WO2015188777A1 - Inhibiteurs particuliers de protéines kinases - Google Patents

Inhibiteurs particuliers de protéines kinases Download PDF

Info

Publication number
WO2015188777A1
WO2015188777A1 PCT/CN2015/081332 CN2015081332W WO2015188777A1 WO 2015188777 A1 WO2015188777 A1 WO 2015188777A1 CN 2015081332 W CN2015081332 W CN 2015081332W WO 2015188777 A1 WO2015188777 A1 WO 2015188777A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino
methyl
ethyl
pyrimidin
dimethylamino
Prior art date
Application number
PCT/CN2015/081332
Other languages
English (en)
Inventor
Tongshuang Li
Xingdong ZHAO
Qiang Tian
Weipeng Zhang
Hongbin Liu
Xianlong WANG
Haohan TAN
Rui Tan
Qihong Liu
Lihua Jiang
Yanxin Liu
Li LINGHU
Min Lin
Jing Sun
Weibo Wang
Original Assignee
Shanghai Fochon Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=54832920&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2015188777(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Shanghai Fochon Pharmaceutical Co Ltd filed Critical Shanghai Fochon Pharmaceutical Co Ltd
Priority to CN201580031253.8A priority Critical patent/CN106660993B/zh
Priority to CN202010883627.1A priority patent/CN111892579B/zh
Priority to CN202010883613.XA priority patent/CN111875585B/zh
Publication of WO2015188777A1 publication Critical patent/WO2015188777A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention relates to novel amino pyrimidine ring derivatives and the pharmaceutically acceptable salts thereof.
  • the compounds of the present invention are mutant-selective epidermal growth factor receptor (EGFR) kinase inhibitors.
  • EGFR epidermal growth factor receptor
  • the compounds of this invention are useful for the treatment of hyper-proliferative diseases such as cancer, in mammals and especially in humans.
  • This invention also relates to the use of the compounds in the treatment of cancer and the pharmaceutical preparations containing them.
  • Protein tyrosine kinases catalyze the transfer of a phosphate group from ATP or GTP to a tyrosine residue located on a protein substrate.
  • Protein tyrosine kinase can be broadly classified as receptor (e.g. EGFR, HER-2, VEGFR, FGFR) or non-receptor (e.g. Src, Jak, Abl) .
  • Receptor tyrosine kinases act to transmit signals from the outside of a cell to the inside by activating secondary messaging effectors via a phosphorylation event. A variety of cellular processes are promoted by these signals, including proliferation, carbohydrate utilization, protein synthesis, angiogenesis, cell growth, and cell survival.
  • the first-generation reversible, ATP-competitive EGFR kinase inhibitors are effective clinical therapies for non-small cell lung cancers that harbor activating mutations in the EGFR kinase domain.
  • first-generation EGFR inhibitors showed encouraging clinical responses, almost all patients developed resistance to these inhibitors over time, such as by mutation of gatekeeper residue T790M, which accounts for about half of all resistance to gefitinib and erlotinib (Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 2070-2075) .
  • T790M may also be pre-existing; there may be an independent, oncogenic role for the T790M mutation.
  • Second-generation covalent inhibitors such as afatinib, neratinib, canertinib and dacomitinib
  • second-generation covalent inhibitors such as afatinib, neratinib, canertinib and dacomitinib
  • mutant-selective EGFR kinase inhibitors useful as therapeutic agents.
  • mutant-selective EGFR inhibitors were disclosed in the arts, e.g., WO 2013014448 and WO 2012061299, there is still a need for new mutant-selective EGFR inhibitors that have at least one advantageous property selected from potency, stability, selectivity, toxicity and pharmacodynamics properties as an alternative for the treatment of hyper-proliferative diseases.
  • a novel class of mutant-selective EGFR inhibitors is provided herein.
  • Q is selected from aryl and heteroaryl
  • X is selected from N and C;
  • Y is selected from N and C;
  • R 1 is selected from hydrogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, and heterocyclyl-C 1-4 alkyl, wherein alkyl, cycloalkyl, and heterocyclyl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R 6a ;
  • R 1’ is selected from hydrogen and halogen
  • R 2 and R 3 are independently selected from hydrogen, halogen, hydroxyl, CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents independently selected from R 6a , and each aryl and heteroaryl is unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R 6b ; or R 2 and R 3 together with the carbon atoms to which they are
  • each R 4 is independently selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, -OR 8 , -NR 7 S (O) r R 8 , -NO 2 , -halogen, -S (O) r R 7 , -SR 8 , -S (O) 2 OR 7 , -OS (O) 2 R 8 , -S (O) r NR 7 R 8 , -NR 7 R 8 , -O (CR 9 R 10 ) t NR 7 R 8 , -C (O) R 7 , -CO 2 R 8 , -CO 2 (CR 9 R 10 ) t CONR 7 R 8 , -OC (O) R 7 , -CN, -C (O) NR 7 R 8 , -NR 7 C (O) R 8 , -OC (O) NR 7 R 8 , -NR 7 C (O)
  • each R 5 is independently selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, and heteroaryl-C 1-4 alkyl, -OR 8 , -NR 7 S (O) r R 8 , -NO 2 , halogen, -S (O) r R 7 , -SR 8 , -S (O) 2 OR 7 , -OS (O) 2 R 8 , -S (O) r NR 7 R 8 , -NR 7 R 8 , -O (CR 9 R 10 ) t NR 7 R 8 , -C (O) R 7 , -CO 2 R 8 , -CO 2 (CR 9 R 10 ) t CONR 7
  • each R 6a is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, -OR 8 , -NR 7 S (O) r R 8 , -NO 2 , halogen, -S (O) r R 7 , -SR 8 , -S (O) 2 OR 7 , -OS (O) 2 R 8 , -S (O) r NR 7 R 8 , -NR 7 R 8 , - (CR 9 R 10 ) t OR 8 , - (CR 9 R 10 ) t NR 7 R 8 , - (CR 9 R 10 ) t SR 8 , - (CR 9 R 10 ) t S (O) r R 8 , - (CR 9 R 10 ) t CO 2 R 8 , - (CR 9 R 10 ) t CONR 7 R 8 , - (CR 9 R 10 ) t NR 7
  • each R 6b is independently selected from R 6a , aryl, aryl-C 1-4 alkyl, heteroaryl, and heteroaryl-C 1-4 alkyl;
  • each R 7 and each R 8 are independently selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents independently selected from R 6a , and aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents independently selected from R 6b ; or R 7 and R 8 together with the atom (s) to which they are attached form a heterocyclic ring of 4 to 12 members
  • each R 9 and each R 10 are independently selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, and heteroaryl-C 1-4 alkyl; or R 9 and R 10 together with the carbon atom (s) to which they are attached form a ring of 3 to 7 members containing 0, 1, or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1or 2 R 6a groups;
  • n is independently selected from 0, 1, 2, and 3;
  • n is independently selected from 0, 1, 2, and 3;
  • each r is independently selected from 1 and 2;
  • each t is independently selected from 1, 2, and 3.
  • compositions comprising at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
  • a therapeutically effective amount of at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof comprising administering to a system or a subject in need thereof, a therapeutically effective amount of at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, thereby modulating said mutant EGFR.
  • a condition which responds to inhibition of mutant EGFR comprising administering to a system or subject in need of such treatment an effective amount of at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof or pharmaceutical compositions thereof, and optionally in combination with a second therapeutic agent, thereby treating said condition.
  • a condition mediated by mutant EGFR a condition mediated by mutant EGFR.
  • the compounds of the disclosure may be used alone or in combination with a second therapeutic agent to treat a condition mediated by mutant EGFR, wherein said condition is an autoimmune disease, a transplantation disease, an infectious disease or a cell proliferative disorder.
  • a cell proliferative disorder comprising administering to a system or subject in need of such treatment an effective amount of at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof or pharmaceutical compositions thereof, and optionally in combination with a second therapeutic agent, thereby treating said condition.
  • the compounds of the disclosure may be used alone or in combination with a chemotherapeutic agent to treat a cell proliferative disorder, including but not limited to, lymphoma, osteosarcoma, melanoma, or a tumor of breast, renal, prostate, colorectal, thyroid, ovarian, pancreatic, neuronal, lung, uterine or gastrointestinal tumor.
  • a chemotherapeutic agent to treat a cell proliferative disorder, including but not limited to, lymphoma, osteosarcoma, melanoma, or a tumor of breast, renal, prostate, colorectal, thyroid, ovarian, pancreatic, neuronal, lung, uterine or gastrointestinal tumor.
  • At least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof may be administered to a system comprising cells or tissues, or to a mammalian subject such as a human or animal subject.
  • alkyl refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Unless otherwise specified, “alkyl” refers to C l -C 10 alkyl. For example, C 1-6 , as in “C l-6 alkyl” is defined to include groups having 1, 2, 3, 4, 5, or 6 carbons in a linear or branched arrangement. For example, “C l-8 alkyl” includes but is not limited to methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl, hexyl, heptyl, and octyl.
  • cycloalkyl means a saturated aliphatic cyclic hydrocarbon group having the specified number of carbon atoms. Unless otherwise specified, “cycloalkyl” refers to C 3-l0 cycloalkyl. For example, “cycloalkyl” includes but is not limited to cyclopropyl, methyl-cyclopropyl, 2, 2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, and cyclohexyl.
  • alkenyl refers to a non-aromatic hydrocarbon radical, straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. In some embodiments, one carbon to carbon double bond is present, and up to four non-aromatic carbon-carbon double bonds may be present.
  • C 2-6 alkenyl means an alkenyl radical having from 2 to 6 carbon atoms.
  • Alkenyl groups include but are not limited to ethenyl, propenyl, butenyl, 2-methylbutenyl and cyclohexenyl. The straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated.
  • alkynyl refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond. In some embodiments, up to three carbon-carbon triple bonds may be present.
  • C 2-6 alkynyl means an alkynyl radical having from 2 to 6 carbon atoms.
  • Alkynyl groups include but are not limited to ethynyl, propynyl, butynyl, and 3-methylbutynyl.
  • the straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is indicated.
  • aryl encompasses 5-and 6-membered carbocyclic aromatic rings, for example, benzene; bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, naphthalene, indane, and 1, 2, 3, 4-tetrahydroquinoline; and tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, fluorene.
  • the aryl substituent is bicyclic or tricyclic and at least one ring is non-aromatic, it is understood that attachment is via the aromatic ring.
  • aryl includes 5-and 6-membered carbocyclic aromatic rings fused to a 5-to 7-membered heterocyclic ring containing one or more heteroatoms selected from N, O, and S, provided that the point of attachment is at the carbocyclic aromatic ring.
  • Bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals.
  • Bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in "-yl” by removal of one hydrogen atom from the carbon atom with the free valence are named by adding "-idene” to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene.
  • Aryl does not encompass or overlap in any way with heteroaryl, separately defined below. Hence, if one or more carbocyclic aromatic rings are fused with a heterocyclic aromatic ring, the resulting ring system is heteroaryl, not aryl, as defined herein.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • heteroaryl refers to aryl
  • 8-to 12-membered bicyclic rings containing one or more, for example, from 1 to 4, or, in some embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring; and
  • 11-to 14-membered tricyclic rings containing one or more, for example, from 1 to 4, or in some embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring.
  • the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1.
  • heteroaryl groups include, but are not limited to, (as numbered from the linkage position assigned priority 1) , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2, 3-pyrazinyl, 3, 4-pyrazinyl, 2, 4-pyrimidinyl, 3, 5-pyrimidinyl, 1-pyrazolyl, 2, 3-pyrazolyl, 2, 4-imidazolinyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothienyl, furyl, benzofuryl, benzoimidazolinyl, indolinyl, pyridizinyl, triazolyl, quinolinyl, pyrazolyl, and 5, 6, 7, 8-tetrahydroisoquinoline.
  • heteroaryl groups include but are not limited to pyrrolyl, isothiazolyl, triazinyl, pyrazinyl, pyridazinyl, indolyl, benzotriazolyl, quinoxalinyl, and isoquinolinyl.
  • heteroaryl is also understood to include the N-oxide derivative of any nitrogen-containing heteroaryl.
  • Bivalent radicals derived from univalent heteroaryl radicals whose names end in "-yl” by removal of one hydrogen atom from the atom with the free valence are named by adding "-idene" to the name of the corresponding univalent radical, e.g., a pyridyl group with two points of attachment is a pyridylidene.
  • Heteroaryl does not encompass or overlap with aryl as defined above.
  • heteroaryl substituent is bicyclic or tricyclic and at least one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively.
  • heterocycle broadly refers to a single aliphatic ring, usually with 3 to 12 ring atoms, containing at least 2 carbon atoms in addition to one or more, preferably one to three heteroatoms independently selected from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms.
  • a heterocycle as defined above may be multicyclic ring system (e.g. bicyclic) in which two or more rings may be fused or bridged together, wherein at least one such ring contains one or more heteroatoms independently selected from oxygen, sulfur, and nitrogen.
  • Heterocycle also refers to 5-to 7-membered heterocyclic ring containing one or more heteroatoms selected from N, O, and S fused with 5-and 6-membered carbocyclic aromatic ring, provided that the point of attachment is at the heterocyclic ring.
  • the rings may be saturated or have one or more double bonds (i.e. partially unsaturated) .
  • the heterocycle can be substituted by oxo.
  • the point of the attachment may be carbon or heteroatom in the heterocyclic ring, provided that attachment results in the creation of a stable structure.
  • the heterocyclic ring has substituents, it is understood that the substituents may be attached to any atom in the ring, whether a heteroatom or a carbon atom, provided that a stable chemical structure results.
  • Heterocycle does not overlap with heteroaryl.
  • Suitable heterocycles include, for example (as numbered from the linkage position assigned priority 1) , 1-pyrrolidinyl, 2-pyrrolidinyl, 2, 4-imidazolidinyl, 2, 3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, and 2, 5-piperazinyl.
  • Morpholinyl groups are also contemplated, including 2-morpholinyl and 3-morpholinyl (numbered wherein the oxygen is assigned priority 1) .
  • Substituted heterocycle also includes ring systems substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and 1, 1-dioxo-1-thiomorpholinyl.
  • Bicyclic heterocycles include, for example:
  • arylalkyl refers to an alkyl moiety substituted by an aryl group.
  • Example arylalkyl groups include benzyl, phenethyl, and naphthylmethyl groups. In some embodiments, arylalkyl groups have from 7 to 20 or 7 to 11 carbon atoms.
  • arylC l-4 alkyl the term “C 1-4 ” refers to the alkyl portion of the moiety and does not describe the number of atoms in the aryl portion of the moiety.
  • arylC 1-10 alkyl refers to the alkyl portion of the moiety and does not describe the number of atoms in the aryl portion of the moiety.
  • heterocyclylalkyl refers to alkyl substituted by heterocyclyl.
  • C 1-6 alkyl refers to the alkyl portion of the moiety and does not describe the number of atoms in the heterocyclyl portion of the moiety.
  • cycloalkylalkyl refers to alkyl substituted by cycloalkyl.
  • C 3-10 cycloalkylalkyl refers to the cycloalkyl portion of the moiety and does not describe the number of atoms in the alkyl portion of the moiety.
  • C 3-7 cycloalkylalkyl refers to the cycloalkyl portion of the moiety and does not describe the number of atoms in the alkyl portion of the moiety.
  • C 3-8 cycloalkylalkyl refers to the cycloalkyl portion of the moiety and does not describe the number of atoms in the alkyl portion of the moiety.
  • C 1-10 alkyl refers to the alkyl portion of the moiety and does not describe the number of atoms in the cycloalkyl portion of the moiety.
  • heteroarylalkyl refers to alkyl substituted by heteroaryl.
  • C 1-4 refers to the alkyl portion of the moiety and does not describe the number of atoms in the heteroaryl portion of the moiety.
  • C 1-10 refers to the alkyl portion of the moiety and does not describe the number of atoms in the heteroaryl portion of the moiety.
  • substitution of alkyl, cycloalkyl, heterocyclyl, aryl, and/or heteroaryl refers to substitution of each of those groups individually as well as to substitutions of combinations of those groups. That is, if R 1 is arylalkyl, the aryl portion may be unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R 6b and the alkyl portion may also be unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituens, independently selected from R 6a .
  • salts derived from inorganic bases may be selected, for example, from aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, and zinc salts. Further, for example, the pharmaceutically acceptable salts derived from inorganic bases may be selected from ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in one or more crystal structures, and may also be in the form of hydrates.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases may be selected, for example, from salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N, N'-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, and tripropylamine, tromethamine.
  • salts may be prepared using at least one pharmaceutically acceptable non-toxic acid, selected from inorganic and organic acids.
  • acid may be selected, for example, from acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, and p-toluenesulfonic acids.
  • such acid may be selected, for example, from citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.
  • protecting group refers to a substituent that can be commonly employed to block or protect a certain functionality while reacting other functional groups on the compound.
  • an "amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include but are not limited to acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC) , benzyloxycarbonyl (CBZ) and 9-fluorenylmethylenoxycarbonyl (Fmoc) .
  • a "hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality.
  • Suitable protecting groups include but are not limited to acetyl and silyl.
  • a "carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Common carboxy-protecting groups include --CH 2 CH 2 SO 2 Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenylsulfenyl) ethyl, 2- (diphenylphosphino) -ethyl, nitroethyl and the like.
  • protecting groups and their use see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley &Sons, New York, 1991.
  • administering at least one compound and/or at least one pharmaceutically acceptable salt should be understood to mean providing at least one compound and/or at least one pharmaceutically acceptable salt thereof to the individual in recognized need of treatment.
  • the term "effective amount” means the amount of the at least one compound and/or at least one pharmaceutically acceptable salt 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.
  • composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • composition in relation to a pharmaceutical composition is intended to encompass a product comprising the active ingredient (s) , and the inert ingredient (s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • pharmaceutically acceptable it is meant compatible with the other ingredients of the formulation and not unacceptably deleterious to the recipient thereof.
  • Q is selected from aryl and heteroaryl
  • X is selected from N and C;
  • Y is selected from N and C;
  • R 1 is selected from hydrogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, and heterocyclyl-C 1-4 alkyl, wherein alkyl, cycloalkyl, and heterocyclyl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R 6a ;
  • R 1’ is selected from hydrogen and halogen
  • R 2 and R 3 are independently selected from hydrogen, halogen, hydroxyl, CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents independently selected from R 6a , and each aryl and heteroaryl is unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R 6b ; or R 2 and R 3 together with the carbon atoms to which they are
  • each R 4 is independently selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, -OR 8 , -NR 7 S (O) r R 8 , -NO 2 , -halogen, -S (O) r R 7 , -SR 8 , -S (O) 2 OR 7 , -OS (O) 2 R 8 , -S (O) r NR 7 R 8 , -NR 7 R 8 , -O (CR 9 R 10 ) t NR 7 R 8 , -C (O) R 7 , -CO 2 R 8 , -CO 2 (CR 9 R 10 ) t CONR 7 R 8 , -OC (O) R 7 , -CN, -C (O) NR 7 R 8 , -NR 7 C (O) R 8 , -OC (O) NR 7 R 8 , -NR 7 C (O)
  • each R 5 is independently selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, and heteroaryl-C 1-4 alkyl, -OR 8 , -NR 7 S (O) r R 8 , -NO 2 , halogen, -S (O) r R 7 , -SR 8 , -S (O) 2 OR 7 , -OS (O) 2 R 8 , -S (O) r NR 7 R 8 , -NR 7 R 8 , -O (CR 9 R 10 ) t NR 7 R 8 , -C (O) R 7 , -CO 2 R 8 , -CO 2 (CR 9 R 10 ) t CONR 7
  • each R 6a is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, -OR 8 , -NR 7 S (O) r R 8 , -NO 2 , halogen, -S (O) r R 7 , -SR 8 , -S (O) 2 OR 7 , -OS (O) 2 R 8 , -S (O) r NR 7 R 8 , -NR 7 R 8 , - (CR 9 R 10 ) t OR 8 , - (CR 9 R 10 ) t NR 7 R 8 , - (CR 9 R 10 ) t SR 8 , - (CR 9 R 10 ) t S (O) r R 8 , - (CR 9 R 10 ) t CO 2 R 8 , - (CR 9 R 10 ) t CONR 7 R 8 , - (CR 9 R 10 ) t NR 7
  • each R 6b is independently selected from R 6a , aryl, aryl-C 1-4 alkyl, heteroaryl, and heteroaryl-C 1-4 alkyl;
  • each R 7 and each R 8 are independently selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents independently selected from R 6a , and aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents independently selected from R 6b ; or R 7 and R 8 together with the atom (s) to which they are attached form a heterocyclic ring of 4 to 12 members
  • each R 9 and each R 10 are independently selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, and heteroaryl-C 1-4 alkyl; or R 9 and R 10 together with the carbon atom (s) to which they are attached form a ring of 3 to 7 members containing 0, 1, or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1or 2 R 6a groups;
  • n is independently selected from 0, 1, 2, and 3;
  • n is independently selected from 0, 1, 2, and 3;
  • each r is independently selected from 1 and 2;
  • each t is independently selected from 1, 2, and 3.
  • At least one compound of 1 and/or at least one pharmaceutically acceptable salt thereof wherein X is selected from N and C, and Y is C.
  • At least one compound of any one of 1-2 and/or at least one pharmaceutically acceptable salt thereof wherein: when both X and Y are C, and
  • one R 5 is (3R) -3- (dimethylamino) pyrrolidin-1-yl, (3S) -3- (dimethylamino) pyrrolidin-1-yl, 3- (dimethylamino) azetidin-1-yl, [2- (dimethylamino) ethyl] - (methyl) amino, [2- (methylamino) ethyl] (methyl) amino, 5-methyl-2, 5-diazaspiro [3.4] oct-2-yl, (3aR, 6aR) -5-methylhexa-hydro-pyrrolo [3, 4-b] pyrrol-1 (2H) -yl, 1-methyl-1, 2, 3, 6-tetrahydropyridin-4-yl, 4-methylpiperizin-1-yl, 4- [2- (dimethylamino) -2-oxoethyl] piperazin-1-yl, methyl [2- (4-methylpiperazin-1-yl)
  • R 1 , R 1’ a nd R 2 are hydrogen, and R 3 is H, F, Cl, CH 3 or CN,
  • Q is not 4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyridine-3-yl, pyrazolo [1, 5-a] pyridin-3-yl or 1H-indol-3-yl.
  • At least one compound selected from
  • a pharmaceutical composition comprising at least one compound of any one of 1-18 and pharmaceutically acceptable salts thereof, wherein the composition is adapted for administration by a route selected from the group consisting of orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent) , subcutaneously, intraadiposally, intraarticularly, and intrathecally.
  • kits comprising at least one compound of any one of 1-18 and pharmaceutically acceptable salts thereof, and instructions which comprise one or more forms of information selected from the group consisting of indicating a disease state for which the composition is to be administered, storage information for the composition, dosing information and instructions regarding how to administer the composition.
  • the kit comprises the compound in a multiple dose form.
  • an article of manufacture comprising at least one compound of any one of 1-18 and pharmaceutically acceptable salts thereof, and packaging materials.
  • the packaging material comprises a container for housing the compound.
  • the container comprises a label indicating one or more members of the group consisting of a disease state for which the compound is to be administered, storage information, dosing information and/or instructions regarding how to administer the compound.
  • the article of manufacture comprises the compound in a multiple dose form.
  • a therapeutic method comprising administering to a subject at least one compound of any one of 1-18 and pharmaceutically acceptable salts thereof.
  • a method of inhibiting a mutant EGFR kinase comprising contacting the mutant EGFR with at least one compound of any one of 1-18 and pharmaceutically acceptable salts thereof.
  • a method of inhibiting a mutant EGFR comprising causing at least one compound of any one of 1-18 and pharmaceutically acceptable salts thereof to be present in a subject in order to inhibit the mutant EGFR in vivo.
  • a method of treating a disease state for which a mutant EGFR possesses activity that contributes to the pathology and/or symptomology of the disease state comprising causing at least one compound of any one of 1-18 and pharmaceutically acceptable salts thereof to be present in a subject in a therapeutically effective amount for the disease state.
  • the disease state is selected from the group consisting of cancerous hyperproliferative disorders (e.g., brain, lung, squamous cell, bladder, gastric, pancreatic, breast, head, neck, renal, kidney, ovarian, prostate, colorectal, epidermoid, esophageal, testicular, gynecological or thyroid cancer) ; non-cancerous hyperproliferative disorders (e.g., benign hyperplasia of the skin (e.g., psoriasis) , restenosis, and benign prostatic hypertrophy (BPH) ) ; pancreatitis; kidney disease; pain; preventing blastocyte implantation; treating diseases related to vasculogenesis or angiogenesis (e.g., tumor angiogenesis, acute and chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, exzema, and s
  • a method of treating a disease state for which a mutation in the mutant EGFR gene contributes to the pathology and/or symptomology of the disease state including, for example, melanomas, lung cancer, colon cancer and other tumor types.
  • the present invention relates to the use of at least one compound of any one of 1-18 and pharmaceutically acceptable salts thereof as a medicament. In yet another of its aspects, the present invention relates to the use of at least one compound of any one of 1-18 and pharmaceutically acceptable salts thereof in the manufacture of a medicament for inhibiting a mutant EGFR.
  • the present invention relates to the use of at least one compound of any one of 1-18 and pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating a disease state for which a mutant EGFR possesses activity that contributes to the pathology and/or symptomology of the disease state.
  • compounds of the disclosure will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents.
  • a therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors known to those of ordinary skill in the art.
  • the required dosage will also vary depending on the mode of administration, the particular condition to be treated and the effect desired.
  • an indicated daily dosage in the larger mammal may be in the range from about 0.5 mg to about 2000 mg, or more particularly, from about 0.5 mg to about 1000 mg, conveniently administered, for example, in divided doses up to four times a day or in retard form.
  • Suitable unit dosage forms for oral administration comprise from ca. 1 to 50 mg active ingredient.
  • Compounds of the disclosure may be administered as pharmaceutical compositions by any conventional route; for example, enterally, e.g., orally, e.g., in the form of tablets or capsules; parenterally, e.g., in the form of injectable solutions or suspensions; or topically, e.g., in the form of lotions, gels, ointments or creams, or in a nasal or suppository form.
  • enterally e.g., orally, e.g., in the form of tablets or capsules
  • parenterally e.g., in the form of injectable solutions or suspensions
  • topically e.g., in the form of lotions, gels, ointments or creams, or in a nasal or suppository form.
  • compositions comprising a compound of the present disclosure in free form or in a pharmaceutically acceptable salt form in association with at least one pharmaceutically acceptable carrier or diluent may be manufactured in a conventional manner by mixing, granulating, coating, dissolving or lyophilizing processes.
  • pharmaceutical compositions comprising a compound of the disclosure in association with at least one pharmaceutical acceptable carrier or diluent may be manufactured in conventional manner by mixing with a pharmaceutically acceptable carrier or diluent.
  • Unit dosage forms for oral administration contain, for example, from about 0.1 mg to about 500 mg of active substance.
  • the pharmaceutical compositions are solutions of the active ingredient, including suspensions or dispersions, such as isotonic aqueous solutions.
  • suspensions or dispersions such as isotonic aqueous solutions.
  • dispersions or suspensions can be made up before use.
  • the pharmaceutical compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers.
  • Suitable preservatives include but are not limited to antioxidants such as ascorbic acid, or microbicides, such as sorbic acid or benzoic acid.
  • solutions or suspensions may further comprise viscosity-increasing agents, including but not limited to, sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone, gelatins, or solubilizers, e.g. Tween 80 (polyoxyethylene (20) sorbitan mono-oleate) .
  • viscosity-increasing agents including but not limited to, sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone, gelatins, or solubilizers, e.g. Tween 80 (polyoxyethylene (20) sorbitan mono-oleate) .
  • Suspensions in oil may comprise as the oil component the vegetable, synthetic, or semi-synthetic oils customary for injection purposes.
  • oils customary for injection purposes.
  • Examples include liquid fatty acid esters that contain as the acid component a long-chained fatty acid having from 8 to 22 carbon atoms, or in some embodiments, from 12 to 22 carbon atoms.
  • Suitable liquid fatty acid esters include but are not limited to lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid or corresponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, brassidic acid and linoleic acid, and if desired, may contain antioxidants, for example vitamin E, 3-carotene or 3, 5-di-tert-butyl-hydroxytoluene.
  • the alcohol component of these fatty acid esters may have six carbon atoms and may be monovalent or polyvalent, for example a mono-, di-or trivalent, alcohol. Suitable alcohol components include but are not limited to methanol, ethanol, propanol, butanol or pentanol or isomers thereof; glycol and glycerol.
  • Suitable fatty acid esters include but are not limited ethyl-oleate, isopropyl myristate, isopropyl palmitate, M 2375, (polyoxyethylene glycerol) , M 1944 CS (unsaturated polyglycolized glycerides prepared by alcoholysis of apricot kernel oil and comprising glycerides and polyethylene glycol ester) , LABRASOL TM (saturated polyglycolized glycerides prepared by alcoholysis of TCM and comprising glycerides and polyethylene glycol ester; all available from GaKefosse, France) , and/or 812 (triglyceride of saturated fatty acids of chain length C8 to C12 from Hüls AG, Germany) , and vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil, or groundnut oil.
  • vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, ses
  • compositions for oral administration may be obtained, for example, by combining the active ingredient with one or more solid carriers, and if desired, granulating a resulting mixture, and processing the mixture or granules by the inclusion of additional excipients, to form tablets or tablet cores.
  • Suitable carriers include but are not limited to fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations, and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starches, for example corn, wheat, rice or potato starch, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, carboxymethyl starch, crosslinked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate.
  • Additional excipients include flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, or derivatives thereof.
  • Tablet cores may be provided with suitable, optionally enteric, coatings through the use of, inter alia, concentrated sugar solutions which may comprise gum arable, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments may be added to the tablets or tablet coatings, for example for identification purposes or to indicate different doses of active ingredient.
  • concentrated sugar solutions which may comprise gum arable, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate.
  • Dyes or pigments may be added to the tablets or tablet coatings,
  • compositions for oral administration may also include hard capsules comprising gelatin or soft-sealed capsules comprising gelatin and a plasticizer, such as glycerol or sorbitol.
  • the hard capsules may contain the active ingredient in the form of granules, for example in admixture with fillers, such as corn starch, binders, and/or glidants, such as talc or magnesium stearate, and optionally stabilizers.
  • the active ingredient may be dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilizers and detergents, for example of the polyoxyethylene sorbitan fatty acid ester type, may also be added.
  • suitable liquid excipients such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilizers and detergents, for example of the polyoxyethylene sorbitan fatty acid ester type, may also be added.
  • compositions suitable for rectal administration are, for example, suppositories comprising a combination of the active ingredient and a suppository base.
  • Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
  • compositions suitable for parenteral administration may comprise aqueous solutions of an active ingredient in water-soluble form, for example of a water-soluble salt, or aqueous injection suspensions that contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if desired, stabilizers.
  • the active ingredient optionally together with excipients, can also be in the form of a lyophilizate and can be made into a solution before parenteral administration by the addition of suitable solvents. Solutions such as are used, for example, for parenteral administration can also be employed as infusion solutions.
  • the manufacture of injectable preparations is usually carried out under sterile conditions, as is the filling, for example, into ampoules or vials, and the sealing of the containers.
  • the compounds of the disclosure may be administered as the sole active ingredient, or together with other drugs useful against neoplastic diseases or useful in immunomodulating regimens.
  • the compounds of the disclosure may be used in accordance with the disclosure in combination with pharmaceutical compositions effective in various diseases as described above, e.g.
  • cyclophosphamide 5-fluorouracil, fludarabine, gemcitabine, cisplatinum, carboplatin, vincristine, vinblastine, etoposide, irinotecan, paclitaxel, docetaxel, rituxan, doxorubicine, gefitinib, or imatinib; or also with cyclosporins, rapamycins, ascomycins or their immunosuppressive analogs, e.g. cyclosporin A, cyclosporin G, FK-506, sirolimus or everolimus, corticosteroids, e.g.
  • prednisone cyclophosphamide, azathioprene, methotrexate, gold salts, sulfasalazine, antimalarials, brequinar, leflunomide, mizoribine, mycophenolic acid, mycophenolate, mofetil, 15-deoxyspergualine, immuno-suppressive monoclonal antibodies, e.g. monoclonal antibodies to leukocyte receptors, e.g.
  • kits comprising a) a first agent which is a compound of the disclosure as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent.
  • the kit can comprise instructions for its administration.
  • the at least one compound of formula (I) can also be prepared as a pharmaceutically acceptable acid addition salt by, for example, reacting the free base form of the at least one compound with a pharmaceutically acceptable inorganic or organic acid.
  • a pharmaceutically acceptable base addition salt of the at least one compound of formula (I) can be prepared by, for example, reacting the free acid form of the at least one compound with a pharmaceutically acceptable inorganic or organic base.
  • Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compounds of formula (I) are set forth in the definitions section of this Application.
  • the salt forms of the compounds of formula (I) can be prepared using salts of the starting materials or intermediates.
  • the free acid or free base forms of the compounds of formula (I) can be prepared from the corresponding base addition salt or acid addition salt form.
  • a compound of formula (I) in an acid addition salt form can be converted to the corresponding free base thereof by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like) .
  • a compound of formula (I) in a base addition salt form can be converted to the corresponding free acid thereof by, for example, treating with a suitable acid (e.g., hydrochloric acid, etc) .
  • N-oxides of the at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof can be prepared by methods known to those of ordinary skill in the art.
  • N-oxides can be prepared by treating an unoxidized form of the compound of formula (I) with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at approximately 0 to 80 °C.
  • an oxidizing agent e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or the like
  • a suitable inert organic solvent e.g., a halogenated hydrocarbon such as dichloromethane
  • Compounds of formula (I) in an unoxidized form can be prepared from N-oxides of compounds of formula (I) by, for example, treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, and the like) in an suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, and the like) at 0 to 80 °C.
  • a reducing agent e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, and the like
  • an inert organic solvent e.g., acetonitrile, ethanol, aqueous dioxane, and the like
  • Protected derivatives of the compounds of formula (I) can be made by methods known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protecting groups and their removal can be found in T.W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley &Sons, Inc. 1999.
  • references to ether or Et 2 O are to diethyl ether; brine refers to a saturated aqueous solution of NaCl. Unless otherwise indicated, all temperatures are expressed in °C (degrees Centigrade) . All reactions were conducted under an inert atmosphere at RT unless otherwise noted.
  • MS mass spectra
  • ESI electrospray ionization
  • UV detector 220 and 254 nm
  • ELSD evaporative light scattering detector
  • Thin-layer chromatography was performed on 0.25 mm E. Merck silica gel plates (60F-254) , visualized with UV light, 5%ethanolic phosphomolybdic acid, ninhydrin, or p-anisaldehyde solution. Flash column chromatography was performed on silica gel (230-400 mesh, Merck) .
  • At least one compound of formula I and/or at least one pharmaceutically acceptable salt thereof may be synthesized according to a variety of reaction schemes. Some illustrative schemes are provided below and in the examples. Other reaction schemes could be readily devised by those skilled in the art in view of the present disclosure.
  • the compound of formula I of the present disclosure can be prepared as shown in Scheme 1. Coupling of intermediates such as those of formula III with amino-arene such as IV using such coupling conditions as Buchwald amination reaction or amination conditions known in the literature provides the intermediate VII or VI. Reduction of the nitro group in intermediate VII using conditions such as Fe/NH 4 Cl in a solvent or mixture of solvents such as EtOH and H 2 O provides amine VIII. Alternatively intermediate VIII can be prepared by cleavage of the protecting group on the amine of intermediate VI. Intermediate VI can be obtained by the coupling between intermediate III and amino-arene V. Coupling of amine VIII with acid IX or acyl chloride X provides compound I. Compound of formula I can also be synthesized via a two-step sequence by reacting amine VIII with acyl chloride XI followed by elimination reaction in the presence of a base such as NaOH in a solvent such as H 2 O.
  • compound of formula I can be prepared by coupling of intermediate III with intermediate VIa under the conditions as described in Scheme 1 or Scheme 2 as shown in Scheme 3.
  • VIaa One preparation of VIaa is illustrated in Scheme 4. Starting from the commercially available dichloropyridine 1, intermediate VIaa can be prepared via a sequence of region-selective displacement of chloride, bromination, amination, deprotection, acylation and reduction.
  • N 1 - (6-Methoxy-5-nitropyridin-2-yl) -N 1 , N 2 , N 2 -trimethylethane-1, 2-diamine (1b) (1.33 g, 5.24 mmol) in acetonitrile (30 mL) at 0°C was added NBS (1.40 g, 7.82 mmol) .
  • NBS (1.40 g, 7.82 mmol
  • 6-chloro-2-ethoxy-3-nitropyridine (5a) was prepared according to the synthetic method of 1a by replacing methanol with ethanol. MS-ESI (m/z) : 203 [M + 1] + .
  • the title compound 8 (6.3 mg, 75%) was prepared according to the synthetic method of Example 6 by replacing N- (6-Ethoxy-2- (methyl (2- (methylamino) ethyl) amino) -5- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino) pyridin-3-yl) acrylamide (5) with N- (6-Isopropoxy-2- (methyl (2- (methylamino) ethyl) amino) -5- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino) pyridin-3-yl) acr ylamide (7) .
  • MS-ESI (m/z) 529 [M + 1] + .
  • the title compound 10 (5.2 mg) was prepared according to the synthetic method of Example 6 by replacing N- (6-Ethoxy-2- (methyl (2- (methylamino) ethyl) amino) -5- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino) pyridin-3-yl) acrylamide (5) with N- (6-methoxy-5- ( (4- (1-methyl- 1H-indol-3-yl) pyrimidin-2-yl) amino) -2- (piperazin-1-yl) pyridin-3-yl) acrylamide (9) .
  • MS-ESI (m/z) : 499 [M + 1] + .
  • the title compound 11 (55 mg) was prepared according to the synthetic method of Example 2 by replacing methyl (2- (methylamino) ethyl) carbamate (2a) with tert-butyl piperazine-1-carboxylate and replacing 6-Chloro-2-methoxy-3-nitropyridine (1a) with 6-chloro-2-ethoxy-3-nitropyridine (5a) respectively.
  • MS-ESI (m/z) : 499 [M + 1] + .
  • the title compound 12 (7.2 mg) was prepared according to the synthetic method of Example 6 by replacing N- (6-Ethoxy-2- (methyl (2- (methylamino) ethyl) amino) -5- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino) pyridin-3-yl) acrylamide (5) with N- (6-ethoxy-5- ( (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) amino) -2- (piperazin-1-yl) pyridin-3-yl) acrylamide (11) .
  • MS-ESI (m/z) : 513 [M + 1] + .
  • the title compound 13 (75 mg) was prepared according to the synthetic method of Example 2 by replacing tert-butyl methyl (2- (methylamino) ethyl) carbamate (2a) with tert-butyl piperazine-1-carboxylate and replacing 6-Chloro-2-methoxy-3-nitropyridine (1a) with 6-chloro-2-isopropoxy-3-nitropyridine (7a) respectively.
  • MS-ESI m/z
  • N 1 - (6-chloro-3-nitropyridin-2-yl) -N 1 , N 2 , N 2 -trimethylethane-1, 2-diamine (15a) (23.8 g, 91.9 mmol) in methanol (200 mL) was added sodium methoxide (10.8 g, 183.8 mmol) at 0-5°C.
  • the mixture was heated to reflux for 2 h.
  • the mixture was cooled to r.t. and methanol was evaporated, diluted with water (200 mL) and extracted with dichloromethane (200 mL ⁇ 2) .
  • N 1 - (6-methoxy-3-nitropyridin-2-yl) -N 1 , N 2 , N 2 -trimethylethane-1, 2-diamine (15b) (11.0 g, 43.1 mmol) in glacial acetic acid (120 mL) was added N-iodosuccinimide (11.6 g, 51.8 mmol) for 3 batches at 0-5°C, and the mixture was stirred at room temperature for 4.5 h. Then solvent was evaporated under reduced pressure, diluted with water (300 mL) and extracted with ethyl acetate (200 mL ⁇ 3) .
  • the reaction was quenched by saturated aqueous sodium bicarbonate (20 mL) , and the resulting mixture was extracted with dichloromethane (20 mL ⁇ 3) . The organic layers were combined, washed with water (20 mL ⁇ 3) and brine (20 mL) , and dried over Na 2 SO 4 . The solids were filtered out and the filtrate was concentrated in vacuum.
  • 5-bromo-3-methoxy-2-nitropyridine (22a) was prepared according to the synthetic method described in US2006/84665.
  • the title compound 23a was prepared according to the synthetic method of Example 2 by replacing N 1 - (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N 1 , N 2 , N 2 -trimethylethane-1, 2-diamine (2g) with N 2 - (2- (dimethylamino) ethyl) -6-methoxy-N 2 -methyl-3-nitropyridine-2, 5-diamine (15e) .
  • MS-ESI (m/z) 477 [M + 1] + .
  • the title compound 23b was prepared according to the synthetic method of 15i by replacing N 1 - (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N 1 , N 2 , N 2 -trimethylethane-1, 2-diamine (15h) with N 2 - (2- (dimethylamino) ethyl) -6-methoxy-N 2 -methyl-N 5 - (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -3-nitropy9ridine-2, 5-diamine (23a) .
  • MS-ESI (m/z) 447 [M + 1] + .
  • the title compound 24 was prepared according to the synthetic method of Example 23 by replacing N 2 - (2- (dimethylamino) ethyl) -6-methoxy-N 2 -methyl-3-nitropyridine-2, 5-diamine (15e) with N 1 - (2- (dimethylamino) ethyl) -5-methoxy-N 1 -methyl-2-nitrobenzene-1, 4-diamine (24a) .
  • MS-ESI (m/z) 517 [M + 1] + .
  • the title compound 25 was prepared according to the synthetic method of Example 15 by replacing N 1 - (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N 1 , N 2 , N 2 -trimethylethane-1, 2-diamine (15h) with N 2 - (2- (dimethylamino) ethyl) -6-methoxy-N 2 -methyl-N 5 - (4- (1-methylindolizin-3-yl) pyrimidin-2-yl) -3-nitropyridine-2, 5-diamine (25g) .
  • MS-ESI (m/z) 501 [M + 1] + .
  • the title compound 26 was prepared according to the synthetic method of Example 25 by replacing N 1 - (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N 1 , N 2 , N 2 -trimethylethane-1, 2-diamine (15c) with N 1 - (4-iodo-5-methoxy-2-nitrophenyl) -N 1 , N 2 , N 2 -trimethylethane-1, 2-diamine (26a) .
  • MS-ESI (m/z) 500 [M + 1] + .
  • the title compound 27 was prepared according to the synthetic method of Example 25 by replacing ethyl 1-methylindolizine-3-carboxylate (25b) with ethyl 1-cyanoindolizine-3-carboxylate (27b) .
  • MS-ESI (m/z) 501 [M + 1] + .
  • the title compound 28 was prepared according to the synthetic method of Example 27 by replacing N 1 - (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N 1 , N 2 , N 2 -trimethylethane-1, 2-diamine (15c) with N 1 - (4-iodo-5-methoxy-2-nitrophenyl) -N 1 , N 2 , N 2 -trimethylethane-1, 2-diamine (26a) .
  • MS-ESI (m/z) 511 [M + 1] + .
  • the title compound 30 was prepared according to the synthetic method of Example 29 by replacing N 1 - (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N 1 , N 2 , N 2 -trimethylethane-1, 2-diamine (15c) with N 1 - (4-iodo-5-methoxy-2-nitrophenyl) -N 1 , N 2 , N 2 -trimethylethane-1, 2-diamine (26a) .
  • MS-ESI (m/z) 486 [M + 1] + .
  • the title compound 31 was prepared according to the synthetic method of Example 25 by replacing compound ethyl 1-methylindolizine-3-carboxylate (25b) with ethyl 1-chloroindolizine-3-carboxylate (31b) .
  • MS-ESI (m/z) 521 [M + 1] + .
  • the title compound 32 was prepared according to the synthetic method of Example 31 by replacing N 1 - (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N 1 , N 2 , N 2 -trimethylethane-1, 2-diamine (15c) with N 1 - (4-iodo-5-methoxy-2-nitrophenyl) -N 1 , N 2 , N 2 -trimethylethane-1, 2-diamine (26a) .
  • MS-ESI (m/z) 520 [M + 1] + .
  • the title compound 33 was prepared according to the synthetic method of Example 15 by replacing N 1 - (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N 1 , N 2 , N 2 -trimethylethane-1, 2-diamine (15h) with compound N 2 - (2- (dimethylamino) ethyl) -6-methoxy-N 2 -methyl-N 5 - (4- (3-methylindolizin-1-yl) pyrimidin-2-yl) -3-nitropyridine-2, 5-diamine (33f) .
  • MS-ESI (m/z) 501 [M + 1] + .
  • the title compound 34 was prepared according to the synthetic method of Example 33 by replacing N 1 - (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N 1 , N 2 , N 2 -trimethylethane-1, 2-diamine (15c) with N 1 - (4-iodo-5-methoxy-2-nitrophenyl) -N 1 , N 2 , N 2 -trimethylethane-1, 2-diamine (26a) .
  • MS-ESI (m/z) 500 [M + 1] + .
  • the title compound 35 was prepared according to the synthetic method of Example 33 by replacing 4- (3-methylindolizin-1-yl) pyrimidin-2-amine (33e) with 1- (2-aminopyrimidin-4-yl) indolizine-3-carbonitrile (35c) .
  • MS-ESI (m/z) 512 [M + 1] + .
  • the title compound 36 was prepared according to the synthetic method of Example 35 by replacing N 1 - (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N 1 , N 2 , N 2 -trimethylethane-1, 2-diamine (15c) with N 1 - (4-iodo-5-methoxy-2-nitrophenyl) -N 1 , N 2 , N 2 -trimethylethane-1, 2-diamine (26a) .
  • MS-ESI (m/z) 511 [M + 1] + .
  • the title compound 37 was prepared according to the synthetic method of Example 35 by replacing 1-acetylindolizine-3-carbonitrile (35a) with1- (indolizin-1-yl) ethan-1-one (37c) .
  • MS-ESI (m/z) 487 [M + 1] + .
  • the title compound 38 was prepared according to synthetic the method of Example 37 by replacing N 1 - (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N 1 , N 2 , N 2 -trimethylethane-1, 2-diamine (15c) with N 1 - (4-iodo-5-methoxy-2-nitrophenyl) -N 1 , N 2 , N 2 -trimethylethane-1, 2-diamine (26a) .
  • MS-ESI (m/z) 486 [M + 1] + .
  • the title compound 39 was prepared according to the synthetic method of Example 35 by replacing 1-acetylindolizine-3-carbonitrile (35a) with1- (3-chloroindolizin-1-yl) ethan-1-one (39a) .
  • MS-ESI (m/z) 521 [M + 1] + .
  • the title compound 40 was prepared according to the synthetic method of Example39by replacing N 1 - (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N 1 , N 2 , N 2 -trimethylethane-1, 2-diamine (15c) withN 1 - (4-iodo-5-methoxy-2-nitrophenyl) -N 1 , N 2 , N 2 -trimethylethane-1, 2-diamine (26a) .
  • MS-ESI (m/z) 520 [M + 1] + .
  • the title compound 43 (4.9 mg) was prepared according to the synthetic method of Example 6 by replacing N- (6-Ethoxy-2- (methyl (2- (methylamino) ethyl) amino) -5- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino) pyridin-3-yl) acrylamide (5) with N- (4-methoxy-5- ( (4- (3-methyl-1H-indol-1-yl) pyrimidin-2-yl) amino) -2- (piperazin-1-yl) phenyl) acrylamide (43a) .
  • MS-ESI (m/z) : 499 [M + 1] + .
  • the title compound 44 was prepared according to the synthetic method of Example 42 by replacing N 1 , N 1 , N 2 -trimethylethane-1, 2-diamine with 1-methylpiperazine. MS-ESI (m/z) : 498 [M + 1] + .
  • the title compound 46 (5 mg) was prepared according to the synthetic method of Example 45 by replacing N 2 - (2- (dimethylamino) ethyl) -6-methoxy-N 2 -methyl-3-nitropyridine-2, 5-diamine (15e) with N 1 - (2- (dimethylamino) ethyl) -5-methoxy-N 1 -methyl-2-nitrobenzene-1, 4-diamine (24a) .
  • MS-ESI (m/z) 511 [M + 1] + .
  • the title compound (47) was prepared according to the synthetic method of Example 15 by replacing N 2 - (2- (dimethylamino) ethyl) -N 5 - (4- (7-fluoro-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -6-methoxy-N 2 -methyl-3-nitropyridine-2, 5-diamine (15h) with N 1 - (4- (1-chloroimidazo [1, 5-a] pyridin-3-yl) pyrimidin-2-yl) -N 4 - (2- (dimethylamino) ethyl) -2-methoxy -N 4 -methyl-5-nitrobenzene-1, 4-diamine (47f) .
  • MS-ESI (m/z) 468 [M + 1] + .
  • the title compound (48) was prepared according to the synthetic method of Example 47 by replacing N 2 - (2- (dimethylamino) ethyl) -6-methoxy-N 2 -methyl-3-nitropyridine-2, 5-diamine (15e) with N 1 - (4-iodo-5-methoxy-2-nitrophenyl) -N 1 , N 2 , N 2 -trimethylethane-1, 2-diamine (24a) .
  • MS-ESI (m/z) 521 [M + 1] + .
  • the title compound 49 was prepared according to the synthetic method of Example 47 by replacing 1-chloro-3- (2- (methylthio) pyrimidin-4-yl) imidazo [1, 5-a] pyridine (47c) with 3- (2- (methylthio) pyrimidin-4-yl) -1- (trifluoromethyl) imidazo [1, 5-a] pyridine (49b) .
  • MS-ESI (m/z) 556 [M + 1] +
  • the title compound 50 was prepared according to the synthetic method of Example 47 by replacing N 2 - (2- (dimethylamino) ethyl) -6-methoxy-N 2 -methyl-3-nitropyridine-2, 5-diamine (15e) with N 1 - (2- (dimethylamino) ethyl) -5-methoxy-N 1 -methyl-2-nitrobenzene-1, 4-diamine (24a) .
  • MS-ESI (m/z) 555 [M + 1] + .
  • the title compound 51a was prepared according to the synthetic method of 47b by replacing pyridin-2-ylmethanamine with 1- (pyridin-2-yl) ethan-1-amine. MS-ESI (m/z) : 257 [M + 1] + .
  • the title compound 51b was prepared according to the synthetic method of 47e by replacing 1-chloro-3- (2- (methylthio) pyrimidin-4-yl) imidazo [1, 5-a] pyridine (47c) with 1-methyl-3- (2- (methylthio) pyrimidin-4-yl) imidazo [1, 5-a] pyridine (51a) .
  • MS-ESI (m/z) 245 [M + 1] + .
  • the title compound (51c) was prepared according to the synthetic method of 15i by replacing 3- (2-chloropyrimidin-4-yl) -7-fluoro-1-methyl-1H-indole (15g) with 3- (2-chloropyrimidin-4-yl) -1-methylimidazo [1, 5-a] pyridine (51b) .
  • MS-ESI (m/z) 448 [M + 1] + .
  • the title compound 51 was prepared according to the synthetic method of Example 15 by replacing N 2 - (2- (dimethylamino) ethyl) -N 5 - (4- (7-fluoro-1-methyl-1H-indol-3-yl) pyrimidin-2-yl) -6-methoxy-N 2 -methylpyridine-2, 3, 5-triamine (15i) with N 2 - (2- (dimethylamino) ethyl) -6-methoxy-N 2 -methyl-N 5 - (4- (1-methylimidazo [1, 5-a] pyridin-3-yl) pyrimidin-2-yl) pyridine-2, 3, 5-tri amine (51c) .
  • MS-ESI (m/z) 502 [M + 1] + .
  • the title compound 52 was prepared according to the synthetic method of Example 51 by replacing N 2 - (2- (dimethylamino) ethyl) -6-methoxy-N 2 -methyl-3-nitropyridine-2, 5-diamine (15e) with N 1 - (2- (dimethylamino) ethyl) -5-methoxy-N 1 -methyl-2-nitrobenzene-1, 4-diamine (24a) .
  • MS-ESI (m/z) 501 [M + 1] + .
  • the title compound (53) was prepared according to the method of Example 23 by replacing N 2 - (2- (dimethylamino) ethyl) -6-methoxy-N 2 -methyl-N 5 - (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) pyridine-2, 3, 5-triamine (23b) with N 2 - (2- (dimethylamino) ethyl) -6-methoxy -N 2 -methyl-N 5 - (4- (1-methylimidazo [1, 5-a] pyridin-3-yl) pyrimidin-2-yl) pyridine-2, 3, 5-triamine (51c) .
  • MS-ESI (m/z) 520 [M + 1] + .
  • the title compound 54 (5.0 mg) was prepared by using the same procedure as described for 15 by replacing 3- (2-chloropyrimidin-4-yl) -7-fluoro-1-methyl-1H-indole (15g) with 5- (2-chloropyrimidin-4-yl) -1, 2-dihydropyrrolo [3, 2, 1-hi] indole (54f) .
  • MS-ESI (m/z) : 513 [M + 1] + .
  • the title compound (55) was prepared according to the synthetic method of Example 54 by replacing N 1 - (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N 1 , N 2 , N 2 -trimethylethane-1, 2-diamine (15c) withN 1 - (4-iodo-5-methoxy-2-nitrophenyl) -N 1 , N 2 , N 2 -trimethylethane-1, 2-diamine (24a) .
  • MS-ESI (m/z) 512 [M + 1] + .
  • the title compound 58 was prepared according to the synthetic method of Example 25 by replacing 1- (1-methylindolizin-3-yl) ethanone (25d) with 1- (1-methyl-1H-indazol-3-yl) ethanone (58a) .
  • MS-ESI (m/z) 502 [M + 1] + .
  • the compound 59a was prepared according to the synthetic method of Example 25 by replacing 1- (1-methylindolizin-3-yl) ethanone (25d) with 1- (1-methyl-1H-indazol-3-yl) ethanone (58a) .
  • MS-ESI (m/z) 448 [M + 1] + .
  • the title compound 59b was prepared according to the synthetic method of 15i by replacing N 1 - (5-iodo-6-methoxy-3-nitropyridin-2-yl) -N 1 , N 2 , N 2 -trimethylethane-1, 2-diamine (15h) with N 2 - (2- (dimethylamino) ethyl) -6-methoxy-N 2 -methyl-N 5 - (4- (1-methyl-1H-indazol-3-yl) pyrimidin-2-yl) -3-nitropyridine-2, 5-diamine (59a) .
  • MS-ESI (m/z) 447 [M + 1] + .
  • the title compound (59) was prepared according to the synthetic method of Example 23 by replacing N 2 - (2- (dimethylamino) ethyl) -6-methoxy-N 2 -methyl-N 5 - (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) pyridine-2, 3, 5-triamine (23b) with N 2 - (2- (dimethylamino) ethyl) -6-methoxy -N 2 -methyl-N 5 - (4- (1-methyl-1H-indazol-3-yl) pyrimidin-2-yl) pyridine-2, 3, 5-triamine (59b) .
  • MS-ESI (m/z) 520 [M + 1] + .
  • the title compound 60a was prepared according to the synthetic method described in literature: Journal of Chemical society., 1955, 2834.
  • the title compound 60 was prepared according to the synthetic method of Example 25 by replacing 1- (1-methylindolizin-3-yl) ethanone (25d) with 1- (3-methylimidazo [1, 5-a] pyridin-1-yl) ethan-1-one (60a) .
  • MS-ESI (m/z) 502 [M + 1] + .
  • the compound 61a was prepared according to the synthetic method of Example 25 by replacing 1- (1-methylindolizin-3-yl) ethanone (25d) with 1- (3-methylimidazo [1, 5-a] pyridin-1-yl) ethan-1-one (60a) .
  • MS-ESI (m/z) 448 [M + 1] + .
  • the title compound 61 was prepared according to the synthetic method of Example 23 by replacing N 2 - (2- (dimethylamino) ethyl) -6-methoxy-N 2 -methyl-N 5 - (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) pyridine-2, 3, 5-triamine (23b) with N 2 - (2- (dimethylamino) ethyl) -6-methoxy -N 2 -methyl-N 5 - (4- (3-methylimidazo [1, 5-a] pyridin-1-yl) pyrimidin-2-yl) pyridine-2, 3, 5-triamine (61a) .
  • MS-ESI (m/z) 520 [M + 1] + .
  • H1975 cells were cultured in culture flasks to 40-80%confluence in RPMI-1640 plus 10%fetal bovine serum. Cells were collected and plated onto 96-well plates at desired cell density (3000 cells/well) . Plates were incubated overnight at 37°C, with 5%CO 2 to adhere.
  • A431 cell was cultured in culture flasks to 40-80%confluence in DMEM plus 10%fetal bovine serum. Cells were collected and plated onto 96-well plates at desired cell density (3000 cells/well) . Plates were incubated overnight at 37°C, with 5%CO 2 to adhere. Compounds were added to the plates, the final compound concentrations were 10000, 3333.3, 1111.1, 270.4, 123.5, 41.2, 13.7, 4.6 and 1.5 nM.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des inhibiteurs sélectifs mutants et particuliers de l'EGFR - récepteur du facteur de croissance de l'épiderme -, des compositions pharmaceutiques de ceux-ci, et des procédés d'utilisation correspondants.
PCT/CN2015/081332 2014-06-12 2015-06-12 Inhibiteurs particuliers de protéines kinases WO2015188777A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CN201580031253.8A CN106660993B (zh) 2014-06-12 2015-06-12 一类激酶抑制剂
CN202010883627.1A CN111892579B (zh) 2014-06-12 2015-06-12 一类激酶抑制剂
CN202010883613.XA CN111875585B (zh) 2014-06-12 2015-06-12 一类激酶抑制剂

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201462011109P 2014-06-12 2014-06-12
US62/011,109 2014-06-12
US201462090360P 2014-12-11 2014-12-11
US62/090,360 2014-12-11

Publications (1)

Publication Number Publication Date
WO2015188777A1 true WO2015188777A1 (fr) 2015-12-17

Family

ID=54832920

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/081332 WO2015188777A1 (fr) 2014-06-12 2015-06-12 Inhibiteurs particuliers de protéines kinases

Country Status (2)

Country Link
CN (3) CN111875585B (fr)
WO (1) WO2015188777A1 (fr)

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016105525A3 (fr) * 2014-12-23 2016-09-29 Dana-Farber Cancer Institute, Inc. Nouvelles pyrimidines en tant qu'inhibiteurs d'egfr et procédés de traitement de troubles
CN106117185A (zh) * 2015-08-31 2016-11-16 广州科擎新药开发有限公司 2,4‑二含氮基团取代嘧啶类化合物及其制备方法和应用
CN106279160A (zh) * 2016-03-18 2017-01-04 海南越康生物医药有限公司 N‑苯基‑2‑氨基嘧啶类化合物制备方法和用途
WO2017111076A1 (fr) 2015-12-24 2017-06-29 協和発酵キリン株式会社 COMPOSÉ AMIDE α, β INSATURÉ
CN106928150A (zh) * 2015-12-31 2017-07-07 恩瑞生物医药科技（上海）有限公司 丙烯酰胺苯胺衍生物及其药学上的应用
CN106957304A (zh) * 2017-04-25 2017-07-18 耿岳 一种石墨烯负载FeCl3催化剂的制备方法及其在制备抗癌药物中间体的用途
EP3207035A4 (fr) * 2014-10-13 2018-03-14 Yuhan Corporation Composés et compositions destinés à moduler les activités kinase de l'egfr mutant
CN107827875A (zh) * 2017-09-25 2018-03-23 文韬创新药物研究（北京）有限责任公司 一种苯并咪唑类衍生物作为周期蛋白依赖性激酶4/6抑制剂的应用
WO2018235926A1 (fr) 2017-06-23 2018-12-27 協和発酵キリン株式会社 COMPOSÉ AMIDE α, β-INSATURÉ
US10179784B2 (en) 2014-11-05 2019-01-15 Inventisbio Shanghai Ltd. Pyrimidine or pyridine compounds, preparation method therefor and pharmaceutical uses thereof
US20190023689A1 (en) * 2016-01-07 2019-01-24 Cs Pharmatech Limited Selective inhibitors of clinically important mutants of the egfr tyrosine kinase
US10428081B2 (en) * 2014-10-11 2019-10-01 Shanghai Hansoh Biomedical Co., Ltd. EGFR inhibitor, preparation method and use thereof
US10513509B2 (en) 2016-05-26 2019-12-24 Recurium Ip Holdings, Llc EGFR inhibitor compounds
US10738067B2 (en) 2018-11-01 2020-08-11 Syros Pharmaceuticals, Inc. Inhibitors of cyclin-dependent kinase 7 (CDK7)
WO2020230091A1 (fr) * 2019-05-14 2020-11-19 Janssen Biotech, Inc. Polythérapies avec des anticorps anti-egfr/c-met bispécifiques et des inhibiteurs de tyrosine kinase egfr de troisième génération
US10906901B2 (en) 2017-07-19 2021-02-02 Hainan Yuekang Biomedicines Co., Ltd. Crystal form and salt form of N-phenyl-2-aminopyrimidine compound, and preparation method therefor
USRE48687E1 (en) 2014-07-29 2021-08-17 Shanghai Allist Pharmaceuticals Co., Ltd. Pyridinylaminopyrimidine derivatives, preparation process and use thereof
WO2021177343A1 (fr) * 2020-03-04 2021-09-10 国立研究開発法人理化学研究所 Procédé de libération d'un composé
AU2020255100A8 (en) * 2019-03-29 2021-12-02 Shenzhen Forward Pharmaceuticals Co., Ltd. N-heteroaromatic amide derivatives for treatment of cancer
US11311542B2 (en) 2018-01-16 2022-04-26 Syros Pharmaceuticals, Inc. Inhibitors of cyclin dependent kinase 7 (CDK7)
US11459391B2 (en) 2019-02-26 2022-10-04 Janssen Biotech, Inc. Combination therapies and patient stratification with bispecific anti-EGFR/c-Met antibodies
WO2022271861A1 (fr) * 2021-06-22 2022-12-29 Dana-Farber Cancer Institute, Inc. Inhibiteurs (1h-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl-amino-phényl-acrylamide de l'egfr pour l'utilisation dans le traitement de tumeurs cérébrales
US11708362B2 (en) 2017-07-28 2023-07-25 Yuhan Corporation Process for preparing aminopyrimidine derivatives
US11918592B2 (en) 2018-01-16 2024-03-05 Syros Pharmaceuticals, Inc. Inhibitors of cyclin dependent kinase 7 (CDK7)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110857292A (zh) * 2018-08-22 2020-03-03 上海艾力斯医药科技有限公司 一种egfr激酶抑制剂及其制备方法和应用
CN110041302B (zh) * 2019-03-01 2021-11-30 南方医科大学 2-氨基-4-取代吡啶衍生物及其合成方法和应用
CN111303123B (zh) * 2020-03-31 2021-08-31 南京雷正医药科技有限公司 2-(2,4,5-取代苯胺基)嘧啶化合物及其应用
CN115701429B (zh) * 2021-08-02 2024-03-12 上海和誉生物医药科技有限公司 4-(1h-吲哚-1-基)嘧啶-2-氨基衍生物及其制备方法和应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102083800A (zh) * 2008-06-27 2011-06-01 阿维拉制药公司 杂芳基化合物和其用途
CN103702990A (zh) * 2011-07-27 2014-04-02 阿斯利康(瑞典)有限公司 2-(2,4,5-取代苯胺)嘧啶衍生物作为egfr调谐子用于治疗癌症

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105085489B (zh) * 2014-11-05 2019-03-01 益方生物科技（上海）有限公司 嘧啶或吡啶类化合物、其制备方法和医药用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102083800A (zh) * 2008-06-27 2011-06-01 阿维拉制药公司 杂芳基化合物和其用途
CN103702990A (zh) * 2011-07-27 2014-04-02 阿斯利康(瑞典)有限公司 2-(2,4,5-取代苯胺)嘧啶衍生物作为egfr调谐子用于治疗癌症

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
RICHARD A. WARD ET AL.: "Structure- and Reactivity-Based Development of Covalent Inhibitors of the Activating and Gatekeeper Mutant Forms of the Epidermal Growth Factor Receptor (EGFR", J. MED. CHEM., vol. 56, no. 17, 9 August 2013 (2013-08-09), pages 7025 - 7048, XP002734712, ISSN: 0022-2623 *

Cited By (58)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE48687E1 (en) 2014-07-29 2021-08-17 Shanghai Allist Pharmaceuticals Co., Ltd. Pyridinylaminopyrimidine derivatives, preparation process and use thereof
USRE49851E1 (en) 2014-07-29 2024-02-27 Shanghai Allist Pharmaceuticals Co., Ltd. Pyridinylaminopyrimidine derivatives, preparation process and use thereof
US10428081B2 (en) * 2014-10-11 2019-10-01 Shanghai Hansoh Biomedical Co., Ltd. EGFR inhibitor, preparation method and use thereof
KR102487451B1 (ko) 2014-10-13 2023-01-11 주식회사유한양행 Egfr 돌연변이 키나아제 활성을 조절하기 위한 화합물 및 조성물
EP3929190A1 (fr) * 2014-10-13 2021-12-29 Yuhan Corporation Composés et compositions de modulation des activités de kinase mutant egfr
EP3604294A1 (fr) * 2014-10-13 2020-02-05 Yuhan Corporation Composés et compositions de modulation des activités de kinase mutant egfr
KR20210011068A (ko) * 2014-10-13 2021-01-29 주식회사유한양행 Egfr 돌연변이 키나아제 활성을 조절하기 위한 화합물 및 조성물
JP2019163277A (ja) * 2014-10-13 2019-09-26 ユハン コーポレーションＹｕｈａｎ Ｃｏｒｐｏｒａｔｉｏｎ Ｅｇｆｒ変異型キナーゼ活性をモジュレートするための化合物および組成物
EP3207035A4 (fr) * 2014-10-13 2018-03-14 Yuhan Corporation Composés et compositions destinés à moduler les activités kinase de l'egfr mutant
US11203589B2 (en) 2014-11-05 2021-12-21 InventisBio Co., Ltd. Pyrimidine or pyridine compounds, preparation method therefor and pharmaceutical uses thereof
US11498921B1 (en) 2014-11-05 2022-11-15 InventisBio Co., Ltd. Pyrimidine or pyridine compounds, preparation method therefor and pharmaceutical uses thereof
US10179784B2 (en) 2014-11-05 2019-01-15 Inventisbio Shanghai Ltd. Pyrimidine or pyridine compounds, preparation method therefor and pharmaceutical uses thereof
US10266517B2 (en) 2014-12-23 2019-04-23 Dana-Farber Cancer Institute, Inc. Pyrimidines as EGFR inhibitors and methods of treating disorders
US11673882B2 (en) 2014-12-23 2023-06-13 Dana-Farber Cancer Institute, Inc. Pyrimidines as EGFR inhibitors and methods of treating disorders
US10870636B2 (en) 2014-12-23 2020-12-22 Dana-Farber Cancer Institute, Inc. Pyrimidines as EGFR inhibitors and methods of treating disorders
WO2016105525A3 (fr) * 2014-12-23 2016-09-29 Dana-Farber Cancer Institute, Inc. Nouvelles pyrimidines en tant qu'inhibiteurs d'egfr et procédés de traitement de troubles
US11267802B2 (en) 2015-08-31 2022-03-08 Bebetter Med Inc. 2,4-bis(nitrogen-containing group)-substituted pyrimidine compound, preparation method and use thereof
EP3345900A4 (fr) * 2015-08-31 2019-04-10 Guangzhou Bebetter Medicine Technology Co., Ltd. Composé pyrimidine à substitution 2,4-di-(groupe azoté), son procédé de préparation et son utilisation
CN106117185B (zh) * 2015-08-31 2017-11-07 广州必贝特医药技术有限公司 2,4‑二含氮基团取代嘧啶类化合物及其制备方法和应用
CN106117185A (zh) * 2015-08-31 2016-11-16 广州科擎新药开发有限公司 2,4‑二含氮基团取代嘧啶类化合物及其制备方法和应用
US11332455B2 (en) 2015-12-24 2022-05-17 Kyowa Kirin Co., Ltd. α,β-unsaturated amide compound
WO2017111076A1 (fr) 2015-12-24 2017-06-29 協和発酵キリン株式会社 COMPOSÉ AMIDE α, β INSATURÉ
EP3401309A4 (fr) * 2015-12-24 2019-11-27 Kyowa Kirin Co., Ltd. Insaturé amide compose alpha, beta
US10787428B2 (en) 2015-12-24 2020-09-29 Kyowa Kirin Co., Ltd. α,β-unsaturated amide compound
AU2021204307B2 (en) * 2015-12-24 2023-06-01 Kyowa Kirin Co., Ltd. a, ß unsaturated amide compound
AU2016382515B2 (en) * 2015-12-31 2020-12-17 Ancureall Pharmaceutical (Shanghai) Co., Ltd. Acrylanilide derivative, preparation method therefor, and applications thereof in pharmacy
JP2019506449A (ja) * 2015-12-31 2019-03-07 恩瑞生物医▲薬▼科技（上▲海▼）有限公司Ａｎｃｕｒｅａｌｌ Ｐｈａｒｍａｃｅｕｔｉｃａｌ（Ｓｈａｎｇｈａｉ）Ｃｏ．，Ｌｔｄ． アクリルアニリド誘導体、その製造方法及びその薬学的な応用
CN106928150A (zh) * 2015-12-31 2017-07-07 恩瑞生物医药科技（上海）有限公司 丙烯酰胺苯胺衍生物及其药学上的应用
RU2742372C2 (ru) * 2015-12-31 2021-02-05 Энкьюриэлл Фармасьютикал (Шанхай) Ко., Лтд. Производное акриланилида, способ его получения и его применения в фармакологии
EP3398939A4 (fr) * 2015-12-31 2019-02-13 Ancureall Pharmaceutical (Shanghai) Co., Ltd. Dérivé d'acrylanilide, son procédé de préparation et ses applications en pharmacie
US20190023689A1 (en) * 2016-01-07 2019-01-24 Cs Pharmatech Limited Selective inhibitors of clinically important mutants of the egfr tyrosine kinase
US10435388B2 (en) 2016-01-07 2019-10-08 Cs Pharmatech Limited Selective inhibitors of clinically important mutants of the EGFR tyrosine kinase
CN106279160A (zh) * 2016-03-18 2017-01-04 海南越康生物医药有限公司 N‑苯基‑2‑氨基嘧啶类化合物制备方法和用途
CN106279160B (zh) * 2016-03-18 2017-09-26 海南越康生物医药有限公司 N‑苯基‑2‑氨基嘧啶类化合物制备方法和用途
US10513509B2 (en) 2016-05-26 2019-12-24 Recurium Ip Holdings, Llc EGFR inhibitor compounds
US11098030B2 (en) 2016-05-26 2021-08-24 Recurium Ip Holdings, Llc EGFR inhibitor compounds
CN106957304A (zh) * 2017-04-25 2017-07-18 耿岳 一种石墨烯负载FeCl3催化剂的制备方法及其在制备抗癌药物中间体的用途
JP7221202B2 (ja) 2017-06-23 2023-02-13 協和キリン株式会社 α、β不飽和アミド化合物
JPWO2018235926A1 (ja) * 2017-06-23 2020-05-21 協和キリン株式会社 α、β不飽和アミド化合物
KR20200019979A (ko) 2017-06-23 2020-02-25 쿄와 기린 가부시키가이샤 α, β 불포화 아미드 화합물
US11447471B2 (en) 2017-06-23 2022-09-20 Kyowa Kirin Co., Ltd. α,β-unsaturated amide compound
AU2018289759B2 (en) * 2017-06-23 2022-03-10 Kyowa Kirin Co., Ltd. Alpha, beta-unsaturated amide compound
WO2018235926A1 (fr) 2017-06-23 2018-12-27 協和発酵キリン株式会社 COMPOSÉ AMIDE α, β-INSATURÉ
US10906901B2 (en) 2017-07-19 2021-02-02 Hainan Yuekang Biomedicines Co., Ltd. Crystal form and salt form of N-phenyl-2-aminopyrimidine compound, and preparation method therefor
US11708362B2 (en) 2017-07-28 2023-07-25 Yuhan Corporation Process for preparing aminopyrimidine derivatives
CN107827875A (zh) * 2017-09-25 2018-03-23 文韬创新药物研究（北京）有限责任公司 一种苯并咪唑类衍生物作为周期蛋白依赖性激酶4/6抑制剂的应用
CN107827875B (zh) * 2017-09-25 2021-07-09 文韬创新药物研究（北京）有限责任公司 一种苯并咪唑类衍生物作为周期蛋白依赖性激酶4/6抑制剂的应用
US11311542B2 (en) 2018-01-16 2022-04-26 Syros Pharmaceuticals, Inc. Inhibitors of cyclin dependent kinase 7 (CDK7)
US11918592B2 (en) 2018-01-16 2024-03-05 Syros Pharmaceuticals, Inc. Inhibitors of cyclin dependent kinase 7 (CDK7)
US10738067B2 (en) 2018-11-01 2020-08-11 Syros Pharmaceuticals, Inc. Inhibitors of cyclin-dependent kinase 7 (CDK7)
US11459391B2 (en) 2019-02-26 2022-10-04 Janssen Biotech, Inc. Combination therapies and patient stratification with bispecific anti-EGFR/c-Met antibodies
AU2020255100B2 (en) * 2019-03-29 2022-11-24 Shenzhen Forward Pharmaceuticals Co., Ltd. N-heteroaromatic amide derivatives for treatment of cancer
AU2020255100C1 (en) * 2019-03-29 2023-02-23 Shenzhen Forward Pharmaceuticals Co., Ltd. N-heteroaromatic amide derivatives for treatment of cancer
AU2020255100A8 (en) * 2019-03-29 2021-12-02 Shenzhen Forward Pharmaceuticals Co., Ltd. N-heteroaromatic amide derivatives for treatment of cancer
US11879013B2 (en) 2019-05-14 2024-01-23 Janssen Biotech, Inc. Combination therapies with bispecific anti-EGFR/c-Met antibodies and third generation EGFR tyrosine kinase inhibitors
WO2020230091A1 (fr) * 2019-05-14 2020-11-19 Janssen Biotech, Inc. Polythérapies avec des anticorps anti-egfr/c-met bispécifiques et des inhibiteurs de tyrosine kinase egfr de troisième génération
WO2021177343A1 (fr) * 2020-03-04 2021-09-10 国立研究開発法人理化学研究所 Procédé de libération d'un composé
WO2022271861A1 (fr) * 2021-06-22 2022-12-29 Dana-Farber Cancer Institute, Inc. Inhibiteurs (1h-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl-amino-phényl-acrylamide de l'egfr pour l'utilisation dans le traitement de tumeurs cérébrales

Also Published As

Publication number Publication date
CN106660993B (zh) 2020-09-11
CN111875585B (zh) 2023-06-23
CN106660993A (zh) 2017-05-10
CN111875585A (zh) 2020-11-03
CN111892579A (zh) 2020-11-06
CN111892579B (zh) 2023-07-25

Similar Documents

Publication Publication Date Title
WO2015188777A1 (fr) Inhibiteurs particuliers de protéines kinases
EP3149008B1 (fr) Inhibiteurs particuliers de protéines kinases
JP6570001B2 (ja) Ａｌｋキナーゼ阻害剤
US10022374B2 (en) Certain protein kinase inhibitors
EP3224248B1 (fr) Inhibiteurs de certaines protéines kinases
US20160145244A1 (en) Certain protein kinase inhibitors

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15806251

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15806251

Country of ref document: EP

Kind code of ref document: A1