EP2498608A1 - Benzene sulfonamide thiazole and oxazole compounds - Google Patents

Benzene sulfonamide thiazole and oxazole compounds

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Publication number
EP2498608A1
EP2498608A1 EP10830388A EP10830388A EP2498608A1 EP 2498608 A1 EP2498608 A1 EP 2498608A1 EP 10830388 A EP10830388 A EP 10830388A EP 10830388 A EP10830388 A EP 10830388A EP 2498608 A1 EP2498608 A1 EP 2498608A1
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EP
European Patent Office
Prior art keywords
cancer
mmol
formula
compound
chloro
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP10830388A
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German (de)
French (fr)
Other versions
EP2498608A4 (en
Inventor
Jerry Leroy Adams
Thomas Faitg
Jiri Kasparec
Xin Peng
Jeffrey Ralph
Tara Renae Rheault
Alex Gregory Waterson
Kimberly Petrov
David Edward Uehling
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GlaxoSmithKline LLC
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GlaxoSmithKline LLC
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Publication of EP2498608A1 publication Critical patent/EP2498608A1/en
Publication of EP2498608A4 publication Critical patent/EP2498608A4/en
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms 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
    • C07D417/04—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 directly linked by a ring-member-to-ring-member bond
    • 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

Definitions

  • the present invention relates to benzene sulfonamide thiazole and oxazole compounds, compositions containing the same, as well as processes for the preparation and methods of using such compounds and compositions.
  • RTKs Receptor tyrosine kinases
  • Ras-Raf-MEK-ERK kinase pathway Downstream of the several RTKs lie several signaling pathways, among them is the Ras-Raf-MEK-ERK kinase pathway. It is currently understood that activation of Ras GTPase proteins in response to growth factors, hormones, cytokines, etc. stimulates phosphorylation and activation of Raf kinases. These kinases then phosphorylate and activate the intracellular protein kinases MEK1 and MEK2, which in turn phosphorylate and activate other protein kinases, ERK1 and 2. This signaling pathway, also known as the mitogen-activated protein kinase (MAPK) pathway or cytoplasmic cascade, mediates cellular responses to growth signals.
  • MAPK mitogen-activated protein kinase
  • the ultimate function of this is to link receptor activity at the cell membrane with modification of cytoplasmic or nuclear targets that govern cell proliferation, differentiation, and survival. Mutations in various Ras GTPases and the B-Raf kinase have been identified that can lead to sustained and constitutive activation of the MAPK pathway, ultimately resulting in increased cell division and survival. As a consequence of this, these mutations have been strongly linked with the establishment, development, and progression of a wide range of human cancers.
  • the biological role of the Raf kinases, and specifically that of B-Raf, in signal transduction is described in Davies, H., et al., Nature (2002) 9:1 -6; Garnett, M.J.
  • central nervous system tumors including primary CNS tumors such as
  • glioblastomas astrocytomas and ependymomas
  • secondary CNS tumors i.e., metastases to the central nervous system of tumors originating outside of the central nervous system
  • colorectal cancer including large intestinal colon carcinoma (Yuen et al
  • leukemias Garnett et al., Cancer Cell (2004) supra, particularly acute lymphoblastic leukemia (Garnett et al., Cancer Cell (2004) supra and Gustafsson et al Leukemia (2005) 19(2) 310- 312)
  • AML acute myelogenous leukemia
  • AML acute myelogenous leukemia
  • myelodysplastic syndromes Christiansen et al Leukemia (2005) supra
  • chronic myelogenous leukemia Mizuchi et al Biochem. Biophys. Res. Commun.
  • pancreatic cancer Ishimura et al Cancer Lett. (2003) 199(2) 169-173
  • pituitary adenoma (De Martino et al J. Endocrinol. Invest. (2007) 30(1 ) RC1 - 3)
  • prostate cancer Cho et al Int. J. Cancer (2006) 1 19(8) 1858-1862
  • renal cancer Nagy et al Int. J. Cancer (2003) 106(6) 980-981
  • Raf family kinases By virtue of the role played by the Raf family kinases in these cancers and exploratory studies with a range of preclinical and therapeutic agents, including one selectively targeted to inhibition of B-Raf kinase activity (King A.J ., et al., (2006) Cancer Res. 66:1 1 100-1 1 105), it is generally accepted that inhibitors of one or more Raf family kinases will be useful for the treatment of such cancers or other condition associated with Raf kinase.
  • B-Raf has also been implicated in other conditions, including cardio-facio cutaneous syndrome (Rodriguez-Viciana et al Science (2006) 31 1 (5765) 1287-1290) and polycystic kidney disease (Nagao et al Kidney Int. (2003) 63(2) 427-437).
  • the invention encompasses the compounds of formula (I)
  • W is selected from -O- and -S-;
  • R is selected from ci-c6alkyl, haloalkyl, and C 3-c 6 cycloalkyl;
  • R 3 is selected from Het1 , pyridinyl, and ci-c6alkyl optionally substituted with -
  • R 4 is selected from H, -NH-R 7 and -CH 2 -R 7 ;
  • R 5 and R 6 are independently selected from H, F, and CI;
  • R 7 is selected from H, C i-c6alkylene-R 8 , and -co-c3alkylene-Het1 , and ci-c6alkyl optionally substituted with -( C o-c6alkylene-(OH) m ) n ;
  • R 8 is selected from haloalkyl-, CN, OH, and -SO 2 -ci-c3alkyl;
  • each Het1 is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N and O and optionally substituted with 1 or 2 substituents
  • each m is 1 or 2;
  • each n is 1 or 2;
  • compositions comprising the compounds, methods of treating susceptible neoplasms with the compounds, processes for preparing the compounds, and use of the compounds in the treatment of susceptible neoplasms.
  • W is selected from -O- and -S-;
  • R 1 is selected from ci-c6alkyl, haloalkyl, and c3-c6cycloalkyl;
  • R 3 is selected from Het1 , pyridinyl, and ci-c6alkyl optionally substituted with
  • R 4 is selected from H, -NH-R 7 and -CH 2 -R 7 ;
  • R 5 and R 6 are independently selected from H, F, and CI;
  • R 7 is selected from H, C i-c6alkylene-R 8 , and -co-c3alkylene-Het1 , and ci-c6alkyl optionally substituted with -( C o-c6alkylene-(OH) m ) n ;
  • R 8 is selected from haloalkyl-, CN, OH, and -SO 2 -ci-c3alkyl;
  • each Het1 is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N and O and optionally substituted with 1 or 2 substituents
  • each m is 1 or 2;
  • each n is 1 or 2;
  • R 1 is selected from ci-c6alkyl and haloalkyl.
  • R 3 is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N and O and optionally substituted with 1 or 2 substituents independently selected from ci-c3alkyl, -SO2-ci-c3alkyl, and -ci-c3alkylene-OH.
  • compounds of formula (I) as in the first aspect wherein R 1 is selected from ci-c6alkyl and haloalkyl.
  • R 3 is selected from
  • R 1 is selected from ci-c6alkyl, haloalkyl, and C 3-c 6 cycloalkyl;
  • R 3 is selected from Het1 , pyridinyl, and ci-c6alkyl optionally substituted with -
  • R 4 is selected from H, -NH-R 7 and -CH 2 -R 7 ;
  • R 5 and R 6 are independently selected from H, F, and CI;
  • R 7 is selected from H, C i-c6alkylene-R 8 , and -co-c3alkylene-Het1 , and ci-c6alkyl optionally substituted with -( C o-c6alkylene-(OH) m ) n ;
  • R 8 is selected from haloalkyl-, CN, OH, and -SO2-ci-c3alkyl;
  • each Het1 is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N and O and optionally substituted with 1 or 2 substituents
  • each m is 1 or 2;
  • each n is 1 or 2;
  • compounds of formula (la) as in the second aspect wherein R 3 is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N and O and optionally substituted with 1 or 2 substituents independently selected from ci-c3alkyl, -SO2-ci-c3alkyl, and -ci c3alkylene-OH.
  • R 3 is selected from
  • R1 is selected from propyl and tri-flouro-propyl.
  • R 1 is selected from ci-c6alkyl, haloalkyl, and C 3-c6cycloalkyl;
  • R 3 is selected from Het1 , pyridinyl, and ci-c6alkyl optionally substituted with
  • R 4 is selected from -NH-R 7 and -CH 2 -R 7 ;
  • R 5 and R 6 are independently selected from H, F, and CI;
  • R 7 is selected from H, C i-c6alkylene-R 8 , and -co-c3alkylene-Het1 , and ci-c6alkyl optionally substituted with -(co-c6alkylene-(OH) m ) n ;
  • R 8 is selected from haloalkyl-, CN, OH, and -SO2-ci-c3alkyl;
  • each Het1 is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N and O and optionally substituted with 1 or 2 substituents
  • each m is 1 or 2;
  • each n is 1 or 2;
  • R 3 is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N and O and optionally substituted with 1 or 2 substituents independently selected from ci-c3alkyl, -SO2-ci-c3alkyl, and -ci-c3alkylene-OH.
  • R 3 is selected from
  • a pharmaceutical composition comprising a compound of formula (I) (including any particular sub-generic formula described herein) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition further comprises one or more of pharmaceutically acceptable carriers, diluents or excipients.
  • a method of treating a susceptible neoplasm in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) (including any particular sub-generic formula described herein) or a pharmaceutically acceptable salt thereof.
  • Susceptible neoplasms include e.g., Barret's adenocarcinoma; billiary tract carcinomas; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors including primary CNS tumors such as glioblastomas, astrocytomas (e.g., glioblastoma multiforme) and ependymomas, and secondary CNS tumors (i.e., metastases to the central nervous system of tumors originating outside of the central nervous system); colorectal cancer including large intestinal colon carcinoma; gastric cancer; carcinoma of the head and neck including squamous cell carcinoma of the head and neck; hematologic cancers including leukemias and lymphomas such as acute lymphoblastic leukemia, acute myelogenous leukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma,
  • erythroleukemia hepatocellular carcinoma
  • lung cancer including small cell lung cancer and non-small cell lung cancer
  • ovarian cancer endometrial cancer
  • pancreatic cancer pituitary adenoma
  • prostate cancer renal cancer
  • sarcoma skin cancers including melanomas
  • thyroid cancers include melanomas
  • a method of treating a susceptible neoplasm in a mammal, particularly a human, in need thereof comprising administering to the mammal (e.g. human) a
  • a method of treating breast cancer, cholangiocarcinoma, colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, or thyroid cancer in a mammal, particularly a human, in need thereof, comprising administering to the mammal (e.g. human) a therapeutically effective amount of a compound of formula (Ilia)
  • R 10 is halo or thiomethyl
  • a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises reacting a compound of formula (XVIII):
  • a compound of formula (I), (including any particular sub-generic formula described herein) or a pharmaceutically acceptable salt thereof for use in therapy is provided.
  • a compound of formula (I) (including any particular sub-generic formula described herein) or a pharmaceutically acceptable salt thereof for use in the treatment of a susceptible neoplasm (e.g., Barret's adenocarcinoma; bil Nary tract carcinomas; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors including primary CNS tumors such as glioblastomas, astrocytomas (e.g., glioblastoma multiforme) and ependymomas, and secondary CNS tumors (i.e., metastases to the central nervous system of tumors originating outside of the central nervous system); colorectal cancer including large intestinal colon carcinoma; gastric cancer; carcinoma of the head and neck including squamous cell carcinoma of the head and neck; hematologic cancers including leukemias and lymphomas such as acute lymphoblastic leukemia, acute myelogenous leukemia (AML), myel
  • AML acute my
  • cholangiocarcinoma cholangiocarcinoma, colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, or thyroid cancer in a mammal (e.g., human) in need thereof.
  • a susceptible neoplasm e.g., Barret's adenocarcinoma; billiary tract carcinomas; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors including primary CNS tumors such as glioblastomas, astrocytomas (e.g., glioblastoma multiforme) and ependymomas, and secondary CNS tumors (i.e., metastases to the central nervous system of tumors originating outside of the central nervous system); colorectal cancer including large intestinal colon carcinoma; gastric cancer; carcinoma of the head and neck including squamous cell carcinoma of the head and neck; hematologic cancers including leukemias and lymphomas such as acute lymphoblastic leukemia,
  • a susceptible neoplasm e.g., Barret's adenocarcinoma; billiary tract carcinomas; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors including primary
  • hepatocellular carcinoma including small cell lung cancer and non-small cell lung cancer; ovarian cancer; endometrial cancer; pancreatic cancer; pituitary adenoma; prostate cancer; renal cancer; sarcoma; skin cancers including melanomas; and thyroid cancers
  • a mammal e.g., human
  • a compound of formula (I) (including any particular sub-generic formula described herein) or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in the treatment of breast cancer, cholangiocarcinoma, colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, or thyroid cancer in a mammal (e.g., human) in need thereof.
  • a pharmaceutical composition comprising a compound of formula (I) (including any particular sub-generic formula described herein) or a pharmaceutically acceptable salt thereof for use in the treatment of a susceptible neoplasm (e.g., Barret's adenocarcinoma; billiary tract carcinomas; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors including primary CNS tumors such as glioblastomas, astrocytomas (e.g., glioblastoma multiforme) and ependymomas, and secondary CNS tumors (i.e., metastases to the central nervous system of tumors originating outside of the central nervous system); colorectal cancer including large intestinal colon carcinoma; gastric cancer; carcinoma of the head and neck including squamous cell carcinoma of the head and neck; hematologic cancers including leukemias and lymphomas such as acute lymphoblastic leukemia, acute myelogenous le
  • a pharmaceutical composition comprising a compound of formula (I) (including any particular sub-generic formula described herein) or a pharmaceutically acceptable salt thereof for use in the treatment of breast cancer, colorectal cancer,
  • melanoma non-small cell lung cancer, ovarian cancer, or thyroid cancer in a mammal (e.g., human) in need thereof.
  • Raf family kinase refers to Raf kinases including A- Raf, B-Raf and c-Raf (also known as Raf-1 ). Unless distinguished herein, the term refers to both wildtype and mutant variations thereof.
  • compound(s) of formula (I) means any compound having the structural formula (I) as defined by the variable definitions provided, possible solvates, including hydrates thereof, and amorphous and crystal forms, including one or more polymorphic forms and mixtures thereof.
  • the compounds may be in the form of a racemic mixture, or one or more isomerically enriched or pure stereoisomers, including enantiomers and diastereomers thereof.
  • “compound(s) of formula (I)” includes the racemic form as well as the enriched or pure enantiomers and diastereomers.
  • Enantiomerically enriched or pure compounds will be designated using conventional nomenclature, including the designations +, -, R, S, d, I, D and L, according to the predominant isomer present.
  • a compound of the invention contains an alkenyl or alkenylene group, cis (E) and trans (Z) isomerism may also occur. In such embodiments,
  • compound(s) of the invention means a compound of formula (I) (as defined above) in any version, i.e., as the free base or as a pharmaceutically acceptable salt thereof.
  • the compound as any version may be in any form, including amorphous or crystalline forms, specific polymorphic forms, solvates, including hydrates (e.g., mono-, di- and hemi- hydrates), and mixtures of various forms. Intermediates may also be present as salts.
  • alkyl refers to linear or branched hydrocarbon chains having from 1 to 8 carbon atoms, unless a different number of atoms is specified.
  • alkyl as used herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, sec-butyl, isobutyl, and tert-butyl.
  • alkyl and variations thereof (i.e., "Ci -4 alkyl”) is intended to independently describe each member of the genus.
  • alkylene refers to linear or branched divalent hydrocarbon chains containing from 1 to 8 carbon atoms, unless a different number of atoms is specified.
  • alkylene as used herein include, but are not limited to, methylene, ethylene, propylene, butylene, and isobutylene.
  • alkylene and variations thereof (i.e., “Ci-3alkylene") is intended to be
  • alkenyl refers to linear or branched hydrocarbon chains having from 2 to 8 carbon atoms, unless a different number of atoms is specified, and at least one and up to three carbon-carbon double bonds.
  • alkenyl examples include, but are not limited to ethenyl and propenyl.
  • alkenyl and variations thereof (i.e., "C2 -4 alkenyl") is intended to independently describe each member of the genus.
  • cycloalkyl refers to a saturated monocyclic carbocyclic ring having from 3 to 8 carbon atoms, unless a different number of atoms is specified.
  • Cycloalkyl includes by way of example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • Preferred cycloalkyl groups include substituted and unsubstituted C3-6cycloalkyl.
  • cycloalkyl and variations thereof (i.e., "C3-6cycloalkyl) is intended to independently describe each member of the genus.
  • halo and “halogen” are synonymous and refer to fluoro, chloro, bromo and iodo. In particular embodiments, “halo” refers to fluoro and chloro.
  • haloalkyi refers to an alkyl, as defined above, substituted by one or more halogen atoms, fluoro, chloro, bromo or iodo. According to one embodiment, haloalkyi defineds an alkyl substituted by one to three fluoro atoms. Where the haloalkyi group has less than 8 carbon atoms, the number of carbon atoms in the group is indicated as, for example, "haloCi-3alkyl", which indicates that the haloalkyi group has 1 , 2 or 3 carbon atoms.
  • haloalkyi examples include, but are not limited to
  • haloalkyi and variations thereof (i.e., “haloCi-3alkyl") is intended to independently describe each member of the genus.
  • heterocycle and “heterocyclic” are synonymous and refer to monocyclic saturated or unsaturated non-aromatic groups, having from 4 to 6 members (unless a different number of members is specified) and including 1 , 2, or 3 heteroatoms selected from N, O and S, unless a different number of heteroatoms is specified.
  • the heterocycle includes 2 or more heteroatoms
  • the heteroatoms may be the same or different and are independently selected from N, O and S.
  • the compound of formula (I) includes two or more heterocyclic groups
  • the heterocyclic groups may be the same or different and are independently selected.
  • heterocyclic groups include but are not limited to tetrahydrofuran, dihydropyran, tetrahydropyran, pyran, thietane, 1 ,4-dioxane, 1 ,3-dioxane, 1 ,3-dioxalane, piperidine, piperazine, pyrrolidine, morpholine, thiomorpholine, thiazolidine, oxazolidine, tetrahydrothiopyran, tetrahydrothiophene and the like.
  • heterocycle and variations thereof (i.e., "N-heterocycle) is intended to independently describe each member of the genus.
  • N-heterocycle refers to monocyclic saturated or unsaturated non-aromatic groups having from 4 to 6 members, including at least one N and optionally 1 or 2 additional heteroatoms selected from N, O and S, unless a different number of additional heteroatoms is specified.
  • additional heteroatoms is meant 1 or 2 heteroatoms in addition to the N already specified in the N-heterocycle ring.
  • the heteroatoms may be the same or different and are independently selected from N, O and S.
  • N- heterocycles include both groups bound through the N of the N-heterocycle and groups bound through a C or S of the N-heterocycle.
  • the N-heterocyclic groups may be the same or different and are independently selected.
  • Examples of N-heterocycles include piperidine, piperazine, pyrrolidine, morpholine, thiomorpholine and the like.
  • heteroaryl refers to aromatic, monocyclic groups having 5 or 6 members (unless a different number of members is specified) including 1 , 2 or 3 heteroatoms selected from N, O and S, unless a different number of heteroatoms is specified.
  • the heteroaryl includes 2 or more heteroatoms, the heteroatoms may be the same or different and are independently selected from N, O and S.
  • the compound of formula (I) includes two or more heteroaryl groups, the heteroaryl groups may be the same or different and are independently selected.
  • heteroaryl groups include but are not limited to furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, and triazine.
  • heteroaryl and variations thereof (i.e., "N-heteroaryl”) is intended to independently describe each member of the genus.
  • N-heteroaryl refers to aromatic, monocyclic groups having 5 or 6 members (unless a different number of members is specified) including at least one N and optionally 1 or 2 additional heteroatoms selected from N, O and S, unless a different number of heteroatoms is specified.
  • additional heteroatoms is meant 1 or 2 heteroatoms in addition to the N already specified in the N-heteroaryl ring.
  • the heteroaryl includes 1 or more additional heteroatoms, the heteroatoms may be the same or different and are independently selected from N, O and S.
  • N- heteroaryls include both groups bound through the N of the N-heteroaryl and groups bound through a C or S of the N-heteroaryl.
  • the N-heteroaryl groups may be the same or different and are independently selected.
  • Examples of N-heteroaryls include pyrrole, imidazole, pyrazole, thiazole, isoxazole, pyridine, pyridazine, pyrazine, pyrimidine and triazine.
  • the term "members" (and variants thereof e.g., “membered") in the context of heterocyclic and heteroaryl groups refers to the total number of ring atoms, including carbon and heteroatoms N, O and/or S.
  • an example of a 6-membered heterocyclic ring is piperidine and an example of a 6-membered heteroaryl ring is pyridine.
  • optionally substituted means unsubstituted groups or rings (e.g., cycloalkyl, heterocycle, and heteroaryl rings) and rings substituted with one or more specified substituents.
  • the invention encompasses the compounds of formula (I)
  • W is selected from -O- and -S-;
  • R 1 is selected from ci-c6alkyl, haloalkyl, and C 3-c 6 cycloalkyl;
  • R 3 is selected from Het1 , pyridinyl, and ci-c6alkyl optionally substituted with - (co-c6alkylene-(OH) m ) n ;
  • R 4 is selected from H, -NH-R 7 and -CH 2 -R 7 ;
  • R 5 and R 6 are independently selected from H, F, and CI;
  • R 7 is selected from H, C i-c6alkylene-R 8 , and -co-c3alkylene-Het1 , and ci-c6alkyl optionally substituted with -( C o-c6alkylene-(OH) m ) n ;
  • R 8 is selected from haloalkyl-, CN, OH, and -SO2-ci-c3alkyl;
  • each Het1 is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N and O and optionally substituted with 1 or 2 substituents
  • each m is 1 or 2;
  • each n is 1 or 2;
  • compositions comprising the compounds, methods of treating susceptible neoplasms with the compounds, processes for preparing the compounds, and use of the compounds in the treatment of susceptible neoplasms.
  • W is selected from -O- and -S-;
  • R 1 is selected from ci-c6alkyl, haloalkyl, and c3-c6cycloalkyl;
  • R 3 is selected from ci-c6alkyl optionally substituted with -( C o-c6alkylene-
  • R 4 is selected from H, -NH-R 7 and -CH 2 -R 7 ;
  • R 5 and R 6 are independently selected from H, F, and CI;
  • R 7 is selected from H, C i-c6alkylene-R 8 , and -co-c3alkylene-Het1 , and ci-c6alkyl optionally substituted with -( C o-c6alkylene-(OH) m ) n ;
  • R 8 is selected from haloalkyl-, CN, OH, and -SO2-ci-c3alkyl;
  • each Het1 is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N and O and optionally substituted with 1 or 2 substituents
  • each m is 1 or 2;
  • each n is 1 or 2;
  • R 1 is a linear or branched ci-c6alkyl. More particularly, R1 is advantageously selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. In another aspect, there is provided compounds of formula (I) as in the first aspect wherein R 1 is advantageously a haloalkyl. More particularly, R 1 is advantageously selected from tri-fluoroethylene and tri-fluoropropylene.
  • R 1 is selected from propyl and tri-flouro-propylene.
  • R 3 is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N and O and optionally substituted with 1 or 2 substituents independently selected from ci-c3alkyl, -SO2-ci-c3alkyl, and -ci-c3alkylene-OH.
  • R 3 is selected from
  • R 1 is selected from ci-c6alkyl, haloalkyl, and c 3 -c 6 cycloalkyl;
  • R 3 is selected from Het1 , pyridinyl, and ci-c6alkyl optionally substituted with -
  • R 4 is selected from H, -NH-R 7 and -CH 2 -R 7 ;
  • R 5 and R 6 are independently selected from H, F, and CI;
  • R 7 is selected from H, C i-c6alkylene-R 8 , and -co-c3alkylene-Het1 , and ci-c6alkyl optionally substituted with -( C o-c6alkylene-(OH) m ) n ;
  • R 8 is selected from haloalkyl-, CN, OH, and -SO2-ci-c3alkyl;
  • each Het1 is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N and O and optionally substituted with 1 or 2 substituents
  • each m is 1 or 2;
  • each n is 1 or 2;
  • R 1 is a linear or branched ci-c6alkyl. More particul R1 is advantageously selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
  • R 1 is advantageously a haloalkyl. More particularly, R 1 is advantageously selected from tri-fluoroethylene and tri-fluoropropylene.
  • R 1 is selected from propyl and tri-flouro-propyl.
  • R 3 is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N and O and optionally substituted with 1 or 2 substituents independently selected from ci-c3alkyl, -SO 2 -ci-c3alkyl, and - C i- c3alkylene-OH.
  • compounds of formula (la) as in the second aspect wherein R 4 is -CH 2 -R 7 .
  • R 4 is selected from ethyl, 1 -propanol, and 2-methyl-2-butanol.
  • R 1 is selected from ci-c6alkyl, haloalkyl, and C 3-c 6 cycloalkyl;
  • R 3 is selected from Het1 , pyridinyl, and ci-c6alkyl optionally substituted with - (co-c6alkylene-(OH) m ) n ;;
  • R 4 is selected from -NH-R 7 and -CH 2 -R 7 ;
  • R 5 and R 6 are independently selected from H, F, and CI;
  • R 7 is selected from H, C i-c6alkylene-R 8 , and -co-c3alkylene-Het1 , and ci-c6alkyl optionally substituted with -( C o-c6alkylene-(OH) m ) n ;
  • R 8 is selected from haloalkyl-, CN, OH, and -SO2-ci-c3alkyl;
  • each Het1 is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N and O and optionally substituted with 1 or 2 substituents
  • R 1 is a linear or branched ci-c6alkyl . More particularly, R1 is advantageously selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
  • R 1 is advantageously a haloalkyl. More particularly, R 1 is advantageously selected from tri-fluoroethylene and tri-fluoropropylene. In another aspect, there is provided compounds of formula (Ic) as in the third aspect, wherein R 1 is selected from propyl and tri-flouro-propyl.
  • R 3 is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N and O and optionally substituted with 1 or 2 substituents independently selected from ci-c3alkyl, -SO2-ci-c3alkyl, and -ci-c3alkylene-OH.
  • R 3 is selected from
  • the compounds of formula (I) may be utilized as a pharmaceutically acceptable salt version thereof.
  • the pharmaceutically acceptable salts of the compounds of formula (I) include conventional salts formed from pharmaceutically acceptable (i.e., non-toxic) inorganic or organic acids or bases as well as quaternary ammonium salts.
  • Representative salts include the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, ethanol amine, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate (methanesulfonate), methylbromide, methylnitrate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate
  • the compound of formula (I) is in the form of the free base.
  • the compound of formula (I) is in the form of the mesylate salt.
  • the compound of formula (I) is in the form of the sulfate salt.
  • the compound of formula (I) is in the form of the hydrochloride salt.
  • the compound of formula (I) is in the form of the sodium salt.
  • Certain salt versions of the compounds may be solvates, particularly hydrates.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is in the form of a mono-, di-, tri- or hemi- hydrate.
  • Raf inhibitor a Raf family kinases
  • B- Raf inhibitor B- Raf inhibitor
  • Compounds of the invention may be Raf inhibitors and optionally also inhibit one or more ErbB family kinases (i.e., EGFR, ErbB2 and ErbB4). Certain compounds of the invention may inhibit B-Raf and also inhibit one or more ErbB family kinases (i.e., EGFR, ErbB2 and ErB4).
  • Some compounds of the invention may be selective inhibitors of Raf family kinases ("selective Raf inhibitor"), meaning that preferential inhibition of one or more Raf family kinases is significantly greater than that of any number of other kinases, for example by a factor of 5-fold or more.
  • the present invention is not limited to compounds which are selective inhibitors of one or more Raf family kinases rather, the present invention expressly contemplates that certain compounds of the invention may possess activity against multiple kinases, including kinases other than Raf family kinases.
  • particular compounds of the invention may possess activity against multiple other kinases, including but not limited to EGFR, ErbB2, ErbB4, IGF-1 R, IR, IRR, Src, VEGFR, PDGFR, Met, Lyn, Lck, Alk5, Aurora A and B, JNK, Syk, p38, BTK, FAK, Abl, CK1 .
  • a Raf inhibitor is a compound that exhibits a plC 5 o of greater than about 6 against at least one Raf family kinase in the Raf inhibition enzyme assay described below and/or an IC 5 o of not greater than about 5 ⁇ potency against at least one cell line that expresses mutated B-Raf kinase (e.g., A375P, Colo205, HT-29, SK-MEL-3, SK-MEL-28) in the methylene blue and/or the CellTiter-Glo cellular proliferation assays described below.
  • mutated B-Raf kinase e.g., A375P, Colo205, HT-29, SK-MEL-3, SK-MEL-28
  • a Raf inhibitor refers to a compound of the invention that exhibits a plC 5 o of greater than about 6.5 against at least one Raf family kinase in the Raf inhibition enzyme assay described below and an IC 50 of not greater than about 500nM potency against at least one cell line that expresses mutated B-Raf kinase in the methylene blue and/or the CellTiter- Glo cellular proliferation assays described below.
  • a "B-Raf inhibitor” refers to a compound of the invention that exhibits a plC 5 o of greater than about 6.5 against B-Raf (including B-Raf mutants) in the Raf inhibition enzyme assay described below and an IC 5 o of not greater than about 500nM potency against at least one cell line that expresses mutated B- Raf kinase in the methylene blue and/or the CellTiter-Glo cellular proliferation assay described below.
  • the present invention provides compounds for use in medical therapy in a mammal, e.g., a human, in need thereof.
  • the present invention provides methods for the treatment of several conditions in a mammal, in need thereof, all of which comprise the step of administering a therapeutically effective amount of a compound of the invention. All methods described herein are applicable to mammals, and particularly to humans.
  • treatment refers to alleviating the specified condition, eliminating or reducing the symptoms of the condition, slowing or eliminating the progression, invasion, or metastatic spread of the condition and preventing or delaying the reoccurrence of the condition in a previously afflicted subject.
  • the present invention further provides use of the compounds of the invention for the preparation of a medicament for the treatment of several conditions in a mammal (e.g., human) in need thereof.
  • the present invention provides compounds for use in the treatment of a condition mediated by at least one Raf family kinases (e.g., B- Raf) in a mammal in need thereof.
  • the present invention provides a method for treating a condition mediated by at least one Raf family kinase (e.g., B- Raf) in a mammal (e.g., a human) in need thereof, which method comprises administering to the mammal a therapeutically effective amount of the compound of the invention.
  • the invention provides compounds for use in regulating, modulating, binding or inhibiting one or more Raf family kinases (e.g., B-Raf) in a mammal.
  • the invention also provides methods of
  • Raf family kinase e.g., B-Raf
  • regulating, modulating, binding, or inhibiting at least one Raf family kinase refers to regulating, modulating, binding or inhibiting the activity of at least one Raf family kinase, as well as regulating, modulating, binding or inhibiting overexpression of an upstream regulator of at least one Raf family kinase in order to inhibit the cellular potency of its signaling ability.
  • the invention provides compounds for use in the treatment of a condition mediated by inappropriate activity of one or more Raf family kinases (e.g., B-Raf), or an upstream activator of one or more Raf family kinases in a mammal.
  • the invention further provides methods for the treatment of a condition mediated by inappropriate activity of one or more Raf family kinases (particularly B-Raf), in a mammal in need thereof, comprising administering to the mammal, a therapeutically effective amount of a compound of the invention.
  • the present invention provides the use of a compound of the invention for the preparation of a medicament for the treatment of a condition mediated by inappropriate activity of one or more Raf family kinases (particularly B-Raf), in a mammal.
  • a condition mediated by inappropriate activity of one or more Raf family kinases includes neoplasms.
  • inappropriate activity is meant Raf family kinase activity that deviates from the expected activity for that kinase or for an upstream activator of that kinase in a particular mammal.
  • the inappropriate activity of a Raf family kinase may arise from one or more of A-Raf, B-Raf or c-Raf or an upstream activator of a Raf family kinase.
  • Inappropriate Raf family kinase activity may take the form of, for instance, an abnormal increase in activity, or an aberration in the timing and/or control of Raf family kinase activity.
  • Such inappropriate activity may result, for example, from overexpression or mutation of the kinase, upstream activator, receptor or ligand leading to inappropriate or uncontrolled activation of the corresponding kinase or receptor.
  • unwanted Raf family kinase activity may reside in an abnormal source, such as a neoplasm.
  • the level of Raf family kinase activity does not need to be abnormal to be considered inappropriate in the case where the activity derives from an abnormal source including, but not limited to, upstream activators (e.g., activated mutant Ras GTPases) or neoplasm.
  • upstream activators e.g., activated mutant Ras GTPases
  • inappropriate Raf family kinase activity not resulting from mutation or overexpression of a Raf family kinase inappropriate activity of a Ras GTPase may result from mutation or overexpression of Ras GTPase, for example the G13D mutation in KRas2, and may lead to overactivation of the MAPK pathway mediated by Raf family kinase activity.
  • the present invention provides compounds for use in the treatment of a condition which directly or indirectly results from a mutation of a Raf family kinase or overexpression of a Raf family kinase, or a mutation of an upstream activator of a Raf family kinase or overexpression of an upstream activator of a Raf family kinase in a mammal in need thereof.
  • the present invention provides methods for the treatment of a condition which directly or indirectly results from mutation of a Raf family kinase or
  • overexpression of a Raf family kinase or a mutation of an upstream activator of a Raf family kinase or overexpression of an upstream activator of a Raf family kinase in a mammal in need thereof, comprising administering to the mammal, a therapeutically effective amount of a compound of the invention.
  • the present invention provides the use of a compound of the invention for the preparation of a medicament for the treatment of a condition which directly or indirectly results from mutation of a Raf family kinase or overexpression of a Raf family kinase, or a mutation of an upstream activator of a Raf family kinase or overexpression of an upstream activator of a Raf family kinase in a mammal.
  • Conditions which are mediated by at least one Raf family kinase, and particularly conditions mediated by inappropriate activity of one or more Raf family kinases, including those which directly or indirectly result from mutation of a Raf family kinase, overexpression of a Raf family kinase, or mutation of an upstream activator of a Raf family kinase or overexpression of an upstream activator of a Raf family kinase are known in the art and include but are not limited to neoplasms.
  • Compounds of the invention may also be used in the treatment of conditions attenuated by inhibition of a Raf family kinase (particularly B-Raf). Further provided are methods for treating a condition attenuated by inhibition of a Raf family kinase (particularly B-Raf) in a mammal in need thereof, comprising administering to the mammal, a therapeutically effective amount of a compound of the invention. Also provided is the use of a compound of the invention for the preparation of a medicament for the treatment of a condition attenuated by inhibition of a Raf family kinase (particularly B-Raf) in a mammal.
  • Conditions attenuated by inhibition of a Raf family kinase include but are not limited to neoplasms. Accordingly, compounds of the invention may be used in the treatment of a neoplasm, particularly a susceptible neoplasm (a cancer or tumor) in a mammal.
  • the present invention also provides a method for treating a neoplasm, particularly a susceptible neoplasm in a mammal in need thereof, which method comprises administering to the mammal a therapeutically effective amount of the compound of the invention.
  • the invention also provides the use of a compound of the invention for the preparation of a medicament for the treatment of neoplasm, particularly a susceptible neoplasm, in a mammal.
  • “Susceptible neoplasm” as used herein refers to neoplasms which are susceptible to treatment by a kinase inhibitor and particularly neoplasms that are susceptible to treatment by a Raf inhibitor.
  • Neoplasms which have been associated with inappropriate activity of one or more Raf family kinases and particularly neoplasms which are exhibit mutation of a Raf family kinase, overexpression of a Raf family kinase, or mutation of an upstream activator of a Raf family kinase or overexpression of an upstream activator of a Raf family kinase, and are therefore susceptible to treatment with an Raf inhibitor are known in the art, and include both primary and metastatic tumors and cancers. See, Catalogue of Somatic Mutations in Cancer (COSMIC), the Wellcome Trust Sanger Institute,
  • central nervous system tumors including primary CNS tumors such as
  • glioblastomas astrocytomas (including glioblastoma multiforme) and ependymomas
  • secondary CNS tumors i.e., metastases to the central nervous system of tumors originating outside of the central nervous system
  • colorectal cancer including large intestinal colon carcinoma
  • carcinoma of the head and neck including squamous cell carcinoma of the head and neck;
  • hematologic cancers including leukemias and lymphomas such as acute
  • lymphoblastic leukemia acute myelogenous leukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia, multiple myeloma and erythroleukemia;
  • lung cancer including small cell lung cancer and non-small cell lung cancer; ovarian cancer;
  • endometrial cancer pancreatic cancer
  • skin cancers including melanomas
  • the susceptible neoplasm is a neoplasm which exhibits a mutation in BRaf.
  • the present invention provides a method for the treatment of any of Barret's adenocarcinoma; billiary tract carcinomas; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors including primary CNS tumors such as glioblastomas, astrocytomas (e.g., glioblastoma multiforme) and ependymomas, and secondary CNS tumors (i.e., metastases to the central nervous system of tumors originating outside of the central nervous system); colorectal cancer including large intestinal colon carcinoma; gastric cancer; carcinoma of the head and neck including squamous cell carcinoma of the head and neck; hematologic cancers including leukemias and lymphomas such as acute lymphoblastic leukemia, acute myelogenous leukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphom
  • the method comprises administering a therapeutically effective amount of a compound of the invention to the mammal (e.g., human).
  • the present invention provides a method for treating breast cancer, cholangiocarcinoma, colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, or thyroid cancer, or any subset thereof. In one particular embodiment, the present invention provides a method for treating cholangiocarcinoma, colorectal cancer, melanoma, or thyroid cancer, or any subset thereof.
  • the present invention provides a method for treating melanoma in a mammal (e.g., human) in need thereof.
  • the method comprises administering to the mammal (e.g. human) a therapeutically effective amount of a compound of formula (I).
  • the compound is selected from
  • the present invention also provides the a compound of formula (I) for use in the treatment of Barret's adenocarcinoma; bill iary tract carcinomas; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors including primary CNS tumors such as glioblastomas, astrocytomas (e.g., glioblastoma multiforme) and ependymomas, and secondary CNS tumors (i.e., metastases to the central nervous system of tumors originating outside of the central nervous system); colorectal cancer including large intestinal colon carcinoma; gastric cancer; carcinoma of the head and neck including squamous cell carcinoma of the head and neck; hematologic cancers including leukemias and lymphomas such as acute lymphoblastic leukemia, acute myelogenous leukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia, Hodgkin's lymphoma, non-Ho
  • the present invention further provides the use of a compound of formula (I) for the preparation of a medicament for the treatment of Barret's
  • adenocarcinoma billiary tract carcinomas; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors including primary CNS tumors such as glioblastomas, astrocytomas (e.g., glioblastoma multiforme) and ependymomas, and secondary CNS tumors (i.e., metastases to the central nervous system of tumors originating outside of the central nervous system); colorectal cancer including large intestinal colon carcinoma; gastric cancer; carcinoma of the head and neck including squamous cell carcinoma of the head and neck; hematologic cancers including leukemias and lymphomas such as acute lymphoblastic leukemia, acute myelogenous leukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia, multiple myeloma and erythroleuk
  • tumors may metastasize from a first or primary locus of tumor to one or more other body tissues or sites.
  • metastases to the central nervous system i.e., secondary CNS tumors
  • the brain i.e., brain metastases
  • tumors and cancers such as breast, lung, melanoma, renal and colorectal.
  • neoplasm in a subject includes use for and treatment of the primary neoplasm, tumor or cancer, and where appropriate, also the use for and treatment of metastases (i.e., metastatic tumor growth) as well.
  • the susceptible neoplasm is colorectal cancer and the invention provides compounds for use in the treatment of colorectal cancer in a mammal (e.g., human) and the use of such compounds for the preparation of a medicament for the treatment of colorectal cancer in a mammal (e.g., human).
  • the susceptible neoplasm is melanoma
  • the invention provides compounds for use in the treatment of melanoma in a mammal (e.g., human) and the use of such compounds for the preparation of a medicament for the treatment of melanoma in a mammal (e.g., human).
  • the susceptible neoplasm is cholangiocarcinoma
  • the invention provides compounds for use in the treatment of
  • cholangiocarcinoma in a mammal e.g., human
  • a mammal e.g., human
  • use of such compounds for the preparation of a medicament for the treatment of cholangiocarcinoma in a mammal (e.g., human).
  • the susceptible neoplasm is thyroid cancer
  • the invention provides compounds for use in the treatment of thyroid cancer in a mammal (e.g., human) and the use of such compounds for the preparation of a medicament for the treatment of thyroid cancer in a mammal (e.g., human).
  • the susceptible neoplasm is breast cancer and the invention provides compounds for use in the treatment of breast cancer in a mammal (e.g., human) and the use of such compounds for the preparation of a medicament for the treatment of breast cancer in a mammal (e.g., human).
  • the susceptible neoplasm is ovarian cancer and the invention provides compounds for use in the treatment of ovarian cancer in a mammal (e.g., human) and the use of such compounds for the preparation of a medicament for the treatment of ovarian cancer in a mammal (e.g., human).
  • the susceptible neoplasm is non-small cell lung cancer, and the invention provides compounds for use in the treatment of non-small cell lung cancer in a mammal (e.g., human) and the use of such compounds for the preparation of a medicament for the treatment of non- small cell lung cancer in a mammal (e.g., human).
  • the compounds of the invention can be used alone in the treatment of each of the foregoing conditions or can be used to provide additive or potentially synergistic effects with certain existing chemotherapies, radiation, biological or immunotherapeutics (including monoclonal antibodies) and vaccines.
  • the compounds of the invention may be useful for restoring effectiveness of certain existing chemotherapies and radiation and or increasing sensitivity to certain existing chemotherapies and/or radiation.
  • the compounds of the invention may also be used in the treatment of other conditions attenuated by inhibition of a Raf family kinase, such as cardio-facio cutaneous syndrome and polycystic kidney disease.
  • the present invention provides a method for treating a susceptible neoplasm in a mammal in need thereof comprising the steps of:
  • the activating mutation present in the coding sequence for BRAF results in a BRAF having an amino acid substitution selected from the group consisting of R462I, I463S, G464V, G464E, G466A, G466E, G466V, G469A, G469E, D594V, F595L, G596R, L597V, L597R, T599I, V600E, V600D, V600K, V600R, T1 19S, and K601 E. See, for example, Figure 2 of Halilovic and Solvit (2008) Current Opinion in Pharmacology 8:419-26.
  • the present invention provides a method for treating a susceptible neoplasm in a mammal in need thereof comprising the steps of:
  • step (c) administering a therapeutically effective amount of a compound of the present invention to the mammal selected in step (b).
  • the V600E amino acid substitution in B-Raf is described, for example, in Kumar et al. (2004) J Invest Dermatol. 122(2):342-8. This mutation commonly results from a T1799A mutation in the coding sequence for human B-Raf. Accordingly, in one embodiment of the present invention, the step of analyzing a sample from said neoplasm to determine whether a mutation encoding a V600E amino acid substitution is present in the coding sequence for B-Raf is performed by determining whether the coding sequence for B-Raf in cells of the neoplasm contains the T1799A mutation.
  • the neoplasm may be selected from Barret's adenocarcinoma; billiary tract carcinomas; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors including primary CNS tumors such as glioblastomas, astrocytomas (e.g., glioblastoma multiforme) and ependymomas, and secondary CNS tumors (i.e., metastases to the central nervous system of tumors originating outside of the central nervous system); colorectal cancer including large intestinal colon carcinoma; gastric cancer; carcinoma of the head and neck including squamous cell carcinoma of the head and neck; hematologic cancers including leukemias and lymphomas such as acute lymphoblastic leukemia, acute myelogenous leukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia, Hodgkin's lymphoma, non- Hodgkin's lymphoma, megakaryoblastic le
  • the neoplasm is selected from breast cancer, cholangiocarcinoma, colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, and thyroid cancer.
  • the neoplasm is melanoma.
  • the mammal is a human.
  • the sample of the neoplasm to be analyzed for the presence of B-raf activating mutations can be derived from a variety of sources including, but not limited to, single cells, a collection of cells, tissue, cell culture, bone marrow, blood, or other bodily fluids.
  • the tissue or cell source may include a tissue biopsy sample, a cell sorted population, cell culture, or a single cell. In selecting a sample, the percentage of the sample that constitutes neoplastic cells should be considered.
  • the sample from the neoplasm is fixed using a preservative prior to analyzing for the presence of an activating mutation.
  • the step of analyzing a sample from the neoplasm to determine whether an activating mutation is present in the coding sequence for B-Raf in cells of said neoplasm may be performed using any method known in the art.
  • the coding sequence for B-raf in cells of the sample may be analyzed to determine if it contains a mutation which results in the expression of activated B-Raf.
  • Methods for detecting such mutations are well known in the art. See, for example, Whitcombe et al. (1999) Nature Biotechnology 17:804-7, Gibson (2006) Clinica Chimica Acta 363: 32-47, Kim and Misra
  • activating mutations in B-Raf may be identified by directly detecting the activated B-raf protein using an agent (e.g. an antibody) that selectively binds activated B-raf.
  • an agent e.g. an antibody
  • therapeutically effective amount means an amount of a compound of the invention which is sufficient, in the subject to which it is administered, to elicit a biological or medical response of a cell culture, tissue, system, mammal (including human) that is being sought, for instance, by a researcher or clinician.
  • the term also includes within its scope amounts effective to enhance normal physiological function. For example, a
  • a therapeutically effective amount of a compound of the invention for the treatment of a condition mediated by at least one Raf family kinase is an amount sufficient to treat the condition in the particular subject.
  • a therapeutically effective amount of a compound of the invention for the treatment of a susceptible neoplasm is an amount sufficient to treat the particular susceptible neoplasm in the subject.
  • a therapeutically effective amount of a compound of the invention is an amount sufficient to regulate, modulate, bind or inhibit at least one Raf family kinase. More particularly, in such embodiment, the
  • therapeutically effective amount of a compound of the invention is an amount sufficient to regulate, modulate, bind or inhibit B-Raf.
  • the precise therapeutically effective amount of the compounds of the invention will depend on a number of factors. There are variables inherent to the compounds including, but not limited to, the following: molecular weight, inhibitory activity at the target kinase, absorption, bioavailability, distribution in the body, tissue penetration, half-life, metabolism, protein binding, and excretion. These variables determine what dose of compound needs to be administered in order to inhibit the target kinase by a sufficient percentage and for a sufficient amount of time to have the desired effect on the condition being treated (e.g., neoplasm). In general, the goal will be to inhibit the target kinase by 50% or more for as long as possible. The duration of drug exposure will be limited only by the compound half-life, and side effects from treatment requiring cessation of dosing. The amount of compound
  • the compound of the invention will be given for treatment in the range of 0.01 to 30 mg/kg body weight of recipient (mammal) per day or per dose or per cycle of treatment and more usually in the range of 0.1 to 10 mg/kg body weight per day or per dose or per cycle of treatment.
  • the actual amount per day or per dose or per cycle of treatment would usually be from 1 to 2000 mg and this amount may be given in a single or multiple doses per day or per dose or per cycle of treatment.
  • Dosing regimens may vary significantly and will be determined and altered based on clinical experience with the compound. The full spectrum of dosing regimens may be employed ranging from continuous dosing (with daily doses) to intermittent dosing.
  • a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula (I) may be determined as a proportion of the
  • the invention further provides a pharmaceutical composition comprising a compound of the invention.
  • the pharmaceutical composition may further comprise one or more pharmaceutically acceptable carriers, diluents, and/or excipients.
  • the carrier(s), diluent(s) and/or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • a process for the preparation of a pharmaceutical formulation including admixing a compound of the invention with one or more
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a compound of the invention (as a free-base, solvate (including hydrate) or salt, in any form), depending on the condition being treated, the route of administration, and the age, weight and condition of the patient.
  • Preferred unit dosage formulations are those containing a daily dose, weekly dose, monthly dose, a sub-dose or an appropriate fraction thereof, of an active ingredient.
  • formulations may be prepared by any of the methods well known in the pharmacy art.
  • compositions may be adapted for administration by any appropriate route, for example by the oral (including capsules, tablets, liquid- filled capsules, disintegrating tablets, immediate, delayed and controlled release tablets, oral strips, solutions, syrups, buccal and sublingual), rectal, nasal, inhalation, topical (including transdermal), vaginal or parenteral
  • formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s), excipient(s) or diluent.
  • the carrier, excipient or diluent employed in the pharmaceutical formulation is "non-toxic,” meaning that it/they is/are deemed safe for consumption in the amount delivered in the pharmaceutical composition, and "inert” meaning that it/they does/do not appreciably react with or result in an undesired effect on the therapeutic activity of the active ingredient.
  • compositions adapted for oral administration may be
  • the active drug component can be combined with an oral pharmaceutically acceptable carrier such as ethanol, glycerol, water and the like.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.
  • Solid capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • disintegrating agents and coloring agents can also be incorporated into the mixture.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an alginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • a binder such as carboxymethylcellulose, an alginate, gelatin, or polyvinyl pyrrolidone
  • a solution retardant such as paraffin
  • a resorption accelerator such as a quaternary salt
  • an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil.
  • the lubricated mixture is then compressed into tablets.
  • the compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of
  • Oral fluids such as solutions, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
  • Solutions and syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a pharmaceutically acceptable alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound in a
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.
  • unit dosage formulations for oral administration can be microencapsulated.
  • the formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
  • the compounds of the invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • the compounds of the invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include
  • polyvinylpyrrolidone polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl- methacrylamidephenol, polyhydroxyethylaspartamidephenol, or
  • the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polycentric acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • a drug for example, polycentric acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research (1986) 3(6):318.
  • compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • the formulations may be applied as a topical ointment or cream.
  • the active ingredient may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
  • Pharmaceutical formulations adapted for topical may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • the formulations may be applied as a topical ointment or cream.
  • the active ingredient may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredient may be formulated in a cream with an oil-in-
  • administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
  • a suitable carrier especially an aqueous solvent.
  • Pharmaceutical formulations adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.
  • Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or as enemas.
  • compositions adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.
  • Fine particle dusts or mists which may be generated by means of various types of metered dose pressurized aerosols, metered dose inhalers, dry powder inhalers, nebulizers or insufflators.
  • compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation of pharmaceutically acceptable tonicity with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use.
  • sterile liquid carrier for example water for injection
  • suspensions may be prepared from sterile powders, granules and tablets.
  • formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • a compound of the invention may be employed alone, in combination with one or more other compounds of the invention or in combination with other therapeutic methods or agents.
  • combination with other chemotherapeutic, biologic, hormonal, antibody and supportive care agents is envisaged as well as combination with surgical therapy and radiotherapy.
  • Supportive care agents include analgesics, anti-emetics and agents used to treat heamatologic side effects such as neutropenia.
  • Analgesics are well known in the art.
  • Antiemetics include but are not limited to 5HT 3 antagonists such as ondansetron, granisetron, dolasetron, palonosetron and the like; prochlorperazine;
  • metaclopromide diphenhydramine; promethazine; dexamethasone;
  • lorazepam haloperidol
  • dronabinol dronabinol
  • olanzapine olanzapine
  • neurokinin-1 antagonists such as aprepitant, fosaprepitant and casopitant administered alone or in various combinations.
  • chemotherapeutic refers to any chemical agent having a therapeutic effect on the subject to which it is administered.
  • “Chemotherapeutic” agents include but are not limited to anti-neoplastic agents.
  • anti-neoplastic agents include both cytotoxic and cytostatic agents including biological, immunological and vaccine therapies.
  • Combination therapies according to the invention thus comprise the administration of at least one compound of the invention and the use of at least one other treatment method.
  • combination therapies according to the invention comprise the administration of at least one compound of the invention and surgical therapy.
  • combination therapies according to the invention comprise the administration of at least one compound of the invention and radiotherapy. In one
  • combination therapies according to the invention comprise the administration of at least one compound of the invention and at least one supportive care agent (e.g., at least one anti-emetic agent).
  • at least one supportive care agent e.g., at least one anti-emetic agent.
  • combination therapies according to the present invention comprise the administration of at least one compound of the invention and at least one other chemotherapeutic agent.
  • the invention comprises the administration of at least one compound of the invention and at least one anti-neoplastic agent.
  • the present invention provides the methods of treatment and uses as described above, which comprise administering a compound of the invention together with at least one chemotherapeutic agent.
  • the chemotherapeutic agent is an antineoplastic agent.
  • the invention provides a
  • compositions as described above further comprising at least one other chemotherapeutic agent, more particularly, the chemotherapeutic agent is an anti-neoplastic agent.
  • the invention also provides methods of treatment and uses as described above, which comprise administering a compound of the invention together with at least one supportive care agent (e.g., anti-emetic agent).
  • the compounds of the invention and at least one additional anti-neoplastic or supportive care therapy may be employed in combination concomitantly or sequentially in any therapeutically appropriate combination.
  • administration of a compound of the invention with one or more other antineoplastic agents may be in combination in accordance with the invention by administration concomitantly in one unitary pharmaceutical composition including both or all compounds or two or more separate pharmaceutical compositions each including one or more of the compounds.
  • components of the combination may be administered separately in a sequential manner wherein one active ingredient is administered first and the other(s) second or vice versa. Such sequential administration may be close in time or remote in time.
  • the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
  • the appropriate dose of the compound(s) of the invention and the other therapeutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect, and are within the expertise and discretion of the attendant clinician.
  • any chemotherapeutic agent that has activity against a susceptible neoplasm being treated may be utilized in combination with the compounds of the invention, provided that the particular agent is clinically compatible with therapy employing a compound of the invention.
  • Typical anti-neoplastic agents useful in the present invention include, but are not limited to: alkylating agents, anti-metabolites, antitumor antibiotics, antimitotic agents,
  • topoisomerase I and II inhibitors include hormones and hormonal analogues;
  • retinoids include inhibitors of cell growth or growth factor function, angiogenesis inhibitors, and serine/threonine or other kinase inhibitors; cyclin dependent kinase inhibitors; antisense therapies and immunotherapeutic agents, including monoclonals, vaccines or other biological agents.
  • Alkylating agents are non-phase specific anti-neoplastic agents and strong electrophiles. Typically, alkylating agents form covalent linkages, by alkylation, to DNA through nucleophilic moieties of the DNA molecule such as phosphate, amino, and hydroxyl groups. Such alkylation disrupts nucleic acid function leading to cell death. Alkylating agents may be employed in combination with the compounds of the invention in the compositions and methods described above.
  • alkylating agents include but are not limited to nitrogen mustards such as cyclophosphamides, temozolamide, melphalan, and chlorambucil; oxazaphosphor-ines; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; triazenes such as dacarbazine; and platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin.
  • Antimetabolite neoplastic agents are phase specific anti-neoplastic agents that act at S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA synthesis.
  • Antimetabolite neoplastic agents may be employed in combination with the compounds of the invention in the compositions and methods described above.
  • antimetabolite anti-neoplastic agents include but are not limited to purine and pyrimidine analogues and anti-folate compounds, and more specifically, hydroxyurea, cytosine, arabinoside, ralitrexed, tegafur, fluorouracil (e.g., 5FU), methotrexate, cytarabine, mecaptopurine and thioguanine.
  • Antitumor antibiotic agents are non-phase specific agents, which bind to or intercalate with DNA. Typically, such action disrupts ordinary function of the nucleic acids, leading to cell death. Antitumor antibiotics may be employed in combination with the compounds of the invention in the compositions and methods described above. Examples of antitumor antibiotic agents include, but are not limited to, actinomycins such as dactinomycin; anthracydines such as daunorubicin, doxorubicin, idarubicin, epirubicin and mitoxantrone;
  • Antimicrotubule or antimitotic agents are phase specific agents active against the microtubules of tumor cells during M or the mitosis phase of the cell cycle.
  • Antimitotic agents may be employed in combination with the compounds of the invention in the compositions and methods described above.
  • antimitotic agents include, but are not limited to, diterpenoids, vinca alkaloids, polo-like kinase (Plk) inhibitors and CenpE inhibitors. Examples of
  • diterpenoids include, but are not limited to, paclitaxel and its analog docetaxel.
  • vinca alkaloids include, but are not limited to, vinblastine, vincristine, vindesine and vinorelbine. Plk inhibitors are discussed further below.
  • Topoisomerase inhibitors include inhibitors of Topoisomerase II and inhibitors of Topoisomerase I.
  • Topoisomerase II inhibitors such as
  • epipodophyllotoxins are anti-neoplastic agents derived from the mandrake plant, that typically affect cells in the S and G2 phases of the cell cycle by forming a ternary complex with topoisomerase II and DNA, causing DNA strand breaks. The strand breaks accumulate and cell death follows.
  • Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide.
  • Camptothecins including camptothecin and camptothecin derivatives, are available or under development as Topoisomerase I inhibitors.
  • Examples of camptothecins include, but are not limited to amsacrine, irinotecan, topotecan, and the various optical forms of 7-(4- methylpiperazino-methylene)-10,1 1 -ethylenedioxy-20-camptothecin.
  • Topoisomerase inhibitors may be employed in combination with the compounds of the invention in the compositions and methods described above.
  • Hormones and hormonal analogues are useful compounds for treating cancers in which there is a relationship between the hormone(s) and growth and/or lack of growth of the cancer.
  • Antitumor hormones and hormonal analogues may be employed in combination with the compounds of the invention in the compositions and methods described above.
  • hormones and hormonal analogues believed to be useful in the treatment of neoplasms include, but are not limited to antiestrogens, such as tamoxifen, toremifene, raloxifene, fulvestrant, iodoxyfene and droloxifene; anti- androgens; such as flutamide, nilutamide, bicalutamide and cyproterone acetate; adrenocorticosteroids such as prednisone and prednisolone;
  • antiestrogens such as tamoxifen, toremifene, raloxifene, fulvestrant, iodoxyfene and droloxifene
  • anti- androgens such as flutamide, nilutamide, bicalutamide and cyproterone acetate
  • adrenocorticosteroids such as prednisone and predni
  • aminoglutethimide and other aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestane
  • progestrins such as megestrol acetate
  • 5a-reductase inhibitors such as finasteride and dutasteride
  • gonadotropin-releasing hormones GnRH
  • analogues thereof such as Leutinizing Hormone-releasing Hormone (LHRH) agonists and antagonists such as goserelin luprolide, leuprorelin and buserelin.
  • LHRH Leutinizing Hormone-releasing Hormone
  • Retinoid(s) are compounds that bind to and activate at least one retinoic acid receptor selected from RARa, RAR , and RARy and/or compounds that bind to and activate at least one of RARa, RAR , and RARy and also at least one retinoic X receptor (RXR), including RXRa, RXR , and RXRy.
  • RXR retinoic X receptor
  • Retinoids for use in the present invention typically have affinity for RAR, and particularly for RARa and/or RAR .
  • certain synthetic retinoids, such as 9-cis- retinoic acid also have affinity for both RAR and RXR.
  • the retinoid has affinity for RARa (and RARa agonist).
  • retinoids examples include: retinoic acid; all-trans-retinoic acid (“ATRA” also known as “tretinoin”); tamibarotene (“Am80”); 9-cis-retinoic acid ((2E,4E,6Z,8E)-3,7-Dimethyl-9-(2,6,6-trimethylcyclohex-1 -enyl)nona- 2,4,6,8-tetraenoic Acid) (also known as “9-cis-Tretinoin”) (available from Sigma); Isotretinoin ((2Z,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 - cyclohexenyl)nona-2,4,6,8-tetraenoic acid) (also known as "13-cis-retinoic acid”) (ACCUTANE®); Am580 (4-(5,6,7,8-tetrahydro-5,
  • TTNPB (4-[E-2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1 - propenyl]benzoic acid) (also known as "Ro 13-7410") See, M.F. Boehm et al. J. Med. Chem. 1994 37:2930 and R.P. Bissonnette et al., Mol. Cell. Biol.
  • RARa agonists known the art may also be used in the present invention.
  • Signal transduction pathway inhibitors are those inhibitors which block or inhibit a chemical process which evokes an intracellular change. As used herein these changes include, but are not limited to, cell proliferation or differentiation or survival.
  • Signal transduction pathway inhibitors useful in the present invention include, but are not limited to, inhibitors of receptor tyrosine kinases, non-receptor tyrosine kinases, SH2/SH3 domain blockers, serine/threonine kinases, phosphatidyl inositol-3-OH kinases, myoinositol signaling, and Ras oncogenes. Signal transduction pathway inhibitors may be employed in combination with the compounds of the invention in the compositions and methods described above.
  • protein tyrosine kinases catalyze the phosphorylation of specific tyrosine residues in various proteins involved in the regulation of cell growth.
  • protein tyrosine kinases can be broadly classified as receptor or nonreceptor kinases.
  • Receptor tyrosine kinase inhibitors which may be combined with the
  • growth factor receptor inhibitors include but are not limited to inhibitors of: insulin growth factor receptors (IGF-1 R, IR and IRR); epidermal growth factor family receptors (EGFR, ErbB2, and ErbB4); platelet derived growth factor receptors (PDGFRs), vascular endothelial growth factor receptors (VEGFRs), tyrosine kinase with immunoglobulin-like and epidermal growth factor homology domains (TIE-2), macrophage colony stimulating factor (c-fms), c-kit, c-met, fibroblast growth factor receptors (FGFRs), hepatocyte growth factor receptors (HGFRs), Trk receptors (TrkA, TrkB, and TrkC), ephrin (Eph) receptors and the RET protooncogene.
  • IGF-1 R insulin growth factor receptors
  • IR and IRR epidermal growth factor family receptors
  • PDGFRs platelet derived growth factor receptors
  • VEGFRs
  • Trastuzumab (Herceptin®) is an example of an anti-erbB2 antibody inhibitor of growth factor function.
  • An anti-erbB1 antibody inhibitor of growth factor function is cetuximab (ErbituxTM, C225).
  • Bevacizumab (Avastin®) is an example of a monoclonal antibody directed against VEGFR.
  • small molecule inhibitors of epidermal growth factor receptors include but are not limited to lapatinib (TykerbTM) and erlotinib (TARCEVA®). Imatinib
  • VEGFR inhibitors include pazopanib, ZD6474, AZD2171 , PTK787, sunitinib and sorafenib.
  • the invention provides methods of treatment of any of the various conditions enumerated above comprising administering a compound of the invention in combination with an EGFR or ErbB inhibitor.
  • the methods of the present invention comprise administering a compound of the invention in combination with lapatinib.
  • the methods of the present invention comprise administering a compound of the invention in combination with trastuzumab.
  • the methods of the present invention comprise administering a compound of the invention in combination with erlotinib.
  • the methods of the present invention comprise administering a compound of the invention in combination with gefitinib.
  • the present invention provides methods of treatment of any of the various conditions enumerated above comprising administering a compound of the invention in combination with a VEGFR inhibitor.
  • the methods of the present invention comprise administering a compound of the invention in combination with pazopanib.
  • Tyrosine kinases that are not transmembrane growth factor receptor kinases are termed non-receptor, or intracellular tyrosine kinases.
  • Inhibitors of nonreceptor tyrosine kinases are sometimes referred to as "anti-metastatic agents" and are useful in the present invention.
  • Targets or potential targets of anti-metastatic agents include, but are not limited to, c-Src, Lck, Fyn, Yes, Jak, Abl kinase (c-Abl and Bcr-AbI), FAK (focal adhesion kinase) and Bruton's tyrosine kinase (BTK).
  • Non-receptor kinases and agents, which inhibit nonreceptor tyrosine kinase function are described in Sinha, S. and Corey, S.J., (1999) J. Hematother. Stem Cell Res. 8:465-80; and Bolen, J.B. and Brugge, J.S., (1997) Annu. Rev. of Immunol. 15:371 -404.
  • SH2/SH3 domain blockers are agents that disrupt SH2 or SH3 domain binding in a variety of enzymes or adaptor proteins including, but not limited to, PI3-K p85 subunit, Src family kinases, adaptor molecules (She, Crk, Nek, Grb2) and Ras-GAP.
  • Src inhibitors include, but are not limited to, dasatinib and BMS-354825 (J.Med.Chem (2004) 47:6658-6661 ).
  • Inhibitors of serine/threonine kinases may also be used in combination with the compounds of the invention in any of the compositions and methods described above.
  • serine/threonine kinase inhibitors that may also be used in combination with a compound of the present invention include, but are not limited to, polo-like kinase inhibitors (Plk family e.g., Plk1 , Plk2, and Plk3), which play critical roles in regulating processes in the cell cycle including the entry into and the exit from mitosis; MAP kinase cascade blockers, which include other Ras/Raf kinase inhibitors, mitogen or
  • extracellular regulated kinases MEKs
  • extracellular regulated kinases ERKs
  • Aurora kinase inhibitors including inhibitors of Aurora A and Aurora B
  • protein kinase C (PKC) family member blockers including inhibitors of PKC subtypes (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta);
  • IkB kappa-B
  • IKK-alpha IKK-beta
  • PKB/Akt kinase family inhibitors inhibitors of TGF-beta receptor kinases.
  • the present invention provides methods of treatment of any of the various conditions enumerated above comprising administering a compound of the invention in combination with a Plk inhibitor.
  • the methods of the present invention comprise administering a compound of the invention in combination with 5- ⁇ 6-[(4-Methylpiperazin-1 -yl)methyl]-1 H-benzimidazol-1 -yl ⁇ -3- ⁇ (1 R)-1 -[2- (trifluoromethyl)phenyl]ethoxy ⁇ thiophene-2-carboxamide.
  • Urokinase also referred to as urokinase-type Plasminogen Activator (uPA) is a serine protease. Activation of the serine protease plasmin triggers a proteolysis cascade which is involved in thrombolysis or extracellular matrix degradation. Elevated expression of urokinase and several other components of the plasminogen activation system have been correlated with tumor malignancy including several aspects of cancer biology such as cell adhesion, migration and cellular mitotic pathways as well. Inhibitors of urokinase expression may be used in combination with the compounds of the invention in the compositions and methods described above. Inhibitors of Ras oncogene may also be useful in combination with the compounds of the present invention.
  • inhibitors include, but are not limited to, inhibitors of farnesyltransferase, geranyl-geranyl transferase, and CAAX proteases as well as anti-sense oligonucleotides, ribozymes and immunotherapy. Such inhibitors have been shown to block Ras activation in cells containing mutant Ras, thereby acting as antiproliferative agents.
  • Inhibitors of kinases involved in the IGF-1 R signaling axis may also be useful in combination with the compounds of the present invention.
  • Such inhibitors include but are not limited to inhibitors of JNK1/2/3, PI3K, AKT and MEK, and 14.3.3 signaling inhibitors. Examples of AKT inhibitors are described in PCT Publication No. WO 2007/058850, published 24 May 2007 which corresponds to PCT Application No. PCT/US2006/043513, filed 9 Nov 2006.
  • AKT inhibitor disclosed therein is 4-(2-(4-amino-1 ,2,5-oxadiazol-3- yl)-1 -ethyl-7- ⁇ [(3S)-3-piperidinylmethyl]oxy ⁇ -1 H-imidazo[4,5-c]pyridin-4-yl)-2- methyl-3-butyn-2-ol .
  • Cell cycle signaling inhibitors including inhibitors of cyclin dependent kinases (CDKs) are also useful in combination with the compounds of the invention in the compositions and methods described above.
  • CDKs cyclin dependent kinases
  • Examples of cyclin dependent kinases, including CDK2, CDK4, and CDK6 and inhibitors for the same are described in, for instance, Rosania G. R., et al., Exp. Opin. Ther. Patents (2000) 10:215-230.
  • Receptor kinase angiogenesis inhibitors may also find use in the present invention. Inhibitors of angiogenesis related to VEGFR and TIE-2 are discussed above in regard to signal transduction inhibitors (both are receptor tyrosine kinases). Other inhibitors may be used in combination with the compounds of the invention.
  • anti-VEGF antibodies which do not recognize VEGFR (the receptor tyrosine kinase), but bind to the ligand; small molecule inhibitors of integrin (alpha v betas) that inhibit angiogenesis; endostatin and angiostatin (non-RTK) may also prove useful in combination with the compounds of the invention.
  • VEGFR antibody is bevacizumab (AVASTIN®).
  • Inhibitors of phosphatidyl inositol-3-OH kinase family members including blockers of PI3-kinase, ATM, DNA-PK, and Ku may also be useful in combination with the present invention.
  • myo-inositol signaling inhibitors such as phospholipase C blockers and myoinositol analogues.
  • siRNA, RNAi, locked nucleic acid polynucleotides, and antisense therapies may also be used in combination with the compounds of the invention.
  • antisense therapies include those directed towards the targets described above such as ISIS 2503 and gene therapy approaches such as those using thymidine kinase or cytosine deaminase.
  • Agents used in immunotherapeutic regimens may also be useful in combination with the compounds of the invention.
  • Immunotherapeutic regimens include ex-vivo and in-vivo approaches to increasing immunogenicity of patient tumor cells such as transfection with cytokines (eg. IL-2, IL-4, GMCFS and MCFS), approaches to increase T-cell activity, approaches with transfected immune cells and approaches with anti-idiotypic antibodies.
  • cytokines eg. IL-2, IL-4, GMCFS and MCFS
  • Another potentially useful immunotherapeutic regimen is monoclonal antibodies with wild-type Fc receptors that may illicit an immune response in the host (e.g., IGF-1 R monoclonal antibodies).
  • Agents used in proapoptotic regimens e.g., Bcl-2 antisense oligonucleotides
  • Bcl-2 antisense oligonucleotides may also be used in combination with the compounds of the invention.
  • Bcl-2 family of proteins block apoptosis. Upregulation of Bcl- 2 has therefore been linked to chemoresistance. Studies have shown that the epidermal growth factor (EGF) stimulates anti-apoptotic members of the Bcl-2 family (i.e., mcl-1 ). Therefore, strategies designed to downregulate the expression of Bcl-2 in tumors have demonstrated clinical benefit and are now in Phase ll/lll trials, namely Genta's G3139 bcl-2 antisense oligonucleotide. Such proapoptotic strategies using the antisense oligonucleotide strategy for Bcl-2 are discussed in Water, J.S., et al., J. Clin. Oncol. (2000) 18:1812-1823; and Kitada, S., et al., Antisense Res. Dev. (1994) 4:71 -79.
  • EGF epidermal growth factor
  • R 10 is halo (preferably chloro) or thiomethyl
  • E is a suitable carboxylic ester or carboxylic ester equivalent
  • R a is H or CH 3 ;
  • alk is alkyl or alkenyl
  • NBS N- bromosuccinimide
  • Compounds of formula (I) wherein R 4 is alkyl, haloalkyl, alkenyl, -R 11 -OR 12 , R 11 -CO 2 R 12 , -R 1 1 -SO 2 R 12 , -R 1 1 -Het1 or -R 11 -NR 12 R 13 may be prepared by reacting a compound of formula (VIII) with an alkyl or alkenyl metal reagent such as compounds having the formula Alk n MX m or X m MR 11 -CO 2 R 12
  • Alk is alkyl or alkenyl
  • n 1 , 2, 3 or 4;
  • M is a transition metal such as Zn, B or Sn;
  • X is halo, particularly CI or Br
  • n 0, 1 or 2;
  • R 4a is alkyl, haloalkyl, alkenyl, -R 11 -OR 12 , or R 11 -CO 2 R 12 ;
  • alkyl or alkenyl metal reagents include but not limited to dialkylzinc, alkylzinc halides, alkylboranes, alkenylboranes, alkenylborates and alkenylstannanes, either found commercially or which can be prepared by those of ordinary skill in the art by conventional means.
  • the reaction is performed in the presence of a palladium source, optionally a phosphine ligand and optionally a base in a suitable inert solvent.
  • Suitable palladium sources include but are not limited to bis(tri-t- butylphosphine)palladium (0), tris(dibenzylideneacetone)dipalladium (0), dichlorobis(triphenylphosphine)-palladium (II) or acetato(2'-di-f- butylphosphino-1 ,1 '-biphenyl-2-yl)palladium (II).
  • suitable phosphine ligands include but are not limited to 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene and triphenylphosphine.
  • Suitable bases include but are not limited to potassium acetate, cesium carbonate, sodium methoxide, and triethylamine.
  • suitable inert solvents include but are not limited to THF, toluene, ⁇ /,/V-dimethylformamide or 1 ,4-dioxane, or isopropanol in the case of alkenylborates.
  • the reaction may be carried out at a temperature of about 25 °C to 100°C.
  • a compound of formula (I 2 ) wherein R 4 is alkenyl may be converted to a compound of formula (I) wherein R 4 is -R 11 -SO 2 R 12 , -R 1 1 -Het1 or -R 11 - NR 12 R 13 by reaction with an appropriate nucleophile.
  • a compound of formula (I) wherein R 4 is -R 11 -SO 2 R 12 , or -R 11 NR 12 R 13 may be prepared by reacting a compound of formula (I 2 ) wherein R4 is alkenyl with a thiol or amine, respectively. Reaction conditions for such transformations are known to those skilled in the art.
  • Suitable alcohols include but not limited to methanol, ethanol, n-propanol or n-butanol.
  • the reaction may optionally be carried out in the presence of a base such as, but not limited to cesium carbonate, sodium methoxide, and triethylamine.
  • the reaction is typically carried out at a temperature of about 50-120 °C, at atmospheric or elevated pressure and optionally in a microwave.
  • R a is H or CH 3 and all other variables are as defined above.
  • R 10 is halo (preferably chloro)
  • the reaction is generally performed in a solvent or neat.
  • suitable solvents include but are not limited to isopropanol, methanol, 1 ,4-dioxane, ethanol, dimethylacetamide, triflouroethanol, and N,N- dimethylformamide.
  • the reaction is typically carried out at a temperature of from about 30 to about 120°C, or optionally in a microwave apparatus.
  • R 4 is NH 2
  • the reaction is carried out with a source of ammonia, for example, ammonia in methanol or preferably ammonium hydroxide.
  • the reaction is typically carried out without the addition of other solvents and at temperatures of about 60 °C to about 120 °C, in a sealed reaction vessel or optionally in a microwave apparatus.
  • appropriate protecting groups prior to reacting the compound of formula (VIII) with the compound of formula (IX).
  • R 4 is a group containing a pendant primary or secondary amine
  • the addition is preferably carried out when the pendant amine is protected as, for example, its corresponding t-butyl carbamate or trifluoracetamide.
  • the choice, installation and removal of appropriate protecting groups for reactions such as this is conventional in the art.
  • Compounds of formula (IX) are commercially available or may be synthesized using techniques conventional in the art.
  • the thiomethyl may first be converted to a more suitable leaving group, for example sulfoxide, sulfone, or chloride.
  • the thiomethyl can be converted into a sulfoxide or sulfone by oxidation with an appropriate oxidizing agent, for example oxone, sodium periodate, or meta- chloroperbenzoic acid, in an appropriate solvent, for example
  • reaction are generally performed in a suitable solvent, for example 2- propanol, dimethylacetamide, or dioxane, optionally with the addition of acid, for example hydrochloric acid, and at a temperature of 25-1 10°C, preferably 70-90°C, or in a microwave reactor at a temperature of 90-220°C, preferably 160-190°C.
  • a suitable solvent for example 2- propanol, dimethylacetamide, or dioxane
  • acid for example hydrochloric acid
  • the pyrimidinyl sulfoxide or sulfone can be converted to the corresponding hydroxyl pyrimidine by reaction with an appropriate aqueous acid, for example hydrochloric acid or acetic acid, at a temperature of 25- 1 10°C, preferably 70-90°C.
  • the hydroxyl pyrimidine can then be converted to a chloride using an appropriate chlorinating reagent, for example
  • Compounds of formula (VIII) may be prepared by reacting a compound of formula (XI) with a suitable brominating reagent, particularly bromine or NBS, followed by reacting with one of: 1 ) a thiourea, 2) a formamide 3) an amide 4) a thioamide or 5) a urea depending upon whether the thiazole or oxazole and
  • a suitable brominating reagent particularly bromine or NBS
  • thiourea unsubstituted thiourea, formamide, amide, thioamide or urea and substituted analogs thereof.
  • the thiourea, formamide, amide, thioamide or urea may be substituted with the desired group R 3 .
  • substituted analogs of thiourea, formamide, amide, thioamide or urea are commercially available or may be prepared using conventional techniques.
  • the reaction can be accomplished by the initial bromination of a compound of formula (XI) using an appropriate brominating reagent, for example bromine in solvent such as acetic acid or
  • the reaction is typically carried out in an appropriate solvent, for example dichloromethane, ⁇ , ⁇ -dimethylformamide, or ⁇ , ⁇ -dimethylacetamide, and at a temperature of 25-50°C, particularly 25°C.
  • the brominated analog i.e., a compound of formula (Xl-A)
  • thiourea an appropriately substituted thiourea
  • W is S
  • R 3a is -NR 12 R 13 or Het1 and all other variables are as defined above.
  • the reaction is typically carried out in an appropriate solvent, for example, N,N-dimethylformamide, ⁇ , ⁇ -dimethylacetamide, dichloromethane, tetrahydrofuran, dioxane, or acetonitrile, optionally in the presence of a suitable base, for example magnesium carbonate or sodium bicarbonate, and at a temperature of 25-90°C, particularly 25-50°C.
  • a suitable base for example magnesium carbonate or sodium bicarbonate
  • a compound such as a compound of formula (VIII), wherein R 3 is an amino group (i.e., -NR 12 R 13 ), may be further converted to a corresponding compound wherein R 3 is other than amino (or substituted amino) using the techniques described herein and those conventional in the art.
  • the aminothiazole compound of formula (Vlll-A) wherein R 3 is an amino group may be converted to an unsubstituted thiazole (i.e., a compound of formula (VIII) wherein R 3 is H) using methods familiar to those of skill in the art.
  • the thiazole may be prepared by reacting the aminothiazole with an appropriate reagent, for example i-butyl nitrite, in an appropriate solvent, for example tetrahydrofuran, and at a temperature of 35-75°C, particularly 40-60°C.
  • an aminothiazole of formula (VIII) may be modified according to methods that will be familiar to those skilled in the art.
  • the aminothiazole compound of formula (Vlll-A) may be converted to a compound of formula (Vlll-B) by reaction with reagents capable of replacing the amino group with a halide, preferably a bromide.
  • Hal is halo, preferably Br; and all other variables are as defined above.
  • the conversion to a halo-thiazole of formula (Vlll-B) may be carried out by reaction with for example, i-butyl nitrite and copper (II) bromide in a suitable solvent, such as tetrahydrofuran or acetonitrile, and at a temperature from - 10°C to 50°C, preferably 0°C to 25°C.
  • a suitable solvent such as tetrahydrofuran or acetonitrile
  • the halo-thiazole of formula (Vlll-B) may then be reacted under a variety of conditions known to those in the art to produce different thiazole compounds of formula (Vlll-C) wherein R 3 can be a variety of substituents consistent with the definition of R 3 in reference to compounds of Formula (I).
  • R 3c is alkyl, haloalkyl or alkyl-OH.
  • halo-thiazole of formula (Vlll-B) may be reacted with a boronic acid, boronate ester, alkyl tin, alkyl zinc or Grignard reagent, in an appropriate solvent, for example tetrahydrofuran, dioxane, or
  • palladiumdicholorobistriphenylphosphine and at a temperature of 25-150°C, preferably 25-60°C.
  • a suitable base such as aqueous sodium carbonate, cesium carbonate, or triethylamine
  • a suitable ligand for the palladium species for example a trialkylphosphine or a triarylphosphine, for example triphenylphosphine.
  • Another example of such a reaction involves the reaction of the halo-thiazole of formula (V-B) with a reagent capable of displacing the bromide, for example an amine, such as piperidine, methylamine, or methyl piperazine.
  • a reagent capable of displacing the bromide for example an amine, such as piperidine, methylamine, or methyl piperazine.
  • Hal is halogen
  • R 3d is -NR 12 R 13 ;
  • dimethylformamide at a temperature of 25°C to 150°C, preferably 50-90°C, optionally in the presence of a suitable acid, for example hydrochloric acid.
  • a compound of formula (Xl-A) is reacted with a thioamide, for example thio lkyl.
  • Alkyl substituted thioamides for use in this process are commercially available or may be prepared using conventional techniques.
  • the reaction is carried out in an appropriate solvent, for example, dichloromethane, tetrahydrofuran, dimethylformamide, ⁇ , ⁇ -dimethylacetamide, or acetonitrile, particularly dimethylformamide or ⁇ , ⁇ -dimethylacetamide, optionally in the presence of a suitable base, for example magnesium carbonate or sodium bicarbonate, and at a temperature of 35-100°C, preferably 50-80°C.
  • an appropriate solvent for example, dichloromethane, tetrahydrofuran, dimethylformamide, ⁇ , ⁇ -dimethylacetamide, or acetonitrile, particularly dimethylformamide or ⁇ , ⁇ -dimethylacetamide, optionally in the presence of a suitable base, for example magnesium carbonate or sodium bicarbonate, and at a temperature of 35-100°C, preferably 50-80°C.
  • reaction can be accomplished by reacting the compound of formula (Xl-A) with formamide in the presence of an acid, such as sulfuric acid, and at a temperature of 60-150°C, preferably 90-130°C.
  • an acid such as sulfuric acid
  • a substituted oxazole of formula (Vlll-F) may be prepared from the compound of form -A).
  • R 3e is Het1 or -NR 12 R 13 and all other variables are as defined above.
  • the reaction may be carried out by reacting the compound of formula (Xl-A) with urea or substituted urea in an appropriate solvent, for example, N,N- dimethylformamide, ⁇ /,/V-dimethylacetamide dichloromethane,
  • tetrahydrofuran, dioxane, or acetonitrile optionally in the presence of a suitable base, for example magnesium carbonate or sodium bicarbonate, and at a temperature of 25-170°C, particularly 60-150°C or in a microwave reactor at a temperature of 100-190°C, particularly 120-160°C.
  • a suitable base for example magnesium carbonate or sodium bicarbonate
  • substituted ureas that may be employed in the foregoing method to prepare compounds of formula (Vlll-F) wherein R 3e is as defined above.
  • a substituted urea for use in this method is 1 - pyrrolidinecarboxamide. Suitable substituted ureas are commercially available or can be made using techniques known to those skilled in the art.
  • a substituted oxazole of formula (Vlll-G), may also be prepared from a compound of formula (Xl-A).
  • reaction may be carried out by reacting the compound of formula (Xl-A) with an amide (i.e., a compound of formula R 3f -C(O)NH 2 ), for example acetamide, in an appropriate solvent, for example, dichloromethane, tetrahydrofuran, dimethylformamide, or acetonitrile, particularly
  • an amide i.e., a compound of formula R 3f -C(O)NH 2
  • an appropriate solvent for example, dichloromethane, tetrahydrofuran, dimethylformamide, or acetonitrile, particularly
  • dimethylformamide or neat optionally in the presence of a suitable base, for example magnesium carbonate or sodium bicarbonate, and at a temperature of 35-170°C, preferably 60-150°C or in a microwave reactor at a temperature of 100-190°C, particularly 130-170°C.
  • a suitable base for example magnesium carbonate or sodium bicarbonate
  • Suitable amides for use in this reaction will be apparent to those skilled in the art and are commercially available or may be prepared using conventional techniques.
  • Vlll-F oxazole of formula (Vlll-F) (wherein R 3 is an amine or substituted amino group)
  • R 3 is an amine or substituted amino group
  • Compounds of formula (XI) may be prepared by reacting a compound of formula (X) with a substituted pyrimidine of formula (III).
  • the reaction is generally performed by reacting a compound of formula (X) and a compound of formula (III) in the presence of a suitable base capable of deprotonating a compound of formula (III), for example lithium
  • a compound of formula (X) may be prepared by reacting the compound of formula (II) with a compound of formula (VII).
  • This reaction may be carried out using conditions conventional in the art for such coupling reactions, including the use of a solvent such as
  • Compounds of formula (II) wherein R 5 and R 6 are H are commercially available.
  • Compounds of formula (II) wherein one of R 5 and R 6 are halogen may be prepared by reduction of the compound of formula (XIII).
  • Appropriate conditions for the reduction reaction will be apparent to those skilled in the art and include palladium on carbon under a hydrogen atmosphere, sulfided platinum on carbon under a hydrogen atmosphere, or iron powder in acetic acid.
  • the reduction may be effected using Raney nickel under a hydrogen atmosphere.
  • the reaction may be carried out in an inert solvent at either atmospheric or elevated pressure. Suitable inert solvents include but are not limited to ethanol, methanol, and ethyl acetate.
  • Compounds of formula (XIII) may be prepared by oxidation of the compound of formula (XX) using an appropriate oxidizing agent such as but not limited to chromium trioxide or potassium permanganate to yield compounds of formula (XXI).
  • an appropriate oxidizing agent such as but not limited to chromium trioxide or potassium permanganate to yield compounds of formula (XXI).
  • the reaction is performed with chromium trioxide under strongly acidic conditions such as in the presence of sulfuric acid.
  • the reaction may be carried out at a temperature of about 80 °C to 100°C.
  • compounds of formula (II) wherein one of R 5 and R 6 are halogen may be prepared by reaction of the compound of formula (XV) with a nitrogen source such as benzophenone imine or t-butyl carbamate using conditions conventional in the art for Buchwald cross-coupling reactions.
  • a nitrogen source such as benzophenone imine or t-butyl carbamate
  • a palladium source optionally a phosphine ligand, and a base in a suitable inert solvent.
  • suitable palladium sources include but are not limited to tris(dibenzylideneacetone)dipalladium (0),
  • suitable phosphine ligands include but are not limited to 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene and triphenylphosphine.
  • suitable bases include but are not limited to potassium acetate, cesium carbonate, sodium methoxide, and triethylamine.
  • Suitable inert solvents include but are not limited to toluene, N,N-dimethylformamide or 1 ,4- dioxane.
  • the reaction may be carried out at a temperature of about 80 °C to 15 °C, optionally in the microwave.
  • X is halo, particularly Br
  • P is protected nitrogen, particularly benzophenone imine or t-butyl carbamate; and all other variables are as defined above.
  • Conversion of compounds of formula (XVI) to compounds of formula (II) can be achieved by reaction with a strong acid in a suitable organic solvent using conventional acidic deprotection techniques. Suitable acids used in such transformations include but are not limited to hydrochloric acid. Suitable solvents for such transformations include but are not limited to tetrahydrofuran and 1 ,4-dioxane. See, Kocienski, P.J. Protecting Groups, Georg Thieme Verlag, Stuttgart, 1994; and Greene, T.W., Wuts, P. G. M. Protecting Groups in Organic Synthesis (2 nd Edition), J. Wiley and Sons, 1991 .
  • R 10 is halo (preferably chloro) or thiomethyl
  • E is a suitable carboxylic ester or ester equivalent, particularly a methyl ester, ethyl ester, or Weinreb's amide;
  • Alloc is allylchlorofornnate
  • BusSnH is tri-n-butyl tin hydride
  • the installation and removal of the Alloc protecting group may be achieved using conventional means.
  • the compound of formula (II) may be reacted with allylchloroformate using conventional acylation conditions to those skilled in the art for the installation of carbamate protecting groups. Removal of the protecting group may be achieved by reacting the compound of formula (V) with tributyltin hydride in the presence of a Pd catalyst and weak acid.
  • dichlorobis(triphenylphosphine)-palladium (II) was used along with acetic acid.
  • solvents may be used including but not limited to dichloromethane, toluene, diethyl ether, acetone and N,N- dimethylformamide. See, Kocienski, P.J. Protecting Groups, Georg Thieme Verlag, Stuttgart, 1994; and Greene, T.W., Wuts, P. G. M. Protecting Groups in Organic Synthesis (2 nd Edition), J. Wiley and Sons, 1991 .
  • R 10 is halo (preferably chloro) or thiomethyl, and all other variables are as defined above.
  • a compound of formula (I) may be converted to another compound of formula (I) using techniques well known in the art.
  • compounds of formula (I) may be modified using conventional techniques to modify or diversify the groups defined by the variable R 3 and thereby provide different compounds of formula (I).
  • the present invention can readily convert a compound of formula (I) or a pharmaceutically acceptable salt thereof into a different compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • the present invention also provides radiolabeled compounds of formula (I) and biotinylated compounds of formula (I) and solid-support-bound versions thereof, i.e.
  • Radiolabeled compounds of formula (I) and biotinylated compounds of formula (I) can be prepared using conventional techniques.
  • radiolabeled compounds of formula (I) can be prepared by reacting the compound of formula (I) with tritium gas in the presence of an appropriate catalyst to produce radiolabeled compounds of formula (I).
  • the compounds of formula (I) are tritiated.
  • the radiolabeled compounds of formula (I) and biotinylated compounds of formula (I) are useful in assays for the identification of compounds which inhibit at least one Raf family kinase, for the identification of compounds for the treatment of a condition capable of being treated with a Raf inhibitor, e.g., for the treatment of neoplasms susceptible to treatment with a Raf inhibitor.
  • the present invention also provides an assay method for identifying such compounds, which method comprises the step of specifically binding a radiolabeled compound of the invention or a biotinylated compound of the invention to the target protein or cellular homogenate. More specifically, suitable assay methods will include competition binding assays.
  • radiolabeled compounds of the invention and biotinylated compounds of the invention and solid-support-bound versions thereof can also be employed in assays according to the methods conventional in the art.
  • the following examples are intended for illustration only and are not intended to limit the scope of the invention in any way. The invention is defined by the claims which follow.
  • i. v. intravenous
  • ATP adenosine triphosphate
  • ml_ milliliters
  • BSA bovine serum albumin
  • ⁇ _ microliters
  • 45 CHCIs chloroform
  • mM millimolar
  • mCPBA metal-chloroperbenzoic mol (moles); acid
  • DCM CH 2 CI 2 ; dichloromethane
  • rt room temperature
  • DIEA ⁇ /,/V-Diisopropylethylamine
  • DME (1 ,2-dimethoxyethane); LDA (lithium diisopropylamide); DMEM (Dulbecco's modified ⁇ HMDS (lithium
  • Eagle medium Eagle medium
  • hexamethyldisilazide hexamethyldisilazide
  • DMF A/,dimethylformamide
  • LiOH lithium hydroxide
  • DMSO dimethylsulfoxide
  • LiOH H 2 O lithium hydroxide DPPA (diphenylphosphoryl azide); monohydrate
  • EDC ethylcarbodiimide m-CPBA (meta- hydrochloride); Chloroperoxybenzoic acid);
  • Et ethyl; -CH 2 CH 3
  • MgCO 3 magnesium carbonate
  • EtOH ethanol
  • MgSO 4 magnesium sulfate
  • EtOAc ethyl acetate
  • NaCI sodium chloride
  • HCI hydrochloric acid
  • NaHSO 4 sodium bisulfate
  • K2CO3 potassium carbonate
  • PE pertroleum ether
  • POCI3 phosporyl chloride
  • TBAB tetra butyl ammonium bromide
  • TBAF tetrabutylammonium fluoride
  • TFA trifluoroacetic acid
  • TIPS triisopropylsilyl
  • TMSE (2-(trimethylsilyl)ethyl); and TsOH (p-Toluenesulfonic acid).
  • MS mass spectra
  • MS-AX505HA Low-resolution mass spectra
  • Agilent LC/MSD SL JOEL SX-102
  • SCIEX-APIiii a Finnegan MSQ
  • Waters SQD Waters ZQ
  • Finnegan LCQ spectrometer high resolution MS were obtained using a JOEL SX-102A spectrometer.
  • All mass spectra were taken under electrospray ionization (ESI), chemical ionization (CI), electron impact (El) or by fast atom bombardment (FAB) methods.
  • ESI electrospray ionization
  • CI chemical ionization
  • El electron impact
  • FAB fast atom bombardment
  • Flash column chromatography was performed on silica gel (230-400 mesh, Merck) or using automated silica gel chromatography (Isco, Inc. Sq 16x or 100sg Combiflash) or (Analogix, Intelliflash).
  • Reported HPLC retention times (RT) were obtained on a Waters 2795 instrument attached to a Waters 996 diode array detector reading 210-500 nm or using Anilgent 120 series HPLC.
  • the column used was a Synergi Max-RP (50 x 2 mm) model #00B-4337-B0. Solvent gradient was 15% MeOH:water to 100% MeOH (0.1 % formic acid) over 6 min. Flow rate was 0.8 mL/min. Injection volume was 3 ⁇ .
  • Step 2 2-Propen-1 -yl ⁇ 3-[(2-chloro-4-pyrimidinyl)acetyl]-2- fluorophenyljcarbamate
  • reaction was quenched by the addition of the saturated aqueous NH CI (800 mL) at 0 °C.
  • the reaction mixture was extracted with EtOAc (1 L x 3). The combined organic layers were washed with water and brine successively, dried over Na2SO 4 , filtered and
  • the reaction mixture was quenched by adding saturated NaHCO3 (300 mL) slowly. The two layers were separated. The aqueous layer was extracted with DCM (1 L x 2). The combined organic layers were washed with water and brine successively, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The crude product was washed with petroleum ether (500 mL) to afford the title compound.
  • Step 1 Methyl 2-chloro-3- ⁇ [ -propen-1 -yloxy)carbonyl]amino ⁇ benzoate
  • Step 3 2-Propen-1 -yl ⁇ 2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4- morpholinyl)-1 ,3-thiazol-4-yl]phenyl ⁇ carbamate
  • Step 4 ⁇ 2-Chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4- yl]phenyl ⁇ amine
  • Step 1 2-Propen-1 -yl ⁇ 3-[5-(2-amino-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)- 1 ,3- thiazol-4-yl]-2-fluorophenyl ⁇ carbamate
  • Step 2 4-[4-(3-Amino-2-fluorophenyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-5-yl]-2- py midinamine
  • Step 4 Methyl 2,6-difluoro-3- ⁇ [(2-propen-1 -yloxy)carbonyl]amino ⁇ benzoate
  • Step 5 2-Propen-1 -yl ⁇ 3-[(2-chloro-4-pyrimidinyl)acetyl]-2,4- difluorophenyljcarbamate
  • Step 6 2-Propen-1 -yl ⁇ 3-[5-(2-chloro-4-pynmidinyl)-2-(4-morpholinyl)-1 ,3- thiazol-4-yl]-2,4-difluorophenyl ⁇ carbamate
  • Step 7 3-[5-(2-Chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]-2,4- difluoroaniline
  • Step 1 Ethyl 3- ⁇ [(2-prope -1 -yloxy)carbonyl]amino ⁇ benzoate
  • Step 2 2-Propen-1 -yl ⁇ 3-[(2-chloro-4-pyrimidinyl)acetyl]phenyl ⁇ carbamate
  • Step 1 methyl 2-fluoro-3- ropylsulfonyl)amino]benzoate
  • Example 39 Following a procedure analogous to the one described in Example 39 using A/- ⁇ 2-chloro-3-[(2-chloro-4-pyhmidinyl)acetyl]phenyl ⁇ -1 -propanesulfonamide (1 .5 g, 3.86 mmol) in ⁇ /,/V-Dimethylacetamide (DMA) (7.73 ml) and treated with NBS (NBS (0.653 g, 3.67 mmol) to give the intermediate A/- ⁇ 3-[bromo(2- chloro-4-pyrimidinyl)acetyl]-2-chlorophenyl ⁇ -1 -propanesulfonamide.
  • DMA ⁇ /,/V-Dimethylacetamide
  • NBS NBS
  • Example 39 Following a procedure analogous to the one described in Example 39 using A/- ⁇ 3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl ⁇ -1 -propanesulfonamide (1 .2 g, 3.23 mmol) in ⁇ /,/V-dimethylacetamide (DMA) (6.45 mL) to produce intermediate A/- ⁇ 3-[bromo(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl ⁇ -1 - propanesulfonamide.
  • DMA ⁇ /,/V-dimethylacetamide
  • a vessel was charged with a suspension of A/- ⁇ 2-chloro-3-[5-(2-chloro-4- pyrimidinyl)-2-(4-piperidinyl)-1 ,3-thiazol-4-yl]phenyl ⁇ -3,3,3-trifluoro-1 - propanesulfonamide (480 mg, 0.847 mmol) in 1 ,2-dichloroethane (DCE) (4237 ⁇ _).
  • DCE 1,2-dichloroethane
  • Step 1 - ⁇ [(1 ,1 -dimethylethyl)oxy]carbonyl ⁇ piperazin-1 -ium thiocyanate
  • Step 2 1 -dimethylethyl 4-(5-(2-chloro-4-pyrimidinyl)-4- ⁇ 2-fluoro-3- [(propylsulfonyl)amino]phenyl ⁇ -1 ,3-thiazol-2-yl)-1 -piperazinecarboxylate
  • a 100 mL round-bottomed flask was charged with A/- ⁇ 3-[(2-chloro-4- pyrimidinyl)acetyl]-2-fluorophenyl ⁇ -1 -propanesulfonamide (1 .5 g, 4.03 mmol) in A/,A/-dimethylacetamide (DMA) (13.45 ml) to give a brown solution at room temperature under nitrogen.
  • DMA A/,A/-dimethylacetamide
  • NBS (0.682 g, 3.83 mmol) was added to the reaction mixture.
  • the reaction mixture was stirred at room temperature for 1 h.
  • previously prepared boc-piperazinium thiocyanate salt from step 1 (0.990 g, 4.03 mmol) was added in one portion.
  • This reaction mixture was stirred at room temperature for 18 h before being diluted with water (20 mL) and EtOAc (25 mL). After decantation, the water layer was extracted with EtOAc (2 X 50 mL). The combined organic phases were washed with water (3 x 30 mL), dried over Na2SO4, filtered, and concentrated to dryness.
  • Step 1 2,2,5-trimethyl-1 ,3-dioxane-5-carboxylic acid
  • Step 2 2,2,5-trimethyl-1 ,3-dioxane-5-carboxamide
  • a vessel was charged with 2,2,5-trimethyl-1 ,3-dioxane-5-carboxylic acid (3.39 g, 19.46 mmol) and ⁇ , ⁇ '-carbonyldiimidazole (CDI) (3.79 g, 23.35 mmol) in tetrahydrofuran (THF) (64.9 mL) and stirred at room temperature for 1 .5h.
  • THF tetrahydrofuran
  • the solution was stirred at 0 °C for 30 min and then let warm up to room temperature overnight.
  • Step 3 2,2,5-trimethyl-1 ,3-dioxane-5-carbothioamide
  • a vessel was charged with 2,5-trimethyl-1 ,3-dioxane-5-carboxamide (2.65 g, 15.30 mmol) in tetrahydrofuran 20 ml_ and Lawesson's reagent (6.19 g, 15.30 mmol).
  • the reaction mixture was heated at reflux under nitrogen for 3h.
  • the reaction mixture was then allowed to stir at room temperature overnight before being concentrated under reduced pressure.
  • the residue was dissolved in EtOAc 200ml_ and washed with 10% NaHCO 3 and brine.
  • the organic phase was dried over MgSO 4 and evaporated to dryness.
  • reaction mixture was stirred at -10 °C for 30 min, and warmed to room temperature with stirring overnight.
  • the reaction mixture was cooled to 0°C and quenched by addition of the saturated aqueous NH CI (800ml).
  • the reaction mixture was extracted with ethyl acetate (800 mL x 3).
  • Example 1 A/- ⁇ 2-fluoro-3-[5-(2- ⁇ r2-(1 -pyrrolidinyl)ethyl1amino)-4-Pyrimidinyl)-2- (tetrahvdro-2H-pyran-4-yl)-1 ,3-thiazol-4-yllphenyl)-1 -propanesulfonamide
  • Example 2 A/- ⁇ 2-fluoro-3-[5-(2- ⁇ [2-( 1 -piperidinyl)ethyl1amino)-4-pyrimidinyl)-2- (tetrahvdro-2H-pyran-4-yl)-1 ,3-thiazol-4-yllphenyl)-1 -propanesulfonamide
  • Example 3 A/- ⁇ 3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahvdro-2H-pyran-4-yl)-1 ,3- thiazol-4-yl1-2-fluorophenyl)-1 -propanesulfonamide
  • a 5 mL microwave tube was charged with A/- ⁇ 3-[5-(2-chloro-4-pyrimidinyl)-2- (tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4-yl]-2-fluorophenyl ⁇ -1 - propanesulfonamide (250 mg, 0.503 mmol) and ammonium hydroxide (10 ml, 257 mmol) to give a yellow solution at room temperature under nitrogen.
  • the sealed reaction mixture was microwaved at 90°C for 1 h. After 1 h, the reaction mixture was concentrated.
  • Example 4 A/- ⁇ 2-fluoro-3-[5-(2- ⁇ [2-(4-methyl-1 -piperazinyl)ethyl1amino)-4- pyrimidinyl)-2-(tetrahvdro-2H-pyran-4-yl)-1 ,3-thiazol-4-yllphenyl)-1 - propanesulfonamide
  • Example 6 /V- ⁇ 2-fluoro-3-[5-(2- ⁇ [2-(4-morpholinyl)ethyl1amino)-4-pyhmidinyl)- 2- tetrahvdro-2H-pyran-4-yl)-1 ,3-thiazol-4-yllphenyl)-1 -propanesulfonamide
  • Example 7 A/-(2-fluoro-3-f5-(2-r(2-hvdroxyethyl)aminol-4-pyrimidinyl ⁇ -2- (tetrah dro-2H-pyran-4-yl)-1 ,3-thiazol-4-yllprienyl)-1-propanesulfonamide
  • Example 8 A/-(2-fluoro-3-r5-(2- ⁇ [(2R)-2-hvdroxypropynamino)-4-pyrimidinyl)-2- (4-morpholinyl)-1 ,3-thiazol-4-yllphenyl)-1 -propanesulfonamide
  • Example 10 A/- ⁇ 2-fluoro-3-r5-(2- ⁇ r(2S)-tetrahvdro-2-furanylmethyl1amino)-4- Pyrimidinyl)-2-(tetrahvdro-2H-pyran-4-yl)-1 ,3-thiazol-4-yllphenyl)-1 -
  • Example 1 1 A/- ⁇ 2-fluoro-3-r5-(2- ⁇ r(1 R)-2-hvdroxy-1 -methylethyl1amino)-4- pyrimidinyl)-2-(tetrahvdro-2H-pyran-4-yl)-1 ,3-thiazol-4-yllphenyl)-1 - propanesulfonamide

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Abstract

The present invention provides thiazole sulfonamide and oxazole sulfonamide compounds, compositions containing the same, as well as processes for the preparation and methods for their use as pharmaceutical agents.

Description

BENZENE SULFONAMIDE THIAZOLE AND OXAZOLE COMPOUNDS
FIELD OF THE INVENTION
The present invention relates to benzene sulfonamide thiazole and oxazole compounds, compositions containing the same, as well as processes for the preparation and methods of using such compounds and compositions.
BACKGROUND OF THE INVENTION
Both receptor tyrosine kinases and serine/threonine kinases have been implicated in cellular signaling pathways that control cell function, division, growth, differentiation, and death (apoptosis) through reversible
phosphorylation of the hydroxyl groups of tyrosine or serine and threonine residues, respectively, in proteins. In signal transduction, for example, extracellular signals are transduced via membrane receptor activation, with amplification and propagation using a complex choreography of cascades of protein phosphorylation, and protein dephosphorylation events to avoid uncontrolled signaling. These signaling pathways are highly regulated, often by complex and intermeshed kinase pathways where each kinase may itself be regulated by one or more other kinases and protein phosphatases. The biological importance of these finely tuned systems is such that a variety of cell proliferative disorders have been linked to defects in one or more of the various cell signaling pathways mediated by tyrosine or serine/threonine kinases.
Receptor tyrosine kinases (RTKs) catalyze phosphorylation of certain tyrosyl amino acid residues in various proteins, including themselves, which govern cell growth, proliferation and differentiation.
Downstream of the several RTKs lie several signaling pathways, among them is the Ras-Raf-MEK-ERK kinase pathway. It is currently understood that activation of Ras GTPase proteins in response to growth factors, hormones, cytokines, etc. stimulates phosphorylation and activation of Raf kinases. These kinases then phosphorylate and activate the intracellular protein kinases MEK1 and MEK2, which in turn phosphorylate and activate other protein kinases, ERK1 and 2. This signaling pathway, also known as the mitogen-activated protein kinase (MAPK) pathway or cytoplasmic cascade, mediates cellular responses to growth signals. The ultimate function of this is to link receptor activity at the cell membrane with modification of cytoplasmic or nuclear targets that govern cell proliferation, differentiation, and survival. Mutations in various Ras GTPases and the B-Raf kinase have been identified that can lead to sustained and constitutive activation of the MAPK pathway, ultimately resulting in increased cell division and survival. As a consequence of this, these mutations have been strongly linked with the establishment, development, and progression of a wide range of human cancers. The biological role of the Raf kinases, and specifically that of B-Raf, in signal transduction is described in Davies, H., et al., Nature (2002) 9:1 -6; Garnett, M.J. & Marais, R., Cancer Cell (2004) 6:313-319; Zebisch, A. & Troppmair, J., Cell. Mol. Life Sci. (2006) 63:1314-1330; Midgley, R.S. & Kerr, D.J., Crit. Rev. Onc/Hematol. (2002) 44:109-120; Smith, R.A., et al., Curr. Top. Med. Chem. (2006) 6:1071 -1089; and Downward, J., Nat. Rev. Cancer (2003) 3:1 1 -22.
Naturally occurring mutations of the B-Raf kinase that activate MAPK pathway signaling have been found in a large percentage of human melanomas
(Davies (2002) supra) and thyroid cancers (Cohen et al J. Nat. Cancer Inst. (2003) 95(8) 625-627 and Kimura et al Cancer Res. (2003) 63(7) 1454-1457), as well as at lower, but still significant, frequencies in the following:
Barret's adenocarcinoma (Garnett et al., Cancer Cell (2004) 6 313-319 and Sommerer et al Oncogene (2004) 23(2) 554-558),
billiary tract carcinomas (Zebisch et al., Cell. Mol. Life Sci. (2006) 63 1314- 1330),
breast cancer (Davies (2002) supra),
cervical cancer (Moreno-Bueno et al Clin. Cancer Res. (2006) 12(12) 3865- 3866),
cholangiocarcinoma (Tannapfel et al Gut (2003) 52(5) 706-712),
central nervous system tumors including primary CNS tumors such as
glioblastomas, astrocytomas and ependymomas (Knobbe et al Acta Neuropathol. (Berl.) (2004) 108(6) 467-470, Davies (2002) supra, and Garnett et al., Cancer Cell (2004) supra) and secondary CNS tumors (i.e., metastases to the central nervous system of tumors originating outside of the central nervous system),
colorectal cancer, including large intestinal colon carcinoma (Yuen et al
Cancer Res. (2002) 62(22) 6451 -6455, Davies (2002) supra and Zebisch et al., Cell. Mol. Life Sci. (2006),
gastric cancer (Lee et al Oncogene (2003) 22(44) 6942-6945),
carcinoma of the head and neck including squamous cell carcinoma of the head and neck (Cohen et al J. Nat. Cancer Inst. (2003) 95(8) 625-627 and Weber et al Oncogene (2003) 22(30) 4757-4759),
hematologic cancers including leukemias (Garnett et al., Cancer Cell (2004) supra, particularly acute lymphoblastic leukemia (Garnett et al., Cancer Cell (2004) supra and Gustafsson et al Leukemia (2005) 19(2) 310- 312), acute myelogenous leukemia (AML) (Lee et al Leukemia (2004) 18(1 ) 170-172, and Christiansen et al Leukemia (2005) 19(12) 2232- 2240), myelodysplastic syndromes (Christiansen et al Leukemia (2005) supra) and chronic myelogenous leukemia (Mizuchi et al Biochem. Biophys. Res. Commun. (2005) 326(3) 645-651 ); Hodgkin's lymphoma (Figl et al Arch. Dermatol. (2007) 143(4) 495-499), non-Hodgkin's lymphoma (Lee et al Br. J. Cancer (2003) 89(10) 1958-1960), megakaryoblastic leukemia (Eychene et al Oncogene (1995) 10(6) 1 159-1 165) and multiple myeloma (Ng et al Br. J. Haematol. (2003) 123(4) 637-645),
hepatocellular carcinoma (Garnett et al., Cancer Cell (2004),
lung cancer (Brose et al Cancer Res. (2002) 62(23) 6997-7000, Cohen et al J.
Nat. Cancer Inst. (2003) supra and Davies (2002) supra), including small cell lung cancer (Pardo et al EMBO J. (2006) 25(13) 3078-3088) and non-small cell lung cancer (Davies (2002) supra),
ovarian cancer (Russell & McCluggage J. Pathol. (2004) 203(2) 617-619 and Davies (2002) supr), endometrial cancer (Garnett et al., Cancer Cell (2004) supra, and Moreno-Bueno et al Clin. Cancer Res. (2006) supra),
pancreatic cancer (Ishimura et al Cancer Lett. (2003) 199(2) 169-173), pituitary adenoma (De Martino et al J. Endocrinol. Invest. (2007) 30(1 ) RC1 - 3),
prostate cancer (Cho et al Int. J. Cancer (2006) 1 19(8) 1858-1862), renal cancer (Nagy et al Int. J. Cancer (2003) 106(6) 980-981 ),
sarcoma (Davies (2002) supra), and
skin cancers (Rodriguez-Viciana et al Science (2006) 31 1 (5765) 1287-1290 and Davies (2002) supra).
Overexpression of c-Raf has been linked to AML (Zebisch et al., Cancer Res. (2006) 66(7) 3401 -3408, and Zebisch {Cell. Mol. Life Sci. (2006)) and erythroleukemia (Zebisch et la., Cell. Mol. Life Sci. (2006).
By virtue of the role played by the Raf family kinases in these cancers and exploratory studies with a range of preclinical and therapeutic agents, including one selectively targeted to inhibition of B-Raf kinase activity (King A.J ., et al., (2006) Cancer Res. 66:1 1 100-1 1 105), it is generally accepted that inhibitors of one or more Raf family kinases will be useful for the treatment of such cancers or other condition associated with Raf kinase.
Mutation of B-Raf has also been implicated in other conditions, including cardio-facio cutaneous syndrome (Rodriguez-Viciana et al Science (2006) 31 1 (5765) 1287-1290) and polycystic kidney disease (Nagao et al Kidney Int. (2003) 63(2) 427-437).
SUMMARY OF THE INVENTION
The invention encompasses the compounds of formula (I)
wherein:
W is selected from -O- and -S-;
R is selected from ci-c6alkyl, haloalkyl, and C3-c6cycloalkyl; R3 is selected from Het1 , pyridinyl, and ci-c6alkyl optionally substituted with -
(co-c6alkylene-(OH)m)n;
R4 is selected from H, -NH-R7 and -CH2-R7;
R5 and R6 are independently selected from H, F, and CI;
R7 is selected from H, Ci-c6alkylene-R8, and -co-c3alkylene-Het1 , and ci-c6alkyl optionally substituted with -(Co-c6alkylene-(OH)m)n;
R8 is selected from haloalkyl-, CN, OH, and -SO2-ci-c3alkyl;
each Het1 is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N and O and optionally substituted with 1 or 2 substituents
independently selected from ci-c3alkyl, -SO2-ci-c3alkyl, and -ci-c3alkylene- OH;
each m is 1 or 2; and
each n is 1 or 2;
and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising the compounds, methods of treating susceptible neoplasms with the compounds, processes for preparing the compounds, and use of the compounds in the treatment of susceptible neoplasms.
In a first aspect of the present invention, there is provided compounds of formula (I):
wherein:
W is selected from -O- and -S-;
R1 is selected from ci-c6alkyl, haloalkyl, and c3-c6cycloalkyl;
R3 is selected from Het1 , pyridinyl, and ci-c6alkyl optionally substituted with
(co-c6alkylene-(OH)m)n;
R4 is selected from H, -NH-R7 and -CH2-R7;
R5 and R6 are independently selected from H, F, and CI; R7 is selected from H, Ci-c6alkylene-R8, and -co-c3alkylene-Het1 , and ci-c6alkyl optionally substituted with -(Co-c6alkylene-(OH)m)n;
R8 is selected from haloalkyl-, CN, OH, and -SO2-ci-c3alkyl;
each Het1 is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N and O and optionally substituted with 1 or 2 substituents
independently selected from ci-c3alkyl, -SO2-ci-c3alkyl, and -ci-c3alkylene-
OH;
each m is 1 or 2; and
each n is 1 or 2;
and pharmaceutically acceptable salts thereof.
In another aspect, there is provided compounds of formula (I) as in the first aspect, wherein R1 is selected from ci-c6alkyl and haloalkyl. In another aspect, there is provided compounds of formula (I) as in the first aspect, wherein R3 is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N and O and optionally substituted with 1 or 2 substituents independently selected from ci-c3alkyl, -SO2-ci-c3alkyl, and -ci-c3alkylene-OH. In another aspect, there is provided compounds of formula (I) as in the first
aspect, wherein R3 is selected from
In another aspect, there is provided compounds of formula (I) as in the first aspect, wherein R1 is selected from propyl and tri-flouro-propyl. In a second aspect of the present invention, there is provided compounds of formula (la):
wherein:
R1 is selected from ci-c6alkyl, haloalkyl, and C3-c6cycloalkyl;
R3 is selected from Het1 , pyridinyl, and ci-c6alkyl optionally substituted with -
(co-c6alkylene-(OH)m)n;
R4 is selected from H, -NH-R7 and -CH2-R7;
R5 and R6 are independently selected from H, F, and CI;
R7 is selected from H, Ci-c6alkylene-R8, and -co-c3alkylene-Het1 , and ci-c6alkyl optionally substituted with -(Co-c6alkylene-(OH)m)n;
R8 is selected from haloalkyl-, CN, OH, and -SO2-ci-c3alkyl;
each Het1 is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N and O and optionally substituted with 1 or 2 substituents
independently selected from ci-c3alkyl, -SO2-ci-c3alkyl, and -ci-c3alkylene- OH;
each m is 1 or 2; and
each n is 1 or 2;
and pharmaceutically acceptable salts thereof.
In another aspect, there is provided compounds of formula (la) as in the second aspect, wherein R1 is selected from ci-c6alkyl and haloalkyl.
In another aspect, there is provided compounds of formula (la) as in the second aspect, wherein R3 is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N and O and optionally substituted with 1 or 2 substituents independently selected from ci-c3alkyl, -SO2-ci-c3alkyl, and -ci c3alkylene-OH. In another aspect, there is provided compounds of formula (la) as in the second aspect, wherein R3 is selected from In another aspect, there is provided compounds of formula (la) as in the second aspect, wherein R1 is selected from propyl and tri-flouro-propyl.
In another aspect, there is provided a compound of formula (lb):
and pharmaceutically acceptable salts thereof. In another aspect, there is provided the free base of the compound of formula (lb).
In a third aspect of the present invention, there is provided compounds of formula (lc):
wherein:
R1 is selected from ci-c6alkyl, haloalkyl, and C3-c6cycloalkyl;
R3 is selected from Het1 , pyridinyl, and ci-c6alkyl optionally substituted with
(co-c6alkylene-(OH)m)n;
R4 is selected from -NH-R7 and -CH2-R7; R5 and R6 are independently selected from H, F, and CI;
R7 is selected from H, Ci-c6alkylene-R8, and -co-c3alkylene-Het1 , and ci-c6alkyl optionally substituted with -(co-c6alkylene-(OH)m)n;
R8 is selected from haloalkyl-, CN, OH, and -SO2-ci-c3alkyl;
each Het1 is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N and O and optionally substituted with 1 or 2 substituents
independently selected from ci-c3alkyl, -SO2-ci-c3alkyl, and -Ci-c3alkylene-
OH;
each m is 1 or 2; and
each n is 1 or 2;
and pharmaceutically acceptable salts thereof.
In another aspect, there is provided compounds of formula (Ic) as in the third aspect, wherein R1 is selected from ci-c6alkyl and haloalkyl.
In another aspect, there is provided compounds of formula (Ic) as in the third aspect, wherein R3 is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N and O and optionally substituted with 1 or 2 substituents independently selected from ci-c3alkyl, -SO2-ci-c3alkyl, and -ci-c3alkylene-OH.
In another aspect, there is provided compounds of formula (Ic) as in the third
aspect, wherein R3 is selected from
In another aspect, there is provided compounds of formula (Ic) as in the third aspect, wherein R1 is selected from propyl and tri-flouro-propyl.
In another aspect, there is provided a compound of formula (Id)
and pharmaceutically acceptable salts thereof. In another aspect, there is provided the free base of the compound of formula (Id). In another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) (including any particular sub-generic formula described herein) or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition further comprises one or more of pharmaceutically acceptable carriers, diluents or excipients.
In another aspect of the present invention, there is provided a method of treating a susceptible neoplasm in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) (including any particular sub-generic formula described herein) or a pharmaceutically acceptable salt thereof. Susceptible neoplasms include e.g., Barret's adenocarcinoma; billiary tract carcinomas; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors including primary CNS tumors such as glioblastomas, astrocytomas (e.g., glioblastoma multiforme) and ependymomas, and secondary CNS tumors (i.e., metastases to the central nervous system of tumors originating outside of the central nervous system); colorectal cancer including large intestinal colon carcinoma; gastric cancer; carcinoma of the head and neck including squamous cell carcinoma of the head and neck; hematologic cancers including leukemias and lymphomas such as acute lymphoblastic leukemia, acute myelogenous leukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia, multiple myeloma and
erythroleukemia; hepatocellular carcinoma; lung cancer including small cell lung cancer and non-small cell lung cancer; ovarian cancer; endometrial cancer; pancreatic cancer; pituitary adenoma; prostate cancer; renal cancer; sarcoma; skin cancers including melanomas; and thyroid cancers.
In another aspect of the present invention, there is provided a method of treating breast cancer, cholangiocarcinoma, colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, or thyroid cancer, in a mammal, particularly a human, in need thereof, comprising administering to the mammal (e.g. human) a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In another aspect of the present invention, there is provided a method of treating a susceptible neoplasm in a mammal, particularly a human, in need thereof, comprising administering to the mammal (e.g. human) a
thera eutically effective amount of a compound of formula (Ilia)
and pharmaceutically acceptable salts thereof.
In another aspect of the present invention, there is provided a method of treating breast cancer, cholangiocarcinoma, colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, or thyroid cancer, in a mammal, particularly a human, in need thereof, comprising administering to the mammal (e.g. human) a therapeutically effective amount of a compound of formula (Ilia)
pharmaceutically acceptable salts thereof.
In another aspect of the present invention, there is provided a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof. The process comprises reacting a compound of formula (VIII):
VIM
wherein R10 is halo or thiomethyl;
with one of:
i) molecular hydrogen, or
ii) an alkyl metal reagent or alkenyl metal reagent, or
iii) an alcohol, or
iv) a compound of formula (IX): N(Ra)-R8, wherein Ra is H or CH3 and R! is as defined above;
to prepare a compound of formula (I).
In another aspect of the present invention, there is provided a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof. The process comprises reacting a compound of formula (XVIII): In another aspect of the present invention, there is provided a compound of formula (I), (including any particular sub-generic formula described herein) or a pharmaceutically acceptable salt thereof for use in therapy.
In another aspect, there is provided a compound of formula (I) (including any particular sub-generic formula described herein) or a pharmaceutically acceptable salt thereof for use in the treatment of a susceptible neoplasm (e.g., Barret's adenocarcinoma; bil Nary tract carcinomas; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors including primary CNS tumors such as glioblastomas, astrocytomas (e.g., glioblastoma multiforme) and ependymomas, and secondary CNS tumors (i.e., metastases to the central nervous system of tumors originating outside of the central nervous system); colorectal cancer including large intestinal colon carcinoma; gastric cancer; carcinoma of the head and neck including squamous cell carcinoma of the head and neck; hematologic cancers including leukemias and lymphomas such as acute lymphoblastic leukemia, acute myelogenous leukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia, multiple myeloma and erythroleukemia; hepatocellular carcinoma; lung cancer including small cell lung cancer and non-small cell lung cancer; ovarian cancer; endometrial cancer; pancreatic cancer; pituitary adenoma; prostate cancer; renal cancer; sarcoma; skin cancers including melanomas; and thyroid cancers) in a mammal (e.g., human) in need thereof. In another aspect, there is provided a compound of formula (I) (including any particular sub-generic formula described herein) or a pharmaceutically acceptable salt thereof for use in the treatment of breast cancer,
cholangiocarcinoma, colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, or thyroid cancer in a mammal (e.g., human) in need thereof.
In a another aspect of the present invention, there is provided the use of a compound of formula (I) (including any particular sub-generic formula described herein) or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in the treatment of a susceptible neoplasm (e.g., Barret's adenocarcinoma; billiary tract carcinomas; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors including primary CNS tumors such as glioblastomas, astrocytomas (e.g., glioblastoma multiforme) and ependymomas, and secondary CNS tumors (i.e., metastases to the central nervous system of tumors originating outside of the central nervous system); colorectal cancer including large intestinal colon carcinoma; gastric cancer; carcinoma of the head and neck including squamous cell carcinoma of the head and neck; hematologic cancers including leukemias and lymphomas such as acute lymphoblastic leukemia, acute myelogenous leukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia, multiple myeloma and erythroleukemia;
hepatocellular carcinoma; lung cancer including small cell lung cancer and non-small cell lung cancer; ovarian cancer; endometrial cancer; pancreatic cancer; pituitary adenoma; prostate cancer; renal cancer; sarcoma; skin cancers including melanomas; and thyroid cancers) in a mammal (e.g., human) in need thereof.
In a another aspect of the present invention, there is provided the use of a compound of formula (I) (including any particular sub-generic formula described herein) or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in the treatment of breast cancer, cholangiocarcinoma, colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, or thyroid cancer in a mammal (e.g., human) in need thereof. In another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) (including any particular sub-generic formula described herein) or a pharmaceutically acceptable salt thereof for use in the treatment of a susceptible neoplasm (e.g., Barret's adenocarcinoma; billiary tract carcinomas; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors including primary CNS tumors such as glioblastomas, astrocytomas (e.g., glioblastoma multiforme) and ependymomas, and secondary CNS tumors (i.e., metastases to the central nervous system of tumors originating outside of the central nervous system); colorectal cancer including large intestinal colon carcinoma; gastric cancer; carcinoma of the head and neck including squamous cell carcinoma of the head and neck; hematologic cancers including leukemias and lymphomas such as acute lymphoblastic leukemia, acute myelogenous leukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia, multiple myeloma and erythroleukemia; hepatocellular carcinoma; lung cancer including small cell lung cancer and non-small cell lung cancer; ovarian cancer; endometrial cancer; pancreatic cancer; pituitary adenoma; prostate cancer; renal cancer; sarcoma; skin cancers including melanomas; and thyroid cancers) in a mammal (e.g., human) in need thereof.
In another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) (including any particular sub-generic formula described herein) or a pharmaceutically acceptable salt thereof for use in the treatment of breast cancer, colorectal cancer,
melanoma, non-small cell lung cancer, ovarian cancer, or thyroid cancer in a mammal (e.g., human) in need thereof.
These and other aspects of the invention are described further in the Detailed Description and Examples which follow. DETAILED DESCRIPTION OF THE INVENTION As used herein, the term "Raf family kinase" refers to Raf kinases including A- Raf, B-Raf and c-Raf (also known as Raf-1 ). Unless distinguished herein, the term refers to both wildtype and mutant variations thereof.
As used herein, "compound(s) of formula (I)" means any compound having the structural formula (I) as defined by the variable definitions provided, possible solvates, including hydrates thereof, and amorphous and crystal forms, including one or more polymorphic forms and mixtures thereof. In the case of compounds of formula (I) which possess one or more chiral centers, the compounds may be in the form of a racemic mixture, or one or more isomerically enriched or pure stereoisomers, including enantiomers and diastereomers thereof. In such embodiments, "compound(s) of formula (I)" includes the racemic form as well as the enriched or pure enantiomers and diastereomers. Enantiomerically enriched or pure compounds will be designated using conventional nomenclature, including the designations +, -, R, S, d, I, D and L, according to the predominant isomer present. Where a compound of the invention contains an alkenyl or alkenylene group, cis (E) and trans (Z) isomerism may also occur. In such embodiments,
"compound(s) of formula (I)" includes the individual stereoisomers of the compound of the invention, which will be indicated using conventional, cis/trans nomenclature. It should also be understood that compounds of formula (I) may exist in tautomeric forms other than that shown in the formula and alternative tautomeric forms are also included within "compound(s) of formula (I)."
As used herein, "compound(s) of the invention" means a compound of formula (I) (as defined above) in any version, i.e., as the free base or as a pharmaceutically acceptable salt thereof. The compound as any version may be in any form, including amorphous or crystalline forms, specific polymorphic forms, solvates, including hydrates (e.g., mono-, di- and hemi- hydrates), and mixtures of various forms. Intermediates may also be present as salts. Thus, in reference to
intermediates, the phrase "compound(s) of formula (number)" means a compound having that structural formula or a pharmaceutically acceptable salt thereof.
The term "alkyl" as used herein refers to linear or branched hydrocarbon chains having from 1 to 8 carbon atoms, unless a different number of atoms is specified. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, sec-butyl, isobutyl, and tert-butyl. The term "alkyl" and variations thereof (i.e., "Ci-4alkyl") is intended to independently describe each member of the genus. Similarly, the term "alkylene" refers to linear or branched divalent hydrocarbon chains containing from 1 to 8 carbon atoms, unless a different number of atoms is specified. Examples of "alkylene" as used herein include, but are not limited to, methylene, ethylene, propylene, butylene, and isobutylene. The term
"alkylene" and variations thereof (i.e., "Ci-3alkylene") is intended to
independently describe each member of the genus.
As used herein, the term "alkenyl" refers to linear or branched hydrocarbon chains having from 2 to 8 carbon atoms, unless a different number of atoms is specified, and at least one and up to three carbon-carbon double bonds.
Examples of "alkenyl" as used herein include, but are not limited to ethenyl and propenyl. The term "alkenyl" and variations thereof (i.e., "C2-4alkenyl") is intended to independently describe each member of the genus.
As used herein, the term "cycloalkyl" refers to a saturated monocyclic carbocyclic ring having from 3 to 8 carbon atoms, unless a different number of atoms is specified. "Cycloalkyl" includes by way of example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Preferred cycloalkyl groups include substituted and unsubstituted C3-6cycloalkyl. The term "cycloalkyl" and variations thereof (i.e., "C3-6cycloalkyl") is intended to independently describe each member of the genus. The terms "halo" and "halogen" are synonymous and refer to fluoro, chloro, bromo and iodo. In particular embodiments, "halo" refers to fluoro and chloro.
As used herein, "haloalkyi" refers to an alkyl, as defined above, substituted by one or more halogen atoms, fluoro, chloro, bromo or iodo. According to one embodiment, haloalkyi defineds an alkyl substituted by one to three fluoro atoms. Where the haloalkyi group has less than 8 carbon atoms, the number of carbon atoms in the group is indicated as, for example, "haloCi-3alkyl", which indicates that the haloalkyi group has 1 , 2 or 3 carbon atoms.
Examples of haloalkyi as used herein include, but are not limited to
fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, trifluoroethyl, and the like. The term "haloalkyi" and variations thereof (i.e., "haloCi-3alkyl") is intended to independently describe each member of the genus. The term "oxo" as used herein refers to the group =O attached directly to a carbon atom of a hydrocarbon ring (e.g., cycloalkyl or cycloalkenyl) or a C, N or S of a heterocyclic or heteroaryl ring to result in oxides, N-oxides, sulfones and sulfoxides. As used herein, the terms "heterocycle" and "heterocyclic" are synonymous and refer to monocyclic saturated or unsaturated non-aromatic groups, having from 4 to 6 members (unless a different number of members is specified) and including 1 , 2, or 3 heteroatoms selected from N, O and S, unless a different number of heteroatoms is specified. In all embodiments wherein the heterocycle includes 2 or more heteroatoms, the heteroatoms may be the same or different and are independently selected from N, O and S. In all embodiments wherein the compound of formula (I) includes two or more heterocyclic groups, the heterocyclic groups may be the same or different and are independently selected. Examples of particular heterocyclic groups include but are not limited to tetrahydrofuran, dihydropyran, tetrahydropyran, pyran, thietane, 1 ,4-dioxane, 1 ,3-dioxane, 1 ,3-dioxalane, piperidine, piperazine, pyrrolidine, morpholine, thiomorpholine, thiazolidine, oxazolidine, tetrahydrothiopyran, tetrahydrothiophene and the like. The term "heterocycle" and variations thereof (i.e., "N-heterocycle") is intended to independently describe each member of the genus.
As used herein, the term "N-heterocycle" refers to monocyclic saturated or unsaturated non-aromatic groups having from 4 to 6 members, including at least one N and optionally 1 or 2 additional heteroatoms selected from N, O and S, unless a different number of additional heteroatoms is specified. By "additional heteroatoms" is meant 1 or 2 heteroatoms in addition to the N already specified in the N-heterocycle ring. In all embodiments wherein the heterocycle includes 1 or more additional heteroatoms, the heteroatoms may be the same or different and are independently selected from N, O and S. N- heterocycles include both groups bound through the N of the N-heterocycle and groups bound through a C or S of the N-heterocycle. In all embodiments wherein the compound of formula (I) includes two or more N-heterocyclic groups, the N-heterocyclic groups may be the same or different and are independently selected. Examples of N-heterocycles include piperidine, piperazine, pyrrolidine, morpholine, thiomorpholine and the like.
As used herein, the term "heteroaryl" refers to aromatic, monocyclic groups having 5 or 6 members (unless a different number of members is specified) including 1 , 2 or 3 heteroatoms selected from N, O and S, unless a different number of heteroatoms is specified. In all embodiments wherein the heteroaryl includes 2 or more heteroatoms, the heteroatoms may be the same or different and are independently selected from N, O and S. In all embodiments wherein the compound of formula (I) includes two or more heteroaryl groups, the heteroaryl groups may be the same or different and are independently selected. Examples of particular heteroaryl groups include but are not limited to furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, and triazine. The term "heteroaryl" and variations thereof (i.e., "N-heteroaryl") is intended to independently describe each member of the genus. As used herein, the term "N-heteroaryl" refers to aromatic, monocyclic groups having 5 or 6 members (unless a different number of members is specified) including at least one N and optionally 1 or 2 additional heteroatoms selected from N, O and S, unless a different number of heteroatoms is specified. By "additional heteroatoms" is meant 1 or 2 heteroatoms in addition to the N already specified in the N-heteroaryl ring. In all embodiments wherein the heteroaryl includes 1 or more additional heteroatoms, the heteroatoms may be the same or different and are independently selected from N, O and S. N- heteroaryls include both groups bound through the N of the N-heteroaryl and groups bound through a C or S of the N-heteroaryl. In all embodiments wherein the compound of formula (I) includes two or more N-heteroaryl groups, the N-heteroaryl groups may be the same or different and are independently selected. Examples of N-heteroaryls include pyrrole, imidazole, pyrazole, thiazole, isoxazole, pyridine, pyridazine, pyrazine, pyrimidine and triazine.
As used herein, the term "members" (and variants thereof e.g., "membered") in the context of heterocyclic and heteroaryl groups refers to the total number of ring atoms, including carbon and heteroatoms N, O and/or S. Thus, an example of a 6-membered heterocyclic ring is piperidine and an example of a 6-membered heteroaryl ring is pyridine.
As used herein, the term "optionally substituted" means unsubstituted groups or rings (e.g., cycloalkyl, heterocycle, and heteroaryl rings) and rings substituted with one or more specified substituents.
Throughout this disclosure, a list of alternatives, such as those provided above and below, is intended to particularly describe each species individually as well as sub-groups of one or more species within the list of alternatives (e.g., "or subset thereof).
The invention encompasses the compounds of formula (I)
wherein:
W is selected from -O- and -S-;
R1 is selected from ci-c6alkyl, haloalkyl, and C3-c6cycloalkyl;
R3 is selected from Het1 , pyridinyl, and ci-c6alkyl optionally substituted with - (co-c6alkylene-(OH)m)n;
R4 is selected from H, -NH-R7 and -CH2-R7;
R5 and R6 are independently selected from H, F, and CI;
R7 is selected from H, Ci-c6alkylene-R8, and -co-c3alkylene-Het1 , and ci-c6alkyl optionally substituted with -(Co-c6alkylene-(OH)m)n;
R8 is selected from haloalkyl-, CN, OH, and -SO2-ci-c3alkyl;
each Het1 is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N and O and optionally substituted with 1 or 2 substituents
independently selected from ci-c3alkyl, -SO2-ci-c3alkyl, and -ci-c3alkylene- OH;
each m is 1 or 2; and
each n is 1 or 2;
and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising the compounds, methods of treating susceptible neoplasms with the compounds, processes for preparing the compounds, and use of the compounds in the treatment of susceptible neoplasms.
In a first aspect of the present invention, there is provided compounds of formula (I):
wherein:
W is selected from -O- and -S-;
R1 is selected from ci-c6alkyl, haloalkyl, and c3-c6cycloalkyl;
R3 is selected from ci-c6alkyl optionally substituted with -(Co-c6alkylene-
(OH)m)n, Het1 , pyridinyl;
R4 is selected from H, -NH-R7 and -CH2-R7;
R5 and R6 are independently selected from H, F, and CI;
R7 is selected from H, Ci-c6alkylene-R8, and -co-c3alkylene-Het1 , and ci-c6alkyl optionally substituted with -(Co-c6alkylene-(OH)m)n;
R8 is selected from haloalkyl-, CN, OH, and -SO2-ci-c3alkyl;
each Het1 is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N and O and optionally substituted with 1 or 2 substituents
independently selected from ci-c3alkyl, -SO2-ci-c3alkyl, and -ci-c3alkylene-
OH;
each m is 1 or 2; and
each n is 1 or 2;
and pharmaceutically acceptable salts thereof.
In another aspect, there is provided compounds of formula (I) as in the first aspect, wherein R1 is selected from ci-c6alkyl and haloalkyl.
In another aspect, there is provided compounds of formula (I) as in the first aspect wherein R1 is a linear or branched ci-c6alkyl. More particularly, R1 is advantageously selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. In another aspect, there is provided compounds of formula (I) as in the first aspect wherein R1 is advantageously a haloalkyl. More particularly, R1 is advantageously selected from tri-fluoroethylene and tri-fluoropropylene.
In another aspect, there is provided compounds of formula (I) as in the first aspect, wherein R1 is selected from propyl and tri-flouro-propylene.
In another aspect, there is provided compounds of formula (I) as in the first aspect, wherein R3 is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N and O and optionally substituted with 1 or 2 substituents independently selected from ci-c3alkyl, -SO2-ci-c3alkyl, and -ci-c3alkylene-OH.
In another aspect, there is provided compounds of formula (I) as in the first
aspect, wherein R3 is selected from
In another aspect, there is provided compounds of formula (I) as in the first aspect, wherein R4 is -NH-R7. In another more particular aspect, there is provided compounds of formula (I) as in the first aspect, wherein R4 is -NH2
In another aspect, there is provided compounds of formula (I) as in the first aspect, wherein R4 is -CH2-R7. In another more particular aspect, there is provided compounds of formula (I) as in the first aspect, wherein R4 is selected from ethyl, 1 -propanol, and 2-methyl-2-butanol. In a second aspect of the present invention, there is provided compounds of formula (la):
wherein:
R1 is selected from ci-c6alkyl, haloalkyl, and c3-c6cycloalkyl;
R3 is selected from Het1 , pyridinyl, and ci-c6alkyl optionally substituted with -
(co-c6alkylene-(OH)m)n;
R4 is selected from H, -NH-R7 and -CH2-R7;
R5 and R6 are independently selected from H, F, and CI;
R7 is selected from H, Ci-c6alkylene-R8, and -co-c3alkylene-Het1 , and ci-c6alkyl optionally substituted with -(Co-c6alkylene-(OH)m)n;
R8 is selected from haloalkyl-, CN, OH, and -SO2-ci-c3alkyl;
each Het1 is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N and O and optionally substituted with 1 or 2 substituents
independently selected from ci-c3alkyl, -SO2-ci-c3alkyl, and -Ci-c3alkylene- OH;
each m is 1 or 2; and
each n is 1 or 2;
and pharmaceutically acceptable salts thereof.
In another aspect, there is provided compounds of formula (la) as in the second aspect, wherein R1 is selected from ci-c6alkyl and haloalkyl.
In another aspect, there is provided compounds of formula (la) as in the second aspect wherein R1 is a linear or branched ci-c6alkyl. More particul R1 is advantageously selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. In another aspect, there is provided compounds of formula (la) as in the second aspect wherein R1 is advantageously a haloalkyl. More particularly, R1 is advantageously selected from tri-fluoroethylene and tri-fluoropropylene. In another aspect, there is provided compounds of formula (la) as in the second aspect, wherein R1 is selected from propyl and tri-flouro-propyl.
In another aspect, there is provided compounds of formula (la) as in the second aspect, wherein R3 is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N and O and optionally substituted with 1 or 2 substituents independently selected from ci-c3alkyl, -SO2-ci-c3alkyl, and -Ci- c3alkylene-OH.
In another aspect, there is provided compounds of formula (la) as in the
from
In another aspect, there is provided compounds of formula (la) as in the second aspect, wherein R4 is -NH-R7. In another more particular aspect, there is provided compounds of formula (la) as in the second aspect, wherein R4 is -NH2.
In another aspect, there is provided compounds of formula (la) as in the second aspect, wherein R4 is -CH2-R7. In another more particular aspect, there is provided compounds of formula (la) as in the second aspect, wherein R4 is selected from ethyl, 1 -propanol, and 2-methyl-2-butanol.
In another aspect, there is provided a compound of formula (lb):
and pharmaceutically acceptable salts thereof. In another aspect, there is provided the free base of the compound of formula (lb). In a third aspect of the present invention, there is provided compounds of formula (lc):
wherein:
R1 is selected from ci-c6alkyl, haloalkyl, and C3-c6cycloalkyl;
R3 is selected from Het1 , pyridinyl, and ci-c6alkyl optionally substituted with - (co-c6alkylene-(OH)m)n;;
R4 is selected from -NH-R7 and -CH2-R7;
R5 and R6 are independently selected from H, F, and CI;
R7 is selected from H, Ci-c6alkylene-R8, and -co-c3alkylene-Het1 , and ci-c6alkyl optionally substituted with -(Co-c6alkylene-(OH)m)n;
R8 is selected from haloalkyl-, CN, OH, and -SO2-ci-c3alkyl;
each Het1 is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N and O and optionally substituted with 1 or 2 substituents
independently selected from ci-c3alkyl, -SO2-ci-c3alkyl, and -ci-c3alkylene- OH;
each m is 1 or 2; and each n is 1 or 2;
and pharmaceutically acceptable salts thereof.
In another aspect, there is provided compounds of formula (Ic) as in the third aspect, wherein R1 is selected from ci-c6alkyl and haloalkyl.
In another aspect, there is provided compounds of formula (Ic) wherein R1 is a linear or branched ci-c6alkyl . More particularly, R1 is advantageously selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
In another aspect, there is provided compounds of formula (Ic) wherein R1 is advantageously a haloalkyl. More particularly, R1 is advantageously selected from tri-fluoroethylene and tri-fluoropropylene. In another aspect, there is provided compounds of formula (Ic) as in the third aspect, wherein R1 is selected from propyl and tri-flouro-propyl.
In another aspect, there is provided compounds of formula (Ic) as in the third aspect, wherein R3 is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N and O and optionally substituted with 1 or 2 substituents independently selected from ci-c3alkyl, -SO2-ci-c3alkyl, and -ci-c3alkylene-OH.
In another aspect, there is provided compounds of formula (Ic) as in the third
aspect, wherein R3 is selected from
In another aspect, there is provided compounds of formula (Ic) as in the third aspect, wherein R4 is -NH-R7. In another more particular aspect, there is provided compounds of formula (Ic) as in the third aspect, wherein R4 is -NH2
In another aspect, there is provided compounds of formula (Ic) as in the third aspect, wherein R4 is -CH2-R7. In another more particular aspect, there is provided compounds of formula (lc) as in the third aspect, wherein R4 is selected from ethyl, 1 -propanol, and 2-methyl-2-butanol.
In another as ect, there is provided a compound of formula (Id)
and pharmaceutically acceptable salts thereof. In another aspect, there is provided the free base of the compound of formula (Id).
It will be appreciated by those skilled in the art that the compounds of formula (I) may be utilized as a pharmaceutically acceptable salt version thereof. The pharmaceutically acceptable salts of the compounds of formula (I) include conventional salts formed from pharmaceutically acceptable (i.e., non-toxic) inorganic or organic acids or bases as well as quaternary ammonium salts. Representative salts include the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, ethanol amine, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate (methanesulfonate), methylbromide, methylnitrate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate (methylbenzenesulfonate), triethiodide,
trimethylammonium and valerate. Other salts, such as oxalic and
trifluoroacetic, which are not themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining compounds of this invention and these form a further aspect of the invention. In one embodiment, the compound of formula (I) is in the form of the free base. In one embodiment, the compound of formula (I) is in the form of the mesylate salt. In one embodiment, the compound of formula (I) is in the form of the sulfate salt. In one embodiment, the compound of formula (I) is in the form of the hydrochloride salt. In one embodiment, the compound of formula (I) is in the form of the sodium salt. Certain salt versions of the compounds may be solvates, particularly hydrates. In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is in the form of a mono-, di-, tri- or hemi- hydrate.
Processes for preparing pharmaceutically acceptable salts of compounds such as the compounds of formula (I) are conventional in the art. See, e.g., Burger's Medicinal Chemistry And Drug Discovery 5th Edition, Vol 1 :
Principles And Practice.
As will be apparent to those skilled in the art, in the processes described below for the preparation of compounds of formula (I), certain intermediates, may be in the form of pharmaceutically acceptable salts of the compound. Processes for preparing pharmaceutically acceptable salts of intermediates are known in the art and are analogous to the processes for preparing pharmaceutically acceptable salts of other compounds such as the
compounds of formula (I). Compounds of the invention are believed to inhibit of one or more kinases and in particular one or more Raf family kinases ("Raf inhibitor"). Compounds of the invention may also inhibit one or more other kinases, and particularly tyrosine kinases. Certain compounds of the invention may inhibit B-Raf ("B- Raf inhibitor"). It is well documented that Raf inhibitors, including B-Raf inhibitors, are believed to be useful as anticancer and antitumor agents. See, e.g., Davies (2002) supra, Garnett (2004) supra, and Zebisch (2006) supra. The anticancer and antitumor effects of these kinase inhibitors is currently believed to result from inhibition of one or more Raf family kinases, and the effect of such inhibition on cell lines whose growth and/or viability is
dependent on the kinase activity of Raf family kinases.
Compounds of the invention may be Raf inhibitors and optionally also inhibit one or more ErbB family kinases (i.e., EGFR, ErbB2 and ErbB4). Certain compounds of the invention may inhibit B-Raf and also inhibit one or more ErbB family kinases (i.e., EGFR, ErbB2 and ErB4).
Some compounds of the invention may be selective inhibitors of Raf family kinases ("selective Raf inhibitor"), meaning that preferential inhibition of one or more Raf family kinases is significantly greater than that of any number of other kinases, for example by a factor of 5-fold or more.
However, the present invention is not limited to compounds which are selective inhibitors of one or more Raf family kinases rather, the present invention expressly contemplates that certain compounds of the invention may possess activity against multiple kinases, including kinases other than Raf family kinases. For example, particular compounds of the invention may possess activity against multiple other kinases, including but not limited to EGFR, ErbB2, ErbB4, IGF-1 R, IR, IRR, Src, VEGFR, PDGFR, Met, Lyn, Lck, Alk5, Aurora A and B, JNK, Syk, p38, BTK, FAK, Abl, CK1 . cKit, Epherin receptors (for example EphB4), FGFR, Fit, Fyn, Hck, JAK, MLK, ΡΚΟμ, Ret, Yes, and BRK, as well. Particular compounds of the invention may be deemed to be unselective or non-selective, meaning that they are not considered by one skilled in the art to be selective for any particular kinase over others.
As used herein, a Raf inhibitor is a compound that exhibits a plC5o of greater than about 6 against at least one Raf family kinase in the Raf inhibition enzyme assay described below and/or an IC5o of not greater than about 5 μΜ potency against at least one cell line that expresses mutated B-Raf kinase (e.g., A375P, Colo205, HT-29, SK-MEL-3, SK-MEL-28) in the methylene blue and/or the CellTiter-Glo cellular proliferation assays described below. In a particular embodiment, a Raf inhibitor refers to a compound of the invention that exhibits a plC5o of greater than about 6.5 against at least one Raf family kinase in the Raf inhibition enzyme assay described below and an IC50 of not greater than about 500nM potency against at least one cell line that expresses mutated B-Raf kinase in the methylene blue and/or the CellTiter- Glo cellular proliferation assays described below.
A "B-Raf inhibitor" refers to a compound of the invention that exhibits a plC5o of greater than about 6.5 against B-Raf (including B-Raf mutants) in the Raf inhibition enzyme assay described below and an IC5o of not greater than about 500nM potency against at least one cell line that expresses mutated B- Raf kinase in the methylene blue and/or the CellTiter-Glo cellular proliferation assay described below. The present invention provides compounds for use in medical therapy in a mammal, e.g., a human, in need thereof. The present invention provides methods for the treatment of several conditions in a mammal, in need thereof, all of which comprise the step of administering a therapeutically effective amount of a compound of the invention. All methods described herein are applicable to mammals, and particularly to humans.
As used herein, the term "treatment" or "treating" in the context of therapeutic methods, refers to alleviating the specified condition, eliminating or reducing the symptoms of the condition, slowing or eliminating the progression, invasion, or metastatic spread of the condition and preventing or delaying the reoccurrence of the condition in a previously afflicted subject. The present invention further provides use of the compounds of the invention for the preparation of a medicament for the treatment of several conditions in a mammal (e.g., human) in need thereof.
More particularly, the present invention provides compounds for use in the treatment of a condition mediated by at least one Raf family kinases (e.g., B- Raf) in a mammal in need thereof. The present invention provides a method for treating a condition mediated by at least one Raf family kinase (e.g., B- Raf) in a mammal (e.g., a human) in need thereof, which method comprises administering to the mammal a therapeutically effective amount of the compound of the invention. In another embodiment, the invention provides compounds for use in regulating, modulating, binding or inhibiting one or more Raf family kinases (e.g., B-Raf) in a mammal. The invention also provides methods of
regulating, modulating, binding, or inhibiting at least one Raf family kinase (e.g., B-Raf) by administering a therapeutically effective amount of a compound of the invention. "Regulating, modulating, binding or inhibiting at least one Raf family kinase" refers to regulating, modulating, binding or inhibiting the activity of at least one Raf family kinase, as well as regulating, modulating, binding or inhibiting overexpression of an upstream regulator of at least one Raf family kinase in order to inhibit the cellular potency of its signaling ability.
In a particular embodiment, the invention provides compounds for use in the treatment of a condition mediated by inappropriate activity of one or more Raf family kinases (e.g., B-Raf), or an upstream activator of one or more Raf family kinases in a mammal. The invention further provides methods for the treatment of a condition mediated by inappropriate activity of one or more Raf family kinases (particularly B-Raf), in a mammal in need thereof, comprising administering to the mammal, a therapeutically effective amount of a compound of the invention. In an additional aspect, the present invention provides the use of a compound of the invention for the preparation of a medicament for the treatment of a condition mediated by inappropriate activity of one or more Raf family kinases (particularly B-Raf), in a mammal. One example of a condition mediated by inappropriate activity of one or more Raf family kinases includes neoplasms.
By "inappropriate activity" is meant Raf family kinase activity that deviates from the expected activity for that kinase or for an upstream activator of that kinase in a particular mammal. The inappropriate activity of a Raf family kinase may arise from one or more of A-Raf, B-Raf or c-Raf or an upstream activator of a Raf family kinase. Inappropriate Raf family kinase activity may take the form of, for instance, an abnormal increase in activity, or an aberration in the timing and/or control of Raf family kinase activity. Such inappropriate activity may result, for example, from overexpression or mutation of the kinase, upstream activator, receptor or ligand leading to inappropriate or uncontrolled activation of the corresponding kinase or receptor. Furthermore, it is also contemplated that unwanted Raf family kinase activity may reside in an abnormal source, such as a neoplasm. Thus, the level of Raf family kinase activity does not need to be abnormal to be considered inappropriate in the case where the activity derives from an abnormal source including, but not limited to, upstream activators (e.g., activated mutant Ras GTPases) or neoplasm. In one example of
inappropriate Raf family kinase activity not resulting from mutation or overexpression of a Raf family kinase, inappropriate activity of a Ras GTPase may result from mutation or overexpression of Ras GTPase, for example the G13D mutation in KRas2, and may lead to overactivation of the MAPK pathway mediated by Raf family kinase activity.
Thus, in one embodiment, the present invention provides compounds for use in the treatment of a condition which directly or indirectly results from a mutation of a Raf family kinase or overexpression of a Raf family kinase, or a mutation of an upstream activator of a Raf family kinase or overexpression of an upstream activator of a Raf family kinase in a mammal in need thereof. The present invention provides methods for the treatment of a condition which directly or indirectly results from mutation of a Raf family kinase or
overexpression of a Raf family kinase, or a mutation of an upstream activator of a Raf family kinase or overexpression of an upstream activator of a Raf family kinase in a mammal in need thereof, comprising administering to the mammal, a therapeutically effective amount of a compound of the invention. In an additional aspect, the present invention provides the use of a compound of the invention for the preparation of a medicament for the treatment of a condition which directly or indirectly results from mutation of a Raf family kinase or overexpression of a Raf family kinase, or a mutation of an upstream activator of a Raf family kinase or overexpression of an upstream activator of a Raf family kinase in a mammal. Conditions which are mediated by at least one Raf family kinase, and particularly conditions mediated by inappropriate activity of one or more Raf family kinases, including those which directly or indirectly result from mutation of a Raf family kinase, overexpression of a Raf family kinase, or mutation of an upstream activator of a Raf family kinase or overexpression of an upstream activator of a Raf family kinase are known in the art and include but are not limited to neoplasms.
Compounds of the invention may also be used in the treatment of conditions attenuated by inhibition of a Raf family kinase (particularly B-Raf). Further provided are methods for treating a condition attenuated by inhibition of a Raf family kinase (particularly B-Raf) in a mammal in need thereof, comprising administering to the mammal, a therapeutically effective amount of a compound of the invention. Also provided is the use of a compound of the invention for the preparation of a medicament for the treatment of a condition attenuated by inhibition of a Raf family kinase (particularly B-Raf) in a mammal. Conditions attenuated by inhibition of a Raf family kinase (including B-Raf) include but are not limited to neoplasms. Accordingly, compounds of the invention may be used in the treatment of a neoplasm, particularly a susceptible neoplasm (a cancer or tumor) in a mammal. The present invention also provides a method for treating a neoplasm, particularly a susceptible neoplasm in a mammal in need thereof, which method comprises administering to the mammal a therapeutically effective amount of the compound of the invention. The invention also provides the use of a compound of the invention for the preparation of a medicament for the treatment of neoplasm, particularly a susceptible neoplasm, in a mammal. "Susceptible neoplasm" as used herein refers to neoplasms which are susceptible to treatment by a kinase inhibitor and particularly neoplasms that are susceptible to treatment by a Raf inhibitor. Neoplasms which have been associated with inappropriate activity of one or more Raf family kinases and particularly neoplasms which are exhibit mutation of a Raf family kinase, overexpression of a Raf family kinase, or mutation of an upstream activator of a Raf family kinase or overexpression of an upstream activator of a Raf family kinase, and are therefore susceptible to treatment with an Raf inhibitor are known in the art, and include both primary and metastatic tumors and cancers. See, Catalogue of Somatic Mutations in Cancer (COSMIC), the Wellcome Trust Sanger Institute,
http://www.sanqer.ac.uk/genetics/CGP/cosmic/ and those references cited in the background. Specific examples of susceptible neoplasms within the scope of the invention include, but are not limited to:
Barret's adenocarcinoma;
billiary tract carcinomas;
breast cancer;
cervical cancer;
cholangiocarcinoma;
central nervous system tumors including primary CNS tumors such as
glioblastomas, astrocytomas (including glioblastoma multiforme) and ependymomas, and secondary CNS tumors (i.e., metastases to the central nervous system of tumors originating outside of the central nervous system),
colorectal cancer, including large intestinal colon carcinoma;
gastric cancer;
carcinoma of the head and neck including squamous cell carcinoma of the head and neck;
hematologic cancers including leukemias and lymphomas such as acute
lymphoblastic leukemia, acute myelogenous leukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia, multiple myeloma and erythroleukemia;
hepatocellular carcinoma;
lung cancer including small cell lung cancer and non-small cell lung cancer; ovarian cancer;
endometrial cancer; pancreatic cancer;
pituitary adenoma;
prostate cancer;
renal cancer;
sarcoma;
skin cancers including melanomas; and
thyroid cancers.
The foregoing list is intended to disclose each of the recited neoplasms individually. In one particular embodiment, the susceptible neoplasm is a neoplasm which exhibits a mutation in BRaf.
Accordingly, in one embodiment, the present invention provides a method for the treatment of any of Barret's adenocarcinoma; billiary tract carcinomas; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors including primary CNS tumors such as glioblastomas, astrocytomas (e.g., glioblastoma multiforme) and ependymomas, and secondary CNS tumors (i.e., metastases to the central nervous system of tumors originating outside of the central nervous system); colorectal cancer including large intestinal colon carcinoma; gastric cancer; carcinoma of the head and neck including squamous cell carcinoma of the head and neck; hematologic cancers including leukemias and lymphomas such as acute lymphoblastic leukemia, acute myelogenous leukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia, multiple myeloma and
erythroleukemia; hepatocellular carcinoma; lung cancer including small cell lung cancer and non-small cell lung cancer; ovarian cancer; endometrial cancer; pancreatic cancer; pituitary adenoma; prostate cancer; renal cancer; sarcoma; skin cancers including melanomas; and thyroid cancers, or any subset thereof, in a mammal (e.g., human) in need thereof. The method comprises administering a therapeutically effective amount of a compound of the invention to the mammal (e.g., human). In one embodiment, the present invention provides a method for treating breast cancer, cholangiocarcinoma, colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, or thyroid cancer, or any subset thereof. In one particular embodiment, the present invention provides a method for treating cholangiocarcinoma, colorectal cancer, melanoma, or thyroid cancer, or any subset thereof.
In one preferred embodiment, the present invention provides a method for treating melanoma in a mammal (e.g., human) in need thereof. The method comprises administering to the mammal (e.g. human) a therapeutically effective amount of a compound of formula (I). In one preferred embodiment, the compound is selected from
A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-methyl-1 -piperazinyl)-1 ,3-thiazol-4-yl]-2- chlorophenyl}-3,3,3-trifluoro-1 -propanesulfonamide; and
A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-oxazol-4-yl]-
2-fluorophenyl}-1 -propanesulfonamide;
and pharmaceutically acceptable salts thereof. The present invention also provides the a compound of formula (I) for use in the treatment of Barret's adenocarcinoma; bill iary tract carcinomas; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors including primary CNS tumors such as glioblastomas, astrocytomas (e.g., glioblastoma multiforme) and ependymomas, and secondary CNS tumors (i.e., metastases to the central nervous system of tumors originating outside of the central nervous system); colorectal cancer including large intestinal colon carcinoma; gastric cancer; carcinoma of the head and neck including squamous cell carcinoma of the head and neck; hematologic cancers including leukemias and lymphomas such as acute lymphoblastic leukemia, acute myelogenous leukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia, multiple myeloma and erythroleukemia;
hepatocellular carcinoma; lung cancer including small cell lung cancer and non-small cell lung cancer; ovarian cancer; endometrial cancer; pancreatic cancer; pituitary adenoma; prostate cancer; renal cancer; sarcoma; skin cancers including melanomas; and thyroid cancers, or any subset thereof, in a mammal (e.g., human). The present invention further provides the use of a compound of formula (I) for the preparation of a medicament for the treatment of Barret's
adenocarcinoma; billiary tract carcinomas; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors including primary CNS tumors such as glioblastomas, astrocytomas (e.g., glioblastoma multiforme) and ependymomas, and secondary CNS tumors (i.e., metastases to the central nervous system of tumors originating outside of the central nervous system); colorectal cancer including large intestinal colon carcinoma; gastric cancer; carcinoma of the head and neck including squamous cell carcinoma of the head and neck; hematologic cancers including leukemias and lymphomas such as acute lymphoblastic leukemia, acute myelogenous leukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia, multiple myeloma and erythroleukemia; hepatocellular carcinoma; lung cancer including small cell lung cancer and non-small cell lung cancer; ovarian cancer; endometrial cancer; pancreatic cancer; pituitary adenoma; prostate cancer; renal cancer; sarcoma; skin cancers including melanomas; and thyroid cancers, or any subset thereof, in a mammal (e.g., human).
As is well known in the art, tumors may metastasize from a first or primary locus of tumor to one or more other body tissues or sites. In particular, metastases to the central nervous system (i.e., secondary CNS tumors), and particularly the brain (i.e., brain metastases), are well documented for tumors and cancers, such as breast, lung, melanoma, renal and colorectal. As used herein, reference to uses or methods for treatment or treatments for a
"neoplasm," "tumor" or "cancer" in a subject includes use for and treatment of the primary neoplasm, tumor or cancer, and where appropriate, also the use for and treatment of metastases (i.e., metastatic tumor growth) as well. In another embodiment, the susceptible neoplasm is colorectal cancer and the invention provides compounds for use in the treatment of colorectal cancer in a mammal (e.g., human) and the use of such compounds for the preparation of a medicament for the treatment of colorectal cancer in a mammal (e.g., human).
In another embodiment, the susceptible neoplasm is melanoma, and the invention provides compounds for use in the treatment of melanoma in a mammal (e.g., human) and the use of such compounds for the preparation of a medicament for the treatment of melanoma in a mammal (e.g., human).
In another embodiment, the susceptible neoplasm is cholangiocarcinoma, and the invention provides compounds for use in the treatment of
cholangiocarcinoma in a mammal (e.g., human) and the use of such compounds for the preparation of a medicament for the treatment of cholangiocarcinoma in a mammal (e.g., human).
In another embodiment, the susceptible neoplasm is thyroid cancer, and the invention provides compounds for use in the treatment of thyroid cancer in a mammal (e.g., human) and the use of such compounds for the preparation of a medicament for the treatment of thyroid cancer in a mammal (e.g., human).
In one particular embodiment, the susceptible neoplasm is breast cancer and the invention provides compounds for use in the treatment of breast cancer in a mammal (e.g., human) and the use of such compounds for the preparation of a medicament for the treatment of breast cancer in a mammal (e.g., human).
In another embodiment, the susceptible neoplasm is ovarian cancer and the invention provides compounds for use in the treatment of ovarian cancer in a mammal (e.g., human) and the use of such compounds for the preparation of a medicament for the treatment of ovarian cancer in a mammal (e.g., human). In another embodiment, the susceptible neoplasm is non-small cell lung cancer, and the invention provides compounds for use in the treatment of non-small cell lung cancer in a mammal (e.g., human) and the use of such compounds for the preparation of a medicament for the treatment of non- small cell lung cancer in a mammal (e.g., human).
The compounds of the invention can be used alone in the treatment of each of the foregoing conditions or can be used to provide additive or potentially synergistic effects with certain existing chemotherapies, radiation, biological or immunotherapeutics (including monoclonal antibodies) and vaccines. The compounds of the invention may be useful for restoring effectiveness of certain existing chemotherapies and radiation and or increasing sensitivity to certain existing chemotherapies and/or radiation. In addition to the treatment of susceptible neoplasms, the compounds of the invention may also be used in the treatment of other conditions attenuated by inhibition of a Raf family kinase, such as cardio-facio cutaneous syndrome and polycystic kidney disease. In one aspect, the present invention provides a method for treating a susceptible neoplasm in a mammal in need thereof comprising the steps of:
(a) analyzing a sample from said neoplasm to determine whether an activating mutation is present in the coding sequence for B-Raf in cells of said neoplasm;
(b) selecting a mammal having a neoplasm with an activating mutation in the coding sequence for B-Raf; and
(c) administering a therapeutically effective amount of a compound of the present invention to the mammal selected in step (b). In certain embodiments, the activating mutation present in the coding sequence for BRAF results in a BRAF having an amino acid substitution selected from the group consisting of R462I, I463S, G464V, G464E, G466A, G466E, G466V, G469A, G469E, D594V, F595L, G596R, L597V, L597R, T599I, V600E, V600D, V600K, V600R, T1 19S, and K601 E. See, for example, Figure 2 of Halilovic and Solvit (2008) Current Opinion in Pharmacology 8:419-26.
In one embodiment, the present invention provides a method for treating a susceptible neoplasm in a mammal in need thereof comprising the steps of:
(a) analyzing a sample from said neoplasm to determine whether a mutation encoding a V600E amino acid substitution is present in the coding sequence for B-Raf in cells of said neoplasm;
(b) selecting a mammal having a neoplasm with a mutation encoding the V600E amino acid substitution in B-Raf; and
(c) administering a therapeutically effective amount of a compound of the present invention to the mammal selected in step (b).
The V600E amino acid substitution in B-Raf is described, for example, in Kumar et al. (2004) J Invest Dermatol. 122(2):342-8. This mutation commonly results from a T1799A mutation in the coding sequence for human B-Raf. Accordingly, in one embodiment of the present invention, the step of analyzing a sample from said neoplasm to determine whether a mutation encoding a V600E amino acid substitution is present in the coding sequence for B-Raf is performed by determining whether the coding sequence for B-Raf in cells of the neoplasm contains the T1799A mutation.
The neoplasm may be selected from Barret's adenocarcinoma; billiary tract carcinomas; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors including primary CNS tumors such as glioblastomas, astrocytomas (e.g., glioblastoma multiforme) and ependymomas, and secondary CNS tumors (i.e., metastases to the central nervous system of tumors originating outside of the central nervous system); colorectal cancer including large intestinal colon carcinoma; gastric cancer; carcinoma of the head and neck including squamous cell carcinoma of the head and neck; hematologic cancers including leukemias and lymphomas such as acute lymphoblastic leukemia, acute myelogenous leukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia, Hodgkin's lymphoma, non- Hodgkin's lymphoma, megakaryoblastic leukemia, multiple myeloma and erythroleukemia; hepatocellular carcinoma; lung cancer including small cell lung cancer and non-small cell lung cancer; ovarian cancer; endometrial cancer; pancreatic cancer; pituitary adenoma; prostate cancer; renal cancer; sarcoma; skin cancers including melanomas; and thyroid cancers.
In particular embodiments, the neoplasm is selected from breast cancer, cholangiocarcinoma, colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, and thyroid cancer. In one preferred embodiment, the neoplasm is melanoma.
In one embodiment, the mammal is a human.
The sample of the neoplasm to be analyzed for the presence of B-raf activating mutations can be derived from a variety of sources including, but not limited to, single cells, a collection of cells, tissue, cell culture, bone marrow, blood, or other bodily fluids. The tissue or cell source may include a tissue biopsy sample, a cell sorted population, cell culture, or a single cell. In selecting a sample, the percentage of the sample that constitutes neoplastic cells should be considered. In some embodiments, the sample from the neoplasm is fixed using a preservative prior to analyzing for the presence of an activating mutation.
The step of analyzing a sample from the neoplasm to determine whether an activating mutation is present in the coding sequence for B-Raf in cells of said neoplasm may be performed using any method known in the art. For example, the coding sequence for B-raf in cells of the sample may be analyzed to determine if it contains a mutation which results in the expression of activated B-Raf. Methods for detecting such mutations are well known in the art. See, for example, Whitcombe et al. (1999) Nature Biotechnology 17:804-7, Gibson (2006) Clinica Chimica Acta 363: 32-47, Kim and Misra
(2007) Annual Review of Biomedical Engineering 9:289-320, and U.S. Patent Nos. 6,326,145 and 6,270,967). Alternatively, activating mutations in B-Raf may be identified by directly detecting the activated B-raf protein using an agent (e.g. an antibody) that selectively binds activated B-raf. As used herein, the term "therapeutically effective amount" means an amount of a compound of the invention which is sufficient, in the subject to which it is administered, to elicit a biological or medical response of a cell culture, tissue, system, mammal (including human) that is being sought, for instance, by a researcher or clinician. The term also includes within its scope amounts effective to enhance normal physiological function. For example, a
therapeutically effective amount of a compound of the invention for the treatment of a condition mediated by at least one Raf family kinase is an amount sufficient to treat the condition in the particular subject. Similarly, a therapeutically effective amount of a compound of the invention for the treatment of a susceptible neoplasm is an amount sufficient to treat the particular susceptible neoplasm in the subject. In one embodiment of the present invention, a therapeutically effective amount of a compound of the invention is an amount sufficient to regulate, modulate, bind or inhibit at least one Raf family kinase. More particularly, in such embodiment, the
therapeutically effective amount of a compound of the invention is an amount sufficient to regulate, modulate, bind or inhibit B-Raf. The precise therapeutically effective amount of the compounds of the invention will depend on a number of factors. There are variables inherent to the compounds including, but not limited to, the following: molecular weight, inhibitory activity at the target kinase, absorption, bioavailability, distribution in the body, tissue penetration, half-life, metabolism, protein binding, and excretion. These variables determine what dose of compound needs to be administered in order to inhibit the target kinase by a sufficient percentage and for a sufficient amount of time to have the desired effect on the condition being treated (e.g., neoplasm). In general, the goal will be to inhibit the target kinase by 50% or more for as long as possible. The duration of drug exposure will be limited only by the compound half-life, and side effects from treatment requiring cessation of dosing. The amount of compound
administered will also depend on factors related to patients and disease including, but not limited to, the following: the age, weight, concomitant medications and medical condition of the subject being treated, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration. Ultimately the dose will be at the discretion of the attendant physician or veterinarian. Typically, the compound of the invention will be given for treatment in the range of 0.01 to 30 mg/kg body weight of recipient (mammal) per day or per dose or per cycle of treatment and more usually in the range of 0.1 to 10 mg/kg body weight per day or per dose or per cycle of treatment. Thus, for a 70kg adult human being treated for a condition mediated by or correlated to at least one Raf family kinase, the actual amount per day or per dose or per cycle of treatment would usually be from 1 to 2000 mg and this amount may be given in a single or multiple doses per day or per dose or per cycle of treatment. Dosing regimens may vary significantly and will be determined and altered based on clinical experience with the compound. The full spectrum of dosing regimens may be employed ranging from continuous dosing (with daily doses) to intermittent dosing. A therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula (I) may be determined as a proportion of the
therapeutically effective amount of the compound of formula (I) as the free base. It is envisaged that similar dosages would be appropriate for treatment of the susceptible neoplasms described above.
While it is possible that, for use in therapy, a therapeutically effective amount of a compound of the invention may be administered as the raw chemical, it is typically presented as the active ingredient of a pharmaceutical composition or formulation. Accordingly, the invention further provides a pharmaceutical composition comprising a compound of the invention. The pharmaceutical composition may further comprise one or more pharmaceutically acceptable carriers, diluents, and/or excipients. The carrier(s), diluent(s) and/or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. In accordance with another aspect of the invention there is also provided a process for the preparation of a pharmaceutical formulation including admixing a compound of the invention with one or more
pharmaceutically acceptable carriers, diluents and/or excipients. Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a compound of the invention (as a free-base, solvate (including hydrate) or salt, in any form), depending on the condition being treated, the route of administration, and the age, weight and condition of the patient. Preferred unit dosage formulations are those containing a daily dose, weekly dose, monthly dose, a sub-dose or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical
formulations may be prepared by any of the methods well known in the pharmacy art.
Pharmaceutical formulations may be adapted for administration by any appropriate route, for example by the oral (including capsules, tablets, liquid- filled capsules, disintegrating tablets, immediate, delayed and controlled release tablets, oral strips, solutions, syrups, buccal and sublingual), rectal, nasal, inhalation, topical (including transdermal), vaginal or parenteral
(including subcutaneous, intramuscular, intravenous or intradermal) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s), excipient(s) or diluent. Generally, the carrier, excipient or diluent employed in the pharmaceutical formulation is "non-toxic," meaning that it/they is/are deemed safe for consumption in the amount delivered in the pharmaceutical composition, and "inert" meaning that it/they does/do not appreciably react with or result in an undesired effect on the therapeutic activity of the active ingredient.
Pharmaceutical formulations adapted for oral administration may be
presented as discrete units such as liquid-filled or solid capsules; immediate, delayed or controlled release tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; oil-in- water liquid emulsions, water-in-oil liquid emulsions or oral strips, such as impregnated gel strips. For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral pharmaceutically acceptable carrier such as ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.
Solid capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation. A
disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
Moreover, when desired or necessary, suitable binders, lubricants,
disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets. A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an alginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.
Oral fluids such as solutions, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Solutions and syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a pharmaceutically acceptable alcoholic vehicle.
Suspensions can be formulated by dispersing the compound in a
pharmaceutically acceptable vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added. Where appropriate, unit dosage formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like. The compounds of the invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. The compounds of the invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include
polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl- methacrylamidephenol, polyhydroxyethylaspartamidephenol, or
polyethyleneoxide-polylysine substituted with palmitoyl residues.
Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polycentric acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels. Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research (1986) 3(6):318.
Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. For treatments of external tissues, such as skin, the formulations may be applied as a topical ointment or cream. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base. Pharmaceutical formulations adapted for topical
administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent. Pharmaceutical formulations adapted for topical administration in the mouth include lozenges, pastilles and mouth washes. Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or as enemas.
Pharmaceutical formulations adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.
Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered dose pressurized aerosols, metered dose inhalers, dry powder inhalers, nebulizers or insufflators.
Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation of pharmaceutically acceptable tonicity with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and
suspensions may be prepared from sterile powders, granules and tablets.
It should be understood that in addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
In the above-described methods of treatment and uses, a compound of the invention may be employed alone, in combination with one or more other compounds of the invention or in combination with other therapeutic methods or agents. In particular, in methods of treating a condition attenuated by inhibition of at least one Raf family kinase and in methods of treating susceptible neoplasms, combination with other chemotherapeutic, biologic, hormonal, antibody and supportive care agents is envisaged as well as combination with surgical therapy and radiotherapy. Supportive care agents include analgesics, anti-emetics and agents used to treat heamatologic side effects such as neutropenia. Analgesics are well known in the art. Antiemetics include but are not limited to 5HT3 antagonists such as ondansetron, granisetron, dolasetron, palonosetron and the like; prochlorperazine;
metaclopromide; diphenhydramine; promethazine; dexamethasone;
lorazepam; haloperidol; dronabinol; olanzapine; and neurokinin-1 antagonists such as aprepitant, fosaprepitant and casopitant administered alone or in various combinations.
The term "chemotherapeutic" as used herein refers to any chemical agent having a therapeutic effect on the subject to which it is administered.
"Chemotherapeutic" agents include but are not limited to anti-neoplastic agents. As used herein, "anti-neoplastic agents" include both cytotoxic and cytostatic agents including biological, immunological and vaccine therapies. Combination therapies according to the invention thus comprise the administration of at least one compound of the invention and the use of at least one other treatment method. In one embodiment, combination therapies according to the invention comprise the administration of at least one compound of the invention and surgical therapy. In one embodiment, combination therapies according to the invention comprise the administration of at least one compound of the invention and radiotherapy. In one
embodiment, combination therapies according to the invention comprise the administration of at least one compound of the invention and at least one supportive care agent (e.g., at least one anti-emetic agent). In one
embodiment, combination therapies according to the present invention comprise the administration of at least one compound of the invention and at least one other chemotherapeutic agent. In one particular embodiment, the invention comprises the administration of at least one compound of the invention and at least one anti-neoplastic agent.
As an additional aspect, the present invention provides the methods of treatment and uses as described above, which comprise administering a compound of the invention together with at least one chemotherapeutic agent. In one particular embodiment, the chemotherapeutic agent is an antineoplastic agent. In another embodiment, the invention provides a
pharmaceutical composition as described above further comprising at least one other chemotherapeutic agent, more particularly, the chemotherapeutic agent is an anti-neoplastic agent. The invention also provides methods of treatment and uses as described above, which comprise administering a compound of the invention together with at least one supportive care agent (e.g., anti-emetic agent). The compounds of the invention and at least one additional anti-neoplastic or supportive care therapy may be employed in combination concomitantly or sequentially in any therapeutically appropriate combination. The
administration of a compound of the invention with one or more other antineoplastic agents may be in combination in accordance with the invention by administration concomitantly in one unitary pharmaceutical composition including both or all compounds or two or more separate pharmaceutical compositions each including one or more of the compounds. The
components of the combination may be administered separately in a sequential manner wherein one active ingredient is administered first and the other(s) second or vice versa. Such sequential administration may be close in time or remote in time.
When a compound of the invention is used in combination with an antineoplastic and/or supportive care agent, the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art. The appropriate dose of the compound(s) of the invention and the other therapeutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect, and are within the expertise and discretion of the attendant clinician.
Typically, any chemotherapeutic agent that has activity against a susceptible neoplasm being treated may be utilized in combination with the compounds of the invention, provided that the particular agent is clinically compatible with therapy employing a compound of the invention. Typical anti-neoplastic agents useful in the present invention include, but are not limited to: alkylating agents, anti-metabolites, antitumor antibiotics, antimitotic agents,
topoisomerase I and II inhibitors, hormones and hormonal analogues;
retinoids, signal transduction pathway inhibitors including inhibitors of cell growth or growth factor function, angiogenesis inhibitors, and serine/threonine or other kinase inhibitors; cyclin dependent kinase inhibitors; antisense therapies and immunotherapeutic agents, including monoclonals, vaccines or other biological agents.
Alkylating agents are non-phase specific anti-neoplastic agents and strong electrophiles. Typically, alkylating agents form covalent linkages, by alkylation, to DNA through nucleophilic moieties of the DNA molecule such as phosphate, amino, and hydroxyl groups. Such alkylation disrupts nucleic acid function leading to cell death. Alkylating agents may be employed in combination with the compounds of the invention in the compositions and methods described above. Examples of alkylating agents include but are not limited to nitrogen mustards such as cyclophosphamides, temozolamide, melphalan, and chlorambucil; oxazaphosphor-ines; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; triazenes such as dacarbazine; and platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin. Antimetabolite neoplastic agents are phase specific anti-neoplastic agents that act at S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA synthesis. The end result of discontinuing S phase is cell death. Antimetabolite neoplastic agents may be employed in combination with the compounds of the invention in the compositions and methods described above. Examples of antimetabolite anti-neoplastic agents include but are not limited to purine and pyrimidine analogues and anti-folate compounds, and more specifically, hydroxyurea, cytosine, arabinoside, ralitrexed, tegafur, fluorouracil (e.g., 5FU), methotrexate, cytarabine, mecaptopurine and thioguanine.
Antitumor antibiotic agents are non-phase specific agents, which bind to or intercalate with DNA. Typically, such action disrupts ordinary function of the nucleic acids, leading to cell death. Antitumor antibiotics may be employed in combination with the compounds of the invention in the compositions and methods described above. Examples of antitumor antibiotic agents include, but are not limited to, actinomycins such as dactinomycin; anthracydines such as daunorubicin, doxorubicin, idarubicin, epirubicin and mitoxantrone;
.mitomycin C and bleomycins.
Antimicrotubule or antimitotic agents are phase specific agents active against the microtubules of tumor cells during M or the mitosis phase of the cell cycle. Antimitotic agents may be employed in combination with the compounds of the invention in the compositions and methods described above. Examples of antimitotic agents include, but are not limited to, diterpenoids, vinca alkaloids, polo-like kinase (Plk) inhibitors and CenpE inhibitors. Examples of
diterpenoids include, but are not limited to, paclitaxel and its analog docetaxel. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, vindesine and vinorelbine. Plk inhibitors are discussed further below.
Topoisomerase inhibitors include inhibitors of Topoisomerase II and inhibitors of Topoisomerase I. Topoisomerase II inhibitors, such as
epipodophyllotoxins, are anti-neoplastic agents derived from the mandrake plant, that typically affect cells in the S and G2 phases of the cell cycle by forming a ternary complex with topoisomerase II and DNA, causing DNA strand breaks. The strand breaks accumulate and cell death follows.
Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide. Camptothecins, including camptothecin and camptothecin derivatives, are available or under development as Topoisomerase I inhibitors. Examples of camptothecins include, but are not limited to amsacrine, irinotecan, topotecan, and the various optical forms of 7-(4- methylpiperazino-methylene)-10,1 1 -ethylenedioxy-20-camptothecin.
Topoisomerase inhibitors may be employed in combination with the compounds of the invention in the compositions and methods described above.
Hormones and hormonal analogues are useful compounds for treating cancers in which there is a relationship between the hormone(s) and growth and/or lack of growth of the cancer. Antitumor hormones and hormonal analogues may be employed in combination with the compounds of the invention in the compositions and methods described above. Examples of hormones and hormonal analogues believed to be useful in the treatment of neoplasms include, but are not limited to antiestrogens, such as tamoxifen, toremifene, raloxifene, fulvestrant, iodoxyfene and droloxifene; anti- androgens; such as flutamide, nilutamide, bicalutamide and cyproterone acetate; adrenocorticosteroids such as prednisone and prednisolone;
aminoglutethimide and other aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestane; progestrins such as megestrol acetate; 5a-reductase inhibitors such as finasteride and dutasteride; and
gonadotropin-releasing hormones (GnRH) and analogues thereof, such as Leutinizing Hormone-releasing Hormone (LHRH) agonists and antagonists such as goserelin luprolide, leuprorelin and buserelin.
Retinoid(s) are compounds that bind to and activate at least one retinoic acid receptor selected from RARa, RAR , and RARy and/or compounds that bind to and activate at least one of RARa, RAR , and RARy and also at least one retinoic X receptor (RXR), including RXRa, RXR , and RXRy. Retinoids for use in the present invention typically have affinity for RAR, and particularly for RARa and/or RAR . However, certain synthetic retinoids, such as 9-cis- retinoic acid also have affinity for both RAR and RXR. In one embodiment, the retinoid has affinity for RARa (and RARa agonist).
Examples of specific retinoids that may be used in combination with the compounds of the invention include: retinoic acid; all-trans-retinoic acid ("ATRA" also known as "tretinoin"); tamibarotene ("Am80"); 9-cis-retinoic acid ((2E,4E,6Z,8E)-3,7-Dimethyl-9-(2,6,6-trimethylcyclohex-1 -enyl)nona- 2,4,6,8-tetraenoic Acid) (also known as "9-cis-Tretinoin") (available from Sigma); Isotretinoin ((2Z,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1 - cyclohexenyl)nona-2,4,6,8-tetraenoic acid) (also known as "13-cis-retinoic acid") (ACCUTANE®); Am580 (4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphtamido) benzoic acid), See, M. Gianni, Blood 1996 87(4):1520-1531 ; TTNPB (4-[E-2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1 - propenyl]benzoic acid) (also known as "Ro 13-7410") See, M.F. Boehm et al. J. Med. Chem. 1994 37:2930 and R.P. Bissonnette et al., Mol. Cell. Biol. 1995 15:5576; and BMS753 (4-[[(2,3-dihydro-1 ,1 ,3,3-tetramethyl-2-oxo-1 H-inden- 5-yl)carbonyl]amino]benzoic acid) See, USPN 6184256.
Other RARa agonists known the art may also be used in the present invention.
Signal transduction pathway inhibitors are those inhibitors which block or inhibit a chemical process which evokes an intracellular change. As used herein these changes include, but are not limited to, cell proliferation or differentiation or survival. Signal transduction pathway inhibitors useful in the present invention include, but are not limited to, inhibitors of receptor tyrosine kinases, non-receptor tyrosine kinases, SH2/SH3 domain blockers, serine/threonine kinases, phosphatidyl inositol-3-OH kinases, myoinositol signaling, and Ras oncogenes. Signal transduction pathway inhibitors may be employed in combination with the compounds of the invention in the compositions and methods described above.
Several protein tyrosine kinases catalyze the phosphorylation of specific tyrosine residues in various proteins involved in the regulation of cell growth. Such protein tyrosine kinases can be broadly classified as receptor or nonreceptor kinases.
Receptor tyrosine kinase inhibitors which may be combined with the
compounds of the invention include those involved in the regulation of cell growth, which receptor tyrosine kinases are sometimes referred to as "growth factor receptors." Examples of growth factor receptor inhibitors, include but are not limited to inhibitors of: insulin growth factor receptors (IGF-1 R, IR and IRR); epidermal growth factor family receptors (EGFR, ErbB2, and ErbB4); platelet derived growth factor receptors (PDGFRs), vascular endothelial growth factor receptors (VEGFRs), tyrosine kinase with immunoglobulin-like and epidermal growth factor homology domains (TIE-2), macrophage colony stimulating factor (c-fms), c-kit, c-met, fibroblast growth factor receptors (FGFRs), hepatocyte growth factor receptors (HGFRs), Trk receptors (TrkA, TrkB, and TrkC), ephrin (Eph) receptors and the RET protooncogene.
Several inhibitors of growth factor receptors are under development and include ligand antagonists, antibodies, tyrosine kinase inhibitors, anti-sense oligonucleotides and aptamers. Any of these growth factor receptor inhibitors may be employed in combination with the compounds of the invention in any of the compositions and methods/uses described herein. Trastuzumab (Herceptin®) is an example of an anti-erbB2 antibody inhibitor of growth factor function. One example of an anti-erbB1 antibody inhibitor of growth factor function is cetuximab (Erbitux™, C225). Bevacizumab (Avastin®) is an example of a monoclonal antibody directed against VEGFR. Examples of small molecule inhibitors of epidermal growth factor receptors include but are not limited to lapatinib (Tykerb™) and erlotinib (TARCEVA®). Imatinib
(GLEEVEC®) is one example of a PDGFR inhibitor. Examples of VEGFR inhibitors include pazopanib, ZD6474, AZD2171 , PTK787, sunitinib and sorafenib.
In one embodiment, the invention provides methods of treatment of any of the various conditions enumerated above comprising administering a compound of the invention in combination with an EGFR or ErbB inhibitor. In one particular embodiment, the methods of the present invention comprise administering a compound of the invention in combination with lapatinib. In one particular embodiment, the methods of the present invention comprise administering a compound of the invention in combination with trastuzumab. In one particular embodiment, the methods of the present invention comprise administering a compound of the invention in combination with erlotinib. In one particular embodiment, the methods of the present invention comprise administering a compound of the invention in combination with gefitinib.
In another embodiment, the present invention provides methods of treatment of any of the various conditions enumerated above comprising administering a compound of the invention in combination with a VEGFR inhibitor. In one particular embodiment, the methods of the present invention comprise administering a compound of the invention in combination with pazopanib.
Tyrosine kinases that are not transmembrane growth factor receptor kinases are termed non-receptor, or intracellular tyrosine kinases. Inhibitors of nonreceptor tyrosine kinases are sometimes referred to as "anti-metastatic agents" and are useful in the present invention. Targets or potential targets of anti-metastatic agents, include, but are not limited to, c-Src, Lck, Fyn, Yes, Jak, Abl kinase (c-Abl and Bcr-AbI), FAK (focal adhesion kinase) and Bruton's tyrosine kinase (BTK). Non-receptor kinases and agents, which inhibit nonreceptor tyrosine kinase function, are described in Sinha, S. and Corey, S.J., (1999) J. Hematother. Stem Cell Res. 8:465-80; and Bolen, J.B. and Brugge, J.S., (1997) Annu. Rev. of Immunol. 15:371 -404.
SH2/SH3 domain blockers are agents that disrupt SH2 or SH3 domain binding in a variety of enzymes or adaptor proteins including, but not limited to, PI3-K p85 subunit, Src family kinases, adaptor molecules (She, Crk, Nek, Grb2) and Ras-GAP. Examples of Src inhibitors include, but are not limited to, dasatinib and BMS-354825 (J.Med.Chem (2004) 47:6658-6661 ). Inhibitors of serine/threonine kinases may also be used in combination with the compounds of the invention in any of the compositions and methods described above. Examples of serine/threonine kinase inhibitors that may also be used in combination with a compound of the present invention include, but are not limited to, polo-like kinase inhibitors (Plk family e.g., Plk1 , Plk2, and Plk3), which play critical roles in regulating processes in the cell cycle including the entry into and the exit from mitosis; MAP kinase cascade blockers, which include other Ras/Raf kinase inhibitors, mitogen or
extracellular regulated kinases (MEKs), and extracellular regulated kinases (ERKs); Aurora kinase inhibitors (including inhibitors of Aurora A and Aurora B); protein kinase C (PKC) family member blockers, including inhibitors of PKC subtypes (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta);
inhibitors of kappa-B (IkB) kinase family (IKK-alpha, IKK-beta); PKB/Akt kinase family inhibitors; and inhibitors of TGF-beta receptor kinases.
Examples of Plk inhibitors are described in PCT Publication No.
WO04/014899 and WO07/03036. Other examples of serine/threonine kinase inhibitors are known in the art. In another embodiment, the present invention provides methods of treatment of any of the various conditions enumerated above comprising administering a compound of the invention in combination with a Plk inhibitor. In one particular embodiment, the methods of the present invention comprise administering a compound of the invention in combination with 5-{6-[(4-Methylpiperazin-1 -yl)methyl]-1 H-benzimidazol-1 -yl}-3-{(1 R)-1 -[2- (trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide. Urokinase, also referred to as urokinase-type Plasminogen Activator (uPA), is a serine protease. Activation of the serine protease plasmin triggers a proteolysis cascade which is involved in thrombolysis or extracellular matrix degradation. Elevated expression of urokinase and several other components of the plasminogen activation system have been correlated with tumor malignancy including several aspects of cancer biology such as cell adhesion, migration and cellular mitotic pathways as well. Inhibitors of urokinase expression may be used in combination with the compounds of the invention in the compositions and methods described above. Inhibitors of Ras oncogene may also be useful in combination with the compounds of the present invention. Such inhibitors include, but are not limited to, inhibitors of farnesyltransferase, geranyl-geranyl transferase, and CAAX proteases as well as anti-sense oligonucleotides, ribozymes and immunotherapy. Such inhibitors have been shown to block Ras activation in cells containing mutant Ras, thereby acting as antiproliferative agents.
Inhibitors of kinases involved in the IGF-1 R signaling axis may also be useful in combination with the compounds of the present invention. Such inhibitors include but are not limited to inhibitors of JNK1/2/3, PI3K, AKT and MEK, and 14.3.3 signaling inhibitors. Examples of AKT inhibitors are described in PCT Publication No. WO 2007/058850, published 24 May 2007 which corresponds to PCT Application No. PCT/US2006/043513, filed 9 Nov 2006. One particular AKT inhibitor disclosed therein is 4-(2-(4-amino-1 ,2,5-oxadiazol-3- yl)-1 -ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1 H-imidazo[4,5-c]pyridin-4-yl)-2- methyl-3-butyn-2-ol .
Cell cycle signaling inhibitors, including inhibitors of cyclin dependent kinases (CDKs) are also useful in combination with the compounds of the invention in the compositions and methods described above. Examples of cyclin dependent kinases, including CDK2, CDK4, and CDK6 and inhibitors for the same are described in, for instance, Rosania G. R., et al., Exp. Opin. Ther. Patents (2000) 10:215-230. Receptor kinase angiogenesis inhibitors may also find use in the present invention. Inhibitors of angiogenesis related to VEGFR and TIE-2 are discussed above in regard to signal transduction inhibitors (both are receptor tyrosine kinases). Other inhibitors may be used in combination with the compounds of the invention. For example, anti-VEGF antibodies, which do not recognize VEGFR (the receptor tyrosine kinase), but bind to the ligand; small molecule inhibitors of integrin (alphav betas) that inhibit angiogenesis; endostatin and angiostatin (non-RTK) may also prove useful in combination with the compounds of the invention. One example of a VEGFR antibody is bevacizumab (AVASTIN®). Inhibitors of phosphatidyl inositol-3-OH kinase family members including blockers of PI3-kinase, ATM, DNA-PK, and Ku may also be useful in combination with the present invention.
Also of potential use in combination with the compounds of the invention are myo-inositol signaling inhibitors such as phospholipase C blockers and myoinositol analogues. siRNA, RNAi, locked nucleic acid polynucleotides, and antisense therapies may also be used in combination with the compounds of the invention.
Examples of such antisense therapies include those directed towards the targets described above such as ISIS 2503 and gene therapy approaches such as those using thymidine kinase or cytosine deaminase.Agents used in immunotherapeutic regimens may also be useful in combination with the compounds of the invention. Immunotherapeutic regimens include ex-vivo and in-vivo approaches to increasing immunogenicity of patient tumor cells such as transfection with cytokines (eg. IL-2, IL-4, GMCFS and MCFS), approaches to increase T-cell activity, approaches with transfected immune cells and approaches with anti-idiotypic antibodies. Another potentially useful immunotherapeutic regimen is monoclonal antibodies with wild-type Fc receptors that may illicit an immune response in the host (e.g., IGF-1 R monoclonal antibodies). Agents used in proapoptotic regimens (e.g., Bcl-2 antisense oligonucleotides) may also be used in combination with the compounds of the invention.
Members of the Bcl-2 family of proteins block apoptosis. Upregulation of Bcl- 2 has therefore been linked to chemoresistance. Studies have shown that the epidermal growth factor (EGF) stimulates anti-apoptotic members of the Bcl-2 family (i.e., mcl-1 ). Therefore, strategies designed to downregulate the expression of Bcl-2 in tumors have demonstrated clinical benefit and are now in Phase ll/lll trials, namely Genta's G3139 bcl-2 antisense oligonucleotide. Such proapoptotic strategies using the antisense oligonucleotide strategy for Bcl-2 are discussed in Water, J.S., et al., J. Clin. Oncol. (2000) 18:1812-1823; and Kitada, S., et al., Antisense Res. Dev. (1994) 4:71 -79.
Connpounds of the invention may be prepared using the processes described below. In all of the schemes described below, it is understood that protecting groups may be employed where necessary in accordance with general principles known to those of skill in the art, for example, see Green, T.W. and Wuts, P.G.M. (1991 ) Protecting Groups in Organic Synthesis, John Wiley & Sons. The selection of a particular protecting group and processes for installation and removal of protecting groups is within the skill of those in the art. The selection of processes for installation and removal of protecting groups as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of the invention. Compounds of the invention, may be conveniently prepared by the methods outlined in Scheme 1 below.
Scheme 1
wherein: R10 is halo (preferably chloro) or thiomethyl;
E is a suitable carboxylic ester or carboxylic ester equivalent,
particularly a methyl ester, ethyl ester, or Weinreb's amide; Ra is H or CH3;
alk is alkyl or alkenyl; and
all other variables are as defined above.
In this and subsequent reaction Schemes, NBS is N- bromosuccinimide. The process for preparing the compounds of the invention according to Scheme 1 (all formulas and all variables having been defined above) comprises the steps of:
a) reacting a compound of formula (II) with a compound of formula (VII) to prepare a compound of formula (X);
b) condensing the compound of formula (X) with a substituted pyrimidine of formula (III) to prepare a compound of formula (XI);
c) reacting the compound of formula (XI) with a suitable brominating
agent, followed by reacting with one of:
i) a thiourea,
ii) a formamide,
iii) an amide,
iv) a thioamide, or
v) a urea;
to prepare a compound of formula (VIII);
d) reacting the compound of formula (VIII) with one of:
i) molecular hydrogen
ii) an alkyl metal reagent or alkenyl metal reagent
iii) an alcohol, or
iv) a compound of formula (IX): N(Ra)-R14, wherein Ra is H or CH3, to prepare a compound of formula (I);
e) optionally converting the compound of formula (I) to a pharmaceutically acceptable salt thereof; and f) optionally converting the compound of formula (I) or a pharmaceutically acceptable salt thereof to a different compound of formula (I) or a pharmaceutically acceptable salt thereof. The order of the foregoing steps is not critical to the processes of the present invention and the process may be carried out using any suitable order of steps.
Compounds of formula (I) wherein R4 is alkyl, haloalkyl, alkenyl, -R11-OR12, R11-CO2R12, -R1 1-SO2R12, -R1 1-Het1 or -R11-NR12R13, may be prepared by reacting a compound of formula (VIII) with an alkyl or alkenyl metal reagent such as compounds having the formula AlknMXm or XmMR11-CO2R12
wherein Alk is alkyl or alkenyl;
n is 1 , 2, 3 or 4;
M is a transition metal such as Zn, B or Sn;
X is halo, particularly CI or Br;
m is 0, 1 or 2; and
all other variables are as defined above.
wherein
R4a is alkyl, haloalkyl, alkenyl, -R11-OR12, or R11-CO2R12 ; and
all other variables are as defined above.
Specific examples of suitable alkyl or alkenyl metal reagents include but not limited to dialkylzinc, alkylzinc halides, alkylboranes, alkenylboranes, alkenylborates and alkenylstannanes, either found commercially or which can be prepared by those of ordinary skill in the art by conventional means. In particular, the reaction is performed in the presence of a palladium source, optionally a phosphine ligand and optionally a base in a suitable inert solvent. Examples of suitable palladium sources include but are not limited to bis(tri-t- butylphosphine)palladium (0), tris(dibenzylideneacetone)dipalladium (0), dichlorobis(triphenylphosphine)-palladium (II) or acetato(2'-di-f- butylphosphino-1 ,1 '-biphenyl-2-yl)palladium (II). Examples of suitable phosphine ligands include but are not limited to 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene and triphenylphosphine. Examples of suitable bases include but are not limited to potassium acetate, cesium carbonate, sodium methoxide, and triethylamine. Examples of suitable inert solvents include but are not limited to THF, toluene, Λ/,/V-dimethylformamide or 1 ,4-dioxane, or isopropanol in the case of alkenylborates. The reaction may be carried out at a temperature of about 25 °C to 100°C. A compound of formula (I2) wherein R4 is alkenyl, may be converted to a compound of formula (I) wherein R4 is -R11-SO2R12, -R1 1-Het1 or -R11- NR12R13 by reaction with an appropriate nucleophile. For example a compound of formula (I) wherein R4 is -R11-SO2R12, or -R11 NR12R13 may be prepared by reacting a compound of formula (I2) wherein R4 is alkenyl with a thiol or amine, respectively. Reaction conditions for such transformations are known to those skilled in the art.
Compounds of formula (I) wherein R4 is -OR12, are prepared by reacting a compound of formula (VIII) with a suitable alcohol.
VIII I3
wherein all variables are as defined above. Specific examples of suitable alcohols include but not limited to methanol, ethanol, n-propanol or n-butanol. The reaction may optionally be carried out in the presence of a base such as, but not limited to cesium carbonate, sodium methoxide, and triethylamine.
The reaction is typically carried out at a temperature of about 50-120 °C, at atmospheric or elevated pressure and optionally in a microwave.
Compounds of formula (I) wherein R4 is N(H)R14 (i.e., compounds of formula (I4)) are prepared by reacting a compound of formula (VIII) with a compound of formula (IX).
wherein Ra is H or CH3 and all other variables are as defined above.
Those skilled in the art will recognize that the conditions required for the above reaction will differ depending upon the definition of R10. When R10 is halo (preferably chloro), the reaction is generally performed in a solvent or neat. Suitable solvents include but are not limited to isopropanol, methanol, 1 ,4-dioxane, ethanol, dimethylacetamide, triflouroethanol, and N,N- dimethylformamide. The reaction is typically carried out at a temperature of from about 30 to about 120°C, or optionally in a microwave apparatus. In the embodiment where R4 is NH2, the reaction is carried out with a source of ammonia, for example, ammonia in methanol or preferably ammonium hydroxide. The reaction is typically carried out without the addition of other solvents and at temperatures of about 60 °C to about 120 °C, in a sealed reaction vessel or optionally in a microwave apparatus. As will be apparent to those skilled in the art of organic chemistry, it may also be desirable to install appropriate protecting groups prior to reacting the compound of formula (VIII) with the compound of formula (IX). For example, in the embodiment, wherein R4 is a group containing a pendant primary or secondary amine, the addition is preferably carried out when the pendant amine is protected as, for example, its corresponding t-butyl carbamate or trifluoracetamide. The choice, installation and removal of appropriate protecting groups for reactions such as this is conventional in the art. Compounds of formula (IX) are commercially available or may be synthesized using techniques conventional in the art.
When R10 is thiomethyl, the thiomethyl may first be converted to a more suitable leaving group, for example sulfoxide, sulfone, or chloride. The thiomethyl can be converted into a sulfoxide or sulfone by oxidation with an appropriate oxidizing agent, for example oxone, sodium periodate, or meta- chloroperbenzoic acid, in an appropriate solvent, for example
dichloromethane, methanol, or water. Those skilled in the art will recognize that this will produce an analogue of the compound of formula (VIII) in which R10 is a sulfoxide or sulfone. The oxidized product can then be reacted with the compound of formula (IX) to prepare a compound of formula (I).
These reactions are generally performed in a suitable solvent, for example 2- propanol, dimethylacetamide, or dioxane, optionally with the addition of acid, for example hydrochloric acid, and at a temperature of 25-1 10°C, preferably 70-90°C, or in a microwave reactor at a temperature of 90-220°C, preferably 160-190°C. Alternately, the pyrimidinyl sulfoxide or sulfone can be converted to the corresponding hydroxyl pyrimidine by reaction with an appropriate aqueous acid, for example hydrochloric acid or acetic acid, at a temperature of 25- 1 10°C, preferably 70-90°C. The hydroxyl pyrimidine can then be converted to a chloride using an appropriate chlorinating reagent, for example
phosphorous oxychloride or thionyl chloride, optionally in a solvent, for example dichloromethane, at a temperature of 25-120°C, preferably 60-80°C. Those skilled in the art will recognize that this process will produce a compound of formula (VIII) wherein R10 is chloro, which can be reacted with a compound of formula (IX) as described above. Compounds of formula (VIII) may be prepared by reacting a compound of formula (XI) with a suitable brominating reagent, particularly bromine or NBS, followed by reacting with one of: 1 ) a thiourea, 2) a formamide 3) an amide 4) a thioamide or 5) a urea depending upon whether the thiazole or oxazole and
wherein all variables are as defined above.
In this and subsequent Schemes, reference to thiourea, formamide, amide, thioamide or urea in connection with this type of reaction refers to
unsubstituted thiourea, formamide, amide, thioamide or urea and substituted analogs thereof. In particular, the thiourea, formamide, amide, thioamide or urea may be substituted with the desired group R3. Suitably substituted analogs of thiourea, formamide, amide, thioamide or urea are commercially available or may be prepared using conventional techniques.
When an aminothiazole (i.e., the compound of formula (VIII) wherein W is S and R3 is -NR12R13 or Het1 is desired, the reaction can be accomplished by the initial bromination of a compound of formula (XI) using an appropriate brominating reagent, for example bromine in solvent such as acetic acid or
The reaction is typically carried out in an appropriate solvent, for example dichloromethane, Ν,Ν-dimethylformamide, or Ν,Ν-dimethylacetamide, and at a temperature of 25-50°C, particularly 25°C. The brominated analog (i.e., a compound of formula (Xl-A)) is then reacted with an appropriately substituted thiourea.
Vlll-A
wherein W is S, R3a is -NR12R13 or Het1 and all other variables are as defined above. The reaction is typically carried out in an appropriate solvent, for example, N,N-dimethylformamide, Ν,Ν-dimethylacetamide, dichloromethane, tetrahydrofuran, dioxane, or acetonitrile, optionally in the presence of a suitable base, for example magnesium carbonate or sodium bicarbonate, and at a temperature of 25-90°C, particularly 25-50°C. Those skilled in the art will recognize that the thiourea can be unsubstituted, thus resulting in a
compound of formula (VIII) wherein R3 is NH2; or the thiourea may bear one or more additional substituents on one of the nitrogen atoms.
In this and subsequent reactions, a compound, such as a compound of formula (VIII), wherein R3 is an amino group (i.e., -NR12R13), may be further converted to a corresponding compound wherein R3 is other than amino (or substituted amino) using the techniques described herein and those conventional in the art.
For example, the aminothiazole compound of formula (Vlll-A) wherein R3 is an amino group, may be converted to an unsubstituted thiazole (i.e., a compound of formula (VIII) wherein R3 is H) using methods familiar to those of skill in the art. For example, the thiazole may be prepared by reacting the aminothiazole with an appropriate reagent, for example i-butyl nitrite, in an appropriate solvent, for example tetrahydrofuran, and at a temperature of 35-75°C, particularly 40-60°C.
When a substituted thiazole is desired, an aminothiazole of formula (VIII) may be modified according to methods that will be familiar to those skilled in the art. For example, the aminothiazole compound of formula (Vlll-A) may be converted to a compound of formula (Vlll-B) by reaction with reagents capable of replacing the amino group with a halide, preferably a bromide.
wherein Hal is halo, preferably Br; and all other variables are as defined above.
The conversion to a halo-thiazole of formula (Vlll-B) may be carried out by reaction with for example, i-butyl nitrite and copper (II) bromide in a suitable solvent, such as tetrahydrofuran or acetonitrile, and at a temperature from - 10°C to 50°C, preferably 0°C to 25°C. The halo-thiazole of formula (Vlll-B), may then be reacted under a variety of conditions known to those in the art to produce different thiazole compounds of formula (Vlll-C) wherein R3 can be a variety of substituents consistent with the definition of R3 in reference to compounds of Formula (I).
One example of such a reaction is similar to the method of J. Tsuji "Palladium Reagents and Catalysts: Innovations in Organic Synthesis", Wiley,
Chichester, UK, 1995, involving reaction of the halo-thiazole of formula (VIII- B) with a reagent capable of undergoing palladium-based coupling to prepare compounds of formula (Vlll-C) wherein R3c is alkyl, haloalkyl, or alkenyl.
Vlll-B R Vlll-C R wherein Hal is halogen;
R3c is alkyl, haloalkyl or alkyl-OH; and
all other variables are as defined above.
For example the halo-thiazole of formula (Vlll-B) may be reacted with a boronic acid, boronate ester, alkyl tin, alkyl zinc or Grignard reagent, in an appropriate solvent, for example tetrahydrofuran, dioxane, or
dimethylformamide, in the presence of a catalyst capable of inducing such a transformation, particularly a palladium catalyst, for example
palladiumdicholorobistriphenylphosphine, and at a temperature of 25-150°C, preferably 25-60°C. Those skilled in the art will recognize that these coupling reactions will often require the addition of a suitable base, such as aqueous sodium carbonate, cesium carbonate, or triethylamine and/or the addition of a suitable ligand for the palladium species, for example a trialkylphosphine or a triarylphosphine, for example triphenylphosphine.
Another example of such a reaction involves the reaction of the halo-thiazole of formula (V-B) with a reagent capable of displacing the bromide, for example an amine, such as piperidine, methylamine, or methyl piperazine.
wherein Hal is halogen;
R3d is -NR12R13; and
all other variables are as defined above. In the case of reacting a halo-thiazole of formula (Vlll-B) with an amine or substituted amine (e.g., dimethylamine) the reaction is generally performed by reacting the compound of formula (V-B) with the amine or substituted amine optionally in a suitable solvent, such as 2-propanol, dioxane, or
dimethylformamide, at a temperature of 25°C to 150°C, preferably 50-90°C, optionally in the presence of a suitable acid, for example hydrochloric acid.
According to another process of producing a substituted thiazole of formula (VIII), a compound of formula (Xl-A) is reacted with a thioamide, for example thio lkyl.
wherein all variables are as defined above.
Alkyl substituted thioamides for use in this process are commercially available or may be prepared using conventional techniques. Typically, the reaction is carried out in an appropriate solvent, for example, dichloromethane, tetrahydrofuran, dimethylformamide, Ν,Ν-dimethylacetamide, or acetonitrile, particularly dimethylformamide or Ν,Ν-dimethylacetamide, optionally in the presence of a suitable base, for example magnesium carbonate or sodium bicarbonate, and at a temperature of 35-100°C, preferably 50-80°C.
In the embodiment wherein an oxazole of formula (VIII) is desired wherein R3 is H, the reaction can be accomplished by reacting the compound of formula (Xl-A) with formamide in the presence of an acid, such as sulfuric acid, and at a temperature of 60-150°C, preferably 90-130°C.
wherein all variables are as defined above.
A substituted oxazole of formula (Vlll-F) may be prepared from the compound of form -A).
wherein R3e is Het1 or -NR12R13 and all other variables are as defined above. The reaction may be carried out by reacting the compound of formula (Xl-A) with urea or substituted urea in an appropriate solvent, for example, N,N- dimethylformamide, Λ/,/V-dimethylacetamide dichloromethane,
tetrahydrofuran, dioxane, or acetonitrile, optionally in the presence of a suitable base, for example magnesium carbonate or sodium bicarbonate, and at a temperature of 25-170°C, particularly 60-150°C or in a microwave reactor at a temperature of 100-190°C, particularly 120-160°C. Those skilled in the art will envision substituted ureas that may be employed in the foregoing method to prepare compounds of formula (Vlll-F) wherein R3e is as defined above. One example of a substituted urea for use in this method is 1 - pyrrolidinecarboxamide. Suitable substituted ureas are commercially available or can be made using techniques known to those skilled in the art.
A substituted oxazole of formula (Vlll-G), may also be prepared from a compound of formula (Xl-A).
wherein R is alkyl or haloalkyl and all other variables are as defined above. Typically, the reaction may be carried out by reacting the compound of formula (Xl-A) with an amide (i.e., a compound of formula R3f-C(O)NH2), for example acetamide, in an appropriate solvent, for example, dichloromethane, tetrahydrofuran, dimethylformamide, or acetonitrile, particularly
dimethylformamide or neat, optionally in the presence of a suitable base, for example magnesium carbonate or sodium bicarbonate, and at a temperature of 35-170°C, preferably 60-150°C or in a microwave reactor at a temperature of 100-190°C, particularly 130-170°C. Suitable amides for use in this reaction will be apparent to those skilled in the art and are commercially available or may be prepared using conventional techniques.
As will be appreciated by those skilled in the art a bromo-substituted oxazole of formula (Vlll-H),
wherein all other variables are as defined above;
may also be prepared by conversion of an oxazole of formula (Vlll-F) (wherein R3 is an amine or substituted amino group) to the bromo analog using techniques known to those of skill in the art, including those described above.
Those of skill in the art will recognize that some of the reactions described above may be incompatible with compounds of formula (VIII) in which R10 is chloride. In such embodiments, the foregoing reactions may be performed using compounds of formula (XI) wherein R10 is thiomethyl, and subsequently converting the thiomethyl to a more suitable leaving group, such as a sulfoxide, sulfone or chloride using techniques conventional in the art, including those described above.
Compounds of formula (XI) may be prepared by reacting a compound of formula (X) with a substituted pyrimidine of formula (III).
wherein all variables are as defined above.
The reaction is generally performed by reacting a compound of formula (X) and a compound of formula (III) in the presence of a suitable base capable of deprotonating a compound of formula (III), for example lithium
hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide, or lithium diisopropylamide, particularly LiHMDS, in an appropriate solvent, such as THF, and at a temperature of about -78°C to about 25°C, particularly about 0°C to about 25°C. A compound of formula (X) may be prepared by reacting the compound of formula (II) with a compound of formula (VII).
This reaction may be carried out using conditions conventional in the art for such coupling reactions, including the use of a solvent such as
tetrahydrofuran, 1 ,4-dioxane or dichloromethane at room temperature or with heating from about 40°C to about 100°C. Those skilled in the art will recognize that it may be desirable to carry out this reaction in the presence of a suitable base, for example pyridine or triethylamine. Compounds of formula (VII) are commercially available or may be synthesized using techniques conventional in the art.
Compounds of formula (II) wherein R5 and R6 are H are commercially available. Compounds of formula (II) wherein one of R5 and R6 are halogen may be prepared by reduction of the compound of formula (XIII). Appropriate conditions for the reduction reaction will be apparent to those skilled in the art and include palladium on carbon under a hydrogen atmosphere, sulfided platinum on carbon under a hydrogen atmosphere, or iron powder in acetic acid. In one embodiment, the reduction may be effected using Raney nickel under a hydrogen atmosphere. The reaction may be carried out in an inert solvent at either atmospheric or elevated pressure. Suitable inert solvents include but are not limited to ethanol, methanol, and ethyl acetate.
Compounds of formula (XIII) may be prepared by oxidation of the compound of formula (XX) using an appropriate oxidizing agent such as but not limited to chromium trioxide or potassium permanganate to yield compounds of formula (XXI). In one embodiment, the reaction is performed with chromium trioxide under strongly acidic conditions such as in the presence of sulfuric acid. The reaction may be carried out at a temperature of about 80 °C to 100°C.
Compounds of formula (XXI) can be then converted to compounds of formula (XIII) by esterification of the acid functionality using conditions standard for such transformations, specifically in methanol in the presence of catalytic sulfuric acid.
wherein all variables are as defined above.
Alternatively, compounds of formula (II) wherein one of R5 and R6 are halogen may be prepared by reaction of the compound of formula (XV) with a nitrogen source such as benzophenone imine or t-butyl carbamate using conditions conventional in the art for Buchwald cross-coupling reactions. In particular, in the presence of a palladium source, optionally a phosphine ligand, and a base in a suitable inert solvent. Examples of suitable palladium sources include but are not limited to tris(dibenzylideneacetone)dipalladium (0),
dichlorobis(triphenylphosphine)-palladium (II) or acetato(2'-di-/1- butylphosphino-1 ,1 '-biphenyl-2-yl)palladium (II). Examples of suitable phosphine ligands include but are not limited to 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene and triphenylphosphine. Examples of suitable bases include but are not limited to potassium acetate, cesium carbonate, sodium methoxide, and triethylamine. Examples of suitable inert solvents include but are not limited to toluene, N,N-dimethylformamide or 1 ,4- dioxane. The reaction may be carried out at a temperature of about 80 °C to 15 °C, optionally in the microwave.
wherein X is halo, particularly Br;
P is protected nitrogen, particularly benzophenone imine or t-butyl carbamate; and all other variables are as defined above. Conversion of compounds of formula (XVI) to compounds of formula (II) can be achieved by reaction with a strong acid in a suitable organic solvent using conventional acidic deprotection techniques. Suitable acids used in such transformations include but are not limited to hydrochloric acid. Suitable solvents for such transformations include but are not limited to tetrahydrofuran and 1 ,4-dioxane. See, Kocienski, P.J. Protecting Groups, Georg Thieme Verlag, Stuttgart, 1994; and Greene, T.W., Wuts, P. G. M. Protecting Groups in Organic Synthesis (2nd Edition), J. Wiley and Sons, 1991 .
As noted above, the order of the foregoing steps is not critical to the practice of the present invention. In another embodiment, compounds of the invention may also be prepared according to Scheme 2, which demonstrates an alternative order of the steps of Scheme 1 .
Scheme 2
wherein: R10 is halo (preferably chloro) or thiomethyl;
E is a suitable carboxylic ester or ester equivalent, particularly a methyl ester, ethyl ester, or Weinreb's amide;
Alloc is allylchlorofornnate;
BusSnH is tri-n-butyl tin hydride; and
all other variables are as defined above.
The process according to Scheme 2 comprises the steps of:
a) installing a protecting group such as allylchlorofornnate, on a compound of formula (II) to prepare a compound of formula (ll-A);
b) condensing the compound of formula (ll-A) with a substituted pyrimidine compound of formula (III) to prepare a compound of formula (IV);
c) reacting the compound of formula (IV) with a suitable brominating agent followed by one of:
i) a thiourea,
ii) a formamide,
iii) an amide,
iv) a thioamide, or
v) a urea;
to prepare a compound of formula (V);
d) reacting the compound of formula (V) in the presence of a Palladium
catalyst to prepare a compound of formula VI;
e) reacting a compound of formula (VI) with a compound of formula (VII) to prepare a compound of formula (VIII);
f) reacting the compound of formula (VIII) with one of:
i) molecular hydrogen
ii) an alkyl metal reagent or alkenyl metal reagent
iii) an alcohol, or
iv) a compound of formula (IX),
to prepare a compound of formula (I);
g) optionally converting the compound of formula (I) to a pharmaceutically acceptable salt thereof; and h) optionally converting the compound of formula (I) or a pharmaceutically acceptable salt thereof to a different compound of formula (I) or a pharmaceutically acceptable salt thereof. The installation and removal of the Alloc protecting group may be achieved using conventional means. For example, the compound of formula (II) may be reacted with allylchloroformate using conventional acylation conditions to those skilled in the art for the installation of carbamate protecting groups. Removal of the protecting group may be achieved by reacting the compound of formula (V) with tributyltin hydride in the presence of a Pd catalyst and weak acid. In one embodiment dichlorobis(triphenylphosphine)-palladium (II) was used along with acetic acid. A variety of solvents may be used including but not limited to dichloromethane, toluene, diethyl ether, acetone and N,N- dimethylformamide. See, Kocienski, P.J. Protecting Groups, Georg Thieme Verlag, Stuttgart, 1994; and Greene, T.W., Wuts, P. G. M. Protecting Groups in Organic Synthesis (2nd Edition), J. Wiley and Sons, 1991 .
The remaining steps of the reaction may be carried out generally in the manner described above for the analogous steps in Scheme 1 .
As a further example of changing the order of the steps, compounds of the invention may also be prepared according to Scheme 3.
Scheme 3
wherein R10 is halo (preferably chloro) or thiomethyl, and all other variables are as defined above.
Generally, the process for preparing the compounds of the invention according to Scheme 3 (all formulas and all variables having been defined above) comprises the steps of:
a) reacting the compound of formula (V) with one of:
i) molecular hydrogen
ii) an alkyl or alkenyl metal reagent
iii) an alcohol, or
iv) a compound of formula (IX),
to prepare a compound of formula (XVIII);
b) reacting the compound of formula (XVII) in the presence of a Palladium catalyst to prepare a compound of formula (XVIII);
c) reacting the compound of formula (XVIII) with a compound of formula (VII) to prepare a compound of formula (I);
d) optionally converting the compound of formula (I) to a pharmaceutically acceptable salt thereof; and
e) optionally converting the compound of formula (I) or a pharmaceutically acceptable salt thereof to a different compound of formula (I) or a pharmaceutically acceptable salt thereof.
Each of the foregoing steps may be carried out using the techniques described above for analogous reactions with different starting materials.
It will be appreciated by those skilled in the art that the optimal choice of the reaction sequence employed to prepare a particular compound of the invention may depend upon the specific compound of the invention that is desired as well as the preference and availability of starting materials.
As will be apparent to those skilled in the art, a compound of formula (I) may be converted to another compound of formula (I) using techniques well known in the art. For example, compounds of formula (I) may be modified using conventional techniques to modify or diversify the groups defined by the variable R3 and thereby provide different compounds of formula (I). Based upon this disclosure and the examples contained herein one skilled in the art can readily convert a compound of formula (I) or a pharmaceutically acceptable salt thereof into a different compound of formula (I), or a pharmaceutically acceptable salt thereof. The present invention also provides radiolabeled compounds of formula (I) and biotinylated compounds of formula (I) and solid-support-bound versions thereof, i.e. a compound of formula (I) having a radiolabel or biotin bound thereto. Radiolabeled compounds of formula (I) and biotinylated compounds of formula (I) can be prepared using conventional techniques. For example, radiolabeled compounds of formula (I) can be prepared by reacting the compound of formula (I) with tritium gas in the presence of an appropriate catalyst to produce radiolabeled compounds of formula (I). In one
embodiment, the compounds of formula (I) are tritiated. The radiolabeled compounds of formula (I) and biotinylated compounds of formula (I) are useful in assays for the identification of compounds which inhibit at least one Raf family kinase, for the identification of compounds for the treatment of a condition capable of being treated with a Raf inhibitor, e.g., for the treatment of neoplasms susceptible to treatment with a Raf inhibitor. The present invention also provides an assay method for identifying such compounds, which method comprises the step of specifically binding a radiolabeled compound of the invention or a biotinylated compound of the invention to the target protein or cellular homogenate. More specifically, suitable assay methods will include competition binding assays. The radiolabeled compounds of the invention and biotinylated compounds of the invention and solid-support-bound versions thereof, can also be employed in assays according to the methods conventional in the art. The following examples are intended for illustration only and are not intended to limit the scope of the invention in any way. The invention is defined by the claims which follow.
EXAMPLES
As used herein, the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Standard single-letter or three-letter abbreviations are generally used to designate amino acid residues, which are assumed to be in the L-configuration unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification: atm (atmosphere); 35 Tr (retention time);
g (grams); RP (reverse phase;
mg (milligrams); H2 (hydrogen);
h (hour(s)); N2 (nitrogen)
min (minutes); Ac (acetyl);
Hz (Hertz); 40 ACN (acetonitrile);
MHz (megahertz); Ac2O (acetic anhydride);
i. v. (intravenous); ATP (adenosine triphosphate);
L (liters); BOC (tert-butyloxycarbonyl);
ml_ (milliliters); BSA (bovine serum albumin) μΙ_ (microliters); 45 CHCIs (chloroform);
M (molar); CH3CN (acetonitrile);
mM (millimolar); mCPBA (meta-chloroperbenzoic mol (moles); acid);
mmol (millimoles); DCC (dicyclohexylcarbodiimide); mp (melting point); 50 DCE (dichloroethane);
psi (pounds per square inch); DCM (CH2CI2; dichloromethane); rt (room temperature); DIEA (Λ/,/V-Diisopropylethylamine);
TLC (thin layer chromatography); DMA ( dimethyl acetamide); LCMS (liquid chromatography- DMAP (4-dimethylaminopyridine); mass spectrometry);
DME (1 ,2-dimethoxyethane); LDA (lithium diisopropylamide); DMEM (Dulbecco's modified □HMDS (lithium
Eagle medium); hexamethyldisilazide); DMF (A/,dimethylformamide); LiOH (lithium hydroxide);
DMSO (dimethylsulfoxide); LiOH H2O (lithium hydroxide DPPA (diphenylphosphoryl azide); monohydrate);
EDC (ethylcarbodiimide m-CPBA (meta- hydrochloride); Chloroperoxybenzoic acid);
EDTA (ethylenediaminetetraacetic Me (methyl; -CH3)
acid); MeOH (methanol);
Et (ethyl; -CH2CH3) MgCO3 (magnesium carbonate); EtOH (ethanol); MgSO4 (magnesium sulfate); EtOAc (ethyl acetate); NaCI (sodium chloride);
FMOC (9- Na2CO3 (sodium carbonate);
fluorenylmethoxycarbonyl); NaHCO3 (sodium bicarbonate); HATU (0-(7-Azabenzotriazol-1 -yl- NaH (sodium hydride);
Ν,Ν,Ν',Ν'- NaNO2 (sodium nitrite);
tetramethyluronium NaOH (sodium hydroxide);
hexafluorophosphate); Na2SO4 (sodium sulfate);
HCI (hydrochloric acid) NaHSO4 (sodium bisulfate);
HEPES (4-(2-hydroxyethyl)-1 - NBS (/V-bromosuccinamide);
piperazine NH4CI (ammonium, chloride); ethane sulfonic acid); NH4OH (ammonium hydroxide); Hex (hexanes); Pd(PPh3)2CI2
HOAc (acetic acid); (bis(triphenylphosphine)- HPLC (high pressure liquid palladium (II) chloride); chromatography); PdCI2(dppf)
H2SO4 (sulphuric acid); (dichloro[ ,1 'bis(diphenyl- i-PrOH (isopropanol); phosphino)ferrocene]palladium (II) IPA ((isopropanol); dichloromethane adduct);
K2CO3 (potassium carbonate);
KOH (potassuim hydroxide); Pd(PPh3)4
(tetrakis(triphenylphosphine) palladium(O));
PE (pertroleum ether)
POCI3 (phosporyl chloride);
S1O2 (silica gel);
TBAB (tetra butyl ammonium bromide);
TBAF ( tetrabutylammonium fluoride);
TEA (triethylamine);
tetra kis
(tetrakis(triphenylphosphine) palladium(O));
TFA (trifluoroacetic acid);
THF (tetrahydrofuran);
TIPS (triisopropylsilyl);
TMS (trimethylsilyl); and
TMSE (2-(trimethylsilyl)ethyl); and TsOH (p-Toluenesulfonic acid).
All references to ether are to diethyl ether; brine refers to a saturated aqueous solution of NaCI. Unless otherwise indicated, all temperatures are expressed in °C (degrees Centigrade). All reactions are conducted under an inert atmosphere at rt unless otherwise noted.
1 H-NMR spectra were recorded on a Varian VXR-300, a Varian Unity-300, a Varian Unity-400 instrument, a General Electric QE-300, a Bruker 300, or a Bruker 400 . Chemical shifts are expressed in parts per million (ppm, units). Coupling constants are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad).
Low-resolution mass spectra (MS) were recorded on a JOEL JMS-AX505HA, Agilent LC/MSD SL, JOEL SX-102, a SCIEX-APIiii, a Finnegan MSQ, Waters SQD, Waters ZQ, or a Finnegan LCQ spectrometer; high resolution MS were obtained using a JOEL SX-102A spectrometer. All mass spectra were taken under electrospray ionization (ESI), chemical ionization (CI), electron impact (El) or by fast atom bombardment (FAB) methods. Infrared (IR) spectra were obtained on a Nicolet 510 FT-IR spectrometer using a 1 -mm NaCI cell. All reactions were monitored by thin-layer chromatography on 0.25 mm E. Merck silica gel plates (60F-254), visualized with UV light, 5% ethanolic
phosphomolybdic acid or p-anisaldehyde solution or mass spectrometry (electrospray or AP). Flash column chromatography was performed on silica gel (230-400 mesh, Merck) or using automated silica gel chromatography (Isco, Inc. Sq 16x or 100sg Combiflash) or (Analogix, Intelliflash). Reported HPLC retention times (RT) were obtained on a Waters 2795 instrument attached to a Waters 996 diode array detector reading 210-500 nm or using Anilgent 120 series HPLC. The column used was a Synergi Max-RP (50 x 2 mm) model #00B-4337-B0. Solvent gradient was 15% MeOH:water to 100% MeOH (0.1 % formic acid) over 6 min. Flow rate was 0.8 mL/min. Injection volume was 3 μί.
Descriptions of intermediates and methods of making intermediates are provided below. For each intermediate, a sample was prepared generally in accordance with the descriptions below. Characterization of the resulting intermediate is provided where indicated.
Intermediate 1 : Methyl 3-amino-2-fluorobenzoate
Step 1 : Methyl 3-bromo-2-fluorobenzoate
To a 100 mL round bottom flask was added 3-bromo-2-fluorobenzoic acid (10.4 g, 47.5 mmol), MeOH (100 mL, 2472 mmol) and sulfuric acid (6 mL, 1 13 mmol). The reaction mixture was refluxed for 1 hr. After cooling to rt, the MeOH was removed under reduced pressure and the acidic residue was poured into cold water and EtOAc, the layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were combined, washed with brine, dried over NaSO and concentrated under reduced pressure to afford methyl 3-bromo-2-fluorobenzoate. 10.02 g. 1H-NMR (400 MHz, DMSO-de) δ 7.95 (ddd, J = 8.1 , 6.4, and 1 .7 Hz, 1 H), 7.82 - 7.87 (m, 1 H), 7.26 (t, J =7.9 Hz, 1 H), and 3.86 (s, 3 H).
Step 2: Methyl 3-amino-2-fluorobenzoate
In a 500 mL flask was placed 1 ,1 -dimethylethyl carbamate (6.03 g, 51 .5 mmol), methyl 3-bromo-2-fluorobenzoate (10 g, 42.9 mmol), Pd2(dba)3 »CHCI
(0.89 g, 0.86 mmol), xantphos (1 .49 g, 2.57 mmol) and cesium carbonate (16.8 g, 51 .5 mmol). The flask was sealed with a rubber septum, placed under high vacuum, and toluene (200 mL) was added. Three cycles of high vacuum/N2 were performed and the reaction mixture was stirred at 90°C overnight. The reaction was filtered through a pad of celite with EtOAc washing and concentrated. To the residue was added DCM (200 ml_) followed by TFA (50 ml_, 649 mmol), and the mixture was stirred at rt for 1 h. The volatiles were removed under reduced pressure and the residue was taken up in EtOAc and washed with saturated NaHCO3 and brine. The organic layer was dried over NaSO4, loaded onto silica and column
chromatographed on silica with 5% to 50% EtOAc:hexane to give the title compound. 5.53 g (76% yield). 1 H-NMR (400 MHz, DMSO-d6) δ 6.92 - 7.01 (m, 3 H), 5.37 (s, 2 H), and 3.81 (s, 3 H). MS (ESI): 170 [M+H]+.
Alternative method of preparing methyl 3-amino-2-fluorobenzoate
(intermediate 1 , above)
Step 1 : 2-fluoro-3-nitrobenzoic acid
Concentrated sulfuric acid (195 ml_) was added carefully with stirring to a solution of 2-fluoro-3-nitrotoluene (100 g, 645 mmol) in acetic acid (1000 ml_). The mixture was warmed up to 95 °C and a solution of chromium trioxide (226 g, 2.25 mol) in water (200 ml) was added dropwise with stirring over 2h. After addition the mixture was heated with stirring for another 3h, allowed to cool down to room temperature and poured into water (3 L). The mixture was extracted with ethyl acetate (3 x 1 L), the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford a light green solid, which was washed with dichloromethane (3 x 300 ml_) and dried under vacuum to afford the title compound as a light yellow solid in the amount of 75 g (62.8% yield). 1 H NMR(300MHz, DMSO) δ ppm 8.27 (m, 1 H), 8.15 (m, 1 H), 7.48 (m, 1 H).
Step 2: methyl 2-fluoro-3-nitrobenzoate
2-Fluoro-3-nitrobenzoic acid (75 g) was dissolved in 300 mL of methanol, and then 20 mL of concentrated H2SO was added. The mixture was stirred at 70 °C overnight and cooled to room temperature. The resulting solid was filtered and washed with water (3 x 200 mL), to the filtered was added water (400 mL), the resulting precipitate was filtered and washed with water (2 x 100 mL) to afford another batch of product. The solids were combined and dried under vacuum to afford the title compound as a light yellow solid in the amount of 78 g (96% yield).
Step 3: methyl 3-amino-2-fluorobenzoate
To a solution of methyl 2-fluoro-3-nitrobenzoate (78 g) in THF (400 mL) and methanol (100 mL) was added Raney Ni (40 g), the mixture was heated to 70 °C, and then 25 mL of hydrazine hydrate (Ν2Η Ή2Ο, 85%) was added dropwise. The reaction was monitored by TLC, when the starting material was totally consumed the addition of hydrazine was stopped. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum to leave a brown oil, which was purified by chromatography (SiO2, 300-400 mesh, PE: EtOAc=1 1 :2) to afford the title compound as a yellow oil. 45 g (68% yield). 1H NMR (300MHz, DMSO) δ ppm 6.96 (m, 3H), 5.36 (s, 2H), 3.81 (s, 3H).
Intermediate 2: 2-Propen-1 -yl {3-[(2-chloro-4-pyrimidinyl)acetvH-2- fluorophenyl!carbamate
Methyl 3-(allyloxycarbonylamino)-2-fluorobenzoate
To a solution of methyl 3-amino-2-fluorobenzoate (200.0 g, 1 183 mmol, 1 eq) in THF (500 mL), saturated NaHCO3 (1600 mL) was added. Then 2-propen- 1 -yl chloridocarbonate (170.0 g, 1420 mmol, 1 .2 eq) was added dropwise at 0 °C. The mixture was stirred at rt for 2 h. The solution was extracted with EtOAc (1 L x 3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product (used in the next step). 260 g (86.9% yield). 1H NMR (400 MHz, DMSO-c/6) δ ppm 9.66 (s, 1 H), 7.96 (t, J = 7.6 Hz, 1 H), 7.64 (t, J = 6.4 Hz, 1 H),7.33 (t, J = 8.0 Hz, 1 H), 6.07-6.00 (m, 1 H), 5.43 (dd, J = 1 .6, 17.6 Hz, 1 H), 5.30 (dd, J = 1 .2, 10.4 Hz, 1 H) 4.67 (d, J = 5.6 Hz, 2 H), 3.91 (s, 3 H).
Step 2: 2-Propen-1 -yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2- fluorophenyljcarbamate
To a solution of methyl 3-(allyloxycarbonylamino)-2-fluorobenzoate (86.7g, 342 mmol, 1 eq) in dry THF (500 mL) at -10 °C, LiHMDS (1 M in THF, 1 198 mmol, 1 198 mL, 3.5 eq) was added dropwise and the solution was allowed to stir for 1 h at 0 °C. A solution of 2-chloro-4-methylpyrimidine (48.0 g, 376 mmol, 1 .2 eq) in THF (200 mL) was then added dropwise to the solution of ester and base at 0 °C over 20 min. The solution was allowed to stir 1 h at room temperature. The reaction was quenched by the addition of the saturated aqueous NH CI (800 mL) at 0 °C. The reaction mixture was extracted with EtOAc (1 L x 3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and
concentrated under reduced pressure. The crude product was purified by flash column on silica gel, eluting with DCM. This solution was concentrated to obtain a solid. The solid was triturated with a small amount of EtOAc and filtered, and rinsing with diethyl ether to give the product. 240.1 g (67.0% yield, three batches combined). 1H NMR (400 MHz, DMSO-c/6) δ ppm 13.70 (s, 1 H), 8.52 (dd, J = 0.8, 4.8 Hz, 0.3 H), 8.34 (dd, J = 0.8, 5.2 Hz, 1 H), 8.27 (s, 0.4 H), 8.10 (s, 1 H), 7.47 (t, J = 8.0 Hz, 1 .4 H), 7.22-7.12 (m, 1 .8 H), 6.96 (s, 1 .4 H), 6.85 (d, J = 4.2 Hz, 1 H), 6.07 (s, 1 H), 5.97-5.86 (m, 1 .4 H), 5.32 (d, J = 15.6 Hz.1 .4 H), 5.24 (d, J = 6.4 Hz, 1 .4 H), 4.64 (d, J = 6.0 Hz, 2.8 H), 4.38 (d, J = 2.8 Hz, 0.8 H).
Intermediate 3: 2-Propen-1 -yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(1 -methylethyl)- 1 ,3-thiazol-4-yl1-2-fluorophenyl)carbamate
2-Propen-1 -yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate (10 g, 28.6 mmol) and A/,A/-dimethylacetamide (50 ml_) were combined and treated with recrystallized NBS (5.1 1 g, 28.7 mmol). The reaction mixture was stirred at room temperature for 15 min after which added
2-methylpropanethioamide (3.54 g, 34.3 mmol) was added. The reaction mixture was heated to 55 °C for 30 min and then poured into 500 ml_ of water. The water was decanted off and residue was dissolved in EtOAc. The residue was added to the EtOAc solution, concentrated and purified on silica gel [100% DCM to 60% (3:1 DCM: EtOAc)]. The combined fractions were diluted with water and extracted three times with EtOAc. The combined EtOAc layers were dried over Na2SO4, filtered, concentrated and put on vacuum pump overnight. The combined impure fractions from the first column and the residue from the water extractions were concentrated onto silica gel. The residue was purified by silica gel chromatography eluting with 100% DCM to 60% (3:1 DCM:EtOAc). The combined clean fractions from both
chromatography and initial workup were triturated in diethyl ether and filtered to obtain a solid. The diethyl ether filtrate was concentrated and triturated with EtOH and filtered to obtain a solid. The EtOH filtrate was concentrated and triturated again in diethyl ether and filtered to obtain a solid. 4.4 g (35% yield, the three batches combined) 1H NMR (400 MHz, DMSO-c/6) δ ppm 9.50 (s, 1 H) 8.57 (d, J=5.4 Hz, 1 H) 7.72 - 7.87 (m, 1 H) 7.20 - 7.36 (m, 2 H) 7.00 (d, J=5.3 Hz, 1 H) 5.80 - 6.03 (m, 1 H) 5.31 (dd, J=17.3, 1 .1 Hz, 1 H) 5.18 (dd, J=10.5, 0.9 Hz, 1 H) 4.56 (d, J=5.3 Hz, 2 H) 3.20 - 3.49 (m, 1 H) 1 .35 (d, J=6.9 Hz, 6 H).
Intermediate 4: 3-(5-(2-Chloropyrimidin-4-yl)-2-isopropylthiazol-4-yl)-2- fluoroaniline
To a solution of 2-propen-1 -yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(1 -methylethyl)- 1 ,3-thiazol-4-yl]-2-fluorophenyl}carbamate (15 g, 34.7 mmol) in DCM (500 ml_), acetic acid (5 g, 83.3 mmol), Pd(PPh3)2CI2 (0.5 g, 0.69 mmol) were added. Then tri-n-butyl tin hydride (15 g, 52 mmol) was added dropwise to the mixture at 0 °C. The mixture was stirred at room temperature for 30 min. The reaction was quenched by adding saturated NaHCO3 (200 mL) slowly. The two layers were separated. The aqueous layer was extracted with DCM (1 L x 2). The combined organic layers were washed with water and brine successively, dried over Na2SO , filtered and concentrated under reduced pressure to give the crude product, which was washed with petroleum ether (200 mL) to afford the title compound. (10.5 g, 87.6% yield) 1 H NMR (400 MHz, DMSO-c/6) δ ppm 8.58 (d, J=5.2 Hz, 1 H), 7.01 - 6.96 (m, 2 H), 6.89 - 6.85 (m, 1 H), 6.63 - 6.59 (m, 1 H), 5.29 (br. s., 2 H), 3.38 - 3.30 (m, 1 H), 1 .37 (d, J=6.8 Hz, 6 H).
Intermediate 5 : 2-Propen-1 -yl {3-[5-(2-chloro-4-pyrinnidinyl)-2-(1 ,1 - dimethylethyl)-1 ,3-thiaz -4-yl1-2-fluorophenyl)carbamate
To a solution of 2-propen-1 -yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2- fluorophenyl}carbamate (30 g, 85.9 mmol) in DMA (300 ml_), NBS (15.3 g, 85.9 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Then 2,2-dimethylpropanethioamide (1 1 .0 g, 94.5 mmol) was added at 0 °C. The mixture was stirred at room temperature for 2 h. The mixture was poured into water and extracted with EtOAc (200 ml_ x 3). The combined organic layers were washed with water and brine successively, dried over Na2SO , filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel
(DCM etroleum ether 2:1 ) to afford the title compound. 1 1 g (35.4 % yield) 1 H NMR (400 MHz, CDCI3) δ ppm 8.29 (d, J=5.27 Hz, 1 H), 8.12-8.19 (m, 1 H), 7.12-7.25 (m, 2H), 6.80-6.88 (m, 2H), 5.85-5.98 (m, 1 H), 5.20-5.37 (m, 2H), 4.61 -4.67 (m, 2H). MS (ES+): 447 [M+H]+ .
Intermediate 6: 3-r5-(2-Chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-
4-yl1-2-fluoroaniline
In a round bottom flask 2-propen-1 -yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 - dimethylethyl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}carbamate (800 mg, 1 .79 mmol) was dissolved in DCM (30 ml_) and water (0.5 ml). Tri-n-butyltin hydride (0.480 ml_, 1 .79 mmol) was added followed by
tetrakis(triphenylphosphine)palladium (0) (103 mg, 0.090 mmol). This mixture was stirred for 3 h at room temperature. The reaction was concentrated to dryness. The crude product was then dissolved into a small amount of DCM and injected onto a 25 g silica gel column. The column was eluted with EtOAc and hexanes. The title compound was obtained. 0.594 g (82 % yield) 1 H NMR (400 MHz, DMSO-c/6) δ ppm 8.62 (d, J=5.3 Hz, 1 H), 6.96 - 7.08 (m, 2H), 6.91 (t, J=8.2 Hz, 1 H), 6.64 (t, J=6.7 Hz, 1 H), 5.33 (s, 2H), 1 .44 (s, 9H).
Intermediate 7: 2-Propen-1 -yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)- -thiazol-4-yl1-2-fluorophenyl)carbamate
To a solution of 2-propen-1 -yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2- fluorophenyl}carbamate (20 g, 57 mmol) in DMA (300 ml_) was added NBS (10.2 g, 57 mmol). The reaction mixture was stirred at room temperature for 1 h. Then 4-morpholinecarbothioamide (9.2 g, 63 mmol) was added at 0 °C. The mixture was stirred at room temperature for 2 h. The mixture was poured into water and extracted with EtOAc (1 L x 3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (DCM etroleum ether 2:1 ) to afford the title compound. 20 g (83.5% yield) 1 H NMR (400 MHz, CDCI3) δ ppm 8.20- 8.27 (m, 1 H), 8.19 (d, J=5.5 Hz, 1 H), 7.20-7.26 (m, 1 H), 7.08-7.12 (m, 1 H), 6.92-6.98 (br, 1 H), 6.62 (d, J=5.5 Hz, 1 H), 5.90-6.03 (m, 1 H), 5.25-5.41 (m, 2H), 5.65-5.70 (m, 2H), 3.57-3.63 (m, 4H), 3.77-3.86 (m, 4H). m/z (ES+): 476 [M+H]+ Intermediate 8: 3-(5-(2-Chloropyhmidin-4-yl)-2-morpholinothiazol-4-yl)-2- fluoroaniline
To a solution of 2-propen-1 -yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)- 1 ,3-thiazol-4-yl]-2-fluorophenyl}carbamate (57 g, 120 mmol) in DCM (500 mL) was added acetic acid (17.3 g, 288 mmol) and Pd(PPh3)2CI2 (1 .68 g, 2.4 mmol). Then tri-n-butyltin hydride (38.4 g, 132 mmol) was added dropwise to the mixture at 0 °C. The mixture was stirred at room temperature for 30 min. The reaction mixture was quenched by adding saturated NaHCO3 (300 mL) slowly. The two layers were separated. The aqueous layer was extracted with DCM (1 L x 2). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was washed with petroleum ether (500 mL) to afford the title compound. 43 g (91 .6% yield) 1H NMR (400 MHz, CDCIs) δ ppm 8.15 (d, J=5.5 Hz, 1 H), 6.95-7.07 (m, 1 H), 6.83-6.92 (m, 1 H), 6.74-6.80 (m, 1 H), 6.70 (d, J=5.5 Hz, 1 H), 3.57-3.63 (m, 4H), 3.75-3.88 (m, 4H). Intermediate 9: 2-Propen-1 -yl {3-[5-(2-chloro-4-pynnnidinyl)-2-(tetrahvdro-2/-/- pyran-4-yl)-1 ,3-thiazol-4-yl1-2-fluorophenyl)carbamate
To a solution of 2-propen-1 -yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2- fluorophenyl}carbamate (85 g, 243 mmol) in DMA (700 mL) was added NBS (43.2 g, 243 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. Then tetrahydro-2H-pyran-4-carbothioamide (42.3 g, 291 .6 mmol) was added at room temperature. The mixture was stirred at 60 °C for 1 .5 h. The mixture was poured into water and extracted with EtOAc (400 mL x 3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (DCM:petroleum ether 2:1 ) to afford the title compound. 40 g (35% yield) 1 H NMR (400 MHz, DMSO-c/6) δ ppm 9.48-9.54 (br, 1 H), 8.58 (d, J=5.3 Hz, 1 H), 7.76-7.83 (m, 1 H), 7.23-7.32 (m, 2H), 7.02 (d, J=5.3 Hz, 1 H), 5.87- 5.98 (m, 1 H), 5.27-5.36 (m, 1 H), 5.16-5.21 (m, 1 H), 4.54-4.60 (m, 2H), 3.87- 3.94 (m, 2H), 3.41 -3.50 (m, 2H), 3.27-3.37 (m, 1 H), 1 .97-2.04 (m, 2H), 1 .69- 1 .82 (m, 2H). Intermediate 10: 3-r5-(2-Chloro-4-pyrimidinyl)-2-(tetrahvdro-2/-/-pyran-4-yl)- 1 ,3-thiazol-4-yl1-2-fluoroaniline
To a solution of 2-propen-1 -yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2/-/- pyran-4-yl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}carbamate (28 g, 59 mmol) in DCM (300 mL) was added acetic acid (8.5 g, 141 .6 mmol) and Pd(PPh3)2Cl2 (0.827 g, 1 .18 mmol). Then tri-n-butyl tin hydride (27 g, 88.5 mmol) was added dropwise to the mixture at 0 °C. The mixture was stirred at room temperature for 30 min. The reaction was quenched by addition of saturated NaHCO3 (200 mL) slowly. The two layers were separated. The aqueous layer was extracted with DCM (300 mL x 2). The combined organic layers were washed with water and brine successively, dried over Na2SO , filtered and
concentrated under reduced pressure. The crude product was washed with petroleum ether (200 mL) to afford the title compound. 22.5 g (97.8% yield) 1 H NMR (400 MHz, CDCIs) δ ppm 8.35 (d, J=5.3 Hz, 1 H), 7.01 -7.08 (m, 1 H), 6.98 (d, J=5.3 Hz, 1 H), 6.85-6.92 (m, 1 H), 6.79-6.85 (m, 1 H), 4.05-4.12 (m, 2H), 3.79-3.86 (br, 2H), 3.51 -3.59 (m, 2H), 3.23-3.34 (m, 1 H), 2.07-2.15 (m, 2H), 1 .89-2.01 (m, 2H). Intermediate 14: Methyl 3-amino-2-chlorobenzoate
Step 1 : Methyl 2-chloro-3-nitrobenzoate
To a suspension of 2-chloro-3-nitrobenzoic acid (100 g, 495 mmol) in MeOH (600 mL) was added TsOH (20 g, 10%). Then the mixture was heated to reflux overnight. The solvent was removed. The residue was diluted with EtOAc (1 L). Then the pH was adjusted to 9 by adding saturated NaHCO3. The organic layer was separated. The aqueous layer was extracted with EtOAc (1 L x 3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound. 96 g (90.6 % yield) 1H NMR (400 MHz, CDCI3) δ ppm 7.90 (dd, J=1 .8 Hz, 7.9Hz, 1 H), 7.81 (dd, J=1 .5 Hz, 7.7 Hz, 1 H), 7.45 (dd, J=7.7 Hz, 7.9 Hz, 1 H), 3.94 (s, 1 H). Step 2: Methyl 3-amino-2-chlorobenzoate
To a solution of methyl 2-chloro-3-nitrobenzoate (25 g, 1 16 mmol) in MeOH (150 ml_) was added Raney Ni (3 g). The mixture was stirred under H2 atmosphere (50 psi at 25 °C) for 3.5 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by recrystallization in EtOAc to afford the title compound. 69 g (83.5% yield, four batches combined) 1H NMR (400 MHz, CDCIs) δ ppm 6.70-7.25 (m, 3H), 4.40-4.50 (br, 2H), 3.87 (s, 3H).
Intermediate 15: {2-Chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3- thiazol-4-yllphenyl)amine
Step 1 : Methyl 2-chloro-3-{[ -propen-1 -yloxy)carbonyl]amino}benzoate
To a solution of methyl 3-amino-2-chlorobenzoate (29 g, 0.162 mol) in THF (50 ml_) and saturated NaHCO3 (200 ml_) was added 2-propen-1 -yl chloridocarbonate (24 g, 0.194 mol) dropwise at 0 °C. The reaction mixture was allowed to warm to room temperature for 2 h. The reaction was extracted with EtOAc (2 x 200 ml_). The organic layer was dried over Na2SO4, and the solvent was removed to give a crude product. 42 g (96.3% yield) 1H NMR (400 MHz, CDCI3) δ ppm 8.30-8.37 (m, 1 H), 7.47-7.51 (m, 1 H), 7.35-7.43 (br, 1 H), 7.28-7.33 (m, 1 H), 5.90-6.06 (m, 1 H), 5.25-5.41 (m, 2H), 4.68-4.70 (m, 2H), 3.91 (s, 3H). Step 2: 2-Propen-1 -yl {2-chloro-3-[(E)-2-(2-chloro-4-pyrimidinyl)-1 - hydroxyethenyl]phenyl}carbamate
Following a procedure analogous to the procedure described in Step 2 of Intermediate 2 using methyl 2-chloro-3-{[(2-propen-1 - yloxy)carbonyl]amino}benzoate (30 g, 0.1 1 mol) and 2-chloro-4- methylpyrimidine (15.8 g, 0.12 mol) the title compound was prepared. 29 g (79.6% yield) 1H NMR (400 MHz, CDCI3) δ ppm 13.52-13.58 (br, 0.9H), 8.41 - 8.42 (m, 1 H), 8.22-8.27 (m, 1 H), 7.28-7.35 (m, 2.2 H), 7.21 -7.24 (m, 1 .2H), 6.85-6.88 (m, 1 H), 5.91 -6.02 (m, 1 H), 5.73 (s, 1 H), 5.23-5.40 (m, 2H), 4.66- 4.70 (m, 2H).
Step 3: 2-Propen-1 -yl {2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4- morpholinyl)-1 ,3-thiazol-4-yl]phenyl}carbamate
Following a procedure analogous to the procedure described in Example 9 using 2-propen-1 -yl {2-chloro-3-[(2-chloro-4- pyrimidinyl)acetyl]phenyl}carbamate (3.00 g, 8.19 mmol), NBS (1 .531 g, 8.60 mmol) and 4-morpholinecarbothioamide (1 .677 g, 1 1 .47 mmol) the title compound was obtained. 4.03 g (7.86 mmol, 96 % yield) 1 H NMR (400 MHz, DMSO-c/e) δ ppm 9.29 (s, 1 H), 8.33 (d, J=5.5 Hz, 1 H), 7.67 - 7.84 (m, 1 H), 7.48 (t, J=7.8 Hz, 1 H), 7.29 (dd, J=7.7, 1 .5 Hz, 1 H), 6.41 (d, J=5.5 Hz, 1 H), 5.83 - 6.08 (m, 1 H), 5.36 (dd, J=17.2, 1 .5 Hz, 1 H), 5.23 (dd, J=10.4, 1 .5 Hz, 1 H), 4.62 (d, J=5.3 Hz, 2 H), 3.73 (t, J=4.8 Hz, 4 H), 3.57 (t, J=4.8 Hz, 4 H). MS (ESI): 491 .98 [M+H]+.
Step 4: {2-Chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4- yl]phenyl}amine
Following a procedure analogous to the procedure described in Intermediate 13 using 2-propen-1 -yl {2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4- morpholinyl)-1 ,3-thiazol-4-yl]phenyl}carbamate (2.50 g, 5.08 mmol) the title compound was obtained. (2.08 g (4.99 mmol, 98 % yield) MS (ESI): 407.97 [M+H]+.
Intermediate 16: 4-r4-(3-Amino-2-fluoroDhenyl)-2-(1 .1 -dimethylethyl)-1 .3- thiazol-5-yl1-2-pyhmidinami
In a microwave reaction vessel 3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 - dimethylethyl)-1 ,3-thiazol-4-yl]-2-fluoroaniline (590 mg, 1 .626 mmol) was combined with
NH4OH 28-30% (15 mL, 385 mmol) and 1 ,4-dioxane (4 mL). The mixture was heated in the microwave for 40 min at 130 °C. The crude product was then diluted with water (100 mL) followed by extraction with EtOAc (100 mL). The EtOAc layer was washed with brine then dried over Na2SO4. The organics were filtered and concentrated to dryness. The crude material was dissolved in DCM (2 mL), injected onto the top of a silica gel column then purified using EtOAc and hexanes. The desired fractions were concentrated to dryness to give the title compound. 490 mg, (1 .355 mmol, 83% yield) 1 H NMR (400 MHz, DMSO-c/e) δ ppm 8.06 (d, J=5.1 Hz, 1 H), 6.97 (t, J=7.8 Hz, 1 H), 6.86 (t, J=8.2 Hz, 1 H), 6.71 (s, 2H), 6.58 (t, J=6.2 Hz, 1 H), 6.15 (d, J=5.1 Hz, 1 H), 5.26 (s, 2H), 1 .42 (s, 9H).
Intermediate 17: 4-r4-(3-Amino-2-fluorophenyl)-2-(1 ,1 -dimethylethyl)-1 ,3- thiazol-5-yl1-2-pyhmidinamine
Step 1 : 2-Propen-1 -yl {3-[5-(2-amino-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)- 1 ,3- thiazol-4-yl]-2-fluorophenyl}carbamate
A solution of 2-propen-1 -yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)- 1 ,3-thiazol-4-yl]-2-fluorophenyl}carbamate (535 mg, 1 .197 mmol) and ammonia in MeOH 7N (6 ml, 42.0 mmol) was heated to 80 °C for 24 h. The crude reaction mixture was evaporated onto silica gel and chromatographed, (0-15% MeOH in DCM). The title compound was obtained. 233 mg (41 % yield) MS (ESI): 428.1 [M+H]+.
Step 2: 4-[4-(3-Amino-2-fluorophenyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-5-yl]-2- py midinamine
A solution of 2-propen-1 -yl {3-[5-(2-amino-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)- 1 ,3-thiazol-4-yl]-2-fluorophenyl}carbamate (220 mg, 0.515 mmol) in TBAF (1 mL, 1 .0 mmol) in 1 M THF was heated in a microwave reactor at 130 °C for 10 min. The crude reaction mixture was evaporated onto silica gel and chromatographed (1 :9:90 NH4OH:MeOH:DCM in DCM 10-80%). The title compound was obtained as a white solid in the amount of 100 mg (56% yield) MS (ESI): 344.1 [M+H]+. Intermediate 18: 3-[5-(2-Chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4- -2,4-difluoroaniline
Step 1 : Methyl 2,6-difluorobenzoate
To a suspension of 2,6-difluorobenzoic acid (50 g, 316 mmol) in MeOH (800 mL) was added TsOH ( 6 g, 10%), the mixture was heated to reflux overnight. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with saturated NaHCO3 and brine
successively. The organic layer was separated, dried over Na2SO and concentrated under reduced pressure to give methyl 2,6-difluorobenzoate. 41 g (75.9% yield) 1 H NMR (400 MHz, CDCI3) δ ppm 7.37-7.46 (m, 1 H), 6.91 - 6.98 (m, 2H), 3.95 (s, 3H).
Step 2: Methyl 2,6-difluoro-3-nitrobenzoate
Fuming nitric acid (1 1 g, 174 mmol) was added to a solution of methyl 2,6- difluorobenzoate (25 g, 145 mmol) in concentrated sulfuric acid (50 ml_) at 0 °C, and the reaction was stirred for 30 min at 0°C. The reaction mixture was poured over ice-water. The precipitate was filtered to give the title compound 25.1 g (80.6 % yield) 1H NMR (400 MHz, CDCI3) δ ppm 8.13-8.20 (m, 1 H), 7.02-7.10 (m, 1 H), 3.93 (s, 3H).
Step 3: Methyl 3-amino-2,6-difluorobenzoate
To a solution of methyl 2,6-difluoro-3-nitrobenzoate (25 g, 1 15 mmol) in MeOH (150 ml_) was added 5% palladium on carbon (2.5 g). The mixture was stirred under H2 atmosphere (50 psi/25 °C) for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under the reduced pressure to give the product. 20 g (93 % yield) 1 H NMR (400 MHz, DMSO-c/6) δ ppm 6.95-7.10 (m, 2H), 3.86 (s, 3H)
Step 4: Methyl 2,6-difluoro-3-{[(2-propen-1 -yloxy)carbonyl]amino}benzoate
To a solution of methyl 3-amino-2,6-difluorobenzoate (75 g, 401 mmol) in THF (300 ml_), was added saturated NaHCO3 (1400 ml_). Then 2-propen-1 -yl chloridocarbonate (67.0 g, 561 mmol) was added dropwise at 0 °C. The mixture was stirred at room temperature for 2 h. The solution was extracted with EtOAc (500 ml_ x 3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound. 92.5 g (85.6% yield) 1H NMR (400 MHz, CDCI3) δ ppm 8.05-8.20 (br, 1 H), 6.88-6.95 (m, 1 H), 5.86- 6.01 (m, 1 H), 5.21 -5.40 (m, 2H), 4.54-4.69 (m, 2H), 3.92 (s, 3H).
Step 5: 2-Propen-1 -yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2,4- difluorophenyljcarbamate
Following a procedure analogous to the procedure described in Step 2 of Intermediate 2 using methyl 2,6-difluoro-3-{[(2-propen-1 - yloxy)carbonyl]amino}benzoate (80 g, 295 mmol) and 2-chloro-4- methylpyrimidine (41 .6g, 324 mmol) the title compound was obtained.
Material produced in general accordance with this description was prepared in the amount of 65 g (60.2% yield) 1H NMR (400 MHz, DMSO-c/6) δ ppm 9.49-9.60 (m, 1 H), 8.72-8.77 (m, 0.3 H), 8.58-8.64 (m, 0.6 H), 7.57-7.83 (m, 2H), 7.15-7.25 (m, 1 H), 5.89-6.01 (m, 1 H), 5.75-5.82 (m, 0.6 H), 5.20-5.40 (m, 2H), 4.55-4.62 (m, 2H), m/z (ES+): 368 [M+H]+ . Step 6: 2-Propen-1 -yl {3-[5-(2-chloro-4-pynmidinyl)-2-(4-morpholinyl)-1 ,3- thiazol-4-yl]-2,4-difluorophenyl}carbamate
Following a procedure analogous to the procedure described in Intermediate 12 using 2-propen-1 -yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2,4- difluorophenyl}carbamate (4.0 g, 10.88 mmol), NBS (2.033 g, 1 1 .42 mmol) and 4-morpholinecarbothioamide (1 .749 g, 1 1 .97 mmol) the title compound was obtained. Material produced in general accordance with this description was prepared as a yellow solid in the amount of 5.1 1 g (95% yield) 1 H NMR (400 MHz, DMSO-c/6) δ ppm 9.56 (br. s., 1 H), 8.41 -8.51 (m, 1 H), 7.83 (d, J=5.9 Hz, 1 H), 7.27 (t, J=8.7 Hz, 1 H), 6.76 (d, J=5.3 Hz, 1 H), 5.88-6.03 (m, 1 H), 5.34 (d, J=17.2 Hz, 1 H), 5.22 (d, J=10.1 Hz, 1 H), 4.61 (d, J=5.1 Hz, 2 H), 3.70-3.76 (m, 4 H), 3.57 (d, J=4.4 Hz, 4 H). MS (ESI): 493 [M+H]+.
Step 7: 3-[5-(2-Chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]-2,4- difluoroaniline
Following a procedure analogous to the procedure described in Intermediate 4 using 2-propen-1 -yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(4-nnorpholinyl)-1 ,3- thiazol-4-yl]-2,4-difluorophenyl}carbamate (5.1 1 g, 10.35 mmol) the title compound. Material produced in general accordance with this description was prepared as a light yellow solid in the amount of 2.71 g (64% yield) 1H NMR (400 MHz, DMSO-c/6) δ ppm 8.44 (d, J=5.5 Hz, 1 H), 6.90-7.00 (m, 2 H), 6.73 (d, J=5.5 Hz, 1 H), 5.23 (s, 2 H), 3.71 -3.76 (m, 4 H), 3.54-3.60 (m, 4 H). MS (ESI): 409 [M+H]+.
Intermediate 19: 2-Propen-1 -yl {3-[(2-chloro-4-
Step 1 : Ethyl 3-{[(2-prope -1 -yloxy)carbonyl]amino}benzoate
A solution of ethyl-3-aminobenzoate (25.0 g, 151 .33 mmol) in DCM (500 ml_) was cooled to 0 °C. 2,6-Lutidine (19.46 g, 181 .60 mmol) was added to the solution followed by the addition of 2-propen-1 -yl chloridocarbonate (20.07 g, 166.46 mmol). Following addition, the reaction was removed from the ice bath and stirred at room temperature for 30 min. The reaction was quenched with saturated NaHCO3 and the layers were separated. The mixture was extracted with DCM (3 times), and the combined organics were washed with 10% HCI/H2O (3 times), dried over MgSO4 and the solvent was removed to give the title compound. 38.80 g (80% yield) 1H-NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1 H), 8.15 (s, 1 H), 7.66 - 7.72 (m, 1 H), 7.59 (d, J = 7.7 Hz, 1 H), 7.43 (t, J = 7.9 Hz, 1 H), 5.94 - 6.04 (m, 1 H), 5.37 (dd, J = 17.4 and 1 .7 Hz, 1 H), 5.24 (dd, J = 10.6 and 1 .5 Hz, 1 H), 4.63 (d, J = 5.5 Hz, 2 H), 4.31 (q, J = 7.3 Hz, 2 H), and 1 .31 (t, J = 7.1 Hz, 3 H); ES-LCMS m/z 250 (M+H).
Step 2: 2-Propen-1 -yl {3-[(2-chloro-4-pyrimidinyl)acetyl]phenyl}carbamate
Ethyl 3-{[(2-propen-1 -yloxy)carbonyl]amino}benzoate (20.0 g, 80.24 mmol) was dissolved in 1 M LiHMDS in THF (260 mL) and cooled to 0 °C. A solution containing 2-chloro-4-methylpyrimidine (10.32 g, 80.24 mmol) in 20 mL dry THF was added to the reaction mixture. The reaction was stirred at 0 °C for 2 h, quenched with MeOH (100 mL), dried directly onto silica, and purified via flash chromatography EtOAc/CH2Cl2 0-100% gradient run over 60 min. The desired fractions were combined and the solvent was removed to give the title compound. 13.6 g (51 % yield) ES-LCMS m/z 332 (M+H). Intermediate 20: Tetrahydro-2A - ran-4-carbothioamide
A solution of tetrahydro-2H-pyran-4-carboxamide (9.47 g, 73.3 mmol) and Lawesson's reagent (14.83 g, 36.7 mmol) in THF (98 mL) was heated to reflux for 6 h. The reaction was cooled to room temperature, poured into saturated aqueous NaHCO3 (200 mL) and extracted with diethyl ether (4 x 100 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residual solid was triturated with 1 : 1 EtOAc:hexanes (100 mL) and filtered to collect the solid. The filtrate was concentrated and re- subjected to trituration and filtration using the same conditions. The combined solids were dried under vacuum to afford tetrahydro-2A -pyran-4- carbothioamide. 4.91 g (32.1 mmol, 43.8 % yield) as a white solid 1H NMR (400 MHz, CDCb) δ ppm 7.49 (br. s., 1 H), 6.84 (br. s., 1 H), 3.94 - 4.32 (m, 2 H), 3.31 - 3.62 (m, 2 H), 2.52 - 3.03 (m, 1 H), 1.81 - 1.93 (m, 4 H).
Intermediate 21 : 2,2-Dimethylpropanethioamide
The title compound was prepared from 2,2-dimethylpropanamide (7.59 g, 75.0 mmol) and 2,4-bis(4-methoxyphenyl)-1 ,3-dithia-2,4-diphosphetane-2,4- disulfide (15.17 g, 37.51 mmol) by a procedure analogous to Intermediate 20. 3.2 g (36% yield) 1 H-NMR (400 MHz, CDCI3) δ 7.92 (brs, 1 H), 7.03 (brs, 1 H), and 1 .38 (s, 9 H).
Intermediate 22: 2-Methylpropanethioamide
A solution of 2-methylpropanamide (6.53 g, 75.0 mmol) and 2,4-bis(4- methoxyphenyl)-1 ,3-dithia-2,4-diphosphetane-2,4-disulfide (15.17 g, 37.51 mmol) in THF (100 mL) was heated to reflux for 4 h. The reaction mixture was then cooled to room temperature and poured into saturated aqueous NaHCO3 (200 mL). The mixture was extracted with ether (4 x 100 mL). The organic fractions were combined, dried over Na2SO , filtered, and
concentrated. Purification by flash column chromatography (20%
EtOAc:hexanes) afforded the title compound. 4.77 g (62% yield) 1H-NMR (400 MHz, CDCI3) δ 7.63 (brs, 1 H), 6.90 (brs, 1 H), 2.88 (m, 1 H), and 1 .27 (d, 6H, J = 6.8 Hz). Intermediate 23: methyl 2-fluoro-3-[(propylsulfonyl)amino1benzoate
Step 1 : methyl 2-fluoro-3- ropylsulfonyl)amino]benzoate
A 500 mL round-bottomed flask was charged with methyl 3-amino-2- fluorobenzoate (20 g, 1 18 mmol) and pyridine (10.52 mL, 130 mmol) in dichloromethane (DCM) (100 mL) to give a yellow/clear solution at 0 °C. After 5 min, 1 -propanesulfonyl chloride (13.26 mL, 1 18 mmol) was added to the reaction and warmed to room temperature. After 24 h, the reaction mixture was diluted with EtOAc (200 mL) and concentrated to a volume of 50 mL. The reaction mixture was diluted with EtOAc (200 mL) and water (200 mL) and stirred. After stirring, the EtOAc layer was separated from the water layer. The EtOAc layer was diluted with water (200 mL). After stirring, the EtOAc layer was separated from the water layer. The EtOAc layer was dried over Na2SO4, filtered, and concentrated to 50 mL. While stirring, the reaction mixture was diluted with EtOAc (50 mL) and hexanes (200 mL) and stirred. The solids were filtered and washed with hexanes. The product was put into drying oven for 1 day to obtain methyl 2-fluoro-3- [(propylsulfonyl)amino]benzoate. 28.9 g (105 mmol, 89 % yield) MS: 276 [M+H]+.
Step 2: methyl 2-fluoro-3-[(propylsulfonyl)amino]benzoate
A 500 mL round-bottomed flask was charged with methyl 2-fluoro-3- [(propylsulfonyl)amino]benzoate (28.9 g, 105 mmol) in tetrahydrofuran (THF) (150 mL) to give a yellow solution at room temperture under Argon. The reaction mixture was stirred at -5 °C. LiHMDS (325 mL, 325 mmol) was added to the reaction mixture. 2-Chloro-4-methylpyrimidine (13.63 g, 106 mmol) in tetrahydrofuran (THF) (150 mL) was added to the reaction mixture. After 1 h, the reaction mixture was diluted with 4.5 N HCI (200 mL) and EtOAc (250 mL) and stirred. After stirring, the EtOAc layer was separated from the water layer. The EtOAc mixture was diluted with 4.5 N (200 mL) and stirred. After stirring, the EtOAc layer was separated from the water layer. The EtOAc layer was dried over Na2SO4, filtered, and concentrated. MeCN (100 mL) was added to the crude product and warmed to 50 °C until all the solid dissolved. After 10 min, the reaction mixture was cooled to 0 °C then diluted with water (100 mL). The mixture was filtered, and the solid was washed with EtOAc to obtain N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-1 - propanesulfonamide. (30.93 g, 79 % yield) as orange solid MS: 372, 374 [M+H]+.
Intermediate 24: 1 ,1 -dimethylethyl 4-[5-(2-chloro-4-pyrimidinyl)-4-(2-fluoro-3- {[(2-propen-1 -yloxy)carbonyl1amino)phenyl)-1 ,3-thiazol-2-yl1-4-methyl-1 - piperidinecarboxylate
To a solution of 2-propen-1 -yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2- fluorophenyl}carbamate (1 .8 g, 5.15 mmol) in Ν,Ν-dimethylacetamide (DMA) (20 mL) was added NBS (0.916 g, 5.15 mmol), and the reaction mixture was stirred for 50 min. 1 ,1 -Dimethylethyl 4-(aminocarbonothioyl)-4-methyl-1 - piperidinecarboxylate (1 .330 g, 5.15 mmol) was added and the mixture was heated to 80 °C for 30 min. The reaction mixture was cooled, quenched with water (20 mL), and extracted with EtOAc (3x). The extract was dried over Na2SO4, filtered and concentrated. The residue was purified using column chromatography, eluting with 0 to 100% EtOAc/hexanes, to afford the product. (1 .56 g, 52% yield) 1HNMR (400 MHz, CDCI3): δ ppm 8.40-8.41 (d, J = 4.0 Hz, 1 H), 7.20-7.31 (m, 2H), 6.94-6.95 (m, 2H), 5.94-6.17 (m, 1 H), 5.29-5.44 (m, 2H), 4.71 -4.72 (d, J = 4.0 Hz, 2H), 3.21 -3.30 (m, 2H), 3.05 (m, 2H), 2.27- 3.31 (m, 2H), 1 .78 (m, 2H), 1 .48 (s, 9H), 1 .41 (s, 3H); MS: 588.0 [M+H]+.
Intermediate 25: 1 ,1 -dimethylethyl 4-[4-(3-amino-2-fluorophenyl)-5-(2-chloro- 4-pyrimidinyl)-1 ,3-thiazol-2-yl1-4-methyl-1 -piperidinecarboxylate
To a solution of 1 ,1 -dimethylethyl 4-[5-(2-chloro-4-pyrimidinyl)-4-(2-fluoro-3- {[(2-propen-1 -yloxy)carbonyl]amino}phenyl)-1 ,3-thiazol-2-yl]-4-methyl-1 - piperidinecarboxylate (670 mg, 1 .139 mmol) in dichloromethane (DCM) (8 ml_) were added tributylstannane (332 mg, 1 .139 mmol),
bis(triphenylphosphine)palladium (II) chloride (65.8 mg, 0.057 mmol) and water (66 μΙ_, 3.66 mmol). The reaction mixture was stirred for 1 h. The reaction mixture was concentrated and residue was purified using column chromatography eluting with 20% to 80% EtOAc/hexanes to give the product. (482 mg, 56% yield) 1 HNMR (400 MHz, CDCI3): δ ppm 8.38-8.39 (d, J = 4.0 Hz, 1 H), 6.64-7.10 (m, 4H), 3.85 (s, 1 H), 3.69 (m, 2H), 3.33-3.39 (m, 2H), 2.30-2.33 (m, 2H), 1 .75-1 .80 (m, 2H), 1 .48 (m, 12H); MS: 504.2 [M+H]+.
Intermediate 26: 1 ,1 -dimethylethyl 4-(5-(2-chloro-4-pyrimidinyl)-4-{2-fluoro-3- [(propylsulfonyl)aminolphenyl)-1 ,3-thiazol-2-yl)-4-methyl-1 - piperidinecarboxylate
To a solution of 1 ,1 -dimethylethyl 4-[4-(3-amino-2-fluorophenyl)-5-(2-chloro-4- pyrimidinyl)-1 ,3-thiazol-2-yl]-4-methyl-1 -piperidinecarboxylate (600 mg, 1 .190 mmol) in pyridine (5 ml_) was added 1 -propanesulfonyl chloride (0.187 ml_, 1 .667 mmol) at 0 °C. The reaction mixture was stirred for 5h at 0 °C then at room temperature overnight. The reaction mixture was quenched with water (15 ml_) and extracted with EtOAc (3x). The extract was dried over Na2SO4 and concentrated. The residue was purified using column chromatography by eluting with 20 to 100%, EtOAc/hexanes to give the product. (649 mg, 89% yield) 1 HNMR (400 MHz, CDCI3): δ ppm 8.43-8.44 (d, J = 4.0 Hz, 1 H), 7.68- 7.76 (m, 1 H), 7.32-7.33 (m, 1 H), 6.96-6.97 (d, J = 4.0 Hz, 1 H), 6.61 -6.62 (m, 1 H), 3.41 -3.69 (m, 2H), 3.35-3.41 (m, 2H), 3.12-3.16 (m, 2H), 2.27-2,31 (m, 2H), 1 .88-1 .94 (m, 2H), 1 .81 (m, 2H), 1 .49 (s, 3H), 1 .48 (s, 9H), 1 .04-1 .08 (t, J = 8.0 Hz, 3H); MS: 610.2 [M+H]+. Intermediate 27: 1 ,1 -dimethylethyl 4-(5-(2-amino-4-pyrimidinyl)-4-{2-fluoro-3- [(propylsulfonyl)anninolphenyl)-1 ,3-thiazol-2-yl)-4-methyl-1 - piperidinecarboxylate
To a 5-mL microwave tube were added 1 ,1 -dimethylethyl 4-(5-(2-chloro-4- pyrimidinyl)-4-{2-fluoro-3-[(propylsulfonyl)amino]phenyl}-1 ,3-thiazol-2-yl)-4- methyl-1 -piperidinecarboxylate (120 mg, 0.197 mmol) and ammonium hydroxide solution (38%, 2 ml_, 51 .4 mmol), and the tube was sealed. The reaction mixture was heated at 90 °C under the microwave conditions for 3h. The tube was cooled using an acetone/dry ice bath and opened. The mixture was concentrated to give crude product, which was used for the next reaction without further purification. 1 15 mg 1HNMR (400 MHz, DMSO-d6): δ ppm 8.07-8.09 (m, 1 H), 7.52-7,56 (t, J = 8.0 Hz, 1 H), 7.42 (m, 1 H), 7.30-7.34 (d, J = 8.0 Hz ,1 H), 6.79 (m, 2H), 6.1 1 -6.12 (d, J = 4.0 Hz, 1 H), 3.52-3.57 (m, 2H), 3.33 (m, 2H), 3.02-3.06 (m, 2H), 2.07-2.12 (m, 2H), 1 .65-1 .74 (m, 4H), 1 .40- 1 .41 (m, 12H), 0.90-0.94 (t, J = 8.0 Hz, 3H); MS: 591 .2 [M+H]+.
Intermediate 28: A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-methyl-4-piperidinyl)- 1 ,3-thiazol-4-yl1-2-fluorophenyl)-1 -propanesulfonamide
To a solution of 1 ,1 -dimethylethyl 4-(5-(2-chloro-4-pyrimidinyl)-4-{2-fluoro-3- [(propylsulfonyl)amino]phenyl}-1 ,3-thiazol-2-yl)-4-methyl-1 - piperidinecarboxylate (170 mg, 0.279 mmol) in dichloromethane (DCM) (3 ml_) was added TFA (0.5 ml_, 6.49 mmol), and the reaction mixture was stirred for 1 .5h. The reaction mixture was concentrated and the residue was treated with saturated NaHCO3 solution and extracted with EtOAc. The extract was dried over Na2SO4 and concentrated to give the product. (140 mg, 99% yield) 1 HNMR (400 MHz, DMSO-d6): δ ppm 8.65-8.66 (d, J = 4.0 Hz, 1 H), 7.57-7.61 (m, 1 H), 7.49 (m, 1 H), 7.35-7.39 (d, J = 8.0 Hz, 1 H), 7.14-7.15 (m, 1 H), 3.22 (m, 2H), 3.06-3.10 (m, 4H), 2.33-2,37 (m, 2H), 1 .96 (m, 2H), 1 .67- 1 .71 (m, 2H), 1 .50 (s, 3H), 0.91 -0.95 (t, J = 8.0 Hz, 3H); MS: 510.1 [M+H]+. Intermediate 29: A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,4-dimethyl-4-pipehdinyl)-
1 ,3-thiazol-4-yl1-2-fluorophenyl)-1 -propanesulfonamide
To a solution of A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-methyl-4-piperidinyl)-1 ,3- thiazol-4-yl]-2-fluorophenyl}-1 -propanesulfonamide (138 mg, 0.271 mmol) in methanol (3 ml_) were added formaldehyde in water (0.10 ml_, 1 .343 mmol) and sodium cyanoborohydride (51 .0 mg, 0.812 mmol). The reaction mixture was stirred for 1 h. The reaction mixture was then quenched with saturated NaHCO3 solution (5 ml) and extracted with DCM. The DCM layer was dried over Na2SO and concentrated. The residue was purified using reverse-phase HPLC under the acidic conditions to give the product as a TFA salt. (72 mg) 1 HNMR (400 MHz, DMSO-d6): δ ppm 9.78 (s, 1 H), 8.64-8.67 (m, 1 H), 7.46- 7.61 (m, 2H), 7.37-7.41 (d, J = 8.0 Hz, 1 H), 7.13-7.18 (m, 1 H), 3.42 (m, 2H), 3.05-3.29 (m, 4H), 2.75-2.86 (m, 3H), 2.00-2.56 (m, 4H), 1 .69-1 .73 (m, 2H), 1 .42-1 .61 (m, 3H), 0.91 -0.95 (m, 3H); MS: 524.4 [M+H]+. Intermediate 30: 1 ,1 -dimethylethyl 4-(4-{2-fluoro-3-
[(propylsulfonyl)aminolphenyl)-5-{2-[(2-hvdroxyethyl)amino1-4-pyrimidinyl)-1 ,3- thiazol-2-yl)-4-methyl-1 -piperidinecarboxylate
To a 5-mL microwave tube were added 1 ,1 -dimethylethyl 4-(5-(2-chloro-4- pyrimidinyl)-4-{2-fluoro-3-[(propylsulfonyl)amino]phenyl}-1 ,3-thiazol-2-yl)-4- methyl-1 -piperidinecarboxylate (130 mg, 0.213 mmol), ethanolamine (0.064 ml_, 1 .065 mmol), and toluene (2 ml_). The tube was sealed and the mixture was heated at 90 °C under the microwave conditions for 8h. The reaction mixture was concentrated and the residue was purified using column chromatography, eluting with 20% to 100% EtOAc/hexanes, to afford the product. (104 mg, 77% yield) 1HNMR (400 MHz, CDCI3): δ ppm 8.10-8.1 1 (d, J = 4.0 Hz, 1 H), 7.67-7,71 (m, 1 H), 7.37-7.41 (m, 1 H), 7.26-7.30 (m, 2H), 6.33-6.35 (d, J = 8.0 Hz, 1 H), 5.55-5.58 (m,1 H), 3.81 (m, 2H), 3.68 (m, 2H), 3.54 (m, 2H), 3.38-3.41 (m, 2H), 3.08-3.12 (m, 2H), 2.26-2.30 (m, 2H), 1 .86- 1 .91 (m, 2H), 1 .75-1 .82 (m, 2H), 1 .48 (m, 12H), 0.89-0.93 (t, J = 8.0 Hz, 3H); MS: 635.5 [M+H]+. Intermediate 31 : 4-methyltetrahvdro-2H- yran-4-carbothioamide
To a solution of 4-methyltetrahydro-2H-pyran-4-carboxamide (720 mg, 5.03 mmol) in THF (25 mL) was added Lawesson's reagent (2034 mg, 5.03 mmol), and the mixture was heated at 50 °C for 30 min. The reaction mixture was cooled and concentrated. The residue was partitioned between EtOAc (50 mL) and water (20 mL). The organic layer was washed with saturated
NaHCO3 and dried. The reaction mixture was filtered and concentrated. The residue was purified using column chromatography eluting with 0 to 100% EtOAc/hexanes to give the product. (460 mg, 57% yield) 1HNMR (400 MHz, CDCIs): δ ppm 3.74-3.77 (m, 4H), 2.16-2.23 (m, 2H), 1 .72-1 .78 (m, 2H), 1 .40 (s, 3H); MS: 159.8 [M+H]+. Intermediate 32: 2-propen-1 -yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(4- methyltetrahvdro-2H-pyran-4-yl)-1 ,3-thiazol-4-yl1-2-fluorophenyl)carbamate
To a solution of 2-propen-1 -yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2- fluorophenyljcarbamate (1 g, 2.86 mmol) in Ν,Ν-dimethylacetamide (DMA) (12 mL) was added NBS (0.509 g, 2.86 mmol), and the reaction mixture was stirred for 1 h. 4-Methyltetrahydro-2H-pyran-4-carbothioamide (0.455 g, 2.86 mmol) was added and the reaction mixture was heated to 80 °C for 40 min. The reaction mixture was cooled, quenched with water (30 mL) and extracted with EtOAc (3x). The extract was dried over Na2SO4, filtered and
concentrated. The residue was purified using column chromatography eluting with 0 to 100% EtOAc/hexanes to give the product. (920 mg, 66% yield) 1 HNMR (400 MHz, CDCI3): δ ppm 8.40-8.42 (d, J = 8.0 Hz, 1 H), 7.21 -7.32 (m, 2H), 6.90-6.96 (m, 2H), 5.95-6.03 (m, 1 H), 5.30-5.44 (m, 2H), 3.84-3.87 (m, 2H), 3.67-3.72 (m, 2H), 2.331 -2.36 (m, 2H), 1 .87-1 .91 (m, 2H), 1 .51 (s, 3H); MS: 489.2 [M+H]+. Intermediate 33: {3-r5-(2-chloro-4-pyrimidinyl)-2-(4-methyltetrahvdro-2H- pyran-4-yl)-1 ,3-thiazol-4-yl1-2-fluorophenyl)amine 3-[5-(2-chloro-4-pyrimidinyl)-
2-(4-methyltetrahvdro-2H- ran-4-yl)-1 ,3-thiazol-4-yl1-2-fluoroaniline
To a solution of 2-propen-1 -yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(4- methyltetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}carbamate (0.91 g, 1 .861 mmol) in dichloromethane (DCM) (10 mL) were added tributylstannane (0.542 g, 1 .861 mmol), tetrakis (0.108 g, 0.093 mmol) and water (0.107 mL, 5.96 mmol), and the reaction mixture was stirred for 1 h. The reaction mixture was then concentrated and the residue was purified using column chromatography, eluting with 20% to 90% EtOAc/hexanes, to give the product. (570 mg, 76% yield) 1HNMR (400 MHz, CDCI3): δ ppm 8.38-8.40 (m, 1 H), 7.07-7.1 1 (t, J = 8.0 Hz, 1 H), 7.40 (m, 1 H), 7.00-7.02 (m, 2H), 6.86- 6.94 (m, 2H), 3.84-3.88 (m, 4H), 3.69-3.73 (m, 2H), 2.33-2.37 (m, 2H), 1 .86- 1 .90 (m, 2H), 1 .51 (s, 3H); MS: 405.3 [M+H]+.
Intermediate 34: N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-methyltetrahvdro-2H- pyran-4-yl)-1 ,3-thiazol-4-yl1-2-fluorophenyl)-1 -propanesulfonamide
To a solution of {3-[5-(2-chloro-4-pyhnnidinyl)-2-(4-nnethyltetrahydro-2H-pyran- 4-yl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}amine (320 mg, 0.790 mmol) in pyridine (4 mL) was added 1 -propanesulfonyl chloride (0.133 mL, 1 .186 mmol), and the reaction mixture was stirred at room temperature for 5h and overnight at 0
°C. The reaction mixture was quenched with water (15 mL) and extracted with EtOAc (3x). The extract was dried over Na2SO4 and concentrated. The residue was purified using column chromatography, eluting with 20% to 80% EtOAc/hexanes, to give the product. (340 mg, 84% yield) 1 HNMR (400 MHz, CDCIs): δ ppm 8.44-8.45 (d, J = 4.0 Hz, 1 H), 7.71 -7.74 (m, 1 H), 7.40 (m, 1 H), 7.32 (m, 1 H), 6.97-6.98 (m, 1 H), 6.53 (s, 1 H), 3.84-4.15 (m, 2H), 3.69-3.84 (m, 2H), 3.12-3.16 (m, 2H), 2.30-2.36 (m, 2H), 1 .86-1 .93 (m, 4H), 1 .52 (s, 3H), 1 .05-1 .09 (t, J = 8.0 Hz, 3H); MS: 51 1 .1 [M+H]+.
Intermediate 35: 2-propen-1 -yl {2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4- methyltetrahvdro-2H-pyran-4-yl)-1 ,3-thiazol-4-yllphenyl)carbamate
To a solution of 2-propen-1 -yl {2-chloro-3-[(2-chloro-4- pyrimidinyl)acetyl]phenyl}carbamate (0.73 g, 1 .993 mmol) in N,N- dimethylacetamide (DMA) (10 mL) was added NBS (0.355 g, 1 .993 mmol), and the reaction mixture was stirred for 1 h. 4-Methyltetrahydro-2H-pyran-4- carbothioamide (0.317 g, 1 .993 mmol) was added and the reaction mixture was heated to 80 °C for 40 min. The mixture was cooled, quenched with water (30 mL) and extracted with EtOAc (3x). The extract was dried over Na2SO4, filtered and concentrated. The residue was purified using column
chromatography, eluting with 20% to 80% EtOAc/hexanes, to give the product. (510 mg, 51 % yield) 1HNMR (400 MHz, CDCI3): δ ppm 8.34-8.35 (d, J = 4.0 Hz, 1 H), 7.42-7.46 (t, J = 8.0 Hz, 1 H), 7.34 (m, 1 H), 7.14-7.16 (d, J = 4.0 Hz, 1 H), 6.69-6.70 (d, J = 4.0 Hz, 1 H), 5.97-6.07 (m, 1 H), 5.32-5.45 (m, 2H), 4.73-4.75 (d, J = 8.0 Hz, 2H), 3.84-3.89 (m, 2H), 3.68-3.75 (m, 2H), 2.32- 2.36 (m, 2H), 1 .86-1 .91 (m, 2H), 1 .51 (s, 3H); MS: 505.1 [M+H]+.
Intermediate 36: {2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-methyltetrahvdro- 2H-pyran-4-yl)-1 ,3-thiazol-4-yllphenyl)amine
To a solution of 2-propen-1 -yl {2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4- methyltetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4-yl]phenyl}carbamate (310 mg, 0.613 mmol) in dichloromethane (DCM) (5 mL) were added tributylstannane (179 mg, 0.613 mmol), tetrakis(triphenylphosphine) palladium(O) (35.4 mg, 0.031 mmol) and water (0.035 mL, 1 .963 mmol), and the reaction mixture was stirred for 1 h. The reaction mixture was then concentrated and the residue was purified using column chromatography, eluting with 20% to 90%
EtOAc/hexanes, to give the product. (230 mg, 89% yield) 1HNMR (400 MHz, CDCIs): δ ppm 8.33-8.34 (d, J = 4.0 Hz, 1 H), 7.19-7.23 (t, J = 8.0 Hz,1 H), 6.92-6.94 (m, 1 H),6.78-6.81 (s, 2H), 4.27 (s, 2H), 3.83-3.89 (m, 2H), 3.68-3.73 (m, 2H), 2.34-2.37 (m, 2H), 1 .87-1 .91 (m, 2H), 1 .51 (s, 3H); MS [M+H]+.
Intermediate 37: /V-l2-chloro-3-r5-(2-chloro-4-pyrimidinyl)-2-(4- methyltetrahvdro-2H-pyran-4-yl)-1 ,3-thiazol-4-yllphenyl)-1 - propanesulfonamide
To a solution of {2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-methyltetrahydro- 2H-pyran-4-yl)-1 ,3-thiazol-4-yl]phenyl}amine (240 mg, 0.570 mmol) in pyridine (4 mL) was added 1 -propanesulfonyl chloride (1 14 mg, 0.797 mmol). The reaction mixture was stirred for 6h and then kept at 5 °C for 30 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3x). The extract was dried over Na2SO and concentrated. The residue was purified using column chromatography, eluting with 20% to 90%
EtOAc/hexanes, to give the product. (210 mg, 70% yield) 1HNMR (400MHz, CDCIs): δ ppm 8.37-8.38 (d, J = 4.0 Hz, 1 H), 7.85-7.87 (dd, J = 8.0, 4.0, 1 H), 7.44-7.48 (t, J = 8.0 Hz, 1 H), 7.25-J.27 (m, 1 H), 6.88-6.89 (d, J = 4.0 Hz, 1 H), 3.84-3.78 (m, 2H), 3.68-3.73 (m, 2H), 3.15-3.19 (m, 2H), 2.31 -2.36 (m, 2H), 1 .87-1 .97 (m, 4H), 1 .52 (s, 3H), 1 .06-1 .10 (t, J = 8.0 Hz, 3H); MS: 527.3
[M+H]+.
Intermediate 38: 1 ,1 -dimethylethyl 4-(5-(2-amino-4-pyrimidinyl)-4-{2-chloro-3-
[(propylsulfonyl)aminolphenyl)-1 ,3-thiazol-2-yl)-4-methyl-1 - piperidinecarboxylate
A suspension of 1 ,1 -dimethylethyl 4-[4-{2-chloro-3- [(propylsulfonyl)amino]phenyl}-5-(2-chloro-4-pyrinnidinyl)-1 ,3-thiazol-2-yl]-4- methyl-1 -pipehdinecarboxylate (47 mg, 0.075 mmol) in ammonium hydroxide aqueous solution (28%, 1 ml_) sealed in a 5-mL microwave tube was heated at 90 °C for 2h under the microwave conditions. The mixture was
concentrated and the residue was further dried under high vacuum to give the crude product, which was used for next reaction without further purification. 45 mg 1HNMR (400MHz, DMSO-d6): δ ppm 8.03-8.04 (d, J = 4.0 Hz, 1 H),
7.61 -7.63 (d, J = 8.0 Hz, 1 H), 7.45-7.49 (t, J = 8.0, 4.0 Hz, 1 H), 7.36-7.38 (m, 1 H), 6.77 (m, 2H), 5.86-5.87 (d, J = 4.0 Hz, 1 H), 3.55-3.59 (m, 2H), 3.25 (m, 2H), 3.10-3.14 (t, J = 4.0 Hz, 2H), 2.09 (m, 2H), 1 .67-1 .77 (m, 4H), 1 .40 (m, 3H), 0.92-0.96 (m, J = 8.0 Hz, 3H); MS: 607.4 [M+H]+.
Intermediate 39: A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-methyl-1 -piperazinyl)-
1 ,3-thiazol-4-yl1-2-fluorophenyl)-1 -propanesulfonamide
A 100mL round-bottomed flask was charged with A/-{3-[(2-chloro-4- pyrimidinyl)acetyl]-2-fluorophenyl}-1 -propanesulfonamide (1 .5 g, 4.03 mmol) in Λ/,/V-dimethylacetamide (DMA) (20.17 mL) to give a brown solution at room temperature under nitrogen. To this reaction mixture, NBS (0.661 g, 3.71 mmol) was added. After 1 h, 4-methyl-1 -piperazinecarbothioamide (0.964 g, 6.05 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then diluted with water (20mL) and EtOAc (25 mL). After decantation and separation, the water layer was extracted with EtOAc (2 X 50 mL). The combined organic layers were washed with water (3 x 10 mL) and then dried over Na2SO4, filtered, and concentrated. The residue was chromatographed on silica gel column and eluted with MeOH in CHCIs (gradient 10 to 70%) to obtain A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4- methyl-1 -piperazinyl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}-1 -propanesulfonamide. (1 .23 g, 2.287 mmol, 56.7 % yield) LC/MS: MH+ 51 1 , 513.
Intermediate 40: A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-methyl-1 - piperazinyl)-1 ,3-thiazol-4-yllphenyl)-1 -propanesulfonamide
Following a procedure analogous to the one described in Example 39 using A/-{2-chloro-3-[(2-chloro-4-pyhmidinyl)acetyl]phenyl}-1 -propanesulfonamide (1 .5 g, 3.86 mmol) in Λ/,/V-Dimethylacetamide (DMA) (7.73 ml) and treated with NBS (NBS (0.653 g, 3.67 mmol) to give the intermediate A/-{3-[bromo(2- chloro-4-pyrimidinyl)acetyl]-2-chlorophenyl}-1 -propanesulfonamide. Without further purification, this solution was treated with 4-methyl-1 - piperazinecarbothioamide (0.738 g, 4.64 mol) to give the title product. (1 .21 g, 2.179 mol, 56.4 % yield) MS: M+ = 527 Intermediate 41 : /\/-{3-[5-(2-chloro-4-pyrinnidinyl)-2-(4-piperidinyl)-1 , 3-thiazol- 4-yl1-2-fluorophenyl)-1 -propanesulfonamide
1 ,1 -Dimethylethyl 4-(5-(2-chloro-4-pyrimidinyl)-4-{2-fluoro-3- [(propylsulfonyl)amino]phenyl}-1 ,3-thiazol-2-yl)-1 -piperidinecarboxylate (1 .4 g, 2.348 mmol) in dichloromethane (DCM) (30 ml_) was treated with
trifluoroacetic acid (TFA) (15 ml_) for 30 min. The reaction mixture progress was followed by HPLC. After the reaction was complete, the reaction mixture was concentrated and the crude oil was diluted with DCM (50 ml_) and was brought by 10% NaHCO3 to pH about 8.0. The final crude oil was
chromatographed on a silica gel column and eluted with dichloromethane (DCM): MeOH: NH4OH (90:10:0.1 ) in dichloromethane (DCM) from 5 to 80% to afford the title compound. (885 mg, 1 .695 mmol, 72.2 % yield) MS M+ = 496
Intermediate 42: A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1 -methyl-4-pipehdinyl)-
1 ,3-thiazol-4-yl1-2-fluorophenyl)-1 -propanesulfonamide
A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-piperidinyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-1 -propanesulfonamide (880 mg, 1 .774 mmol) was dissolved in methanol (17 mL) and treated with an aqueous 36% solution of formaldehyde (339 μΙ_, 4.44 mmol) and sodium borohydride (NaBH4) (168 mg, 4.44 mmol), which was added in 3 portions. The reaction mixture was stirred at room temperature and followed by HPLC and LCMS. The reaction mixture was then partitioned between saturated NaHCO3 and CHCI3. The organic phase was separated and concentrated to dryness. The residue was
chromatographed on a silica gel column and eluted with
chloroform/methanol/ammonium hydroxide (90:9:0.1 ) in chloroform from 5 to 80% to obtain the title compound. (339 mg, 0.598 mmol, 33.7 % yield) MS: (M+H)+ = 510, 512.
Intermediate 43: 1 ,1 -dimethylethyl 4-(5-(2-chloro-4-pyrimidinyl)-4-{2-fluoro-3- [(propylsulfonyl)aminolphenyl)-1 ,3-thiazol-2-yl)-1 -piperidinecarboxylate
Following a procedure analogous to the one described in Example 39 using A/-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-1 -propanesulfonamide (1 .2 g, 3.23 mmol) in Λ/,/V-dimethylacetamide (DMA) (6.45 mL) to produce intermediate A/-{3-[bromo(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-1 - propanesulfonamide. The crude intermediate was then treated with 1 ,1 - dimethylethyl 4-(aminocarbonothioyl)-1 -piperidinecarboxylate (0.789 g, 3.23 mmol) to give the title compound. (1 .62 g, 2.58 mmol, 80 % yield) MS M+ = 596
Intermediate 44: A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-pyhdinyl)-1 ,3- thiazol-4-yllphenyl)-1 -propanesulfonamide
Following a procedure analogous to the one described in Example 39 using /V-{2-chloro-3-[(2-chloro-4-pyrimidinyl)acetyl]phenyl}-1 -propanesulfonamide (1 .5g, 3.86 mmol) in Λ/,/V-dimethylacetannide (DMA) (7.73 ml_) and treated with NBS (0.653 g, 3.67 mmol) which gave the intermediate A/-{3-[bromo(2- chloro-4-pyrimidinyl)acetyl]-2-chlorophenyl}-1 -propanesulfonamide. The reaction mixture was treated with 4-pyridinecarbothioamide (0.534 g, 3.86 mmol) to give the title compound. (650mg, 1 .219 mmol, 31 .6 % yield) MS: M+ = 506
Intermediate 45: /V-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(2-pyhdinyl)-1 ,3- thiazol-4-yllphenyl)-1 -propanesulfonamide
Following a procedure analogous to the one described in Example 39 using A/-{2-chloro-3-[(2-chloro-4-pyhmidinyl)acetyl]phenyl}-1 -propanesulfonamide (1 .5g, 3.86 mmol) in Ν,Ν-dimethylacetamide (DMA) (7.73 ml_) and treated with NBS (0.653 g, 3.67 mmol) to give the intermediate A/-{3-[bromo(2-chloro- 4-pyrimidinyl)acetyl]-2-chlorophenyl}-1 -propanesulfonamide. The
intermediate solution was further treated with 2-pyridinecarbothioamide (0.534 g, 3.86 mmol) to give the title compound. (489 mg, 0.917 mmol, 23.74 % yield) MS M+ = 506 Intermediate 46: A/-(3-{5-(2-chloro-4-pynmidinyl)-2-r4-(2-hvdroxyethyl)-1■ piperidinylH ,3-thiazol-4-yl -2-fluorophenyl)-1 -propanesulfonamide
Following a procedure analogous to the one described in Example 39 using A/-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-1 -propanesulfonamide (697 mg, 1 .875 mmol) in Λ/,/V-dimethylacetamide (DMA) (3750 μΙ) and treated with NBS (317 mg, 1 .781 mmol) which gave the intermediate A/-{3-[bromo(2- chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-1 -propanesulfonamide. To this mixture 4-(2-hydroxyethyl)-1 -piperidinecarbothioamide (353 mg, 1 .875 mmol) was added. The title compound was obtained. (1 .01 g, 1 .777 mmol, 95 % yield) MS M+ = 540
Intermediate 47: A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-methyl-1 - piperazinyl)-1 , 3-thiazol-4-yllphenyl)-3, 3, 3-trifluoro-l -propanesulfonamide
Following a procedure analogous to the one described in Example 39 using A/-{2-chloro-3-[(2-chloro-4-pyrimidinyl)acetyl]phenyl}-3,3,3-trifluoro-1 - propanesulfonamide (1 .2 g, 2.71 mmol) in Ν,Ν-dimethylacetamide (DMA) (13.57 mL) and treated with NBS (0.459 g, 2.58 mmol) gave the intermediate A/-{3-[bromo(2-chloro-4-pyrimidinyl)acetyl]-2-chlorophenyl}-3,3,3-trifluoro-1 - propanesulfonamide. 4-Methyl-1-piperazinecarbothioamide (0.454 g, 2.85 mmol) was then added in one portion to give the title compound as a solid. (1.2 g, 1.961 mmol, 72.3 % yield) MS (M+H)+ = 581
Intermediate 48: A/-(3-r5-(2-chloro-4-pyrimidinyl)-2-(4-methyl-1 -piperazinyl)- I .S-thiazol^-yll^-fluorophenvD-S.S.S-trifluoro-l-propanesulfonamide
Following a procedure analogous to the one described in Example 39 using V-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-3,3,3-trifluoro-1- propanesulfonamide (1.2 g, 2.82 mmol) in Ν,Ν-dimethylacetamide (DMA) (13.57 mL) and treated with NBS (0.477 g, 2.68 mmol), and followed by 4- methyl-1-piperazinecarbothioamide (0.471 g, 2.96 mmol). The title compound was obtained. (1.2 g, 2.018 mmol, 71.6 % yield) MS: M+ = 565
Intermediate 49: 1 ,1-dimethylethyl 4-r5-(2-chloro-4-pyrimidinyl)-4-(2-chloro-3-
(r(3,3,3-thfluoropropyl)sulfonyl1amino)phenyl)-1 ,3-thiazol-2-yl1-1- piperidinecarboxylate
Following a procedure analogous to the one described in Example 39
using A/-{2-chloro-3-[(2-chloro-4-pyrimidinyl)acetyl]phenyl}-3,3,3-thfluoro-1 - propanesulfonamide (1 .5 g, 3.39 mmol) in /V,/V-dimethylacetamide (DMA) (6.78 ml_) and treated with NBS (0.586 g, 3.29 mmol) gave the intermediate A/-{3-[bromo(2-chloro-4-pyrimidinyl)acetyl]-2-chlorophenyl}-3,3,3-trifluoro-1 - propanesulfonamide. To this reaction mixture, 1 ,1 -dimethylethyl 4- (aminocarbonothioyl)-l -piperidinecarboxylate (0.829 g, 3.39 mmol) in one portion was added in order to obtain the title compound. (1 .4 g, 1 .995 mmol, 58.8 % yield) MS (M+H)+ = 667.
Intermediate 50: 1 ,1 -dimethylethyl 4-[5-(2-amino-4-pyrimidinyl)-4-(2-chloro-3- {[(3,3,3-trifluoropropyl)sulfonyl1amino)phenyl)-1 ,3-thiazol-2-yl1-1 - piperidinecarboxylate
Following a procedure analogous to the one described in Example 93 using 1 -dimethylethyl 4-[5-(2-chloro-4-pyrimidinyl)-4-(2-chloro-3-{[(3,3,3- trifluoropropyl)sulfonyl]amino}phenyl)-1 ,3-thiazol-2-yl]-1 -piperidinecarboxylate (400 mg, 0.600 mmol) in ammonium hydroxide (4674 μΙ, 120 mmol), the title compound was obtained. (250 mg, 0.367 mmol, 61 .2 % yield) MS M+ = 647
Intermediate 51 : A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-piperidinyl)-1 ,3- thiazol-4-yllphenyl)-3,3,3-trifluoro-1 -propanesulfonamide
Following a procedure analogous to the one described in Example 41 using 1 -dimethylethyl 4-[5-(2-chloro-4-pyrimidinyl)-4-(2-chloro-3-{[(3,3,3- trifluoropropyl)sulfonyl]amino}phenyl)-1 ,3-thiazol-2-yl]-1 -piperidinecarboxylate (700 mg, 1 .050 mmol) in dichloromethane (DCM) (5251 μΙ_) and treated with TFA (81 μΙ_, 1 .050 mmol). The title compound was obtained as a yellow solid (500 mg, 0.839 mmol, 80 % yield) MS: M+ = 566
Intermediate 52: A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1 -methyl-4- piperidinyl)-1 ,3-thiaz -4-yllphenyl)-3,3,3-trifluoro-1 -propanesulfonamide
A vessel was charged with a suspension of A/-{2-chloro-3-[5-(2-chloro-4- pyrimidinyl)-2-(4-piperidinyl)-1 ,3-thiazol-4-yl]phenyl}-3,3,3-trifluoro-1 - propanesulfonamide (480 mg, 0.847 mmol) in 1 ,2-dichloroethane (DCE) (4237 μΙ_). To this suspension, paraformaldehyde (50.9 mg, 1 .695 mmol) and sodium triacetoxyborohydride (359 mg, 1 .695 mmol) were added. The reaction mixture was stirred at room temperature. After 4.0 h, LC/MS showed a mixture of desired product and starting material. Therefore another 2.0 g of paraformaldehyde (50.9 mg, 1 .695 mmol) was added. The reaction mixture was then stirred at room temperature overnight. The reaction was diluted with DCM (50 mL) and washed by water (30 mL x 2) and dried over Na2SO4 which afforded the title compound as a yellow solid (436 mg, 0.751 mmol, 89 % yield) MS: M+ = 580 Intermediate 53: 1 -dimethylethyl 4-(5-(2-chloro-4-pyrimidinyl)-4-{2-fluoro-3- [(propylsulfonyl)aminolphenyl)-1 ,3-thiazol-2-yl)-1 -piperazinecarboxylate
Step 1 : -{[(1 ,1 -dimethylethyl)oxy]carbonyl}piperazin-1 -ium thiocyanate
1 -Dimethylethyl 1 -piperazinecarboxylate (5.0 g, 26.8 mmol) in tetrahydrofuran (THF) (207 mL) was treated with 4.0 M HCI (6.71 mL, 26.8 mmol) and potassium thiocyanate (2.61 g, 26.8 mmol) dissolved in minimal amount of water. The reaction mixture was stirred at room temperature overnight; the volatiles were removed under vacuum. The residue was taken up in methanol (25mL) and filtered to remove inorganic salts. Filtrate was concentrated to dryness. The cycle was repeated two more times, to give a light pink solid. This solid was then triturated with 20 mL of ethyl acetate and ether (in 2:1 ratio) for 30 min to give 4-{[(1 ,1 -dimethylethyl)oxy]carbonyl}piperazin-1 -ium thiocyanate. (1 .68 g, 66%).
Step 2: 1 -dimethylethyl 4-(5-(2-chloro-4-pyrimidinyl)-4-{2-fluoro-3- [(propylsulfonyl)amino]phenyl}-1 ,3-thiazol-2-yl)-1 -piperazinecarboxylate A 100 mL round-bottomed flask was charged with A/-{3-[(2-chloro-4- pyrimidinyl)acetyl]-2-fluorophenyl}-1 -propanesulfonamide (1 .5 g, 4.03 mmol) in A/,A/-dimethylacetamide (DMA) (13.45 ml) to give a brown solution at room temperature under nitrogen. NBS (0.682 g, 3.83 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 1 h. To this reaction mixture, previously prepared boc-piperazinium thiocyanate salt from step 1 , (0.990 g, 4.03 mmol) was added in one portion. This reaction mixture was stirred at room temperature for 18 h before being diluted with water (20 mL) and EtOAc (25 mL). After decantation, the water layer was extracted with EtOAc (2 X 50 mL). The combined organic phases were washed with water (3 x 30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was chromatographed on silica gel column and eluted with EtOAc in Hexane from 10 to 80% affording the title compound. (1 .68 g, 2.67 mmol, 66.3 % yield) MS M+ = 598
Intermediate 54: 1 ,1 -dimethylethyl 4-[5-(2-chloro-4-pyrimidinyl)-4-(2-fluoro-3- {[(3,3,3-trifluoropropyl)sulfonyl1amino)phenyl)-1 ,3-thiazol-2-yl1-1 - piperazinecarboxylat
Following a procedure analogous to the one described in Example 53 using A/-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-3,3,3-thfluoro-1 - propanesulfonamide (1 .1 g, 2.58 mmol) in Λ/,/V-dimethylacetamide (DMA) (8.61 mL) was treated with NBS (0.437 g, 2.454 mmol) which gave the A/-{3- [bromo(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-3,3,3-trifluoro-1 - propanesulfonamide. The intermediate solution was further treated 4-{[(1 , 1 - dimethylethyl)oxy]carbonyl}piperazin-1 -ium thiocyanate complex salt (0.634 g, 2.58 mmol) as one portion. The title compound was obtained. (980 mg, 1 .430 mmol, 55.3 % yield) MS: (M+H)+ = 546 Intermediate 55: 1 ,1 -dimethylethyl 4-[5-(2-annino-4-pynnnidinyl)-4-(2-fluoro-3-
{[(3,3,3-trifluoropropyl)sulfonyl1amino)phenyl)-1 ,3-thiazol-2-yl1-1 - piperazinecarboxylate
Following a procedure analogous to the one described in Example 93 using A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-methyl-1 -piperazinyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-3,3,3-trifluoro-1 -propanesulfonamide (120 mg, 0.212 mmol) and ammonium hydroxide (2481 μΙ_, 63.7 mmol). The title compound was obtained. (280 mg, 0.430 mmol, 68.5 % yield) MS: (M+H)+ = 632
Intermediate 56: 1 ,1 -dimethylethyl 4-[5-(2-chloro-4-pyhmidinyl)-4-(2-chloro-3- {[(3,3,3-trifluoropropyl)sulfonyl1amino)phenyl)-1 ,3-thiazol-2-yl1-1 - piperazinecarboxylate
Following a procedure analogous to the one described in Example 54 using N-{2-chloro-3-[(2-chloro-4-pyrimidinyl)acetyl]phenyl}-3,3,3-trifluoro-1 - propanesulfonamide (1 .1 g, 2.487 mmol) in Ν,Ν-dimethylacetamide (DMA) and treated with NBS (0.421 g, 2.363 mmol) which gave the intermediate /V- {3-[bromo(2-chloro-4-pyrimidinyl)acetyl]-2-chlorophenyl}-3,3,3-trifluoro-1 - propanesulfonamide. Without further purification, this intermediate solution was treated with by 4-{[(1 , 1 -dimethylethyl)oxy]carbonyl}piperazin-1 -ium thiocyanate complex salt (0.610 g, 2.49 mmol) to give the title compound. (1 .17 g, 1 .612 mmol, 64.8 % yield) MS M+ = 667
Intermediate 57: 2,2,5-trimethvl-1 ,3-dioxane-5-carbothioamide
Step 1 : 2,2,5-trimethyl-1 ,3-dioxane-5-carboxylic acid
To a stirred solution of 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoic acid (20 g, 149 mmol) in dichloromethane (DCM) (150 mL) was added 2, 2- bis(methyloxy)propane (55.5 ml, 452 mmol) and tosic acid (0.284 g, 1 .491 mmol). The resulting solution was stirred at room temperature for 4 hours before being neutralized with triethylamine (10 mL). After 20 min, more DCM (300 mL) was added. The reaction mixture was washed with 100 mL of water. The organic phase was separated, dried over Na2SO4, filtered and
concentrated to give an oil. This oil was recrystallized by Hexane:Et2O = 9 : 1 (by volume) to give 2,2,5-trimethyl-1 ,3-dioxane-5-carboxylic acid. (3.5 g, 13 % yield) 1 H NMR (DMSO-d6) δ ppm 12.53 (br. s., 2 H) 4.01 (d, J=1 1 .62 Hz, 2 H) 3.56 (d, J=1 1 .37 Hz, 2 H) 1 .18 - 1 .40 (m, 6 H) 1 .07 (s, 3 H)
Step 2: 2,2,5-trimethyl-1 ,3-dioxane-5-carboxamide A vessel was charged with 2,2,5-trimethyl-1 ,3-dioxane-5-carboxylic acid (3.39 g, 19.46 mmol) and Ν,Ν'-carbonyldiimidazole (CDI) (3.79 g, 23.35 mmol) in tetrahydrofuran (THF) (64.9 mL) and stirred at room temperature for 1 .5h. To this solution 2.0 M ammonia in MeOH solution (24.33 mL, 48.7 mmol) was added at 0 °C . The solution was stirred at 0 °C for 30 min and then let warm up to room temperature overnight. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc 200 ml_ and washed with 5% citric acid (2x 30 ml_) then 10% NaHCOs and brine. The organic phase was dried over MgSO , filtered and evaporated to dryness to give a white solid 2,2,5-thmethyl-l ,3-dioxane-5-carboxamide. (1 .05 g, 5.76 mmol, 29.6 % yield) 1 H NMR (DMSO-d6) δ ppm 6.97 - 7.17 (m, 2 H) 3.95 (d, J=1 1 .62 Hz, 2 H) 3.56 (d, J=1 1 .62 Hz, 2H) 1 .24 - 1 .37 (m, 6 H) 1 .07 (s, 1 H) 1 .05 (s, 3 H).
Step 3: 2,2,5-trimethyl-1 ,3-dioxane-5-carbothioamide A vessel was charged with 2,5-trimethyl-1 ,3-dioxane-5-carboxamide (2.65 g, 15.30 mmol) in tetrahydrofuran 20 ml_ and Lawesson's reagent (6.19 g, 15.30 mmol). The reaction mixture was heated at reflux under nitrogen for 3h. The reaction mixture was then allowed to stir at room temperature overnight before being concentrated under reduced pressure. The residue was dissolved in EtOAc 200ml_ and washed with 10% NaHCO3 and brine. The organic phase was dried over MgSO4 and evaporated to dryness. The residue was chromatographed on a silica gel column and eluted with 0 to 5% methanol in chloroform. The title compound was obtained as a white solid. (580 mg, 3.06 mmol, 20.03 % yield) 1 H NMR (DMSO-d6) δ ppm 9.71 (br. s., 1 H) 8.83 (br. s., 1 H) 4.07 (d, J=1 1 .87 Hz, 2 H) 3.65 (d, J=1 1 .62 Hz, 2 H) 1 .28 - 1 .36 (m, 6 H) 1 .25 (s, 3 H)
Intermediate 58: A/-(3-{5-(2-chloro-4-pyhmidinyl)-2-[2-hydroxy-1 - (hvdroxymethvD-1 -methylethyll-1 ,3-thiazol-4-yl)-2-fluorophenyl)-1 - propanesulfonamide
Following a procedure analogous to the one described in Example 1 using N- {3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-1 -propanesulfonamide (1 157 mg, 3.1 1 mmol) in Ν,Ν-dimethylacetamide (DMA) (6224 μΙ_), which was treated with NBS (526 mg, 2.96 mmol), to give the intermediate N-{3- [bromo(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-1 -propanesulfonamide. To this solution, 2,2,5-trimethyl-1 ,3-dioxane-5-carbothioamide (589 mg, 3.1 1 mmol) was added in one portion. The title compound was obtained. (788 mg, 1 .494 mmol, 48.0 % yield) 1H NMR (DMSO-d6) δ ppm 9.75 (s, 1 H) 8.61 (d, J=5.31 Hz, 1 H) 8.32 (s, 1 H) 7.54 - 7.61 (m, 1 H) 7.45 - 7.52 (m, 1 H) 7.36 (t, J=7.83 Hz, 1 H) 7.1 1 (d, J=5.56 Hz, 1 H) 5.03 (t, J=5.43 Hz, 2 H) 3.56 - 3.76 (m, 4 H) 2.99 - 3.1 1 (m, 2 H) 1 .60 - 1 .77 (m, 2 H) 1 .35 (s, 3 H) 0.92 (t, J=7.45 Hz, 3 H); MS: (M+H)+ = 501
Intermediate 59: methyl 2-chloro-3-{[(3,3,3- trifluoropropyDsulfonyllaminolbenzoate
To a solution of methyl 3-amino-2-chlorobenzoate (20 g, 108 mmol) in pyridine (300 ml_) was added dropwise a solution of 3,3,3-trifluoro-1 - propanesulfonyl chloride (21 .18 g, 108 mmol) in 30 ml_ of pyridine. After 16 hours at room temperature, 3, 3,3-trifluoro-1 -propanesulfonyl chloride (4 g) was added to the reaction mixture. After another 24 hours, the reaction solution was concentrated. The crude residue was partioned between EtOAc and water. The phases were separated. The aqueous phase was further extracted with EtOAc twice more and the combined organic phases were washed with 1 N HCI, water, brine and dried over MgSO4, filtered and concentrated to obtain title compound. Intermediate 60: /V-{2-chloro-3-[(2-chloro-4-pynmidinyl)acetyllphenyl)-3,3,3- trifluoro-1 -propanesulfonamide
A solution of methyl 2-chloro-3-{[(3,3,3-trifluoropropyl)sulfonyl]amino}benzoate (20 g, 57.8 mmol) and 2-chloro-4-methylpyrimidine (8.18 g, 63.6 mmol) in tetrahydrofuran (THF) (500 mL) was cooled in 0 °C. Lithium
bis(trimethylsilyl)amide (185 mL, 185 mmol) was added dropwise and warmed to room temperature overnight. The reaction was treated with 4M HCI dropwise till pH = 2. The reaction was diluted with 200 mL of EtOAc and washed with water, brine, dried over MgSO4, filtered and concentrated to obtain title compound. Intermediate 61 : methyl 2-fluoro-3-{[(3.3.3- trifluoropropyDsulfonyllaminolbenzoate
A stirred solution of methyl 3-amino-2-fluorobenzoate (7.32 g, 43.3 mmol) in pyridine (20 ml, 247 mmol) under argon was cooled in an ice-bath and treated portion-wise with 3,3,3-trifluoro-1 -propanesulfonyl chloride (10.0 g, 50.9 mmol) over 1 hour. The viscous orange-yellow mixture was magnetically stirred at room temperature overnight. The reaction mixture was partitioned between DCM and 4 M HCI (500 mL) and the separated organic phase was washed with water and brine (100 mL), dried (MgSO^, filtered and
evaporated to obtain title compound (1 .82 g) a light purple solid. Intermediate 62: A/-{3-[(2-chloro-4-pyrinniclinyl)acetyl1-2-fluorophenyl)-3,3,3- trifluoro-1 -propanesulfonamide
A 1 L, 3 neck RB, fitted with a low temp thermometer, argon bubbler and a septum cap was charged with methyl 2-fluoro-3-{[(3,3,3- trifluoropropyl)sulfonyl]amino}benzoate (12.28 g, 37.3 mmol), methyl 3- {bis[(3,3,3-trifluoropropyl)sulfonyl]amino}-2-fluorobenzoate (1 .72 g, 3.51 mmol) and 2-chloro-4-methylpyrimidine (5.25 g, 40.81 mmol) dissolved in tetrahydrofuran (THF) (280 ml). The stirring solution was cooled to -15 °C. A 1 M THF solution of LiHMDS (1 16 ml, 1 16 mmol) was added slowly via a syringe, maintaining temperature below -10 °C for the duration of the addition, following which the temperature was allowed to rise to -5 °C. The reaction was quenched with saturated aqueous NH4CI (300 mL) and the cooling bath was removed. After 20 minutes at room temperature, the reaction mixture was poured into EtOAc (1 L) and stirred. The separated organic phase was partitioned with 4M HCI (1 L) and stirred for 10 minutes. After separation, the organic layer was washed with water, brine (500 mL each), dried (MgSO^, filtered and the filtrate evaporated to obtain title compound. 16.17 g as a brown gum.
Intermediate 63: met -chloro-3-(propylsulfonamido)benzoate
To a solution of methyl 3-amino-2-chlorobenzoate (40 g, 216 mmol) in pyridine (45 mL) stirred at 0°C was added a solution of propane-1 -sulfonyl chloride (29.1 mL, 259 mmol) dropwise during 30 min. The reaction mixture was stirred at 30 °C for 6 h. After 6 h, the reaction mixture was cooled and 80 mL of water and dichloromethane (100 mL) was added. The organic layer was separated and aqueous layer was extracted with dichloromethane(100 mL x 3). The combined organic layers were dried over Na2SO4, and concentrated. The residue was purified silica gel chromatography and was eluted with Hex/EtOAc (4:1 ) to afford methyl 2-chloro-3- (propylsulfonamido)benzoate. (56g, 89 % yield) as a yellow solid MS: 309 [M+H]+. Intermediate 64: A/-(2-chloro-3-(2-(2-chloropyrimidin-4- yl)acetyl)phenyl)propane-1 -sulfonamide
To a solution of methyl 2-chloro-3-(propylsulfonamido)benzoate (83 g, 284 mmol) in tetrahydrofuran (THF) (450 mL) stirred under nitrogen at -30°C was added a solution of LiHMDS (996 mL, 996 mmol) in tetrahydrofuran (THF) (463 mL, 1 M) dropwise during 1 hour. The reaction mixture was stirred at -10 °C for 2 hrs. A solution of 2-chloro-4-methylpyrimidine (43.9 g, 341 mmol) in tetrahydrofuran (THF) (50 mL) was added to the reaction mixture. The reaction mixture was stirred at -10 °C for 30 min, and warmed to room temperature with stirring overnight. The reaction mixture was cooled to 0°C and quenched by addition of the saturated aqueous NH CI (800ml). The reaction mixture was extracted with ethyl acetate (800 mL x 3). The
combined organic layers were washed with water, brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel
chromatography, eluting with hexanes/EtOAc (4:1 ) to afford A/-(2-chloro-3-(2- (2-chloropyrimidin-4-yl)acetyl)phenyl)propane-1 -sulfonamide. (45 g, 39 % yield) as a light yellow solid MS: 388 [M+H]+.
Intermediate 65: /V-{3-[5-(2-chloro-4-pyhmidinyl)-2-(tetrahvdro-2H-pyran-4-yl)- 1 ,3-oxazol-4-yl1-2-fluorophenyl)-1 -propanesulfonamide
A 100 mL two neck flask was charged with A/-{3-[bromo(2-chloro-4- pyhmidinyl)acetyl]-2-fluorophenyl}-1 -propanesulfonannide (4.0 g, 8.87 mmol) and tetrahydro-2H-pyran-4-carboxamide (5.73 g, 44.4 mmol) in 1 ,4-dioxane (17.75 ml). The reaction mixture was refluxed at 120 °C. After 10 hours, the reaction mixture was cooled and diluted with 50 mL of DCM and stirred at room temperature for 30 min. The solids were filtered. The filtrate was evaporated to dryness then re-dissolved in DCM 10 mL and loaded on silica gel column and eluted with DCM in (10% MeOH in DCM) from 2 to 30%. The clean fractions were concentrated to obtain A/-{3-[5-(2-chloro-4-pyrimidinyl)-2- (tetrahydro-2H-pyran-4-yl)-1 ,3-oxazol-4-yl]-2-fluorophenyl}-1 - propanesulfonamide. (1 .89 g, 42 % yield) MS (ESI): 481 [M+H]+.
Example 1 : A/-{2-fluoro-3-[5-(2-{r2-(1 -pyrrolidinyl)ethyl1amino)-4-Pyrimidinyl)-2- (tetrahvdro-2H-pyran-4-yl)-1 ,3-thiazol-4-yllphenyl)-1 -propanesulfonamide
A 5 mL microwave tube was charged with A/-{3-[5-(2-chloro-4-pyrimidinyl)-2- (tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}-1 - propanesulfonamide (200 mg, 0.402 mmol) and 1 -(2-aminoethyl)pyrrolidine (0.152 mL, 1 .207 mmol) in toluene (3 mL) to give a colorless solution at room temperature under nitrogen. The sealed reaction mixture was heated at 90
°C for 1 h. After 1 h, the reaction mixture was concentrated. The residue was chromatographed on a silica gel column and eluted with chloroform and chloroform with 10% MeOH (5% to 75%) obtain A/-{2-fluoro-3-[5-(2-{[2-(1 - pyrrolidinyl)ethyl]amino}-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3- thiazol-4-yl]phenyl}-1 -propanesulfonamide (60 mg, 25.4 % yield). 1H NMR (400 MHz, DMSO-c/e) ppm 9.82 (br. s., 1 H) 8.12 (d, J=5.31 Hz, 1 H) 7.47 - 7.59 (m, 1 H) 7.23 - 7.43 (m, 2 H) 7.16 (t, J=5.81 Hz, 1 H) 6.22 - 6.10 (m, 1 H) 3.94 (dt, J=9.66, 2.12 Hz, 2 H) 3.48 (td, J=1 1 .62, 1 .77 Hz, 2 H) 3.29 - 3.35 (m, 3H) 2.92 - 3.10 (m, 2 H) 2.57 (t, J=6.95 Hz, 2 H) 1 .95 - 2.10 (m, 2 H) 1 .59 - 1 .86 (m, 12 H) 0.79 - 1 .02 (m, 3 H); MS: 575 [M+H]+.
Example 2: A/-{2-fluoro-3-[5-(2-{[2-( 1 -piperidinyl)ethyl1amino)-4-pyrimidinyl)-2- (tetrahvdro-2H-pyran-4-yl)-1 ,3-thiazol-4-yllphenyl)-1 -propanesulfonamide
Following a procedure analogous to the procedure described in Example 1 using N-{3-[5-(2-chloro-4-pyhmidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol- 4-yl]-2-fluorophenyl}-1 -propanesulfonamide (200 mg, 0.402 mmol) and 2-(1 - piperidinyl)ethanamine (0.171 ml_, 1 .207 mmol), the title compound was obtained (80 mg, 33.1 % yield). 1 H NMR (400 MHz, DMSO-c/6) ppm 9.75 (br. s., 1 H) 8.12 (d, J=5.05 Hz, 1 H) 7.44 - 7.61 (m, 1 H) 7.24 - 7.44 (m, 2 H) 7.08 (t, J=5.68 Hz, 1 H) 6.15 (br. s., 1 H) 3.94 (dt, J=9.66, 1 .99 Hz, 2 H) 3.48 (td, J=1 1 .49, 1 .77 Hz, 2 H) 3.30 (dd, J=7.83, 3.79 Hz, 2 H) 2.94 - 3.08 (m, 2 H) 2.36 - 2.49 (m, 5 H) 2.27 - 2.36 (m, 2 H) 1 .96 - 2.1 1 (m, 2 H) 1 .59 - 1 .86 (m, 4 H) 1 .49 (quin, J=5.37 Hz, 4 H) 1 .38 (br. s., 2 H) 0.87 - 0.95 (m, 3 H). MS: 589 [M+H]+.
Example 3: A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahvdro-2H-pyran-4-yl)-1 ,3- thiazol-4-yl1-2-fluorophenyl)-1 -propanesulfonamide
A 5 mL microwave tube was charged with A/-{3-[5-(2-chloro-4-pyrimidinyl)-2- (tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}-1 - propanesulfonamide (250 mg, 0.503 mmol) and ammonium hydroxide (10 ml, 257 mmol) to give a yellow solution at room temperature under nitrogen. The sealed reaction mixture was microwaved at 90°C for 1 h. After 1 h, the reaction mixture was concentrated. The reaction mixture was diluted with CH2CI2 (50 mL) and water (50 mL) and stirred. The pH of the reaction mixture was adjusted to pH = 7. After stirring, the CH2CI2 layer was separated form the water layer. The water layer was extracted with CH2CI2 (3x). The CH2CI2 layers were dried over Na2SO4, filtered, and concentrated. The residue was dissolved in IPA (5 ml) and heated to reflux and cooled to 0 °C. The solids were filtered and washed with IPA to obtain N-{3-[5-(2-amino-4-pyrimidinyl)-2- (tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}-1 - propanesulfonamide (193 mg, 79 % yield). 1H NMR (400 MHz, DMSO-c/6) ppm 9.75 (s, 1 H) 8.07 (d, J=5.05 Hz, 1 H) 7.48 - 7.61 (m, 1 H) 7.38 - 7.44 (m, 1 H), 7.30 - 7.34 (m, 1 H) 6.79 (s, 2 H) 6.09 (d, J=5.05 Hz, 1 H) 3.94 (dt, J=9.47, 2.21 Hz, 2 H) 3.48 (td, J=1 1 .62, 2.02 Hz, 2 H) 3.24 - 3.39 (m, 1 H) 2.97 - 3.12 (m, 2 H) 1 .94 - 2.10 (m, 2 H) 1 .58 - 1 .86 (m, 4 H) 0.92 (t, J=7.45 Hz, 3 H); MS: 478 [M+H]+.
Example 4: A/-{2-fluoro-3-[5-(2-{[2-(4-methyl-1 -piperazinyl)ethyl1amino)-4- pyrimidinyl)-2-(tetrahvdro-2H-pyran-4-yl)-1 ,3-thiazol-4-yllphenyl)-1 - propanesulfonamide
Following a procedure analogous to the procedure described in Example 1 using A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol- 4-yl]-2-fluorophenyl}-1-propanesulfonamide (200 mg, 0.402 mmol) and 2-(4- methyl-1-piperazinyl)ethanamine (173 mg, 1.207 mmol), the title compound was obtained (30 mg, 12 % yield). 1H NMR (400 MHz, DMSO- /6) ppm 9.78 (br. s., 1 H) 8.12 (d, J=5.05 Hz, 1 H) 7.44 - 7.63 (m, 1 H) 7.34 - 7.44 (m, 1 H) 7.23 - 7.34 (m, 1 H) 7.08 (t, J=5.68 Hz, 1 H) 6.16 (br. s„ 1 H) 3.94 (dt, J=9.47, 2.08 Hz, 2 H) 3.43 - 3.57 (m, 2 H) 3.28 - 3.36 (m, 1 H) 2.97 - 3.08 (m, 2 H) 2.26 - 2.43 (m, 12 H) 2.15 (s, 3 H) 2.02 (dd, J=12.63, 2.02 Hz, 2 H) 1.58 - 1.86 (m, 4 H) 0.86 - 0.95 (m, 3 H) ; MS: 604 [M+H]+.
Example 5: A/-{2-fluoro-3-f5-f2-(methylamino)-4-pyrimidinvn-2-(tetrahydro-2H-
Following a procedure analogous to the procedure described in Example 1 using /V-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol- 4-yl]-2-fluorophenyl}-1 -propanesulfonamide (200 mg, 0.402 mmol),
methylamine in THF (0.805 ml_, 1 .610 mmol) in 1 ,4-dioxane (3 ml_), the title compound was obtained (1 10 mg, 52 % yield). 1 H NMR (400 MHz, DMSO-c/6) ppm 9.62 (br. S., 1 H) 8.13 (d, J=5.05 Hz, 1 H) 7.45 - 7.62 (m, 1 H) 7.35 - 7.44 (m, 1 H) 7.31 (t, J=7.83 Hz, 1 H) 7.21 (d, J=4.80 Hz, 1 H) 6.17 (br. s., 1 H) 3.94 (dt, J=9.41 , 2.12 Hz, 2 H) 3.43 - 3.54 (m, 2 H) 3.24 - 3.39 (m, 4 H) 2.95 - 3.08 (m, 2 H) 2.03 (dd, J=12.88, 2.02 Hz, 2 H) 1 .55 - 1 .84 (m, 4 H) 0.80 - 1 .02 (m, 3 H); MS: 492 [M+H]+.
Example 6: /V-{2-fluoro-3-[5-(2-{[2-(4-morpholinyl)ethyl1amino)-4-pyhmidinyl)- 2- tetrahvdro-2H-pyran-4-yl)-1 ,3-thiazol-4-yllphenyl)-1 -propanesulfonamide
Following a procedure analogous to the procedure described in Example 1 using A/-{3-[5-(2-chloro-4-pyhmidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol- 4-yl]-2-fluorophenyl}-1 -propanesulfonamide (200 mg, 0.402 mmol) and 4-(2- aminoethyl)morpholine (0.157 ml_, 1 .207 mmol), the title compound was obtained (60 mg, 25 % yield). 1H NMR (400 MHz, DMSO-c/6) ppm 9.74 (s, 1 H) 8.12 (d, J=5.05 Hz, 1 H) 7.46 - 7.61 (m, 1 H) 7.36 - 7.45 (m, 1 H) 7.25 - 7.36 (m, 1 H) 7.13 (t, J=5.81 Hz, 1 H) 6.16 (br. s., 1 H) 3.94 (dt, J=9.60, 2.15 Hz, 2 H) 3.56 (t, J=4.55 Hz, 4 H) 3.48 (td, J=1 1 .62, 2.02 Hz, 2 H) 3.28 - 3.36 (m, 1 H) 2.95 - 3.09 (m, 2 H) 2.37 - 2.48 (m, 8 H) 1 .92 - 2.1 1 (m, 2 H) 1 .58 - 1 .88 (m, 4 H) 0.81 - 1 .10 (m, 3 H); MS: 591 [M+H]+. Example 7: A/-(2-fluoro-3-f5-(2-r(2-hvdroxyethyl)aminol-4-pyrimidinyl}-2- (tetrah dro-2H-pyran-4-yl)-1 ,3-thiazol-4-yllprienyl)-1-propanesulfonamide
Following a procedure analogous to the procedure described in Example 1 using A/-{3-[5-(2-chioro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol- 4-yl]-2-fluorophenyl}-1-propanesulfonamide (150 mg, 0.302 mmol) and 2- aminoethanol (0.073 mL, 1.207 mmol), the title compound was obtained (80 mg, 50 % yield). 1H NMR (400 MHz, DMSO-c/6) ppm 9.74 (s, 1 H) 8.12 (d, J=5.05 Hz, 1 H) 7.54 (t, J=7.07 Hz, 1 H) 7.23 - 7.47 (m, 2 H) 7.17 (t, J=5.56 Hz, 1 H) 6.14 (br. s., 1 H) 4.65 (br. s., 1 H) 3.80 - 4.04 (m, 2 H) 3.41 - 3.59 (m, 4 H) 3.28 - 3.32 (m, 3 H) 2.93 - 3.1 (m, 2 H) 1.94 - 2.07 (m, 2 H) 1.57 - 1.86 (m, 4 H) 0.88 - 0.95 (m, 3 H); MS: 522 [M+H]+.
Example 8: A/-(2-fluoro-3-r5-(2-{[(2R)-2-hvdroxypropynamino)-4-pyrimidinyl)-2- (4-morpholinyl)-1 ,3-thiazol-4-yllphenyl)-1 -propanesulfonamide
Following a procedure analogous to the procedure described in Example 1 using A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-1-propanesulfonamide (150 mg, 0.301 mmol) and (2R)-1-amino- 2-propanol (22 mg, 0.301 mmol), the title compound was obtained (50 mg, 30 % yield). H NMR (400 MHz, DMSO- /6) ppm 9.76 (s, 1 H) 7.95 (d, J=5.31 Hz, 1 H) 7.42 - 7.68 (m, 1 H) 7.16 - 7.42 (m, 2 H) 6.92 (br. s., 1 H) 5.89 (d, J=5.05 Hz, 1 H) 4.67 (br. s., 1 H) 3.67 - 3.85 (m, 5 H) 3.40 - 3.60 (m, 4 H) 3.10 - 3.25 (m, 2 H) 2.99 - 3.10 (m, 2 H) 1.65 - 1.77 (m, 2 H) 1.05 (d, J=6.06 Hz, 3 H) 0.92 (t, J=1A5 Hz, 3 H); MS: 536.7 [M+H]+.
Example 9: /V-(3-r5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3- thiazol-4-vn-2-chlorophenyl)-1-propanesulfonamide
Following a procedure analogous to the procedure described in Example 3 using A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)- 1 ,3-thiazol-4-yl]phenyl}-1-propanesulfonamide (175 mg, 0.341 mmol) and ammonium hydroxide (3 ml_, 77 mmol) for 1 h, the title compound was obtained (70 mg, 41 % yield). 1H NMR (400 MHz, DMSO-cfe) ppm 9.58 (s, 1 H) 8.02 (d, J=5.31 Hz, 1 H) 7.62 (dd, J=8.08, 1.77 Hz, 1 H) 7.48 (t, J=7.83 Hz, 1 H) 7.36 (dd, J=7.58, .52 Hz, 1 H) 6.77 (s, 2 H) 5.84 (d, J=5.05 Hz, 1 H) 3.94 (dt, =9.54, 2.05 Hz, 2 H) 3.48 (td, J=11 .49, 2.02 Hz, 2 H) 3.30 - 3.32 (m, 1 H) 2.99 - 3.13 (m, 2 H) 1.92 - 2.10 (m, 2 H) 1.56 - 1.85 (m, 4 H) 0.94 (t, J=7.45 Hz, 3 H) ; MS: 494, 496 [M+H]+. Example 10: A/-{2-fluoro-3-r5-(2-{r(2S)-tetrahvdro-2-furanylmethyl1amino)-4- Pyrimidinyl)-2-(tetrahvdro-2H-pyran-4-yl)-1 ,3-thiazol-4-yllphenyl)-1 -
Following a procedure analogous to the procedure described in Example 1 using with A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3- thiazol-4-yl]-2-fluorophenyl}-1 -propanesulfonamide (230 mg, 0.463 mmol) and S-(+)tetrahydrofurfurylamine (140 mg, 1 .388 mmol) in 1 ,4-dioxane (3 mL), the title compound was obtained (120 mg, 44 % yield). 1 H NMR (400 MHz, DMSO-c/6) ppm 9.75 (br. s., 1 H) 8.1 1 (d, J=5.05 Hz, 1 H) 7.48 - 7.61 (m, 1 H) 7.34 - 7.36 (m, 1 H) 7.26 - 7.34 (m, 1 H) 7.09 (t, J=5.81 Hz, 1 H) 6.14 (br. s., 1 H) 4.63 (br. s., 1 H) 3.94 (dt, J=9.54, 2.18 Hz, 2 H) 3.39 - 3.59 (m, 3 H) 3.19 - 3.32 (m, 3 H) 2.92 - 3.08 (m, 2 H) 2.02 (dd, J=12.76, 2.15 Hz, 2 H) 1 .58 - 1 .85 (m, 4 H) 1 .19 - 1 .44 (m, 2 H) 0.84 - 0.97 (m, 7 H); MS: 562 [M+H]+.
Example 1 1 : A/-{2-fluoro-3-r5-(2-{r(1 R)-2-hvdroxy-1 -methylethyl1amino)-4- pyrimidinyl)-2-(tetrahvdro-2H-pyran-4-yl)-1 ,3-thiazol-4-yllphenyl)-1 - propanesulfonamide
Following a procedure analogous to the procedure described in Example 1 using A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol- 4-yl]-2-fluorophenyl}-1 -propanesulfonamide (200 mg, 0.402 mmol) and H- alaninol (30.2 mg, 0.402 mmol) in 1 ,4-dioxane (3 mL), the title compound was obtained (106 mg, 48 % yield). 1H NMR (400 MHz, DMSO-cf6) ppm 9.75 (s, 1 H) 8.1 1 (d, =5.05 Hz, 1 H) 7.54 (td, J=7.71 , 1.77 Hz, 1 H) 7.38 (d, J=6.06 Hz, 1 H) 7.23 - 7.35 (m, 1 H) 6.96 (d, J=8.08 Hz, 1 H) 6.1 1 (br. s., 1 H) 4.66 (t, J=5.56 Hz, 1 H) 2.80 - 3.96 (m, 3 H) 3.39 - 3.58 (m, 3 H) 3.26 - 3.33 (m, 2 H) 2.96 - 3.14 (m, 2 H) 2.02 (dd, J=12.63, 2.02 Hz, 2 H) .58 - 1 .86 (m, 4 H) 1 .10 (d, J=6.57 Hz, 3 H) 0.91 (t, J=7.45 Hz, 3 H); MS: 536 [M+H]+.
Example 12: Λ/-Γ3-(2-(1 ,1 -dimethylethyl)-5-(2-f(2-hvdroxyethyl)amino1-4- pyrimidinyl}-1 ,3-thiazol-4-yl)-2-fluorophenvn-1 -propanesulfonamide
Following a procedure analogous to the procedure described in Example 1 using A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-1 -propanesulfonamide (150 mg, 0.320 mmol) and 2- aminoethanol (0.077 mL, 1 .279 mmol) in toluene (3 mL), the title compound was obtained (65 mg, 0.129 mmol, 40.3 % yield). 1H NMR (400 MHz, DMSO- c/6) ppm 9.73 (s, 1 H) 8.1 1 (d, J=5.05 Hz, 1 H) 7.53 (t, J=7.07 Hz, 1 H) 7.36 - 7.45 (m, 1 H) 7.26 - 7.36 (m, 1 H) 7.14 (t, J=5.43 Hz, 1 H) 6.14 (br. s., 1 H) 4.65 (br. s., 1 H) 3.49 (q, J=5.89 Hz, 2 H) 2.96 - 3.12 (m, 2 H) 1 .61 - 1 .78 (m, 2 H) 1 .44 (s, 9 H) 0.91 (t, J=7.33 Hz, 3 H); MS: 494 [M+H]+.
Example 13: N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahvdro-2H-pyran-4-yl)-1 ,3- thiazol-4-yl1-2-chlorophenyl)-3,3,3-trifluoro-1 -propanesulfonamide
Following a procedure analogous to the procedure described in Example 3 using N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)- 1 ,3-thiazol-4-yl]phenyl}-3,3,3-trifluoro-1 -propanesulfonamide (250 mg, 0.441 mmol) and ammonium hydroxide (3 mL, 77 mmol) for 1 h, the title compound was obtained (102 mg, 41 % yield). 1 H NMR (400 MHz, DMSO-c/6) ppm 9.98 (s, 1 H) 8.01 (d, J=5.31 Hz, 1 H) 7.64 (dd, J=8.08, 1 .52 Hz, 1 H) 7.50 (t, J=7.83 Hz, 1 H) 7.41 (dd, J=7.71 , 1 .64 Hz, 1 H) 6.76 (s, 2 H) 5.85 (d, J=5.05 Hz, 1 H) 3.94 (dt, J=9.54, 2.05 Hz, 2 H) 3.38 - 3.56 (m, 4 H) 3.24 - 3.32 (m, 1 H) 2.70 - 2.91 (m, 2 H) 1 .95 - 2.10 (m, 2 H) 1 .65 - 1 .89 (m, 2 H); MS: 548, 550 [M+H]+. Example 14: A/-{2-chloro-3-[5-{2-[(2-hvdroxy-2-nnethylpropyl)annino1-4- Pvnmidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4-yllphenyl)-3,3,3- trifluoro-1 -propanesulfonamide
Following a procedure analogous to the procedure described in Example 1 using A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)- 1 ,3-thiazol-4-yl]phenyl}-3, 3, 3-trifluoro-l -propanesulfonamide (503 mg, 0.886 mmol) and 1 -amino-2-methyl-2-propanol (237 mg, 2.66 mmol) in 1 ,4-dioxane (15 ml_), the title compound was obtained (288 mg, 0.451 mmol, 50.8 % yield). 1 H NMR (400 MHz, DMSO-c/6) ppm 9.97 (s, 1 H) 8.06 (d, J=5.31 Hz, 1 H) 7.63 (d, J=6.82 Hz, 1 H) 7.49 (t, J=7.83 Hz, 1 H) 7.39 (d, J=7.58 Hz, 1 H) 6.90 (br. s., 1 H) 5.95 (br. s., 1 H) 4.49 (br. s., 1 H) 3.94 (dt, J=9.54, 2.05 Hz, 2 H) 3.36 - 3.57 (m, 4 H) 3.17 - 3.42 (m,3 H) 2.70 - 2.90 (m, 2 H) 2.02 (dd, J=12.63, 2.02 Hz, 2 H) 1 .66 - 1 .87 (m, 2 H) 1 .09 (s, 6 H); MS: 620, 621 , 622 [M+H]+.
Example 15: /V-{2-fluoro-3-[5-(2-{r(2S)-2-hvdroxypropyl1amino)-4-Pyrimidinyl)-
2-(4-morpholinyl)-1 ,3-thiazol-4-yllphenyl)-1 -propanesulfonamide
Following a procedure analogous to the procedure described in Example 1 using A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-1-propanesulfonamide (150 mg, 0.301 mmol) and (2S)-1-amino- 2-propanol (22.62 mg, 0.301 mmol) in toluene (3 mL), the title compound was obtained (60 mg, 36 % yield). 1H NMR (400 MHz, DMSO- /6) ppm 9.76 (s, 1 H) 7.95 (d, J=5.31 Hz, 1 H) 7.48 - 7.56 (m, 1 H) 7.16 - 7.36 (m, 2 H) 6.92 (br. s., 1 H) 5.88 (br. s., 1 H) 4.67 (br. s., 1 H) 3.65 - 3.83 (m, 5 H) 3.49 (t, J=4.67 Hz, 4 H) 3.00 - 3.24 (m, 4 H) 1.64 - 1.76 (m, 2 H) 1.05 (d, J=6.06 Hz, 3 H) 0.92 (t, J=7.45 Hz, 3 H); MS: 536, 538 [M+H]+.
Example 16: A/-(2-fluoro-3-r5-(2-(f(2R)-tetrahvdro-2-furanylmethyllamino)-4-
Pyrimidinyl)-2-(tetrahvdro-2H-pyran-4-yl)-1 ,3-thiazol-4-vnphenyl)-1- propanesulfonamide
Following a procedure analogous to the procedure described in Example 1 using A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol- 4-yl]-2-fluorophenyl}-1 -propanesulfonamide (223 mg, 0.449 mmol) and R-(- )tetrahydrofurfurylamine (136 mg, 1 .346 mmol) in 1 ,4-dioxane (3 mL), the title compound was obtained (141 mg, 53 % yield). 1H NMR (400 MHz, DMSO-c/6) ppm 9.75 (s, 1 H) 8.12 (d, J=5.31 Hz, 1 H) 7.45 - 7.60 (m, 1 H) 7.36 - 7.44 (m, 1 H) 7.21 - 7.36 (m, 2 H) 6.18 (br. s., 1 H) 3.83 - 4.05 (m, 3 H) 3.68 - 3.83 (m, 1 H) 3.55 - 3.67 (m, 1 H) 3.48 (td, J=1 1 .56, 1 .89 Hz, 2 H) 3.27 - 3.36 (m, 3 H) 2.98 - 3.09 (m, 2 H) 2.02 (dd, J=12.63, 2.02 Hz, 2 H) 1 .48 - 1 .92 (m, 8 H) 0.91 (t, J=7.45 Hz, 3 H); MS: 562 [M+H]+. Example 17: A/-{2-chloro-3-[5-{2-[(2-methylpropyl)amino1-4-pynmidinyl)-2-(4- morpholinyl)-1 ,3-thiazol-4-yllphenyl)-3,3,3-trifluoro-1 -propanesulfonamide
Following a procedure analogous to the procedure described in Example 1 using A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4- yl]phenyl}-3,3,3-trifluoro-1 -propanesulfonamide (200 mg, 0.352 mmol) and 1 - amino-2-methyl-2-propanol (94 mg, 1 .056 mmol) in 1 ,4-doxane (3 mL), the title compound was obtained (150 mg, 67 % yield). 1 H NMR (400 MHz, DMSO-c/e) ppm 9.97 (s, 1 H) 7.87 (d, J=5.31 Hz, 1 H) 7.61 (dd, J=8.08, 1 .52 Hz, 1 H) 7.47 (t, J=7.83 Hz, 1 H) 7.34 (d, J=7.07 Hz, 1 H) 7.14 (br. s., 1 H) 5.62 (br. s., 1 H) 3.69 - 3.76 (m, 4 H) 3.45 - 3.52 (m, 4 H) 3.37 - 3.45 (m, 2 H) 2.91 - 3.12 (m, 2 H) 2.71 - 2.90 (m, 2 H) 1 .73 - 1 .88 (m, 1 H) 0.87 (d, J=6.57 Hz, 6 H) ; MS: 605, 606, 607 [M+H]+. Example 18: A -(3-r2-(1 .1 -dimethylethyl)-5-(2-(r(2S)-2-hvdroxypropyl1amino)-4- pyrimidinyl)-1 ,3-thiazol-4-yl1-2-fluorophenyl)-1 -propanesulfonamide
Following a procedure analogous to the procedure described in Example 1 using A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-1 -propanesulfonamide (150 mg, 0.320 mmol) and (S)-(+)-1 - amino-2-propanol (0.101 ml_, 1 .279 mmol) in toluene (3 ml_), the title compound was obtained (51 mg, 31 % yield). 1H NMR (400 MHz, DMSO-c/6) ppm 9.73 (s, 1 H) 8.1 1 (d, J=5.05 Hz, 1 H) 7.53 (t, J=6.95 Hz, 1 H) 7.36 - 7.45 (m, 1 H) 7.32 (t, J=7.83 Hz, 1 H) 7.10 (br. s., 1 H) 6.15 (br. s., 1 H) 4.66 (br. s., 1 H) 3.68 - 3.85 (m, 1 H) 3.25 - 3.05 (m, 2H) 2.98 - 3.07 (m, 2 H) 1 .69 (sxt, J=7.58 Hz, 2 H) 1 .44 (s, 9 H) 1 .04 (d, J=6.32 Hz, 3 H) 0.85 - 0.96 (m, 3 H); MS: 508 [M+H]+. Example 19: Λ/-Ι3-Γ2-Π .1 -dimethylethyl)-5-(2-{r(2R)-2-hvdroxypropyllamino)-4- pyrinnidinyl)-1 ,3-thiazol-4-yl1-2-fluorophenyl)-1 -propanesulfonamide
Following a procedure analogous to the procedure described in Example 1 using A/-{3-[5-(2-chloro-4-pyhmidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-1 -propanesulfonamide (150 mg, 0.320 mmol) and (R)-(+)-1 - amino-2-propanol (0.101 ml_, 1 .279 mmol) in toluene (3 ml_), the title compound was obtained (62 mg, 37 % yield). 1H NMR (400 MHz, DMSO-c/6) ppm 9.73 (s, 1 H) 8.1 1 (d, J=5.05 Hz, 1 H) 7.53 (t, J=6.95 Hz, 1 H) 7.36 - 7.45 (m, 1 H) 7.32 (t, J=7.83 Hz, 1 H) 7.10 (br. s., 1 H) 6.15 (br. s., 1 H) 4.66 (br. s., 1 H) 3.68 - 3.85 (m, 1 H) 3.25 - 3.05 (m, 2H) 2.98 - 3.07 (m, 2 H) 1 .69 (sxt, J=7.58 Hz, 2 H) 1 .44 (s, 9 H) 1 .04 (d, J=6.32 Hz, 3 H) 0.85 - 0.96 (m, 3 H); MS: 508 [M+H]+.
Example 20: A/-{2-chloro-3-[5-(2-{[(2R)-2-hvdroxypropyl1amino)-4-pyrimidinyl)-
2-(4-morpholinyl)-1 ,3-thiazol-4-yllphenyl)-3,3,3-trifluoro-1 -propanesulfonamide
Following a procedure analogous to the procedure described in Example 1 using with A/-{2-chloro-3-[5-(2-chloro-4-pyrinnidinyl)-2-(4-nnorpholinyl)-1 ,3- thiazol-4-yl]phenyl}-3,3,3-trifluoro-1 -propanesulfonannide (200 mg, 0.352 mmol) and (2R)-1 -amino-2-propanol (0.083 mL, 1 .056 mmol) in 1 ,4-dioxane (3 mL), the title compound was obtained (157 mg, 70 % yield). 1H NMR (400 MHz, DMSO-c/e) ppm 9.97 (s, 1 H) 7.89 (d, J=5.31 Hz, 1 H) 7.61 (dd, J=7.96,
1 .64 Hz, 1 H) 7.48 (t, J=7.83 Hz, 1 H) 7.28 - 7.42 (m, 1 H) 6.88 (br. s., 1 H)
5.65 (d, J=4.80 Hz, 1 H) 4.67 (d, J=4.04 Hz, 1 H) 3.67 - 3.83 (m, 4 H) 3.45 - 3.56 (m, 4 H) 3.37 - 3.45 (m, 2 H) 3.01 - 3.27 (m, 2 H) 2.70 - 2.91 (m, 2 H)
0.82 - 1 .1 1 (m, 6 H); MS: 607, 608, 609 [M+H]+.
Example 21 A/-{2-chloro-3-[5-{2-r(2-hvdroxy-2-methylpropyl)amino1-4- Pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yllphenyl)-3,3,3-thfluoro-1 - propanesulfonamide
Following a procedure analogous to the procedure described in Example 1 using with /V-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3- thiazol-4-yl]phenyl}-3,3,3-trifluoro-1-propanesulfonamide (200 mg, 0.352 mmol)) and 1-amino-2-methyl-2-propanol (94 mg, 1.056 mmol) in 1 ,4-doxane (3 mL), the title compound was obtained (150 mg, 67 % yield). 1H NMR (400 MHz, DMSO- /6) ppm 9.97 (s, 1 H) 7.89 (d, J=5.31 Hz, 1 H) 7.61 (dd, J=8.08, 1.52 Hz, 1 H) 7.48 (t, J=7.83 Hz, 1 H) 7.35 (d, J=7.07 Hz, 1 H) 6.69 (br. s„ 1 H) 5.66 (d, J=4.55 Hz, 1 H) 4.50 (br. s., 1 H) 3.68 - 3.82 (m, 5 H) 3.46 - 3.54 (m, 4 H) 3.38 - 3.45 (m, 2 H) 3.22 (br. s., 2 H) 2.71 - 2.90 (m, 2 H) 1.06 - 1.15 (m, 6 H); MS: 621 , 622, 623 [M+H]+.
Example 22: A/-(2-fluoro-3-r5-(2-r(2-hvdroxybutyl)amino1-4-pyrimidinyl)-2- (tetrahvdro-2H-pyran-4-yl)-1 ,3-thiazol-4-yllphenyl)-1-propanesulfonamide
Following a procedure analogous to the procedure described in Example 1 using with A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3- thiazol-4-yl]-2-fluorophenyl}-1-propanesulfonamide (200 mg, 0.402 mmol) and 1-amino-2-butanol (108 mg, 1.207 mmol) in 1 ,4-dioxane (3 mL), the title compound was obtained (93 mg, 39 % yield). 1H NMR (400 MHz, DMSO-ofe) ppm 9.75 (br. s., 1 H) 8.11 (d, =5.05 Hz, 1 H) 7.48 - 7.61 (m, 1 H) 7.25 - 7.45 (m, 2 H) 7.09 (t, J=5.81 Hz, 1 H) 6.14 (br. s„ 1 H) 4.63 (br. s., 1 H) 3.94 (dt, =9.54, 2.18 Hz, 2 H) 3.42 - 3.57 (m, 3 H) 3.19 - 3.32 (m, 2 H) 2.98 - 3.09 (m, 2 H) 2.02 (dd, J=12.76, 2.15 Hz, 2 H) 1.57 - 1.86 (m, 4 H) 1.44 (br. s„ 1 H) 1.17 - 1.37 (m, 1 H) 0.85 - 0.96 (m, 6 H); MS: 550 [M+H]+.
Example 23: A/-(2-chloro-3-f5-(2-r(2-hvdroxy-2-methylpropyl)amino1-4- PVrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-vnphenyl)-1-propanesulfonamide
Following a procedure analogous to the procedure described in Example 1 using with A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3- thiazol-4-yl]phenyl}-1-propanesulfonamide (350 mg, 0.680 mmol) and 1- amino-2-methyl-2-propanol (182 mg, 2.041 mmol) in 1 ,4-dioxane (4 mL), the title compound was obtained (35 mg, 8.62 % yield). 1H NMR (400 MHz, DMSO-cfe) ppm 9.56 (s, 1 H) 7.90 (d, J=5.31 Hz, 1 H) 7.60 (dd, =8.08, 1.52 Hz, 1 H) 7.46 (t, =7.96 Hz, 1 H) 7.26 - 7.37 (m, 1 H) 6.69 (br. s„ 1 H) 5.65 (br. s„ 1 H) 4.52 (br. s., 1 H) 3.73 (t, J=4.80 Hz, 4 H) 3.40 - 3.58 (m, 4 H) 3.17 - 3.25 (m, 2H) 3.03 - 3.16 (m, 2 H) 1.64 - .82 (m, 2 H) 1.09 (s, 6 H) 0.94 (t, J=7.45 Hz, 3 H); MS: 567, 568, 569 [M+H]+. Example 24: A/-{2-fluoro-3-[5-(2-{[(2R)-2-hvdroxypropyl1annino)-4-pyrinnidinyl)- 2-(tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4-yllphenyl)-1 -propanesulfonamide
Following a procedure analogous to the procedure described in Example 1 using with A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3- thiazol-4-yl]-2-fluorophenyl}-1 -propanesulfonamide (150 mg, 0.302 mmol) and (R)-(+)-1 -amino-2-propanol (0.095 mL, 1 .207 mmol) in toluene (3 mL), the title compound was obtained (65 mg, 39 % yield). 1H NMR (400 MHz, DMSO-c/6) ppm 9.74 (br. s., 1 H) 8.12 (d, J=5.30 Hz, 1 H) 7.54 (t, J=7.20 Hz, 1 H) 7.36 - 7.45 (m, 1 H) 7.25 - 7.36 (m, 1 H) 7.13 (br. s., 1 H) 6.15 (br. s., 1 H) 4.67 (br. s., 1 H) 3.85 - 4.06 (m, 2 H) 3.77 (dt, J=1 1 .37, 5.94 Hz, 1 H) 3.40 - 3.55 (m, 2 H) 3.26 - 3.31 (m, 1 H) 3.09 - 3.25 (m, 2 H) 2.95 - 3.08 (m, 2 H) 1 .95 - 2.09 (m, 2 H) 1 .60 - 1 .85 (m, 4 H) 1 .05 (d, J=6.32 Hz, 3 H) 0.89 - 0.95 (m, 3 H) ; MS: 536 [M+H]+.
Example 25: A/-{2-fluoro-3-[5-(2-{[(2S)-2-hvdroxypropyl1amino)-4-pyrimidinyl)-
2-(tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4-yllphenyl)-1 -propanesulfonamide
Following a procedure analogous to the procedure described in Example 1 using with A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3- thiazol-4-yl]-2-fluorophenyl}-1-propanesulfonamide (150 mg, 0.302 mmol) and (S)-(+)-1-amino-2-propanol (0.095 mL, 1.207 mmol) in toluene (3 mL), the title compound was obtained (60 mg, 36 % yield). 1H NMR (400 MHz, DMSO-cfe) ppm 9.74 (br. s„ 1 H) 8.12 (d, J=5.30 Hz, 1 H) 7.54 (t, J=7.20 Hz, 1 H) 7.36 - 7.45 (m, 1 H) 7.25 - 7.36 (m, 1 H) 7.13 (br. s., 1 H) 6.15 (br. s., 1 H) 4.67 (br. s., 1 H) 3.85 - 4.06 (m, 2 H) 3.77 (dt, J=11.37, 5.94 Hz, 1 H) 3.40 - 3.55 (m, 2 H) 3.26 - 3.31 (m, 1 H)3.09 - 3.25 (m, 2H) 2.95 - 3.08 (m, 2 H) 1.95 - 2.09 (m, 2 H) 1.60 - 1.85 (m, 4 H) 1.05 (d, =6.32 Hz, 3 H) 0.89 - 0.95 (m, 3 H); MS: 536 [M+H]+.
Example 26: A/-(2-chloro-3-r5-(2-(r(2S)-2-hvdroxypropynamino)-4-pyrimidinyl)- 2-(4-morpholinyl)-1 ,3-thiazol-4-vnphenyl)-3,3,3-trifluoro-1-propanesulfonamide
Following a procedure analogous to the procedure described in Example 1 using with A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3- thiazol-4-yl]phenyl}-3,3,3-trifluoro-1 -propanesulfonamide (200 mg, 0.352 mmol) and (2S)-1-amino-2-propanol (0.083 mL, 1.056 mmol) in 1 ,4-dioxane (3 mL), the title compound was obtained (163 mg, 72 % yield). 1H NMR (400 MHz, DMSO- /e) ppm 9.97 (s, 1 H) 7.89 (d, J=5.31 Hz, 1 H) 7.62 (dd, J=8.08, 1 .52 Hz, 1 H) 7.48 (t, J=7.83 Hz, 1 H) 7.35 (dd, J=7.58, 1.52 Hz, 1 H) 6.89 (br. s., 1 H) 5.65 (d, J=5.31 Hz, 1 H) 4.67 (d, J=3.79 Hz, 1 H) 3.66 - 3.87 (m, 5 H) 3.38 - 3.56 (m, 6 H) 3.16 (t, J=5.94 Hz, 2 H) 2.69 - 2.93 (m, 2 H) 0.98 - 1.1 1 (m, 3 H); MS: 607, 608, 609 [M+Hf.
Example 27: /V-(2-fluoro-3-r5-{2-r(2-methylpropyl)amino1-4-pyrimidinylV2- (tetrahvdro-2H-pyran-4-yl)-1 ,3-thiazol-4-vnphenyl)-1 -propanesulfonamide
Following a procedure analogous to the procedure described in Example 1 using with A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3- thiazol-4-yl]-2-fluorophenyl}-1-propanesulfonamide (200 mg, 0.402 mmol) and isobutylamine (88 mg, 1.207 mmol) in 1 ,4-dioxane (3 mL), the title compound was obtained (120 mg, 52 % yield). 1H NMR (400 MHz, DMSO-d6) ppm 9.74 (s, 1 H) 8.1 1 (d, J=5.05 Hz, 1 H) 7.45 - 7.59 (m, 1 H) 7.19 - 7.45 (m, 3 H) 6.17 (br. s., 1 H) 3.94 (dt, J=9.47, 2.21 Hz, 2 H) 3.48 (td, J=1 1.56, 1 .89 Hz, 2 H) 3.27 - 3.33 (m, 1 H) 2.97 - 3.09 (m, 4 H) 2.02 (dd, J=12.63, 2.02 Hz, 2 H) 1 .58 - 1 .88 (m, 5 H) 0.78 - 0.94 (m, 9 H); MS: 534 [M+H]+. Example 28: A/-r2-fluoro-3-(2-(tetrahvdro-2H-pyran-4-yl)-5-(2-r(3,3,3- trifluoropropyl)aminol-4-pyrimidinyl)-1 ,3-thiazol-4-yl)phenyl1-1- propanesulfonamide
Following a procedure analogous to the procedure described in Example 1 using with A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3- thiazol-4-yl]-2-fluorophenyl}-1-propanesulfonamide (200 mg, 0.402 mmol) and 3,3,3-trifluoropropylamine (137 mg, 1.207 mmol) in 1 ,4-dioxane (3 mL), the title compound was obtained (86 mg, 0.142 mmol, 35.4 % yield). 1H NMR (400 MHz, DMSO- 6) ppm 9.75 (s, 1 H) 8.17 (d, J=5.05 Hz, 1 H) 7.44 - 7.64 (m, 2 H) 7.36 - 7.44 (m, 1 H) 7.24 - 7.36 (m, 1 H) 6.24 (br. s., 1 H) 3.95 (dt, J=9.54, 2.18 Hz, 2 H) 3.29 - 3.51 (m, 7 H) 2.95 - 3.13 (m, 2 H) 1.94 - 2.10 (m, 2 H) 1.59 - 1.88 (m, 4 H) 0.84 - 0.95 (m, 3 H); MS: 574 [M+H]+. Example 29: A/-f2-fluoro-3-(2-(tetrahvdro-2H-pyran-4-yl)-5-(2-[(3,3,3-thfluoro-
2-hvdroxypropyl)amino1-4-pyrimidinyl)-1 ,3-thiazol-4-yl)phenyn-1- propanesulfonamide
Following a procedure analogous to the procedure described in Example 1 using with A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3- thiazol-4-yl]-2-fluorophenyl}-1 -propanesulfonamide (200 mg, 0.402 mmol) and 3-amino-1 ,1 ,1-trifluoropropan-2-ol (156 mg, 1.207 mmol) in 1 ,4-dioxane (3 ml_), the title compound was obtained (100 mg, 39 % yield). 1H NMR (400 MHz, DMSO-Gk) ppm 9.75 (s, 1 H) 8.16 (d, J=5.05 Hz, 1 H) 7.50 - 7.60 (m, 1 H) 7.34 - 7.54 (m, 2 H) 7.30 - 7.34 (m, 1 H) 641 (d, J=5.81 Hz, 1 H) 6.18 (br. s„ 1 H) 4.20 (br. s., 1 H) 3.82 - 4.01 (m, 2 H) 3.52 - 3.62 (m, 1 H) 3.48 (td, J=11.62, 2.02 Hz, 2 H) 3.16 - 3.32 (m, 2 H) 2.96 - 3.14 (m, 2 H) 1.95 - 2.10 (m, 2 H) 1.57 - 1.83 (m, 4 H) 0.88 - 0.94 (m, 3 H); MS: 590, 591 [M+H]+.
Example 30: /V-(3-r5-(2-[(2-cvanoethyl)amino1-4-pyrimidinyl)-2-(tetrahydro-2H- ran^-vD- .S-thiazol^-yll^-fluorophenvD-l -propanesulfonamide
A 5 mL microwave tube was charged with A/-{3-[5-(2-chloro-4-pyrimidinyl)-2- (tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}-1- propanesulfonamide (200 mg, 0.402 mmol) and 3-aminopropionitrile fumarate (155 mg, 1.207 mmol) and cesium fluoride (245 mg, 1.610 mmol) in dimethyl sulfoxide (DMSO) to give a yellow solution at room temperature under nitrogen. The sealed reaction mixture was heated (oil bath) at 90 °C for 3h. After 3h, the reaction was diluted with water and EtOAc. After stirring, the EtOAc layer was separated form the water layer. The EtOAc layer was washed with water, dried over Na2SC>4, filtered, and concentrated. The residue was chromatographed on a silica gel column and eluted with CHCI3 and CHCI3 with 10% MeOH (5% to 50%) to obtain A/-{3-[5-{2-[(2- cyanoethyl)amino]-4-pyhnnidinyl}-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4- yl]-2-fluorophenyl}-1 -propanesulfonamide (120 mg, 55 % yield). 1H NMR (400 MHz, DMSO-c/6) ppm 9.74 (s, 1 H) 8.19 (d, J=5.05 Hz, 1 H) 7.64 (t, J=5.68 Hz, 1 H) 7.54 (t, J=7.07 Hz, 1 H) 7.36 - 7.46 (m, 1 H) 7.25 - 7.36 (m, 1 H) 6.29 (br. s., 1 H) 3.95 (dt, J=9.54, 2.05 Hz, 2 H) 3.29 - 3.51 (m, 5 H) 2.94 - 3.12 (m, 2 H) 2.58 - 2.74 (m, 2 H) 1 .92 - 2.10 (m, 2 H) 1 .57 - 1 .85 (m, 4 H) 0.91 (t, J=7.33 Hz, 3 H); MS: 531 [M+H]+. Example 31 : A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4- -2-chlorophenyl)-3,3,3-trifluoro-1 -propanesulfonamide
Following a procedure analogous to the procedure described in Example 3 using A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)- 1 ,3-thiazol-4-yl]phenyl}-1 -propanesulfonamide (175 mg, 0.341 mmol) and ammonium hydroxide (3 ml_, 77 mmol) for 1 h, the title compound was obtained (70 mg, 40 % yield). 1H NMR (400 MHz, DMSO-c/6) ppm 9.98 (s, 1 H) 7.85 (d, J=5.31 Hz, 1 H) 7.62 (dd, J=8.08, 1 .52 Hz, 1 H) 7.48 (t, J=7.83 Hz, 1 H) 7.35 (d, J=6.57 Hz, 1 H) 6.56 (s, 2 H) 5.63 (d, J=5.31 Hz, 1 H) 3.67 - 3.76 (m, 4 H) 3.45 - 3.54 (m, 4 H) 3.36 - 3.45 (m, 2 H) 2.71 - 2.91 (m, 2 H); MS: 549, 550, 551 [M+H]+.
Example 32: A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4- yl1-2-fluorophenyl)methanesulfonamide
Step 1 : 3-[5-(2-chloro-4-pynmidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]-2- fluoroaniline
2-Propen-1 -yl {3-[5-(2-chloro-4-pyrinnidinyl)-2-(4-nnorpholinyl)-1 ,3-thiazol-4-yl]- 2-fluorophenyl}carbamate (5 g, 10.51 mmol) and
bis(triphenylphosphine)palladiunn (II) chloride (0.369 g, 0.525 mmol) were added to a 200 ml_ pear flask purged with nitrogen. Dichloromethane (DCM) (88 ml_) and acetic acid (1 .443 ml_, 25.2 mmol) were added to the reaction mixture. After 10 minutes, tri-n-butyltin hydride (4.49 ml_, 16.81 mmol) was added to the reaction mixture slowly with syringe with stirring for 30 minutes. The residue was chromatographed on a silica gel column and eluted with 100% methylene chloride to 50% methylene chloride:(9:1 :1 methylene chloride:MeOH:ammonium hydroxide) to 100% 90:9:1 methylene
chloride:MeOH:ammonium hydroxide to obtain 3-[5-(2-chloro-4-pyrimidinyl)-2- (4-morpholinyl)-1 ,3-thiazol-4-yl]-2-fluoroaniline (3.6 g, 87%). MS: 392 [M+H]+.
Step 2: A/-{3-[5-(2-chloro-4-pyhmidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]-2- fluorophenyljmethanesulfonamide
3-[5-(2-Chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]-2-fluoroanili (160 mg, 0.408 mmol) was suspended in pyridine (1 .5 ml_). The reaction mixture was stirred for 5 minutes and methanesulfonyl chloride (0.038 ml_, 0.490 mmol) was added. After 48 h, methanesulfonyl chloride (10 μΙ_) was added to the reaction mixture. After another 24 h, DCM and silica gel were added to the reaction mixture and concentrated. The residue was chromatographed on a silica gel column and eluted with 10% EtOAc in hexane to 100% EtOAc, then 90:9:1 methylene chloride:methanol:ammonium hydroxide to obtain A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3- thiazol-4-yl]-2-fluorophenyl}methanesulfonamide (130 mg, 67%). MS: 470 [M+H]+.
Step 3: A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]-2- fluorophenyljmethanesulfonamide
Following a procedure analogous to the procedure described in Example 3 using A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]-2- fluorophenyljmethanesulfonamide (130 mg, 0.277 mmol) and ammonia in methanol (5 ml_) in oil bath at 80 °C for 2 days, the title compound was obtained (41 mg, 33 % yield). MS: 451 [M+H]+.
Example 33: A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4- yl1-2-fluorophenyl)ethanesulfonamide
Step 1 : A/-{3-[5-(2-chloro-4-pynmidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}ethanesulfonamide
Following a procedure analogous to the procedure described in step 2 of Example 32 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(4-nnorpholinyl)-1 ,3-thiazol- 4-yl]-2-fluoroaniline (150 mg, 0.383 mmol)and ethanesulfonyl chloride (45.3 μΙ, 0.478 mmol), the title compound was obtained (100 mg, 54 % yield). MS: 484 [M+H]+.
Step 2: A/-{3-[5-(2-amino-4-pyhmidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]-2- fluorophenyljethanesulfonamide Following a procedure analogous to the procedure described in Example 3 using A/-{3-[5-(2-chloro-4-pyhmidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]-2- fluorophenyljethanesulfonamide (184 mg, 0.380 mmol) and ammonia in methanol (7 ml_) in a sealed tube and heated to 80 °C for 4 days, the title compound was obtained (31 mg, 17 % yield). MS: 465 [M+H]+. Example 34: /V-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4- y -2-fluorophenyl)-2-propanesulfonamide
Step 1 : A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-2-propanesulfonamide
Following a procedure analogous to the procedure described in step 2 of Example 32 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol- 4-yl]-2-fluoroaniline (200 mg, 0.5100 mmol)and 2-propanesulfonyl chloride (0.085 ml_, 0.766 mmol), the title compound was obtained (39 mg, 15 % yield). MS: 498 [M+H]+.
Step 2: A/-{3-[5-(2-amino-4-pyhmidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]-2- fluorophenyljethanesulfonamide
Following a procedure analogous to the procedure described in Example 3 using A/-{3-[5-(2-chloro-4-pyhmidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-2-propanesulfonamide ( 81 mg, 0.162 mmol) and ammonium hydroxide (6 ml) microwaved for 40 min at 120 °C, the title compound was obtained (19 mg). MS: 479 [M+H]+. Example 35: /V-{3-[5-(2-amino-4-pynmidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4- y -2-fluorophenyl)-2-methyl-1 -propanesulfonamide
Step 1 : A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-2-methyl-1 -propanesulfonamide
Following a procedure analogous to the procedure described in step 2 of Example 32 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol- 4-yl]-2-fluoroaniline (150 mg, 0.383 mmol)and 2-propanesulfonyl chloride (0.047 ml_, 0.421 mmol), the title compound was obtained (23 mg, 12 % yield).
Step 2: A/-{3-[5-(2-amino-4-pyhmidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-2-methyl-1 -propanesulfonamide
Following a procedure analogous to the procedure described in Example 3 using A/-{3-[5-(2-chloro-4-pyhmidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-2-methyl-1 -propanesulfonamide (200 mg, 0.391 mmol) and ammonia hydroxide (3 ml_) microwaved to 120 °C for 40 minutes, the title compound was obtained (97 mg, 50 % yield). MS: 493 [M+H]+.
Ste 1 : methyl 2,6-difluoro-3-[(propylsulfonyl)amino]benzoate
Following a procedure analogous to the procedure described in step 2 of Example 32 using methyl 3-amino-2,6-difluorobenzoate (15 g, 80.2 mmol) and 1 -propanesulfonyl chloride (14.8 g, 104.3 mmol) for 12 h, the title compound was obtained (24 g).
Step 2: A/-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2,4-difluorophenyl}-1 - propanesulfonamide
To a solution of methyl 2,6-difluoro-3-[(propylsulfonyl)amino]benzoate (24g, 81 .9 mmol) in THF (300 ml_), LiHMDS (286 ml_, 286 mmol) was added dropwise at -10 °C over 45 min. After 30 min, 2-chloro-4-methylpyrimidine (1 1 .5 g, 90.1 mmol) in THF (25 ml_) was added dropwise to the reaction mixture. The reaction mixture was stirred for 30 min and quenched with saturated NH4CI. The layers were separated. The organic layer was washed with brine. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was chromatographed on silica gel column to obtain A/-{3-[(2-chloro-4- pyrimidinyl)acetyl]-2,4-difluorophenyl}-1 -propanesulfonamide (12.5 g, 40 %).
Step 3: A/-{3-[5-(2-chloro-4-pyhmidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]-2,4- difluorophenyl}-1 -propanesulfonamide
To a solution of A/-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2,4-difluorophenyl}-1 - propanesulfonamide (9.5 g, 24.4 mmol) in DMA (100 mL) was added NBS
(44.34 g, 24.4 mmol) at 0 °C. After 30 min, 4-morpholinecarbothioamide (4.28 g, 29.3 mmol) was added to the reaction mixture and heated at 60 °C for 4h.
The reaction mixture was poured into water and extracted with EtOAc (2x).
The combined organic layer were washed with water, brine, dried, filtered, and concentrated. The residue was chromatographed on a silica gel column and eluted with (CH2CI2: EtOAc, 20:1 ) to obtain A/-{3-[5-(2-chloro-4- pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]-2,4-difluorophenyl}-1 - propanesulfonamide (4.8 g, 39%). MS: 516 [M+H]+. Step 4: A/-{2,4-difluoro-3-[5-{2-[(1 -methylethyl)amino]-4-pyhmidinyl}-2-(4- morpholinyl)-1 ,3-thiazol-4-yl]phenyl}-1 -propanesulfonamide
Following a procedure analogous to the procedure described in Example 1 using with A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]- 2,4-difluorophenyl}-1 -propanesulfonamide (200 mg, 0.402 mmol) and isopropylamine (0.248 ml, 2.91 mmol) in isopropanol (4 mL) and heated at 80 °C for 5h, the title compound was obtained (95 mg, 54 % yield). MS: 539
[M+H]+.
Example 37: A/-(2-fluoro-3-{2-(4-morDholinyl)-5-r2-(tetrahvdro-2/-/-Dyran-4-
Step 1 : 2-propen-1 -yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3- thiazol-4-yl]-2-fluorophenyl}carbamate
To a solution of 2-propen-1 -yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2- fluorophenyljcarbamate (12.2 g, 35.1 mmol) in DCM (250 mL) was added NBS (6.25g, 35.1 1 mmol). After 30 min, the reaction mixture was
concentrated. The residue was dissolved in DMA (200 mL), and 4- morpholinecarbothioamide (6.16 g, 42.13 mmol) was added. The reaction mixture was stirred for 30 h at room temperature. The reaction mixture was diluted with water and extracted with EtOAc. The EtOAc layer was dried over Na2SO , filtered and concentrated to obtain the title compound (16 g, 95%).
Step 2:3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]-2- fluoroaniline
Following a procedure analogous to the procedure described in step 1 of Example 32 using 2-propen-1 -yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(4- morpholinyl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}carbamate (16 g, 33.6 mmol), the title compound was obtained (1 1 .5 g, 87 % yield).
Step 3:/V-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-1 -propanesulfonamide
Following a procedure analogous to the procedure described in step 2 of Example 32 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol- 4-yl]-2-fluoroaniline (14 g, 35.7 mmol)and 1 -propanesulfonyl chloride (7.64 g, 53.6 mmol), the title compound was obtained (9.2 g, 52 % yield). Step 4: A/-(2-fluoro-3-{2-(4-morpholinyl)-5-[2-(tetrahydro-2/-/-pyran-4-ylamino)- 4-pyrimidinyl]-1 ,3-thiazol-4-yl}phenyl)-1 -propanesulfonamide
Following a procedure analogous to the procedure described in step 4 of Example 1 using A/-{3-[5-(2-chloro-4-pyhmidinyl)-2-(4-morpholinyl)-1 ,3- thiazol-4-yl]-2-fluorophenyl}-1 -propanesulfonamide (150 mg, 0.301 mmol) and 4-aminotetrahydropyran (150 μΙ_, 1 .427 mmol), the title compound was obtained (126 mg, 74). MS: 563 [M+H]+. Example 38: A/-r2-fluoro-3-(2-(1 -methylethyl)-5-{2-r(2-methylpropyl)amino1-4- pyrimidinylH ,3-thiazol-4-yl)phenyl1methanesulfonamide
Following a procedure analogous to the procedure described in Example 1 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1 -methylethyl)-1 ,3-thiazol-4-yl]-2- fluorophenyljmethanesulfonamide (70 mg, 0.164 mmol), isopropanol (2 ml), and isobutylamine (0.164 ml, 1 .640 mmol), the title compound was obtained (41 mg, 54 %). MS: 563 [M+H]+.
Example 39: Λ/-Γ3-(2-(1 .1 -dimethylethyl)-5-{2-r(1 -methylethyl)aminol-4- PyrimidinvD-1 ,3-thiazol-4-yl)-2-fluorophenyl1-1 -propanesulfonamide
Step 1 : 2-propen-1 -yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3- thiazol-4-yl]-2-fluorophenyl}carbamate
Following a procedure analogous to the procedure described in Example 23 using propyl {3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4- yl]-2-fluorophenyl}carbamate (85 g, 190.6 mmol), the title compound was obtained (60.9 g, 98 % yield).
Step 2: 3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]-2- fluoroaniline
Following a procedure analogous to the procedure described in step 1 of Example 32 using propyl {3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)- 1 ,3-thiazol-4-yl]-2-fluorophenyl}carbamate (85 g, 190.6 mmol), the title compound was obtained (60.9 g, 98 % yield). Step 3: A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]- 2-fluorophenyl}-1 -propanesulfonamide
Following a procedure analogous to the procedure described in step 2 of Example 32 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3- thiazol-4-yl]-2-fluoroaniline (15 g, 41 .4 mmol)and 1 -propanesulfonyl chloride (3.38 g, 62.1 mmol), the title compound was obtained (8.0 g, 25 % yield).
Step 4: A -[3-(2-(1 ,1 limethylethyl)-5-{2-[(1 -methylethyl)amino]-4-pyrimidinyl}- 1 ,3-thiazol-4-yl)-2-fluorophenyl]-1 -propanesulfonamide Following a procedure analogous to the procedure described in Example 1 using with A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4- yl]-2-fluorophenyl}-1 -propanesulfonamide (150 mg, 0.320 mmol) and isoproylamine (0.255 mL, 2.99 mmol) in isopropanol (4 mL) and heated at 60 °C overnight, the title compound was obtained (86 mg, 55 % yield). MS: 491 [M+H]+.
Example 40: A/-(2,4-difluoro-3-{2-(4-morpholinyl)-5-r2-(tetrahvdro-2/-/-pyran-4- ylamino)-4-pyrimidinyl1-1 ,3-thiazol-4-yl)phenyl)-1 -propanesulfonamide
Following a procedure analogous to the procedure described in Example 1 using with A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]- 2,4-difluorophenyl}-1 -propanesulfonamide (150 mg, 0.291 mmol) and 4- aminotetrahydropyran (0.153 ml, 1 .454 mmol) in isopropanol (1 .25 mL) and heated at 80 °C overnight, the title compound was obtained (103 mg, 61 % yield). MS: 581 [M+H]+. Example 41 : /V-{2-fluoro-3-[5-{2-[(1 -methylethyl)amino1-4-pyrimidinyl)-2-(4-
Following a procedure analogous to the procedure described in Example 1 using with A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]- 2-fluorophenyl}-1 -propanesulfonamide (150 mg, 0.301 mmol) and
isopropylamine (0.257 ml, 3.01 mmol) in isopropanol (4 mL) and heated at 75 °C, the title compound was obtained (105 mg, 67 % yield). MS: 521 [M+H]+.
Example 42: /V-{2-fluoro-3-[5-{2-[(2-methylpropyl)amino1-4-pyrimidinyl)-2-(4-
Following a procedure analogous to the procedure described in Example 1 using with A/-{2-fluoro-3-[5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-2-(4- morpholinyl)-1 ,3-thiazol-4-yl]phenyl}-1 -propanesulfonamide (90 mg, 0.181 mmol) and isobutylamine (152 mL, 2.07 mmol) in isopropanol (2 mL) and heated at 60 °C overnight, the title compound was obtained (44 mg, 44 % yield). MS: 535 [M+H]+.
Example 43: Λ/-(3-Ι2-(1 .1 -dimethylethyl)-5-r2-(tetrahvdro-2/-/-Dyran-4-ylamino)- 4-pyrimidinyl1-1 ,3-thiazol-4-yl)-2-fluorophenyl)-1 -propanesulfonamide
Following a procedure analogous to the procedure described in Example 1 using with A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4- yl]-2-fluorophenyl}-1 -propanesulfonamide (146 mg, 0.31 1 mmol) and 4- aminotetrahydropyran (150 μΙ_, 1 .427 mmol) in isopropanol (1 .25 mL) and heated at 80 °C overnight, the title compound was obtained (1 16 mg, 70 % yield). MS: 534 [M+H]+.
Example 44: A/-{2,4-difluoro-3-[5-{2-r(2-methylpropyl)amino1-4-pyrimidinyl)-2- ( -morpholinyl)-1 ,3-thiazol-4-yllphenyl)-1 -propanesulfonamide
Following a procedure analogous to the procedure described in Example 1 using with A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]- 2,4-difluorophenyl}-1 -propanesulfonamide (1 12 mg, 0.217 mmol) and isobutylamine (0.218 mL, 2.171 mmol) in isopropanol (3 mL) and heated at 70 °C, the title compound was obtained (72 mg, 60 % yield). MS: 553 [M+H]+. Example 45: Λ/-Γ3-(2-(1 ,1 -dimethylethyl)-5-{2-r(2-methylpropyl)amino1-4- pyrimidinyl>-1 ,3-thiazol-4-yl)-2-fluorophenyl1-1 -propanesulfonamide
Following a procedure analogous to the procedure described in Example 1 using with A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4- yl]-2-fluorophenyl}-1 -propanesulfonamide (150 mg, 0.320 mmol) and isobutylamine (0.321 mL, 3.20 mmol) in isopropanol (4 mL) and heated at 60 °C, the title compound was obtained (1 10 mg, 68 % yield). MS: 506 [M+H]+. Example 46: A/-{2-fluoro-3-[5-(2-{[1 -(methylsulfonyl)-4-piperidinyl1amino)-4- pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yllphenyl)-1 -propanesulfonamide
Following a procedure analogous to the procedure described in Example 1 using with A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]- 2-fluorophenyl}-1 -propanesulfonamide (90 mg, 0.181 mmol) and 1 -
(methylsulfonyl)-4-piperidinamine (219 mg, 1 .229 mmol) in isopropanol (2 mL) and heated at 72 °C, the title compound was obtained (56 mg, 48 % yield). MS: 640 [M+H]+. Example 47: A/-r2-fluoro-3-(2-(1 -methylethyl)-5-{2-r(2-methylpropyl)amino1-4-
PyrimidinvD-1 ,3-thiazol-4-yl)phenyl1-1 -propanesulfonamide
Following a procedure analogous to the procedure described in Example 1 using with A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1 -methylethyl)-1 ,3-thiazol-4-yl]- 2-fluorophenyl}-1 -propanesulfonamide (92 mg, 0.203 mmol) and
isobutlyamine (0.203 ml, 2.027 mmol) in isopropanol (2 mL) and heated at 65 °C overnight, the title compound was obtained (42 mg, 42 % yield). MS: 492 [M+H]+.
Example 48: /V-{2-fluoro-3-i2-(1 -methylethyl)-5-(2-{i1 -(methylsulfonyl)-4- pipendinvHamino)-4-pyrimidinyl)-1 ,3-thiazol-4-yllphenyl)-1 - propanesulfonamide
Following a procedure analogous to the procedure described in Example 1 using with A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1 -methylethyl)-1 ,3-thiazol-4-yl]- 2-fluorophenyl}-1 -propanesulfonamide (92 mg, 0.203 mmol) and 1 -
[methyl(methylidene)oxido-l4-sulfanyl]-4-piperidinamine (314 mg, 1 .762 mmol) in isopropanol (2 mL) and heated at 70 °C, the title compound was obtained (41 mg, 34 % yield). MS: 597 [M+H]+. Example 49: A/-{2,4-difluoro-3-[5-(2-methyl-4-pyrimidinyl)-2-(4-morpholinyl)- 1 ,3-thiazol-4-yllphenyl)-1 -propanesulfonamide
/V-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]-2,4- difluorophenyl}-1 -propanesulfonamide (200 mg, 0.388 mmol) and PdCI2(dppf)- DCM adduct (50 mg, 0.061 mmol) were stirred in 1 ,4-dioxane (4 mL) at room temperature under nitrogen. The reaction flask was rendered inert by pulling a vacuum on the reaction, followed by back filling with nitrogen (3x). 2 M dimethylzinc in toluene (0.400 mL, 0.800 mmol) was added by syringe and the reaction was heated to 80 °C and stirred for 1 hour. The reaction was cooled to room temperature, and the reaction quenched by adding methanol. The reaction mixture was concentrated under vacuum and the residue was chromatographed on silica gel (40 g) eluting with a 0-to-50% A-to-B gradient (A is DCM; B is 10% MeOH/DCM with 1 % NH4OH) to give 188 mg (93%) of the product as a light yellow solid. MS: 496 [M+H]+. Example 50: A/-{3-[2-(1 ,1 -dimethylethyl)-5-(2-methyl-4-pyrimidinyl)-1 ,3-thiazol-
4-yl1-2,4-difluorophenyl)-1 -propanesulfonamide
Following a procedure analogous to the procedure described in Example 49 using with N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4- yl]-2,4-difluorophenyl}-1 -propanesulfonamide (137 mg, 0.281 mmol) and 2 M dimethylzinc in toluene (0.30 ml_, 0.600 mmol), the title compound was obtained (100 mg, 72 % yield). MS: 467 [M+H]+. Example 51 : A/-{2,4-difluoro-3-[2-(4-morpholinyl)-5-(4-pynmidinyl)-1 ,3-thiazol- 4-yllphenyl)-1 -propanesulfonamide
A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]-2,4- difluorophenyl}-1 -propanesulfonamide (250 mg, 0.485 mmol) and ammonium formate (306 mg, 4.85 mmol) were stirred in ethyl acetate (10 ml_) and methanol (10.00 ml_) at room temperature under nitrogen. Palladium hydroxide on carbon (20% weight) (272 mg, 0.388 mmol) was added and the reaction was heated to 60 °C and stirred for 1 hour. The reaction was cooled to room temperature, diluted with MeOH and EtOAc and poured through Celite, washing with DCM, MeOH and EtOAc. The eluent was concentrated under vacuum and the residue was chromatographed on silica gel (40 g) eluting with a O-to-50% A-to-B gradient (A is DCM; B is 10% MeOH/DCM with 1 % NH4OH) to give 177 mg (72%) of the title compound as a light yellow solid. MS: 482 [M+H]+.
Example 52: Λ/-Ι3-Γ2-Π .1 -dimethylethyl)-5-(4-pyrimidinyl)-1 .3-thiazol-4-yll-2.4- difluorophenylH -propanesulfonamide
Following a procedure analogous to the procedure described in Example 51 using with N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4- yl]-2,4-difluorophenyl}-1 -propanesulfonamide (150 mg, 0.308 mmol) and ammonium formate (194 mg, 3.08 mmol), the title compound was obtained (85 mg, 57 % yield). MS: 453, 454 [M+H]+.
Example 53: A/-{3-r5-(2-amino-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol- 4-yl1-2,4-difluorophenyl)-1 -propanesulfonamide
A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]-2,4- difluorophenyl}-1 -propanesulfonamide (150 mg, 0.308 mmol) was stirred in concentrated ammonium hydroxide (2.50 ml_, 17.97 mmol) in a microwave reaction vial. The vial was sealed and heated in the microwave at 130 °C for 15 minutes. After cooling to room temperature, the reaction was treated with 1 M aqueous HCI until the pH was neutral. The resulting solution was extracted with DCM (3x). The combined organic layers were dried over MgSO4 and concentrated under vacuum to give 139 mg (92%) of the product as a light white solid. MS: 468 [M+H]+. Example 54: Λ/-(3-(2-(1 .1 -dimethylethyl)-5-r2-(3-hvdroxy-3-methylbutyl)-4- pyrimidinyll-1 ,3-thiazol-4-yl)-2-fluorophenyl)-1 -propanesulfonamide
To 2-methyl-3-buten-2-ol (0.100 ml, 0.959 mmol) in a screw-top vial was added 9-borobicyclo[3.3.1 ]-nonane (2.5 ml, 1 .250 mmol). After stirring overnight, A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4- yl]-2-fluorophenyl}-1 -propanesulfonamide (0.15 g, 0.320 mmol), Cs2CO3 (0.834 g, 2.56 mmol), and PdCI2 (dppf) (0.023 g, 0.032 mmol) were added to the solution and stirred at 60 °C for 2 hours. The reaction was diluted with EtOAc and added to stirring half-saturated NH4CI. The mixture was extracted
2 times with EtOAc, dried over MgSO4, filtered, and concentrated. The residue was purifed on HPLC eluting with 10% to 90% acetonitrile to water (both with TFA). The pure fractions were combined and stirred with NaHCO3
(aq) and extracted 2 times with EtOAc. The organic extracts were dried over MgSO4, filtered, and concentrated to obtain A/-(3-{2-(1 ,1 -dimethylethyl)-5-[2-
(3-hydroxy-3-methylbutyl)-4-pyrimidinyl]-1 ,3-thiazol-4-yl}-2-fluorophenyl)-1 - propanesulfonamide (167 mg, 63%). MS: 521 [M+H]+.
Example 55: A/-(3-{2-(1 ,1 -dimethylethyl)-5-[2-(3-hvdroxypropyl)-4-pyrimidinyl1- 1 ,3-thiazol-4-yl)-2-fluorophenyl)-1 -propanesulfonamide
Following a procedure analogous to the procedure described in Example 54 using A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1 , 1 -d i methylethy I )- 1 ,3-thiazol-4-yl]-2- fluorophenyl}-1 -propanesulfonamide (0.15 g, 0.320 mmol), and 2-propen-1 -ol (0.065 ml_, 0.959 mmol), the title compound was obtained (34 mg, 21 % yield). MS: 493 [M+H]+. Example 56: /V-{2-fluoro-3-[5-(2-methyl-4-pynmidinyl)-2-(4-morpholinyl)-1 ,3- thiazol-4-yllphenyl)-1 -propanesulfonamide
Following a procedure analogous to the procedure described in Example 49 using A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-1 -propanesulfonamide (200 mg, 0.402 mmol) and 2 M dimethylzinc in toluene (0.402 ml_, 0.803 mmol), the title compound was obtained (57 mg, 30 % yield). MS: 478 [M+H]+.
Example 58 : A/-{3-r5-(2-amino-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol- 4-yl1-2-fluorophenyl)-2-butanesulfonamide
Step 1 : A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]- 2-fluorophenyl}-2-butanesulfonamide
Following a procedure analogous to the procedure described in step 2 of Example 32 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3- thiazol-4-yl]-2-fluoroaniline (200 mg, 0.551 mmol)and isobutyl sulfonyl chloride (86 mg, 0.551 mmol), the title compound was obtained (106 mg, 90 % yield). MS: 483, 484 [M+H]+. Step 2: A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]- 2-fluorophenyl}-2-butanesulfonamide Following a procedure analogous to the procedure described in Example 3 using A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-2-butanesulfonamide (109 mg, 0.226 mmol) and 1 .5 ml_ of ammonium hydroxide (1 .5 ml_) and 1 ,4-dioxane (0.5 mL) and microwaved to
130 °C for 15 min, the title compound was obtained (57 mg, 51 % yield). MS: 464 [M+H]+.
Example 59: A/-{3-r5-(2-amino-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol- 4-yl1-2-fluorophenyl)-1 -butanesulfonamide
Step:1 A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]- 2-fluorophenyl}-1 -butanesulfonamide
Following a procedure analogous to the procedure described in step 2 of Example 32 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3- thiazol-4-yl]-2-fluoroaniline (200 mg, 0.551 mmol)and 1 -butanesulfonyl chloride (86 mg, 0.551 mmol), the title compound was obtained (195 mg, 95 % yield). MS: 483 [M+H]+.
Step 2: A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]- 2-fluorophenyl}-1 -butanesulfonamide
Following a procedure analogous to the procedure described in Example 3 using A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-1 -butanesulfonamide (195 mg, 0.404 mmol) and 1 .5 mL of ammonium hydroxide (1 .5 mL) and 1 ,4-dioxane (0.5 mL) and microwave to 130 °C for 15 min, the title compound was obtained (134 mg, 68 % yield). MS: 464 [M+H]+.
Example 60: A/-{3-r5-(2-amino-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol- 4-yl1-2-fluorophenyl)-1 -propanesulfonamide
Step 1 : 2-propen-1 -yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3- thiazol-4-yl]-2-fluorophenyl}carbamate
To a solution of 2-propen-1 -yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2- fluorophenyljcarbamate (20 g, 57.2 mmol) in Ν,Ν-dimethylacetamide (DMA) (150 ml) was added NBS (10.18 g, 57.2 mmol) and the solution was allowed to stirred at rt for 1 h. 2,2-Dimethylpropanethioamide (6.70 g, 57.2 mmol) was added and the reaction mixture was heated to 80 °C for 1 h. After 1 h, the reaction was diluted with 300 ml_ water. The aqueous layer was decanted, and the residue was partitioned between water and ethyl acetate. The organic layer was washed with 3 x 300 ml_ water, dried over anhydrous sodium sulfate, and concentrated to a brown solid. The solid was triturated with isopropanol, collected by vacuum filtration, and dried in vacuo to generate 20 g (44.8 mmol, 78 %) of title compound as a yellow powder. MS: 446, 448 [M+H]+. Step 2: 3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]-2- fluoroaniline
Following a procedure analogous to the procedure described in step 1 of Example 32 using 2-propen-1 -yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 - dimethylethyl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}carbamate (10 g, 22.3 mmol) and tri-n-butlytin hydride (9.56 ml, 35.8 mmol), the title compound was obtained (7.03 g, 87 % yield). MS: 363, 364 [M+H]+. Step 3: 4-[4-(3-amino-2-fluorophenyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-5-yl]-2- p rimidinamine
To a microwave vial containing 3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 - dimethylethyl)-1 ,3-thiazol-4-yl]-2-fluoroaniline (2.55 g, 7.03 mmol) was added ammonium hydroxide (10 ml). The suspension was irradiated in a microwave reactor for 20 minutes at 120 °C. The crude reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to a brown solid. The solid was triturated with ether and dried in vacuo to generate 1 .68 g (4.89 mmol, 69.6 %) of title compound as a tan powder. MS: 344 [M+H]+.
Step 4: A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]- 2-fluorophenyl}-1 -propanesulfonamide Following a procedure analogous to the procedure described in step 2 of Example 32 using 4-[4-(3-amino-2-fluorophenyl)-2-(1 ,1 -dimethylethyl)-1 ,3- thiazol-5-yl]-2-pyrimidinamine (0.1 g, 0.291 mmol), pyridine (1 mL), 1 - propanesulfonyl chloride (0.1 15 mL, 1 .165 mmol), the title compound was obtained (28 mg, 20 % yield). MS: 450 [M+H]+.
Example 61 : A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4- yl1-2-fluorophenyl)-3,3,3-trifluoro-1 -propanesulfonamide
Step 1 : 3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]-2- fluoroaniline
Following a procedure analogous to the procedure described in step 1 of Example 32 using 2-propen-1 -yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(4- morpholinyl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}carbamate (1 g, 2.1 mmol) and tri-n-butlytin hydride (0.975 mL, 3.36 mmol), the title compound was obtained (690 mg, 80 % yield).
Step 2: N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-3,3,3-trifluoro-1 -propanesulfonamide
Following a procedure analogous to the procedure described in step 2 of
Example 32 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol- 4-yl]-2-fluoroaniline (690 mg, 1 .761 mmol), pyridine (0.045 mL), 3,3,3-trifluoro- 1 -propanesulfonyl chloride (0.1 15 mL, 1 .165 mmol), the title compound was obtained (51 mg, 5 % yield). MS: 551 .9, 553.9 [M+H]+.
Step 3: A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-3,3,3-trifluoro-1 -propanesulfonamide
Following a procedure analogous to the procedure described in Example 3 using A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-3,3,3-trifluoro-1 -propanesulfonamide (51 mg, 0.092 mmol) and ammonium hydroxide (540 pL) and microwaved to 120 °C for 20 min, the title compound was obtained (25 mg, 48 % yield). MS: 533 [M+H]+.
Example 62: A/-{3-r5-(2-amino-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol- 4-yl1-2-fluorophenyl)-2,2,2-trifluoroethanesulfonamide
Following a procedure analogous to the procedure described in step 2 of
Example 32 using 4-[4-(3-amino-2-fluorophenyl)-2-(1 ,1 -dimethylethyl)-1 ,3- thiazol-5-yl]-2-pyrimidinamine (0.1 g, 0.291 mmol), pyridine (0.024 mL), 2,2,2- trifluoroethanesulfonyl chloride (53 mg, 0.291 mmol), the title compound was obtained (32 mg, 21 % yield). MS: 490 [M+H]+. Example 63: A -(3-r5-(2-amino-4-pyrimidinyl)-2-(1 .1 limethylethyl)-1 .3-thiazol- 4-yl1-2-fluorophenyl)-3,3,3-trifluoro-1 -propanesulfonamide
Step 1 : A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]- 2-fluorophenyl}-3,3,3-trifluoro-1 -propanesulfonamide
Following a procedure analogous to the procedure described in step 2 of Example 32 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3- thiazol-4-yl]-2-fluoroaniline (200 mg, 0.551 mmol), pyridine (0.045 mL), 3,3,3- trifluoro-1 -propanesulfonyl chloride (108 mg, 0.551 mmol), the title compound was obtained (170 mg, 56 % yield). MS: 523 [M+H]+.
Step 2: N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]- 2-fluorophenyl}-3,3,3-trifluoro-1 -propanesulfonamide
Following a procedure analogous to the procedure described in Example 3 using A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-3,3,3-trifluoro-1 -propanesulfonamide (170 mg, 0.325 mmol) and ammonium hydroxide (1 .5 mL) and microwaved to 130 °C for 15 min, the title compound was obtained (51 mg, 29 % yield). MS: 504 [M+H]+.
Example 64: /V-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahvdro-2/-/-pyran-4-yl)-1 ,3- thiazol-4-yl1-2-fluorophenyl)-3, 3, 3-trifluoro-1 -propanesulfonamide
Step 1 : A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2/-/-pyran-4- thiazol-4- l]-2-fluorophenyl}-3,3,3-trifluoro-1 -propanesulfonamide
Following a procedure analogous to the procedure described in step 2 of Example 32 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)- 1 ,3-thiazol-4-yl]-2-fluoroaniline (610 mg, 1 .56 mmol), pyridine (0.133 ml_), 3,3,3-trifluoro-1 -propanesulfonyl chloride (322 mg, 1 .64 mmol), the title compound was obtained (294 mg, 32 % yield). MS: 551 [M+H]+.
Step 2: A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2/-/-pyran-4-yl)-1 ,3- thiazol-4-yl]-2-fluorophenyl}-3,3,3-trifluoro-1 -propanesulfonamide
Following a procedure analogous to the procedure described in Example 3 using A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol- 4-yl]-2-fluorophenyl}-3,3,3-trifluoro-1 -propanesulfonamide (100 mg, 0.181 mmol) and ammonium hydroxide (1 ml_) and microwaved to 120 °C for 20 min, the title compound was obtained (86 mg, 85 % yield). MS: 532 [M+H]+. Example 65: A/-{3-r5-(2-amino-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol- 4-yl1-2-chlorophenyl)-3,3,3-trifluoro-1 -propanesulfonamide
Step 1 : 2-propen-1 -yl {2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 - dimeth lethyl)-1 ,3-thiazol-4-yl]phenyl}carbamate
To a solution of 2-propen-1 -yl {2-chloro-3-[(2-chloro-4- pyrimidinyl)acetyl]phenyl}carbamate (1 .4 g, 3.82 mmol) in N,N- dimethylacetamide (DMA) (10 ml) was added NBS (0.714 g, 4.01 mmol). After 30min at room temperture; the reaction mixture was charged with 2,2- dimethylpropanethioamide (0.672 g, 5.73 mmol) and stiired at room
temperature overnight. The reaction was then heated to 60 °C for 2 h. The reaction mixture was charged with EtOAc and H2O. The EtOAc layer was washed with water, brine, and concentrated. The residue was
chromatographed on a silica gel column and eluted with EtOAc/hexanes to obtain 2-propen-1 -yl {2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 - dimethylethyl)-1 ,3-thiazol-4-yl]phenyl}carbamate (1 .17 g, 59.4 % yield).
Step 2: 2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol- 4-yl]aniline
Following a procedure analogous to the procedure described in step 1 of
Example 32 using 2-propen-1 -yl {2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 - dimethylethyl)-1 ,3-thiazol-4-yl]phenyl}carbamate (1 .17 g, 2.52 mmol) and tri- N-butlytin hydride (0.680 ml_, 2.52 mmol), the title compound was obtained (805 mg, 80 % yield). MS: 380 [M+H]+.
Step 3: A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)- 1 ,3- thiazol-4-yl]phenyl}-3,3,3-trifluoro-1 -propanesulfonamide
Following a procedure analogous to the procedure described in step 2 of
Example 32 using 2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)- 1 ,3-thiazol-4-yl]aniline (340 mg, 0.896 mmol), pyridine (0.087 ml_), 3,3,3- trifluoro-1 -propanesulfonyl chloride (299 mg, 0.986 mmol), the title compound was obtained (299 mg, 58 % yield). MS: 539 [M+H]+.
Step 4: A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]- 2-chlorophenyl}-3,3,3-trifluoro-1 -propanesulfonamide
Following a procedure analogous to the procedure described in Example 3 using A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3- thiazol-4-yl]phenyl}-3,3,3-trifluoro-1 -propanesulfonamide (145 mg, 0.269 mmol) and ammonium hydroxide (1 mL) and microwaved to 120 °C for 10 min, the title compound was obtained (49 mg, 35 % yield). MS: 520 [M+H]+.
Example 66: A/-(3-(5-(2-aminopyrimidin-4-yl)-2-(1 -hydroxy-2-methylpropan-2- yl)thiazol-4-yl)-2-chlorophenyl)propane-1 -sulfonamide
Step 1 : N-(3-(2-bromo-2-(2-chloropyrimidin-4-yl)acetyl)-2- chlorophenyl)propane-1 -sulfonamide
To a solution of A/-(2-chloro-3-(2-(2-chloropyrimidin-4- yl)acetyl)phenyl)propane-1 -sulfonamide (1 .0 g, 2.58 mmol) in N,N- dimethylacetamide (DMA) (5 mL) stirred under nitrogen at 25°C was added NBS (0.458 g, 2.58 mmol). The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was used in the next step without purification. MS: 467 [M+H]+.
Step 2: A/-(2-chloro-3-(5-(2-chloropyrimidin-4-yl)-2-(1 -hydroxy-2- methylpropan-2-yl)thiazol-4-yl)phenyl)propane-1 -sulfonamide
To a solution of A/-(3-(2-bromo-2-(2-chloropyrimidin-4-yl)acetyl)-2- chlorophenyl)propane-1 -sulfonamide (1 .19 g, 2.55 mmol) in N,N- dimethylacetamide (DMA) (5 mL) stirred under nitrogen at 25°C was added 3-hydroxy-2,2-dimethylpropanethioamide (0.373 g, 2.80 mmol) in one charge The reaction mixture was stirred at 85 °C for 3 h. The reaction mixture was cooled, diluted with 30 mL of water, and extracted with ethyl acetate (40 mL x 3). The organic layers were combined and dried (Na2SO4). The residue was chromatographed on silica gel column and eluted with Hex/EtOAc (3:2) to obtain A/-(2-chloro-3-(5-(2-chloropyrimidin-4-yl)-2-(1 -hydroxy-2-methylpropan- 2-yl)thiazol-4-yl)phenyl)propane-1 -sulfonamide (350 mg, 27.4 % yield) as a yellow solid. MS: 501 [M+H]+.
Step 3: A/-(3-(5-(2-aminopyrimidin-4-yl)-2-(1 -hydroxy-2-methylpropan-2- yl)thiazol-4-yl)-2-chlorophenyl)propane-1 -sulfonamide Following a procedure analogous to the procedure described in Example 3 using N-(2-chloro-3-(5-(2-chloropyrimidin-4-yl)-2-(1 -hydroxy-2-methylpropan- 2-yl)thiazol-4-yl)phenyl)propane-1 -sulfonamide (350 mg, 0.698 mmol) and ammonium hydroxide (6 mL, 154 mmol) in a sealed reactor heated to 100 °C for 3h, the title compound was obtained (130 mg, 37 % yield). 1 HNMR
(DMSO-d6): δ 9.576 (s, 1 H), 8.023-8.010(d, J=5.2Hz, 1 H),7.634-7.610 (dd, Ji=8.0Hz, J2=1 .6Hz, 1 H), 7.498-7.459(t, J=8.0Hz, 1 H), 7.370-7.347(dd, Ji=7.6Hz, J2=1 .6Hz, 1 H),6.750(s, 2H ), 5.857-5.843 (d, J=5.6Hz, 1 H), 5.121 - 5.093(t, J=5.6Hz, 1 H), 3.550-3.536(d, J=5.6Hz, 2H), 3.136-3.098 (m, 2 H), 1 .791 -1 .696(m, 2 H), 1 .356 (s, 6 H), 0.961 -0.923(t, J=7.6Hz, 3H). MS: 482 [M+H]+.
Example 67: A/-{2-chloro-3-[5-{2-[(2-hvdroxy-2-methylpropyl)amino1-4- Pyrimidinyl)-2-(tetrahvdro-2/-/-pyran-4-yl)-1 ,3-thiazol-4-yllphenyl)-1 - propanesulfonamide
Step 1 : /V-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)- 1 3-thiazol-4-yl]phenyl}-1 -propanesulfonamide
To a 200 mL round bottom flask was added A/-{2-chloro-3-[(2-chloro-4- pyrimidinyl)acetyl]phenyl}-1 -propanesulfonamide (3.0 g, 7.73 mmol) in DCM
(50 mL) at 25 °C to give a yellow solution. NBS (1 .37 g, 7.73 mmol) was added to the reaction mixture. After 1 h, the reaction mixture was diluted with water (50 mL) and DCM (20 mL). The DCM layer was separated from the water layer, washed with water (2x), dried over Na2SO4, filtered and concentrated to obtain the crude bromoketone which was used without further purification.
A 250 mL RB flask was charged with the crude bromoketone and tetrahydro- 2H-pyran-4-carbothioamide (1 .68 g, 1 1 .59 mmol) in N,N-dimethylacetamide (DMA) (60 mL) to give a yellow solution at 25 °C under nitrogen. The reaction solution was stirred and heated to 90 °C. After 4 h, the reaction mixture was diluted with water (100 mL) and EtOAc (100 mL). The EtOAc layer was separated from the water layer. The EtOAc layer was washed with water (2x), dried over Na2SO4, filtered, and concentrated. The residue was chromatographed on a silica gel column and eluted with EtOAc/ hexanes (2:1 ). The product fractions were combined and concentrated under vacuum to obtain A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4- yl)-1 ,3-thiazol-4-yl]phenyl}-1 -propanesulfonamide (1 .7 g, 3.31 mmol, 42.9 % yield) as a light yellow foam. LCMS (ES) m/z 513 (M)+. Step 2: A/-{2-chloro-3-[5-{2-[(2-hydroxy-2-methylpropyl)amino]-4-pyrimidinyl}- 2-(tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4-yl]phenyl}-1 -propanesulfonamide
A 50 mL round-bottomed flask was charged with N-{2-chloro-3-[5-(2-chloro-4- pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4-yl]phenyl}-1 - propanesulfonamide (0.35 g, 0.68 mmol) in dioxane (10 mL) to give a yellow solution at 25 °C under nitrogen. 1 -Amino-2-methyl-2-propanol (0.182 g, 2.045 mmol) was added to the reaction mixture which was then heated to 90 °C. After 16 h, the reaction mixture was concentrated and the residue was chromatographed on a silica gel column eluted with EtOAc. The product fractions were concentrated to obtain A/-{2-chloro-3-[5-{2-[(2-hydroxy-2- methylpropyl)amino]-4-pyrimidinyl}-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4- yl]phenyl}-1 -propanesulfonamide (360 mg, 0.63 mmol, 92 % yield) as a light yellow foam. LC-MS (ES) m/z 566 (M)+; 1 H NMR (400 MHz, CDCI3) δ ppm 8.04 (d, J =5.2 Hz, 1 H), 7.83 (d, J = 8.0 Hz,1 H), 7.42 (m, 1 H), 7.28 (m., 2H), 7.00 (br.s, 1 H), 6.07 (br.s, 1 H), 5.57 (m, 1 H), 4.1 1 (m, 2H), 3.59 (t, J = 1 1 .6 Hz, 2H), 3.42 (m, 2H), 3.31 (m, 1 H), 3.14 (m, 2H), 2.1 1 - 1 .86 (m, 5H), 1 .29 (s, 6H), 1 .05 (t, J = 7.2 Hz, 3H).
Example 68: A/-{2-fluoro-3-[5-{2-[(2-hvdroxy-2-methylpropyl)amino1-4- pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4-yllphenyl)-1 - propanesulfonamide
/V-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4-yl]- 2-fluorophenyl}-1 -propanesulfonamide (190 mg, 0.382 mmol) and 2-amino-2- methylpropan-2-ol (102 mg, 1 .147 mmol) were dissolved in toluene (4 mL) and the yellow solution stirred in a 90 °C oil bath in a sealed 20 mL microwave tube for 5 days. The reaction mixture was evaporated and the residue, dissolved in methylene chloride, onto adsorbed to silica gel. Chromatography on a short silica gel pad, eluting with CH2CI2 /methanol gradient (0% to 7%) and collecting -100 mL fractions, afforded N-{2-fluoro-3-[5-{2-[(2-hydroxy-2- methylpropyl)amino]-4-pyrimidinyl}-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4- yl]phenyl}-1 -propanesulfonamide as a pale yellow foam (274 mg).
Crystallization from ethanol/hexanes provided white needles (1 12 mg). 1 H- NMR (DMSO-d6): δ ppm 9.75 (br s, 1 H), 8.12 (d, J=5.31 Hz, 1 H), 7.50 - 7.57 (dt, J=1 .5, 7.6 Hz, 1 H) 7.36 - 7.43 (t, J=6.3 Hz, 1 H), 7.28 - 7.36 (t, J=8.2 Hz, 1 H), 6.93 (t, J=5.68 Hz, 1 H), 6.17 (br s, 1 H), 4.49 (br s, 1 H), 3.95 (dt,
J=9.47, 2.21 Hz, 2 H), 3.40 - 3.53 (dt, J=2.0, 1 1 .6 Hz, 2 H), 3.17 - 3.37 (m, 4H), 2.99 - 3.07 (m, 2 H), 2.03 (m, 2 H), 1 .63 - 1 .83 (m, 4 H), 1 .09 (s, 6H) and 0.91 (t, J=7.45 Hz, 3 H); MS: 550 [MH]+. Example 69: /V-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-methyltetrahvdro-2H-pyran- -yl)-1 ,3-thiazol-4-yl1-2-fluorophenyl)-3,3,3-trifluoro-1 -propanesulfonamide
Step 1 : /V-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-methyltetrahydro-2H-pyran-4-yl)- 1 -thiazol-4-yl]-2-fluorophenyl}-3,3,3-trifluoro-1 -propanesulfonamide
A/-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-3,3,3-trifluoro-1 - propanesulfonamide (0.49 g, 1 .151 mmol) was dissolved in DMA (3 mL) and the solution stirred at room temperature. Solid 1 -bromo-2,5-pyrrolidinedione (0.215 g, 1 .208 mmol) was added and the solution stirred at room
temperature. After 10 minutes, the mixture was treated with a solution of 4- methyltetrahydro-2H-pyran-4-carbothioamide (0.183 g, 1 .151 mmol) in N,N- dimethylacetamide (DMA) (1 .0 mL) and heated to 70 °C. After 20 minutes, the mixture was cooled to room temperature, diluted with EtOAc (100 mL) and washed with water, brine, dried (MgSO^, filtered and concentrated. The sample was re-dissolved in DMA (4 mL) and the stirred solution heated to 80 °C for 30 mins, then raised to 90 °C for 1 hour. The reaction mixture was cooled and diluted with EtOAc (75 mL). After washing with water and brine (50 mL each), the solution was dried (MgSO^, filtered and filtrate evaporated.
Chromatography of residue on a short silica gel pad, eluting with a
CH2CI2/EtOAc gradient (0% to 25%) afforded N-{3-[5-(2-chloro-4-pyrimidinyl)- 2-(4-methyltetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}-3,3,3- trifluoro-1 -propanesulfonamide as a pale yellow foam (350 mg). 1H-NMR
(DMSO-d6): δ ppm 10.08 (s, 1 H), 8.62 (d, J=5.31 Hz, 1 H), 7.50 - 7.63 (m, 2 H), 7.39 (t, J=7.96 Hz, 1 H), 7.15 (d, J=5.05 Hz, 1 H), 3.74 (ddd, J=1 1 .31 , 6.63, 3.79 Hz, 2 H), 3.57 (ddd, J=1 1 .56, 8.15, 3.28 Hz, 2 H), 3.30 - 3.41 (m, 2 H), 2.70 - 2.83 (m, 2 H), 2.18 (ddd, J=13.39, 5.81 , 3.28 Hz, 2 H), 1 .80 (ddd, J=13.14, 8.59, 3.54 Hz, 2 H), 1 .38 - 1 .50 (m, 3 H); MS: 565, 567 [MH]+. Step 2: /V-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-methyltetrahydro-2H-pyran-4-yl)- 1 ,3-thiazol-4-yl]-2-fluorophenyl}-3,3,3-trifluoro-1 -propanesulfonamide
/V-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-methyltetrahydro-2H-pyran-4-yl)-1 ,3- thiazol-4-yl]-2-fluorophenyl}-3,3,3-trifluoro-1 -propanesulfonamide (345 mg, 0.61 1 mmol) and ammonium hydroxide (4 mL, 0.61 1 mmol) were mixed and heated (sealed in a 5 mL tube) in a microwave reactor at 90 °C for 3 hrs, then allowed to stand at room temperature overnight. The reaction mixture was partitioned between EtOAc (80 mL) and water (40 mL). The organic phase was separated and washed with brine, dried (MgSO4), filtered and evaporated to a yellow gum (0.3g). Chromatography of the gum on a short silica gel pad, eluting with a CH2CI2/EtOAc gradient (0% to 80%) afforded the title compound as a pale-yellow gum (225 mg). Re-crystallization from isopropanol/hexanes provided pale-yellow crystalline A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(4- methyltetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}-3,3,3- trifluoro-1 -propanesulfonamide (1 13 mg). 1 H-NMR (DMSO-d6): δ ppm 10.07 (s, 1 H), 8.06 (d, J=5.31 Hz, 1 H), 7.56 (dt, J=1 .7, 7.9 Hz, 1 H), 7.42 - 7.49 (m, 1 H), 7.35 (t, J=7.83 Hz, 1 H), 6.77 (br s, 2 H), 6.13 (d, J=5.05 Hz, 1 H), 3.73 (ddd, J=1 1 .24, 6.57, 3.66 Hz, 2 H), 3.56 (ddd, J=1 1 .56, 8.27, 3.16 Hz, 2 H), 3.34 - 3.40 (m, 2 H), 2.68 - 2.83 (m, 2 H), 2.15 (ddd, J=13.64, 5.94, 3.16 Hz, 2 H), 1 .77 (ddd, J=13.14, 8.59, 3.54 Hz, 2 H), 1 .43 (s, 3 H); MS: 546 [MH]+.
Example 70: 3,3,3-trifluoro-/V-{2-fluoro-3-r5-(2-{r(2R)-2-hvdroxypropyllamino)- 4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4-yllphenyl)-1 - propanesulfonamide
Step 1 : A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-;
thiazol-4-yl]-2-fluorophenyl}-3,3,3-trifluoro-1 -propanesulfonamide
Following a procedure analogous to that described in step 1 of Example 69 using A/-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-3,3,3-trifluoro-1 - propanesulfonamide (2.07 g, 4.86 mmol) in DMA (4 ML), 1 -bromo-2,5- pyrrolidinedione (0.909 g, 5.10 mmol), and tetrahydro-2H-pyran-4- carbothioamide (0.777 g, 5.35 mmol) in DMA (2.5 ml_) at 90 °C, the title compound was obtained as a pale-yellow foam (1 .78 g). 1H-NMR (DMSO-d6): δ ppm 10.08 (s, 1 H), 8.61 (d, J=5.56 Hz, 1 H), 7.59 (m, dt, J=7.9, 1 .5 Hz,1 H), 7.47 - 7.55 (m, 1 H), 7.38 (t, J=7.83 Hz, 1 H), 7.12 (d, J=5.31 Hz, 1 H), 3.91 - 3.98 (m, 2 H), 3.43 - 3.54 (dt, J=1 1 .7, 2.0 Hz, 2 H), 3.29 - 3.43 (m, 3 H), 2.68 - 2.82 (m, 2 H), 2.01 - 2.08 (m, 2 H), 1 .73 - 1 .85 (m, 2 H); MS: 551 [MH]+.
Step 2: 3,3,3-trifluoro-/V-{2-fluoro-3-[5-(2-{[(2R)-2-hydroxypropyl]amino}-4- pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4-yl]phenyl}-1 - propanesulfonamide
Following a procedure analogous to that described in Example 68 using A/-{3- [5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-3,3,3-trifluoro-1 -propanesulfonamide (346 mg, 0.628 mmol) and (2R)-1 -amino-2-propanol (0.148 mL, 1 .884 mmol) in 1 ,4-dioxane (4 mL) at 90 °C for 4 hours and 100 °C for 1 hour the crude title compound was obtained as yellow gum. Chromatography of crude product on a short silica gel pad, eluting with a CH2CI2 /methanol gradient (0% to 7%) afforded the title compound as a pale yellow foam (268 mg). Re-crystallization from ethanol / hexanes provided 3,3,3-trifluoro-/V-{2-fluoro-3-[5-(2-{[(2R)-2- hydroxypropyl]amino}-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol- 4-yl]phenyl}-1 -propanesulfonamide as a white crystalline solid (190 mg). 1H- NMR (DMSO-d6): δ ppm 10.06 (s, 1 H), 8.10 (d, J=5.31 Hz, 1 H), 7.50 - 7.58 (m, 1 H), 7.40 - 7.47 (m, 1 H), 7.34 (t, J=7.83 Hz, 1 H), 7.12 (t, J=5.81 Hz, 1 H), 6.18 (br. s., 1 H), 4.66 (br. s., 1 H), 3.94 (dt, J=9.47, 2.21 Hz, 2 H), 3.77 (dt, J=1 1 .31 , 5.84 Hz, 1 H), 3.48 (td, J=1 1 .56, 1 .89 Hz, 2 H), 3.26 - 3.41 (m, 6 H), 3.15 (br. s., 2 H), 2.66 - 2.83 (m, 2 H), 2.02 (dd, J=12.76, 1 .89 Hz, 2 H), 1 .77 (qd, J=12.17, 4.17 Hz, 2 H), 1 .04 (d, J=6.32 Hz, 3 H); MS: 590 [MH]+. Example 71 : A/-{2-chloro-3-[5-(2-{[(2R)-2-hvdroxypropyl1amino)-4-pyrimidinyl)- 2-(tetrahvdro-2H-Dyran-4-yl)-1 .3-thiazol-4-yllDhenyl)-3.3.3-trifluoro-1 - propanesulfonamide
Step 1 : /V-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)- 1 -thiazol-4-yl]phenyl}-3,3,3-trifluoro-1 -propanesulfonamide
Following a procedure analogous to the procedure described in step 1 of Example 69 using A/-{2-chloro-3-[(2-chloro-4-pyrimidinyl)acetyl]phenyl}-3,3,3- trifluoro-1 -propanesulfonamide (513 mg, 1 .160 mmol) in DMA (3 mL), 1 - bromo-2,5-pyrrolidinedione (217 mg, 1 .218 mmol) and tetrahydro-2H-pyran-4- carbothioamide (168 mg, 1 .160 mmol) in Ν,Ν-dimethylacetamide DMA (3.0 mL) at 90 °C for 20 minutes, the title compound was obtained as a pale yellow foam (260 mg). MS: 567, 569 [M+H]+:
Step 2: A/-{2-chloro-3-[5-(2-{[(2R)-2-hydroxypropyl]amino}-4-pyrimidinyl)-2- (tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4-yl]phenyl}-3,3,3-trifluoro-1 - propanesulfonamide
Following a procedure analogous to that described in Example 68 using A/-{2- chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4- yl]phenyl}-3,3,3-trifluoro-1 -propanesulfonamide (260 mg, 0.458 mmol) and (2R)-1 -amino-2-propanol (0.108 mL, 1 .375 mmol) in 1 ,4-dioxane (4 mL) at 90 °C for 5 hours, the crude title compound was obtained as yellow gum.
Chromatography of the crude product on a short silica gel pad, eluting with a CH2CI2/methanol gradient (0% to 6%) afforded the title compound as a pale- yellow foam (268 mg). Re-crystallization from ethanol/hexanes provided A/-{2- chloro-3-[5-(2-{[(2R)-2-hydroxypropyl]amino}-4-pyrimidinyl)-2-(tetrahydro-2H- pyran-4-yl)-1 ,3-thiazol-4-yl]phenyl}-3,3,3-trifluoro-1 -propanesulfonamide. 1H- NMR (DMSO-d6): δ ppm 9.98 (s, 1 H), 8.06 (d, J=5.31 Hz, 1 H), 7.64 (dd, J=8.1 , 1 .5 Hz, 1 H), 7.50 (t, J=7.83 Hz, 1 H), 7.40 (dd, J=7.58, 1 .52 Hz, 1 H), 7.10 (t, J=5.68 Hz, 1 H), 5.93 (br. s., 1 H), 4.67 (d, J=3.28 Hz, 1 H), 3.89 - 3.99 (m, 2 H), 3.78 (dt, J=1 1 .31 , 5.84 Hz, 1 H), 3.38 - 3.54 (m, 4 H), 3.27 - 3.33 (m, 1 H), 3.15 (br. s., 2 H), 2.73 - 2.89 (m, 2 H), 1 .97 - 2.08 (m, 2 H), 1 .76 (qd, J=12.08, 4.17 Hz, 2 H), 1 .05 (d, J=6.32 Hz, 3 H); MS: 606, 608 [M+H]+.
Example 72: A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-methyltetrahvdro-2H-pyran- -yl)-1 ,3-thiazol-4-yl1-2-chlorophenyl)-3,3,3-trifluoro-1 -propanesulfonamide
Step 1 : A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-methyltetrahydro-2H- pyran-4-yl)-1 ,3-thiazol-4-yl]phenyl}-3,3,3-trifluoro-1 -propanesulfonamide
Following a procedure analogous to the procedure described in step 1 of
Example 69 using A/-{2-chloro-3-[(2-chloro-4-pyrimidinyl)acetyl]phenyl}-3,3,3- trifluoro-1 -propanesulfonamide (480 mg, 1 .085 mmol) in DMA (3 mL), 1 - bromo-2,5-pyrrolidinedione (203 mg, 1 .140 mmol) and 4-methyltetrahydro-2H- pyran-4-carbothioamide (173 mg, 1 .085 mmol) in DMA (1 .0 mL) at 90 °C for 2 hours, the title compound was obtained as a pale yellow foam (0.334 g). MS: 581 , 583 [M+H]+: Step 2: A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-methyltetrahydro-2H-pyran-4-yl)- 1 ,3-thiazol-4-yl]-2-chlorophenyl}-3,3,3-trifluoro-1 -propanesulfonamide
Following a procedure analogous to that described in step 2 of Example 69 using A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-methyltetrahydro-2H- pyran-4-yl)-1 ,3-thiazol-4-yl]phenyl}-3,3,3-trifluoro-1 -propanesulfonamide (330 mg, 0.568 mmol) in ammonium hydroxide (4 mL, 103 mmol) for 2 hours, the crude title compound was obtained. Chromatography of the crude product on a short silica gel pad, eluting with a CH2CI2 /methanol gradient (0% to 7%) and collecting 100 mL fractions afforded the title compound as a pale-yellow glassy residue (320 mg). Re-crystallization from ethanol provided a pale- yellow solid that was collected by filtration (204mg). 1 H-NMR (DMSO-d6): δ ppm 9.98 (s, 1 H), 8.02 (d, J=5.31 Hz, 1 H), 7.65 (dd, J=7.96, 1 .64 Hz, 1 H), 7.50 (t, J=7.83 Hz, 1 H), 7.42 (dd, J=7.71 , 1 .64 Hz, 1 H), 6.76 (br s, 2 H), 5.88 (d, J=5.05 Hz, 1 H), 3.73 (ddd, J=10.1 1 , 7.20, 3.66 Hz, 1 H), 3.55 (ddd, J=1 1 .62, 8.72, 2.91 Hz, 1 H), 3.40 - 3.47 (m, 2 H), 2.73 - 2.87 (m, 2 H), 2.10 - 2.19 (m, 2 H), 1 .77 (ddd, J=13.26, 8.84, 3.66 Hz, 2 H), 1 .42 (s, 1 H). MS: 562 [M+H]+:
Example 73: /V-{2-chloro-3-[5-(2-{[(2R)-2-hvdroxypropyl1amino)-4-pyrimidinyl)- -(4-morpholinyl)-1 ,3-thiazol-4-yllphenyl)-1 -propanesulfonamide
Step 1 : 2-propen-1 -yl {2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)- 1 ,3-thiazol-4-yl]phenyl}carbamate
To a solution of 2-propen-1 -yl {2-chloro-3-[(2-chloro-4- pyrimidinyl)acetyl]phenyl}carbamate (5 g, 13.65 mmol) in N,N- dimethylacetamide (DMA) (50 mL) was added NBS (2.430 g, 13.65 mmol) at
0 °C. The reaction mixture was stirred at room temperature for 1 h. 4- Morpholinecarbothioamide (2.396 g, 16.38 mmol) was added at room temperature and the mixture was stirred at 60 °C for 1 .5 h. The mixture was poured into water and filtered. 2-Propen-1 -yl {2-chloro-3-[5-(2-chloro-4- pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]phenyl}carbamate (5 g, 9.14 mmol, 66.9 % yield) was isolated as yellow solid. 1 H NMR (400 MHz,
CHLOROFORM-c/) ppm 3.53 - 3.73 (m, 4 H) 3.78 - 3.94 (m, 4 H) 4.71 (d, J=5.81 Hz, 2 H) 5.30 (dd, J=10.36, 1 .26 Hz, 1 H) 5.40 (dd, J=17.18, 1 .26 Hz,
1 H) 5.86 - 6.08 (m, 1 H) 6.41 (d, J=5.56 Hz, 1 H) 7.1 1 (dd, J=7.58, 1 .52 Hz, 1 H) 7.42 (t, J=8.08 Hz, 1 H) 8.16 (d, J=5.56 Hz, 1 H) 8.35 (d, J=8.08 Hz, 1 H).
MS (ESI): 492.0, 494.2 [M+H]+. Step 2: {2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4- yl]phenyl}amine To a solution of 2-propen-1 -yl {2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4- morpholinyl)-1 ,3-thiazol-4-yl]phenyl}carbamate (5.47 g, 1 1 .10 mmol) in dichloromethane (DCM) (100 mL) were added acetic acid (1 .525 mL, 26.6 mmol), and Pd(PPh3)2CI2 (0.390 g, 0.555 mmol). Then tri-n-butyl tin hydride (3.53 mL, 13.32 mmol) was added dropwise to the mixture at 0 °C. The mixture was stirred at room temperature for 30 min. The reaction was quenched by addition of saturated NaHCO3 (100 mL) slowly. The two layers were separated. The aqueous layer was extracted with DCM (100 mL). The combined organic layers were washed with water and brine successively, dried over MgSO4, filtered and concentrated under reduced pressure to give the crude product, which was washed with diethylether (200 mL) to afford the {2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4- yl]phenyl}amine (4 g, 9.80 mmol, 88 % yield). 1H NMR (400 MHz,
CHLOROFORM-c/) ppm 3.57 - 3.70 (m, 4 H) 3.75 - 3.93 (m, 4 H) 4.26 (s, 2 H) 6.51 (d, J=5.56 Hz, 1 H) 6.77 (dd, J=7.45, 1 .39 Hz, 1 H) 6.90 (dd, J=8.08, 1 .52 Hz, 1 H) 7.19 (t, J=7.83 Hz, 1 H) 8.14 (d, J=5.56 Hz, 1 H); MS (ESI): 408.1 , 409.9 [M+H]+.
Step 3: A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol- 4-yl]phenyl}-1 -propanesulfonamide
To a solution of {2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3- thiazol-4-yl]phenyl}amine (4g, 9.80 mmol) in dichloromethane (DCM) (30 mL) was added pyridine (0.792 mL, 9.80 mmol) and 1 -propanesulfonyl chloride (1 .647 mL, 14.69 mmol). The reaction was stirred 18 h at room temperature. The reaction mixture was concentrated and purified by flash column chromatography on silica gel (5 to 100% EtOAc:DCM) affording the N-{2- chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]phenyl}- 1 -propanesulfonamide (2.2 g, 4.28 mmol, 43.7 % yield) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-c/) ppm 1 .07 (t, J=7.45 Hz, 3 H) 1 .90 (dq, J=15.47, 7.47 Hz, 2 H) 3.07 - 3.21 (m, 2 H) 3.60 - 3.71 (m, 4 H) 3.79 - 3.93 (m, 4 H) 6.38 (d, J=5.56 Hz, 1 H) 6.96 (s, 1 H) 7.23 (dd, J=7.58, 1 .52 Hz, 1 H) 7.45 (t, J=7.96 Hz, 1 H) 7.84 (dd, J=8.21 , 1 .39 Hz, 1 H) 8.17 (d, J=5.56 Hz, 1 H); MS (ESI): 514.2, 516.1 [M+H]+.
Step 4: A/-{2-chloro-3-[5-(2-{[(2R)-2-hydroxypropyl]amino}-4-pyrimidinyl)-2-(4- morpholinyl)-1 ,3-thiazol-4-yl]phenyl}-1 -propanesulfonamide
To the solution of A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)- 1 ,3-thiazol-4-yl]phenyl}-1 -propanesulfonamide (100 mg, 0.194 mmol) in 1 ,4- dioxane (2 ml_) was added (R)-(-)-1 -aminopropanol (73.0 mg, 0.972 mmol) and the reaction mixture heated in microwave for 30 min at 140 °C. The solution was purified by flash column chromatography on silica gel (10 % MeOH:EtOAc). A/-{2-chloro-3-[5-(2-{[(2R)-2-hydroxypropyl]amino}-4- pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]phenyl}-1 -propanesulfonamide (60 mg, 0.103 mmol, 53.0 % yield) was isolated as yellow foam. 1 H NMR (400 MHz, CHLOROFORM-c/) ppm 1 .05 (t, J=7.45 Hz, 3 H) 1 .25 (d, J=6.32 Hz, 3 H) 1 .81 - 1 .98 (m, 2 H) 3.07 - 3.20 (m, 2 H) 3.26 - 3.39 (m, 1 H) 3.54 (ddd, J=14.21 , 6.38, 2.91 Hz, 1 H) 3.58 - 3.65 (m, 4 H) 3.76 - 3.91 (m, 4 H) 4.05 (m, J=6.47, 6.47, 6.47, 6.47, 2.91 Hz, 1 H) 5.64 (br. s., 1 H) 5.81 (d, J=5.56 Hz, 1 H) 7.25 (dd, J=7.58, 1 .52 Hz, 1 H) 7.41 (t, J=7.96 Hz, 1 H) 7.79 (dd, J=8.34, 1 .52 Hz, 1 H) 7.87 (d, J=5.31 Hz, 1 H); MS (ESI): 553.4 [M+H]+.
Example 74:. /V-{2-chloro-3-r5-(2-{r(2S)-2-hvdroxypropyl1amino)-4- pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yllphenyl)-1 -propanesulfonamide
Following a procedure analogous to the procedure described in step 4 of Example 73 using A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)- 1 ,3-thiazol-4-yl]phenyl}-1 -propanesulfonamide (100 mg, 0.194 mmol) and (2S)-1 -amino-2-propanol (73.0 mg, 0.972 mmol)) and purification by flash column chromatography on silica gel (10 % MeOH:EtOAc) afforded N-{2- chloro-3-[5-(2-{[(2S)-2-hydroxypropyl]amino}-4-pyrimidinyl)-2-(4-morpholinyl)- 1 ,3-thiazol-4-yl]phenyl}-1 -propanesulfonamide (45 mg, 0.081 mmol, 41 .9 % yield) as an yellow foam. 1H NMR (400 MHz, CHLOROFORM-c/) ppm 1 .05 (t, J=7.45 Hz, 3 H) 1 .25 (d, J=6.32 Hz, 3 H) 1 .81 - 1 .96 (m, 2 H) 3.08 - 3.21 (m, 2 H) 3.26 - 3.38 (m, 1 H) 3.54 (ddd, J=14.02, 6.19, 2.27 Hz, 1 H) 3.58 - 3.68 (m, 4 H) 3.78 - 3.92 (m, 4 H) 4.05 (td, J=6.63, 2.65 Hz, 1 H) 5.51 (br. s., 1 H) 5.82 (d, J=5.56 Hz, 1 H) 7.25 (dd, J=7.58, 1 .52 Hz, 1 H) 7.36 - 7.49 (m, 1 H) 7.80 (dd, J=8.34, 1 .52 Hz, 1 H) 7.89 (d, J=5.56 Hz, 1 H); MS (ESI): 553.4 [M+H]+
Example 75: A/-{2-chloro-3-[5-(2-{[2-hvdroxy-1 -(hvdroxymethyl)ethyl1amino)-4-
Pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yllphenyl)-1 -propanesulfonamide
Following a procedure analogous to the procedure described in step 4 of Example 73 using A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)- 1 ,3-thiazol-4-yl]phenyl}-1 -propanesulfonamide (100 mg, 0.194 mmol) and serinol (89 mg, 0.972 mmol) and purification by flash column chromatography on silica gel (10 % MeOH:EtOAc) afforded A/-{2-chloro-3-[5-(2-{[2-hydroxy-1 - (hydroxymethyl)ethyl]amino}-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4- yl]phenyl}-1 -propanesulfonamide (30 mg, 0.053 mmol, 27.1 % yield) as a yellow foam. 1 H NMR (400 MHz, DMSO-c/6) ppm 0.94 (t, J=7.45 Hz, 3 H) 1 .75 (sxt, J=7.58 Hz, 2 H) 3.07 - 3.17 (m, 2 H) 3.43 - 3.56 (m, 8 H) 3.66 - 3.78 (m, 4 H) 3.78 - 3.93 (m, 1 H) 4.61 (t, J=4.80 Hz, 2 H) 5.63 (d, J=5.31 Hz, 1 H) 6.36 - 6.57 (m, 1 H) 7.31 (dd, J=7.58, 1 .52 Hz, 1 H) 7.46 (t, J=7.83 Hz, 1 H) 7.61 (dd, J=8.08, 1 .52 Hz, 1 H) 7.91 (d, J=5.31 Hz, 1 H) 9.58 (s, 1 H); MS (ESI): 569.2 [M+H]+ Example 76: A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3- thiazol-4-yllphenyl)-1 -propanesulfonamide
Following a procedure analogous to the procedure described in step 4 of Example 73 using A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)- 1 ,3-thiazol-4-yl]phenyl}-1 -propanesulfonamide (100 mg, 0.194 mmol) and ethanolamine (59.4 mg, 0.972 mmol) and purification by flash column chromatography on silica gel (10 % MeOH:EtOAc) afforded A/-{2-chloro-3-[5- {2-[(2-hydroxyethyl)amino]-4-pyrimidinyl}-2-(4-morpholinyl)-1 ,3-thiazol-4- yl]phenyl}-1 -propanesulfonamide (30 mg, 0.056 mmol, 28.6 % yield) as a white foam. 1H NMR (400 MHz, DMSO-c/6) ppm 0.94 (t, J=7.45 Hz, 3 H) 1 .74 (sxt, J=7.53 Hz, 2 H) 3.02 - 3.15 (m, 2 H) 3.21 - 3.33 (m, 2 H) 3.39 - 3.57 (m, 6 H) 3.64 - 3.79 (m, 4 H) 4.65 (t, J=5.56 Hz, 1 H) 5.65 (d, J=5.05 Hz, 1 H) 6.93 (t, J=5.43 Hz, 1 H) 7.30 (dd, J=7.58, 1 .26 Hz, 1 H) 7.45 (t, J=7.83 Hz, 1 H) 7.60 (dd, J=8.08, 1 .52 Hz, 1 H) 7.91 (d, J=5.31 Hz, 1 H) 9.57 (s, 1 H); MS (ESI): 539.1 [M+H]+
Example 77: /V-{2-chloro-3-[5-{2-[(2-methylpropyl)amino1-4-pyrimidinyl)-2-(4- morpholinyl)-1 ,3-thiazol-4-yllphenyl)-1 -propanesulfonamide
Following a procedure analogous to the procedure described in step 4 of
Example 73 using A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)- 1 ,3-thiazol-4-yl]phenyl}-1 -propanesulfonamide (100 mg, 0.194 mmol) and (2- methylpropyl)amine (71 .1 mg, 0.972 mmol) and purification by prep HPLC (5 to 95 % acetonitrile:water using 0.1 % formic acid as modifier) afforded N-{2- chloro-3-[5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-2-(4-morpholinyl)-1 ,3- thiazol-4-yl]phenyl}-1 -propanesulfonamide (30 mg, 0.052 mmol, 26.6 % yield) as a yellow powder. 1 H NMR (400 MHz, DMSO-c/6) ppm 0.87 (d, J=6.57 Hz, 6 H) 0.94 (t, J=7.45 Hz, 3 H) 1 .74 (dq, J=15.32, 7.53 Hz, 2 H) 1 .83 (dt, J=13.39, 6.69 Hz, 1 H) 3.02 (t, J=6.06 Hz, 2 H) 3.07 - 3.21 (m, 2 H) 3.42 - 3.60 (m, 4 H) 3.67 - 3.84 (m, 4 H) 5.62 (d, J=4.80 Hz, 1 H) 7.14 (br. s., 1 H) 7.29 (d, J=7.33 Hz, 1 H) 7.45 (t, J=7.83 Hz, 1 H) 7.59 (dd, J=8.08, 1 .52 Hz, 1 H) 7.89 (d, J=5.31 Hz, 1 H);MS (ESI): 551 .3 [M+H]+
Example 78: A/-{2-chloro-3-[5-{2-[(2-hvdroxyethyl)amino1-4-pyrimidinyl)-2- (tetrahvdro-2H-pyran-4-yl)-1 ,3-thiazol-4-yllphenyl)-1 -propanesulfonamide
Step 1 : /V-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)- 1 ,3-thiazol-4-yl]phenyl}-1 -propanesulfonamide To a solution of A/-{2-chloro-3-[(2-chloro-4-pyrimidinyl)acetyl]phenyl}-1 - propanesulfonamide (1 g, 2.58 mmol) in Ν,Ν-dimethylacetamide (DMA) (30 ml_) was added NBS (0.504 g, 2.83 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. Then tetrahydro-2H-pyran-4- carbothioamide (0.41 1 g, 2.83 mmol) was added at room temperature. The mixture was stirred at 60 °C for 1 .5 h and then was poured into water. The suspension was extracted with ethyl acetate (2 x 50 ml_) and the organics were combined, washed with brine, dried and evaporated. The oil was purified by flash column chromatography on silica gel (50 % EtOAc:Hex) to give A/-{2- chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4- yl]phenyl}-1 -propanesulfonamide (400 mg, 0.740 mmol, 28.7 % yield) as white foam.
1 H NMR (400 MHz, CHLOROFORM-c/) ppm 1 .07 (t, J=7.45 Hz, 3 H) 1 .85 - 2.05 (m, 4 H) 2.15 (dd, J=12.88, 2.02 Hz, 2 H) 3.02 - 3.23 (m, 2 H) 3.33 (tt, J=1 1 .59, 3.95 Hz, 1 H) 3.58 (td, J=1 1 .75, 2.02 Hz, 2 H) 4.01 - 4.26 (m, 2 H) 6.69 (d, J=5.31 Hz, 1 H) 6.94 (s, 1 H) 7.25 (dd, J=7.58, 1 .26 Hz, 1 H) 7.46 (t, J=7.96 Hz, 1 H) 7.87 (dd, J=8.21 , 1 .39 Hz, 1 H) 8.37 (d, J=5.31 Hz, 1 H); MS (ESI): 513.6 [M+H]+
Step 2: A/-{2-chloro-3-[5-{2-[(2-hydroxyethyl)amino]-4-pyrimidinyl}-2- (tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4-yl]phenyl}-1 -propanesulfonamide To a solution of A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H- pyran-4-yl)-1 ,3-thiazol-4-yl]phenyl}-1 -propanesulfonamide (80 mg, 0.156 mmol) in 1 ,4-dioxane (2 mL) was added ethanolamine (47.6 mg, 0.779 mmol) and the reaction mixture heated in a microwave for 1 h at 140 °C. The solution was then injected on a prep HPLC (5 to 95 % acetonitrile:water using 0.1 % formic acid). A/-{2-chloro-3-[5-{2-[(2-hydroxyethyl)amino]-4-pyrimidinyl}-2- (tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4-yl]phenyl}-1 -propanesulfonamide (40 mg, 0.071 mmol, 45.3 % yield) was isolated as white foam. 1H NMR (400 MHz, DMSO-c/e) ppm 0.94 (t, J=7.45 Hz, 3 H) 1 .61 - 1 .83 (m, 4 H) 2.03 (dd, J=12.63, 2.02 Hz, 2 H) 2.98 - 3.16 (m, 2 H) 3.24 - 3.32 (m, 2 H) 3.42 - 3.56 (m, 4 H) 3.94 (dt, J=9.47, 2.08 Hz, 2 H) 4.65 (br. s., 1 H) 5.92 (br. s., 1 H) 7.13 (t, J=5.68 Hz, 1 H) 7.32 (d, J=7.07 Hz, 1 H) 7.46 (t, J=7.96 Hz, 1 H) 7.61 (dd, J=8.08, 1 .26 Hz, 1 H) 8.07 (d, J=5.30 Hz, 1 H) 9.63 (br. s., 1 H); MS (ESI): 538.1 [M+H]+
Example 79: A/-{2-chloro-3-[5-(2-{r2-hvdroxy-1 -(hvdroxymethyl)ethyl1amino)-4-
Pyrimidinyl)-2-(tetrahvdro-2H-pyran-4-yl)-1 ,3-thiazol-4-yllphenyl)-1 - propanesulfonamide
Following a procedure analogous to the procedure described in step 2 of Example 78 using A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H- pyran-4-yl)-1 ,3-thiazol-4-yl]phenyl}-1 -propanesulfonamide (80 mg, 0.156 mmol) and serinol (71 .0 mg, 0.779 mmol) and purification by prep HPLC (5 to 95 % acetonitrile:water using 0.1 % formic acid) afforded N-{2-chloro-3-[5-(2- {[2-hydroxy-1 -(hydroxymethyl)ethyl]amino}-4-pyrimidinyl)-2-(tetrahydro-2H- pyran-4-yl)-1 ,3-thiazol-4-yl]phenyl}-1 -propanesulfonamide (35 mg, 0.059 mmol, 37.6 % yield) as a white foam. 1 H NMR (400 MHz, DMSO-c/6) ppm 0.84 - 1 .1 1 (m, 3 H) 1 .60 - 1 .91 (m, 4 H) 1 .94 - 2.16 (m, 2 H) 3.05 - 3.26 (m, 2 H) 3.27 - 3.43 (m, 1 H) 3.43 - 3.68 (m, 6 H) 3.80 - 4.06 (m, 3 H) 6.1 1 - 6.52 (m, 2 H) 7.39 (d, J=7.58 Hz, 1 H) 7.50 (t, J=7.96 Hz, 1 H) 7.59 - 7.78 (m, 1 H) 7.85 - 8.35 (m, 2 H) 9.61 (s, 1 H); MS (ESI): 568.6 [M+H]+
Example 80: A/-{2-chloro-3-[5-{2-[(2-methylpropyl)amino1-4-pynmidinyl)-2-
(tetrahvdro-2H-pyran-4-yl)-1 ,3-thiazol-4-yllphenyl)-1 -propanesulfonamide
Following a procedure analogous to the procedure described in step 2 of Example 78 using A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H- pyran-4-yl)-1 ,3-thiazol-4-yl]phenyl}-1 -propanesulfonamide (80 mg, 0.156 mmol) and (2-methylpropyl)amine (57.0 mg, 0.779 mmol) and purification by prep HPLC (5 to 95 % acetonitrile:water using 0.1 % formic acid) afforded /V- {2-chloro-3-[5-{2-[(2-methylpropyl)amino]-4-pyrimidinyl}-2-(tetrahydro-2H- pyran-4-yl)-1 ,3-thiazol-4-yl]phenyl}-1 -propanesulfonamide (32 mg, 0.055 mmol, 35.5 % yield) as a white solid. 1 H NMR (400 MHz, DMSO-c/6) ppm 0.87 (d, J=6.57 Hz, 6 H) 0.94 (t, J=7.45 Hz, 3 H) 1 .62 - 1 .88 (m, 5 H) 1 .96 - 2.10 (m, 2 H) 2.89 - 3.18 (m, 4 H) 3.25 - 3.32 (m, 1 H) 3.48 (td, J=1 1 .49, 1 .52 Hz, 2 H) 3.94 (dt, J=9.47, 2.08 Hz, 2 H) 5.75 - 6.02 (m, 1 H) 7.26 - 7.42 (m, 2 H) 7.46 (t, J=7.83 Hz, 1 H) 7.54 - 7.72 (m, 1 H) 8.06 (d, J=5.05 Hz, 1 H) 9.41 - 9.90 (m, 1 H); MS (ESI): 550.3 [M+H]+
Example 81 : /V-{2-chloro-3-[5-(2-{[(2R)-2-hvdroxypropyl1amino)-4-pyrimidinyl)-
2-(tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4-yllphenyl)-1 -propanesulfonamide
Following a procedure analogous to the procedure described in step 2 of Example 78 using A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H- pyran-4-yl)-1 ,3-thiazol-4-yl]phenyl}-1 -propanesulfonamide (80 mg, 0.156 mmol) and (R)-(-)-1 -aminopropanol (58.5 mg, 0.779 mmol) and purification by prep HPLC (5 to 95 % acetonitrile:water using 0.1 % formic acid) afforded /V- {2-chloro-3-[5-(2-{[(2R)-2-hydroxypropyl]amino}-4-pyrimidinyl)-2-(tetrahydro- 2H-pyran-4-yl)-1 ,3-thiazol-4-yl]phenyl}-1 -propanesulfonamide (40 mg, 0.069 mmol, 44.2 % yield) as a white solid 1H NMR (400 MHz, M ETHAN OL-c/4) ppm 1 .02 (t, J=7.58 Hz, 3 H) 1 .20 (d, J=6.32 Hz, 3 H) 1 .79 - 1 .91 (m, 2 H) 1 .91 - 2.01 (m, 2 H) 2.05 - 2.16 (m, 2 H) 3.04 - 3.16 (m, 2 H) 3.18 - 3.28 (m, 1 H) 3.35 - 3.42 (m, 2 H) 3.61 (td, J=1 1 .75, 2.27 Hz, 2 H) 3.94 (td, J=6.57, 4.55 Hz, 1 H) 4.07 (dt, J=9.54, 2.18 Hz, 2 H) 5.93 - 6.23 (m, 1 H) 7.35 (dd, J=7.71 , 1 .64 Hz, 1 H) 7.49 (t, J=7.96 Hz, 1 H) 7.77 (dd, J=8.08, 1 .52 Hz, 1 H) 8.03 (d, J=5.31 Hz, 1 H); MS (ESI): 552.4 [M+H]+
Example 82: /V-{2-chloro-3-[5-(2-{r(2S)-2-hvdroxypropyl1amino)-4-pyrimidinyl)- 2-(tetrahvdro-2H-pyran-4-yl)-1 ,3-thiazol-4-yllphenyl)-1 -propanesulfonamide
Following a procedure analogous to the procedure described in step 2 of
Example 78 using A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H- pyran-4-yl)-1 ,3-thiazol-4-yl]phenyl}-1 -propanesulfonamide (80 mg, 0.156 mmol) and (2S)-1 -amino-2-propanol (58.5 mg, 0.779 mmol) and purification by prep HPLC (5 to 95 % acetonitrile:water using 0.1 % formic acid) afforded A/-{2-chloro-3-[5-(2-{[(2S)-2-hydroxypropyl]amino}-4-pyrimidinyl)-2-(tetrahydro- 2H-pyran-4-yl)-1 ,3-thiazol-4-yl]phenyl}-1 -propanesulfonamide (45 mg, 0.077 mmol, 49.7 % yield) as a white foam 1 H NMR (400 MHz, METHANOL-c/4) ppm 1 .02 (t, J=7.45 Hz, 3 H) 1 .20 (d, J=6.32 Hz, 3 H) 1 .78 - 1 .90 (m, 2 H) 1 .90 - 2.03 (m, 2 H) 2.05 - 2.16 (m, 2 H) 3.03 - 3.17 (m, 2 H) 3.18 - 3.28 (m, 1 H) 3.35 - 3.42 (m, 2 H) 3.61 (td, J=1 1 .75, 2.02 Hz, 2 H) 3.94 (td, J=6.63, 4.67 Hz, 1 H) 4.07 (dt, J=9.47, 2.21 Hz, 2 H) 6.09 (br. s., 1 H) 7.35 (dd, J=7.58, 1 .52 Hz, 1 H) 7.49 (t, J=7.96 Hz, 1 H) 7.78 (dd, J=8.34, 1 .52 Hz, 1 H) 8.03 (d, J=5.31 Hz, 1 H); MS (ESI): 552.4 [M+H]+
Example 83: A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(1 ,4-dimethyl-4-piperidinyl)-
1 ,3-thiazol-4-yl1-2-fluorophenyl)-1 -propanesulfonamide
A suspension of /V-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,4-dimethyl-4-pipendinyl)- 1 ,3-thiazol-4-yl]-2-fluorophenyl}-1 -propanesulfonamide-TFA (58 mg) in ammonium hydroxide aqueous solution (28%, 2 ml_) sealed in a 5-mL microwave tube was heated at 90 °C for 2h under the microwave conditions. The reaction mixture was concentrated and the residue was dissolved into methanol and purified using prep HPLC under acidic conditions (5%ACN/H2O, 0.1 %TFA to 80% ACN/H2O, 0.1 % TFA). The resulting TFA salt of the product was dissolved into methanol and treated with 1 N HCI solution and
concentrated. The residue was further dried under high vacuum to give the title compound as an HCI salt (10 mg). 1 HNMR (400 MHz, DMSO-d6): δ ppm 9.79 (m, 1 H), 8.14-8.17 (m, 1 H), 7.33-7.59 (m, 4H), 6.22-6.28 (m, 1 H), 3.37- 3.40 (m, 2H), 3.00-3.27 (m, 4H), 2.68-2.80 (m, 3H), 2.33-2.44 (m, 2H), 2.05- 2.15 (m, 2H),1 .70-1 .74 (m, 2H), 1 .40-1 .58 (m, 3H), 0.92-0.95 (m, 3H); MS: 505.1 [M+H]+.
Example 84: A/-{2-fluoro-3-[5-{2-[(2-hvdroxyethyl)amino1-4-pyrimidinyl)-2-(4- methyl-4-piperidinyl)-1 ,3-thiazol-4-yllphenyl)-1 -propanesulfonamide
To a solution of 1 -methylethyl 4-(4-{2-fluoro-3-[(propylsulfonyl)amino]phenyl}- 5-{2-[(2-hydroxyethyl)amino]-4-pyrimidinyl}-1 ,3-thiazol-2-yl)-4-methyl-1 - piperidinecarboxylate (101 mg, 0.159 mmol) in dichloromethane (DCM) (1 ml_) was added TFA (0.3 ml_, 3.89 mmol), and the reaction mixture was stirred for 1 .5h . The mixture was concentrated and the residue was treated with saturated NaHCO3 solution and filtered. The solid was washed with water and dried under high vacuum to give title compound (80 mg, 98% yield).
1 HNMR (400 MHz, DMSO-d6): δ ppm 8.1 1 -8.12 (d, J = 4.0 Hz, 1 H), 7.47-7,51 (t, J = 8.0 Hz, 1 H), 7.17-7.21 (t, J = 8.0 Hz, 1 H), 7.1 1 -7.13 (m, 2H), 6.18 (m ,1 H), 3.48-3.51 (m, 2H), 3.30 (m, 2H), 2.85-2.95 (m, 4H), 2.78 (m, 2H), 2.1 1 - 2.14 (m, 2H), 1 .62-1 .72 (m, 4H), 1 .40 (s, 3H), 0.89-0.93 (t, J = 8.0 Hz, 3H); MS: 535.1 [M+H]+.
Example 85: A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-methyltetrahvdro-2H-pyran- 4-yl)-1 ,3-thiazol-4-yl1-2-fluorophenyl)-1 -propanesulfonamide
A suspension of A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-methyltetrahydro-2H- pyran-4-yl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}-1 -propanesulfonamide (93 mg, 0.182 mmol) in ammonium hydroxide solution (28%, 2 ml_) sealed in a 5-mL microwave tube was heated at 90 °C for 2h under the microwave conditions. The mixture was concentrated and the residue was dissolved into methanol and purified using prep HPLC under the acidic conditions (5% ACN/H2O, 0.1 %TFA to 80% ACN/H2O, 0.1 % TFA) and the resulting TFA salt of the product was treated with saturated NaHCO3 and extracted with EtOAc. The extract was dried over Na2SO and concentrated to give the title compound (64 mg, 70% yield). 1HNMR (400 MHz, DMSO-d6): δ ppm 9.75 (s, 1 H), 8.08- 8.09 (d, J = 4.0 Hz, 1 H), 7.54-7.57 (m, 1 H), 7.40 (m, 1 H), 7.31 -7.35 (t, J = 8.0 Hz, 1 H), 6.79 (s, 2H), 6.1 1 -6.13 (d, J = 4.0 Hz, 1 H), 3.72-3.75 (m, 2H), 3.55- 3.59 (m, 2H), 3.03-3.07 (m, 2H), 2.13-2.17 (m, 2H), 1 .67-1 .80 (m, 4H), 1 .43 (s, 3H), 0.90-0.94 (t, J = 8.0 Hz, 3H); MS: 492.0 [M+H]+. Example 86: /V-{2-fluoro-3-[5-(2-{[(2R)-2-hvdroxypropyl1amino)-4-pyrimidinyl)- 2-(4-methyltetrahvdro-2H-pyran-4-yl)-1 ,3-thiazol-4-yllphenyl)-1 - propanesulfonamide
To a 5-mL microwave tube were added N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4- methyltetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}-1 - propanesulfonamide (90 mg, 0.176 mmol), (2R)-1 -amino-2-propanol (52.9 mg, 0.704 mmol), and toluene (2 ml_). The tube was sealed and the mixture was heated at 90 °C for 8 h under microwave conditions. The mixture was concentrated the residue was purified using column chromatography, eluting with 60% to 100% EtOAc/hexanes, to give the title compound (66 mg, 67% yield). 1 HNMR (400 MHz, DMSO-d6): δ ppm 8.12-8.13 (d, J = 4.0 Hz, 1 H), 7.53-7.55 (t, J = 4.0 Hz,1 H), 7.41 -7.43 (t, J = 4.0 Hz,1 H), 7.30-7.34 (t, J = 8.0 Hz, 1 H), 7.12 (m, 1 H), 6.12-6.19 (m,1 H), 3.72-3.79 (m, 3H), 3.56-3.59 (m, 2H), 3.18 (m, 2H), 3.02-3.06 (t, J = 8.0 Hz 2H), 2.13-2.17 (m, 2H), 1 .67-1 .82 (m, 4H), 1 .44 (s, 3H), 1 .04-1 .05 (d, J = 4.0 Hz, 3H), 0.89-0.93 (m, J = 8.0 Hz, 3H); MS: 550.2 [M+H]+.
Example 87: /V-{2-fluoro-3-[5-(2-{[(2S)-2-hvdroxypropyl1amino)-4-pyrimidinyl)- 2-(4-methyltetrahvdro-2H-pyran-4-yl)-1 ,3-thiazol-4-yllphenyl)-1 - propanesulfonamide
To a 5-mL microwave tube were added A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4- methyltetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}-1 - propanesulfonamide (80 mg, 0.157 mmol), (2S)-1 -amino-2-propanol (47.0 mg, 0.626 mmol), and toluene (2 ml_). The tube was sealed and the mixture was heated at 90 °C for 9 h under microwave conditions. The mixture was concentrated and the residue was purified using reverse-phase HPLC (36% ACN/H2O, 0.1 % TFA to 80% ACN/H2O, 0.1 % TFA) and the resulting TFA salt was then neutralized with saturated NaHCO3 and extracted with EtOAc. The extract was dried over Na2SO4 and concentrated to give the title compound (56 mg, 64% yield). 1HNMR (400 MHz, DMSO-d6): δ ppm 8.12-8.13 (d, J = 4.0 Hz, 1 H), 7.53-7.55 (t, J = 4.0 Hz, 1 H), 7.41 -7.43 (t, J = 4.0 Hz, 1 H), 7.30- 7.34 (t, J = 8.0 Hz, 1 H), 7.12 (m, 1 H), 6.12-6.19 (m,1 H), 3.72-3.79 (m, 3H), 3.57-3.59 (m, 2H), 3.18 (m, 2H), 3.01 -3.05 (t, J = 8.0 Hz 2H), 2.13-2.17 (m, 2H), 1 .66-1 .81 (m, 4H), 1 .44 (s, 3H), 1 .04-1 .05 (d, J = 4.0 Hz, 3H), 0.89-0.93 (m, J = 8.0 Hz, 3H); MS: 550.2 [M+H]+.
Example 88: A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-methyltetrahvdro-2H-pyran- 4-yl)-1 ,3-thiazol-4-yl1-2-chlorophenyl)-1 -propanesulfonamide
A suspension of A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4- methyltetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4-yl]phenyl}-1 - propanesulfonamide (200 mg, 0.379 mmol) in ammonium hydroxide aqueous solution (28%, 2 mL) sealed in a 5-mL microwave tube was heated at 90 °C for 2h under microwave conditions. The mixture was concentrated and the residue was treated with saturated NaHCO3 solution and filtered. The solid was washed with water and methanol and dried to give the title compound (89 mg, 45% yield). 1HNMR (400 MHz, DMSO-d6): δ ppm 9.59 (s, 1 H), 8.03- 8.04 (d, J = 4.0 Hz, 1 H), 7.62-7.64 (d, J = 8.0 Hz, 1 H), 7.46-7.50 (t, J = 8.0, 4.0 Hz, 1 H), 7.37-7.39 (m,1 H), 6.77 (m, 2H), 5.86-5.87 (d, J = 4.0 Hz, 1 H), 3.72-3.76 (m, 2H), 3.54-3.57 (m, 2H), 3.10-3.14 (t, J = 4.0 Hz, 2H), 2.13-2.16 (m, 2H), 1 .71 -1 .80 (m, 4H), 1 .43 (s, 3H), 0.92-0.96 (t, J = 8.0 Hz, 3H); MS: 507.8 [M+H]+. Example 89: A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-methyl-4-piperidinyl)-1 ,3- thiazol-4-yl1-2-chlorophenyl)-1 -propanesulfonamide
To a suspension of 1 ,1 -dimethylethyl 4-(5-(2-amino-4-pyrimidinyl)-4-{2-chloro- 3-[(propylsulfonyl)amino]phenyl}-1 ,3-thiazol-2-yl)-4-methyl-1 - piperidinecarboxylate (45 mg, 0.074 mmol) in dichloromethane (DCM) (1 mL) was added TFA (0.5 mL, 6.49 mmol), and the reaction mixture was stirred for 1 h. the reaction mixture was concentrated and the residue was purified using reverse-phase HPLC (Gilson, 10% ACN/H2O, 0.1 % TFA to 75% ACN/H2O, 0.1 % TFA). The resulting TFA salt of the product was dissolved into methanol and treated with 1 N HCI and concentrated. The residue was further dried under high vacuum to give the title compound as an HCI salt (12 mg). 1 HNMR (400 MHz, DMSO-d6): δ ppm 9.64 (s, 1 H), 9.03 (s, 2H), 8.13-8.15 (d, J = 8.0 Hz, 1 H), 7.65-7.67 (m, 1 H), 7.51 (m, 1 H), 7.42-7.44 (m, 1 H), 6.00-6.01 (d, J = 4.0 Hz, 1 H), 3.24 (m, 2H), 3.13-3.17 (m, 2H), 3.06 (m, 2H), 2.32-2.34 (m, 2H), 1 .97-2.01 (m, 2H), 1.74-1.78 (m, 2H), 1.48 (s, 3H), 0.93-0.97 (t, J = 8.0 Hz, 3H); MS: 507.0 [M+Hf. Example 90: N-(3-r5-(2-amino-4-pyrimidinyl)-2-(4-piperidinyl)-1 ,3-thiazol-4-yll- -chlorophenyl)-1-propanesulfonamide
Step 1 : 1 ,1-dimethylethyl 4-[4-{2-chloro-3-[(propylsulfonyl)amino]phenyl}-5-(2- chloro-4-pyrimidinyl)-1 ,3-thiazol-2-yl]-1-piperidinecarboxylate
A 100 mL RB flask was charged with A/-{2-chloro-3-[(2-chloro-4- pyrimidinyl)acetyl]phenyl}-1-propanesulfonamide (2.0 g, 5. 5 mmol) and DMA (10 mL). NBS (0.917 g, 5.15 mmol) and DMA (3 mL) were added to the solution. A slight exotherm was observed. The yellow reaction was stirred at room temperature for 80 minutes. 1 ,1-dimethylethyl 4-(aminocarbonothioyl)- 1-piperidinecarboxylate (1.259 g, 5. 5 mmol) was added as a solid followed by DMA (1 mL). The reaction became reddish in color. The mixture was stirred for three days at room temperature. The reaction was poured into 150 mL of water and a yellow precipitate was immediately produced. The heterogeneous mixture was stirred for 10 minutes and filtered. The resulting pale yellow solid was washed with water and hexanes in a Buchner funnel. The partially dried solid was washed into a beaker with DCM and the biphasic mixture was transferred to a separatory funnel. The layers were separated and the DCM layer was dried over Na2SO , filtered and concentrated to give a pale yellow solid. This material was purified by chromatography on silica gel (0-3% MeOH:DCM) to give the title compound (1 .708 gm, 54%) as a pale yellow solid. MS(ES)+ m/e 613.7 [M+H].
Step 2: 1 ,1 -dimethylethyl 4-(5-(2-amino-4-pyrimidinyl)-4-{2-chloro-3- [(propylsulfonyl)amino]phenyl}-1 ,3-thiazol-2-yl)-1 -piperidinecarboxylate
1 ,1 -dimethylethyl 4-[4-{2-chloro-3-[(propylsulfonyl)amino]phenyl}-5-(2-chloro- 4-pyrimidinyl)-1 ,3-thiazol-2-yl]-1 -piperidinecarboxylate (0.600g, 0.979 mmol) was mostly dissolved in ammonium hydroxide (12 ml_, 308 mmol). The mixture was heated in the microwave oven at 90 °C for 90 minutes, transferred to a round bottom flask, and concentrated to dryness in vacuo. The residue was dissolved in a mixture of DCM and water and the water layer was made neutral by addition of saturated ammonium chloride. The layers were separated and the DCM layer was dried over Na2SO , filtered, and concentrated to give a yellow solid. The crude solid was purified by chromatography on silica gel (5% MeOH:DCM) to give the title compound (0.435 gm, 75%) as a yellow solid. MS(ES)+ m/e 592.8 [M+H].
Step 3: A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-piperidinyl)-1 ,3-thiazol-4-yl]-2- chlorophenyl}-1 -propanesulfonamide
1 ,1 -dimethylethyl 4-(5-(2-amino-4-pyrimidinyl)-4-{2-chloro-3- [(propylsulfonyl)amino]phenyl}-1 ,3-thiazol-2-yl)-1 -piperidinecarboxylate (0.418 g, 0.705 mmol) was dissolved in DCM (4 ml_) and to this solution was added trifluoroacetic acid (0.054 ml_, 0.705 mmol), dropwise via pipet. The yellow solution turned a reddish color upon addition. The reaction was stirred at room temperature for 30 minutes, concentrated in vacuo, and the residual red oil was suspended in a mixture of DCM and water. The residue did not completely dissolve and the DCM was removed in vacuo. EtOAc was added and the water/EtOAc mixture was sonicated until two clear layers were observed. Sodium bicarbonate solution (5 %) was carefully added until the water layer was neutral. The layers were separated and the EtOAc was washed with water and brine, dried over Na2SO , filtered, and concentrated to give a pale yellow solid. The aqueous layer was concentrated and the residue was triturated with 60 ml_ of 20% MeOH:DCM and filtered. The filtrate was concentrated and pumped under high vacuum overnight to give a white solid. The solid was dissolved in a mixture of 20 ml_ water and 40 ml_ of 10%
IPA:CHCl3. The layers were separated and the water layer was extracted with 6 x 30 ml_ of 10% IPA:CHCl3. The combined organics were dried over Na2SO4, filtered, and concentrated to give a white solid. The solid was dried in a vacuum oven overnight at 60 °C to give the title compound (0.292 g, 84%) as a white solid. MS(ES)+ m/e 492.8 [M+H]. 1 H NMR (400 MHz, DMSO-c/6) ppm 8.04 (d, J=5.1 Hz, 1 H), 7.63 (dd, J=8.1 , 1 .5 Hz, 1 H), 7.47 (t, J=7.8 Hz, 1 H), 7.33 (dd, J=7.6, 1 .5 Hz, 1 H), 6.78 (s, 2 H), 5.86 (d, J=5.3 Hz, 1 H), 3.37 - 3.46 (m, 4 H), 2.99 - 3.16 (m, 4 H), 2.23 (dd, J=2.8 Hz, 2 H), 1 .82 - 1 .98 (m, 2 H), 1 .74 (sxt, J=7.5 Hz, 2 H), 0.94 (t, J=7.5 Hz, 3 H) Example 91 : /V-{3-[5-(2-amino-4-pynmidinyl)-2-(1 -piperazinyl)-1 ,3-thiazol-4-yl1- -chlorophenyl)-1 -propanesulfonamide
Step 1 : 1 ,1 -dimethylethyl 4-[4-{2-chloro-3-[(propylsulfonyl)amino]phenyl}-5-(2- chloro-4-pyrimidinyl)-1 ,3-thiazol-2-yl]-1 -piperazinecarboxylate
A 100 mL RB flask was charged with A/-{2-chloro-3-[(2-chloro-4- pyrimidinyl)acetyl]phenyl}-1 -propanesulfonamide (2.00 g, 5.15 mmol) and DMA (10 mL). NBS (0.917 g, 5.15 mmol) and DMA (3 mL) were added and the yellow solution was stirred at room temperature for 2h. 4-{[(1 ,1 - dimethylethyl)oxy]carbonyl}piperazin-1 -ium thiocyanate (1 .264 g, 5.15 mmol) was added as a solid followed by DMA (1 mL). The reaction was stirred at room temperature for 4 days. The homogeneous reddish reaction was poured into 175 mL of water and stirred for 20 minutes. A yellow precipitate was observed. The solid was filtered and washed with water followed by hexanes in a Buchner funnel. The filtered solid was washed into a beaker with DCM and the DCM solution was transferred to a separatory funnel where the water layer was removed. The DCM layer was dried over Na2SO , filtered, and concentrated to give an orange semi-solid. This material was purified via chromatography on silica gel (0-10% MeOH:DCM) to give an orange oil. This oil was purified via chromatography on silica gel (0-2% MeOH:DCM) to give the title compound (1 .07 g, 34%) as a yellow solid. MS(ES)+ m/e 612.7
[M+H]. Step 2: 1 ,1 -dimethylethyl 4-(5-(2-amino-4-pyrimidinyl)-4-{2-chloro-3- [(propylsulfonyl)amino]phenyl}-1 ,3-thiazol-2-yl)-1 -piperazinecarboxylate
1 ,1 -dimethylethyl 4-[4-{2-chloro-3-[(propylsulfonyl)amino]phenyl}-5-(2-chloro- 4-pyrimidinyl)-1 ,3-thiazol-2-yl]-1 -piperazinecarboxylate (1 .038 g, 1 .692 mmol) was suspended in ammonium hydroxide (12 mL, 308 mmol) and the mixture was heated at 90 °C for 2 hours in the microwave oven. The reaction was concentrated to remove ammonia and some water. DCM was added and the basic water layer was made neutral with saturated ammonium chloride. The layers were separated and the DCM layer was dried over Na2SO , filtered, and concentrated to give an orange solid. This material was purified via chromatography on silica gel (0-5% MeOH:DCM) to give the title compound (0.263 g, 26%) as a yellow solid. MS(ES)+ m/e 593.8 [M+H]. Step 3: A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(1 -piperazinyl)-1 ,3-thiazol-4-yl]-2- chlorophenyl}-1 -propanesulfonamide
1 ,1 -dimethylethyl 4-(5-(2-amino-4-pyrimidinyl)-4-{2-chloro-3- [(propylsulfonyl)amino]phenyl}-1 ,3-thiazol-2-yl)-1 -piperazinecarboxylate (0.248 g, 0.417 mmol) was suspended in DCM (7 mL) and tnfluoroacetic acid (3.5 mL) was added. Addition of TFA caused the heterogeneous reaction to become homogeneous and red. The reaction mixture was stirred at room temperature for 1 hour. The reaction was concentrated in vacuo and the residue was dissolved in a mixture of EtOAc and water. 5% NaHCO3 and 1 N HCI were added to make the water layer neutral. The aqueous layer was filtered to remove a minor amount of insoluble material and the filtrate was extracted with 6 x 40 mL of 10% IPA:CHCl3. The extracts were dried over
Na2SO4, filtered, concentrated, and dried overnight at 70°C in a vacuum oven to give the title compound (0.103 g, 50%) as a yellow solid. MS(ES)+ m/e 493.8 [M+H]. 1 H NMR (400 MHz, DMSO-c/6) d ppm 7.87 (d, J=5.3 Hz, 1 H) 7.60 (dd, J=8.1 , 1 .5 Hz, 1 H) 7.46 (t, J=7.8 Hz, 1 H) 7.29 (dd, J=7.6, 1 .5 Hz, 1 H) 6.56 (br. s., 2 H) 5.63 (d, J=5.3 Hz, 1 H) 3.58 (d, J=3.5 Hz, 4 H) 3.09 - 3.15 (m, 2 H) 3.05 (br. s., 3 H) 1 .71 - 1 .79 (m, 2 H) 0.91 - 1 .00 (m, 3 H)
Example 92: A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(1 -methyl-4-piperidinyl)-1 ,3- thiazol-4-yl1-2-chlorophenyl)-1 -propanesulfonamide
Step 1 : /V-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-piperidinyl)-1 ,3-thiazol- 4-yl]phenyl}-1 -propanesulfonamide
1 ,1 -dimethylethyl 4-[4-{2-chloro-3-[(propylsulfonyl)amino]phenyl}-5-(2-chloro- 4-pyrimidinyl)-1 ,3-thiazol-2-yl]-1 -piperidinecarboxylate (0.980 g, 1 .600 mmol) was dissolved in DCM (12 mL) and trifluoroacetic acid (6.0 mL, 78 mmol) was added via pipet. The homogeneous orange reaction was stirred at room temperature for 1 hour. The reaction was concentrated to remove excess TFA and DCM. The residue was dissolved in a mixture of DCM and water and the water layer was neutralized by addition of saturated sodium
bicarbonate. The layers were separated and the aqueous layer was extracted with DCM. The combined DCM layers were washed with saturated NaCI, dried over Na2SO4, filtered, and concentrated to give the title compound (0.707 g, 86%) as a yellow solid. MS(ES)+ m/e 51 1 .7 [M+H].
Step 2: A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1 -methyl-4-piperidinyl)-1 ,3- thiazol-4-yl]phenyl}-1 -propanesulfonamide
A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-piperidinyl)-1 ,3-thiazol-4- yl]phenyl}-1 -propanesulfonamide (1 .457 g, 2.84 mmol) was dissolved in DCE (75 mL) and to this solution was added sodium triacetoxyborohydride (2.71 g, 12.79 mmol) as a solid. The mixture was stirred for 10 minutes at room temperature. Formaldehyde (0.96 mL of 37% aqueous solution, 13.3 molar, 4.5 eq) was added via syringe and the reaction was stirred overnight at room temperature. A small amount of MeOH was added and 5% NaHCO3 was added to neutralize the mixture. The layers were separated and the DCE layer was dried over Na2SO4, filtered, and concentrated to give a yellow solid. This material was purified via chromatography on silica gel (100% DCM to 60% of 90:9:1 DCM:MeOH:NH4OH) to give the title compound (0.539 g, 36%) as a pale yellow solid. MS(ES)+ 525.8 [M+H[. Step 3: A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(1 -methyl-4-piperidinyl)-1 ,3-thiazol- 4- l]-2-chlorophenyl}-1 -propanesulfonamide
A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1 -methyl-4-piperidinyl)-1 ,3-thiazol- 4-yl]phenyl}-1 -propanesulfonamide (0.515 g, 0.978 mmol) was dissolved in ammonium hydroxide (10 mL) and heated in a microwave oven for 90 minutes at 90 °C. The reaction was concentrated to dryness and the residue was dissolved in DCM containing a small amount of methanol. Celite was added and the flask was carefully concentrated in vacuo to dryness. The Celite dry mixture was purified via chromatography on silica gel (0-75% of 90:9:1
CHCl3:MeOH:NH OH) and the isolated fractions were dried under vacuum to give the title compound (0.08 g, 16.1 %) as a pale yellow solid. MS(ES)+ m/e 507.3 [M+H]. 1H NMR (400 MHz, DMSO-c/6) ppm 9.56 (br. s., 1 H) 8.02 (d, J=5.3 Hz, 1 H) 7.61 (dd, J=8.1 , 1 .5 Hz, 1 H) 7.45 (t, J=8.0 Hz, 1 H) 7.28 - 7.33 (m, 1 H) 6.76 (s, 2 H) 5.85 (d, J=5.1 Hz, 1 H) 3.05 - 3.12 (m, 2 H) 2.99 (tt, J=1 1 .4, 3.5 Hz, 1 H) 2.87 (d, J=1 1 .6 Hz, 2 H) 2.22 (s, 3 H) 2.03 - 2.14 (m, 4 H) 1 .67 - 1 .81 (m, 4 H) 0.94 (t, J=7.3 Hz, 3 H).
Example 93: /V-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-methyl-1 -piperazinyl)-1 , 3- thiazol-4-yl1-2-fluorophenyl)-3,3,3-trifluoro-1 -propanesulfonamide
A 5 ml_ microwave tube was charged with A/-{3-[5-(2-chloro-4-pyrimidinyl)-2- (4-methyl-1 -piperazinyl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}-3,3,3-trifluoro-1 - propanesulfonamide (120 mg, 0.212 mmol) and ammonium hydroxide (2481 μΙ, 63.7 mmol) to give a yellow solution at room temperature under nitrogen gas. The sealed reaction mixture was irradiated in a microwave at 90 °C for 2.0 hour. The reaction mixture was concentrated and dissolved in MeOH 3.0 ml_. This solution was chromatographed on reverse phase HPLC and eluted with 5 to 70% of CH3CN in water with 0.1 % of TFA. Fraction were collected and concentrated to about 10ml_. The resulting water solution was adjusted by saturated NaHCO3 to pH about 8.0. This solution was extracted by 10% IPA in CHCI3 (20ml_ X 3). The organic phase was dried over MgSO and concentrated to give the final product A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(4- methyl-1 -piperazinyl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}-3,3,3-trifluoro-1 - propanesulfonamide (62 mg, 0.108 mmol, 50.8 % yield). 1H NMR (DMSO-d6) δ ppm 10.06 (br. s., 1 H) 7.89 (d, J=5.56 Hz, 1 H) 7.54 (td, J=7.58, 2.02 Hz,1 H) 7.24 - 7.41 (m, 2 H) 6.56 (s, 2 H) 5.88 (d, J=4.55 Hz, 1 H) 3.46 - 3.58 (m, 4 H) 3.35 - 3.40 (m, 2 H) 2.68 -2.85 (m, 2 H) 2.46 (br. s., 4 H) 2.25 (s, 3 H); MS: (M+H)+ = 546.
Example 94: /V-{3-[5-(2-amino-4-pynmidinyl)-2-(4-methyl-1 -piperazinyl)-1 ,3- thiazol-4-yl1-2-chlorophenyl)-1 -propanesulfonamide
Following a procedure analogous to the one described in Example 93 using A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-methyl-1 -piperazinyl)-1 ,3- thiazol-4-yl]phenyl}-1 -propanesulfonamide (150 mg, 0.284 mmol) and ammonium hydroxide (2215 μΙ, 56.9 mmol). The title compound was obtained as a white solid (55 mg, 0.103 mmol, 36.2 % yield). 1 H NMR (DMSO-d6) δ ppm 9.56 (br. s., 1 H) 7.85 (d, J=5.31 Hz, 1 H) 7.59 (dd, J=8.08, 1 .52 Hz, 1 H) 7.44 (t, J=7.83 Hz, 1 H) 7.29 (br. s., 1 H) 6.53 (s, 2 H) 5.62 (s, 1 H) 3.46 - 3.53(m, 4 H) 3.03 - 3.14 (m, 2 H) 2.36 - 2.47 (m, 4 H) 2.24 (s, 3 H) 1 .66 - 1 .80 (m, 2 H) 0.94 (t, J=7.45 Hz, 3H). MS: (M+H)+ = 509.
Example 95: A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(1 -methyl-4-piperidinyl)-1 ,3- thiazol-4-yl1-2-fluorophenyl)-1 -propanesulfonamide
Following a procedure analogous to the one described in Example 93 using A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methyl-4-piperidinyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-1-propanesulfonamide (150 mg, 0.294 mmol) and ammonium hydroxide (5726 μΙ_, 147 mmol). The title compound was obtained as an off- white solid (32 mg, 0.062 mmol, 21 % yield. 1H NMR (DMSO-c6) δ ppm 9.76 (br. s., 1 H) 8.07 (d, =5.05 Hz, 1 H) 7.53 (td, J=7.71 , 1.77 Hz, 2H) 7.31 (d, J=7.83 Hz, 1 H) 6.78 (s, 2 H) 6.09 (d, J=5.31 Hz, 1 H) 2.89 - 3.07 (m, 2 H) 2.83 - 2.85 (m, 1 H) 2.20 (s, 3 H) 1.96 - 2.1 1 (m, 4 H) 1.66 - 1.82 (m, 4 H) 0.92 (t, J=7.45 Hz, 3 H); MS: (M+H)+ = 491
Example 96: A -(2-fluoro-3-r5-f2-r(2-hvdroxy-2-methylpropyl)amino1-4- pyrimidinyl)-2-(1 -methyl-4-piperidinyl)-1 ,3-thiazol-4-vnphenyl)-1 - propanesulfonamide
Following a procedure analogous to the one described in Example 115 using /V-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methyl-4-piperidinyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-1 -propanesulfonamide (200 mg, 0.392 mmol) and 1-amino-2- methyl-2-propanol (140 mg, 1.568 mmol) in 1 ,4-dioxane (3921 pl_). The title compound was obtained as a light yellow solid (62 mg, 0.105 mmol, 27 % yield). 1 H NMR (DMSO-d6) δ ppm 9.70 (br. s., 1 H) 8.1 1 (d, J=5.31 Hz, 1 H) 7.44 - 7.65 (m, 1 H) 7.21 -7.42 (m, 2 H) 6.87 - 6.98 (m, 1 H) 6.17 (br. s., 1 H) 4.50 (br. s., 1 H) 4.10 (q, J=5.39 Hz, 1 H) 3.17 (d, J=5.05Hz, 2 H) 2.96 - 3.06 (m,2 H) 2.85 (d, J=1 1 .87 Hz, 2 H) 2.20 (s, 2 H) 1 .98 - 2.1 1 (m, 4 H) 1 .67 - 1 .83 (m, 4 H)1 .08 (s, 6 H) 0.90 (t, J=7.45 Hz, 3 H); MS: (M+H)+ = 563
Example 97: /V-{2-chloro-3-[5-(2-{[(2f?)-2-hvdroxypropyl1amino)-4-Pyrimidinyl)-
2-(4-methyl-1 -piperazinyl)-1 ,3-thiazol-4-yllphenyl)-1 -propanesulfonamide
Following a procedure analogous to the one described in Example 115 using A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-methyl-1 -piperazinyl)-1 ,3- thiazol-4-yl]phenyl}-1 -propanesulfonamide (150 mg, 0.284 mmol) and (R)-(+)- 1 -amino-2-propanol (0.1 12 ml, 1 .422 mmol). The title compound was obtained as a yellow solid (75 mg, 0.126 mmol, 44 % yield). 1 H NMR (DMSO- d6) δ ppm 9.56 (br. s., 1 H) 7.89 (d, J=5.31 Hz, 1 H) 7.59 (dd, J=8.08, 1 .77 Hz, 1 H) 7.44 (t, J=7.83 Hz, 1 H) 7.29 (d, J=6.32 Hz, 1 H) 6.86 (br. s., 1 H) 5.63 (d, J=5.31 Hz, 1 H) 4.62 - 4.75 (m,1 H) 3.77 (br. s., 1 H) 3.50 (d, J=4.80 Hz, 2 H) 3.04 - 3.21 (m, 4 H) 2.44 (t,J=4.80 Hz, 4 H) 2.24 (s, 3 H) 2.02 - 2.13 (m, 2 H) 1 .74 (sxt, J=7.58 Hz, 2 H) 1 .02 - 1 .09 (m, 2 H) 0.93 ( t, J=7.45 Hz, 3 H); MS: M+ , (M + 2)+ = 566, 568
Example 98: A/-{2-chloro-3-[5-(2-{[(2S)-2-hvdroxypropyl1amino)-4-pyrimidinyl)-
2-(4-methyl-1 -piperazinyl)-1 ,3-thiazol-4-yllphenyl)-1 -propanesulfonamide
Following a procedure analogous to the one described in Example 93 using A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-methyl-1 -piperazinyl)-1 ,3- thiazol-4-yl]phenyl}-1 -propanesulfonamide (150 mg, 0.284 mmol) and (S)-(+)- 1 -amino-2-propanol (0.1 12 ml, 1 .422 mmol). The title compound was obtained as a yellow solid (85 mg, 0.143 mmol, 50 % yield). 1 H NMR (DMSO-d6) δ ppm 9.56 (br. s., 1 H) 7.89 (d, J=5.31 Hz, 1 H) 7.58 (dd, J=8.08, 1 .52 Hz, 1 H) 7.42 (t, J=7.83 Hz, 1 H) 7.26 (br. s., 1 H) 6.85 (br. s., 1 H) 5.64 (d, J=5.31 Hz, 1 H) 4.67 (d, J=4.29 Hz, 1 H) 4.1 1 (q, J=5.22 Hz, 1 H) 3.77 (td, J=6.06, 4.04 Hz, 1 H) 3.43 - 3.54 (m, 4 H) 2.99 - 3.21 (m, 3 H) 2.37 -2.48 (m, 4 H) 2.23 (s, 3 H) 1 .59 - 1 .83 (m, 2 H) 1 .05 (t, J=5.56 Hz, 2 H) 0.94 (t, J=7.45 Hz, 3 H); MS: M+ = 566, 568
Example 99: A/-{3-r5-(2-amino-4-pyrimidinyl)-2-(4-pyridinyl)-1 ,3-thiazol-4-yl1-2- chlorophenylH -propanesulfonamide
Following a procedure analogous to the one described in Example 93 using A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-pyridinyl)-1 ,3-thiazol-4- yl]phenyl}-1 -propanesulfonamide (120 mg, 0.237 mmol) and ammonium hydroxide (9.23 μΙ_, 0.237 mmol). The title compound was obtained as an off white solid (40 mg, 0.078 mmol, 33 % yield). 1H NMR (DMSO-d6) δ ppm 9.65 (br. s., 1 H) 8.70 - 8.84 (m, 2 H) 8.1 1 (d, J=5.05 Hz,1 H) 7.90 - 7.98 (m, 2 H) 7.68 (dd, J=7.96, 1 .64 Hz, 1 H) 7.42 - 7.59 (m, 2 H) 6.89 (s, 2 H) 5.92 (d, J=5.31 Hz, 1 H) 3.01 - 3.18 (m, 2 H) 1 .67 - 1 .83 (m, 2 H) 0.95 (t, J=7.45 Hz, 3 H); MS: (M+H)+ = 487, 489.
Example 100: A/-{2-chloro-3-r5-(2-{r(2f?)-2-hvdroxypropyl1amino)-4- pyri m id i n yl )-2-(4-pyrid i n yl )- 1 ,3-thiazol-4-yllphenyl)-1 -propanesulfonamide
Following a procedure analogous to the one described in Example 93 using A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-pyridinyl)-1 ,3-thiazol-4- yl]phenyl}-1 -propanesulfonamide (150 mg, 0.296mmol) and (2R)-1 -amino-2- propanol (89 mg, 1 .185 mmol). The title compound was obtained as a yellow solid (60 mg, 0.105 mmol, 35 % yield). 1 H NMR (DMSO-d6) δ ppm 9.64 (s, 1 H) 8.64 - 8.88 (m, 2 H) 8.15 (d, J=5.31 Hz, 1 H) 7.96 (d, J=5.81 Hz, 2 H) 7.68 (dd, J=7.96, 1 .64 Hz, 1 H) 7.44 - 7.57 (m, 2 H) 7.23 (s, 1 H) 4.71 (d, J=4.80 Hz, 1 H) 3.70 - 3.88 (m, 1 H) 3.00 - 3.25 (m, 4 H) 1 .69 - 1 .81 (m, 2 H) 1 .08 (d, J=2.02 Hz, 3H) 0.95 (t, J=7.45 Hz, 3 H); MS: M+ = 545 Example 101 : A/-{2-chloro-3-r5-(2-{r(2S)-2-hvdroxypropyl1amino)-4-
Pyrimidinyl)-2-(4-pyridinyl)-1 ,3-thiazol-4-yllphenyl)-1 -propanesulfonamide
Following a procedure analogous to the one described in Example 93 using A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-pyridinyl)-1 ,3-thiazol-4- yl]phenyl}-1 -propanesulfonamide (150 mg, 0.296 mmol) and (2S)-1 -amino-2- propanol (89 mg, 1 .185 mmol). The title compound was obtained as a yellow solid (76 mg, 0.132 mmol, 44 % yield). 1 H NMR (DMSO-d6) δ ppm 9.64 (s, 1 H) 8.67 - 8.85 (m, 2 H) 8.15 (d, J=5.31 Hz, 1 H) 7.96 (d, J=5.81 Hz, 2 H) 7.68 (dd, J=7.96, 1 .64 Hz, 1 H) 7.43 - 7.57 (m, 2 H) 7.23 (t, J=5.68 Hz, 1 H) 4.71 (d, J = 4.55Hz, 1 H) 3.82 (br. s., 1 H) 3.05 - 3.26 (m, 4 H) 1 .62 - 1 .80 (m, 2 H) 1 .08 (d, J=2.02 Hz, 3H) 0.95 (t, J=7.45 Hz, 3 H); MS: M+ = 545
Example 102: A/-{3-r5-(2-amino-4-pyrimidinyl)-2-(2-pyridinyl)-1 ,3-thiazol-4-yl1- 2-chlorophenyl)-1 -propanesulfonamide
Following a procedure analogous to the one described in Example 32 using A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(2-pyridinyl)-1 ,3-thiazol-4- yl]phenyl}-1 -propanesulfonamide (120 mg, 0.237 mmol) and ammonium hydroxide (1845 μΙ_, 47.4 mmol). The title compound was obtained as an off white solid (1 10 mg, 0.215 mmol, 91 % yield) 1H NMR (DMSO-d6) δ ppm 9.63 (s, 1 H) 8.71 (d, J=4.29 Hz, 1 H) 8.15 (d, J=7.83 Hz, 1 H) 8.08 (d, J=5.05 Hz, 1 H) 7.98 (td, J=7.71 , 1 .77 Hz, 1 H) 7.67 (dd, J=7.96, 1 .64 Hz, 1 H) 7.42 - 7.61 (m, 3 H) 6.83(s, 2 H) 5.90 (d, J=5.05 Hz, 1 H) 3.01 - 3.21 (m, 2 H) 1 .64 - 1 .82 (m, 2 H) 0.95 (t, J=7.45 Hz, 3 H); MS: (M+H)+ = 538 Example 103: /V-{3-[5-(2-amino-4-pynmidinyl)-2-(4-pipendinyl)-1 ,3-thiazol-4- yl1-2-fluorophenyl)-1 -propanesulfonamide
Following a procedure analogous to the one described in Example 93 using A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-piperidinyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-1 -propanesulfonamide (300 mg, 0.503 mmol) and ammonium hydroxide (9798 μΙ, 252 mmol) The title compound was obtained as an off white solid. N-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-piperidinyl)-1 ,3-thiazol-4-yl]- 2-fluorophenyl}-1 -propanesulfonamide (45 mg, 0.090 mmol, 18 % yield). 1 H NMR (DMSO-d6) δ ppm 0.92 (t, J=7.45 Hz, 3 H) 1 .53 - 1 .77 (m, 4 H) 2.03 - 2.09 (m, 2 H) 2.68 - 2.82 (m, 2 H) 2.93 - 3.03 (m, 2 H) 3.07 - 3.24 (m, 3 H) 6.1 1 (d, J=5.05 Hz, 1 H)6.77 (s, 2 H) 7.21 - 7.31 (m, 2 H) 7.47 - 7.57 (m, 1 H) 8.07 (d, J=5.05 Hz, 1 H) MS: (M+H)+ = 476
Example 104: A/-(3-{5-(2-amino-4-pyrimidinyl)-2-[4-(2-hvdroxyethyl)-1 - piperidinyll-1 ,3-thiazol-4-yl)-2-fluorophenyl)-1 -propanesulfonamide
Following a procedure analogous to the one described in Example 93 using /V-(3-{5-(2-chloro-4-pyrimidinyl)-2-[4-(2-hydroxyethyl)-1 -piperidinyl]-1 ,3-thiazol- 4-yl}-2-fluorophenyl)-1 -propanesulfonamide (100 mg, 0.185 mmol) ) and ammonium hydroxide (2163 μΙ_, 55.5 mmol). The title compound was obtained as an off-white solid (40 mg, 0.073 mmol, 39 % yield). 1 H NMR (DMSO-d6) δ ppm 9.75 (s, 1 H) 7.89 (d, J=5.56 Hz, 1 H) 7.40 - 7.59 (m, 1 H) 7.29 (d, J=6.57 Hz, 2 H) 6.54 (s, 2 H) 5.77 - 5.91 (m, 1 H) 4.41 (t, J=5.05 Hz, 1 H) 3.94 (d, J=12.38 Hz, 2 H) 3.45 - 3.58 (m, 2 H) 2.98 - 3.14 (m, 4 H) 1 .62 - 1 .81 (m, 4 H) 1 .40 (q, J=6.40 Hz, 2 H) 1 .10 - 1 .31 (m, 2 H) 0.92 (t, J=7.45 Hz, 3 H); MS: (M+H)+ = 521
Example 105: /V-r2-fluoro-3-(2-i4-(2-hvdroxyethyl)-1 -piperidinvn-5-{2-i(2- methylpropyl)amino1-4-pyrimidinyl)-1 ,3-thiazol-4-yl)phenyl1-1 - propanesulfonamide
Following a procedure analogous to the one described in Example 93 using A/-(3-{5-(2-chloro-4-pyrimidinyl)-2-[4-(2-hydroxyethyl)-1 -piperidinyl]-1 ,3-thiazol- 4-yl}-2-fluorophenyl)-1 -propanesulfonamide (120 mg, 0.222 mmol) and 2- methyl-1 -propanamine (48.8 mg, 0.667 mmol). The title compound (56 mg, 0.092 mmol, 41 % yield) was obtained. 1H NMR (DMSO-c^) δ ppm 9.75 (br. s., 1 H) 7.91 (d, J=5.31 Hz, 1 H) 7.46 - 7.56 (m, 1 H) 7.28 (br. s., 2 H) 7.1 1 (br. s., 1 H) 5.85 (br. s., 1 H) 4.41 (t, J=5.05 Hz, 1 H) 3.96 (br. s., 2 H) 3.43 - 3.53 (m, 3 H) 3.03 (d, J=9.60 Hz, 6 H) 1 .62 - 1 .87 (m, 6 H) 1 .34 - 1 .48 (m, 2 H) 1 .23 (br. s., 2 H) 0.73 - 0.95 (m, 9 H); MS: (M+H)+ = 577 Example 106: /V-{3-[5-(2-amino-4-pynmidinyl)-2-(4-methyl-1 -piperazinyl)-1 ,3- thi zol-4-yl1-2-chlorophenyl)-3,3,3-trifluoro-1 -propanesulfonamide
Step 1 : A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-methyl-1 -piperazinyl)- 1 ,3-thiazol-4-yl]phenyl}-3,3,3-trifluoro-1 -propanesulfonamide
A 100 mL round-bottomed flask was charged with A/-{2-chloro-3-[(2-chloro-4- pyrimidinyl)acetyl]phenyl}-3,3,3-trifluoro-1 -propanesulfonamide (1 .2 g, 2.71 mmol) in Λ/,/V-dimethylacetamide (DMA) (13.57 ml) to give a brown solution at room temperature under nitrogen. NBS (0.459 g, 2.58 mmol) was added to the reaction mixture. After 1 h, 4-methyl-1 -piperazinecarbothioamide (0.454 g, 2.85 mmol) was added to the reaction mixture. After 15 h, the reaction mixture was diluted with water (20 mL) and EtOAc (25 mL) and stirred. After stirring, the EtOAc layer was separated from the water layer. The EtOAc (100 mL) was added to water. After stirring, the EtOAc layer was separated from the water layer. The EtOAc layers were washed with water (3 x 10 mL). The EtOAc layer was dried over Na2SO4, filtered, and concentrated. The residue was chromatographed on silica gel column and eluted with MeOH in CHCI3 (10% to 70%) to obtain A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-methyl- 1 -piperazinyl)-1 ,3-thiazol-4-yl]phenyl}-3,3,3-trifluoro-1 -propanesulfonamide (1 .2 g, 72 % yield). MS: M+ = 581 .
Step 2: A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-methyl-1 -piperazinyl)-1 ,3-thiazol- 4-yl]-2-chlorophenyl}-3,3,3-trifluoro-1 -propanesulfonamide A 20 mL sealed microwave tube was charged with A/-{2-chloro-3-[5-(2-chloro- 4-pyrimidinyl)-2-(4-methyl-1 -piperazinyl)-1 ,3-thiazol-4-yl]phenyl}-3,3,3- trifluoro-1 -propanesulfonamide (120 mg, 0.206 mmol) was added ammonium hydroxide (241 1 μΙ, 61 .9 mmol) to give a yellow solution at room temperature. The sealed reaction mixture was microwaved at 95 °C for 90 min. The reaction mixture was concentrated. The reaction mixture was diluted with MeOH (3.0 mL). The crude product was purified on prep-HPLC (5 to 70% of CH3CN in water with 0.1 % of TFA). The clean fractions were concentrated to about 10 mL. The pH of water solution was adjusted with NaHCO3 (2.5 %) to pH of 8.0. The mixture was extratced with 10% IPA in CHCI3 (20 mL x 3). The organic phase was dried over MgSO , and concentrated to obtain A/-{3- [5-(2-amino-4-pyrimidinyl)-2-(4-methyl-1 -piperazinyl)-1 ,3-thiazol-4-yl]-2- chlorophenyl}-3,3,3-trifluoro-1 -propanesulfonamide (60 mg, 49.1 % yield). 1 H NMR (DMSO-d6) δ ppm 9.96 (br. s., 1 H) 7.84 (d, J=5.56 Hz, 1 H) 7.60 (dd, J=8.08, 1 .52 Hz, 1 H) 7.45 (t, J=7.83 Hz, 1 H) 7.30 (d, J=6.82 Hz, 1 H) 6.53 (s, 2 H) 5.63 (d, J=5.31 Hz, 1 H) 3.46 - 3.58 (m, 4 H) 3.36 - 3.44 (m, 2 H) 2.69 - 2.92 (m, 2 H) 2.47 (d, J=4.29 Hz, 4 H) 2.26 (s, 3 H); MS: M+ = 562.
Example 107: /V-{2-chloro-3-r5-(2-{r(2S)-2-hvdroxypropyl1amino)-4- pyrimidinyl)-2-(4-methyl-1 -piperazinyl)-1 ,3-thiazol-4-yllphenyl)-3,3,3-trifluoro- 1 -propanesulfonamide
Following a procedure analogous to the one described in Example 93 using A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-methyl-1 -piperazinyl)-1 ,3- thiazol-4-yl]phenyl}-3,3,3-trifluoro-1 -propanesulfonamide (120 mg, 0.206 mmol) and (S)-(+)-1 -amino-2-propanol (48.7 μΙ_, 0.619 mmol). The title compound was obtained as a yellow solid (74 mg, 0.1 13 mmol, 55 % yield). 1 H NMR (DMSO-d6) δ ppm 9.95 (br. s., 1 H) 7.88 (d, J=5.31 Hz, 1 H) 7.60 (dd, J=8.08, 1 .52 Hz, 1 H) 7.46 (t, J=7.96 Hz, 1 H) 7.32 (dd, J=7.58, 1 .52 Hz, 1 H) 6.86 (br. s., 1 H) 5.64 (d, J=5.31 Hz, 1 H) 4.67 (br.s., 1 H) 3.71 - 3.85 (m, 2 H) 3.51 (m, 4 H) 3.37 - 3.44 (m, 2 H) 3.04 - 3.21 (m, 2 H) 2.71 - 2.89 (m, 2 H) 2.27 (s, 3 H) 1 .04(d, J = 8 Hz 3 H); MS: M+ , (M + 2)+ = 620, 622.
Example 108: 3.3.3-trifluoro-/V-{2-fluoro-3-r5-(2-{r(2S)-2- hvdroxypropyl1amino)-4-Pyrimidinyl)-2-(4-methyl-1 -piperazinyl)-1 ,3-thiazol-4- vIlphenylH -propanesulfonamide
Following a procedure analogous to the one described in Example 93 using A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-methyl-1 -piperazinyl)-1 ,3- thiazol-4-yl]phenyl}-3,3,3-trifluoro-1 -propanesulfonamide (120 mg, 0.212 mmol) and (S)-(+)-1 -amino-2-propanol (66.9 μΙ_, 0.850 mmol). The title compound was obtained as a yellow solid (66 mg, 0.104 mmol, 49 % yield). 1 H NMR (DMSO-d6) ) δ ppm 10.05 (br. s., 1 H) 7.92 (d, J=5.31 Hz, 1 H) 7.53 (td, J=7.52, 2.15 Hz,1 H) 7.28 - 7.38 (m, 2 H) 6.88 (br. s., 1 H) 5.89 (d, J=5.05 Hz, 1 H) 4.67 (br. s., 1 H) 4.35 (d, J=4.29 Hz, 1 H) 3.69 - 3.84 (m, J=6.09, 6.09, 6.09, 6.09, 4.17 Hz, 2 H) 3.44 - 3.55 (m, 4 H) 3.15 - 3.26 (m, 2 H) 2.65 - 2.85 (m, 2H) 2.45 (t, J=4.55 Hz, 4 H) 2.24 (s, 3 H) 1 .04(d, J = 8 Hz 3 H); MS (M+H)+ = 604. Example 109: /V-{3-[5-(2-amino-4-pynmidinyl)-2-(1 -methyl-4-pipendinylV ,3- thiazol-4-yl1-2-chlorophenyl)-3,3,3-trifluoro-1 -propanesulfonamide
Following a procedure analogous to the one described in Example 93 N-{2- chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1 -methyl-4-piperidinyl)-1 ,3-thiazol-4- yl]phenyl}-3,3,3-trifluoro-1 -propanesulfonamide (436 mg, 0.751 mmol) and ammonium hydroxide (8774 μΙ_, 225 mmol). The title compound was obtained as an off white solid (76 mg, 0.129 mmol, 21 % yield). 1H NMR (DMSO-d6) δ ppm 9.65 (bs, 1 H), 8.00 (d, J=5.30 Hz, 1 H) 7.57 (dd, J=8.34, 1 .52 Hz, 1 H) 7.35 (t, J=7.83 Hz, 1 H) 7.10 (d, J=7.58 Hz, 1 H) 6.74 (s, 2 H) 5.90 (d, J=5.31 Hz, 1 H) 3.19 - 3.28 (m, 2 H) 3.00 - 3.15 (m, 3 H) 2.65 - 2.81 (m, 2 H) 2.39 - 2.49 (m, 4 H) 2.10 - 2.22 (m, 2 H) 1 .75 - 1 .87 (m, 2 H); MS: (M+H)+ = 562
Example 1 10: A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-piperidinyl)-1 ,3-thiazol-4- yl1-2-chlorophenyl)-3,3,3-trifluoro-1 -propanesulfonamide
Following a procedure analogous to the one described in Example 41 using 1 ,1 -dimethylethyl 4-[5-(2-amino-4-pyrimidinyl)-4-(2-chloro-3-{[(3,3,3- trifluoropropyl)sulfonyl]amino}phenyl)-1 ,3-thiazol-2-yl]-1 -piperidinecarboxylate (250 mg, 0.386 mmol) in dichloromethane (DCM) (1 .932 ml) and treated with TFA (1 .0 ml, 12.98 mmol). The title compound was obtained as a light yellow solid (62 mg, 0.108 mmol, 28 % yield). 1 H NMR (DMSO-d6) δ ppm 8.33 - 8.15 (bs, 1 H) 7.99 (d, J=5.31 Hz, 1 H) 7.47 (dd, J=8.08, 1 .52 Hz, 1 H) 7.12 (t, J=7.96 Hz, 1 H) 6.70 (s, 2 H) 6.30 - 6.15 ( m, 1 H) 5.98 (d, J=5.31 Hz, 1 H) 3.02 (td, J=12.32, 2.65 Hz, 2 H) 2.91 (m, 1 H) 2.54 -2.70 (m, 2 H) 2.22 (dd, J=13.89, 2.78 Hz, 2 H) 1 .82 - 1 .94 (m, 2 H); MS: M+ , (M + 2)+ = 547, 549.
Example 1 1 1 : /V-{3-[5-(2-amino-4-pyrimidinyl)-2-( 1 -piperazinyl)-1 ,3-thiazol-4- -2-fluorophenyl)-3,3,3-trifluoro-1 -propanesulfonamide
Following a procedure analogous to the one described in Example 112 using 1 ,1 -dimethylethyl 4-[5-(2-amino-4-pyrimidinyl)-4-(2-fluoro-3-{[(3,3,3- trifluoropropyl)sulfonyl]amino}phenyl)-1 ,3-thiazol-2-yl]-1 -piperazinecarboxylate (280 mg, 0.443 mmol) in Dichloromethane (DCM) (2.216 ml_) with TFA (1 .0 ml_, 12.98 mmol). The title compound was obtained as a light yellow solid N- {3-[5-(2-amino-4-pyrimidinyl)-2-(1 -piperazinyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-3,3,3-trifluoro-1 -propanesulfonamide (127 mg, 0.227 mmol, 51 % yield) 1H NMR (DMSO-d6) δ ppm 7.88 (d, J=5.31 Hz, 1 H) 7.50 (td, J=7.77, 1 .89 Hz, 1 H) 7.24 (t,J=7.71 Hz, 2 H) 6.54 (s, 2 H) 5.89 (d, J=4.80 Hz, 1 H) 3.43 - 3.51 (m, 4 H) 3.14 - 3.29 (m, 2 H) 2.81 - 2.95 (m,4 H) 2.62 - 2.75 (m, 2 H); MS: (M+H)+ = 532.
Example 1 12: /V-{3-[5-(2-amino-4-pyrimidinyl)-2-(1 -piperazinyl)-1 ,3-thiazol-4- yl1-2-fluorophenyl)-1 -propanesulfonamide
A 20 mL microwave tube was charged with 1 ,1 -dimethylethyl 4-(5-(2-chloro-4- pyrimidinyl)-4-{2-fluoro-3-[(propylsulfonyl)amino]phenyl}-1 ,3-thiazol-2-yl)-1 - piperazinecarboxylate (150 mg, 0.251 mmol) and ammonium hydroxide (978 μΙ, 25.1 mmol) to give a yellow solution at room temperture . The sealed reaction mixture under nitrogen was irradiated in microwave at 95°C for 90 min. The reaction mixture was concentrated and the residue was diluted with MeOH 3.0 mL, then chromatographed on reverse-phase HPLC and eluted with 5 to 70% of CH3CN in water with 0.1 % of TFA. The fractions were collected and dried on high vacuum to give a yellow solid. This solid was then dissolved in 5.0 mL of dichloromethane with 1 .0 mL of TFA. This reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with dichloromethane 10 mL and washed with 10% NaHCO3 (10 ml), water then brine. The organic layer was separated, dried over Na2SO , filtered then concentrated. The title compound was obtained as yellow solid (32 mg, 0.064 mmol, 25.3 % yield). 1H NMR (DMSO-d6) δ ppm 7.90 (d, J=5.31 Hz, 1 H) 7.52 (td, J=7.07, 3.03 Hz, 1 H) 7.23 - 7.37 (m, 2 H) 6.56 (s, 2 H) 5.86 (d, J=5.56 Hz, 1 H) 3.38 - 3.51 (m, 4 H) 2.98 - 3.12 (m, 2 H) 2.72 - 2.90 (m, 4 H) 1 .58 - 1 .78 (m, 2 H) 0.92 (t, J=7.45 Hz, 3 H).
Example 1 13: A/-{3-[5-(2-amino-4-pyrimidinyl)-2-( 1 -piperazinyl)-1 ,3-thiazol-4- yl1-2-chlorophenyl)-3,3,3-trifluoro-1 -propanesulfonamide
Following a procedure analogous to the one described in Example 112 using 1-dimethylethyl 4-[5-(2-amino-4-pyrimidinyl)-4-(2-chloro-3-{[(3,3,3- trifluoropropyl)sulfonyl]amino}phenyl)-1 ,3-thiazol-2-yl]-1-piperazinecarboxylate (400 mg, 0.599 mmol) and ammonium hydroxide (4667 μΙ_, 120 mmol). The title compound was obtained as off white solid ( 2 mg, 0.194 mmol, 45% yield). H NMR (DMSO-c 5) δ ppm 7.83 (d, J=5.56 Hz, 1 H) 7.54 (dd, J=8.34, 1.52 Hz, 1 H) 7.31 (t, J=7.83 Hz, 1 H) 7.00 (d, J=6.82 Hz, 1 H) 6.51 (s, 2 H) 5.70 (d, J=5.31 Hz, 1 H) 3.45 - 3.57 (m, 4 H) 3.14 -3.25 (m, 2 H) 2.93 - 3.01 (m, 4 H) 2.71 (dd, J=16.29, 10.99 Hz, 2 H). MS: (M+); (M + 2)+ = 548; 550.
Example 114: A/-(3-r5-(2-amino-4-pyrimidinyl)-2-(4-methyl-1-piperazinyl)-1 ,3- thiazol-4-yll-2-fluorophenyl}-1-propanesulfonamide
Following a procedure analogous to the one described in Example 93 using A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-methyl-1-piperazinyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-1-propanesulfonamide (200 mg, 0.391 mmol) and ammonium hydroxide (7620 pL, 96 mmol), the title compound was obtained as a light yellow solid (100 mg, 0.193 mmol, 49 % yield). 1H NMR (DMSO-d6) δ ppm 9.75 (s, 1 H) 7.90 (d, J=5.31 Hz, 1 H) 7.52 (td, J=7.14, 2.91 Hz, 1 H) 7.12 - 7.36 (m, 2 H) 6.57 (s, 2 H) 5.87 (d, J=5.31 Hz, 1 H) 3.43 - 3.57 (m, 4 H) 3.01 3.10 (m, 2 H) 2.36 - 2.46(m, 4 H) 1 .59 - 1 .83 (m, 2 H) 0.92 (t, J=7.45 Hz, 3 H); MS: (M+H)+ = 492.
Example 1 15: /V-{2-fluoro-3-i5-(2-{r(2S)-2-hvdroxypropyl1amino)-4- pyrimidinyl)-2-(4-methyl-1 -piperazinyl)-1 ,3-thiazol-4-yllphenyl)-1 - propanesulfonamide
A 5 ml_ microwave tube was charged with A/-{3-[5-(2-chloro-4-pyrimidinyl)-2- (4-methyl-1 -piperazinyl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}-1 - propanesulfonamide (150 mg, 0.294 mmol) and (S)-(+)-1 -amino-2-propanol (0.092 ml, 1 .174 mmol) in toluene (3 ml) to give a colorless solution at room temperature under nitrogen. The sealed reaction mixture was heated at 90°C oil bath for 18h, and then allowed to cool to room temperature. The final crude material was purified by reverse-phase HPLC and to give the title compound as a yellow solid (79 mg, 0.137 mmol, 46 % yield). 1 H NMR
(DMSO-d6) δ ppm 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.75 (s, 1 H) 7.94 (d, J=5.30 Hz, 1 H) 7.52 (td, J=7.14, 2.91 Hz, 1 H) 7.19 - 7.35 (m, 2 H) 6.89 (br. s., 1 H) 5.88 (d, J=5.31 Hz, 1 H) 5.76 (s, 1 H) 4.67 (br. s., 1 H) 3.71 - 3.83 (m, 1 H) 3.44 - 3.58 (m, 4 H) 3.17 (d, J=5.31 Hz, 2 H) 2.93 - 3.09 (m, 2 H) 2.37 - 2.47 (m, 4 H) 2.24 (s, 3 H) 1 .59 -1 .77 (m, 2 H) 1 .04 (dd, J=6.19, 3.92 Hz, 3 H) 0.92 (t, J=7.45 Hz, 3 H) MS: (M+H)+ = 550.
Example 1 16: /V-{2-fluoro-3-i5-(2-{r(2ffl-2-hvdroxypropyl1amino)-4- pyrimidinyl)-2-(4-methyl-1 -piperazinyl)-1 ,3-thiazol-4-yllphenyl)-1 - propanesulfonamide
Following a procedure analogous to the one described in Example 115 using A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-1 -propanesulfonamide (150 mg, 0.320 mmol) and (R)-(+)-1 - amino-2-propanol (0.092 ml_, 1 .174 mmol). The title compound was obtained as a yellow solid (60mg, 0.104 mmol, 36 % yield). 1H NMR (DMSO-c/6) δ ppm 9.75 (s, 1 H) 7.94 (d, J=5.30 Hz, 1 H) 7.52 (td, J=7.26, 2.91 Hz, 1 H) 7.22 - 7.37 (m, 2 H) 6.89 (br. s., 1 H) 5.88 (d, J=5.05 Hz, 1 H) 4.67 (d, J=3.54 Hz, 1 H) 3.77 (ad, J=6.1 1 , 1 .89 Hz, 1 H) 3.40 - 3.56 (m, 4 H) 3.12 - 3.22 (m, 2 H) 2.98 - 3.10 (m, 2 H) 2.37 - 2.45 (m, 4 H) 2.24 (s, 3 H) 1 .70 (sxt, J=7.53 Hz, 2 H) 1 .04 (dd, J=6.19, 3.92 Hz, 3 H) 0.92 (t, J=7.45 Hz, 3 H); MS: (M+H)+ = 550
Example 1 17: /V-{2-fluoro-3-[5-{2-r(2-hvdroxypropyl)amino1-4-pyrimidinyl)-2-(4- methyl-1 -piperazinvD-1 ,3-thiazol-4-yllphenyl)-1 -propanesulfonamide-d6
Following a procedure analogous to the one described in Example115 using A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-1 -propanesulfonamide 200 mg, 0.391 mmol) and 1 -amino-2- propanol-d6 (95 mg, 1 .174 mmol). The title compound was obtained as yellow solid (75 mg, 0.128 mmol, 33 % yield). 1 H NMR (DMSO-d6) δ ppm 9.96 (br. s., 1 H) 7.88 (d, J=5.31 Hz, 1 H) 7.61 (dd, J=8.08, 1 .52 Hz, 1 H) 7.46 (t, J=7.83 Hz, 1 H) 7.32 (dd, J=7.58, 1 .52 Hz, 1 H) 6.86 (br. s., 1 H) 5.65 (d, J=5.31 Hz, 1 H) 3.68 - 3.83 (m, 2 H) 3.52 - 3.54 (m, 4 H) 3.37 - 3.45 (m, 2 H) 3.05 - 3.21 (m, 2 H) 2.72 - 2.91 (m, 2 H) 2.27 (s, 2 H) 0.92 - 1 .1 1 (m, 3 H) MS: (M+H)+ = 556.
Example 1 18: A/-{2-fluoro-3-[5-{2-[(2-hvdroxyethyl)amino1-4-pyrimidinyl)-2-
(tetrahydro-2/-/-pyran-4-yl)-1 ,3-thiazol-4-yllphenyl)-1 -propanesulfonamide-c/4
Following a procedure analogous to the one described in Example 115 using A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4-yl]- 2-fluorophenyl}-1 -propanesulfonamide (120 mg, 0.241 mmol) and 2- aminoethanol-d4 (47.2 mg, 0.724 mmol). The title compound was obtained as an off white solid (80 mg, 0.145 mmol, 60 % yield). 1 H NMR (DMSO-d6) δ ppm 9.73 (br. s., 1 H) 8.12 (d, J=5.31 Hz, 1 H) 7.53 (td, J=7.77, 1 .64 Hz, 1 H) 7.24 - 7.41 (m, 2 H) 7.15 (s, 1 H) 6.14 (br. s., 1 H) 4.60 (br. s., 1 H) 4.35 (d, J=4.04 Hz, 1 H) 4.60 (br. s., 1 H) 3.94 (dt, J=9.54, 2.18 Hz, 2 H) 3.48 (td, J=1 1 .68, 1 .89 Hz, 2 H) 2.93 - 3.09 (m, 2 H) 2.03 (dd, J=12.76, 2.15 Hz, 2 H) 1 .73 - 1 .83 (m, 2 H) 1 .62 - 1 .73 (m, 2 H) 0.91 (t, J=7.45 Hz, 3 H).
Example 1 19: A/-{2-fluoro-3-[5-{2-[(2-hvdroxy-2-methylpropyl)amino1-4- pyrimidinyl)-2-(4-methyl-1 -piperazinyl)-1 ,3-thiazol-4-yllphenyl)-1 - propanesulfonamide
Following a procedure analogous to the one described in Example 93 using /V-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-methyl-1 -piperazinyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-1 -propanesulfonamide (200 mg, 0.391 mmol) and 1 -amino-2- methyl-2-propanol (105 mg, 1 .174 mmol) in1 ,4-dioxane (1957 μΙ_). The title compound was obtained as a yellow solid (93 mg, 0.157 mmol, 40 % yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.75 (br. s., 1 H) 7.94 (d, J=5.31 Hz, 1 H) 7.51 (d, J=4.80 Hz, 1 H) 7.29 (br. s., 2 H) 6.69 (br. s., 1 H) 5.89 (d, J=5.31 Hz, 1 H) 3.69 - 3.85 (m, 1 H) 3.44 - 3.58 (m, 4 H) 3.21 (m, 2 H) 3.04 (d,J=7.33 Hz, 2 H) 2.37 - 2.47 (m, 4 H) 2.23 (s, 3 H) 1 .65 - 1 .75 (m, 2 H) 1 .04 (d, J=6.06 Hz, 6H) 0.91 (t, J=7.45 Hz, 3 H); MS: (M+H)+ = 564.
Example 120: A/-{2-fluoro-3-r5-{2-r(2-hvdroxyethyl)amino1-4-pyrimidinyl)-2-(4- methyl-1 -piperazinyl)-1 ,3-thiazol-4-yllphenyl)-1 -propanesulfonamide
Following a procedure analogous to the one described in Example 93 using A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-methyl-1 -piperazinyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-1 -propanesulfonamide (150 mg, 0.294 mmol) and 2- aminoethanol (53.8 mg, 0.881 mmol), the title compound was obtained as a yellow solid (150 mg, 0.294 mmol); 1H NMR (DMSO-d6) δ ppm 9.97 (br. s., 1 H) 9.77 (s, 1 H) 7.92 - 8.08 (m, 1 H) 7.51 - 7.62 (m, 1 H) 7.27 - 7.37 (m, 2 H) 5.95 (br. s., 1 H) 4.45 - 4.54 (m, 1 H) 4.15 (br. s., 4 H) 3.51 (t, J=5.94 Hz, 4 H) 3.31 (d,J=4.29 Hz, 2 H) 3.17 (br. s., 2 H) 3.06 - 3.08 (m, 2 H) 2.87 (s, 3 H) 1 .59 - 1 .78 (m, 2 H) 0.83 - 0.97 (m, 3 H); MS: (M+H)+ = 536.
Example 121 : A/-(3-{5-(2-amino-4-pyrimidinyl)-2-[2-hydroxy-1 - (hydroxymethyl)-l -methylethyll-1 ,3-thiazol-4-yl)-2-fluorophenyl)-1 - propanesulfonamide
Following a procedure analogous to the one described in Example 93 using A/-(3-{5-(2-chloro-4-pyrimidinyl)-2-[2-hydroxy-1 -(hydroxymethyl)-1 - methylethyl]-1 ,3-thiazol-4-yl}-2-fluorophenyl)-1 -propanesulfonamide (150 mg, 0.299 mmol) and ammonium hydroxide (5829 μΙ_, 150 mmol). ). The title compound was obtained as a white solid (73 mg, 0.144 mmol, 48 % yield). 1H NMR (DMSO-d6) δ ppm 9.74 (s, 1 H) 8.06 (d, J=5.31 Hz, 1 H) 7.48 - 7.59 (m, 1 H) 7.33 (d,J=7.83 Hz, 2 H) 6.76 (s, 2 H) 6.10 (d, J=5.05 Hz, 1 H) 4.89 - 4.98 (m, 2 H) 3.56 - 3.69 (m, 4 H) 2.96 - 3.09 (m, 2 H) 1 .59 - 1 .79 (m, 2 H) 1 .32 (s, 3 H) 0.92 (t, J=7.45 Hz, 3 H); MS: (M+H)+ = 482. Example 122: A/-r2-fluoro-3-(2-r2-hvdroxy-1 -(hvdroxymethyl)-l -methylethvH-5- {2-[(2-methylpropyl)amino1-4-pyrimidinyl)-1 ,3-thiazol-4-yl)phenyl1-1 - propanesulfonamide
Following a procedure analogous to the one described in Example 115 using A/-(3-{5-(2-chloro-4-pyrimidinyl)-2-[2-hydroxy-1 -(hydroxymethyl)-1 - methylethyl]-1 ,3-thiazol-4-yl}-2-fluorophenyl)-1 -propanesulfonamide (120 mg, 0.240 mmol) and (2-methylpropyl)amine 2-methyl-1 -propanamine (35.0 mg, 0.479 mmol). The title compound was obtained as a yellow (89 mg, 0.157 mmol, 65 % yield). 1 H NMR (DMSO-d6) δ ppm 9.72 (s, 1 H) 8.10 (d, J=5.31 Hz, 1 H) 7.51 (br. s., 1 H) 7.28 - 7.44 (m, 3 H) 6.20 (br. s., 1 H) 4.94 (br. s., 2 H) 3.66 (d, J=1 .52 Hz, 4 H) 2.87 - 3.1 1 (m, 4 H) 1 .63 - 1 .87 (m, 2 H) 1 .33(s, 3 H) 1 .04 (d, J=6.06 0.80 - 0.94 (m, 9 H); MS: (M+H)+ = 538.
Example 123: A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4- yl1-2-chlorophenyl)-1 -propanesulfonamide
Following a procedure analogous to the one described in Example 93 using A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4- yl]phenyl}-1 -propanesulfonamide (180 mg, 0.350 mmol) and ammonium hydroxide (4087 μΙ_, 105 mmol). The title compound was obtained as an off white solid (98 mg, 0.188 mmol, 53 % yield). 1H NMR (DMSO-d6) δ ppm 9.57 (s, 1 H) 7.86 (d, J=5.31 Hz, 1 H) 7.60 (dd, J=8.08, 1 .52 Hz, 1 H)7.45 (t, J=7.83 Hz, 1 H) 7.31 (br. s., 1 H) 6.56 (s, 2 H) 5.63 (d, J=5.31 Hz, 1 H) 3.65 - 3.79 (m, 4 H) 3.44 -3.53 (m, 4 H) 3.06 - 3.14 (m, 2 H) 1 .67 - 1 .80 (m, 2 H) 0.94 (t, J=7.45 Hz, 3 H); MS: M+ , (M + 2)+ = 495, 497. Example 124: /V-{3-[5-(2-Amino-4-pynmidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4- -2-fluorophenyl)-1 -propanesulfonamide
A/-{3-[5-(2-Amino-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-1 -propanesulfonamide
A suspension of A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol- 4-yl]-2-fluorophenyl}-1 -propanesulfonamide (250 mg, 0.50 mmol) and ammonia in methanol (7M, 7.0 ml, 49.0 mmol) was heated in a sealed tube at 80 °C for 24 hours. The solvent was evaporated and the solid was triturated in methanol to give the desired product, A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(4- morpholinyl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}-1 -propanesulfonamide in 41 % yield (103 mg). 1 H NMR (400 MHz, DMSO-c/6) δ ppm 9.70 (br. s., 1 H), 7.86 (d, J=5.4 Hz, 1 H), 7.48 (td, J=7.1 , 2.8 Hz, 1 H), 7.18 - 7.35 (m, 2 H), 6.53 (s, 2 H), 5.83 (d, J=5.3 Hz, 1 H), 3.68 (t, J=4.6 Hz, 4 H), 3.43 (t, J=4.7 Hz, 4 H), 2.96 - 3.08 (m, 2 H), 1 .66 (m, 2 H), 0.87 (t, J=7.5 Hz, 3 H). MS ES: 479.2 [M+H]+.
Example 125: /V-{3-[5-(2-Amino-4-pynmidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4- yl1-2,4-difluorophenyl)-1 -propanesulfonamide
A suspension of A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol- 4-yl]-2,4-difluorophenyl}-1 -propanesulfonamide (150 mg, 0.29 mmol) and ammonia in IPA (2 M, 6.0 ml, 12.0 mmol) was heated in a sealed tube at 85 °C overnight. The temperature was increased to 100 °C and again heated overnight in a sealed tube. The reaction mixture was evaporated onto silica gel and chromatographed with 1 :9 MeOH:EtOAc in DCM. The title
compound, A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]- 2,4-difluorophenyl}-1 -propanesulfonamide, was obtained in 71 % yield (106 mg). 1 H NMR (400 MHz, DMSO-c/6) δ ppm 9.72 (s, 1 H), 7.93 (d, J=5.3 Hz, 1 H), 7.55 (td, J=8.7, 6.3 Hz, 1 H), 7.24 (t, J=8.8 Hz, 1 H), 6.59 (br. s., 2 H), 5.84 (d, J=5.2 Hz, 1 H), 3.69 (d, J=4.5 Hz, 4 H), 3.46 (d, J=4.2 Hz, 4 H), 2.94 - 3.09 (m, 2 H), 1 .67 (m, 2 H), 0.89 (t, J=7.4 Hz, 3 H). MS ES: 497.1 [M+H]+. Example 126: Λ/-Ι3-Γ2-(1 ,1 -dimethylethyl)-5-(4-pyridinyl)-1 ,3-thiazol-4-yll-2- fluorophenylH -propanesulfonamide
Step 1 : 2-Propen-1 -yl {3-[2-(1 ,1 -dimethylethyl)-5-(4-pyridinyl)-1 ,3-thiazol-4-yl]- 2-fluorophenyl}carbamate
To a solution of 2-propen-1 -yl [2-fluoro-3-(4-pyridinylacetyl)phenyl]carbamate (2.2 g, 7.00 mmol) in Λ/,/V-dimethylacetamide (DMA) (25 ml_) was added N- bromosuccinimide (NBS) (1 .495 g, 8.40 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. 2,2-Dimethylpropanethioamide (0.985 g, 8.40 mmol) was added at room temperature and the mixture was stirred at 60 °C for 1 .5 h. The reaction mixture was quenched with water and ethyl acetate. The organic layer was separated, washed with water, dried over MgSO4, filtered and evaporated. The red oil was purified by flash column chromatography on silica gel (100 % EtOAc). 2-Propen-1 -yl {3-[2- (1 ,1 -dimethylethyl)-5-(4-pyridinyl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}carbamate (200 mg, 0.486 mmol, 6.94 % yield) was isolated as white foam. 1 H NMR (400 MHz, DMSO-c/e) ppm 1 .46 (s, 9 H) 4.58 (dt, J=5.31 , 1 .39 Hz, 2 H) 5.22 (dd, J=10.48, 1 .64 Hz, 1 H) 5.34 (dd, J=17.18, 1 .77 Hz, 1 H) 5.84 - 6.04 (m, 1 H) 7.13 - 7.29 (m, 4 H) 7.66 - 7.84 (m, 1 H) 8.40 - 8.57 (m, 2 H) 9.46 (s, 1 H); HPLC Rt= 2.95 min, MS (ESI): 412.1 [M+H]+. Step 2: {3-[2-(1 ,1 -dimethylethyl)-5-(4-pyridinyl)-1 ,3-thiazol-4-yl]-2- fluorophenyljamine
To a solution of 2-propen-1 -yl {3-[2-(1 , 1 -d i methy lethy I )-5-(4-pyrid i nyl )- 1 ,3- thiazol-4-yl]-2-fluorophenyl}carbamate (200 mg, 0.486 mmol) in
dichloromethane (DCM) (10 mL), acetic acid (0.067 mL, 1 .166 mmol), and Pd(PPh3)2CI2 (6.82 mg, 9.71 pmol) were added. Then tri-n-butyl tin hydride (0.193 mL, 0.729 mmol) was added dropwise to the mixture at 0 °C. The mixture was stirred at room temperature for 30 min. The reaction was quenched by adding saturated NaHCO3 (10 mL) slowly. The two layers were separated. The aqueous layer was extracted with DCM (30 mL). The combined organic layers were washed with water and brine successively, dried over MgSO4, filtered and concentrated under reduced pressure to give pure {3-[2-(1 ,1 -dimethylethyl)-5-(4-pyridinyl)-1 ,3-thiazol-4-yl]-2- fluorophenyljamine (200 mg, 0.580 mmol, 1 19 % yield) as white solid. 1 H NMR (400 MHz, DMSO-c/6) ppm 1 .45 (s, 9 H) 5.20 (s, 2 H) 6.40 - 6.66 (m, 1 H) 6.82 (td, J=8.27, 1 .64 Hz, 1 H) 6.93 (t, J=7.71 Hz, 1 H) 7.1 1 - 7.30 (m, 2 H) 8.38 - 8.70 (m, 2 H); HPLC Rt= 2.46 min, MS (ESI): 328.0 [M+H]+. Step 3: Λ/-{3-[2-(1 , 1 -d i methylethyl )-5-(4-pyrid i nyl )- 1 ,3-thiazol-4-yl]-2- fluorophenyl}-1 -propanesulfonamide
To a solution of {3-[2-(1 , 1 -d i methylethyl )-5-(4- pyrid i ny I )- 1 ,3-thiazol-4-yl]-2- fluorophenyljamine (100 mg, 0.305 mmol) in dichloromethane (DCM) (2 ml_) was added 1 -propyl sulfonyl chloride (0.041 ml_, 0.367 mmol) and pyridine (0.037 ml_, 0.458 mmol). The reaction was stirred 96 h at room temperature. The reaction mixture was concentrated. Purification by flash column chromatography (50% EtOAc:DCM) afforded A/-{3-[2-(1 ,1 -dimethylethyl)-5-(4- pyridinyl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}-1 -propanesulfonamide (61 mg, 0.134 mmol, 43.8 % yield) as an off-white solid. 1 H NMR (400 MHz, DMSO- cfe) ppm 0.88 (t, J=7.45 Hz, 3 H) 1 .46 (s, 9 H) 1 .53 - 1 .69 (m, 2 H) 2.83 - 2.99 (m, 2 H) 7.18 - 7.24 (m, 2 H) 7.30 (t, J=7.83 Hz, 1 H) 7.37 - 7.45 (m, 1 H) 7.49 (td, J=7.77, 1 .64 Hz, 1 H) 8.51 (dd, J=4.55, 1 .77 Hz, 2 H) 9.66 (s, 1 H); HPLC Rt= 2.84 min, MS (ESI): 434.1 [M+H]+.
Example 127: A/-{2-fluoro-3-r5-(4-pyridinyl)-2-(tetrahvdro-2H-pyran-4-yl)-1 ,3- thiazol-4-yllphenyl)-1 -propanesulfonamide
Step 1 : 2-propen-1 -yl {2-fluoro-3-[5-(4-pyridinyl)-2-(tetrahydro-2H-pyran-4-yl)- 1 3-thiazol-4-yl]phenyl}carbamate
To a solution of 2-propen-1 -yl [2-fluoro-3-(4-pyridinylacetyl)phenyl]carbamate (2.6 g, 8.27 mmol) in Λ/,/V-dimethylacetamide (DMA) (25 mL) was added NBS (2.208 g, 12.41 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. Tetrahydro-2H-pyran-4-carbothioamide (1 .442 g, 9.93 mmol) was added at room temperature. The mixture was stirred at 60 °C for 1 .5 h. The reaction mixture was quenched with water and ethyl acetate. The organic phase was separated, washed with water, dried over MgSO^ filtered and evaporated. The red oil was purified by a silica gel column (EtOAc) to obtain 2-propen-1 -yl {2-fluoro-3-[5-(4-pyridinyl)-2-(tetrahydro-2H-pyran-4-yl)- 1 ,3-thiazol-4-yl]phenyl}carbamate (2.4 g, 3.82 mmol, 46.2 % yield) as a white solid. MS (ESI): 440 [M+H]+.
Step 2: {2-fluoro-3-[5-(4-pyridinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4- yl]phenyl}amine
To a solution of 2-propen-1 -yl {2-fluoro-3-[5-(4-pyridinyl)-2-(tetrahydro-2H- pyran-4-yl)-1 ,3-thiazol-4-yl]phenyl}carbamate (1 .5 g, 2.389 mmol) in dichloromethane (DCM) (50 mL) were added acetic acid (0.328 mL, 5.73 mmol), and Pd(PPh3)2CI2 (0.034 g, 0.048 mmol). Tri-n-butyl tin hydride (0.950 mL, 3.58 mmol) was added dropwise to the mixture at 0 °C. The mixture was stirred at room temperature for 30 min. The reaction was quenched by addition of the saturated NaHCO3 (50 mL) slowly. The two layers were separated. The aqueous layer was extracted with DCM (100 mL). The combined organic layers were washed with water and brine successively, dried over MgSO , filtered and concentrated under reduced pressure to give the crude product as a mixture of ketone and cyclized material 1 :1 . The solid was dissolved in dichloromethane, filtered and purified by a silica gel column (6 % IPA:DCM) to obtain {2-fluoro-3-[5-(4-pyridinyl)-2-(tetrahydro-2H-pyran-4- yl)-1 ,3-thiazol-4-yl]phenyl}amine (583 mg, 65 % yield) as a yellow foam. MS (ESI): 356 [M+H]+.
Step 3: A/-{2-fluoro-3-[5-(4-pyridinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol- 4-yl]phenyl}-1 -propanesulfonamide
Following a procedure analogous to the procedure described in step 3 of
Example 126 using {2-fluoro-3-[5-(4-pyridinyl)-2-(tetrahydro-2H-pyran-4-yl)- 1 ,3-thiazol-4-yl]phenyl}amine (200 mg, 0.563 mmol) and 1 -propanesulfonyl chloride (100 mg, 0.703 mmol) and purification by flash column
chromatography on silica gel (5% IPA:DCM) afforded A/-{2-fluoro-3-[5-(4- pyridinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4-yl]phenyl}-1 - propanesulfonamide (1 10 mg, 0.238 mmol, 42.4 % yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-c/6) ppm 0.89 (t, J=7.45 Hz, 3 H) 1 .62 (sxt, J=7.48 Hz, 2 H) 1 .70 - 1 .88 (m, 2 H) 2.04 (dd, J=12.63, 2.02 Hz, 2 H) 2.86 - 2.99 (m, 2 H) 3.37 (tt, J=1 1 .53, 3.88 Hz, 1 H) 3.49 (td, J=1 1 .62, 1 .77 Hz, 2 H) 3.96 (dt, J=9.54, 2.05 Hz, 2 H) 7.17 - 7.25 (m, 2 H) 7.29 (t, J=7.96 Hz, 1 H) 7.37 - 7.46 (m, 1 H) 7.49 (td, J=7.77, 1 .64 Hz, 1 H) 8.52 (dd, J=4.42, 1 .64 Hz, 2 H) 9.67 (s, 1 H). HPLC Rt= 2.19 min, MS (ESI): 462.2 [M+H]+.
Example 128: A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-methyltetrahvdro-2H- pyran-4-yl)-1 ,3-oxazol-4-yl1-2-fluorophenyl)-1 -propanesulfonamide
Step 1 : A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-methyltetrahydro-2H-pyran-4-yl)- 1 ,3-oxazol-4-yl]-2-fluorophenyl}-1 -propanesulfonamide
/V-Bromosuccinimide (0.862 g, 4.84 mmol) was added to a solution of A/-{3- [(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-1 -propanesulfonamide (1 .8 g, 4.84 mmol) in dichloromethane (DCM) (50 mL). After 1 hour, the reaction mixture was diluted with 50 mL of DCM and washed with water (5 x 50 mL), dried over MgSO4, filtered and concentrated. The residue was dissolved in Λ/,/V-dimethylacetamide (DMA) (50.0 mL) and added 4-methyltetrahydro-2H- pyran-4-carboxamide (1 .040 g, 7.26 mmol) and heated to 100° for 16 hours. The reaction was diluted with 200 mL of EtOAc and washed with water (5 x 75 mL), brine and dried over MgSO4, filtered and concentrated. The residue was purified via Biotage (Hex/EtOAc, 0 to 40% gradient) to obtain title compound (1 10 mg, 5%). MS (ESI): 494, 496 [M+H]+.
Step 2: A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-methyltetrahydro-2H-pyran-4-yl)- 1 ,3-oxazol-4-yl]-2-fluorophenyl}-1 -propanesulfonamide
A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-methyltetrahydro-2H-pyran-4-yl)-1 ,3- oxazol-4-yl]-2-fluorophenyl}-1 -propanesulfonamide (1 10 mg, 0.222 mmol) and ammonium hydroxide (2 mL, 51 .4 mmol) was microwaved at 90° for 30 minutes. The reaction mixture was concentrated. The reaction mixture was treated with 50 mL of water and ajusted pH to about 7 by addition of 1 N HCI. The reaction mixture was extacted with EtOAc (3 x 50 mL). The combined EtOAc phases were washed with brine and dried over MgSO4, filtered and concentrated. The residue was purified via Biotage (Hex to 50% Hex/EtOAc) to obtained the title compound (75 mg, 71 %). MS (ESI): 476 [M+H]+.
Example 129: A/-{3-r5-(2-amino-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3- oxazol-4-yl1-2-fluorophenyl)-1 -propanesulfonamide
Step 1 : 2-propen-1 -yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3- oxazol-4- l]-2-fluorophenyl}carbamate
A 200 mL round-bottomed flask was charged with 2-propen-1 -yl {3-[(2-chloro- 4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate (5 g, 14.30 mmol) in DCM (50 mL) to give a yellow solution at room temperature under nitrogen. NBS (2.417 g, 13.58 mmol) was added to the reaction mixture. After 1 h, the reaction mixture was diluted with CH2CI2 (20 mL) and water (100 mL) and stirred. After stirring, the CH2CI2 layer was seprated form the water layer. The CH2CI2 layer was washed with water (100 mL). The CH2CI2 layer was dried over Na2SO4, filtered, and concentrated to obtain crude bromo- compound. A 200 mL seal tube was charged with crude bromo-compound and 2,2-dimethylpropanamide (2.169 g, 21 .44 mmol) in N,N- dimethylacetamide (DMA) (60 mL) to give a yellow solution at room
temperture under nitrogen. The reaction mixture was stirred to 90 °C. The reaction mixture was diluted with water (100 mL) and EtOAc (100 mL) and stirred. After stirring, the EtOAc layer was seprated form the water layer. After stirring, the water layer was extracted with EtOAc (50 mL x 2). The EtOAc layers were washed with water (50 mL x 3). The EtOAc layer was dried over Na2SO4, filtered, and concentrated. The residue was
chromatographed on silica gel column and eluted with EtOAc and hexanes (5% to 50%) and collected fractions and concentrated to obtain 2-propen-1 -yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-oxazol-4-yl]-2- fluorophenyljcarbamate (1 .46 g, 23 % yield). MS (ESI): 431 [M+H]+.
Step 2: 3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-oxazol-4-yl]-2- fluoroaniline
A 200 mL round-bottomed flask was charged with 2-propen-1 -yl {3-[5-(2- chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-oxazol-4-yl]-2- fluorophenyl}carbamate (1 .46 g, 3.39 mmol), and acetic acid (0.466 mL, 8.13 mmol) and bis(triphenylphosphine)-palladium(ll) chloride (0.048 g, 0.068 mmol) in dichloromethane (DCM) (10 mL) to give a yellow solution at room temperature under nitrogen. The reaction mixture was stirred. Tri-n-butyltin hydride (1 .448 mL, 5.42 mmol) was added to the reaction mixture. After 1 h, the reaction was reduced to dryness. The reaction mixture was diluted with hexanes (25 mL) and acetonitrile (25 mL) and stirred. After stirring, the acetonitrile layer was separated from the hexanes layer. Hexanes (20 mL) was added to the acetonitrile. After stirring, the acetonitrile layer was separated form the hexanes layer. The acetonitrile layer was dried over Na2SO4, filtered, and concentrated to obtain 3-[5-(2-chloro-4-pyrimidinyl)-2-
(1 ,1 -dimethylethyl)-1 ,3-oxazol-4-yl]-2-fluoroaniline (500 mg, 42 % yield). MS (ESI): 347 [M+H]+.
Step 3: A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-oxazol-4-yl]- 2-fluorophenyl}-1 -propanesulfonamide
A 500 mL round-bottomed flask was charged with 3-[5-(2-chloro-4- pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-oxazol-4-yl]-2-fluoroaniline (500 mg, 1 .442 mmol) and pyridine (0.128 mL, 1 .586 mmol) in dichloromethane (DCM) (100 mL) to give a yellow/clear solution at 0 °C. The reaction was stirred at 0
°C. After 5 min, 1 -propanesulfonyl chloride (0.162 mL, 1 .442 mmol) was added to the reaction and warmed to room temperature. After 24h, the reaction mixture was diluted with added EtOAc (200 mL) and concentrated to 50 mL. The reaction mixture was diluted with EtOAc (200 mL) and water (200 mL) and stirred. After stirring, the EtOAc layer was seprated form the water layer. The EtOAc layer was diluted with water (200 mL). After stirring, the EtOAc layer was seprated form the water layer. The EtOAc layer was dried over Na2SO4, filtered, and concentrated to 50 mL. While stirring, the reaction mixture was diluted with EtOAc (50 mL) and hexanes (200 mL) and stirred. The residue was chromatographed on silica gel column and eluted with hexanes with EtOAc (5% to 75%) and collected fractions. The clean fraction were concentrated to dryness to obtain A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 - dimethylethyl)-1 ,3-oxazol-4-yl]-2-fluorophenyl}-1 -propanesulfonamide (440 mg, 66 % yield). MS (ESI): 453 [M+H]+.
Step 4: A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-oxazol-4-yl]- 2-fluorophenyl}-1 -propanesulfonamide
A 5 mL microwave tube was charged with A/-{3-[5-(2-chloro-4-pyrimidinyl)-2- (1 ,1 -dimethylethyl)-1 ,3-oxazol-4-yl]-2-fluorophenyl}-1 -propanesulfonamide (200 mg, 0.442 mmol) and ammonium hydroxide (3 mL, 77 mmol) to give a yellow suspension at room temperature under nitrogen. The sealed reaction mixture was microwaved at 90 °C for 50 min. The reaction mixture was diluted with water (25 mL) and CH2CI2 (25 mL) and stirred. The pH of water was checked pH = 5. After stirring, the CH2CI2 layer was seprated form the water layer. The water layer was diluted with CH2CI2 (10 mL). After stirring, the CH2CI2 layer was separated form the water layer. The CH2CI2 layers were dried over Na2SC>4, filtered, and concentrated. The reaction mixture was diluted with IPA (5 mL) and hexanes ( 0 mL) and stirred. The reaction mixture was concentrated until solid started to precipitate of solution. The reaction mixture was cool at 0 °C overnight. The solids were filtered and washed with hexanes. The solids were dried in vacuum oven for 2 hours at 50 °C to obtain A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3- oxazol-4-yl]-2-fluorophenyl}-1 -propanesulfonamide (120 mg, 61 % yield) as white solid. MS (ESI): 434 [M+H]+.
Example 130: N-{3- 2-( 1 , 1 -dimethylethyl)-5-(2-(r(2R)-2-hydroxypropynamino)-
4- rimidinyl)-1 ,3-oxazol-4-vn-2-fluorophenyl)-1 -propanesulfonamide
A 5 mL microwave tube was charged with A/-{3-[5-(2-chloro-4-pyrimidinyl)-2- (1 ,1 -dimethylethyl)-1 ,3-oxazol-4-yl]-2-fluorophenyl}-1 -propanesulfonamide (100 mg, 0.221 mmol) and (2R)-1-amino-2-propanol (0.052 mL, 0.662 mmol) in toluene (3 mL) to give a yellow solution at room temperature under nitrogen. The reaction mixture was stirred to 90 °C overnight. The reaction mixture was concentrated to dryness. The residue was chromatographed on silica gel column and eluted with CHCI3 and CHCI3 with 10% MeOH (5% to 50%) and collected fractions. The clean fractions were concentrated to dryness to obtain A/-{3-[2-(1 ,1-dimethylethyl)-5-(2-{[(2R)-2- hydroxypropyl]amino}-4-pyrimidinyl)-1 ,3-oxazol-4-yl]-2-fluorophenyl}-1 - propanesulfonamide (80 mg, 72 % yield) as white solid. MS (ESI): 492
[M+Hf.
Example 131 : N-{3- 2-(-\ .1 -dimethylethyl)-5-(2-(f(2S)-2-hvdroxypropyllamino)-
4- yrimidinyl)-113-oxazol-4-vn-2-fluorophenyl)-1 -propanesulfonamide
A 5 mL microwave tube was charged with A/-{3-[5-(2-chloro-4-pyrimidinyl)-2- (1 ,1 -dimethylethyl)-1 ,3-oxazol-4-yl]-2-fluorophenyl}-1 -propanesulfonamide (100 mg, 0.221 mmol) and (2S)-1 -amino-2-propanol (0.052 mL, 0.662 mmol) in toluene (3 mL) to give a yellow solution at room temperature under nitrogen. The reaction mixture was stirred to 90 °C overnight. The reaction mixture was concentrated to dryness. The residue was chromatographed on silica gel column and eluted with CHCI3 and CHCI3 with 10% MeOH (5% to 50%) and collected fractions. The clean fractions were concentrated to dryness to obtain A/-{3-[2-(1 ,1-dimethylethyl)-5-(2-{[(2S)-2- hydroxypropyl]amino}-4-pyrimidinyl)-1 ,3-oxazol-4-yl]-2-fluorophenyl}-1 - propanesulfonamide (50 mg, 0.100 mmol, 45.1 % yield) as white solid. MS (ESI): 492 [M+H]+. Example 132: /V-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahvdro-2H-pyran-4-yl)- 1 ,3-oxazol-4-yl1-2-fluorophenyl)-1 -propanesulfonamide
Step 1 : 2-propen-1 -yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4- l)-1 ,3-oxazol-4-yl]-2-fluorophenyl}carbamate
A 200 mL round-bottomed flask was charged with 2-propen-1 -yl {3-[(2-chloro- 4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate (8.66 g, 24.76 mmol) in DCM (50 mL) to give a yellow solution at room temperature under nitrogen. NBS (4.19 g, 23.52 mmol) was added to the reaction mixture. The reaction mixture was diluted with water (50 mL) and CH2CI2 (20 mL) and stirred. After stirring, the CH2CI2 layer was seprated form the water layer. The CH2CI2 layer was washed with water (2x). The CH2CI2 layer was dried over Na2SO4, filtered, and concentrated to obtain crude bromoketone. A 200 mL seal tube was charged with crude bromoketone and tetrahydro-2H-pyran-4-carboxamide (4.80 g, 37.1 mmol) in Λ/,/V-dimethylacetamide (DMA) (60 mL) to give a yellow solution at room temperature under nitrogen. The reaction was stirred to 90
°C. After 3 day, the reaction mixture was diluted with water (100 mL) and EtOAc (100 mL) and stirred. After stirring, the EtOAc layer was seprated form the water layer. The EtOAc layer was washed with water (2x). The EtOAc layer was dried over Na2SO4, filtered, and concentrated. The residue was chromatographed on silica gel column and eluted with EtOAc with hexanes (5% to 50%) and collected fractions. The product fractions were concentrated to obtain 2-propen-1 -yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran- 4-yl)-1 ,3-oxazol-4-yl]-2-fluorophenyl}carbamate (2.12 g, 18 % yield) as brown oil/solid. MS (ESI): 459 [M+H]+.
Step 2: 3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-oxazol- 4-yl]-2-fluoroaniline
A 200 mL round-bottomed flask was charged with 2-propen-1 -yl {3-[5-(2- chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-oxazol-4-yl]-2- fluorophenyljcarbamate (2.12 g, 4.62 mmol), acetic acid (0.635 mL, 1 1 .09 mmol), and bis(triphenylphosphine)-palladium(ll) chloride (0.065 g, 0.092 mmol) in dichloromethane (DCM) (20 mL) to give a yellow solution at room temperture under nitrogen. The reaction mixture was stirred. Tri-n-butyltin hydride (2.467 mL, 9.24 mmol) was added to the reaction mixture. After 1 h, the reaction was reduced to dryness. The reaction mixture was diluted with hexanes (25 mL) and acetonitrile (25 mL) and stirred. After stirring, the acetonitrile layer was seprated form the hexanes layer. The hexanes (20 mL) was added the acetonitrile. After stirring, the acetonitrile layer was seprated form the hexanes layer. The acetonitrile layer was dried over Na2SO4, filtered, and concentrated to obtain 3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro- 2H-pyran-4-yl)-1 ,3-oxazol-4-yl]-2-fluoroaniline (1 .7 g, 4.54 mmol, 98 % yield). MS (ESI): 375 [M+H]+. Step 3: N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran oxazol-4- l]-2-fluorophenyl}-1 -propanesulfonamide
A 200 mL round-bottomed flask was charged with 3-[5-(2-chloro-4- pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-oxazol-4-yl]-2-fluoroaniline (2.5 g, 6.67 mmol) in dichloromethane (DCM) (5 mL) to give a yellow solution at room temperture under nitrogen. The reaction mixture was stirred. Pyridine (1 .079 mL, 13.34 mmol) was added to the reaction mixture. Propanesulfonyl chloride (0.748 mL, 6.67 mmol) was added to the reaction mixture. The reaction mixture was diluted with water (20 mL) and CH2CI2 (20 mL) and stirred. After stirring, the CH2CI2 layer was seprated form the water layer. The CH2CI2 layer was dried over Na2SO4, filtered, and concentrated. The residue was chromatographed on silica gel column and eluted with hexanes and EtOAc (5% to 50%) and collected fractions. The clean fraction were concentrated to dryness to obtain A/-{3-[5-(2-chloro-4-pyrimidinyl)-2- (tetrahydro-2H-pyran-4-yl)-1 ,3-oxazol-4-yl]-2-fluorophenyl}-1 - propanesulfonamide (412 mg, 13 % yield). MS (ESI): 481 [M+H]+.
Step 4: A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3- oxazol-4-yl]-2-fluorophenyl}-1 -propanesulfonamide
A 5 mL microwave tube was charged with A/-{3-[5-(2-chloro-4-pyrimidinyl)-2- (tetrahydro-2H-pyran-4-yl)-1 ,3-oxazol-4-yl]-2-fluorophenyl}-1 - propanesulfonamide (412 mg, 0.857 mmol) in ammonium hydroxide (10 mL, 257 mmol) to give a yellow solution at room temperture under nitrogen. The sealed reaction mixture was microwaved at 90 °C for 1 h. The reaction mixture concentrated. The reaction mixture was diluted with water (10 mL) and CH2CI2 (10 mL) and stirred. After stirring, the CH2CI2 layer was seprated form the water layer. The CH2CI2 layer place on top of silica gel column and chromatographed and eluted with CHCI3 and CHCI3 with 10% methanol (5% to 50%) and collected fractions and concentrated. Boiling IPA was added to crude product and and cool to 0 °C. The solids were filtered and washed with hexanes to obtain A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4- yl)-1 ,3-oxazol-4-yl]-2-fluorophenyl}-1 -propanesulfonamide (120 mg, 29 % yield). 1 H NMR (400 MHz, DMSO-c/6) ppm 9.69 (s, 1 H), 8.25 (d, J=5.05 Hz, 1 H), 7.37 - 7.57 (m, 2 H), 7.20 - 7.37 (m, 1 H) ,6.60 (d, J=5.31 Hz, 3 H), 3.83 - 4.02 (m, 2 H), 3.49 (td, J=1 1 .37, 2.02 Hz, 2 H), 3.19 - 3.31 (m, 1 H), 3.00 - 3.15 (m, 2 H), 1 .93 - 2.04 (m, 2 H), 1 .59 - 1 .89 (m, 4 H), 0.95 (t, J=7.45 Hz, 3 H); MS (ESI): 462 [M+H]+.
Example 133: A/-{3-[5-{2-[(2-cvanoethyl)amino1-4-pyrimidinyl)-2-(tetrahydro- 2H-pyran-4-yl)-1 ,3-oxazol-4-yl1-2-fluorophenyl)-1 -propanesulfonamide
A 5 mL microwave tube was charged with A/-{3-[5-(2-chloro-4-pyrimidinyl)-2- (tetrahydro-2H-pyran-4-yl)-1 ,3-oxazol-4-yl]-2-fluorophenyl}-1 - propanesulfonamide (100 mg, 0.208 mmol), cesium fluoride (126 mg, 0.832 mmol) and 3-aminopropionitrile fumarate (80 mg, 0.624 mmol) in dimethyl sulfoxide (DMSO) (3 mL) to give a yellow solution at room temperature under nitrogen. The sealed reaction mixture was heat at 95 °C overnight. After overnight, the reaction mixture was diluted with EtOAc (20 mL) and water (5 mL) and stirred. After stirring, the EtOAc layer was seprated form the water layer. The EtOAc layer was dried over Na2SO4, filtered, and concentrated. The solid was stirred in hot IPA for 30 min then cool to 0 °C overnight. The solids were filtered and washed with hexanes and dried in vacuum over overnight to obtain A/-{3-[5-{2-[(2-cyanoethyl)amino]-4-pyrimidinyl}-2- (tetrahydro-2H-pyran-4-yl)-1 ,3-oxazol-4-yl]-2-fluorophenyl}-1 - propanesulfonamide (30 mg, 27 % yield) as white solid. MS (ESI): 515
[M+H]+.
Example 134: /V-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahvdro-2H-pyran-4-yl)- -oxazol-4-yl1-2-fluorophenyl)-3, 3, 3-trifluoro-1 -propanesulfonamide
Step 1 : A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4- oxazol-4-yl]-2-fluorophenyl}-3,3,3-trifluoro-1 -propanesulfonamide
A 200 mL round-bottomed flask was charged with 3-[5-(2-chloro-4- pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-oxazol-4-yl]-2-fluoroaniline (100 mg, 0.267 mmol) in dichloromethane (DCM) (5 mL) to give a yellow solution at room temperature under nitrogen. The reaction mixture was stirred. Pyridine (0.032 mL, 0.400 mmol) was added to the reaction mixture. 3,3,3-Trifluoro-1 - propanesulfonyl chloride (52.4 mg, 0.267 mmol) was added to the reaction mixture. After overnight, the reaction mixture was diluted with water (20 mL) and CH2CI2 (20 mL) and stirred. After stirring, the CH2CI2 layer was separated from the water layer. The CH2CI2 layer was dried over Na2SO4, filtered, and concentrated. The residue was chromatographed on silica gel column and eluted with hexanes and EtOAc (5% to 50%) and collected fractions. The clean fraction were concentrated to dryness to obtain A/-{3-[5- (2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-oxazol-4-yl]-2- fluorophenyl}-3,3,3-trifluoro-1 -propanesulfonamide (95 mg, 66 % yield). MS (ESI): 535 [M+H]+.
Step 2: A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3- oxazol-4-yl]-2-fluorophenyl}-3,3,3-trifluoro-1 -propanesulfonamide
A 5 mL microwave tube was charged with A/-{3-[5-(2-chloro-4-pyrimidinyl)-2- (tetrahydro-2H-pyran-4-yl)-1 ,3-oxazol-4-yl]-2-fluorophenyl}-3,3,3-trifluoro-1 - propanesulfonamide (95 mg, 0.178 mmol) in ammonium hydroxide (3 mL, 77 mmol) to give a yellow solution at room temperature under nitrogen. The sealed reaction mixture was microwaved at 95 °C for 2 h. After 2 h, the reaction mixture was concentrated. The reaction mixture was diluted with CH2CI2 (20 mL) and water (5 mL) and stirred. After stirring, the CH2CI2 layer was seprated form the water layer. The CH2CI2 layer was dried over
Na2SO4, filtered, and concentrated. The residue was chromatographed on a silica gel column and eluted with CHCI3 and CH2CI2 with 10 % MeOH (5% to 50%). The clean fractions were concentrated to dryness and product was only 88% pure by HPLC. The residue was chromatographed on silica gel column and eluted with EtOAc and hexanes (5% to 18%). The solid was stirred in hot IPA for 30 min then cool to 0 °C overnight. The solids were filtered and washed with hexanes and dried in vacuum overnight to obtain /V- {3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-oxazol-4-yl]-2- fluorophenyl}-3,3,3-trifluoro-1 -propanesulfonamide (30 mg, 32 % yield). MS (ESI): 516 [M+H]+. Example 135: V-{3-r5-(2-amino-4-pyrimidinyl)-2-(tetrahvdro-2H-pyran-4-yl)- -thiazol-4-vn-2-chlorophenyl)-3,3,3-trifluoro-1-propanesulfonamide
Step 1 : N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)- -thiazol-4-yl]phenyl}-3,3,3-trifluoro-1 -propanesulfonamide
A 100 mL round-bottomed flask was charged with 2-chloro-3-[5-(2-chloro-4- pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4-yl]aniline (1.18 g, 2.90 mmol) in dichloromethane (DCM) (10 mL) to give a yellow solution at room temperture under nitrogen. Pyridine (0.351 mL, 4.35 mmol) was added to the reaction mixture. 3,3,3-Trifluoropropan-1 -sulfonyl chloride (0.569 g, 2.90 mmol) was added to the reaction mixture. After 2 day, the reaction mixture was diluted with water (50 mL) and CH2CI2 (50 mL) and stirred. After stirring, the CH2CI2 layer was separated from the water layer. The CH2CI2 layer was dried over Na2SC> , filtered, and concentrated. The residue was
chromatographed on silica gel column and eluted with hexanes and EtOAc (5% to 75%) and thecollected fractions were concentrated to obtain N-{2- chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-th yl]phenyl}-3,3,3-trifluoro-1 -propanesulfonamide (716 mg, 1 .262 mmol, 43.6 % yield). MS (ESI): 568 [M+H]+. Step 2: A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3- thiazol-4-yl]-2-chlorophenyl}-3,3,3-trifluoro-1 -propanesulfonamide
A 5 mL microwave tube was charged with A/-{2-chloro-3-[5-(2-chloro-4- pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4-yl]phenyl}-3,3,3- trifluoro-1 -propanesulfonamide (250 mg, 0.441 mmol) in ammonium hydroxide (3 mL, 77 mmol) to give a yellow solution at room temperture under nitrogen.
The sealed reaction mixture was microwaved at 95 °C for 1 h. After 1 h, the reaction mixture was concentrated. The reaction mixture was diluted with CH2CI2 (20 mL) and water (5 mL) and stirred. After stirring, the CH2CI2 layer was separated from the water layer. The CH2CI2 layer was dried over
Na2SO4, filtered, and concentrated. The residue was chromatographed on silica gel column and eluted with CHCI3 and CHCI3 with 10 % MeOH (5% to 50%) and collected fractions. The clean fractions were concentrated to dryness. The solids were stirred in hot IPA for 30 min then cool to 0 °C overnight. The solids were filtered and washed with hexanes and dried in vacuum over overnight to obtain A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro- 2H-pyran-4-yl)-1 ,3-thiazol-4-yl]-2-chlorophenyl}-3,3,3-trifluoro-1 - propanesulfonamide (102 mg, 41 % yield) as white solid. MS (ESI): 548, 550 [M+H]+.
Example 136: A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahvdro-2H-pyran-4-yl)- 1 ,3-oxazol-4-yl1-2-chlorophenyl)-1 -propanesulfonamide
Step 1 : 2-propen-1 -yl {2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H- ran-4-yl)-1 ,3-oxazol-4-yl]phenyl}carbamate
A 200 mL round-bottomed flask was charged with 2-propen-1 -yl {2-chloro-3- [(2-chloro-4-pyrimidinyl)acetyl]phenyl}carbamate (8.22 g, 22.45 mmol) in DCM (50 mL) to give a yellow solution at room temperature under nitrogen. NBS (3.80 g, 21 .32 mmol) was added to the reaction mixture. After 1 h, the reaction mixture was diluted with CH2CI2 (20 mL) and water (100 mL) and stirred. After stirring, the CH2CI2 layer was separated from the water layer. The CH2CI2 layer was washed with water (100 mL). The CH2CI2 layer was dried over Na2SO4, filtered, and concentrated to obtain crude bromo- compound. A 200 mL seal tube was charged with crude bromo-compound in Λ/,/V-dimethylacetamide (DMA) (60 mL) to give a yellow solution at room temperature under nitrogen. The reaction was stirred to 90 °C. After 2 days, the reaction mixture was diluted with water (100 mL) and EtOAc (100 mL) and stirred. After stirring, the EtOAc layer was separated from the water layer. The EtOAc layer was dried over Na2SO4, filtered, and concentrated. The residue was chromatographed on silica gel column and eluted with EtOAc and hexanes (5% to 75%) and collected fractions. The clean fraction were reduced to dryness to obtain 2-propen-1 -yl {2-chloro-3-[5-(2-chloro-4- pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-oxazol-4-yl]phenyl}carbamate (1 .2 g, 1 1 % yield). MS (ESI): 475, 477.
Step 2: 2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3- oxazol-4-yl]aniline
A 200 mL round-bottomed flask was charged with 2-propen-1 -yl {2-chloro-3- [5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-oxazol-4- yl]phenyl}carbamate (2.05 g, 4.31 mmol), and acetic acid (0.593 mL, 10.35 mmol) and bis(triphenylphosphine)-palladium(ll) chloride (0.061 g, 0.086 mmol) in dichloromethane (DCM) (40 mL) to give a yellow solution at room temperature under nitrogen. The reaction mixture was stirred. Tri-n-butyltin hydride (1 .843 mL, 6.90 mmol) was added to the reaction mixture. After 1 h, the reaction was reduced to dryness. The reaction mixture was diluted with hexanes (25 mL) and acetonitrile (25 mL) and stirred. After stirring, the acetonitrile layer was seprated form the hexanes layer. The hexanes (20 mL) was added the acetonitrile. After stirring, the acetonitrile layer was separated from the hexanes layer. The acetonitrile layers were dried over Na2SO4, filtered, and concentrated. The residue was chromatographed on silica gel column and eluted with EtOAc and hexanes (5% to 75%) and collected fractions to to obtain 2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H- pyran-4-yl)-1 ,3-oxazol-4-yl]aniline (930 mg, 55 % yield). MS (ESI): 391 , 393 [M+H]+. Step 3: N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)- 1 3-oxazol-4-yl]phenyl}-1 -propanesulfonamide
A 5 mL microwave tube was charged with 2-chloro-3-[5-(2-chloro-4- pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-oxazol-4-yl]aniline (300 mg, 0.767 mmol), in pyridine (8 mL) to give a yellow solution at room temperature under nitrogen. 1 -Propanesulfonyl chloride (0.086 mL, 0.767 mmol) was added to the reaction mixture. After 2 days, 1 -propanesulfonyl chloride (0.020 ml) was added to the reaction mixture. After next day, the reaction mixture was diluted with CH2CI2 (25 mL) and water (20 mL) and stirred. After stirring, the CH2CI2 layer was separated from the water layer. The CH2CI2 layer was dried over Na2SO4, filtered, and concentrated. The residue was chromatographed on silica gel column and eluted with EtOAc and hexanes (5% to 50%) and collected fractions. The clean fractions were concentrated to dryness to obtain A/-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro- 2H-pyran-4-yl)-1 ,3-oxazol-4-yl]phenyl}-1 -propanesulfonamide (80 mg, 20.98 % yield). MS (ESI): 497, 499 [M+H]+.
Step 4: N-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3- oxazol-4-yl]-2-chlorophenyl}-1 -propanesulfonamide
A 5 mL microwave tube was charged with A/-{2-chloro-3-[5-(2-chloro-4- pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-oxazol-4-yl]phenyl}-1 - propanesulfonamide (80 mg, 0.161 mmol) in ammonium hydroxide (6.26 pL, 0.161 mmol) to give a yellow solution at room temperature under nitrogen.
The sealed reaction mixture was microwaved at 90 °C for 1 h. After 1 h, the reaction mixture concentrated. The reaction mixture was diluted with water (10 ml_) and CH2CI2 (10 mL) and stirred. After stirring, the CH2CI2 layer was separated from the water layer. The CH2CI2 layer place on top of silica gel column and chromatographed and eluted with CHCI3 and CHCI3 with 10% methanol (5% to 50%) and collected fractions and concentrated. Boiling IPA was added to crude product and and cooled. The solids were filtered and washed with hexanes to obtain A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(tetrahydro- 2H-pyran-4-yl)-1 ,3-oxazol-4-yl]-2-chlorophenyl}-1 -propanesulfonamide (30 mg, 37 % yield). MS (ESI): 478, 480 [M+H]+. Example 137: A/-(3-(5-(2-aminopyrimidin-4-yl)-2-(1 -hvdroxy-2-methylpropan-2- yl)thiazol-4-yl)-2-fluorophenyl)propane-1 -sulfonamide
Step 1 : allyl 3-(5-(2-chloropyrimidin-4-yl)-2-(1 -hydroxy-2-methylpropan-2- yl)thiazol-4-yl)-2-fluorophenylcarbamate
Allyl 3-(2-bromo-2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenylcarbamate (1 .2 g, 2.80 mmol) was dissolved in Λ/,/V-dimethylacetamide (DMA) (20 mL) and allyl 3-(2-bromo-2-(2-chloropyrimidin-4-yl)acetyl)-2- fluorophenylcarbamate (1 .2 g, 2.80 mmol) was added and stirred at room temperature for 2 h.The reaction mixture was added CH2CI2 (20ml_), washed with water (20ml_ x 2), dried over Na2SO4, filtered, and concentrated to obtain allyl 3-(5-(2-chloropyrimidin-4-yl)-2-(1 -hydroxy-2-methylpropan-2-yl)thiazol-4- yl)-2-fluorophenylcarbamate (580 mg, 44 % yield) as a solid. MS: 463 [M+H]+. Step 2: 2-(4-(3-amino-2-fluorophenyl)-5-(2-chloropyrimidin-4-yl)thiazol-2-yl)-2- methylpropan-1 -ol
A mixture of allyl 3-(5-(2-chloropyrimidin-4-yl)-2-(1 -hydroxy-2-methylpropan-2- yl)thiazol-4-yl)-2-fluorophenylcarbamate (800 mg, 1 .728 mmol) and
bis(triphenylphosphine)palladium(ll) chloride (243 mg, 0.346 mmol) in acetic acid (2 mL) and dichloromethane (DCM) (40ml_) was cooled to 0 .
Tributylstannane (1006 mg, 3.46 mmol) was added dropwise and the mixture was heated to 40 °C for 4h. The reaction mixture was concentrated and purified by chromatography (CH2CI2:MeOH, 20:1 ) to obtain 2-(4-(3-amino-2- fluorophenyl)-5-(2-chloropyrimidin-4-yl)thiazol-2-yl)-2-methylpropan-1 -ol (300 mg, 0.792 mmol, 45.8 % yield). MS: 379 [M+H]+. Step 3: A/-(3-(5-(2-chloropyrimidin-4-yl)-2-(1 -hydroxy-2-methylpropan-2- yl)thiazol-4-yl)-2-fluorophenyl)propane-1 -sulfonamide
A mixture of 2-(4-(3-amino-2-fluorophenyl)-5-(2-chloropyrimidin-4-yl)thiazol-2- yl)-2-methylpropan-1 -ol (250mg, 0.660 mmol) in pyridine (3ml) was cooled to 0 °C and propane-1 -sulfonyl chloride (94 mg, 0.660 mmol) was added and stirred at room temperature for 2 h. The reaction mixture was washed with water (20 mL x 2), dried over Na2SO4, filtered, and concentrated The residue was purified by chromatography (EtOAcPE, 1 :2) to obtain A/-(3-(5-(2- chloropyrimidin-4-yl)-2-(1 -hydroxy-2-methylpropan-2-yl)thiazol-4-yl)-2- fluorophenyl)propane-1 -sulfonamide (250 mg, 0.309 mmol, 46.9 % yield) as a yellow solid. MS: 485 [M+H]+.
Step 4: A/-(3-(5-(2-aminopyrimidin-4-yl)-2-(1 -hydroxy-2-methylpropan-2- yl)thiazol-4-yl)-2-fluorophenyl)propane-1 -sulfonamide
A mixture of A/-(3-(5-(2-chloropyrimidin-4-yl)-2-(1 -hydroxy-2-methylpropan-2- yl)thiazol-4-yl)-2-fluorophenyl)propane-1 -sulfonamide (250 mg, 0.515 mmol) in ammonium hydroxide (28%, 5 mL) was heated to 100 °C and stirred for 3 h. The reaction mixture was concentrated. The residue was purified by chromatography (EtOAcPE, 2:1 ) to obtain A/-(3-(5-(2-aminopyrimidin-4-yl)-2- (1 -hydroxy-2-methylpropan-2-yl)thiazol-4-yl)-2-fluorophenyl)propane-1 - sulfonamide (123 mg, 49 % yield) as a yellow solid. 1HNMR (400 MHz, DMSO-d6): δ ppm 0.93 (t,3H), 1 .35(s,6H), 1 .71 (m,2H), 3.04 (t,2H), 3.55 (d,2H), 5.12 (t,1 H), 6.09 (d,2H), 6.76 (s,2H), 7.37 (m,2H), 7.54 (t,1 H), 8.06 (d,1 H), 9.6 (br,1 H); MS: 466 [M+H]+.
Example 138: A/-{3-r5-(2-amino-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3- thiazol-4-yl1-2-fluorophenyl)ethanesulfonamide
A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]-2- fluorophenyljethanesulfonamide (45 mg, 0.099 mmol) in ammonium
hydroxide (1 ml, 25.7 mmol) was microwaved at 120 °C for 15 min. The reaction was partitioned between water and DCM, the organic was washed with saturated NaCI solution and dried over magnesium sulfate. The crude solution was concentrated to a residue and purified by silica gel
chromatography (gradient: 10-100% EtOAc/hexanes) to obtain A/-{3-[5-(2- amino-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]-2- fluorophenyljethanesulfonamide (9 mg, 0.021 mmol, 20.89 % yield) as a white powder. MS: 436 [M+H]+.
Example 139: /V-{3-i5-(2-amino-4-pyrimidinyl)-2-(1 .1 -dimethylethyl)-1 .3- thiazol-4-yl1-2-fluorophenyl)-2-methyl-1 -propanesulfonamide
A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-2-methyl-1 -propanesulfonamide (80 mg, 0.166 mmol) was stirred in 7M ammonia in methanol (5 ml, 35.0 mmol) in a sealed tube and heated to 60 °C for weekend. The reaction was cooled and concentrated to a residue under vacuum. The crude was purified by a silica gel
chromatography (gradient: 10-100% EtOAc/hexanes) and crystallization from diethyl ether to provide A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)- 1 ,3-thiazol-4-yl]-2-fluorophenyl}-2-methyl-1 -propanesulfonamide (25 mg, 32 % yield) as a white powder. MS: 464 [M+H]+.
Example 140: N-{3-r5-(2-amino-4-pyrimidinyl)-2-(1 ,1 -dimethylethyl)-1 ,3- thiazol-4-yl1-2-fluorophenyl)-2-propanesulfonamide
4-[4-(3-amino-2-fluorophenyl)-2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-5-yl]-2- pyrimidinamine (100 mg, 0.291 mmol) and DMAP (35.6 mg, 0.291 mmol) stirred in 2-propanesulfonyl chloride (0.5 mL, 4.56 mmol) at room temperatu for 15 h. The reaction mixture was partitioned between DCM and 10% ammonium hydroxide. The organic was washed with brine and dried over magnesium sulfate. The organic was concentrated and purified by silica gel chromatography (10-100% EtOAc/Hex) and provided crude product. The crude product was stirred in 10 mL MeOH with 500 mg K2CO3 over a weekend. The reaction mixture was purified using prep-HPLC (C-18, 10- 100% water (0.1 % TFA)/acetonitrile (0.1 % TFA)) to obtain TFA salt of the title compound. The TFA salt was partitioned between DCM and saturated aq. NaHCO3. The organic layer was washed with brine, dried with magnesium sulfate, filtered, and concentrated to provide A/-{3-[5-(2-amino-4-pyrimidinyl)- 2-(1 ,1 -dimethylethyl)-1 ,3-thiazol-4-yl]-2-fluorophenyl}-2-propanesulfonamide (15 mg, 1 1 % yield) as a white powder. MS: 450 [M+H]+.
Example 141 : A/-{2-fluoro-3-[5-{2-r(2-hvdroxyethyl)amino1-4-pyrimidinyl)-2-(4-
A/-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-1 -propanesulfonamide (125 mg, 0.251 mmol) was stirred at 60 °C in neat ethanolamine (1 ml, 0.251 mmol). The reaction was stirred at 60 °C for 15 h and then cooled to room temperature. The ethanolamine was removed under vacuum and the residue was purified by silica gel
chromatography (90 DCM:9 MeOH:1 ammonium hydroxide/DCM) to obttain A/-{2-fluoro-3-[5-{2-[(2-hydroxyethyl)amino]-4-pyrimidinyl}-2-(4-morpholinyl)- 1 ,3-thiazol-4-yl]phenyl}-1 -propanesulfonamide (45 mg, 34 % yield) as a yellow powder. MS: 523 [M+H]+. Example 142: A/-{3-r5-(2-{r2-(ethyloxy)ethyl1amino)-4-Pyrimidinyl)-2-(4- morpholinyl)-1 ,3-thiazol-4-yl1-2-fluorophenyl)-1 -propanesulfonamide
/V-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3-thiazol-4-yl]-2- fluorophenyl}-1 -propanesulfonamide (125 mg, 0.251 mmol) was stirred at 60°C in [2-(ethyloxy)ethyl]amine (1 ml, 0.251 mmol). The reaction was stirred at 60 °C for 15 h and then cooled to room temperature. The ethanolamine was removed under vacuum and the residue was purified by silica gel chromatography (90 DCM:9 MeOH:1 ammonium hydroxide)/DCM) to obtain A/-{3-[5-(2-{[2-(ethyloxy)ethyl]amino}-4-pyrimidinyl)-2-(4-morpholinyl)-1 ,3- thiazol-4-yl]-2-fluorophenyl}-1 -propanesulfonamide (66 mg, 47 % yield) as a yellow powder. MS: 550, 552, 552 [M+H]+.
Example 143: A/-{3-[5-(2-amino-4-pyrimidinyl)-2-(4-methyl-4-piperidinyl)-1 ,3- thiazol-4-yl1-2-fluorophenyl)-1 -propanesulfonamide
To a suspension of 1 ,1 -dimethylethyl 4-(5-(2-amino-4-pyrimidinyl)-4-{2-fluoro- 3-[(propylsulfonyl)amino]phenyl}-1 ,3-thiazol-2-yl)-4-methyl-1 - piperidinecarboxylate (1 12 mg, 0.190 mmol) in dichloromethane (DCM) (2 ml_), and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated and the residue was treated with 6N HCI (0.5 ml_) and concentrated. The residue was dried under high vacuum and neutralized with 10% NaHCO3 solution (pH 7). The reaction mixture was then extracted with EtOAc (3x) and the extract was dried over Na2SO4 and concentrated. The residue was dried under high vacuum to give the product (40 mg, 43 % yield). 1 HNMR (400 MHz, DMSO-d6): δ ppm 8.07-8.08 (d, J = 4.0 Hz, 1 H), 7.48-7,52 (t, J = 8.0 Hz, 1 H), 7.16-7.23 (m, 2H), 6.76 (m, 2H), 6.14-6.15 (d, J = 4.0 Hz ,1 H), 2.89-2.97 (m, 4H), 2.79(m, 2H), 2.1 1 -2.15 (m, 2H), 1 .62-1 .74 (m, 4H), 1 .39 (s, 3H), 0.89-0.93 (t, J = 8.0 Hz, 3H); MS: 491 .2 [M+H]+.
Biological Examples
Compounds of the present invention were tested for B-Raf protein kinase inhibitory activity in substrate phosphorylation assays and cell proliferation assays.
A. B-Raf Enzyme Assay:
Compounds of the present invention were tested for B-Raf protein serine kinase inhibitory activity in a B-Raf Accelerated MEK ATPase assay
(BRAMA). Baculovirus-expressed His6-tagged BRAFV600E full-length
(amino acids 2-766) was used in the BRAMA assay.The BRAMA assay is a high sensitivity assay which measures an intrinsic MEK-mediated ATP hydrolysis uncoupled from downstream ERK phosphorylation by coupling the formation of ADP to NADH oxidation through the enzymes pyruvate kinase and lactate dehydrogenase. When ADP production is initiated by addition of catalytic amounts of an activated Raf enzyme and non-phosphorylated MEK, one observes robust ADP production concomitant with Raf-mediated phosphorylation of MEK. The method is disclosed in: C. Rominger, M.
Schaber, E. May. Assay for B-Raf Activity Based on Intrinsic MEK ATPase Activity. Statutory Invention Registration 1 1/084,993 (March, 2005) but includes the following changes: 1 ) the assay was performed with a final MEK concentration of 150 nM and 2) the assay was read as single end point instead of a kinetic read. Acceleration of MEK ATPase activity was determined from the data and plotted as a function of inhibitor concentration to give concentration response curves, from which the plC50 values were generated following standard plC50 fitting protocol. Many of the exemplified compounds Examples 1 -143 were run in the recited assay (A). The results are reported in the following Table 1 in which the average plC50 for the one or more runs of each assayed compound is categorized as indicated. In the following table:
"+" indicates average plC50 measurement less than 7.4 against B-Raf "++" indicates an average plC50 measurement between 7.5 and 8.4; and "+++" indicates an average plC50 measurement of greater than 8.5 against B-Raf.
Table 1 -B-Raf Activity
Example Activity Example Activity Example Activity
98 +++ 1 14 + 129 ++
99 ++ 1 15 ++ 130 +++
100 +++ 1 16 ++ 131 ++
102 ++ 1 17 ++ 132 ++
103 ++ 1 18 +++ 133 +++
104 + 1 19 ++ 134 ++
105 +++ 120 ++ 135 +++
106 + 121 + 136 +++
107 +++ 122 +++ 137 ++
108 +++ 123 ++ 138 +
109 ++ 124 + 139 ++
1 10 ++ 125 + 140 ++
1 1 1 ++ 126 + 141 ++
1 12 ++ 127 + 142 ++
1 13 ++ 128 ++ 143 +++
B. Cellular assays - Cell Growth Inhibition Assay
Human colon tumor cells (Colo205) were cultured in RPMI (Mediatech 50- 020-PB) containing 10% FBS and 1 % penicillin-streptomycin. Human melanoma cancer cells (SK-MEL-28) were cultured in EMEM with
nonessential amino acids (Mediatech 50-01 1 -PB) containing 10% FBS, 1 % sodium pyruvate (JT Baker 3354-04), and 1 % penicillin-streptomycin. All cell lines were maintained at 37°C in a humidified 5% CO2, 95% air incubator. Cells were harvested using trypsin/EDTA (Invitrogen 25200), counted using a haemocytometer, and plated. For 96-well assays (using white full-area NUNC plates cat. #136102), cells were plated in 105 μΙ_ at the following densities (cells/well): Colo205, 500; SK-MEL-28, 500. For 384-well assays (white full- area NUNC plates, cat. #781080), cells were plated in 48 μΙ_ at the following densities (cells/well): Colo205, 500; SK-MEL-28, 500.
The next day, compounds were diluted as follow: For 96-well assays, 13.5 μΙ_ of compound in DMSO were diluted using nine (9) serial 1 :3 dilutions of 4.5 μΙ_ in 9 μΙ_ of DMSO. Medium (270 μΙ_Λ/νβΙΙ of RPMI with 10% FBS and 1 % penicillin-streptomycin) was added to the plates. Aliquots (7 μΙ_) were added to cells in the final assay giving a final DMSO concentration of 0.2%. For 384- well assays, 15 μΙ_ of compound in DMSO were diluted using nine (9) serial 1 :3 dilutions of 5 μΙ_ in 10 μΙ_ of DMSO, followed by a further dilution of 5 μΙ_ of compound with 95 μΙ_ of medium, of which 2 μΙ_ were added to cells in the final assay giving a final DMSO concentration of 0.2%. Cells were incubated at 37°C, 5% CO2 for 3 days.
Total ATP was measured (as a surrogate estimate of cell number) using CellTiter-Glo® reagent (Promega G7571 ). Briefly, plates were removed from the incubator and allowed to equilibrate to room temperature for 30 minutes. CellTiter-Glo® (25 μΙ_ or 55 μΙ_ for 384-well or 96-well assays, respectively) reagent was added to each well and plates were shaken on an orbital plate shaker for 2 minutes. Plates were incubated without shaking for a further 30 minutes and read on an LJL Analyst GT reader in luminometer mode with an integration time of 0.5 seconds per well. Percent inhibition of cell growth was calculated relative to DMSO vehicle-treated control wells.
Calculation of IC50
Concentration of compound required to give 50% inhibition of vehicle-treated control cell growth (IC50) was interpolated using a 4-parameter fit for determining IC50 using the following equation: Y = A + ((B-A)/(1 +((C/X)AD))) where X = IC50.
Calculation of glC50
X can also equate glC50. The glC50 is the concentration of compound that gives 50% inhibition of growth when the Ymin is the number of cells on the day of compound addition and the Ymax is the number of cells after 72 hours growth in absence of compound.
Many of the compounds of Examples 1-143 were run in the recited assay and the results are reported in the following Table 2a. In the following table:
"+" indicates that the compound showed activity (IC50) of >1 μΜ in Colo205 tumor cells;
"++" indicates that the compound showed activity (IC50) of between 100 nM and 1 μΜ in Colo205 tumor cells; and "+++" indicates that the compound showed activity (IC50) of less than 100 nM in Colo205 tumor cells.
Table 2a -Activity in Colo205 Tumor Cells
Many of the compounds of Examples 1-143 were run in the recited assay and the results are reported in the following Table 2b. In the following table:
"+" indicates that the compound showed activity (glC50) of >1 μΜ in Colo205 tumor cells;
"++" indicates that the compound showed activity (glC50) of between 100 nM and 1 μΜ in Colo205 tumor cells; and
"+++" indicates that the compound showed activity (glC50) of less than 100 nM in Colo205 tumor cells.
Example Activity
131 +++
132 ++
133 +++
134 ++
135 +++
136 +++
137 ++
143 +++
Many of the compounds of Examples 1-143 were run in the recited assay and the results are reported in the following Table 3a. In the following table:
"+" indicates that the compound showed activity (IC50) of >1 μΜ in SKMEL28 tumor cells;
"++" indicates that the compound showed activity (IC50) of between 100 nM and 1 μΜ in SKMEL28 tumor cells; and
"+++" indicates that the compound showed activity (IC50) of less than 100 nM in SKMEL28 tumor cells.
Table 3a -Activity in SKMEL28 Tumor Cells (IC50)
Many of the compounds of Examples 1-143 were run in the recited assay and the results are reported in the following Table 3b. In the following table:
"+" indicates that the compound showed activity (glC50) of >1 μΜ in Colo205 tumor cells;
"++" indicates that the compound showed activity (glC50) of between 100 nM and 1 μΜ in SKMel28 tumor cells; and
"+++" indicates that the compound showed activity (glC50) of less than 100 nM in SKMel28 tumor cells.
Table 3b -Activity in SKMEL28 Tumor Cells (glC50)
Example Activity
130 +++
131 +++
132 +++
133 +++
134 ++
135 +++
136 +++
137 ++
143 ++
Pharmaceutical Formulation Example --Preparation of Tablets Containing a
Compound of the Invention (freebase):
Procedure:
1 . Sieve Lactose, Silicon dioxide, Crospovidone and half Povidone.
2. Add API.
3. Granulate in High Shear Granulator with granulating solution containing dissolved Polysorbate 80 and other half of Povidone in Purified water.
4. Mill using Comil 197, 0.375" screen.
5. Dry using Fluid Bed Dryer
6. Mill using Comil 197, 0.075" screen
7. Add Crospofidone, magnesium stearate.
8. Blend 5 minute
9. Compress tablet
10. Aqueous film coat tablet

Claims

That Which is Claimed Is: 1 . A compound of formula (I)
wherein:
W is selected from -O- and -S-;
R1 is selected from ci-c6alkyl, haloalkyl, and c3-c6cycloalkyl;
R3 is selected from Het1 , pyridinyl, and ci-c6alkyl optionally substituted with -(Co- c6alkylene-(OH)m)n;
R4 is selected from H, -NH-R7 and -CH2-R7;
R5 and R6 are independently selected from H, F, and CI;
R7 is selected from H, Ci-c6alkylene-R8, and -co-c3alkylene-Het1 , and ci-c6alkyl
optionally substituted with -(Co-c6alkylene-(OH)m)n;
R8 is selected from haloalkyl-, CN, OH, and -SO2-ci-c3alkyl;
each Het1 is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N and O and optionally substituted with 1 or 2 substituents independently selected from ci-c3alkyl, -SO2-ci-c3alkyl, and -ci-c3alkylene-OH;
each m is 1 or 2; and
each n is 1 or 2;
and pharmaceutically acceptable salts thereof.
2. The compound according to claim 1 , wherein each R1 is selected from Ci- C6alkyl and haloalkyl.
3. The compound according to any of claims 1 -2, wherein R3 is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N and O and optionally substituted with 1 or 2 substituents independently selected from ci-c3alkyl, -SO2-C1- C3alkyl, and -ci-c3alkylene-OH.
4. A compound of formula (la):
(la)
wherein:
R1 is selected from ci-c6alkyl, haloalkyl, and C3-c6cycloalkyl;
R3 is selected from Het1 , pyridinyl, and ci-c6alkyl optionally substituted with -(Co- c6alkylene-(OH)m)n;
R4 is selected from H, -NH-R7 and -CH2-R7;
R5 and R6 are independently selected from H, F, and CI;
R7 is selected from H, Ci-c6alkylene-R8, and -co-c3alkylene-Het1 , and ci-c6alkyl
optionally substituted with -(Co-c6alkylene-(OH)m)n;
R8 is selected from haloalkyl-, CN, OH, and -SO2-ci-c3alkyl;
each Het1 is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N and O and optionally substituted with 1 or 2 substituents independently selected from ci-c3alkyl, -SO2-ci-c3alkyl, and -ci-c3alkylene-OH;
each m is 1 or 2; and
each n is 1 or 2;
and pharmaceutically acceptable salts thereof.
5. The compound according to claim 4, wherein each R1 is selected from Ci- C6alkyl and haloalkyl.
6. The compound according to any of claims 4 and 5 wherein R3 is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N and O and optionally substituted with 1 or 2 substituents independently selected from ci-c3alkyl, -SO2-ci-c3alkyl, and -Ci-c3alkylene-OH.
7. A compound of formula (lc):
(lc)
wherein:
R1 is selected from ci-c6alkyl, haloalkyl, and c3-c6cycloalkyl;
R3 is selected from Het1 , pyridinyl, and ci-c6alkyl optionally substituted with -(Co- c6alkylene-(OH)m)n;
R4 is selected from -NH-R7 and -CH2-R7;
R5 and R6 are independently selected from H, F, and CI;
R7 is selected from H, Ci-c6alkylene-R8, and -Co-c3alkylene-Het1 , and ci-c6alkyl optionally substituted with -(Co-c6alkylene-(OH)m)n;
R8 is selected from haloalkyl-, CN, OH, and -SO2-ci-c3alkyl;
each Het1 is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N and O and optionally substituted with 1 or 2 substituents independently selected from ci-c3alkyl, -SO2-ci-c3alkyl, and -ci-c3alkylene-OH;
each m is 1 or 2; and
each n is 1 or 2;
and pharmaceutically acceptable salts thereof.
8. The compound according to any of claims 1 -3, and 7, wherein the compound of formula I) is a compound of formula (Id):
(Id) or a pharmaceutically acceptable salt thereof.
9. The compound according to any of claims 1 -6, wherein the compound of formula (I) is a compound of formula (lb):
or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising a compound according to any of claims 1 -9 and a pharmaceutically acceptable carrier, diluent or excipient.
1 1 . A method for treating a susceptible neoplasm in a mammal in need thereof, said method comprising administering to the mammal a therapeutically effective amount of a compound according to any of claims 1 -9.
12. The method according to claim 1 1 , wherein said susceptible neoplasm is selected from Barret's adenocarcinoma; billiary tract carcinomas; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors including primary CNS tumors such as glioblastomas, astrocytomas (e.g., glioblastoma multiforme) and ependymomas, and secondary CNS tumors (i.e., metastases to the central nervous system of tumors originating outside of the central nervous system); colorectal cancer including large intestinal colon carcinoma; gastric cancer;
carcinoma of the head and neck including squamous cell carcinoma of the head and neck; hematologic cancers including leukemias and lymphomas such as acute lymphoblastic leukemia, acute myelogenous leukemia (AML), myelodysplasia syndromes, chronic myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia, multiple myeloma and erythroleukemia; hepatocellular carcinoma; lung cancer including small cell lung cancer and non-small cell lung cancer; ovarian cancer; endometrial cancer; pancreatic cancer; pituitary adenoma; prostate cancer; renal cancer; sarcoma; skin cancers including melanomas; and thyroid cancers.
13. The method according to claim 1 1 , wherein said susceptible neoplasm is selected from breast cancer, cholangiocarcinoma, colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, and thyroid cancer.
14. The method according to claim 1 1 , wherein said mammal is a human.
15. A compound according to any of claims 1 -9 for use in therapy.
16. A compound according to any of claims 1 -9 for use in the treatment of a susceptible neoplasm (e.g., Barret's adenocarcinoma; billiary tract carcinomas; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors including primary CNS tumors such as glioblastomas, astrocytomas (e.g.,
glioblastoma multiforme) and ependymomas, and secondary CNS tumors (i.e., metastases to the central nervous system of tumors originating outside of the central nervous system); colorectal cancer including large intestinal colon carcinoma; gastric cancer; carcinoma of the head and neck including squamous cell carcinoma of the head and neck; hematologic cancers including leukemias and lymphomas such as acute lymphoblastic leukemia, acute myelogenous leukemia (AML), myelodysplasia syndromes, chronic myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia, multiple myeloma and erythroleukemia; hepatocellular carcinoma; lung cancer including small cell lung cancer and non-small cell lung cancer; ovarian cancer; endometrial cancer; pancreatic cancer; pituitary adenoma; prostate cancer; renal cancer; sarcoma; skin cancers including
melanomas; and thyroid cancers) in a mammal (e.g., human).
17. The use of a compound according to any of claims 1 -9 for the preparation of a medicament for the treatment of a susceptible neoplasm (e.g., Barret's
adenocarcinoma; billiary tract carcinomas; breast cancer; cervical cancer;
cholangiocarcinoma; central nervous system tumors including primary CNS tumors such as glioblastomas, astrocytomas (e.g., glioblastoma multiforme) and
ependymomas, and secondary CNS tumors (i.e., metastases to the central nervous system of tumors originating outside of the central nervous system); colorectal cancer including large intestinal colon carcinoma; gastric cancer; carcinoma of the head and neck including squamous cell carcinoma of the head and neck;
hematologic cancers including leukemias and lymphomas such as acute
lymphoblastic leukemia, acute myelogenous leukemia (AML), myelodysplasia syndromes, chronic myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia, multiple myeloma and erythroleukemia; hepatocellular carcinoma; lung cancer including small cell lung cancer and non-small cell lung cancer; ovarian cancer; endometrial cancer; pancreatic cancer; pituitary adenoma; prostate cancer; renal cancer; sarcoma; skin cancers including
melanomas; and thyroid cancers) in a mammal (e.g., human) in need thereof.
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