C22Η2,N7O2 as (M+H)+416.3. λ = 211.3, 250.9.
Example 185 (
Preparation of 2-(3-acetamidophenylamino)-4-(l -ethyl- lH-indol-4-ylamino)pyrimidine-5- carboxamide
Figure imgf000154_0001
[0419] The title compound was prepared using the same synthetic scheme demonstrated in Example 184 with 1 -ethyl- lH-indol-4-ylamine to replace 1 -methyl- lH-indol-4-ylamine. MS found for C23H23N7O2 as (M+H)+ 430.3. λ = 215.7, 249.9.
Example 186 ( Preparation of 2-(3-acetamidophenylamino)-4-(2-methyl-2H-indazol-4-ylamino)pyrimidine- 5-carboxamide
Figure imgf000155_0001
[0420] The title compound was prepared using the same synthetic scheme demonstrated in Example 184 with 2-methyl-2H-indazol-4-ylamine to replace 1 -methyl- lH-indol-4-ylamine. MS found for C21H20N8O2 as (M+H)+417.3. λ = 208.6, 251.1.
Example 187 (
2-(3-acetamidophenylamino)-4-(pyridin-2-ylmethylamino)pyrimidine-5-carboxamide
Figure imgf000155_0002
[0421] The title compound was synthesized similar to Example 184, using the 4-sulfoxide intermediate. MS found for C9H19N7O2 as (M+H)+ 378.4. UV: λ = 204, 250 nm. 1H NMR: (CD3OD) δ 8.32 (d, IH), 8.22 (s, IH), 8.03 (s, IH), 7.94 (t, IH), 7.50 (d, IH), 7.43 (m ,1H), 7.24 (t, IH), 7.13 (d, IH), 7.04 (d, IH), 4.95 (s, 2H), 2.16 (s, 3H).
Example 188 (
2-(3-acetamidophenylamino)-4-(pyridin-3-ylmethylamino)pyrimidine-5-carboxamide.
Figure imgf000156_0001
[0422] The title compound was synthesized similar to Example 184 using the A- methylsulfoxide intermediate. MS found for Ci9Hi9N7O2 as (M+H)+ 378.4. UV: λ = 204, 252 nm. 1H NMR: (CD3OD) δ 8.59 (s, IH), 8.55 (d, IH), 3.39 (s, IH), 8.23 (d, IH), 8.08 (s, IH), 7.64 (dd, IH), 7.28 (t, IH), 7.12 (d, IH), 7.08 (d, IH), 4.83 (s, 2H), 2.11 (s, 3H).
Example 189 (
2-(3-acetamidophenylamino)-4-(pyridin-4-ylmethylamino)pyrimidine-5-carboxamide
Figure imgf000156_0002
[0423] The title compound was synthesized similar to Example 184 using the A- methylsulfoxide intermediate. MS found for C9HI9N7O2 as (M+H)+ 378.4. 1H NMR:
(CD3OD) δ 8.57 (d, 2H), 8.43 (s, IH), 7.98 (s, IH), 7.72 (d, 2H), 7.20 (t, IH), 7.07 (d, IH), 7.02 (d, IH), 4.98 (s, 2H), 2.13 (s, 3H).
Example 190 2-(3-acetamidophenylamino)-4-(piperidin-4-ylmethylamino)pyrimidine-5-carboxamide
Figure imgf000156_0003
Scheme 12
Figure imgf000157_0001
Figure imgf000157_0002
HN . .
NH O
O [f ^i N "^ NH2
H H
[0424] The mixture of ethyl 2,4-dichloropyrimidine-5-carboxylate (442 mg, 2.00 mmol), 1- Boc-4-aminomethylpiperidine hydrochloride (502 mg, 2.00 mmol) and DEEA (1.00 mL, 5.75 mmol) in CH3CN (12 mL) was stirred at room temperature for 3 h. Water and EtOAc were added. The organic phase was separated, washed with IN HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give ethyl 4-((l-(tert-butoxycarbonyl)piperidin-4- yl)methylamino)-2-chloropyrimidine-5-carboxylate (797 mg).
[0425] To a solution of ethyl 4-((l-(tert-butoxycarbonyl)piperidin-4-yl)methylamino)-2- chloropyrimidine-5-carboxylate (797 mg, 2.00 mmol) in THF (10 mL), aq. IN NaOH (10 mL, 10.0 mmol) was added. The mixture was stirred at room temperature for 18 h. It was acidified to pH 1-2 with 6N HCl. Water and EtOAc were added. The organic phase was separated, washed with brine, dried over Na2SO4, concentrated in vacuo to give 4-((l-(tert- butoxycarbonyl)piperidin-4-yl)methylamino)-2-chloropyrimidine-5-carboxylic acid (720 mg). [0426] To a solution of 4-((l-(tert-butox ycarbonyl)piperidin-4-yl)methylamino)-2- chloropyrimidine-5-carboxylic acid (720 mg, 1.94 mmol) and HOBt monohydrate (386 mg, 2.52 mmol) in DMF (10 mL), EDC (484 mg, 2.52 mmol) was added. After 1 h of stirring, cone. NH4OH (0.600 mL, ca. 8.40 mmol) was added. The mixture was stirred at room temperature for 18 h. Water and EtOAc were added. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give tert-butyl 4-((2- ((I H-benzo [d] [ 1 ,2,3] triazol- 1 -yloxy)-5-carbamoylpyrimidin-4-ylamino) methyl )piperidine- 1 - carboxylate (722 mg). [0427] A mixture of tert-butyl 4-((2-(QH-benzo[d][l,2,3]triazol-l-yloxy)-5- carbamoyIpyrimidin-4-ylamino)methyl)piperidine-l-carboxylate (107 mg, 0.228 mmol), 3'- amino-acetanilide (41 mg, 0.273 mmol) and pTsOH (50 mg, 0.263 mmol) in dioxane (2 mL) was stirred at 100 C for 5 h. After standing at room temperature overnight, white solids precipitated out, which were collected to give tert-butyl 4-((2-(3-acetamidophenylamino)-5- carbamoylpyrimidin-4-ylamino)methyl)piperidine- 1 -carboxylate ( 100 mg).
[0428] A solution of tert-butyl 4-((2-(3-acetamidophenylamino)-5-carbamoylpyrimidin-4- ylamino)methyl)piperidine-l -carboxylate (100 mg, 0.207 mmol) in TFA (3 mL) was stirred at room temperature for 30 min. TFA was removed in vacuo. The residue was purified by HPLC to give the titled compound (47 mg). MS 384.4 (M+H); UV 200.0, 248.6 nm.
Example 191 (
Preparation of 2-(3-acetamidophenylamino)-4-( 1 -methyl- lH-indazol-4-ylamino)pyrimidine- 5-carboxamide
Figure imgf000158_0001
[0429] The title compound was prepared using the same synthetic scheme demonstrated in Example 184 with l-methyl-lH-indazol-4-ylamine to replace 1 -methyl- lH-indol-4-ylamine. MS found for C2iΗ20N8O2 as (M+H)+417.3. λ = 211.9, 251.5.
Example 192
Preparation of 2-(3-acetamidophenylamino)-4-(benzo[c] [i,2,5]thiadiazo-4- ylamino)pyrimidine-5-carboxamide
Figure imgf000158_0002
[0430] The title compound was prepared using the same synthetic scheme demonstrated in Example 184 with benzo[c][7,2,5/thiadiazo-4-amine to replace 1 -methyl- lH-indol-4- ylamine. MS found for Ci9Hi6N8O2S as (M+H)+ 421.2. λ = 243.0, 282.8, 301.9.
Example 193
(R)-2-(4-chloro-3-ureidophenylamino)-4-( 1 -phenylethylamino) pyrimidine-5-carboxamide.
Figure imgf000159_0001
[0431] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C20H20ClN7O2 as (M+H)+412.3. UV: λ = 208, 247 ran. 1H NMR: (D- DMSO) δ 8.5 (s, IH), 7.3 (m, 5H), 7.1 (d,lH), 6.4 (bs, 2H), 5.4 (t, IH), 1.5 (t, 3H).
Example 194
4-(benzylamino)-2-(4-chloro-3-ureidophenylamino)pyrimidine-5-carboxamide.
Figure imgf000159_0002
[0432] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C19Hi8ClN7O2 as (M+H)+412.3. UV: λ = 207, 244 nm. 1H NMR: (D- DMSO) δ 8.5 (s, IH), 7.3 (m, 4H), 7.2 (t, 2H), 7.1 (d, IH), 4.7 (d, 2H).
Example 195
(R)-2-(4-chloro-3-(3,3-dimethylureido)phenylamino)-4-( 1 -phenylethylamino) pyrimidine-5- carboxamide.
Figure imgf000160_0001
[0433] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C22H24ClN7O2 as (M+H)+ 454.4. UV: λ = 208, 248 nm. 1H NMR: (D- DMSO) δ 8.5 (s, 1H(, 8.1 (s, IH), 7.8 (s, IH), 7.3 (m, 5H), 7.2 (t, 2H), 5.4 (t, IH), 2.9 (s, 6H), 1.5 (d, 3H).
Example 196
4-(benzylamino)-2-(4-chloro-3-(3,3-dimethylureido)phenylamino) pyrimidine-5- carboxamide.
Figure imgf000160_0002
[0434] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C2iH22ClN7O2 as (M+H)+ 440.4. UV: λ = 204, 249 nm. 1H NMR: (D- DMSO) δ 8.5 (s, IH), 7.8 (s, IH), 7.2-7.3 (m, 7H), 4.7 (d, 2H), 2.9 (s, 6H).
Example 200
4-(benzylamino)-2-(2-fluoro-5-(3-methylureido)phenylamino)pyrimidine-5-carboxamide.
Figure imgf000160_0003
[0435] The title compound was synthesized similar to Example 121. MS found for C20H20FN7O2 as (M+H)+410.4. UV: λ = 239 nm. 1H NMR: (CD3OD) δ 8.18 (s, IH), 8.03 (broad s, IH), 7.18 (m, 6H), 7.09 (m, IH), 7.00 (m, IH), 7.62 (s, 2H), 2.61 (s, 3H). Example 201
4-(benzylamino)-2-(5-(3,3-dimethylureido)-2-fluorophenylamino)pyrimidine-5-carboxamide.
Figure imgf000161_0001
[0436] The title compound was synthesized similar to Example 121. MS found for
C21H22FN7O2 as (M+H)+ 424.4. UV: λ = 210, 244 nm. 1H NMR: (CD3OD) δ 8.39 (s, IH), 8.03 (s, IH). 7.03 - 7.22 (m, 7H), 4.63 (s, 2H), 2.84 (s, 6H).
Example 202
(R)-4-(benzylamino)-2-(3-(tetrahydrofuran-2-carboxamido)phenylamino)pyrimidine-5- carboxamide.
Figure imgf000161_0002
[0437] The title compound was synthesized similar to Example 121. MS found for C23H24N6O3 as (M+H)+ 433.4. UV: λ = 202, 246 nm. 1H NMR: (CD3OD) δ 9.51 (s, IH), 8.40 (s, IH), 8.13 (s, IH), 7.13 - 7.22 (m, 8H), 4.71 (s, IH), 4.31 (dd, IH), 3.92 (dd, IH), 3.78 (dd, IH), 2.14 (m, IH), 1.90 (m, IH), 1.79 (m, 2H). Example 203
4-(benzylamino)-2-(3-(tetrahydrofuran-3-carboxamido)phenylamino)pyrimidine-5- carboxamide.
Figure imgf000162_0001
[0438] The title compound was synthesized similar to Example 121. MS found for
C23H24N6O3 as (M+H)+ 433.4. UV: λ = 205, 251 nm. 1H NMR: (CD3OD) δ 9.90 (s, IH), 8.40 (s, IH), 8.13 (s, IH), 7.23 (d,4H), 7.18 (m, 4H), 7.08 (d, IH), 4.71 (s, 2H), 3.87 (s, IH), 3.67 (m, 3H), 3.08 (m, IH), 2.01 (ddd, IH).
Example 204
4-(benzylamino)-2-(2-fluoro-5-(pyrrolidine-l-carboxamido)phenylamino)pyrimidine-5- carboxamide.
Figure imgf000162_0002
[0439] The title compound was synthesized similar to Example 121. MS found for
C23H24FN7O2 as (M+H)+ 450.5. UV: λ = 239 nm. 1H NMR: (CD3OD) δ 8.40 (s, IHO, 8.08 (s, IH), 7.18 (m, 6H), 7.09 (t, IH), 4.62 (s, 2H), 3.30 (m, 4H), 1.80 (m, 4H).
Example 205
(R)-2-(4-chloro-3-(piperidine-l-carboxamido)phenylamino)-4-(l- phenylethylamino)pyrimidine-5-carboxamide.
Figure imgf000163_0001
[0440] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C25H28ClN7O2 as (M+H)+ 494.5. UV: λ = 249 nm. 1H NMR: (D-DMSO) δ 8.5 (s, IH), 8.1 (s, IH), 7.1-7.5 (m, 7H), 5.4 (t, IH), 3.4 (t, 4H), 1.6 (d, 2H), 1.5 (m, 9H).
Example 206
(S)-4-(benzylamino)-2-(3-(tetrahydrofuran-2-carboxamido) phenylamino)pyrimidine-5- carboxamide.
Figure imgf000163_0002
[0441] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C23H24N6O3 as (M+H)+ 433.4. UV: λ = 249 nm. 1H NMR: (D-DMSO) δ 8.5 (s, IH), 8.2 (s, IH), 7.3 (dd, 4H), 7.05-7.15 (m, 4H), 4.7 (d, 2H), 4.35 (t, IH), 2.15 (m, 2H), 1.9 (m, 2H), 1.8 (m, 2H).
Example 207
4-((R)-l-phenylethylamino)-2-(3-((S)-tetrahydrofuran-2-carboxamido) phenylamino)pyrimidine-5-carboxamide.
Figure imgf000163_0003
[0442] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C24H26N6O3 as (M+H)+ 447.5. UV: λ = 249 nm. 1H NMR: (D-DMSO) δ 8.5 (s, IHO, 8.2 (s, IH), 7.3 (dd, 4H), 7.2 (m, 4H), 5.4 (t, IH), 4.4 (t, IH), 2.2, (m, 2H), 1.8 (m, 2H), 1.8 (m, 2H), 1.5 (d, 3H).
Example 208
(S)-4-(3-fluorobenzylamino)-2-(3-(tetrahydrofuran-2-carboxamido) phenylamino)pyrimidine-5-carboxamide.
Figure imgf000164_0001
[0443] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C23H23FN6O3 as (M+H)+ 451.4. UV: λ = 207, 240 nm. 1H NMR: (D- DMSO) δ 8.5 (s, IH), 7.0-7.2 (m, 8H), 4.7 (d, 2H), 4.5 (t, IH), 3.9 (d, IH), 3.8 (d, IH), 2.1 (m, IH), 1.9 (m, IH), 1.8 (d, 2H).
Example 209
4-(benzylamino)-2-(4-chloro-3-(piperidine-l-carboxamido) phenylamino) pyrimidine-5- carboxamide.
Figure imgf000164_0002
[0444] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C24H26ClN7O2 as (M+H)+ 480.5. UV: λ = 207, 249 nm. 1H NMR: (D- DMSO) δ 8.5 (s, IH), 8.0 (s, 2H), 7.2-7.3 (m, 7H), 4.7 (d, 2H), 3.4 (t, 4H), 1.5 (d, 2H), 1.4 (d, 4H). Example 210
(R)-4-(benzylamino)-2-(3-(3-(dimethylamino)pyrrolidine-l- carboxamido)phenylamino)pyrimidine-5-carboxamide
Figure imgf000165_0001
[0445] The title compound was synthesized similar to Example 121. MS found for C25H30N8O2 as (M+H)+ 475.6. UV: λ = 205, 246 nm. 1H NMR: (CD3OD) δ 8.43 (s, IH), 7.92 (s, IH), 7.50 (d, IH), 7.27 (d, 3H), 7.20 (m, IH), 7.12 (m, 2H), 7.04 (m, IH), 4.71 (s, 2H), 3.77 (m, 2H), 3.59 (m, IH), 3.45 (m, IH), 3.38 (m, IH), 3.31 (m, IH), 2.79, s, 6H), 2.31 (m, IH), 2.08 (m, IH).
Example 212
(R)-4-(benzylamino)-2-(3-(3-hydroxypiperidine-l-carboxamido)phenylamino)pyrimidine-5- carboxamide.
Figure imgf000165_0002
[0446] The title compound was synthesized similar to Example 121. MS found for C24H27N7O3 as (M+H)+ 462.5. UV: λ = 249 nm. Example 213
6-(3-acetamidophenylamino)-4-(benzylamino)nicotinamide
Figure imgf000166_0001
[0447] The title compound was synthesized similar Scheme 11 for Example 184, however the final step was accomplished thermally without the use of palladium catalysis. MS found for C21H21N5O2 as (M+H)+ 376.4. UV: λ = 207, 254 nm. 1K NMR: (CD3OD) δ 8.20 (s, IH), 7.78 (s, IH), 7.33 (m, 7H), 6.84 (d, IH), 6.03 (s, IH), 4.52 (s, 2H), 2.17 (s, 3H).
Example 215
Figure imgf000166_0002
[0448] The title compound was synthesized similar to Example 121. MS found for C25H29N7O3 as (M+H)+ 476.6.
Example 216
4-(benzylamino)-2-(3-(4-methylpiperazine- 1 -carboxamido) phenylamino) pyrimidine-5- carboxamide.
Figure imgf000166_0003
[0449] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C24H28N8O2 as (M+H)+ 460.4. UV: λ = 212, 246 nm. 1H NMR: (D- DMSO) δ 8.7 (s, IH), 8.7 (s, IH), 7.9 (s, IH), 7.3 (d, 4H), 7.2 (dd, 3H), 7.1 (t, IH), 7.0 (d, IH), 4.7 (d, 2H), 4.2 (d, 2H), 3.1 (t, 3H), 2.9 (t, 2H), 2.8 (s, 3H).
Example 217
N-(3-(4-(benzylamino)-5-carbamoylpyrimidin-2-ylamino) phenyl)morpholine-4- carboxamide.
Figure imgf000167_0001
[0450] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C23H25N7O3 as (M+H)+ 448.5. UV: λ = 211, 245 nm. 1H NMR: (D-
DMSO) δ 10 (bs, IH), 8.6 (s, IH), 8.5 (s, IH), 7.0 (bs, IH), 7.9 (s, IH), 7.4 (bs, IH), 7.3 (d, 4H), 7.2 (d, IH), 7.1 d, 2H), 7.0 (d, IH), 4.7 (d, 2H), 3.5 (t, 4H), 3.4 (t, 4H).
Example 218
4-(benzylamino)-2-(3-(piperidine- 1 -carboxamido) phenylamino)pyrimidine-5-carboxamide.
Figure imgf000167_0002
[0451] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C24H27N7O2 as (M+H)+ 446.5. UV: λ = 249 nm. 1H NMR: (D-DMSO) δ 8.5 (d, 2H), 8.0 (bs, IH), 7.9 (s, IH), 7.5 (bs, IH), 7.3 (d, 4H), 7.25 (dd, IH), 7.0-7.1 (m, 3H), 4.7 (d, 2H), 3.4 (t, 4H), 1.5 (d, 2H), 1.4 (d, 4H).
Example 219
2-(3-(azetidine-l-carboxamido)phenylamino)-4-(benzylamino) pyrimidine-5-carboxamide.
Figure imgf000168_0001
[0452] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C24H26FN7O2 as (M+H)+ 464.5. UV: λ = 249 nm. 1H NMR: (D-DMSO) δ 8.5 (s, IH), 8.45 (s, IH), 8.0 (s, IH), 7.3 (t, IH), 7.1 (m, 6H), 4.7 (d, 2H), 3.4 (t, 4H), 1.5 (d, 2H), 1.4 (d, 4H).
Example 220
(R)-4-( 1 -phenylethylamino)-2-(3-(piperidine- 1 -carboxamido) phenylamino)pyrimidine-5- carboxamide.
Figure imgf000168_0002
[0453] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C25H29N7O2 as (M+H)+ 460. UV: λ = 249 nm. 1H NMR: (D-DMSO) δ 8.5 (d, 2H), 8.0 (s, IH), 7.3 (m, 4H), 7.2 (d, IH), 7.1 (d, IH), 7.05 (d, IH), 6.95 (s, IH), 5.4 (t, lH),1.5 (d, 2H), 1.4 (dd, 7H).
Example 221
(R)-2-(4-chloro-3 -(pyrrolidine- 1 -carboxamido)phenylamino)-4-( 1 -phenylethylamino) pyrimidine-5-carboxamide.
Figure imgf000168_0003
[0454] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C24H26ClN7O2 as (M+H)+ 480.5. UV: λ = 205, 249 nm. 1H NMR: (D- DMSO) δ 8.5 (s, IH), 8.2 (s, IH), 7.4 (s, IH), 7.3 (m 5H), 7.2 (d, IH), 5.4 (t, IH), 3.3 (t, 4H), 1.9 (s, 4H), 1.4 (d, 3H).
Example 222
2-(3-(azetidine- 1 -carboxamido)phenylamino)-4-(benzylamino) pyrimidine-5-carboxamide.
Figure imgf000169_0001
[0455] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C22H23N7O2 as (M+H)+ 418.5. UV: λ = 249 nm. 1H NMR: (D-DMSO) δ 8.5 (s, IH), 8.3 (s, IH), 7.9 (s, IH), 7.3 (d,4H), 7.2 (t, IH), 7.1 (d, IH), 7.05 (t, IH), 4.7 (d, 2H), 3.9 (t, 4H), 2.2 (dd, 2H).
Example 223
Preparation of 2-(3-acetamido-4-(2-(pyrrolidin- l-yl)ethoxy)phenylamino)-4-(3- fluorobenzylamino)pyrimidine-5-carboxamide
Scheme 13
Figure imgf000169_0002
[0456] Step 1: To a solution of N-(2-hydroxy-5-nitrophenyl)acetamide (870 mg, 4.44 mmol) in DMF (5 rnL) was added NaH (196 mg, 5.32 mmol) and K2CO3 (2.11 g, 13.32 mmol), followed by l-(2-chloroethyl)pyrrolidine hydrochloride (905 mg, 5.32 mmol). After heating at 100 0C for 20 h, the solution was poured to ice, and was extracted with EtOAc, organic layer was washed with Sat. NaHCO3, brine, dried and concentrated to give N-(5- nitro-2-(2-(pyrrolidin-l-yl)ethoxy)phenyl)acetamide (430 mg).
[0457] Step 2: To a solution of N-(5-nitro-2-(2-(pyrrolidin-l-yl)ethoxy)phenyl)acetamide (430 mg) in EtOH (10 niL) was added Pd/C (200 mg) and was charged with H2 (1 atm). After stirring for 3 h, Pd/C was removed by filtration and the filtrate was concentrated to give N-(5- amino-2-(2-(pyrrolidin-l-yl)ethoxy)phenyl)acetamide (380 mg).
[0458] Step 3: To a solution of 2-(lH-benzo[d][i,2,3]triazol-l-yloxy)-4-(3- fluorobenzylamino)pyrimidine-5-carboxamide (57 mg, 0.15 mmol) in NMP (0.6 mL) was added N-(5-amino-2-(2-(pyrrolidin-l-yl)ethoxy)phenyl)acetamide (47 mg, 0.18 mmol) and pTsOΗΗ2O (28 mg, 0.15 mmol). The mixture was heated at 100 0C for 2 h, cooled to room temperature, and purified by preparative HPLC to give 2-(3-acetamido-4-(2-(pyrrolidin-l- yl)ethoxy)phenylamino)-4-(3-fluorobenzylamino)pyrimidine-5-carboxamide (46 mg). MS found for C26H30FN7O3 as (M+H)+ 508.5. λ 248.5.
Example 224
Preparation of 2-(3-acetamido-4-(2-(pyrrolidin- 1 -yl)ethoxy)phenylamino)-4-(2-methyl-2H- indazol-4-ylamino)pyrimidine-5-carboxamide
Figure imgf000170_0001
[0459] The title compound was prepared using the same synthetic scheme demonstrated in Example 223. MS found for C27H31N9O3 as (M+H)+ 530.5. λ = 250.9, 286.5.
Example 225 tert-butyl 3-((2-(3-acetamidophenylamino)-5-carbamoylpyrimidin-4- ylamino)methyl)pyrrolidine- 1 -carboxylate
Figure imgf000171_0001
Scheme 14
Figure imgf000171_0002
Figure imgf000171_0003
[0460] The mixture of ethyl 2,4-dichloropyrimidine-5-carboxylate (332 mg, 1.50 mmol), 1- Boc-3-aminomethylpyrrolidine (300 mg, 1.50 mmol) and DIEA (0.650 mL, 3.73 mmol) in CH3CN (6 mL) was stirred at room temperature for 18 h. Water and EtOAc were added. The organic phase was separated, washed with IN HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give ethyl 4-((l-(tert-butoxycarbonyl)pyrrolidin-3- yl)methylamino)-2-chloropyrimidine-5-carboxylate (544 mg).
[0461] To a solution of ethyl 4-((l-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylamino)-2- chloropyrimidine-5-carboxylate (544 mg, 1.41 mmol) in THF (8 mL), aq. IN NaOH (8 mL, 8.0 mmol) was added. The mixture was stirred at room temperature for 18 h. It was acidified to pH 1-2 with 6N HCl. Water and EtOAc were added. The organic phase was separated, washed with brine, dried over Na2SO4, concentrated in vacuo to give 4-((l-(tert- butoxycarbonyl)pyrrolidin-3-yl)methylamino)-2-chloropyrimidine-5-carboxylic acid (503 mg).
[0462] To a solution of 4-((l-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylamino)-2- chloropyrimidine-5-carboxylic acid (503 mg, 1.41 mmol) and HOBt monohydrate (280 mg, 1.83 mmol) in DMF (8 mL), EDC (352 mg, 1.83 mmol) was added. After 1 h of stirring, cone. NH4OH (0.400 mL, ca. 5.60 mmol) was added. The mixture was stirred at room temperature for 18 h. Water and EtOAc were added. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give tert-butyl 3-((2- ( 1 H-benzo[d] [ 1 ,2,3]triazol- 1 -yloxy)-5-carbamoylpyrimidin-4-ylamino)methyl)pyrrolidine- 1 - carboxylate (472 mg).
[0463] A mixture of tert-butyl 3-((2-(lH-benzo[d][l,2,3]triazol-l-yloxy)-5- carbamoylpyrimidin-4-ylamino)methyl)pyrrolidine-l -carboxylate (118 mg, 0.260 mmol), 3'- amino-acetanilide (47 mg, 0.31 mmol) and pTsOH (57 mg, 0.30 mmol) in dioxane (2 mL) was stirred at 100 C for 18 h, during which time white solids precipitated out, which were collected and purified by HPLC to give the titled compound (69 mg). MS 470.6 (M+H); UV 202.2, 248.6 nm.
Example 226
2-(3-acetamidophenylamino)-4-(pyrrolidin-3-ylmethylamino)pyrimidine-5-carboxylic acid
Figure imgf000172_0001
Scheme 15
Figure imgf000172_0002
[0464] A solution of tert-butyl 3-((2-(3-acetamidophenylamino)-5-carbamoylpyrimidin-4- ylamino)methyl)pyrrolidine- 1 -carboxylate (65 mg, 0.138 mmol) in TFA (1 mL) and CH2Cl2 (1 mL) was stirred at room temperature for 2 h. TFA and CH2Cl2 were removed in vacuo. The residue was purified by HPLC to give the titled compound (25 mg). MS 370.3 (M+H); UV 206.4, 244.2 nm.
Example 227
Preparation of 2-(3-acetamido-4-(2-(pyrrolidin- 1 -yl)ethoxy)phenylamino)-4- (benzo[c][i,2,5]thiadiazo-4-ylamino)pyrimidine-5-carboxamide
Figure imgf000173_0001
[0465] The title compound was prepared using the same synthetic scheme demonstrated in Example 223. MS found for C25H27N9O3S as (M+H)+ 534.3. λ = 203.4, 238.1, 289.0.
Example 228
Preparation of 2-(3-acetamido-4-(2-(dimethylamino)ethoxy)phenylamino)-4-(3- fluorobenylamino)pyrimidine-5-carboxamide
Figure imgf000173_0002
[0466] The title compound was prepared using the same synthetic scheme demonstrated in Example 223. MS found for C24H28FN7O3 as (M+H)+ 482.4. λ = 208.2, 248.5.
Example 229
Preparation of 2-(3-acetamido-4-(2-(dimethylamino)ethoxy)phenylamino)-4-(2-methyl-2H- indazol-4-ylamino)pyrimidine-5-carboxamide
Figure imgf000173_0003
[0467] The title compound was prepared using the same synthetic scheme demonstrated in Example 223. MS found for C25H29N9O3 as (M+H)+ 504.4. λ = 250.9, 285.9.
Example 230
Preparation of 2-(3-acetamido-4-(2-(dimethylamino)ethoxy)phenylamino)-4- (benzo[c][i,2,5]thiadiazo-4-ylamino)pyrimidine-5-carboxamide
Figure imgf000174_0001
[0468] The title compound was prepared using the same synthetic scheme demonstrated in Example 223. MS found for C23H25N9O3S as (M+H)+ 508.4. λ = 241.1, 300.7.
Example 231
Preparation of 2-(3-acetamido-4-(2-(piperidin- 1 -yl)propoxy)phenylamino)-4-(3- fluorobenzylamino)pyrimidine-5-carboxamide
Figure imgf000174_0002
[0469] The title compound was prepared using the same synthetic scheme demonstrated in Example 223. MS found for C28H34FN7O3 as (M+H)+ 536.4. λ = 209.8, 247.5.
Example 232
Preparation of 2-(3-acetamido-4-(2-(piperidin- 1 -yl)propoxy)phenylamino)-4-(2-methyl-2H- indazol-4-ylamino)pyrimidine-5-carboxamide
Figure imgf000175_0001
[0470] The title compound was prepared using the same synthetic scheme demonstrated in Example 223. MS found for C29H35N9O3 as (M+H)+ 558.6. λ = 247.5, 286.6.
Example 233
2-(3-(azetidine- 1 -carboxamido)-4-chlorophenylamino)-4-(benzylamino) pyrimidine-5- carboxamide.
Figure imgf000175_0002
[0471] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C22H22ClN7O2 as (M+H)+ 452.4. UV: λ = 207, 249 nm. 1H NMR: (D- DMSO) δ 8.5 (s, IH), 8.2 (s, IH), 7.7m(s, IH), 7.3 (d, 4H), 7.2 (dd, 2H), 4.7 (d, 2H), 3.9 (t, 4H), 2.1 (dd, 2H).
Example 234
2-(3-(azetidine-l-carboxamido)-4-fluorophenylamino)-4-(benzylamino) pyrimidine-5- carboxamide.
Figure imgf000175_0003
[0472] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C22H22FN7O2 as (M+H)+ 436.4. UV: λ = 207, 244 nm. 1H NMR: (D- DMSO) δ 8.5 (s, IH), 8.0 (s, IH), 7.3 (s, 4H), 7.2 (m, 2H), 7.0 (t, IH), 4.7 (d, 2H), 3.9 (t, 4H), 2.1 (t, 2H).
Example 235
2-(3-acetamidophenylamino)-4-(isobutylamino)pyrimidine-5-carboxamide
Figure imgf000176_0001
[0473] The title compound was synthesized similar to Example 121. MS found for CnH22N6O2 as (M+H)+ 343.3. 1H NMR: (CD3OD) δ 8.38 (s, IH), 8.17 *s, IH), 7.38 (m, 2H), 7.20 (d, IH), 3.44 (d, 2H), 2.16 (s, 3H), 1.98 (m, IH), 1.99 (d, 6H).
Example 236
2-(4-chloro-3-(pyrrolidine-l-carboxamido)phenylamino)-4-(isobutylamino)pyrimidine-5- carboxamide
Figure imgf000176_0002
[0474] The title compound was synthesized similar to Example 121. MS found for C20H26ClN7O2 as (M+H)+ 432.5. 1H NMR: (CD3OD) δ
Example 237
(R)-4-(sec-butylamino)-2-(4-chloro-3-(pyrrolidine-l-carboxamido)phenylamino)pyrimidine- 5-carboxamide
Figure imgf000176_0003
[0475] The title compound was synthesized similar to Example 121. MS found for C20H26ClN7O2 as (M+H)+ 434.5. UV: λ = 202, 247 nm.
Example 238
(R)-2-(3-acetamidophenylamino)-4-(sec-butylamino)pyrimidine-5-carboxamide
Figure imgf000177_0001
[0476] The title compound was synthesized similar to Example 121. MS found for C17H22N6O2 as (M+H)+ 343.4 . UV: λ = 202, 248 nm. 1H NMR: (CD3OD) δ 8.43 (s, IH), 8.13 (s, IH), 7.37 (d, 2H), 7.23 (m, IH), 4.28 (q, IH), 2.17 (s, 3H), 1.66 (m, 2H), 1.30 (d, 3H), 0.8 (t, 3H).
Example 239
4-(benzylamino)-2-(4-methoxy-3-(N-methylpyrrolidine-l- carboxamido)phenylamino)pyrimidine-5-carboxamide
Figure imgf000177_0002
[0477] The title compound was synthesized similar to Example 121. MS found for C25H29N7O3 as (M+H)+ 476.5. UV: λ = 205, 251 nm. 1H NMR: (CD3OD) δ
Example 240
4-(3-fluorobenzylamino)-2-(4-methoxy-3-(N-methylpyrrolidine- 1 - carboxamido)phenylamino)pyrimidine-5-carboxamide
Figure imgf000178_0001
[0478] The title compound was synthesized similar to Example 121. MS found for C25H28FN7O3 as (M+H)+ 494.5. UV: λ = 205, 251 nm. 1H NMR: (CD3OD) δ 8.44 8.55 (s, IH), 7.76 (s, IH), 7.43 (m, 3H), 7.24 (d, IH), 7.17 (d, IH), 7.03 (t, IH), 4.80 (s, 2H), 4.67 (s, 3H), 3.08 (s, 3H), 3.02 (m, 4H), 1.73 (m, 4H).
Example 241
4-(benzylamino)-2-(4-chloro-3-(N-methylpyrrolidine- 1 - carboxamido)phenylamino)pyrimidine-5-carboxamide.
Figure imgf000178_0002
[0479] The title compound was synthesized similar to Example 121. MS found for
C24H26ClN7O2 as (M+H)+ 480.5. UV: λ = 204, 256 nm. 1H NMR: (CD3OD) δ 8.52 (s, IH), 7.79 (s, IH), 7.46 (d, 2H), 7.38 (d, 4H), 7.35 (m, IH), 4.80 (s, 2H), 3.07 (s, 3H), 3.02 (m, 4H), 1.71 (m, 4H).
Example 242
2-(4-chloro-3-(N-methylpyrrolidine-l-carboxamido)phenylamino)-4-(3- fluorobenzylamino)pyrimidine-5-carboxamide
Figure imgf000179_0001
[0480] The title compound was synthesized similar to Example 121. MS found for C24H25ClFN7O2 as (M+H)+ 498.5, 500.5. UV: λ = 204, 257 nm.
Example 243
Preparation of 2-(3-acetamido-4-(2-(piperidin- 1 -yl)propoxy)phenylamino)-4-( benzo[c][i,2,5]thiadiazo-4-ylamino)pyrimidine-5-carboxamide
Figure imgf000179_0002
[0481] The title compound was prepared using the same synthetic scheme demonstrated in Example 223. MS found for C27H31N9O3S as (M+H)+ 562.4. λ = 235.7, 289.0, 300.9.
Example 244
Preparation of 2-(3-acetamido-4-(2-(pyrrolidin- l-yl)ethoxy)phenylamino)-4- (benzylamino)pyrimidine-5-carboxamide
Figure imgf000179_0003
[0482] The title compound was prepared using the same synthetic scheme demonstrated in Example 223. MS found for C26H3iN7O3 as (M+H)+ 490.4. λ = 249.9.
Example 245
Preparation of 2-(3-acetamido-4-(2-(piperidin- 1 -yl)propoxy)phenylamino)-4- (benzylamino)pyrimidine-5-carboxamide
Figure imgf000180_0001
[0483] The title compound was prepared using the same synthetic scheme demonstrated in Example 223. MS found for C28H35N7O3 as (M+H)+ 518.4. λ = 248.7, 279.5.
Example 246
Preparation of 2-(3-acetamido-4-(2-(piperidin-l-yl)propoxy)phenylamino)-4-(l-methyl-lH- indazol-4-ylamino)pyrimidine-5-carboxamide
Figure imgf000180_0002
[0484] The title compound was prepared using the same synthetic scheme demonstrated in Example 223. MS found for C29H35N9O3 as (M+H)+ 558.5. λ = 246.3, 287.8.
Example 247
(S)-2-(3-acetamidophenylamino)-4-(3-methylbutan-2-ylamino)pyrimidine-5-carboxamide
Figure imgf000181_0001
[0485] The title compound was synthesized similar to Example 121. MS found for Cj8H24N6O2 as (M+H)+ 357.4. UV: λ = 208, 150 nm. 1H NMR: (CD3OD) δ 8.40 (s, IH), 8.13 (s, IH), 7.35 (m, 2H), 7.19 (d, IH), 4.24 (m, IH), 2.16 (s, 3H), 1.93 (m, IH), 1.23 (d, 3H), 0.97 (t, 3H).
Example 248
(S)-2-(4-chloro-3-(pyrrolidine-l-carboxamido)phenylamino)-4-(3-methylbutan-2- ylamino)pyrimidine-5-carboxamide.
Figure imgf000181_0002
[0486] The title compound was synthesized similar to Example 121. MS found for
C2IH28ClN7O2 as (M+H)+ 446.5, 448.5. UV: λ = 209, 248 nm. 1H NMR: (CD3OD) δ 8.39 (s, IH), 8.28 (s, IH), 7.43 (d, IH), 7.23 (dd, IH), 4.24 (m, IH), 3.52 (m, 4H), 2.12 (m, 4H), 1.91 (m, IH), 1.22 (d, 3H), 0.98 (t, 3H).
Example 249
2-(3-acetamidophenylamino)-4-(2-methylbutylamino)pyrimidine-5-carboxamide.
Figure imgf000181_0003
[0487] The title compound was synthesized similar to Example 121. MS found for Ci8H24N6O2 as (M+H)+ 357.5. UV: λ = 205, 249 nm. 1H NMR: (CD3OD) δ 8.39 (s, IH), 8.14 (s, IH), 7.36 (m, 2H), 7.20 (d, IH), 3.58 (dd, IH), 3.42 (dd, IH), 2.17 (s, 3H), 1.78 (m, IH), 1.46 (m ,1H), 1.23 (m ,1), 0.98 (d, 3H), 0.96 (t, 3H).
Example 250
Figure imgf000182_0001
[0488] The title compound was synthesized similar to Example 121. MS found for
C21H28ClN7O2 as (M+H)+ 446.5, 448.5. UV: λ = 210, 249 nm. 1H NMR: (CD3OD) δ 8.42 (s, IH), 8.29 (s, IH), 7.47 (d, IH), 7.30 (dd, IH), 3.57 (dd, IH), 3.51 (m, 4H), 3.44 (dd, IH), 2.03 (m, 4H), 1.78 (m, IH), 1.49 (m, IH), 1.25 (m ,1H), 1.00 (d, 3H), 0.97 (t, 3H).
Example 251
2-(3-acetamidophenylamino)-4-(isopentylamino)pyrimidine-5-carboxarnide
Figure imgf000182_0002
[0489] The title compound was synthesized similar to Example 121. MS found for Ci8H24N6O2 as (M+H)+ 357.4. UV: λ = 206, 249 nm. 1H NMR: (CD3OD) δ 8.37 (s, IH), 8.20 (s, IH), 7.35 (m, 2H), 7.18 (d, IH), 3.61 (t, 2H), 2.12 (s, 3H), 1.67 (m, IH), 1.55 (q, 2H), 0.94 (d, 6H).
Example 252
(R)-2-(3-acetamidophenylamino)-4-(3-methylbutan-2-ylamino)pyrimidine-5-carboxamide
Figure imgf000182_0003
[0490] The title compound was synthesized similar to Example 121. MS found for Ci8H24N6O2 as (M+H)+ 357.4. UV: λ = 207, 249 nm. 1H NMR: (CD3OD) δ 8.3.7 (s, IH), 8.09 (s, IH), 7.34 (m, 2H), 7.09 (d, IH), 4.22 (m, IH), 2.13 (s, 3H), 1.91 (m, IH), 1.22 (d, 3H), 0.98 (t, 3H).
Example 253
(R)-2-(4-chloro-3-(pyrrolidine-l-carboxamido)phenylamino)-4-(3-methylbutan-2- ylamino)pyrimidine-5-carboxamide
Figure imgf000183_0001
[0491] The title compound was synthesized similar to Example 121. MS found for C2IH28ClN7O2 as (M+H)+ 446.5, 448.5. UV: λ = 212, 251 nm. 1H NMR: (CD3OD) δ 8.39 (s, IH), 8.29 (s, IH), 7.45 (d, IH), 7.24 (dd, IH), 4.28 (m, IH), 3.52 (m, 4H), 2.03 (m ,4H), 1.91 (m, IH), 1.22 (d, 3H), 0.98 (t, 3H)
Example 254
(R)-2-(3-(4-methylpiperazine-l-carboxamido)phenylamino)-4-(l-phenylethylamino) pyrimidine-5-carboxamide.
Figure imgf000183_0002
[0492] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C25H30N8O2 as (M+H)+ 475.4. UV: λ = 249 nm. 1H NMR: (D-DMSO) δ 8.8 (s, IH), 8.5 (s, IH), 7.9 (s, IH), 7.4 (d, IH), 7.3 (d, 4H), 7.2 (d, IH), 7.15 (d, IH), 7.1 (bs, IH), 5.4 (t, IH), 4.2 (d, 2H), 3.2 (t, 4H), 3 (t, 4HO, 2.8 (s, 3H), 1.5 (d, 3H).
Example 255 (R)-N-(3 -(5 -carbamoyl -4-(l-phenylethylamino)pyrimidin-2-ylamino) phenyl)moφholine-4- carboxamide.
Figure imgf000184_0001
[0493] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C24H27N7O3 as (M+H)+ 462.5. UV: λ = 207, 249 nm. 1H NMR: (D- DMSO) 6 8.6 (s, IH), 8.4 (s, IH), 7.9 (s, IH), 7.3 (d, 2H), 7.2 (d, 2H), 7.1 (t, IH), 7.0 (d, IH), 6.9 (d, IH), 5.4 (t, IH), 3.5 (d, 4H), 3.4 (d, 4H), 1.4 (d, 3H).
Example 256
[0494] Preparation of 2-(3-acetamido-4-(2-(pyrrolidin-l-yl)ethoxy)phenylamino)-4-(l- methyl-lH-indazol-4-ylamino)pyrimidine-5-carboxamide
Figure imgf000184_0002
[0495] The title compound was prepared using the same synthetic scheme demonstrated in Example 223. MS found for C27H31N9O3 as (M+H)+ 530.5. λ = 247.5, 287.8.
Example 257
2-(3-(2-cyanoacetamido)phenylamino)-4-(3-fluorobenzylamino)-pyrimidine-5-carboxamide
Figure imgf000184_0003
Scheme 16:
Figure imgf000185_0001
[0496] Step 8: The compound, M-2 (Scheme 16) (114 mg), was diluted with EtOAc (50 niL), 10 % Pd/C (25 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 18 h. The mixture was filtered through celite and the filtrate was concentrated to yield the free aniline, M-3, as a colorless solid, 78 mg (94 %). UV: 253.8 nm. MS: 378.3 (M+H), C19Hi9N7O2.
[0497] Step 9: The aniline, M-3 (Scheme 16) (48 mg, 0.136 mmol), EDCHCl (41 mg, 0.213 mmol), and cyanoacetic acid (15 mg, 0.176 mmol), in THF-NMP (2 mL/1 mL) ) were stirred at room temperature for 14 h. The reaction mixture was then purified by RP-HPLC to afford the title compound pure, 42 mg (73 %). UV: 249.1 nm. MS: 420.5 (M+H), C21Hi8FN7O2. 1H NMR (400 MHz, DMSO-d6): δ 3.82 (s, 2H), 4.67 (d, 2H, J= 5.8 Hz), 6.92- 7.18 (m, 6H), 7.20-7.45 (m, 6H), 7.78-8.20 (m, 2H), 8.46 (s, IH), 9.88 (br s, IH), 10.06 (br s, IH), 10.25 (br s, IH).
Example 258
4-(3-fluorobenzylamino)-2-(3-(4-methylpiperazine-l-carboxamido) phenylamino)pyrimidine-5-carboxamide.
Figure imgf000186_0001
[0498] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C24H27FN8O2 as (M+H)+ 479.5. UV: λ = 207, 249 nm. 1H NMR: (D- DMSO) δ 8.6 (s, IH), 8.4 (s, IH), 7.8 (s, IH), 7.3 (m, IH), 7.0 (m, 6H), 4.7 (d, 2H), 4.1 (d, 2H), 3.4 (d, 2H), 3.0 (m, 4H), 2.6 (s, 3H).
Example 259
N-(3-(5-carbamoyl-4-(3-fluorobenzylamino)pyrirnidin-2-ylamino) phenyl)morpholine-4- carboxamide.
Figure imgf000186_0002
[0499] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C23H24FN7O3 as (M+H)+ 466.5. UV: λ = 249 nm. 1H NMR: (D-DMSO) δ 8.5 (d, 2H), 7.9 (s, IH). 7.3 (t, 2H), 6.9-7.1 (m, 3H), 4.7 (d, 2H), 3.4 (d, 8H), Example 260
2-(3-acetamido-5-chlorophenylamino)-4-(benzylamino)pyrimidine-5-carboxamide
Figure imgf000187_0001
[0500] The title compound was synthesized similar to Example 121. MS found for C20H19ClN6O2 as (M+H)+ 411.6, 413.5. UV: λ = 211, 251 nm. 1H NMR: (CD3OD) δ 8.49 (s, IH), 0.94 (s, IH), 7.38 (m ,6H), 4.83 (s, 2H), 2.13 (s, 3H).
Example 261
2-(3-acetamido-5-chlorophenylamino)-4-(3-fluorobenzylamino)pyrimidine-5-carboxamide
Figure imgf000187_0002
[0501] The title compound was synthesized similar to Example 121. MS found for
C20H18ClFN6O2 as (M+H)+ 429.3, 431.3. UV: λ = 210, 251 nm. 1H NMR: (CD3OD) δ 8.49 (s, IH), 7.93 (s, IH), 7.50 (s, IH), 7.38 (t, IH), 7.30 (s, IH), 7.18 (d, IH), 7.10 (d, IH), 7.02 (dt, IH), 4.84 (s, 2H), 2.13 (s, 3H).
Example 262
2-(3-acetamidophenylamino)-4-(cyclobutylmethylamino)pyrimidine-5-carboxamide
Figure imgf000187_0003
[0502] The title compound was synthesized similar to Example 121. MS found for Ci8H22N6O2 as (M+H)+ 355.4. UV: λ = 204, 249 nm. 1H NMR: (CD3OD) δ 8.38 (s, IH), 8.19 (s, IH), 3.64 (d, 2H), 2.64 (m ,1H), 2.17 (s, 3H), 2.10 (m, 2H), 1.93 (m, 2H), 1.80 (m, 2H).
Example 263
2-(4-chloro-3 -(pyrrolidine- 1 -carboxamido)phenylamino)-4- (cyclobutylmethylamino)pyrimidine-5-carboxamide
Figure imgf000188_0001
[0503] The title compound was synthesized similar to Example 121. MS found for C21H26ClN7O2 as (M+H)+ 444.4, 446.5. UV: λ = 256, 276 nm. 1H NMR: (CD3OD) δ 8.58 (s, IH), 8.49 (s, IH), 8.02 (s, IH), 7.51 (d, IH), 7.34 (d, IH), 3.60 (d, 2H), 3.52 (m, 4H), 2.63 (m, IH), 1.82 - 2.19 (m, 8H), 2.83 (m, 2H).
Example 264
2-(3-acetamidophenylamino)-4-(4-aminophenylamino) pyrimidine-5-carboxamide
Figure imgf000188_0002
Scheme 17:
Figure imgf000189_0001
1.4 M-5 M-6
Figure imgf000189_0002
M-7 M-8
Figure imgf000189_0003
WI-12
[0504] This compound was synthesized using the reactions described in Scheme 17 and following the procedures described for such compounds in scheme 1. UV: 253.8, 201.0 nm. MS: 378.3 (M+H), Ci9H19N7O2. 1H NMR (400 MHz, DMSOd5): δ 2.041 (s, 3H), 7.10-7.60 (m, 8H), 7.75 (m, 2H), 8.12 (br s, IH), 8.68 (s, IH), 9.85 (br s, IH), 9.94 (s, IH), 11.72 (s, IH).
Example 265 Preparation of 4-(benzylamino)-2-(3-(2-(dimethylamino)acetamido)phenylamino)pyrimidine- 5-carboxamide
Figure imgf000190_0001
[0505] The title compound was prepared using the same synthetic scheme demonstrated in Example 184. MS found for C22H25N7O2 as (M+H)+ 420.4. λ = 249.9.
Example 266
Preparation of 2-(3-(2-(dimethylamino)acetamido)phenylamino)-4-( 1 -methyl- lH-indazol-4- ylamino)pyrimidine-5-carboxamide
Figure imgf000190_0002
[0506] The title compound was prepared using the same synthetic scheme demonstrated in Example 184. MS found for C23H25N9O2 as (MH-H)+ 460.4. λ = 250.1.
Examples 145, 153 and 197-199.
The below compounds were prepared using a procedure similar to that described in the above Schemes.
Figure imgf000191_0001
Example 268
Preparation of 2-(3-acetamidophenylamino)-4-( l-phenylcyclopropylamino)pyrimidine-5- carboxamide
Scheme 18
Figure imgf000192_0001
AcOOH
Figure imgf000192_0002
Figure imgf000192_0003
[0507] Step 1 : To benzonitrile (1.03 g, 10 mmol) in ether (50 ml) at -70 0C was added Ti(OiPr)4 (3.22 ml, 11 mmol) and EtMgBr (3M in ether, 7.34 mL, 22 mmol) dropwise, the resulting yellow suspension was warmed up to room temperature over 1 h. After stirring for additional 30 min, the dark brown solution was added BF3 Et2O (2.47 mL, 20 mL) at room temperature. The mixture was further stirred for Ih, and was quenched by IN HCl (30 mL) and 5N NaOH (30 mL), the suspension was extracted with ether, ether layer was combined, concentrated to give crude residue, which was purified by column (Hexanes/EtOAc, 2: 1 to 1:9 ) to give 1-phenylcyclopropanamine (420 mg).
[0508] Step 2: To a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (550 mg, 2.36 mmol) and 1-phenylcyclopropanamine (420 mg, 3.16 mmol) in CH3CN (6 mL) at room temperature was added DIEA (0.5 mL, 2.60 mmol). The mixture was stirred at room temperature for 3 h and 50 0C for 3 h. The mixture was diluted with EtOAc, washed with IN HCl, Sat. NaHCO3, brine, dried and concentrated to give ethyl 2-(methylthio)-4-(l- phenylcyclopropylamino)pyrimidine-5-carboxylate (810 mg). [0509] Step 3: To a solution of ethyl 2-(methylthio)-4-(l- phenylcyclopropylamino)pyrimidine-5-carboxylate (crude from step 2) in THF (4 mL) was added LiOH H2O (150 mg, 3.57 mmol) in H2O (2 mL). The mixture was stirred at room temperature overnight. THF was removed under vacuum and the residue was acidified with IN HCl, white solids precipitated out, which were collected by filtration, dried on vacuum to give 2-(methylthio)-4-(l-phenylcyclopropylamino) pyrimidine- 5-carboxylic acid (646 mg). MS 302.3 (M+H).
[0510] Step 4: To a solution of 2-(methylthio)-4-(l-phenylcyclopropylamino) pyrimidine- 5-carboxylic acid (646 mg, 2.15 mmol) and HOBfH2O (395 mg, 2.58 mmol) in DMF (3.5 mL), EDC (515 mg, 2.69 mmol) was added. The mixture was stirred at room temperature for 20 min. Ammonium hydroxide (244 mg, 4.30 mmol) was added. It was stirred at room temperature for 1 h. Water was added to induce precipitation, the solids were collected by filtration to give 2-(methylthio)-4-(l-phenylcyclopropylamino) pyrimidine- 5-carboxamide (636 mg). MS 301.2 (M+H).
[0511] Step 5: To a suspension of 2-(methylthio)-4-(l-phenylcyclopropylamino) pyrimidine- 5-carboxamide (636 mg) in AcCN (3 mL) was added AcOOH (39% in AcOH, 0.7 mL). The mixture was stirred at room temperature for 20 h, and the solids were collected by filtration and dried in vacuo to give 2-(methylsulfinyl)-4-(l-phenylcyclopropylamino) pyrimidine- 5-carboxamide (530 mg). MS 317.2 (M+H).
[0512] Step 6: To a solution of 2-(methylsulfinyl)-4-(l-phenylcyclopropylamino) pyrimidine- 5-carboxamide (50 mg, 0.16 mmol) in NMP (1 mL) was added 3- acetamidoaniline (27 mg, 0.18 mmol) and pTsOH H2O (30 mg, 0.16 mmol). The mixture was heated at 100 0C for 2 h, cooled to room temperature, and purified by preparative HPLC to give 2-(3-acetamidophenylamino)-4-( 1 -phenylcyclopropylamino)pyrimidine-5-carboxamide (38 mg). MS found for C22H22N6O2 as (M+H)+ 403.5. λ = 251.1.
Example 269
Preparation of 2-(3-(2-(dimethylamino)acetamido)phenylamino)-4-(l- phenylcyclopropylamino)pyrimidine-5-carboxamide
Figure imgf000194_0001
[0513] The title compound was prepared using the same synthetic scheme demonstrated in Example 268. MS found for C24H27N7O2 as (M+H)+ 446.6. λ = 251.1.
Example 270
Preparation of 2-(3-acetamido-4-methylphenylamino)-4-(l- phenylcyclopropylamino)pyrimidine-5-carboxamide
Figure imgf000194_0002
[0514] The title compound was prepared using the same synthetic scheme demonstrated in Example 268. MS found for C23H24N6O2 as (M+H)+ 417.5. λ = 251.1.
Example 273
Preparation of 4-(benylamino)-2-(3-isobutyraminophenylamino)pyrimidine-5-carboxamide
Figure imgf000194_0003
The title compound was prepared using the same synthetic scheme demonstrated in Example 184. MS found for C22H24N6O2 as (M+H)+ 405.5. λ = 248.7.
Example 274 Preparation of 4-(benylamino)-2-(3-pivalaminophenylamino)pyrimidine-5-carboxamide
Figure imgf000195_0001
[0515] The title compound was prepared using the same synthetic scheme demonstrated in Example 184. MS found for C23H26N6O2 as (M+H)+419.6. λ = 247.5.
Example 275
Preparation of (S)-4-(benylamino)-2-(3-(l-methylpyrrolidine-2- carboxamido)phenylamino)pyrimidine-5-carboxamide
Figure imgf000195_0002
[0516] Step 1: To a solution of (S)-I -methylpyrrolidine-2-carboxylic acid (258 mg, 2 mmol) in DMF (4 mL) was added 3-nitroaniline (276 mg, 2 mmol) and HATU (760 mg).
After stirring for 20 h, it was added with EtOAc, washed with Sat. NaHCO3, brine, dried and concentrated to give (S)-l-methyl-N-(3-nitrophenyl)pyrrolidine-2-carboxamide.
[0517] Step 2: To a solution of (S)-I -methyl -N-(3-nitrophenyl)pyrrolidine-2-carboxamide (crude from step 1) in MeOH (5 ml) was added Pd/C (50 mg), charged with H2 (1 atm), after stirring for 3 h, Pd/C was filtered off and the filtrate was concentrated to give (S)-N-Q- aminophenyl)-l-methylpyrrolidine-2-carboxamide (350 mg).
[0518] Step 3: To a solution of 2-(lH-benzo[d][l,2,3]triazol-l-yloxy)-4- (benzylamino)pyrimidine-5-carboxamide (50 mg, 0.14 mmol) in NMP (1 mL) was added (S)- N-(3-aminophenyl)-l-methylpyrrolidine-2-carboxamide (33 mg, 0.152 mmol) and pTsOH H2O (60 mg, 0.28 mmol). The mixture was heated at 100 0C for 2 h, cooled to room temperature, and purified by preparative HPLC to give of (S)-4-(benylamino)-2-(3-(l- methylpyrrolidine-2-carboxamido)phenylamino)pyrimidine-5-carboxamide (48 mg). MS found for C24H27N7O2 as (M+H)+ 446.5. λ = 247.5.
Example 276
Preparation of 2-(3-acetamidophenylamino)-4-((l -methyl- lH-pyrazol-4- yl)methylamino)pyrimidine-5-carboxamide
Figure imgf000196_0001
[0519] Step 1: To a solution of ethyl 2,4-dichloropyrimidine-5-carboxylate (896 mg, 4 mmol) and (1 -methyl- lH-pyrazol-4-yl)methanamine (445 mg, 4 mmol) in CH3CN (6 mL) at room temperature, DIEA (0.783 mL, 4.4 mmol) was added. The mixture was stirred at room temperature for 24 h, and was concentrated to give ethyl 2-chloro-4-((l -methyl- lH-pyrazol- 4-yl)methylamino)pyrimidine-5-carboxylate as crude oil.
[0520] Step 2: To a solution of give ethyl 2-chloro-4-((l -methyl- lH-pyrazol-4- yl)methylamino)pyrimidine-5-carboxylate (crude from step 1) in TΗF (9 mL), aq. IN LiOH (6.6 mL, 6.6 mmol) was added. The mixture was stirred at room temperature overnight. TΗF was removed under vacuum, and the residue was acidified of with IN HCl, the precipitated white solids were collected, and dried on vacuum to give 2-chloro-4-((l-methyl-lH-pyrazol- 4-yl)methylamino) pyrimidine- 5-carboxylic acid (1 g). MS 268.2, 270.2 (M+Η, Cl pattern).
[0521] Step 3: To a solution of 2-chloro-4-((l-methyl-lH-pyrazol-4-yl)methylamino) pyrimidine- 5-carboxylic acid (1 g, 3.74 mmol) and HOBtH2O (858 mg, 5.61 mmol) in DMF (10 mL), EDC (1.08 g, 5.61 mmol) was added. The mixture was stirred at room temperature for 30 min. Ammonia (0.5 M in dioxane, 15 mL, and 7.5 mmol) was added. It was stirred at room temperature overnight. Dioxane was removed under vacuum, the residue was added water to induce precipitation and the resulting solids were isolated by filtration to give 2-(1H- benzo[d] [ 1 ,2,3]triazol- 1 -yloxy)-4-(( 1 -methyl- lH-pyrazol-4-yl)methylamino)pyrimidine-5- carboxamide (1.04 g). MS 366.4 (M+Η).
[0522] Step 4: To a solution of 2-(lH-benzo[d][l,2,3]triazol-l-yloxy)-4-((l -methyl- IH- pyrazol-4-yl)methylamino)pyrimidine-5-carboxamide (51 mg, 0.14 mmol) in NMP (0.8 mL) was added 3-acetamidoaniline (24 mg, 0.16 mmol) and pTsOΗΗ2O (27 mg, 0.14 mmol). The mixture was heated at 100 °C for 2 h, cooled to room temperature, purified by preparative HPLC to give 2-(3-acetamidophenylamino)-4-((l -methyl- lH-pyrazol-4- yl)methylamino)pyrimidine-5-carboxamide (40 mg). MS found for Ci8Η2oN802 as (M+H)+ 381.5. λ = 242.8.
Example 280
2-(3-acetamidophenylamino)-4-(cyclopentylmethylamino)pyrimidine-5-carboxamide.
Figure imgf000197_0001
[0523] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for CJ9H24N6O2 as (M+H)+ 369.3. UV: λ = 202, 249 nm. 1H NMR: (CD3OD) δ 8.38 (s, IH), 8.17 (s, IH), 7.33 (m, 2H), 7.17 (m, IH), 3.54 (d, 2H), 2.61 (m, IH), 2.15 (s, 3H), 1.80 (m, 2H), 1.50 - 1.67 (m, 4H), 1.31 (m, 2H).
Example 281 (4-(cyclopentylmethylamino)-2-(3-(pyrrolidine-l- carboxamido)phenylamino)pyrimidine-5-carboxamide.
Figure imgf000197_0002
[0524] The title compound was synthesized similar to Example 121. MS found for C22H29N7O2 as (M+H)+ 424.3. UV: λ = 207, 246 nm. 1H NMR: (CD3OD) δ 8.42 (s, IH), 8.00 (s, IH), 7.33 (d, IH), 7.23 (t, IH), 7.09 (m, IH), 3.46 (m, 4H), 2.22 (m, IH), 1.96 (m, 5H), 1.78 (m, IH), 1.63 (m, 2H), 1.57 (m, 2H), 1.29 (m, 2H).
Example 282
(R)-4-(benzylamino)-2-(3-(3-hydroxypyrrolidine-l-carboxamido)phenylamino)pyrimidine-5- carboxamide.
Figure imgf000198_0001
[0525] The title compound was synthesized similar to Example 121. MS found for C23H25N7O3 as (M+H)+ 448.1. UV: λ = 207, 247 nm.
Example 283
(R)-4-(benzylamino)-2-(3-(3-fluoropyrrolidine-l-carboxamido)phenylamino)pyrimidine-5- carboxamide.
Figure imgf000198_0002
[0526] The title compound was synthesized similar to Example 121. MS found for
C23H24FN7O2 as (M+H)+ 450.2. UV: λ = 204, 248 nm. 1H NMR: (CD3OD) δ 8.18 (s, IH), 7.83 (s, IH), 7.20 - 7.38 (m, 6H), 7.13 (d, 2H), 5.29 (d, IH), 4.78 (s, 2H), 3.42 - 3.78 (m, 4H), 2.01 - 2.38 (m, 2H). Example 284
(S)-4-(benzylamino)-2-(3-(3-fluoropyrrolidine-l-carboxamido)phenylamino)pyrimidine-5- carboxamide.
Figure imgf000199_0001
[0527] The title compound was synthesized similar to Example 121. MS found for
C23H24FN7O2 as (M+H)+ 450.2. UV: λ = 204, 249 nm. 1H NMR: (CD3OD) δ 8.18 (s, IH), 7.83 (s, IH), 7.20 - 7.37 (m, 6H), 7.13 (d, IH), 7.08 (d, IH), 5.29 (d, IH), 4.77 (s, 2H), 3.42 - 3.80 (m, 4H), 2.01 - 2.38 (m, 2H).
Example 285
2-(3-acetamidophenylamino)-4-(3-cyanobenzylamino)pyrimidine-5-carboxamide.
Figure imgf000199_0002
[0528] The title compound was synthesized similar to step IV in Scheme 10 for Example 121. MS found for C2iH19N7O2 as (M+H)+ 402.2. UV: λ = 202, 249 nm. 1H NMR: (CD3OD) δ 8.49 (s, IH), 8.13 (s, IH), 7.70 (s, IH), 7.65 (d, 2H), 7.52 (t, IH), 7.29 (t, IH), 7.19 (m, 2H), 4.87 (s, 2H), 2.15 (s, 3H).
Example 286
4-(3-cyanobenzylamino)-2-(4-fluoro-3-(pyrrolidine-l-carboxamido)phenylamino)pyrimidine- 5-carboxamide.
Figure imgf000200_0001
[0529] The title compound was synthesized similar to Example 121. MS found for C24H23FN8O2 as (M+H)+ 475.3. UV: λ = 210, 244 nm. 1H NMR: (CD3OD) δ 8.45 (s, IH), 8.03 (s, IH), 7.64 (m, 3H), 7.52 (t, IH), 7.17 (m, 2H), 4.85 (s, 2H), 3.48 (m, 4H), 2.00 (m, 4H).
Example 287
4-(benzylamino)-2-(3-(3,3-difluoropyrrolidine-l-carboxamido)phenylamino)pyrimidine-5- carboxamide.
Figure imgf000200_0002
[0530] The title compound was synthesized similar to Example 121. MS found for
C23H23F2N7O2 as (M+H)+ 468.1. UV: λ = 214, 246 nm. 1H NMR: (CD3OD) δ 8.42 (s, IH), 8.01 (s, IH), 7.09 - 7.37 (m, 8H), 4.69 (s, 2H), 3.61 - 3.83 (m, 4H), 2.43 (m, 2H).
Example 288
2-(4-fluoro-3 -(pyrrolidine- 1 -carboxamido)phenylamino)-4-(2- fluorobenzylamino)pyrimidine-5-carboxamide.
Figure imgf000201_0001
[0531] The title compound was synthesized similar to Example 121. MS found for C23H23F2N7O2 as (M+H)+ 468.3. UV: λ = 207, 246 nm. 1H NMR: (CD3OD) δ 8.38 (s, IH), 7.91 (s, IH), 7.31 (m, 2H), 7.11 (m, 4H), 4.82 (s, 2H), 3.47 (m, 4H), 1.96 (m, 4H).
Example 289
(R)-4-(2-fluorobenzylamino)-2-(3-(3-fluoropyrrolidine-l- carboxamido)phenylamino)pyrimidine-5-carboxamide.
Figure imgf000201_0002
[0532] The title compound was synthesized similar to Example 121. MS found for C23H23F2N7O2 as (M+H)+ 468.3. UV: λ = 202, 246 nm. 1H NMR: (CD3OD) δ 8.38 (s, IH), 7.81 (s, IH), 7.29 (m, 3H), 7.18 (d, IH), 7.10 (m, 3H), 5.28 (d, IH), 4.81 (s, 2H), 3.68 (m, 2H), 3.51 (m, 2H), 2.23 (m, 2H).
Example 290
2-(3-(azetidine-l-carboxamido)-4-fluorophenylamino)-4-(2-fluorobenzylamino)pyrimidine- 5-carboxamide
Figure imgf000202_0001
[0533] The title compound was synthesized similar to Example 121. MS found for C22H21F2N7O2 as (M+H)+ 454.3. UV: λ = 204, 246 nm. 1U NMR: (CD3OD) δ 8.34 (m, 2H), 7.24 (m, 2H), 7.13 (m, 3H), 7.03 (m, IH), 3.58 (m, 2H), 1.95 (m, 2H).
Example 291
4-(3-fluorobenzylamino)-2-(3-(3,3,3-trifluoropropanamido) phenylamino)- pyrimidine-5- carboxamide
Figure imgf000202_0002
[0534] The aniline, M-3 (70 mg, 0.198 mmol), 3,3,3-trifluoropropionic acid (45 mg, 0.35 mmol), and EDCHCl (200 mg, 1.043 mmol), in NMP (2 ml) were stirred for 16 h. Then the reaction mixture was purified by RP-HPLC to afford the title compound as colorless puffs, 67 mg (73 %). UV: 249.1, 206.7 nm. MS: 463.2 (M+H), C2IHi8F4N6O2. 1H NMR (400 MHz, DMSO-d6): 5 3.43 (q, J= 11.4 Hz), 4.68 (d, J= 6 Hz), 6.88-7.45 (m, 8H), 7.80-8.0 (m, 2H), 8.46 (s, IH), 9.78 (br s, IH), 9.90 (br s, IH), 10.22 (br s, IH).
Example 292.
benzyl 3-(5-carbamoyl-4-(3-fluorobenzylamino)pyrimidin-2-ylamino)phenylcarbamate
Figure imgf000203_0001
[0535] The above compound was prepared according to reactions described in Scheme 16. The compound M-I was prepared using the procedures described in scheme 1 and substituting 3-fluorobenzylamine in the place of cyclobutyl amine.
[0536] Step 7: The -OBt derivative (M-I) (100 mg, 0.263 mmol), 3-cbz-aniline (120 mg, 0.495 mmol) and PTSA.H2O (50 mg, 0.262 mmol), dissolved in NMP (1.0 mL) were heated to 50 0C in a sealed tube for 24 h. Then the reaction mixture was cooled to room temperature, and diluted with water to precipitate the compound, 114 mg (89 %). UV: 244.4, 206.7 nm. MS: 487.2 (M+H), C26H23FN6O3. 1H NMR (400 MHz, DMSO-d6): 54.73 (d, 2H, 7= 5.8 Hz), 5.10 (s, 2H), 6.98-7.16 (m, 6H), 7.28-7.40 (m, 6H), 8.50 (s, IH), 9.76 (br s, IH), 9.84-10.05 (m, 2H).
Example 293:
2-(3-(l-cyanocyclopropanecarboxamido)phenylamino)-4-(3-fluorobenzylamino)pyrimidine- 5-carboxamide
Figure imgf000203_0002
[0537] The aniline, M-3, (Scheme 16) (100 mg, 0.283 mmol), 1-cyano- cyclopropanecarboxylic acid (50 mg, 0.450 mmol), and EDCHCl (257 mg, 1.340 mmol), in NMP (1 mL) were stirred at room temperature for 17 h. Then the reaction mixture was purified by RP-HPLC to afford the title compound, as colorless puffs, 91 mg (72 %). UV: 249.1 nm. MS: 446.1 (M+H), C23H20FN7O2. 1H NMR (400 MHz, DMSO-d6): δ 1.50-1.60 (m, 4H), 4.68 (d, 2H, / = 6 Hz), 6.92-7.50 (m, 8H), 7.82-8.30 (m, 2H), 8.46 (s, IH), 9.85 (br s, IH), 9.96 (br s, IH), 10.02 (br s, IH).
Example 294
4-(2-fluorobenzylamino)-2-(3-(isonicotinamido)-phenylamino)pyrimidine-5-carboxamide
Figure imgf000204_0001
[0538] This compound, was synthesized using the procedure described in example 296, using iso-nicotinic acid. UV: 258.6 nm. MS: 458.3 (M+H), C24H20FN7O2. 1H NMR (400 MHz, DMSO-d6): δ 4.85 (d, 2H, 7=5.80 Hz), 7.02-7.20 (m, 4H), 7.28-7.45 (m, 5H), 7.60 (m, IH), 7.95 (m, 2H), 8.24 (m, IH), 8.32 (s, IH), 8.60 (s, IH), 8.88 (br s, 2H), 10.10 (br s, IH), 10.36 (br s, IH), 10.62 (br s, IH).
Example 295
4-(2-fluorobenzylamino)-2-(3-(picolinamido)-phenylamino)pyrimidine-5-carboxamide
Figure imgf000204_0002
[0539] This compound, was synthesized using the procedure described in example 296, using picolinic acid. UV: 272.8 nm. MS: 458.3 (M+H), C24H20FN7O2. 1H NMR (400 MHz, DMSO-d6): δ 4.78 (d, 2H, 7=6 Hz), 6.95-7.45 (m, 8H), 7.68 (m, IH), 7.95-8.25 (m, 3H), 8.35 (m, IH), 8.52 (s, IH), 8.70 (m, IH), 9.88 (br s, IH), 10.02 (br s, IH), 10.52 (br s, IH). Example 296
4-(2-fluorobenzylamino)-2-(3-(nicotinamido)-phenylamino)pyrimidine-5-carboxamide
Figure imgf000205_0001
[0540] The aniline.TFA (2-(3-aminophenylamino)-4-(2-fluorobenzylamino)pyrimidine-5- carboxamide ) (80 mg, 0.171 mmol), nicotinic acid (32 mg, 0.260 mmol), HATU (104 mg, 0.273 mmol), and DDEA (45 mg, 0.348 mmol), in NMP (2 mL) were stirred at room temperature for 19 h. Then the title compound was obtained by purification through RP- HPLC, 82 mg (84 %). UV: 258.6 nm. MS: 458.3 (M+H), C24H20FN7O2. 1H NMR (400 MHz, DMSO-d6): 64.80 (d, 2H, 7=5.8 Hz), 6.90-7.12 (m, 4 H), 7.22-7.35 (m, 4H), 7.48-7.62 (m, 3H), 8.24 (s, IH), 8.28 (m, IH), 8.53 (s, IH), 8.77 (m, IH), 9.06 (s, IH), 10.08 (br s, IH), 10.32 (br s, IH), 10.48 (br s, IH).
Example 297
4-(2-fluorobenzylamino)-2-(3-(2-(pyridin-3-yl)acetamido)-phenylamino)pyrimidine-5- carboxamide
Figure imgf000205_0002
[0541] This compound was synthesized using the procedure described in example 296, and using 3-pyridine acetic acid as the acid component. UV: 253.8 nm. MS: 472.3 (M+H), C25H22FN7O2. 1H NMR (400 MHz, DMSO-d6): δ 3.88 (s, 2H), 4.70 (d, 2H, 7=5.80 Hz), 6.98- 7.55 (m, 10H), 7.72 (m, IH), 7.92-8.20 (m, 3H), 8.52 (s, IH), 8.65-8.75 (m, 2H), 9.92 (br s,
IH), 10.16 (br s, IH), 10.32 (br s, IH). Example 298
4-(2-fluorobenzylamino)-2-(3-(6-hydroxypicolinamido)-phenylamino)pyrimidine-5- carboxamide
Figure imgf000206_0001
[0542] This compound, was synthesized using the procedure described in example 296, using 6-hydroxy-2-pyridine carboxylic acid. UV: 249.1 nm. MS: 474.3 (M+H), C24H20FN7O3. 1H NMR (400 MHz, DMSOd6): δ 4.70 (d, 2H, 7=6 Hz), 6.75 (m, IH), 6.90- 7.50 (m, 8H), 7.70 (m, IH), 7.95 (m, IH), 8.30 (s, IH), 8.48 (s, IH), 9.88 (br s, IH), 10.10 (br s, 2H).
Example 299
4-(2-fluorobenzylamino)-2-(3-(2-(pyridin-4-yl)acetamido)-phenylamino)pyrimidine-5- carboxamide
Figure imgf000206_0002
[0543] This compound was synthesized using the procedure described in example 296, and using 4-pyridine acetic acid as the acid component. UV: 249.1 nm. MS: 472.4 (M+H),
C25H22FN7O2. 1H NMR (400 MHz, DMSO-d6): δ 3.98 (s, 2H), 4.70 (d, 2H, 7=6 Hz), 6.98- 7.50 (m, 10H), 7.80 (d, IH, 7 =7 Hz), 7.90-8.10 (m, 2H), 8.48 (s, IH), 8.70 (IH, d, 7 =7 Hz), 9.90 (br s, IH), 10.15 (br s, IH), 10.38 (br s, IH) . Example 300
4-(2-fluorobenzylamino)-2-(3-(2-(pyridin-2-yl)acetamido)-phenylamino)pyrimidine-5- carboxamide
Figure imgf000207_0001
[0544] This compound was synthesized using the procedure described in example 296, and using 2-pyridine acetic acid as the acid component. UV: 258.6 nm. MS: 472.2 (M+H), C25H22FN7O2. 1U NMR (400 MHz, DMSOd6): δ 4.0 (s, 2H), 4.64 (d, 2H, J=6 Hz), 6.90- 7.30 (m, 6H), 7.40-7.64 (m, 4H), 7.90-8.16 (m, 3H), 8.44 (s, IH), 8.60 (m, IH), 9.92 (br s, IH), 10.20 (br s, IH), 10. 40 (br s, IH).
Example 301
2-(3-acetamidophenylamino)-4-(4-(2-cyanoacetamido)-phenylamino)pyrimidine-5- carboxamide
Figure imgf000207_0002
[0545] The reaction mixture, comprising of the aniline. HCl, M-9, (114 mg, 0.231 mmol), cyanoacetic acid (30 mg, 0.352 mmol), EDCHCl (133 mg, 0.693 mmol), and DIEA (51 mg, 0.394 mmol), in NMP (1.5 mL), was stirred at room temperature for 18h. Then the title compound was isolated by prep HPLC, 92 mg (71 %). UV: 249.1 nm. MS: 445.2 (M+H), C22H20N8O3. Example 302
2-(3-acetamidophenylamino)-4-(4-(l-cyanocyclopropane-carboxamido) phenylamino)pyrimidine-5-carboxamide
Figure imgf000208_0001
[0546] A mixture of the aniline.HCl, M-9, (117 mg, 0.282 mmol), 1-cyano-cyclopropane carboxylic acid (50 mg, 0.450 mmol), EDCHCl (257 mg, 1.340 mmol), and DIEA (75 mg, 0.580 mmol) in NMP (1.5 mL) was stirred at room temperature for 19h. Then the title compound was obtained by purification using RP-HPLC, 125 mg (76 %). UV: 249.1 nm. MS: 471.1 (M+H), C24H22N8O3. 1H NMR (400 MHz, DMSO-d6): 5 1.661 (s, 4H), 2.02 (s, 3H), 7.10-7.70 (m, 9H), 7.80 (br s, IH), 8.12 (br s, IH), 8.64 (s, IH), 9.90 (m, 2H), 9.88 (s, IH), 11.68 (s, IH).
Example 303:
2-(3-acetamidophenylamino)-4-(4-(3,3,3-trifluoro-propanamido) phenylamino)pyrimidine-5- carboxamide
Figure imgf000208_0002
[0547] The reaction mixture, consisting of the aniline. HCl, M-9, (95 mg, 0.229 mmol), 3,3,3-trifluoropropionic acid (45 mg, 0.351 mmol), EDCHCl (133 mg, 0.693 mmol), and DIEA (88 mg, 0.680 mmol), in NMP (1.5 mL) was stirred at room temperature for 18 h. Then the title compound was isolated by purification on RP-HPLC, 109 mg (79 %). UV: 249.1 nm. MS: 488.1 (M+H), C22H20F3N7O3. 1H NMR (400 MHz, DMSO-d6): δ 1.98 (s, 3H), 3.43 (q, 2H, 7=11 Hz), 7.05-7.65 (m, 8H), 7.75 (s, IH), 8.06 (s, IH), 8.58 (s, IH), 9.84 (br s, 2H), 10.22 (s, IH), 11.62 (s, IH). Example 304
6-(4-fluoro-3-(pyrrolidine-l-carboxamido)phenylamino)-4-(pyridin-3- ylmethylamino)nicotinamide
Figure imgf000209_0001
[0548] The title compound was synthesized as scheme 1 described in following procedures.
Step I, 4,6-Dichloronicotinamide (1)
[0549] A suspension of 4,6-dihydroxynicotinic acid (3.10 g, 20 mmoles) in phosphoryl trichloride (50 mL) was stirred at 100 0C for 4 hrs. After cooled to room temperature, the reaction solution was poured into a cold ammonium hydroxide solution (27-30 %) in several portions and kept the mixture basic. The first portion of desired product as precipitate was collected by filtration. The second portion of desired product was obtained by extraction of mother aqueous liquid with DCM. The total amount of 4,6-Dichloronicotinamide (1) was 2.78 g. MS+: 191.0, UV: λ = 201.0; 269.2 nm, 1H NMR: (CDCl3) δ8.77(s,lH), δ7.45(s,lH), δ6.34(b,lH), 56.21(b,lH).
Step II, 6-chloro-4-(pyridin-3-ylmethylamino)nicotinamide (2)
[0550] A mixture of 4,6-Dichloronicotinamide (1, 950 mg, 5 mmoles), 3-picolylamine (756 mg, 7 mmoles) and DIEA (12 mmoles) in NMP (5 mL) was stirred at 60 0C for 20 hrs. The reaction mixture was concentrated under an oil pump. The residue was washed with water and dried under an oil pump. The desired 6-chloro-4-(pyridin-3-ylmethylamino)nicotinamide (2, 1.085 g) was obtained. MS+: 263.1, UV: λ = 220.9; 260.9 nm. 1H NMR: (CDCl3) δ8.96(s,lH), δ8.60(s,lH), δ8.57(d,J=3.2 Hz,lH), δ8.30(s,lH), δ7.64(d,J=7.6Hz,lH), 67.31 (dd,Jl=7.6Hz,J2=3.2Hz,lH), δ6.51(s,lH), δ5.80(b,2H), δ4.47(s, IH), δ4.45(s, IH).
Step III, N-(5-amino-2-fluorophenyl)pyrrolidine-l-carboxamide (3)
[0551] A mixture of l-fluoro-2-isocyanato-4-nitrobenzene (1.125 g, 6.18 mmoles) and pyrrolidine (485 mg, 6.8 mmoles) in DCM (20 mL) was stirred at r.t. for 14 hrs. After concentrated, the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous citric acid solution and dried over MgSO4, followed by hydrogenation with Pd/C (wet, 10 %, 0.15 g) under a hydrogen balloon overnight. After filtration and concentration, the reasonable pure N-(5-amino-2-fluorophenyl)pyrrolidine-l-carboxamide (3, 1.44 g) was used for the next reactions. MS+: 224.2, UV: λ = 271.6 nm. 1H NMR: (DMSO) 67.44 (s, IH), 66.78 (m, IH), 66.20 (m, IH), 63.32 (m, 4H), 61.83 (m, 4H).
Step IV, 6-(4-fluoro-3-(pyrrolidine- 1 -carboxamido)phenylamino)-4-(pyridin-3- ylmethylamino)nicotinamide (4)
[0552] A mixture of 6-chloro-4-(pyridin-3-ylmethylamino)nicotinamide (2, 27 mg, 0.1 mmoles), N-(5-amino-2-fluorophenyl)pyrrolidine-l-carboxamide (3, 34 mg, 0.15 mmoles), Pd(OAc)2 (2 mg). BINAP (15 mg), Cs2CO3 (100 mg) in dioxane (1 mL) was heated at 120 0C under microwave for 60 min. Purification with reversed phase HPLC, 6-(4-fluoro-3- (pyrrolidine- 1 -carboxamido)phenylamino)-4-(pyridin-3-ylmethylamino)nicotinamide (4, 10 mg) was obtained. MS found for C23H24FN7O2 as (M+H)+ 450.5, UV: λ = 249.1 nm. 1H NMR: (CD3OD) 68.50(s,lH), 68.42(d,lH), 68.26(d,lH), 67.80(dd,lH), 67.60(dd,lH), 67.40(dd,lH), 67.00(dd,lH), 66.91(m,lH), 65.88(d,lH), 64.49(s,2H), 63.48 (m,4H), 61.99 (b,4H).
Example 305
6-(3-(azetidine-l-carboxamido)-4-fluorophenylamino)-4-(3-fluorobenzylamino)nicotinamide
Figure imgf000210_0001
[0553] The title compound was synthesized similar to step I-IV in the Scheme for Example 304. MS found for C23H22F2N6O2 as (M+H)+ 453.3. UV: λ = 245.6 nm. 1H NMR: (CD3OD) 68.13(s,lH), 67.64(dd,lH), 67.35 (m,lH), 67.17(dd,lH), 67.10(d,lH), 67.02(m,2H), 66.84(m,lH), 65.90(s,lH), 64.53(s,2H), 64.12(dd,4H), 62.34 (m,2H). Example 306
(R)-6-(3-(3-(dimethylamino)pyrrolidine-l-carboxamido)phenylamino)-4-(3- fluorobenzylamino)nicotinamide
Figure imgf000211_0001
-N \
[0554] The title compound was synthesized similar to step I-IV in the Scheme for Example 304. MS found for C26H30FN7O2 as (M+H)+ 492.6. UV: λ = 251.5 nm. 1H NMR: (CD3OD) δ8.15(s,lH), δ7.53(s,lH), δ7.33(m,2H), δ7.23(d,lH), δ7.10(d,lH), δ7.02(m,2H), δ6.79(d,lH), δ6.00(s,lH), δ4.53(s,2H), δ3.99 (m,2H), δ3.79 (m,lH), δ3.60(m,2H), δ2.97 (s,6H), δ2.54 (m,lH), δ2.25 (m,lH).
Example 307
(6-(4-fluoro-3-(pyrrolidine-l-carboxamido)phenylamino)-4-(3- fluorobenzylamino)nicotinamide
Figure imgf000211_0002
[0555] The title compound was synthesized similar to step I-IV in the Scheme for Example 304. MS found for C24H24F2N6O2 as (M+H)+ 467.6. UV: λ = 201.0; 250.3 nm.
Example 308
N-(3-(5-carbamoyl-4-(3-fluorobenzylamino)pyridin-2-ylamino)phenyl)morpholine-4- carboxamide
Figure imgf000212_0001
[0556] The title compound was synthesized similar to step I-IV in the Scheme for Example 304. MS found for C24H25FN6O3 as (M+H)+ 465.3. UV: λ = 253.8 nm. 1H NMR: (CD3OD) δ8.15(s,lH), 57.46(s,lH), 57.34(m,lH), 67.29(d,lH), δ7.13(m,2H), δ7.04(m,2H), δ6.79(d,lH), 65.98(s,lH), δ4.53(s,2H), 53.71 (m,4H), δ3.52 (m,4H).
Example 309
4-(3-fluorobenzylamino)-6-(3-(pyrrolidine-l-carboxamido)phenylamino)nicotinamide
Figure imgf000212_0002
[0557] The title compound was synthesized similar to step I-IV in the Scheme for Example 304. MS found for C24H25FN6O2 as (M+H)+ 449.5. UV: λ = 253.8 nm. 1H NMR: (CD3OD) δ8.13(s,lH), δ7.52(s,lH), δ7.32(m,2H), 57.21(d,lH), δ7.11(d,lH), δ7.04(m,2H), δ6.77(d,lH), δ5.97(s,lH), δ4.53(s,2H), 53.46 (b,4H), δl.99 (b,4H).
Example 310
6-(3-acetamidophenylamino)-4-(3-fluorobenzylamino)nicotinamide
[0558] The title compound was synthesized similar to step IV in the Scheme for Example 304. MS found for C2iH20FN5O2 as (M+H)+ 394.5. UV: λ = 253.8 nm. 1H NMR: (CD3OD) δ8.14(s,lH), δ7.74(t,lH), δ7.33(t,2H), δ7.22(d,lH), 57.08(d,lH), 57.01(m,2H), 66.81 (d,lH), δ5.95(s,lH), δ4.51(s,2H), 52.15 (s,3H). Example 311
(S)-6-(3-(azetidine-l-carboxamido)-4-fluorophenylamino)-4-(2-hydroxy-l- phenylethylamino)nicotinamide
Figure imgf000213_0001
[0559] The title compound was synthesized similar to step I-IV in the Scheme for Example 304. MS found for C24H25FN6O3 as (M+H)+ 465.5. UV: λ = 251.5 nm. 1H NMR: (CD3OD) δ8.23(s,lH), 67.49(m,lH), δ7.30(m,5H), 56.90 (t,lH), δ6.67(m,lH), δ5.75(s,lH), 54.48(m,lH), δ4.10(m,4H), δ3.89(m,lH), δ3.70(m,lH), δ2.33 (m,2H).
Example 312
6-(3-((R)-3-(dimethylamino)pyrrolidine-l-carboxamido)phenylamino)-4-((S)-2-hydroxy-l- phenylethylamino)nicotinamide
Figure imgf000213_0002
[0560] The title compound was synthesized similar to step I-IV in the Scheme for Example 304. MS found for C27H33N7O3 as (M+H)+ 504.3. UV: λ = 249.1 nm.
Example 313
(S)-6-(4-fluoro-3-(pyrrolidine- 1 -carboxamido)phenylamino)-4-(2-hydroxy- 1 - phenylethylamino)nicotinamide
Figure imgf000213_0003
[0561] The title compound was synthesized similar to step I- IV in the Scheme for Example 304. MS found for C25H27FN6O3 as (M+H)+ 479.3. UV: λ = 251.1 nm. 1H NMR: (CD3OD) δ8.23(s,lH), δ7.46(m,lH), 67.31(m,5H), 56.93 (t,lH), δ6.68(m,lH), 55.76(s,lH), δ4.49(m,lH), 53.82(m,lH), 53.71(m,lH), 63.48 (b,4H), δl.99 (b,4H).
Example 314
(S)-N-(3-(5-carbamoyl-4-(2-hydroxy-l-phenylethylamino)pyridin-2- ylamino)phenyl)morpholine-4-carboxamide
Figure imgf000214_0001
[0562] The title compound was synthesized similar to step I-IV in the Scheme for Example 304. MS found for C25H28N6O4 as (M+H)+ 477.5. UV: λ = 252.7 nm.
Example 315
(S)-4-(2-hydroxy-l-phenylethylamino)-6-(3-(pyrrolidine-l- carboxamido)phenylamino)nicotinamide
Figure imgf000214_0002
[0563] The title compound was synthesized similar to step I-IV in the Scheme for Example 304. MS found for C25H28N6O3 as (M+H)+ 461.5. UV: λ = 251.5 nm.
Example 316
(S)-6-(3-acetamidophenylamino)-4-(2-hydroxy-l-phenylethylamino)nicotinamide
Figure imgf000215_0001
[0564] The title compound was synthesized similar to step IV in the Scheme for Example 304. MS found for C22H23N5O3 as (M+H)+ 406.5. UV: λ = 253.8 nm. 1H NMR: (CD3OD) δ8.13(s,lH), δ7.41(s,lH), δ7.18(m,5H), 66.97 (m,2H), 56.56 (m,lH), 55.70 (s,lH), 54.52(s,lH), 54.37(m,lH), 53.71(m,lH), 53.58(m,lH), 52.02 (b,3H).
Example 317
6-(3-(azetidine-l-carboxamido)-4-fluorophenylamino)-4-(pyridin-3- ylmethylamino)nicotinamide
Figure imgf000215_0002
[0565] The title compound was synthesized similar to step I-IV in the Scheme for Example 304. MS found for C22H22FN7O2 as (MH-H)+ 436.3. UV: λ = 250.3 nm. 1H NMR: (CD3CN) 58.49(s,lH), 58.43 (m,lH), 58.26 (s,lH), 57.80 (d,lH), 57.63 (m,lH), 57.40 (m,lH), 56.99 (t,lH), 56.89 (m,lH), 55.87 (s,lH), 54.49(s,2H), 54.10(t,4H), 52.33 (m,2H).
Example 318
(R)-6-(3-(3-(dimethylamino)pyrrolidine-l-carboxamido)phenylammo)-4-(pyridin-3- ylmethylamino)nicotinamide
Figure imgf000215_0003
[0566] The title compound was synthesized similar to step I-IV in the Scheme for Example 304. MS found for C25H30N8O2 as (Mn-H)+ 475.6. UV: λ = 252.7 nm. 1H NMR: (CD3OD) 88.50(s,lH), 58.43 (m,lH), 58.26 (s,lH), 57.80 (d,lH), 57.50 (m,lH), 57.40 (m,lH), 57.14 (t,lH), 57.02 (m,lH), 56.82 (m,lH), 55.97 (s,lH),54.50(s,2H), 53.82(m,lH), 53.70(m,lH), 53.48(m,lH), 53.10 (m,lH), 52.48(s,6H), 52.31(m,lH), 51.94(m,lH).
Example 319
N-(3-(5-carbamoyl-4-(pyridin-3-ylmethylamino)pyridin-2-ylamino)phenyl)morpholine-4- carboxamide
Figure imgf000216_0001
[0567] The title compound was synthesized similar to step I-IV in the Scheme for Example 304. MS found for C23H25N7O3 as (M+H)+ 448.2. UV: λ = 251.5 nm.
Example 320
4-(pyridin-3-ylmethylamino)-6-(3-(pyrrolidine-l-carboxamido)phenylamino)nicotinamide
Figure imgf000216_0002
[0568] The title compound was synthesized similar to step I-IV in the Scheme for Example 304. MS found for C23H25N7O2 as (M+H)+ 432.5. UV: λ = 250.3 nm.
Example 321
6-(3-acetamidophenylamino)-4-(pyridin-3-ylmethylamino)nicotinamide
Figure imgf000216_0003
[0569] The title compound was synthesized similar to step IV in the Scheme for Example 304. MS found for C20H20N6O2 as (M+H)+ 477.6. UV: λ = 252.7 nm.
Example 322
(R)-6-(3-acetamidophenylamino)-4-(l-phenylethylamino)nicotinamide.
Figure imgf000217_0001
[0570] The title compound was synthesized similar to step IV in the Scheme for Example 304. MS found for C22H23N5O2 as (M+H)+ 390.2. UV: λ = 205, 256 nm.
Example 323
6-(3-acetamidophenylamino)-4-(isobutylamino)nicotinamide.
Figure imgf000217_0002
[0571] The title compound was synthesized similar to step IV in the Scheme for Example 304. MS found for C18H23N5O2 as (M+H)+ 342.2. UV: λ = 205, 256 nm. 1H NMR: (CD3OD) δ 8.15 (s, IH), 7.88 (s, IH), 7.41 (m, IH), 7.23 (d, IH), 7.01 (d, IH), 6.08 (s, IH), 3.08 (d, 2H), 2.13 (s, 3H), 1.98 (m, IH), 1.03 (d, 6H).
Example 324
4-(isobutylamino)-6-(3-(pyrrolidine-l-carboxamido)phenylamino)nicotinamide.
Figure imgf000217_0003
[0572] The title compound was synthesized similar to step IV in the Scheme for Example 304. MS found for C2iH28N6O2 as (M+H)+ 397.3. UV: λ = 207, 254 nm.
Example 325
(R)-4-( 1 -phenylethylamino)-6-(3-(pyrrolidine- 1 -carboxamido)phenylamino)nicotinamide.
Figure imgf000218_0001
[0573] The title compound was synthesized similar to step IV in the Scheme for Example 304. MS found for C25H28N6O2 as (M+H)+ 445.3. UV: λ = 207, 254 nm. 1H NMR: (CD3OD) δ 8.23 (s, IH), 7.55 (s, IH), 7.39 (t, 2H), 7.28 (m, 5H), 6.65 (m, IH), 5.92 (s, IH), 4, 73 (m, IH), 3.52 (m, 4H), 2.01 (m, 4H), 1.60 (d, 3H).
Example 326
4-(benzylamino)-6-(3-(pyrrolidine-l-carboxamido)phenylamino)nicotinamide
Figure imgf000218_0002
[0574] The title compound was synthesized similar to step IV in the Scheme for Example 304. MS found for C24H26N6O2 as (M+H)+431.2. UV: λ = 204, 254 nm. Example 327
6-(3-acetamidophenylamino)-4-(isopentylamino)nicotinamide.
Figure imgf000219_0001
[0575] The title compound was synthesized similar to step IV in the Scheme for Example 304. MS found for C19H25N5O2 as (M+H)+ 356.3. UV: λ = 205, 254 nm. 1H NMR: (CD3OD) δ 8.20 (s, IH), 7.91 (s, IH), 7.39 (t, IH), 7.23 (d, IH), 7.07 (d, IH), 6.09 (s, IH), 3.24 (m, 2H), 2.15 (s, 3H), 1.72 (m, IH), 1.56 (m, 2H), 0.97 (d, 6H).
Example 328
4-(isopentylamino)-6-(3-(pyrrolidine-l-carboxamido)phenylamino)nicotinamide.
Figure imgf000219_0002
[0576] The title compound was synthesized similar to step IV in the Scheme for Example 304. MS found for C22H30N6O2 as (M+H)+411.3. UV: λ = 207, 254 nm. 1H NMR: (CD3OD) δ 8.12 (s, IH), 7.61 (s, IH), 7.30 (t, IH), 7.16 (d, IH), 6.93 (d, IH), 6.05 (s, IH), 3.47 (m, 4H), 3.23 (m, 2H), 1.98 (m, 4H), 1.70 (m, IH), 1.56 (m, 2H), 0.96 (d, 6H).
Example 329
6-(3-acetamidophenylamino)-4-(cyclopropylmethylamino)nicotinamide.
Figure imgf000219_0003
[0577] The title compound was synthesized similar to step IV in the Scheme for Example 304. MS found for Ci8H2[N5O2 as (M+H)+ 340.2. UV: λ = 204, 254 nm. 1H NMR: (CD3OD) δ 8.11 (s, IH), 7.85 (s, IH), 7.39 (t, IH), 7.21 (d, IH), 7.00 (d, IH), 6.07 (s, IH), 3.12 (d, 2H), 2.15 (s, 3H), 1.27 (m, IH), 0.62 (m, 2H), 0.31 (m, 2H).
Example 330
6-(3-acetamidophenylamino)-4-(cyclopentylamino)nicotinamide.
Figure imgf000220_0001
[0578] The title compound was synthesized similar to step IV in the Scheme for Example 304. MS found for Ci9H23N5O2 as (MH-H)+ 354.3. UV: λ = 354.3 nm. 1H NMR: (CD3OD) δ 8.11 (s, IH), 7.86 (s, IH), 7.39 (m, IH), 7.22 (m, IH), 7.01 (m, IH), 3.88 (m, IH), 2.15 (s, 3H), 2.03 (m, 4H), 1.69 (m, 4H).
Example 331
6-(3-acetamidophenylamino)-4-(cyclobutylmethylamino)nicotinamide.
Figure imgf000220_0002
[0579] The title compound was synthesized similar to step IV in the Scheme for Example 304. MS found for C9H23N5O2 as (M+H)+ 354.3. UV: λ = 205, 256 nm. 1H NMR: (CD3OD) δ 8.14 (s, IH), 7.88 (s, IH), 7.43 (t, IH), 7.24 (d, IH), 7.01 (d, IH), 6.09 (s, IH), 2.18 (m, 5H), 1.98 (m, 2H), 1.80 (m, 2H).
Example 332
6-(3-acetamidophenylamino)-4-(4-fluorobenzylamino)nicotinamide.
Figure imgf000221_0001
[0580] The title compound was synthesized similar to step IV in the Scheme for Example 304. MS found for C21H20FN5O2 as (M+H)+ 394.1. UV: λ = 205, 254 nm. 1H NMR: (CD3OD) δ 8.13 (s, IH), 7.74 (t, IH), 7.35 (t, IH), 7.23 (m, 3H), 7.05 (t, 2H), 6.86 (dd, 2H), 5.95 (s, IH), 4.47 (s, 2H), 2.15 (s, 3H).
Example 333
6-(3-acetamidophenylamino)-4-(2,3-dihydro-lH-inden-2-ylamino)nicotinamide.
Figure imgf000221_0002
[0581] The title compound was synthesized similar to step IV in the Scheme for Example 304. MS found for C23H23N5O2 as (MH-H)+ 402.2. UV: λ = 209, 251 nm. 1H NMR: (CD3OD) 5 8.14 (s, IH), 7.91 (s, IH), 7.41 (t, IH), 7.21 (m, 4H), 7.05 (d, IH), 6.20 (s, IH), 4.38 (m, IH), 3.40 (dd, 2H), 2.96 (dd, 2H), 2.15 (s, 3H).
Example 334
6-(3-acetamidophenylamino)-4-(benzo[d][l,3]dioxol-5-ylmethylamino)nicotinamide
Figure imgf000221_0003
[0582] The title compound was synthesized similar to step IV in the Scheme for Example 304. MS found for C22H2JN5O4 as (M+H)+ 420.1. UV: λ = 202, 254 nm.
Example 335
(S)-6-(3-acetamidophenylamino)-4-(2,3-dihydro-lH-inden-l-ylamino)nicotinamide.
Figure imgf000222_0001
[0583] The title compound was synthesized similar to step IV in the Scheme for Example 304. MS found for C23H23N5O2 as (M+H)+ 402.2. UV: λ = 209,258 nm. 1H NMR: (CD3OD) δ 8.16 (s, IH), 8.60 (t, IH), 7.41 (t, IH), 7.22 (m, 5H), 7.02 (dd, IH), 6.25 (s, IH), 5.12 (t, IH), 3.04 (m, IH), 2.97 (m, IH), 2.62 (m, IH), 1.98 (m, IH).
Example 336
6-(3-acetamidophenylamino)-4-(2,3-difluorobenzylamino)nicotinamide.
[0584] The title compound was synthesized similar to step IV in the Scheme for Example 304. MS found for C2iH19F2N5O2 as (M+H)+ 412.2. UV: λ = 205, 254 nm. 1H NMR: (CD3OD) δ 8.14 (s, IH), 7.78 (s, IH), 7.36 (t, IH), 7.22 (m, 2H), 7.12 (m, 2H), 6.88 (d, IH), 5.98 (s, IH), 4.59 (s, 2H), 2.15 (s, 3H). Example 337
6-(3-acetamidophenylamino)-4-(3-chlorobenzylamino)nicotinamide.
Figure imgf000223_0001
[0585] The title compound was synthesized similar to step IV in the Scheme for Example 304. MS found for C21H20ClN5O2 as (M+H)+410.1. UV: λ = 202, 254 nm. 1H NMR: (CD3OD) δ 8.16 (s, IH), 7.77 (t, IH), 7.31 (m, 4H), 7.19 (m, 2H), 6.83 (d, IH), 5.93 (s, IH), 4.52 (s, 2H), 2.17 (s, 3H).
Example 338
6-(3-acetamidophenylamino)-4-(phenethylamino)nicotinamide.
Figure imgf000223_0002
[0586] The title compound was synthesized similar to step IV in the Scheme for Example 304. MS found for C22H23N5O2 as (M+H)+ 390.1. UV: λ = 205, 256 nm. 1H NMR: (CD3OD) 5 8.09 (s, IH), 7.90 (s, IH), 7.41 (t, IH), 7.12 - 7.27 (m, 6H), 6.97 (d, IH), 6.04 (s, IH), 3.49 (t, 2H), 2.92 (t, 2H), 2.11 (s, 3H).
Example 339
6-(3-acetamidophenylamino)-4-(benzylamino)-N-methylnicotinamide.
Figure imgf000224_0001
[0587] The title compound was synthesized similar to step IV in the Scheme for Example 304. MS found for C22H23N5O2 as (M+H)+ 390.4. UV: λ = 207, 254 nm. 1H NMR: (CD3OD) δ 8.03 (s, IH), 7.78 (t, IH), 7.21 - 7.48 (m, 7H), 6.83 (d, IH), 6.03 (s, IH), 4.52 (s, 2H), 2.89 (s, 3H), 2.17 (s, 3H).
Example 340
6-(3-acetamidophenylamino)-4-(2-fluorobenzylamino)nicotinamide.
Figure imgf000224_0002
[0588] The title compound was synthesized similar to step IV in the Scheme for Example 304. MS found for C2, H20FN5O2 as (M+H)+ 394.4. UV: λ = 205, 254 nm. 1B. NMR: (CD3OD) δ 8.22 (s, IH), 7.83 (s, IH), 7.18 - 7.48 (m, 6H), 6.95 (d, IH), 6.07 (s, IH), 4.57 (s, 2H), 2.15 (s, 3H).
Example 341
4-(3,5-difluorobenzylamino)-6-(3-(pyrrolidine-l-carboxamido)phenylamino)nicotinamide.
Figure imgf000224_0003
[0589] The title compound was synthesized similar to step IV in the Scheme for Example 304. MS found for C24H24F2N6O2 as (M+H)+ 467.3. UV: λ = 219, 261 nm. 1H NMR: (CD3OD) 58.23 (s, IH), 7.48 (t, IH), 7.12 (t, IH), 7.03 (m, IH), 6.91 (m, 2H), 6.80 (m, 2H), 5.88 (s, IH), 4.45 (s, 2H), 3.43 (m, 4H), 1.98 (m, 4H).
Example 342 Kinase Assay Protocols:
[0590] JAK and TYK2 tyrosine phosphorylation activity is measured using the Z'-LYTE™ Technology developed by Invitrogen Corporation (Carlsbad,CA). For JAKl, JAK2 and JAK3 the Z'-LYTE™ Kinase Assay Kit-Tyr6 Peptide (part number PV4122) was used. For TYK2 the Z'-LYTE™ Kinase Assay Kit-Tyr6 Peptide (part number PV3192) was used. The Z'- LYTE™ biochemical assay employs a fluorescence resonance energy transfer (FRET) coupled-enzyme format and is based on the differential sensitivity of phosphorylated and non-phosphorylated peptides to proteolitic cleavage. The assay uses a synthetic peptide substrate that is labelled with a donor fluorophore (coumarin) and an acceptor fluorophore (fluorescein) that make up a FRET pair. In the primary reaction (the Kinase Reaction), the kinase transfers the γ-phosphate of ATP to a single tyrosine residue on the substrate, while the presence of a kinase inhibitor in the primary reaction suppresses phosphorylation. In the secondary reaction (the Development Reaction), a site-specific protease (the Development Reagent) is added. The development buffer quenches the Kinase Reaction, while the protease recognizes and cleaves non-phosphorylated Z'-LYTE™ peptide substrate. Cleavage disrupts FRET between the donor and acceptor fluorophores on the non-phosphoryleted substrate, while uncleaved, phosphorylated substrate maintains FRET.
[0591] To test the ability of candidate molecules to inhibit JAK tyrosine phosphorylation activity, molecules are reconstituted in 100 % DMSO and serially diluted 1:10 in polypropylene v-bottom microtiter plates. The candidate molecules are then diluted 1:25 into kinase buffer and 2.5 μl transferred into duplicate wells of a 384 well low volume black microtiter assay plate (Corning, USA). The final DMSO concentration in the assay is 1%. The kinase reaction contains 2.5μl of a candidate molecule, 5μl of catalytic domain recombinant Kinase enzyme + Tyr peptide substrate (Invitrogen,CA) and 2.5μl ATP (Invitrogen,CA). The kinase reaction is allowed to procede for 1 hour at room temperature. The protease reaction is initiated by the addition of 5μl Development Reagent (Invitrogen,CA). After 1 hour incubation at room temperature the fluorescence is measured using a FlexStation plate reader (Molecular Devices, Sunnyvale, CA). The reader settings used are as follows: Fluorescence mode, endpoint, top read, excitation 400nm, emission 445nm and 520nm, Auto Cutoff 435nm and 515nm, PMT sensitivity high, 6 reads per well. Inhibition of JAK activity is calculated as the percent phosphorylation of substrate in the presence of inhibitor compared to the percent phosphorylation of substrate in the absence of inhibitor. IC50's were derived using Xlfit 4.3 (IDBS, UK), 4 parameter logistic model 205 : Y = (A+((B-A)/(l+((C/x)ΛD)))).
[0592] Inhibition of IL4-induced phospho STAT6 formation was measured by pre- incubating 0.5 million Ramos B lymphocytes (ATCC) with 5 μl compound or DMSO vehicle for 1 hour at 37 0C/ 5 % CO2. Cells were activated by addition of 1 ng/ml [f] TLA (R & D
Research Systems) for 10 min at 37 0C/ 5 % CO2 and then fixed by addition of 1.6 % [f] PFA (Electron Microscopy Services). Following a PBS wash step and permaeabilization with 100 % methanol, cells were incubated with ALEXA-conjugated anti-phosphoSTAT6 (Y641) antibody (BD 612600).The extent of cell associated-fluorescence was determined by flow cytomentry and data expressed as mean fluorescent intensity. The extent of inhibition of the IL4-induced signal was then calculated.
[0593] In the table below, activity in the Jak assays is provided as follows: +++++ = IC50 < 0.0010 μM; ++++ = 0.0010 μM < IC50 < 0.010 μM , +++ = 0.010 μM < IC50 < 0.10 μM, ++ = 0. 10 μM < IC50 < 1 μM, + = IC50 > 1 μM.
Table 1 : Select data for Examples.
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
Figure imgf000234_0001
[0594] The present invention provides a number of embodiments. It is apparent that the examples may be altered to provide other embodiments of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments, which have been represented by way of example.
[0595] All of the above U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet, are incorporated herein by reference, in their entirety. From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.

Claims

WHAT IS CLAIMED IS:
1. A compound having the formula I:
Figure imgf000235_0001
(I)
or a tautomer or pharmaceutically acceptable salt thereof, wherein: Y1 is N or CRlc; Rla is (a) C3_8cycloalkyl, optionally substituted with from 1 to 3 substituents Rld wherein each Rld is independently selected from the group consisting of Ci_8alkyl, C2- 8 alkenyl, C2.8alkynyl, hydroxyl, halogen, Ci-sheteroalkyl, cyano, aryl, heteroaryl, heterocyclyl and heterocyclylcarbonyl; or if on adjacent carbon atoms of the C3-8cycloalkyl, may be combined with the atoms to which each are attached to form an aryl group; (b) Ci-salkyl, optionally substituted with from 1 to 3 substituents selected from the group consisting of C2_8alkenyl, C2-8alkynyl, amino, hydroxyl, halogen, C1-8heteroalkyl, cyano, C3_8cycloalkyl, aryl, haloaryl, Ci_8alkylaryl, Q-salkoxyaryl, heteroaryl, C3. 8heterocyclyl and C3-8heterocyclylcarbonyl; (c) heterocyclyl, optionally substituted with from 1 to 3 substituents selected from the group consisting of Ci_8alkyl, C2_8alkenyl, C2-8alkynyl, hydroxyl, halogen, Ci- sheteroalkyl, cyano, aryl, heteroaryl, heterocyclyl and heterocyclylcarbonyl; (d) aryl, optionally substituted with from 1 to 3 substituents selected from the group consisting of Ci-8alkyl, C2-galkenyl, C2_8alkynyl, hydroxyl, halogen, Ci -sheteroalkyl, cyano, aryl, heteroaryl, heterocyclyl and heterocyclylcarbonyl, amino and alkylsulfonyl; and (e) heteroaryl, optionally substituted with from 1 to 3 substituents selected from the group consisting of Ci_8alkyl, Q-galkenyl, C2-8alkynyl, hydroxyl, halogen, Q- sheteroalkyl, cyano, aryl, heteroaryl, heterocyclyl and heterocyclylcarbonyl; Rlb is H or Ci-8alkyl; Rlc is H, Ci_8alkyl or halogen; R2 is H, Ci-salkyl, Ci_8heteroalkyl, heterocyclylCi_salkoxy, halogen or heterocyclyl; R3 is H or Ci_8alkyl or C3.8cycloalkyl; R4 is selected from the group consisting amino, Q-salkyl, aminoCi_8alkyl, C2. 8alkenyl, C2-8alkynyl, Ci-sheteroalkyl, C3-8cycloalkyl, aryl, heteroaryl and Q.gheterocyclyl; and m is 0, 1, 2 or 3.
2. A compound having the formula I:
RVRlo
R3 H
(I)
or a tautomer or pharmaceutically acceptable salt thereof, wherein: Y1 is N or CRlc; R!a is (a) C3_8cycloalkyl, optionally substituted with from 1 to 3 substituents Rld wherein each Rld is independently selected from the group consisting of Ci-8alkyl, C2. salkenyl, C2_8alkynyl, hydroxyl, halogen, Ci_8heteroalkyl, cyano, aryl, heteroaryl, heterocyclyl and heterocyclylcarbonyl; or if on adjacent carbon atoms of the C3_8cycloalkyl, may be combined with the atoms to which each are attached to form an aryl group; (b) C].8alkyl, optionally substituted with from 1 to 3 substituents selected from the group consisting of C2_8alkenyl, C2_8alkynyl, amino, hydroxyl, halogen, Ci_8heteroalkyl, cyano, C3_8cycloalkyl, aryl, haloaryl, Ci-8alkylaryl, Ci-8alkoxyaryl, heteroaryl, C3_ gheterocyclyl and C3-8heterocyclylcarbonyl; RIb is H or C,_8alkyl; Rlc is H, C1-8alkyl or halogen; R2 is H, Ci_8alkyl, Ci_8alkoxy or halogen; R3 is H or Ci-8alkyl; R4 is selected from the group consisting amino, Q^alkyl, C2_8alkenyl, C2-8alkynyl, Ci.sheteroalkyl, C3-8cycloalkyl, aryl, heteroaryl and C3_8heterocyclyl; and m is 0, 1, 2 or 3.
3. The compound of claim 1 wherein Y1 is N.
4. The compound of claim 1 wherein Y1 is CH.
5. The compound of claim 1 having the formula Ia:
Figure imgf000237_0001
(Ia)
or a tautomer or pharmaceutically acceptable salt thereof, wherein: Rla is (a) C3-8cycloalkyl, optionally substituted with from 1 to 3 substituents Rld wherein each Rld is independently selected from the group consisting of Ci_8alkyl, C2- salkenyl, C2-8alkynyl, hydroxyl, halogen, Ci-gheteroalkyl, cyano, aryl, heteroaryl, heterocyclyl and heterocyclylcarbonyl; or if on adjacent carbon atoms of the C3.8cycloalkyl, may be combined with the atoms to which each are attached to form an aryl group; (b) Ci-8alkyl, optionally substituted with from 1 to 3 substituents selected from the group consisting of C2_8alkenyl, C2-8alkynyl, amino, hydroxyl, halogen, Ci-8heteroalkyl, cyano, C3_8cycloalkyl, aryl, haloaryl, Ci-8alkylaryl, Ci_8alkoxyaryl, heteroaryl, C3. sheterocyclyl and C3-8heterocyclylcarbonyl; Rlb is H or C,.8alkyl; R2 is H, Ci.salkyl, C^alkoxy or halogen; R3 is H or C,_8alkyl; R4 is selected from the group consisting Ci-8alkyl, Ci_8heteroalkyl, C3-8cycloalkyl, and amino; and m is 0, 1, 2 or 3.
6. The compound of claim 1 wherein R3 is H.
7. The compound of claim 1 having the formula (Ib):
Figure imgf000238_0001
(Ib)
or a tautomer or pharmaceutically acceptable salt thereof, wherein: R1 is (a) Cs-gcycloalkyl, optionally substituted with hydroxyl and aryl; (b) Ci-8alkyl, optionally substituted with from 1 to 3 substituents selected from the group consisting of C2_8alkynyl, hydroxyl, halogen, Ci-8alkoxy, cyano, aminocarbonyl, C3_8cyclopropyl, aryl, haloaryl, Q-galkylaryl, Q.salkoxyaryl, heteroaryl, and heterocyclyl, heterocyclylcarbonyl; R2a is H, Ci-salkyl, Ci-8alkoxy or halogen; R2b is H, Ci-βalkyl, d.8alkoxy or halogen; R4 is selected from the group consisting Ci_8alkyl, Ci_8alkoxyCι_8alkylene, C3. scycloalkyl, Ci.8alkoxy, and amino.
8. The compound of any one of the preceding claims wherein R1 is C3. 8cycloalkyl, optionally substituted with hydroxyl.
9. The compound of claim 8 wherein R1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is optionally substituted with hydroxyl.
10. The compound of any one of claims 1 to 7 wherein R1 is Ci_8alkyl, optionally substituted with from 1 to 3 substituents selected from the group consisting of C2. 8alkynyl, hydroxy, halogen, Q-salkoxy, cyano, aminocarbonyl, Q.scycloalkyl, aryl, haloaryl, heteroaryl, heterocyclyl, and heterocyclylcarbonyl.
11. The compound of any one of claims 1 to 7 wherein R1 is -CH3, - CH2CH3, -CH(CH3)2, -C(CH3)3, or -CH2CH2CH(CH3)2.
12. The compound of any one of claims 1 to 7 wherein R1 is
Figure imgf000238_0002
substituted with from 1 to 3 substituents selected from the group consisting of C2_8alkynyl, hydroxy, halogen, Ci-8alkoxy, cyano, aminocarbonyl and C3.8cycloalkyl.
13. The compound of claim 12 wherein R1 is -CH2C≡CH, -CH2CF3, -CH2- cPr, -CH2CH2OCH3, or CH2CH2CH2OCH3.
14. The compound of any one of claims 1 to 7 wherein R1 is Ci_8alkyl, substituted with from 1 to 3 substituents selected from the group consisting of aryl, haloaryl, Ci-8alkylaryl, Ci_8alkoxyaryl, heteroaryl, heterocyclyl and heterocyclylcarbonyl.
15. The compound of any one of claims 1 to 7 wherein R2a is H, methyl, methoxy, fluoro or chloro and R2b is H, methyl, methoxy, fluoro or chloro.
16. The compound of claim 1 having the formula (Ic):
Figure imgf000239_0001
(Ic)
or a tautomer or pharmaceutically acceptable salt thereof, wherein: Y2 is -CH or -CH-CH-; R5 is H, Ci_8alkyl or hydroxyC]_8alkylene; and R6 is C?_8alkynyl, hydroxyl, halogen, Ci.salkoxy, cyano, aminocarbonyl, C3- scyclopropyl, aryl, haloaryl, heteroaryl, heterocyclyl and heterocyclylcarbonyl or Ci-galkyl, optionally substituted with from 1 to 3 substituents selected from the group consisting of C2. 8alkynyl, hydroxyl, halogen, Ci_8alkoxy, cyano, aminocarbonyl, C3-8cyclopropyl, aryl, haloaryl, Ci-8alkylaryl, Ci_8alkoxyaryl, heteroaryl, heterocyclyl and heterocyclylcarbonyl.
17. The compound of claim 16 wherein R4 is Ci_8heteroalkyl, selected from the group consisting of Ci_8alkoxy and Ci_8alkoxyCi.8alkylene.
18. The compound of claim 16 wherein R5 is selected from the group consisting of CH3; and R6 is Ph or
Figure imgf000240_0001
R8 is selected from the group consisting of Q.galkyl, halogen, Ci-8alkoxy, or may be taken together to form a heterocyclic ring; and q is 0, 1 , 2 or 3; the wavy line indicates the point of attachment to the rest of the molecule.
19. The compound of claim 1 having the formula (Id):
Figure imgf000240_0002
(Id)
or a tautomer or pharmaceutically acceptable salt thereof, wherein: R5 is Ci_8alkyl or hydroxyCj-8alkylene; or may be taken together with R8 to form a cyclic ring; R7 is Ci_8alkyl, hydroxyl or Q-galkoxy; R is selected from the group consisting of Ci_8alkyl, halogen and Q-salkoxy, or may be taken together to form a heterocyclic ring; and p is 0, 1, 2, or 3; and q is 0, 1, 2 or 3.
20. The compound of claim 1 having the formula (Ie):
Figure imgf000241_0001
(Ie)
or a tautomer or pharmaceutically acceptable salt thereof, wherein: R5 is Q-galkyl or hydroxyCi^alkylene; or may be taken together with R8a or R8b to form a cyclic ring;
R8a is H, halogen, or may be taken together with R5 to form 5-6 membered carbocyclic ring;
R8b is H, halogen or, or may be taken together with R8a to form a heterocyclic ring;
R8c is H, Ci-8alkyl, halogen or Ci-8alkoxy, or may be taken together with R8b to form a heterocyclic ring;
R8d is H; and
R8e is H, halogen or may be taken together with R5 to form 5-6 membered carbocyclic ring.
21. The compound of claim 1 having the formula If:
Figure imgf000241_0002
(If)
or a tautomer or pharmaceutically acceptable salt thereof, wherein: R9 is heteroCi-8alkyl.
22. The compound of claim 1 wherein R2 is selected from the group consisting of: H and Q.salkyl.
23. The compound of claim 1 wherein R4 is selected from the group consisting of: Q.galkyl and C3_scycloalkyl.
24. The compound of claim 1 wherein R5 is selected from the group consisting of: H and Q-salkyl.
25. The compound of claim 1 having the formula Ig:
Figure imgf000242_0001
(Ig) or a tautomer or pharmaceutically acceptable salt thereof, wherein: R!0 is H or Q-salkyl; or may be taken together with R1 ' and the nitrogen atom to which each is attached to form a heterocyclic ring; and
R1 ' is H or Ci^alkyl; or may be taken together with R10 and the nitrogen atom to which each is attached to form a heterocyclic ring.
26. The compound of claim 1 having the formula Ih:
Figure imgf000242_0002
(Ih)
or a tautomer or pharmaceutically acceptable salt thereof, wherein: R1 and R4 are C3-8cycloalkyl.
27. The compound of claim 1 wherein having formula (Ii):
Figure imgf000243_0001
(Ii)
or a tautomer or pharmaceutically acceptable salt thereof, wherein: R5 is H or Ci.salkyl;
R4 is Ci-8alkyl or heterocyclyl.
28. The compound of claim 1 wherein R4 is selected from the group consisting of -CH3, -CH2CH3, -NH2, -NHCH3, -NCH2CH3, -N(CH3)2, -OCH3, -OCH2CH3, OCH(CH3)2, -CH2OCH3, -CH2CONH2, cPr, and cBu. 29. The compound of claim 1 wherein: R4 has the formula:
Figure imgf000243_0002
wherein R12 is selected from the group consisting of H and OH, r is O or 1 ; and the wavy line indicates the point of attachment to the rest of the molecule. 30. The compound of claim 1 wherein: R4 has the formula:
Figure imgf000243_0003
wherein R12 is selected from the group consisting of H and OH; and the wavy line indicates the point of attachment to the rest of the molecule. 31. The compound of claim 1 selected from the group consisting of: Methyl 3-(5-carbamoyl-4-(2,2,2-trifluoroethylamino)pyrimidin-2- ylamino)phenylcarbamate; 2-(3-(cyclopropanecarboxamido)phenylamino)-4-(2,2,2- trifluoroethylamino)pyrimidine-5-carboxamide; 2-(3-(2-methoxyacetamido)phenylamino)-4- (2,2,2-trifluoroethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(2,2,2- trifluoroethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4- (methylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4- (ethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(prop-2- ynylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4- (isopropylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4- (cyclopropylmethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(tert- butylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(2- methoxyethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4- (cyclopentylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(3- methoxypropylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4- (benzylamino)pyrimidine-5-carboxamide; methyl 5-(5-carbamoyl-4-(2,2,2- trifluoroethylamino)pyrimidin-2-ylamino)-2-chlorophenylcarbamate; 4-(cyclopentylamino)- 2-(3-(cyclopropanecarboxamido)phenylamino)pyrimidine-5-carboxamide; 2-(3- (cyclobutanecarboxamido)phenylamino)-4-(cyclopentylamino)pyrimidine-5-carboxamide; A- (cyclopentylamino)-2-(3-propionamidophenylamino)pyrimidine-5-carboxamide; A- (cyclopentylamino)-2-(3-(2-methoxyacetamido)phenylamino)pyrimidine-5-carboxamide; methyl 3-(5-carbamoyl-4-(cyclopentylamino)pyrimidin-2-ylamino)phenylcarbamate; ethyl 3- (5-carbamoyl-4-(cyclopentylamino)pyrimidin-2-ylamino)phenylcarbamate; methyl 5-(5- carbamoyl-4-(cyclopentylamino)pyrimidin-2-ylamino)-2-chlorophenylcarbamate; A- (benzylamino)-2-(3-(cyclopropanecarboxamido)phenylamino)pyrimidine-5-carboxamide; A- (benzylamino)-2-(3-(cyclobutanecarboxamido)phenylamino)pyrimidine-5-carboxamide; A- (benzylamino)-2-(3-propionamidophenylamino)pyrimidine-5-carboxamide; 4-(benzylamino)- 2-(3-(2-methoxyacetamido)phenylamino)pyrimidine-5-carboxamide; methyl 3-(A- (benzylamino)-5-carbamoylpyrimidin-2-ylamino)phenylcarbamate; ethyl 3-(4- (benzylamino)-5-carbamoylpyrimidin-2-ylamino)phenylcarbamate; methyl 5-(4- (benzylamino)-5-carbamoylpyrimidin-2-ylamino)-2-chlorophenylcarbamate; A- (cyclopentylamino)-2-(3-ureidophenylamino)pyrimidine-5-carboxamide; A- (cyclopentylamino)-2-(3-(3-methylureido)phenylamino)pyrimidine-5-carboxamide; A- (cyclopentylamino)-2-(3-(3,3-dimethylureido)phenylamino)pyrimidine-5-carboxamide; 4- (cyclopentylamino)-2-(3-(3-ethylureido)phenylamino)pyrimidine-5-carboxamide; 4- (cyclopentylamino)-2-(3-(pyrrolidine- 1 -carboxamido)phenylamino)pyrimidine-5- carboxamide; 4-(benzylamino)-2-(3-ureidophenylamino)pyrimidine-5-carboxamide; A- (benzylamino)-2-(3-(3-methylureido)phenylamino)pyrimidine-5-carboxamide; 4- (benzylamino)-2-(3-(pyrrolidine- 1 -carboxamido)phenylamino)pyrimidine-5-carboxamide; isopropyl 3-(4-(benzylamino)-5-carbamoylpyrimidin-2-ylamino)phenylcarbamate; (S)-2-(3- (2-methoxyacetamido)phenylamino)-4-( 1 -phenylethylamino)pyrimidine-5-carboxamide; 2- (3-(2-methoxyacetamido)phenylamino)-4-(4-methylbenzylamino)pyrimidine-5- carboxamide ; 2-(3-(2-methoxyacetamido)phenylamino)-4-(4- methoxybenzylamino)pyrimidine-5-carboxamide; 4-(4-chlorobenzylamino)-2-(3-(2- methoxyacetamido)phenylamino)pyrimidine-5-carboxamide; 4-(3,4-dichlorobenzylamino)-2- (3-(2-methoxyacetamido)phenylaraino)pyrimidine-5-carboxamide; (R)-2-(3-(2- methoxyacetamido)phenylamino)-4-( 1 -phenylethylamino)pyrimidine-5-carboxamide; (S)-2- (3-acetamidophenylamino)-4-(2-hydroxy-2-phenylethylamino)pyrimidine-5-carboxamide; (R)-2-(3-acetamidophenylamino)-4-(2-hydroxy-2-phenylethylamino)pyrimidine-5- carboxamide; 2-(3-acetamidophenylamino)-4-(2-amino-2-oxoethylamino)pyrimidine-5- carboxamide; 2-(3-acetamidophenylamino)-4-(2-phenylcyclopropylamino)pyrimidine-5- carboxamide; 2-(3-acetamidophenylamino)-4-(cyclohexylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-((trans)-2-hydroxycyclopentylamino)pyrimidine-5- carboxamide; 2-(3-acetamidophenylamino)-4-(benzyl(methyl)amino)pyrimidine-5- carboxamide; 4-(cyclobutylamino)-2-(3-(2-methoxyacetamido)phenylamino)pyrimidine-5- carboxamide; 2-(3-acetamidophenylamino)-4-(cyclobutylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(phenethylamino)pyrimidine-5-carboxamide; A- (isopropylamino)-2-(3-(2-methoxyacetamido)phenylamino)pyrimidine-5-carboxamide; 2-(3- (2-methoxyacetamido)phenylamino)-4-(2,3,6-trifluorobenzylamino)pyrimidine-5- carboxamide; 2-(3-acetamidophenylamino)-4-(2,3,6-trifluorobenzylamino)pyrimidine-5- carboxamide; (S)-2-(3-acetamidophenylamino)-4-(2-phenylpropylamino)pyrimidine-5- carboxamide; (S)-2-(3-acetamidophenylamino)-4-(l-hydroxy-3-(lH-imidazol-5-yl)propan-2- ylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(3-amino-3- oxopropylamino)pyrimidine-5-carboxamide; (R)-2-(3-acetamidophenylamino)-4-(l-hydroxy- 4-methylpentan-2-ylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(2- (pyrrolidin-l-yl)ethylamino)pyrimidine-5-carboxamide; (S)-2-(3-acetamidophenylamino)-4- (l-phenylethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(2-oxo-2- (pyrrolidin-l-yl)ethylamino)pyrimidine-5-carboxamide; (R)-2-(3-acetamidophenylamino)-4- (piperidin-3-ylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(4- methylbenzylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(4- methoxybenzylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(4- chlorobenzylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(3,4- dichlorobenzylamino)pyrimidine-5-carboxamide; (R)-2-(3-acetamidophenylamino)-4-(l- phenylethylamino)pyriniidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(2- (methylamino)-2-oxoethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4- ((2S, 3S)- 1 -hydroxy-3-methylpentan-2-ylamino)pyrimidine-5-carboxamide; 2-(3- acetamidophenylamino)-4-(cyanomethylamino)pyrimidine-5-carboxamide; 2-(3- acetamidophenylamino)-4-(tetrahydro-2H-pyran-4-ylamino)pyrimidine-5-carboxamide; (S)- 2-(3-acetamidophenylamino)-4-(l-hydroxy-3-phenylpropan-2-ylamino)pyrimidine-5- carboxamide; 4-(isopropylamino)-2-(3-(N-methylacetamido)phenylamino)pyrimidine-5- carboxamide; 4-(cyclopentylamino)-2-(3-(N-methylacetamido)phenylamino)pyrimidine-5- carboxamide; 4-(benzylamino)-2-(3-(N-methylacetamido)phenylamino)pyrimidine-5- carboxamide; 2-(3-acetamidophenylamino)-4-(2-morpholinoethylamino)pyrimidine-5- carboxamide; (R)-2-(3-acetamidophenylamino)-4-(2-phenylpropylamino)pyrimidine-5- carboxamide; (S)-2-(3-acetamidophenylamino)-4-(2-hydroxypropylamino)pyrimidine-5- carboxamide; (R)-2-(3-acetamidophenylamino)-4-(2,3-dihydroxypropylamino)pyrimidine-5- carboxamide; 2-(3-acetamidophenylamino)-4-(2-methoxy-2-phenylethylamino)pyrimidine-5- carboxamide; (S)-2-(3-acetamidophenylamino)-4-(l -amino- l-oxopropan-2- ylamino)pyrimidine-5-carboxamide; (R)-2-(3-(2-methoxy-N- methylacetamido)phenylamino)-4-(l-phenylethylamino)pyrimidine-5-carboxamide; (R)-2-(3- (N-methylacetamido)phenylamino)-4-(l-phenylethylamino)pyrimidine-5-carboxamide; A- (isopropylamino)-2-(3-(2-methoxy-N-methylacetamido)phenylamino)pyrimidine-5- carboxamide; 4-(cyclopentylamino)-2-(3-(2-methoxy-N- methylacetamido)phenylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(3-(2- methoxy-N-methylacetamido)phenylamino)pyrimidine-5-carboxamide; (R)-2-(3- acetamidophenylamino)-4-(l -amino- l-oxopropan-2-ylamino)pyrimidine-5-carboxamide; 2- (3-acetamidophenylamino)-4-(2,3-dihydro-lH-inden-2-ylamino)pyrimidine-5-carboxamide; (S)-2-(3-acetamidophenylamino)-4-(2-hydroxy-l-phenylethylamino)pyrimidine-5- carboxamide; 2-(3-acetamidophenylamino)-4-(3-fluorobenzylamino)pyrimidine-5- carboxamide; 2-(3-acetamidophenylamino)-4-(2,3-difluorobenzylamino)pyrimidine-5- carboxamide; (S)-2-(3-acetamidophenylamino)-4-(2,3-dihydro-lH-inden-l- 102 ylamino)pyrimidine-5-carboxamide; (R)-2-(3-acetamidophenylamino)-4-(2,3-dihydro-lH-
103 inden-l-ylamino)pyrimidine-5-carboxamide; (R)-2-(3-acetamidophenylamino)-4-(2-hydroxy-
104 l-phenylethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-
105 (benzo[d][l,3]dioxol-5-ylmethylamino)pyrimidine-5-carboxamide; 2-(3-
106 acetamidophenylamino)-4-(2-fluorobenzylamino)pyrimidine-5-carboxamide; 2-(3-
107 acetamidophenylamino)-4-(3-chlorobenzylamino)pyrimidine-5-carboxamide; 2-(3-
108 acetamidophenylamino)-4-(2,5-difluorobenzylamino)pyrimidine-5-carboxamide; 2-(3-
109 acetamidophenylamino)-4-(4-fluorobenzylamino)pyrimidine-5-carboxamide; 4-(4-
110 fluorobenzylamino)-2-(3-(2-methoxyacetamido)phenylamino)pyrimidine-5-carboxamide;
111 (R)-4-( 1 -phenylethylamino)-2-(3-(pyrrolidine- 1 -carboxamido)phenylamino)pyrimidine-5-
112 carboxamide; 2-(3-acetamido-4-chlorophenylamino)-4-(benzylamino)pyrimidine-5-
113 carboxamide; 4-(benzylamino)-2-(4-chloro-3-(2-
114 methoxyacetamido)phenylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(4-chloro-3-
115 (3-cyclobutylureido)phenylamino)pyrimidine-5-carboxamide; (R)-2-(3-acetamido-4-
116 chlorophenylamino)-4-(l-phenylethylamino)pyrimidine-5-carboxamide; (R)-2-(4-chloro-3-
117 (2-methoxyacetamido)phenylamino)-4-(l-phenylethylamino)pyrimidine-5-carboxamide; (R)-
118 2-(4-chloro-3-(cyclopropanecarboxamido)phenylamino)-4-(l-phenylethylamino)pyrimidine-
119 5-carboxamide; (R)-2-(4-chloro-3-(3-cyclobutylureido)phenylarnino)-4-(l-
120 phenylethylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-
121 (benzylamino)-N-niethylpyrimidine-5-carboxamide; 4-(benzylamino)-2-(3-(2-
122 methoxyacetamido)phenylamino)-N-methylpyrimidine-5-carboxamide ;
123 methoxyacetamido)phenylamino)-N-methylpyrimidine-5-carboxamide ; benzyl 3-((2-(3-
124 acetamidophenylamino)-5-carbamoylpyrimidin-4-ylamino)methyl)piperidine-l-carboxylate ;
125 and 6-(3-acetamidophenylamino)-4-(benzylamino)nicotinamide.
1 32. The compound of claim 1 selected from the group consisting of:
2 2-(3-acetamidophenylamino)-4-(piperidin-3-ylmethylamino)pyrimidine-5-carboxamide; 2-(3-
3 acetamidophenylamino)-4-((l-carbamoylpiperidin-3-yl)methylamino)pyrimidine-5-
4 carboxamide; 2-(3-acetamidophenylamino)-4-(( 1 -(4-fluorophenylcarbamoyl)piperidin-3-
5 yl)methylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-((l-
6 acetylpiperidin-3-yl)methylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-
7 4-((l-(methylsulfonyl)piperidin-3-yl)methylamino)pyrimidine-5-carboxamide; (R)-2-(3-(2,5-
8 dihydro- 1 H-pyrrole- 1 -carboxamido)phenylamino)-4-( 1 -phenylethylamino) pyrimidine-5-
9 carboxamide; (R)-2-(3 -(N-methylpyrrolidine- 1 -carboxamido)phenylamino)-4-( 1 - phenylethylamino) pyrimidine-5-carboxamide; 4-(cyclopropylmethylamino)-2-(3- (pyrrolidine- l-carboxamido)phenylamino) pyrimidine-5-carboxamide; A- (cyclopropylmethylamino)-2-(3-(2-methoxyacetamido)phenylamino) pyrimidine-5- carboxamide; 4-(cyclopropylmethylamino)-2-(3-(2-methoxy-N- methylacetamido)phenylamino) pyrimidine-5-carboxamide; 4-(cyclopropylmethylamino)-2- (3-(N-methylacetamido)phenylamino) pyrimidine-5-carboxamide; A- (cyclopropylmethylamino)-2-(3-(N-methylpyrrolidine- 1 -carboxamido) phenylamino)pyrimidine-5-carboxamide; 2-(3-((S)-3-hydroxypyrrolidine-l- carboxamido)phenylamino)-4-((R)-l -phenylethylamino) pyrimidine-5-carboxamide; (R)- methyl 5-(5-carbamoyl-4-( 1 -phenylethylamino)pyrimidin-2-ylamino)-2- chlorophenylcarbamate; 4-(benzylamino)-2-(4-chloro-3-(pyrrolidine- 1 - carboxamido)phenylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(4-chloro-3-(3- methylureido)phenylamino)pyrimidine-5-carboxamide; (R)-2-(4-chloro-3-(3- methylureido)phenylamino)-4-(l -phenylethylamino) pyrimidine-5-carboxamide; 4- (methylamino)-2-(3-(pyrrolidine- l-carboxamido)phenylamino)pyrimidine-5-carboxamide; A- (ethylamino)-2-(3-(pyrrolidine-l-carboxamido)phenylamino)pyrimidine-5-carboxamide; 4- (butylamino)-2-(3-(pyrrolidine-l-carboxamido)phenylamino)pyrimidine-5-carboxamide; 2- (3-(pyrrolidine- 1 -carboxamido)phenylamino)-4-(2,2,2-trifluoroethylamino)pyrimidine-5- carboxamide; 2-(3-((S)-2-methylpyrrolidine-l-carboxamido)phenylamino)-4-((R)-l- phenylethylamino) pyrimidine-5-carboxamide; 2-(3-((S)-2-(methoxymethyl)pyrrolidine-l- carboxamido) phenylamino)-4-((R)-l -phenylethylamino) pyrimidine-5-carboxamide; (S)-4- (benzylamino)-2-(3-(2-methylpyrrolidine-l-carboxamido)phenylamino) pyrimidine-5- carboxamide; (S)-4-(benzylamino)-2-(3-(2-(methoxymethyl)pyrrolidine-l-carboxamido) phenylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(3-(N-methylpyrrolidine-l- carboxamido) phenylarnino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(3-(2,5-dihydro- lH-pyrrole-l-carboxamido)phenylamino) pyrimidine-5-carboxamide; (S)-4-(benzylamino)-2- (3-(3-hydroxypyrrolidine-l-carboxamido)phenylamino) pyrimidine-5-carboxamide; (S)-4- (sec-butylamino)-2-(3-(2-methoxyacetamido)phenylamino)pyrimidine-5-carboxamide; (R)-4- (benzylamino)-2-(3-(2-methylpyrrolidine- 1 -carboxamido) phenylamino)pyrimidine-5- carboxamide; (R)-4-(benzylamino)-2-(3-(2-(methoxymethyl)pyrrolidine-l -carboxamido) phenylamino)pyrimidine-5-carboxamide; 2-(3-((R)-2-methylpyrrolidine- 1 - carboxamido)phenylamino)-4-((R)-l-phenylethylamino)pyrimidine-5-carboxamide; 2-(3- ((R)-2-(methoxymethyl)pyrrolidine- 1 -carboxamido) phenylamino)-4-((R)-l- phenylethylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(3-(N-cyclopropyl-2- methoxyacetamido) phenylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(3-(N- cyclopropylcyclopropanecarboxamido) phenylamino)pyrimidine-5-carboxamide; (R)-2-(3- acetamidophenylamino)-4-(cyclopropyl(phenyl)methylaniino)pyrimidine-5-carboxamide; A- (benzylamino)-2-(4-chloro-3-(3-cyclopropylureido)phenylamino)pyrimidine-5-carboxamide; 2-(3-acetamido-4-methylphenylamino)-4-(benzylamino)pyrimidine-5-carboxamide; 2-(3- acetamido-4-fluorophenylamino)-4-(benzylamino)pyrimidine-5-carboxamide; A- (benzylamino)-2-(4-methyl-3-(3-methylureido)phenylamino)pyrimidine-5-carboxamide; (R)- 2-(3-(N-cyclopropylacetamido)phenylamino)-4-( 1 -phenylethylamino) pyrimidine-5- carboxamide; (R)-2-(3-(N-cyclopropyl-2-methoxyacetamido)phenylamino)-4-(l- phenylethylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(4-methoxy-3-(pyrrolidine- l-carboxamido)phenylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(4-methoxy-3- (3-methylureido)phenylamino)pyrimidine-5-carboxamide; 2-(4-chloro-3-(3- methylureido)phenylamino)-4-(3-chlorobenzylamino)pyrimidine-5-carboxamide; 2-(4- chloro-3-(3-methylureido)phenylamino)-4-(cyclopentylamino)pyrimidine-5-carboxamide; 2- (4-chloro-3-(pyrrolidine- 1 -carboxamido)phenylamino)-4-(cyclopentylamino)pyrimidine-5- carboxamide; 2-(4-chloro-3-(pyrrolidine- 1 -carboxamido)phenylamino)-4-(3- chlorobenzylamino)pyrimidine-5-carboxamide; 2-(4-chloro-3-(pyrrolidine-l- carboxamido)phenylamino)-4-(cyclopropylmethylamino)pyrimidine-5-carboxamide; (S)-4- (sec-butylamino)-2-(4-chloro-3-(3-methylureido)phenylamino)pyrimidine-5-carboxamide; (S)-4-(sec-butylamino)-2-(4-chloro-3-(pyrrolidine- 1 -carboxamido)phenylamino)pyrimidine- 5-carboxamide; 2-(4-chloro-3-(pyrrolidine-l-carboxamido)phenylamino)-4-(3- fluorobenzylamino)pyrimidine-5-carboxamide; 2-(4-chloro-3-(3- methylureido)phenylamino)-4-(cyclopropylmethylamino)pyrimidine-5-carboxamide; 4-(3- fluorobenzylamino)-2-(3-(pyrrolidine- 1 -carboxamido)phenylamino)pyrimidine-5- carboxamide; 4-(3-chlorobenzylamino)-2-(3-(pyrrolidine-l- carboxamido)phenylamino)pyrimidine-5-carboxamide; 4-(2-fluorobenzylamino)-2-(3-(3- methylureido)phenylamino)pyrimidine-5-carboxamide; N-(5-(4-(benzylamino)-5- carbamoylpyrimidin-2-ylamino)-2-chlorophenyl)morpholine-4-carboxamide; (R)-N-(5-(5- carbamoyl-4-( 1 -phenylethylamino)pyrimidin-2-ylamino)-2-chlorophenyl)morpholine-4- carboxamide; 2-(3-acetamidophenylamino)-4-(l -methyl- lH-indol-4-ylamino)pyrimidine-5- carboxamide; 2-(3-acetamidophenylamino)-4-( 1 -ethyl- lH-indol-4-ylamino)pyrimidine-5- carboxamide; 2-(3-acetamidophenylamino)-4-(2-methyl-2H-indazol-4-ylamino)pyrimidine- 5-carboxamide; 2-(3-acetamidophenylamino)-4-(piperidin-4-ylmethylamino)pyrimidine-5- carboxamide; 2-(3-acetamidophenylamino)-4-(l -methyl- lH-indazol-4-ylamino)pyrimidine- 78 5-carboxamide; 2-(3-acetamidophenylarnino)-4-(benzo[c][i,2,5]thiadiazo-4-
79 ylamino)pyrimidine-5-carboxamide; (R)-2-(4-chloro-3-ureidophenylamino)-4-(l-
80 phenylethylamino) pyrimidine-5-carboxamide; 4-(benzylamino)-2-(4-chloro-3-
81 ureidophenylamino)pyrimidine-5-carboxamide; (R)-2-(4-chloro-3-(3,3-
82 dimethylureido)phenylamino)-4-(l -phenylethylamino) pyrimidine-5-carboxamide; A-
83 (benzylamino)-2-(4-chloro-3-(3,3-dimethylureido)phenylamino) pyrimidine-5-carboxamide;
84 4-(benzylamino)-2-(2-fluoro-5-(3-methylureido)phenylamino)pyrimidine-5-carboxamide; 4-
85 (benzylamino)-2-(5-(3,3-dimethylureido)-2-fluorophenylamino)pyrimidine-5-carboxamide;
86 (R)-4-(benzylamino)-2-(3-(tetrahydrofuran-2-carboxamido)phenylamino)pyrimidine-5-
87 carboxamide; 4-(benzylamino)-2-(3-(tetrahydrofuran-3-
88 carboxamido)phenylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(2-fluoro-5-
89 (pyrrolidine- l-carboxamido)phenylamino)pyrimidine-5-carboxamide; (R)-2-(4-chloro-3-
90 (piperidine-l-carboxamido)phenylamino)-4-(l-phenylethylamino)pyrimidine-5-carboxamide;
91 (S)-4-(benzylamino)-2-(3-(tetrahydrofuran-2-carboxamido) phenylamino)pyrimidine-5-
92 carboxamide; 4-((R)- 1 -phenylethylamino)-2-(3-((S)-tetrahydrofuran-2-carboxamido)
93 phenylamino)pyrimidine-5-carboxamide; (S)-4-(3-fluorobenzylamino)-2-(3-(tetrahydrofuran-
94 2-carboxamido) phenylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(4-chloro-3-
95 (piperidine-1-carboxamido) phenylamino) pyrimidine-5-carboxamide; (R)-4-(benzylamino)-
96 2-(3-(3-(dimethylamino)pyrrolidine-l-carboxamido)phenylamino)pyrimidine-5-carboxamide;
97 (R)-4-(benzylamino)-2-(3-(3-hydroxypiperidine-l-carboxamido)phenylamino)pyrimidine-5-
98 carboxamide; (R)-2-(3-(4-hydroxypiperidine-l-carboxamido)phenylamino)-4-(l-
99 phenylethylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(3-(4-methylpiperazine- 1 -
100 carboxamido) phenylamino) pyrimidine-5-carboxamide; N-(3-(4-(benzylamino)-5-
101 carbamoylpyrimidin-2-ylamino) phenyl)morpholine-4-carboxamide; 4-(benzylamino)-2-(3-
102 (piperidine-1-carboxamido) phenylamino)pyrimidine-5-carboxamide; 2-(3-(azetidine-l-
103 carboxamido)phenylamino)-4-(benzylamino) pyrimidine-5-carboxamide; (R)-4-(l-
104 phenylethylamino)-2-(3-(piperidine-l -carboxamido) phenylamino)pyrimidine-5-
105 carboxamide; (R)-2-(4-chloro-3-(pyrrolidine-l-carboxamido)phenylamino)-4-(l-
106 phenylethylamino) pyrimidine-5-carboxamide; 2-(3-(azetidine-l-carboxamido)phenylamino)-
107 4-(benzylamino) pyrimidine-5-carboxamide; 2-(3-acetamido-4-(2-(pyrrolidin-l-
108 yl)ethoxy)phenylamino)-4-(3-fluorobenzylamino)pyrimidine-5-carboxamide; 2-(3-
109 acetamido-4-(2-(pyrrolidin- 1 -yl)ethoxy)phenylamino)-4-(2-methyl-2H-indazol-4-
110 ylamino)pyrimidine-5-carboxamide; tert-butyl 3-((2-(3-acetamidophenylamino)-5-
111 carbamoylpyrimidin-4-ylamino)methyl)pyrrolidine- 1 -carboxylate; 2-(3- 112 acetamidophenylamino)-4-(pyrrolidin-3-ylniethylamino)pyrimidine-5-carboxylic acid; 2-(3-
113 acetamido-4-(2-(pyrrolidin- 1 -yl)ethoxy)phenylamino)-4-(benzo[c] [1,2, 5]thiadiazo-4-
114 ylamino)pyrimidine-5-carboxamide; 2-(3-acetamido-4-(2-
115 (dimethylamino)ethoxy)phenylamino)-4-(3-fluorobenylamino)pyrimidine-5-carboxamide; 2-
116 (3-acetamido-4-(2-(dimethylamino)ethoxy)phenylamino)-4-(2-methyl-2H-indazol-4-
117 ylamino)pyrimidine-5-carboxamide; 2-(3-acetamido-4-(2-
118 (dimethylamino)ethoxy)phenylamino)-4-(benzo[c][i,2,5]thiadiazo-4-ylamino)pyrimidine-5-
119 carboxamide; 2-(3-acetamido-4-(2-(piperidin-l-yl)propoxy)phenylamino)-4-(3-
120 fluorobenzylamino)pyrimidine-5-carboxamide; 2-(3-acetamido-4-(2-(piperidin- 1-
121 yl)propoxy)phenylamino)-4-(2-methyl-2H-indazol-4-ylamino)pyrimidine-5-carboxamide; 2-
122 (3-(azetidine- 1 -carboxamido)-4-chlorophenylamino)-4-(benzylamino) pyrimidine-5-
123 carboxamide; 2-(3-(azetidine-l-carboxamido)-4-fluorophenylamino)-4-(benzylamino)
124 pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(isobutylamino)pyrimidine-5-
125 carboxamide;
126 2-(4-chloro-3-(pyrrolidine-l-carboxamido)phenylamino)-4-(isobutylamino)pyrimidine-5-
127 carboxamide; (R)-4-(sec-butylamino)-2-(4-chloro-3-(pyrrolidine-l-
128 carboxamido)phenylamino)pyrimidine-5-carboxamide; (R)-2-(3-acetamidophenylamino)-4-
129 (sec-butylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(4-methoxy-3-(N-
130 methylpyrrolidine- 1 -carboxamido)phenylamino)pyrimidine-5-carboxamide; 4-(3-
131 fluorobenzylamino)-2-(4-methoxy-3-(N-methylpyrrolidine-l-
132 carboxamido)phenylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(4-chloro-3-(N-
133 methylpyrrolidine- 1 -carboxamido)phenylamino)pyrimidine-5-carboxamide; 2-(4-chloro-3-
134 (N-methylpyrrolidine- 1 -carboxamido)phenylamino)-4-(3-fluorobenzylamino)pyrimidine-5-
135 carboxamide; 2-(3-acetamido-4-(2-(piperidin-l-yl)propoxy)phenylamino)-4-(
136 benzo[c][/,2,5]thiadiazo-4-ylamino)pyrimidine-5-carboxamide; 2-(3-acetamido-4-(2-
137 (pyrrolidin-l-yl)ethoxy)phenylamino)-4-(benzylamino)pyrimidine-5-carboxamide; 2-(3-
138 acetamido-4-(2-(piperidin-l-yl)propoxy)phenylamino)-4-(benzylamino)pyrimidine-5-
139 carboxamide; 2-(3-acetamido-4-(2-(piperidin- 1 -yl)propoxy)phenylamino)-4-( 1 -methyl- IH-
140 indazol-4-ylamino)pyrimidine-5-carboxamide; (S)-2-(3-acetamidophenylamino)-4-(3-
141 methylbutan-2-ylamino)pyrimidine-5-carboxarnide; (S)-2-(4-chloro-3-(pyrrolidine-l -
142 carboxamido)phenylamino)-4-(3-methylbutan-2-ylamino)pyrimidine-5-carboxamide; 2-(3-
143 acetamidophenylamino)-4-(2-methylbutylamino)pyrimidine-5-carboxamide; 2-(4-chloro-3-
144 (pyrrolidine- 1 -carboxamido)phenylamino)-4-(2-methylbutylamino)pyrimidine-5- 145 carboxamide; 2-(3-acetamidophenylamino)-4-(isopentylamino)pyrimidine-5-carboxamide;
146 (R)-2-(3-acetamidophenylamino)-4-(3-methylbutan-2-ylamino)pyrimidine-5-carboxamide;
147 (R)-2-(4-chloro-3-(pyrrolidine-l-carboxamido)phenylamino)-4-(3-methylbutan-2-
148 ylamino)pyrimidine-5-carboxamide; (R)-2-(3-(4-methylpiperazine-l-
149 carboxamido)phenylamino)-4-(l-phenylethylamino) pyrimidine-5-carboxamide; (R)-N-(3-
150 (5-carbamoyl-4-( 1 -phenylethylamino)pyrimidin-2-ylamino) phenyl)morpholine-4-
151 carboxamide; 4-(3-fluorobenzylamino)-2-(3-(4-methylpiperazine- 1 -carboxamido)
152 phenylamino)pyrimidine-5-carboxamide; 2-(3-(2-cyanoacetamido)phenylamino)-4-(3-
153 fluorobenzylamino)-pyrimidine-5-carboxamide ; N-(3-(5-carbamoyl-4-(3-
154 fluorobenzylamino)pyrimidin-2-ylamino) phenyl)morpholine-4-carboxamide ; 2-(3-
155 acetarnido-5-chlorophenylamino)-4-(benzylarnino)pyrimidine-5-carboxamide ; 2-(3-
156 acetamido-5-chlorophenylamino)-4-(3-fluorobenzylamino)pyrimidine-5-carboxamide ; 2-(3-
157 acetamidophenylamino)-4-(cyclobutylmethylamino)pyrimidine-5-carboxamide; 2-(4-chloro-
158 3 -(pyrrolidine- 1 -carboxamido)phenylamino) -4- (cyclobutylmethylamino)pyrimidine- 5 -
159 carboxamide; 2-(3-acetamidophenylamino)-4-(4-aminophenylamino) pyrimidine-5-
160 carboxamide ; 4-(benzylamino)-2-(4-fluoro-3-(3-methylureido)phenylamino)pyrimidine-5-
161 carboxamide; 4-(3-fluorobenzylamino)-2-(3-(3,3,3-trifluoropropanamido) phenylamino)-
162 pyrimidine-5-carboxamide; benzyl 3-(5-carbamoyl-4-(3-fluorobenzylamino)pyrimidin-2-
163 ylamino)phenylcarbamate ; 2-(3-(l-cyanocyclopropanecarboxamido)phenylamino)-4-(3-
164 fluorobenzylamino)pyrimidine-5-carboxamide ; 4-(2-fluorobenzylamino)-2-(3-
165 (isonicotinamido)-phenylamino)pyrimidine-5-carboxamide ; 4-(2-fluorobenzylamino)-2-(3-
166 (picolinamido)-phenylamino)pyrimidine-5-carboxamide; 4-(2-fluorobenzylamino)-2-(3-
167 (nicotinamido)-phenylamino)pyrimidine-5-carboxamide; 4-(2-fluorobenzylamino)-2-(3-(2-
168 (pyridin-3-yl)acetamido)-phenylamino)pyrimidine-5-carboxamide; 4-(2-fluorobenzylamino)-
169 2-(3-(6-hydroxypicolinamido)-phenylamino)pyrimidine-5-carboxamide; 4-(2-
170 fluorobenzylamino)-2-(3-(2-(pyridin-4-yl)acetamido)-phenylamino)pyrimidine-5-
171 carboxamide; 4-(2-fluorobenzylamino)-2-(3-(2-(pyridm-2-yl)acetamido)-
172 phenylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-(4-(2-
173 cyanoacetamido)-phenylamino)pyrimidine-5-carboxamide; 2-(3-acetamidophenylamino)-4-
174 (4-(l-cyanocyclopropane-carboxamido) phenylamino)pyrimidine-5-carboxarnide; 2-(3-
175 acetamidophenylamino)-4-(4-(3,3,3-trifluoro-propanamido) phenylamino)pyrimidine-5-
176 carboxamide; 2-(3-acetamido-4-(2-(pyrrolidin- 1 -yl)ethoxy)phenylamino)-4-( 1 -methyl- IH-
177 indazol-4-ylamino)pyrimidine-5-carboxamide; 4-(benzylamino)-2-(3-(2-
178 (dimethylamino)acetamido)phenylamino)pyrimidine-5-carboxamide; 2-(3-(2- 179 (dimethylamino)acetamido)phenylamino)-4-(l -methyl- lH-indazol-4-ylamino)pyrimidine-5-
180 carboxamide; 2-(3-acetamidophenylamino)-4-(l-phenylcyclopropylamino)pyrimidine-5-
181 carboxamide; 2-(3-(2-(dimethylamino)acetamido)phenylamino)-4-( 1 -
182 phenylcyclopropylamino)pyrimidine-5-carboxamide; 2-(3-acetamido-4-methylphenylamino)-
183 4-(l-phenylcyclopropylamino)pyrimidine-5-carboxamide; 4-(benylamino)-2-(2,2-dimethyl-3-
184 oxo-3,4-dihydro-2H-benzo[έ>][i,4]oxazin-6-ylamino)- pyrimidine-5-carboxamide; 2-(2,2-
185 dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][i,4]oxazin-6-ylamino)-4-(l-
186 phenylcyclopropylamino)pyrimidine-5-carboxamide; 4-(benylamino)-2-(3-
187 isobutyraminophenylamino)pyrimidine-5-carboxamide; 4-(benylamino)-2-(3-
188 pivalaminophenylamino)pyrimidine-5-carboxamide; (S)-4-(benylamino)-2-(3-(l-
189 methylpyrrolidine-2-carboxamido)phenylamino)pyrimidine-5-carboxamide; 2-(3-
190 acetamidophenylamino)-4-((l-methyl-lH-pyrazol-4-yl)methylamino)pyrimidine-5-
191 carboxamide; 4-((l-methyl-lH-pyrazol-4-yl)methylamino)-2-(2-oxo-2,3-
192 dihydrobenzo[<i]oxazol-5-ylamino)- pyrimidine-5-carboxamide; 2-(2,2-dimethyl-3-oxo-3,4-
193 dihydro-2H-benzo[b][i,4]oxazin-6-ylamino)- 4-((l -methyl- lH-pyrazol-4-
194 yl)methylamino)pyrimidine-5-carboxamide; 2-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-
195 benzo[b][7,4]oxazin-6-ylamino)- 4-(pyridine-2-ylmethylamino)pyrimidine-5-carboxamide;
196 2-(3-acetamidophenylamino)-4-(cyclopentylmethylamino)pyrimidine-5-carboxamide; A-
197 (cyclopentylmethylamino)-2-(3-(pyrrolidine-l-carboxamido)phenylamino)pyrimidine-5-
198 carboxamide; (R)-4-(benzylamino)-2-(3-(3-hydroxypyrrolidine-l-
199 carboxamido)phenylamino)pyrimidine-5-carboxamide; (R)-4-(benzylamino)-2-(3-(3-
200 fluoropyrrolidine- 1 -carboxamido)phenylammo)pyrimidine-5-carboxamide; (S)-4-
201 (benzylamino)-2-(3-(3-fluoropyrrolidine-l-carboxamido)phenylamino) pyrimidine-5-
202 carboxamide ; and6-(4-fluoro-3-(pyrrolidine-l-carboxamido)phenylamino)-4-(pyridin-3-
203 ylmethylamino)nicotinamide; 6-(3-(azetidine-l -carboxamido)-4-fluorophenylamino)-4-(3-
204 fluorobenzylamino)nicotinamide; (R)-6-(3-(3-(dimethylamino)pyrrolidine- 1 -
205 carboxamido)phenylamino)-4-(3-fluorobenzylamino)nicotinamide; (6-(4-fluoro-3-
206 (pyrrolidine- l-carboxamido)phenylamino)-4-(3-fluorobenzylamino)nicotinamide; N-(3-(5-
207 carbamoyl-4-(3-fluorobenzylamino)pyridin-2-ylamino)phenyl)moφholine-4-carboxamide; A-
208 (3-fluorobenzylamino)-6-(3-(pyrrolidine-l-carboxamido)phenylamino)nicotinamide; 6-(3-
209 acetamidophenylamino)-4-(3-fluorobenzylamino)nicotinamide; (S)-6-(3-(azetidine-l-
210 carboxamido)-4-fluorophenylamino)-4-(2-hydroxy-l-phenylethylamino)nicotinamide; 6-(3-
211 ((R)-3-(dimethylamino)pyrrolidine-l-carboxamido)phenylamino)-4-((S)-2-hydroxy-l-
212 phenylethylamino)nicotinamide; (S)-6-(4-fluoro-3-(pyrrolidine-l- 213 carboxamido)phenylamino)-4-(2-hydroxy-l-phenylethylamino)nicotinamide; (S)-N-(3-(5-
214 carbamoyl-4-(2-hydroxy-l-phenylethylamino)pyridin-2-ylamino)phenyl)moφholine-4-
215 carboxamide; (S)-4-(2-hydroxy- 1 -phenylethylamino)-6-(3-(pyrrolidine- 1 -
216 carboxamido)phenylamino)nicotinamide; (S)-6-(3-acetamidophenylamino)-4-(2-hydroxy-l-
217 phenylethylamino)nicotinamide; 6-(3-(azetidine- l-carboxamido)-4-fluorophenylamino)-4-
218 (pyridin-3-ylmethylamino)nicotinamide; (R)-6-(3-(3-(dimethylamino)pyrrolidine-l-
219 carboxamido)phenylamino)-4-(pyridin-3-ylmethylamino)nicotinamide; N-(3-(5-carbamoyl-4-
220 (pyridin-3-ylmethylamino)pyridin-2-ylamino)phenyl)moφholine-4-carboxamide; 4-(pyridin-
221 3-ylmethylamino)-6-(3-(pyrrolidine-l-carboxamido)phenylamino)nicotinamide; 6-(3-
222 acetamidophenylamino)-4-(pyridin-3-ylmethylamino)nicotinamide; (R)-6-(3-
223 acetamidophenylamino)-4-(l-phenylethylamino)nicotinamide; 6-(3-acetamidophenylamino)-
224 4-(isobutylamino)nicotinamide; 4-(isobutylamino)-6-(3-(pyrrolidine-l-
225 carboxamido)phenylamino)nicotinamide; (R)-4-( 1 -phenylethylamino)-6-(3-(pyrrolidine- 1 -
226 carboxamido)phenylamino)nicotinamide; 4-(benzylamino)-6-(3-(pyrrolidine-l-
227 carboxamido)phenylamino)nicotinamide; 6-(3-acetamidophenylamino)-4-
228 (isopentylamino)nicotinamide; 4-(isopentylamino)-6-(3 -(pyrrolidine- 1 -
229 carboxamido)phenylamino)nicotinamide; 6-(3-acetamidophenylamino)-4-
230 (cyclopropylmethylamino)nicotinamide; 6-(3-acetamidophenylamino)-4-
231 (cyclopentylamino)nicotinamide; 6-(3-acetamidophenylamino)-4-
232 (cyclobutylmethylamino)nicotinamide; 6-(3-acetamidophenylamino)-4-(4-
233 fluorobenzylamino)nicotinamide; 6-(3-acetamidophenylamino)-4-(2,3-dihydro-lH-inden-2-
234 ylamino)nicotinamide; 6-(3-acetamidophenylamino)-4-(benzo[d][l,3]dioxol-5-
235 ylmethylamino)nicotinamide; (S)-6-(3-acetamidophenylamino)-4-(2,3-dihydro-lH-inden-l-
236 ylamino)nicotinamide.; 6-(3-acetamidophenylamino)-4-(2,3-
237 difluorobenzylamino)nicotinamide; 6-(3-acetamidophenylamino)-4-(3-
238 chlorobenzylamino)nicotinamide; 6-(3-acetamidophenylamino)-4-
239 (phenethylamino)nicotinamide; 6-(3-acetamidophenylamino)-4-(benzylamino)-N-
240 methylnicotinamide; 6-(3-acetamidophenylamino)-4-(2-fluorobenzylamino)nicotinamide;
241 and 4-(3,5-difluorobenzylamino)-6-(3-(pyrrolidine-l-
242 carboxamido)phenylamino)nicotinamide.
1 33. A composition comprising a compound of any one of the preceding
2 claims in combination with a pharmaceutically acceptable carrier or diluent.
34. A method for inhibiting JAK or a signal transduction pathway mediated at least in part by JAK activity comprising the step of contacting a cell with a compound of any one claims 1 to 31.
35. The method of claim wherein said JAK is selected from the group consisting of JAK 1 , J AK2, and J AK3.
36. The method of claim 33, wherein said JAK is JAKl or JAK3.
37. The method of claim 33, wherein said JAK is JAK3.
38. A method for treating a condition or disorder mediated at least in part by JAK activity in a subject comprising the step of administering to a subject in need of such treatment a therapeutically effective amount of a composition of claim 33.
39. The method of claim 38, wherein the condition or disorder is selected from the group consisting of cardiovascular disease, inflammatory disease, immune-related disease, autoimmune disease and cell proliferative disorder.
40. The method of claim 39, wherein said inflammatory disease, immune- related disease, autoimmune disease is selected from the group consisting of organ transplants, asthma, COPD, systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, Crohn's disease, Type I diabetes, psoriasis.
41. A kit comprising a composition of claim 33, packaging and instructions for use.
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