WO2009016410A2 - Chemical compounds 831 - Google Patents

Chemical compounds 831 Download PDF

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Publication number
WO2009016410A2
WO2009016410A2 PCT/GB2008/050644 GB2008050644W WO2009016410A2 WO 2009016410 A2 WO2009016410 A2 WO 2009016410A2 GB 2008050644 W GB2008050644 W GB 2008050644W WO 2009016410 A2 WO2009016410 A2 WO 2009016410A2
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WIPO (PCT)
Prior art keywords
heterocyclyl
carbocyclyl
alkyl
occurrence
optionally substituted
Prior art date
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PCT/GB2008/050644
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French (fr)
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WO2009016410A3 (en
Inventor
Lynsie Almeida
Brian Aquila
Claudio Edmundo Chuaqui
Huiping Guan
Shan Huang
Stephanos Ioannidis
Michelle Lamb
Bo Peng
Jie Shi
Mei Su
Qibin Su
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Astrazeneca Ab
Astrazeneca Uk Limited
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Application filed by Astrazeneca Ab, Astrazeneca Uk Limited filed Critical Astrazeneca Ab
Publication of WO2009016410A2 publication Critical patent/WO2009016410A2/en
Publication of WO2009016410A3 publication Critical patent/WO2009016410A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Definitions

  • the present invention relates to novel compounds, their pharmaceutical compositions and methods of use.
  • the present invention relates to therapeutic methods for the treatment and prevention of cancers and to the use of these compounds in the manufacture of medicaments for the treatment and prevention of myeloproliferative disorders and cancers.lson
  • JAK Janus-associated kinase
  • STAT signal transducers and activators of transcription
  • the JAK family consists of four non-receptor tyrosine kinases Tyk2, JAKl , JAK2, and JAK3 , which play a critical role in cytokine- and growth factor mediated signal transduction. Cytokine and/or growth factor binding to cell-surface receptor(s), promotes receptor dknerization and facilitates activation of receptor-associated JAK by autophosphorylation. Activated JAK phosphorylates the receptor, creating docking sites for SH2 domain-containing signalling proteins, in particular the STAT family of proteins (STATl , 2, 3, 4, 5a, 5b and 6).
  • Receptor- bound STATs are themselves phosphorylated by JAKs, promoting their dissociation from the receptor, and subsequent dimerization and translocation to the nucleus. Once in the nucleus, the STATs bind DNA and cooperate with other transcription factors to regulate expression of a number of genes including genes which apoptosis inhibitors (e.g. BcI-XL, McI-I) and cell cycle regulators (e.g. Cyclin D1/D2, c-myc) (Haura et al., Nature Clinical Practice Oncology, 2005, 2(6), 315-324; Verna et al., Cancer and Metastasis Reviews, 2003, 22, 423-434).
  • apoptosis inhibitors e.g. BcI-XL, McI-I
  • cell cycle regulators e.g. Cyclin D1/D2, c-myc
  • JAK2 JAK2 kinase domain with an oligomerization domain
  • TEL- JAK2 JAK2 kinase domain with an oligomerization domain
  • Bcr-JAK2 oligomerization domain
  • PCM1-JAK2 PCM1-JAK
  • V617F valine-to- phenylalanine
  • ALK alplastic lymphoma kinase
  • ALK a 200kd receptor tyrosine kinase encoded by the ALK gene on chromosome 2p23.
  • ALK belongs to the insulin receptor superfamily. Normal expression of ALK is tightly controlled and limited to the testis, ganglion cells of the intestine and neural tissues. Recent data suggests that ALK is involved in neuronal cell differentiation and regeneration, synapse formation and muscle cell migration.
  • ALK was first identified in a chromosomal translocation associated with some anaplastic large cell lymphomas (ALCL). Approximately 50-60% of cases are associated with the t(2;2)(p23;q35) chromosomal translocation which generates a hybrid gene consisting of the intracellular domain of the ALK tyrosine kinase receptor juxtaposed with nucleophosmin (NPM), a nucleolar protein involved in shuttling ribonucleoproteins.
  • NPM nucleophosmin
  • NPM-ALK has constitutive kinase activity and transforms a variety of immortalized cell lines in vitro and supports tumor formation in vivo by controlling key cellular processes such as cell cycle progression, survival, cell migration and cell shaping (Chiarle et al., Nature Reviews Cancer, 8:11-23, 2008).
  • expression of NPM-ALK driven by a CD4 promoter in transgenic mice resulted in the development of aggressive lymphoma of multiple origins.
  • Several signalling pathways have been implicated in the pathogenesis of NPM-ALK positive ALCLs.
  • NPM-ALK has been shown to activate several members of the signal transducer and activator of transcription (STAT) family, including STAT3 and STAT5 as well as phospholipase C- ⁇ and the PI3- kinase/AKT pathway.
  • STAT signal transducer and activator of transcription
  • ALK fusions partners have been reported in ALCL in addition to CD30-negative diffuse large cell lymphoma, albeit with lower frequency. ALK fusion proteins have also been detected in inflammatory myof ⁇ broblastic tumors, oesophageal squamous cell carcinomas and, more recently, in approximately 6% non small cell lung cancer (NSCLC) (Soda et al, Nature 448:561- 566, 2007).
  • NSCLC non small cell lung cancer
  • a novel translocation was initially identified in which a small inversion within chromosome 2p results in formation of a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) and ALK genes.
  • EML4 echinoderm microtubule-associated protein-like 4
  • Aberrant expression of ALK may represent an alternative mechanism of ALK activation that could contribute to oncogenesis.
  • Aberrant deregulated expression and/or amplification of full length ALK has been documented in B cell NHL, in nervous system derived human cancer cell lines and primary tumors, including neuroblastoma, glioblastoma and retinoblastoma, cell lines derived from solid tumors of ectodermal origin, including melanoma and breast carcinoma and NSCLC (Chiarle et al, Nature Reviews Cancer, 8:11-23, 2008).
  • the present invention provides compounds of Formula (I):
  • Typical compounds of Formula (I) are believed to possess JAK kinase inhibitory activity and are accordingly useful for their anti-proliferation and/or pro-apoptotic activity and in methods of treatment of the human or animal body.
  • the invention also relates to processes for the manufacture of said compound, or pharmaceutically acceptable salts thereof, to pharmaceutical compositions containing it and to its use in the manufacture of medicaments for use in the production of an anti-proliferation and/or pro-apoptotic effect in warm-blooded animals such as man.
  • the applicants provide methods of using said compound, or pharmaceutically acceptable salts thereof, in the treatment of myeloproliferative disorders, myelodysplastic syndrome and cancer.
  • the properties of the compounds of Formula (I) are expected to be of value in the treatment of myeloproliferative disorders, myelodysplastic syndrome, and cancer by inhibiting the tyrosine kinases, particularly the JAK family and more particularly JAK2.
  • Methods of treatment target tyrosine kinase activity, particularly the JAK family activity and more particularly JAK2 activity, which is involved in a variety of myeloproliferative disorders, myelodysplastic syndrome and cancer related processes.
  • inhibitors of tyrosine kinases are expected to be active against myeloproliferative disorders such as chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and neoplastic disease such as carcinoma of the breast, ovary, lung, colon, prostate or other tissues, as well as leukemias, myelomas and lymphomas, tumors of the central and peripheral nervous system, and other tumor types such as melanoma, fibrosarcoma and osteosarcoma.
  • Tyrosine kinase inhibitors, particularly the JAK family inhibitors and more particularly JAK2 inhibitors are also expected to be useful for the treatment other proliferative diseases including autoimmune, inflammatory,
  • the compounds of Formula (I), or pharmaceutically acceptable salts thereof are expected to be of value in the treatment or prophylaxis of against myeloproliferative disorders selected from chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and cancers selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, mesothelioma,
  • Ring A is heterocyclyl, wherein said heterocyclyl is optionally substituted on carbon with one or more R 2 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 2 *;
  • Ring B is selected from carbocyclyl and heterocyclyl, wherein said carbocyclyl and heterocyclyl are optionally substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R *;
  • X is selected from -O-, -NH-, and -S-;
  • R 1 is selected from H, halo, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, -OR la , -SR la , -N(R la ) 2 , -N(R la )C(O)R lb , -N(R la )N(R la ) 2 , -NO 2 , -N(R la )OR la , -ON(R la ) 2 , -C(O)H, -C(O)R lb , -C(O) 2 R 13 , -C(O)N(R la ) 2 , -C(O)N(R la )(OR la ), -OC(O)N(R la ) 2 , -N(R la )C(O) 2 R la , -N(R la )C(0)N(R la ) 2 , -OC
  • C 2-6 alkynyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more R 10 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 10* ;
  • R la in each occurrence is independently selected from H, Chalky 1, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 10 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R ;
  • R lb in each occurrence is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alky!, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 10 and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 10*
  • R 2 is selected from halo, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, -OR 2a , -SR 2a , -N(R 2a ) 2 , -N(R 2a )C(O)R 2b , -N(R 2a )N(R 2a ) 2 , -NO 2 , -N(R 2
  • R 2* in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R 2b , -C(O) 2 R 2c , -C(O)N(R 2a ) 2 , -S(O)R 2b , -S(O) 2 R 2b , -S(O) 2 N(R 2a ) 2 ,
  • R 2a in each occurrence is independently selected from H, C 1-6 alky 1, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 20* ;
  • R 2a in each occurrence is independently selected from H, C 1-6 alky 1, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R ;
  • R 2b in each occurrence is selected from C 1-6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 20 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 20* ;
  • R 2c in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 20* ;
  • R 3 is selected from H, halo, -CN, C 1-6 alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, heterocyclyl, -OR 3a , -SR 3a , -N(R 3a ) 2 , -N(R 3a )C(O)R 3b , -N(R 3a )N(R 3a ) 2 , -NO 2 , -N(R 3a )-OR 3a , -O-N(R 3a ) 2 , -C(O)H, -C(O)R 3b , -C(O) 2 R 3a , -C(O)N(R 3a ) 2 , -C(O)N(R 3a )(OR 3a ), -OC(O)N(R 3a ) 2 , -N(R 3a )C(O) 2 R 3 , -
  • R 3b in each occurrence is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 30 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 30* ;
  • R 4 is selected from halo, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, -OR 4a , -SR 4a , -N(R 4a ) 2 , -N(R 4a )C(O)R 4b , -N(R 4a )N(R 4a ) 2 , -NO 2 , -N
  • R 4b in each occurrence is selected from C 1-6 alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 40 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 40* ;
  • R 4c in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 40 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 40*
  • R 10 in each occurrence is independently selected from halo, -CN, C 1-6 alkyl, C 2-6 alkenyl,
  • R 20 in each occurrence is independently selected from halo, -CN, C 1-6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, heterocyclyl, -OR 20a , -SR 20a , -N(R 20a ) 2 , -N(R 20a )C(O)R 20b , -N(R 20a )N(R 20a ) 2 , -NO 2 , -N(R 20a )-OR 20a , -O-N(R 20a ) 2 , -C(O)H, -C(O)R 20b , -C(O) 2 R 20a , -C(O)N(R 20a ) 2 , -C(O)N(R 20a )(OR 20a ), -OC(O)N(R 20a ) 2 , -N(R 20a )C(O) 2 R 20a
  • R 30 in each occurrence is independently selected from halo, -CN, C 1-6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, heterocyclyl, -OR 30a , -SR 30a , -N(R 30a ) 2 , -N(R 30a )C(O)R 30b , -N(R 30a )N(R 30a ) 2 , -NO 2 , -N(R 30a )-OR 30a , -O-N(R 30a ) 2 , -C(O)H, -C(O)R 30b , -C(O) 2 R 30a , -C(O)N(R 30a ) 2 , -C(O)N(R 30a )(OR 30a ), -OC(O)N(R 30a ) 2 , -N(R 30a )C(O) 2 R 30a
  • R 30a in each occurrence is independently selected from H, C 1-6 alky 1, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R c , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R c ;
  • R 30b in each occurrence is independently selected from C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R c , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 0* ;
  • R 30c in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R c , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 0* ;
  • R 40 in each occurrence is independently selected from halo, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, heterocyclyl, -OR 40a , -SR 40a , -N(R 40a ) 2 , -N(R 40a )C(O)R 40b , -N(R 40a )N(R 40a ) 2 , -NO 2 , -N(R 40a )-OR 40a , -O-N(R 40a ) 2 , -C(O)H, -C(O)R 40b , -C(O) 2 R 40a , -C(O)N(R 40a ) 2 , -C(O)N(R 40a )(OR 40a ), -OC(O)N(R 40a ) 2 , -N(R 40a )C(O) 2 R 40a ,
  • R 40a in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R d , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R d* ;
  • R 40a in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R d , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R d* ;
  • R 40b in each occurrence is independently selected from C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl
  • R m in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl;
  • R" in each occurrence is independently selected from C 1-6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 0 in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, and heterocyclyl.
  • C x _ y as used in terms such as C x _ y alkyl and the like (where x and y are integers) indicates the numerical range of carbon atoms that are present in the group; for example, C ⁇ alkyl includes Cialkyl (methyl), C 2 alkyl (ethyl), Csalkyl (propyl and isopropyl) and C 4 alkyl (butyl, 1-methylpropyl, 2-methylpropyl, and tert-butyl).
  • alkyl refers to both straight and branched chain saturated hydrocarbon radicals having the specified number of carbon atoms.
  • C 1-6 alkyl includes groups such as C 1- salkyl, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, propyl, ri propyl, and hexyl.
  • References to individual alkyl groups such as "propyl” are specific for the straight chain version only and references to individual branched chain alkyl groups such as 'isopropyl' are specific for the branched chain version only.
  • alkenyl refers to both straight and branched chain hydrocarbon radicals having the specified number of carbon atoms and containing at least one carbon-carbon double bond.
  • C 2 - 6 alkenyl includes groups such as C 2 -salkenyl, C 2 - 4 alkenyl, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, and 5-hexenyl.
  • alkynyl refers to both straight and branched chain hydrocarbon radicals having the specified number of carbon atoms and containing at least one carbon-carbon triple bond.
  • C 2 - 6 alkynyl includes groups such as C 2 -salkynyl, C 2 - 4 alkynyl, ethynyl, 2-propynyl, 2-methyl-2-propynyl, 3-butynyl, 4-pentynyl, and 5-hexynyl.
  • Halo refers to fluoro, chloro, bromo and iodo. In one aspect, the term “halo” may refer to fluoro, chloro, and bromo. In another aspect, the term “halo” may refer to fluoro and chloro.
  • Carbocyclyl - refers to a saturated, partially saturated, or unsaturated, mono or bicyclic carbon ring that contains 3 to 12 ring atoms, of which one or more -CH 2 - groups may be optionally replaced with a corresponding number of -C(O)- groups.
  • Carbocyclyl examples include adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, indanyl, naphthyl, oxocyclopentyl, 1-oxoindanyl, phenyl, and tetralinyl.
  • Carbocyclyl may be "3- to 6-membered carbocyclyl.”
  • the term “3- to 6-membered carbocyclyl” refers to a saturated, partially saturated, or unsaturated monocyclic carbon ring containing 3 to 6 ring atoms, of which one or more -CH 2 - groups may be optionally replaced with a corresponding number of -C(O)- groups.
  • heterocyclyl refers to a saturated, partially saturated, or unsaturated, mono or bicyclic ring containing 4 to 12 ring atoms of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and which may, unless otherwise specified, be carbon or nitrogen linked, and of which a -CH2- group can optionally be replaced by a -C(O)-.
  • Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • Ring nitrogen atoms may be optionally oxidized to form N-oxides.
  • Illustrative examples of the term "heterocyclyl" include 1,3-benzodioxolyl, 3,5-dioxopiperidinyl, furanyl, imidazolyl, indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, oxazolyl, 2-oxopyrrolidinyl, oxo- 1,3-thiazolidinyl, piperazinyl, piperidyl, 2H-pyranyl, pyrazolyl, pyridinyl, pyrrolyl, pyrrolidinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 4-pyr
  • heterocyclyl may be non-aromatic heterocyclyl, which refers to a saturated, or partially saturated mono or bicyclic non-aromatic ring containing 4 to 12 ring atoms of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and which may, unless otherwise specified, be carbon or nitrogen linked, and of which a -CH 2 - group can optionally be replaced by a -C(O)-.
  • Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • Ring nitrogen atoms may be optionally oxidized to form N-oxides.
  • non-aromatic heterocyclyl include dioxidotetrahydrothiophenyl,
  • 2,4-dioxoimidazolidinyl 3,5-dioxopiperidinyl, morpholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, oxoimidazolidinyl, 2-oxopyrrolidinyl, 2-oxotetrahydrofuranyl, oxo- 1,3 -thiazolidinyl, piperazinyl, piperidyl, 2H-pyranyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiomorpholinyl, and thiazolidinyl.
  • heterocyclyl may be 5- or 6-membered heterocyclyl, which refers to a saturated, partially saturated, or unsaturated, monocyclic ring containing 5 or 6 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and of which a -C ⁇ 2- group may be optionally replaced by a -C(O)- group.
  • heterocyclyl groups may be carbon or nitrogen linked. Ring nitrogen atoms may be optionally oxidized to form an N-oxide. Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • Illustrative examples of "5- or 6-membered heterocyclyl” include 3,5-dioxopiperidinyl, furanyl, imidazolyl, isothiazolyl, isoxazolyl, morpholinyl, oxazolyl, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, piperazinyl, piperidyl, 2H-pyranyl, pyrazolyl, pyridinyl, pyrrolyl, pyrrolidinyl, pyrrolidinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, 4-pyridonyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolyl, thiadiazolyl, thiazolidinyl, thiomorpholinyl, thiophenyl, and pyridine-N-oxidyl.
  • heterocyclyl and “5- or 6-membered heterocyclyl” may be 4- to 6-membered heterocyclyl.
  • the term “4- to 6-membered heterocyclyl” refers to a saturated, partially saturated, or unsaturated, monocyclic ring containing 4 to 6 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and of which a -CH 2 - group may be optionally replaced by a -C(O)- group.
  • “4- to 6-membered heterocyclyl” groups may be carbon or nitrogen linked.
  • Ring nitrogen atoms may be optionally oxidized to form an N-oxide.
  • Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • Illustrative examples of "4- to 6-membered heterocyclyl" include azetidin-1-yl, dioxidotetrahydrothiophenyl, 2,4-dioxoimidazolidinyl, 3,5-dioxopiperidinyl, furanyl, imidazolyl, isothiazolyl, isoxazolyl, morpholinyl, oxazolyl, oxetanyl, oxoimidazolidinyl, 3-oxo-1- piperazinyl, 2-oxopyrrolidinyl, 2-oxotetrahydrofuranyl, oxo- 1,3 -thiazolidinyl, piperazinyl, piperidyl, 2H-pyranyl, pyrazolyl, pyridin
  • heterocyclyl refers to a saturated, partially saturated, or unsaturated, monocyclic ring containing 6 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and of which a -CH 2 - group may be optionally replaced by a -C(O)- group.
  • 6-membered heterocyclyl groups may be carbon or nitrogen linked. Ring nitrogen atoms may be optionally oxidized to form an ⁇ -oxide.
  • Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • Illustrative examples of "6-membered heterocyclyl” include 3,5-dioxopiperidinyl, morpholinyl, piperazinyl, piperidinyl, 2H-pyranyl, pyrazinyl, pyridazinyl, pyridinyl, and pyrimidinyl.
  • 6-Membered ⁇ eteroaryl In one aspect, “heterocyclyl,” “5- or 6-membered heterocyclyl,” “4- to 6-membered heterocyclyl,” and “6-membered heterocyclyl” may be 6-membered heteroaryl.
  • the term “6-membered heteroaryl” is intended to refer to a monocyclic, aromatic heterocyclyl ring containing 6 ring atoms. Unless otherwise specified, "6-membered heteroaryl” groups may be carbon or nitrogen linked. Ring nitrogen atoms may be optionally oxidized to form an N-oxide. Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • Illustrative examples of "6- membered heteroaryl” include pyrazinyl, pyridazinyl, pyrimidinyl, and pyridinyl.
  • heterocyclyl and “non- aromatic heterocyclyl” may be 4- to 7-membered non-aromatic heterocyclyl.
  • the term “4- to 7- membered non-aromatic heterocyclyl” refers to a non-aromatic, monocyclic ring containing 4 to 7 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and of which a -CH 2 - group may be optionally replaced by a -C(O)- group.
  • 4- to 7-membered non-aromatic heterocyclyl groups may be carbon or nitrogen linked. Ring nitrogen atoms may be optionally oxidized to form an N-oxide. Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • Illustrative examples of "4- to 7-membered non-aromatic heterocyclyl” include azetidin-1-yl, dioxidotetrahydrothiophenyl, 2,4-dioxoimidazolidinyl, 3,5-dioxopiperidinyl, morpholinyl, oxetanyl, oxoimidazolidinyl, 3 -oxo-1 -piperazinyl, 2- oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-oxotetrahydrofuranyl, 1,4-oxazepan-4-yl, piperazinyl, piperidyl, 2H-pyranyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, , thiazolidinyl, and thiomorpholinyl.
  • Ring C the term "nitrogen-containing 4- to 7-membered non-aromatic heterocvclyl" is intended to refer to a 4- to 7-membered non-aromatic heterocyclyl group having at least one ring nitrogen atom, said ring being bonded to the triazine ring via a nitrogen atom.
  • Ring C may thus be nitrogen- containing 4- to 6- membered non-aromatic heterocyclyl, nitrogen-containing 5 or 6-membered non-aromatic heterocyclyl, and nitrogen- containing 6-membered non-aromatic heterocyclyl.
  • heterocyclyl 4- to 6- Membered Non- Aromatic Heterocvclyl -
  • heterocyclyl 4- to 6- Membered Non- Aromatic Heterocvclyl -
  • heterocyclyl 4- to 6- Membered Non- Aromatic Heterocvclyl -
  • heterocyclyl refers to a non-aromatic, monocyclic ring containing 4 to 6 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and of which a -CH 2 - group may be optionally replaced by a -C(O)- group.
  • 4- to 6-membered non-aromatic heterocyclyl groups may be carbon or nitrogen linked. Ring nitrogen atoms may be optionally oxidized to form an N-oxide. Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • Illustrative examples of "4- to 6-membered non-aromatic heterocyclyl” include azetidin-1-yl, dioxidotetrahydrothiophenyl, 2,4-dioxoimidazolidinyl, 3,5-dioxopiperidinyl, morpholinyl, oxetanyl, oxoimidazolidinyl, 3-oxo-1-piperazinyl, 2- oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-oxotetrahydrofuranyl, piperazinyl, piperidyl, 2H- pyranyl, pyrrolidinyl, , tetrahydrofuranyl, tetrahydropyranyl, , thiazolidinyl, and thiomorpholinyl.
  • heterocyclyl 5 or 6-Membered Non- Aromatic ⁇ eterocvclyl
  • heterocyclyl 5 or 6-Membered Non- Aromatic ⁇ eterocvclyl
  • heterocyclyl non-aromatic heterocyclyl
  • 5- or 6-membered heterocyclyl 5- or 6-membered heterocyclyl
  • 4- to 7-membered non-aromatic heterocyclyl “4- to 6-membered heterocyclyl”
  • 4- to 6-membered heterocyclyl may be 5 or 6-membered non-aromatic heterocyclyl.
  • 5- or 6-membered non-aromatic heterocyclyl is intended to refer to a saturated or partially saturated, monocyclic, non-aromatic heterocyclyl ring containing 5 or 6 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and which may, unless otherwise specified, be carbon or nitrogen linked, and of which a -CH 2 - group can optionally be replaced by a -C(O)-.
  • Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • Ring nitrogen atoms may be optionally oxidized to form N-oxides.
  • 5 or 6-membered non-aromatic heterocyclyl include 3,5-dioxopiperidinyl, morpholinyl, 2-oxopyrrolidinyl, oxo- 1,3 -thiazolidinyl, piperazinyl, piperidyl, 2H-pyranyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiomorpholinyl, and thiazolidinyl.
  • heterocyclyl 6-Membered Non- Aromatic ⁇ eterocyclyl
  • heterocyclyl non-aromatic heterocyclyl
  • 5- or 6-membered heterocyclyl “4- to 7-membered non-aromatic heterocyclyl”
  • 4- to 6-membered heterocyclyl “4- to 6-membered non-aromatic heterocyclyl”
  • 5 or 6- membered non-aromatic heterocyclyl may be 6-membered non-aromatic heterocyclyl.
  • 6-membered non-aromatic heterocyclyl is intended to refer to a saturated or partially saturated, monocyclic, non-aromatic heterocyclyl ring containing 6 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and which may, unless otherwise specified, be carbon or nitrogen linked, and of which a -CH2- group can optionally be replaced by a -C(O)-.
  • Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • Ring nitrogen atoms may be optionally oxidized to form N-oxides.
  • 6-membered non-aromatic heterocyclyl include 3,5-dioxopiperidinyl, morpholinyl, piperazinyl, piperidyl, 2H-pyranyl, tetrahydropyranyl, and thiomorpholinyl.
  • the -N(R) 2 group is intended to encompass: 1) those -N(R) 2 groups in which both R substituents are the same, such as those in which both R substituents are, for example, C 1-6 alkyl; and 2) those -N(R) 2 groups in which each R substituent is different, such as those in which one R substituent is, for example, ⁇ , and the other R substituent is, for example, carbocyclyl.
  • the bonding atom of a group may be any suitable atom of that group; for example, propyl includes prop-1-yl and prop-2-yl.
  • Effective Amount means an amount of a compound or composition which is sufficient enough to significantly and positively modify the symptoms and/or conditions to be treated (e.g., provide a positive clinical response).
  • the effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically-acceptable excipient(s)/carrier(s) utilized, and like factors within the knowledge and expertise of the attending physician.
  • an effective amount of a compound of Formula (I) for use in the treatment of cancer is an amount sufficient to symptomatically relieve in a warm-blooded animal such as man, the symptoms of cancer and myeloproliferative diseases, to slow the progression of cancer and myeloproliferative diseases, or to reduce in patients with symptoms of cancer and myeloproliferative diseases the risk of getting worse.
  • leaving group is intended to refer to groups readily displaceable by a nucleophile such as an amine nucleophile, and alcohol nucleophile, or a thiol nucleophile.
  • suitable leaving groups include halo, such as chloro and bromo, and sulfonyloxy group, such as methanesulfonyloxy and toluene-4-sulfonyloxy.
  • Optionally substituted indicates that substitution is optional and therefore it is possible for the designated group to be either substituted or unsubstituted. In the event a substitution is desired, any number of hydrogens on the designated group may be replaced with a selection from the indicated substituents, provided that the normal valency of the atoms on a particular substituent is not exceeded, and that the substitution results in a stable compound.
  • a particular group when a particular group is designated as being optionally substituted with "one or more" substituents, the particular may be unsubstituted.
  • the particular group may bear one substituent.
  • the particular substituent may bear two substituents.
  • the particular group may bear three substituents.
  • the particular group may bear four substituents.
  • the particular group may bear one or two substituents.
  • the particular group may be unsubstituted, or may bear one or two substituents.
  • the term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • Protecting Group is intended to refer to those groups used to prevent selected reactive groups (such as carboxy, amino, hydroxy, and mercapto groups) from undergoing undesired reactions.
  • Suitable protecting groups for a hydroxy group include acyl groups; alkanoyl groups such as acetyl; aroyl groups, such as benzoyl; silyl groups, such as trimethylsilyl; and arylmethyl groups, such as benzyl.
  • the deprotection conditions for the above hydroxy protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • silyl group such as trimethylsilyl may be removed, for example, by fluoride or by aqueous acid; or an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation in the presence of a catalyst such as palladium-on-carbon.
  • suitable protecting groups for an amino group include acyl groups; alkanoyl groups such as acetyl; alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl, and fert-butoxycarbonyl; arylmethoxycarbonyl groups, such as benzyloxycarbonyl; and aroyl groups, such benzoyl.
  • the deprotection conditions for the above amino protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric, phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid, for example boron trichloride).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group, which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine or 2-hydroxyethylamine, or with hydrazine.
  • Another suitable protecting group for an amine is, for example, a cyclic ether such as tetrahydrofuran, which may be removed by treatment with a suitable acid such as trifluoroacetic acid.
  • the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art, or they may be removed during a later reaction step or work-up.
  • Compounds of Formula (I) may form stable pharmaceutically acceptable acid or base salts, and in such cases administration of a compound as a salt may be appropriate.
  • acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate, camphorsulfonate, choline, citrate, cyclohexyl sulfamate, diethylenediamine, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethyl- sulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, maleate, methanesulfonate, meglumine, 2-naphthalenesulfonate, nitrate, oxalate, pamoate, persul
  • base salts include ammonium salts; alkali metal salts such as sodium, lithium and potassium salts; alkaline earth metal salts such as aluminum, calcium and magnesium salts; salts with organic bases such as dicyclohexylamine salts and N-methyl-D-glucamine; and salts with amino acids such as arginine, lysine, ornithine, and so forth.
  • basic nitrogen-containing groups may be quaternized with such agents as: lower alkyl halides, such as methyl, ethyl, propyl, and butyl halides; dialkyl sulfates such as dimethyl, diethyl, dibutyl; diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl halides; arylalkyl halides such as benzyl bromide and others.
  • Non-toxic physiologically-acceptable salts are preferred, although other salts may be useful, such as in isolating or purifying the product.
  • the salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion-exchange resin.
  • Some compounds of Formula (I) may have chiral centers and/or geometric isomeric centers (E- and Z- isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers.
  • the invention further relates to any and all tautomeric forms of the compounds of Formula (I).
  • Additional embodiments of the invention are as follows. These additional embodiments relate to compounds of Formula (I) and pharmaceutically acceptable salts thereof. Such specific substituents may be used, where appropriate, with any of the definitions, claims or embodiments defined hereinbefore or hereinafter.
  • Ring A is heterocyclyl, wherein said heterocyclyl is optionally substituted on carbon with one or more R 2 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 2 *;
  • R 2 is selected from halo, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, -OR 2a , -SR 2a , -N(R 2a ) 2 , -N(R 2a )C(O)R 2b , -N(R 2a )N(R 2a ) 2 , -NO 2 , -N(R 2a )OR 2a , -ON(R 2a ) 2 , -C(O)H, -C(O)R 2b , -C(O) 2 R 2a , -C(O)N(R 2a ) 2 , -C(O)N(R 2a )(OR 2a ) -OC(O)N(R 2a ) 2 , -N(R 2a )C(O) 2 R 2a , -N(R 2a )C
  • R 2* in each occurrence is independently selected from C 1-6 alky 1, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R 2b , -C(O) 2 R 2c , -C(O)N(R 2a ) 2 , -S(O)R 2b , -S(O) 2 R 2b , -S(O) 2 N(R 2a ) 2 ,
  • R 2a in each occurrence is independently selected from H, C 1-6 alky 1, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 20 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 20* ;
  • R 2a in each occurrence is independently selected from H, C 1-6 alky 1, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 20 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 20* ;
  • R 2b in each occurrence is selected from C 1-6 alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 20* ;
  • R 2c in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 20 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 20* ;
  • R 20 in each occurrence is independently selected from hal
  • R 20b in each occurrence is independently selected from C 1-6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 20c in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, and heterocyclyl.
  • Ring A is 6-membered heterocyclyl, wherein said 6-membered heterocyclyl is optionally substituted on carbon with one or more R , and wherein any -NH- moiety of said 6- membered heterocyclyl is optionally substituted with R 2 *;
  • R 2 is selected from halo, -CN, C 1-6 alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, heterocyclyl, -OR 2a , -SR 2a , -N(R 2a ) 2 , -N(R 2a )C(O)R 2b , -N(R 2a )N(R 2a ) 2 , -NO 2 , -N(R 2a )OR 2a , -ON(R 2a ) 2 , -C(O)H, -C(O)R 2b , -C(O) 2 R 2a , -C(O)N(R 2a ) 2 , -C(O)N(R 2a )(OR 2a ) -OC(O)N(R 2a ) 2 ,
  • R 2b in each occurrence is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 20* ;
  • R 2c in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 20 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 20* ;
  • R 20 in each occurrence is independently selected from halo, -CN, C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, heterocyclyl, -OR 20a , -SR 20a , -N(R 20a ) 2 , -N(R 20a )C(O)R 20b , -N(R 20a )N(R 20a ) 2 , -NO 2 , -N(R 20a )-OR 20a , -O-N(R 20a ) 2 , -C(O)H, -C(O)R 20b , -C(O) 2 R 20a , -C(O)N(R 20a ) 2 , -C(O)N(R 20a )(OR 20a ), -OC(O)N(R 20a ) 2 , -N(R 20a )C(O) 2 R 20a
  • R 20b in each occurrence is independently selected from C 1-6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 20c in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, and heterocyclyl.
  • Ring A is 4- to 6-membered heterocyclyl, wherein said 4- to 6-membered heterocyclyl is optionally substituted on carbon with one or more R , and wherein any -NH- moiety of said 4- to 6-membered heterocyclyl is optionally substituted with R 2* ;
  • R 2 in each occurrence is independently selected from halo, -CN, C 1-6 alkyl, -OR 2a , -N(R 2a ) 2 ,
  • R 2* is C 1-6 alkyl
  • R 2a in each occurrence is independently selected from H and C 1-6 alkyl
  • R 2b is C 1-6 alkyl
  • R 20 in each occurrence is independently selected from halo, -CN, 4- to 6-membered heterocyclyl, -OR 20a , -N(R 20a ) 2 , -C(O) 2 R 20a , -C(O)N(R 20a ) 2 , -N(R 20a )C(O) 2 R 20a , and -N(R 20a )S(O) 2 R 20b ;
  • R 20a in each occurrence is independently selected from H and C 1-6 alkyl
  • R 20b is C 1-6 alkyl.
  • Ring A is 4- to 7-membered non-aromatic heterocyclyl, wherein said 4- to 7-membered non-aromatic heterocyclyl is optionally substituted on carbon with one or more R , and wherein any -NH- moiety of said 4- to 7-membered heterocyclyl is optionally substituted with R 2* ;
  • R 2 in each occurrence is independently selected from halo, -CN, C 1-6 alkyl, -OR 2a , -N(R 2a ) 2 ,
  • R 2* is C 1-6 alkyl
  • R 2a in each occurrence is independently selected from H and C 1-6 alkyl
  • R 2b is C 1-6 alkyl
  • R 20 in each occurrence is independently selected from halo, -CN, 4- to 6-membered heterocyclyl, -OR 20a , -N(R 20a ) 2 , -C(O) 2 R 20a , -C(O)N(R 20a ) 2 , -N(R 20a )C(O) 2 R 20a , and -N(R 20a )S(O) 2 R 20b ;
  • R 20a in each occurrence is independently selected from H and C 1-6 alky 1;
  • R 20b is C 1-6 alkyl.
  • Ring A is 4- to 6-membered non-aromatic heterocyclyl, wherein said 4- to 6- membered non-aromatic heterocyclyl is optionally substituted on carbon with one or more R 2 , and wherein any -NH- moiety of said 4- to 6-membered non-aromatic heterocyclyl is optionally substituted with R ;
  • R 2 in each occurrence is independently selected from halo, -CN, C 1-6 alkyl, -OR 2a , -N(R 2a ) 2 ,
  • R 2a in each occurrence is independently selected from H and C 1-6 alkyl
  • R 2b is C 1-6 alkyl
  • R 20 in each occurrence is independently selected from halo, -CN, 4- to 6-membered heterocyclyl,
  • R 20a in each occurrence is independently selected from H and C 1-6 alkyl;
  • R 20b is C 1-6 alkyl.
  • Ring A is heterocyclyl, wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 2 *; and R 2* in each occurrence is independently selected from C 1-6 alkyl.
  • Ring A is 5- or 6-membered heterocyclyl, wherein any -NH- moiety of said 5- or 6-membered heterocyclyl is optionally substituted with R 2 *; and R 2* in each occurrence is independently selected from C 1-6 alkyl.
  • Ring A is 5- or 6-membered non-aromatic heterocyclyl, wherein any -NH- moiety of said 5- or 6-membered non-aromatic heterocyclyl is optionally substituted with R *; and R in each occurrence is independently selected from C 1-6 alkyl.
  • Ring A is selected from azetidinyl, morpholinyl, 1 ,4-oxazepanyl, piperazinyl, piperidinyl, and pyrrolidinyl, wherein said azetidinyl, morpholinyl, 1 ,4-oxazepanyl, piperazinyl, piperidinyl, and pyrrolidinyl are optionally substituted on carbon with one or more R , and wherein any -NH- moiety of said piperazinyl is optionally substituted with R 2* ;
  • R' is halo, -CN, C 1-6 alkyl, -N(R Z3 ) 2 , -OR 2a , and j wherein said C 1-6 alky 1 in each occurrence is optionally and independently substituted with one or more R 20 ;
  • R 2a in each occurrence is independently selected from H and C 1-6 alkyl
  • R 2b is C 1-6 alkyl
  • R 2* is C 1-6 alkyl
  • R 20 in each occurrence is independently selected from halo, -CN, azetidinyl, -OR 20a , -N(R 20a ) 2 ,
  • R 20a in each occurrence is independently selected from H and C 1-6 alky 1;
  • R 20b is C 1-6 alkyl
  • Ring A is selected from azetidinyl, morpholinyl, 1 ,4-oxazepanyl, piperazinyl, piperidinyl, and pyrrolidinyl, wherein said azetidinyl, morpholinyl, 1 ,4-oxazepanyl, piperazinyl, piperidinyl, and pyrrolidinyl are optionally substituted on carbon with one or more R , and wherein any -NH- moiety of said piperazinyl is optionally substituted with R ;
  • R 2 is fluoro, -CN, methyl, ethyl, -N(R 2a ) 2 , -0R 2a , -C(O)N(R 2a ) 2 , -N(H)C(O)R 2b , and
  • R 2a in each occurrence is independently selected from H, tert-butyl, ethyl, and methyl;
  • R 2b is methyl; R 2* is methyl;
  • R 20 in each occurrence is independently selected from fluoro, -CN, azetidinyl, -OR 20a , -N(R 20a ) 2 ,
  • R 20a in each occurrence is independently selected from H, tert-butoxy, ethyl, and methyl;
  • R 20b is methyl
  • Ring A is selected from morpholinyl and piperazinyl, wherein any -NH- moiety of said morpholinyl and piperazinyl is optionally substituted with R *;
  • R 2* is independently selected from C 1-6 alky!.
  • Ring A is selected from morpholinyl and piperazinyl, wherein any -NH- moiety of said morpholinyl and piperazinyl is optionally substituted with R 2 *; and R 2* is independently selected from methyl.
  • Ring A is selected from 3-(acetylamino)azetidin-1-yl,
  • Ring A is morpholin-4-yl.
  • Ring B is morpholin-4-yl.
  • Ring B is selected from carbocyclyl and heterocyclyl, wherein said carbocyclyl and heterocyclyl are optionally substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R *;
  • R 4 is selected from halo, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, -OR 4a , -SR 4a , -N(R 4a ) 2 , -N(R 4a )C(O)R 4b , -N(R 4a )N(R 4a ) 2 , -NO 2 , -N(R 4a )-OR 4a , -O-N(R 4a ) 2 , -C(O)H, -C(O)R 4b , -C(O) 2 R 4a , -C(O)
  • R 4b in each occurrence is selected from C 1-6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 40* ;
  • R 4c in each occurrence is independently selected from C 1-6 alky 1, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 40* ;
  • R 40 in each occurrence is independently selected from halo,
  • R 40* in each occurrence is independently selected from C 1-6 alky 1, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R 40b , -C(O) 2 R 40c , -C(O)N(R 40a ) 2 , -S(O)R 40b , -S(O) 2 R 40b , -S(O) 2 N(R 40a ) 2 ,
  • R 40a in each occurrence is independently selected from H, C 1-6 alky 1, carbocyclyl, and heterocyclyl;
  • R 40b in each occurrence is independently selected from C 1-6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 40c in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, and heterocyclyl.
  • Ring B is heterocyclyl, wherein said heterocyclyl is optionally substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 4 * ;
  • R 4 is selected from halo, -CN, C 1-6 alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, heterocyclyl, -OR 4a , -SR 4a , -N(R 4a ) 2 , -N(R 4a )C(O)R 4b , -N(R 4a )N(R 4a ) 2 , -NO 2 , -N(R 4a )-OR 4a , -O-N(R 4a ) 2 , -C(O)H, -C(O)R 4b , -C(O) 2 R 4a , -C(O)N(R 4a ) 2 , -C(O)N(R 4a )(OR 4a ) -OC(O)N(R 4a ) 2 , -N(R 4a )C(O) 2 R 4a , -N
  • C 2 _6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more R 40 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 40* ;
  • R 4b in each occurrence is selected from C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 40* ;
  • R 4c in each occurrence is independently selected from C 1-6 alky 1, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 40* ;
  • R 40 in each occurrence is independently selected from halo, -CN,
  • R 40a in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl;
  • R 40b in each occurrence is independently selected from C 1-6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 40c in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, and heterocyclyl.
  • Ring B is 6-membered heterocyclyl, wherein said 6-membered heterocyclyl is optionally substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R *;
  • R 4 is selected from halo, -CN, C 1-6 alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, heterocyclyl, -OR 4a , -SR 4a , -N(R 4a ) 2 , -N(R 4a )C(O)R 4b , -N(R 4a )N(R 4a ) 2 , -NO 2 , -N(R 4a )-OR 4a , -O-N(R 4a ) 2 , -C(O)H, -C(O)R 4b , -C(O) 2 R 4a , -C(O)N(R 4a ) 2 , -C(O)N(R 4a )(OR 4a ) -OC(O)N(R 4a ) 2 , -N(R 4a )C(O) 2 R 4a , -N
  • R 4b in each occurrence is selected from d_ 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 40* ;
  • R 4c in each occurrence is independently selected from C 1-6 alky 1, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 40 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 40* ;
  • R 40 in each occurrence is independently selected from halo, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, heterocyclyl, -OR 40a , -SR 40a , -N(R 40a ) 2 , -N(R 40a )C(O)R 40b , -N(R 40a )N(R 40a ) 2 , -NO 2 , -N(R 40a )-OR 40a , -O-N(R 40a ) 2 ,
  • R 40a in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl;
  • R 40b in each occurrence is independently selected from C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, and heterocyclyl; and
  • R 40c in each occurrence is independently selected from C 1-6
  • Ring B is heterocyclyl, wherein said heterocyclyl is optionally substituted oonn ccaarrbboonn ⁇ with one or more R ; and R 4 is halo.
  • Ring B is 6-membered heterocyclyl, wherein said or 6-membered heterocyclyl is optionally substituted on carbon with one or more R 4 ; and R 4 is halo.
  • Ring B is 6-membered heteroaryl, wherein said 6-membered heteroaryl is substituted on carbon with at least one R 4 ; and R 4 is halo.
  • Ring B is 6-membered heteroaryl, wherein said 6-membered heteroaryl is substituted on carbon with one or more R ; and R 4 is halo.
  • Ring B is selected from pyridinyl and pyrimidinyl, wherein said pyridinyl and pyrimidinyl are optionally substituted on carbon with one or more R 4 ; and R 4 is halo.
  • Ring B is selected from pyridinyl and pyrimidinyl, wherein said pyridinyl and pyrimidinyl are optionally substituted with one or more R ; and R 4 is fluoro.
  • Ring B is pyridinyl, wherein said pyridinyl is optionally substituted on carbon with one or more R 4 ; and R 4 is halo.
  • Ring B is pyrimidinyl, wherein said pyrimidinyl is optionally substituted on carbon with one or more R 4 ; and R 4 is halo.
  • Ring B is selected from pyridin-2-yl and pyrimidin-2-yl, wherein said pyridin-2-yl and pyrimidin-2-yl are optionally substituted with one or more R ; and R 4 is fluoro.
  • Ring B is selected from 3,5-difluoropyridin-2-yl, 5-fluoropyridin-2-yl, and 5-fluoropyrimidin-2-yl.
  • Ring B is selected from 5-fluoropyridin-2-yl and 5-fluoropyrimidin-2-yl.
  • Ring B is 5-fluoropyridin-2-yl.
  • Ring B is 5-fluoropyrimidin-2-yl.
  • X is selected from -O- and -NH-.
  • X is -O-.
  • X is -NH-.
  • R 1 is selected from H, halo, -CN, C 1-6 alkyl, C2 -6 alkenyl, C2 -6 alkynyl, carbocyclyl, heterocyclyl, -OR la , -SR la , -N(R la ) 2 , -N(R la )C(O)R lb , -N(R la )N(R la ) 2 , -NO 2 , -N(R la )OR la , -ON(R la ) 2 , -C(O)H, -C(O)R lb , -C(O) 2 R 13 , -C(O)N(R la ) 2 , -C(O)N(R la )(OR la ), -OC(O)N(R la ) 2 , -N(R la )C(O) 2 R la , -N(R la )C(O)N(R la )(OR
  • R lb in each occurrence is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 10 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 10* ;
  • R 10 in each occurrence is independently selected from halo, -CN, C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, heterocyclyl, -OR 10a , -SR 10a , -N(R 10a ) 2 , -N(R 10a )C(O)R 10b , -N(R 10a )N(R 10a ) 2
  • R 1Ob in each occurrence is independently selected from C 1-6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 1Oc in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, and heterocyclyl.
  • R 1 is selected from C 1-6 alkyl, 3- to 6-membered carbocyclyl, and 5- or 6- membered heterocyclyl, wherein said C 1-6 alkyl, 3- to 6-membered carbocyclyl, and 5- or 6- membered heterocyclyl are optionally substituted on carbon with one or more R ;
  • R 10 in each occurrence is independently selected from halo, 3- to 6-membered carbocyclyl, 5- or 6-membered heterocyclyl, and -OR 10a , wherein said 3- to 6-membered carbocyclyl and 5- or 6- membered heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R a ;
  • R 10a is selected from C 1-6 alkyl and 3- to 6-membered carbocyclyl
  • R a in each occurrence is independently selected from halo and -OR m ;
  • R m is C 1-6 alkyl.
  • R 1 is selected from cyclopropyl, ethyl, methyl, phenyl, and thiophenyl, wherein said cyclopropyl, ethyl, methyl, phenyl, and thiophenyl are optionally substituted with one or more R 10 ;
  • R 10 in each occurrence is independently selected from fluoro, -OR 10a , cyclohexyl, imidazolyl, phenyl, and pyridinyl, wherein said cyclohexyl, imidazolyl, phenyl, and pyridinyl in each occurrence are optionally and independently substituted on carbon with one or more R a ;
  • R 10a in each occurrence is independently selected from methyl and phenyl
  • R a in each occurrence is independently selected from fluoro and methoxy.
  • R is selected from 2-cyclohexylethyl, cyclopropyl,
  • R 1 is C 1-6 alkyl.
  • R 1 is methyl
  • R 3 is selected from ⁇ , halo, -CN, C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, heterocyclyl, -OR 3a , -SR 3a , -N(R 3a ) 2 , -N(R 3a )C(O)R 3b , -N(R 3a )N(R 3a ) 2 , -NO 2 , -N(R 3a )-OR 3a , -O-N(R 3a ) 2 , -C(O)H, -C(O)R 3b , -C(O) 2 R 3a , -C(O)N(R 3a ) 2 , -C(O)N(R 3a )(OR 3a ), -OC(O)N(R 3a ) 2 , -N(R 3a )C(O) 2 R 3
  • R 3b in each occurrence is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 30 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 30* ;
  • R 30 in each occurrence is independently selected from halo, -CN, C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, heterocyclyl, -OR 30a , -SR 30a , -N(R 30a ) 2 , -N(R 30a )C(O)R 30b , -N(R 30a )N(R 30a ) 2 ,
  • R 30b in each occurrence is independently selected from C 1-6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 30c in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, and heterocyclyl.
  • R 3 is selected from C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one or more R ;
  • R 30 in each occurrence is independently selected from halo, -CN, -OR 30a ; -C(O)N(R 30a ) 2 ,
  • R 30a in each occurrence is independently selected from H and C 1-6 alkyl; and R 30b is C 1-6 alkyl.
  • R 3 is selected from methyl and ethyl, wherein said methyl and and ethyl are optionally substituted with one or more R 30 ,
  • R 30 in each occurrence is independently selected from fluoro, -CN, and -OR 30a , -C(O)N(R 30a ) 2 , -S(O) 2 N(R 30a ) 2 , and -S(O) 2 Me; and R a is in each occurrence is independently selected from H, methyl, and ethyl.
  • R 3 is C 1-6 alkyl.
  • R 3 is methyl
  • R 3 is selected from (aminocarbonyl)methyl, cyanomethyl, 1 , 1 -difluoro-2-hydroxyethyl, [(dimethylamino)carbonyl]methyl, (dimethylaminosulfonyl)methyl, ethoxymethyl, 1 -hydroxy ethyl, 2-hydroxy ethyl, 1-methoxy ethyl, methoxymethyl, methyl, [(methylamino)carbonyl] methyl, and (methylsulfonyl)methyl.
  • Ring A is heterocyclyl, wherein said heterocyclyl is optionally substituted on carbon with one or more R 2 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 2 *;
  • Ring B is heterocyclyl, wherein said heterocyclyl is optionally substituted on carbon with one or more R 4 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 4 *;
  • X is selected from -O- and -NH-;
  • R 1 is selected from H, halo, -CN, C 1-6 alkyl, C2 -6 alkenyl, C2 -6 alkynyl, carbocyclyl, heterocyclyl, -OR la , -SR la , -N(R la ) 2 , -N(R la )C(O)R lb , -N(R la )N(R la ) 2 , -NO 2 , -N(R la )OR la , -0N(R la ) 2 , -C(O)H, -C(O)R lb , -C(O) 2 R 13 , -C(O)N(R la ) 2 , -C(O)N(R la )(OR la ), -OC(O)N(R la ) 2 ,
  • R lb in each occurrence is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 10* ;
  • R 2 is selected from halo, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, -OR 2a , -SR 2a , -N(R 2a ) 2 , -N(R 2a )C(O)R 2b , -N(R 2a )N(R 2a ) 2 , -NO 2 , -N
  • R 2* in each occurrence is independently selected from C 1-6 alky 1, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R 2b , -C(O) 2 R 2c , -C(O)N(R 2a ) 2 , -S(O)R 2b , -S(O) 2 R 2b , -S(O) 2 N(R 2a ) 2 ,
  • R 2a in each occurrence is independently selected from H, C 1-6 alky 1, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 20 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 20* ;
  • R 2a in each occurrence is independently selected from H, C 1-6 alky 1, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 20 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 20* ;
  • R 2b in each occurrence is selected from C 1-6 alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 20* ;
  • R 2c in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 20 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 20* ;
  • R 3 is selected from H, halo,
  • R 3b in each occurrence is selected from C 1-6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 30* ;
  • R 4 is selected from halo, -CN, C 1-6 alkyl, C 2 _6alkenyl, C 2 _6alkynyl, carbocyclyl, heterocyclyl, -OR 4a , -SR 4a , -N(R 4a ) 2 , -N(R 4a )C(O)R 4b , -N(R 4a )N(R 4a ) 2
  • R 4c in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 40* ;
  • R 10 in each occurrence is independently selected from halo, -CN, C 1-6 alkyl, C 2 - 6 alkenyl,
  • R 10* in each occurrence is independently selected from C 1-6 alky 1, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R 10b , -C(O) 2 R 10c , -C(O)N(R 10a ) 2 , -S(O)R 10b , -S(O) 2 R 10b , -S(O) 2 N(R 10a ) 2 ,
  • R 10a in each occurrence is independently selected from H, C 1-6 alky 1, carbocyclyl, and heterocyclyl;
  • R 1Ob in each occurrence is independently selected from C 1-6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 1Oc in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl;
  • R 20 in each occurrence is independently selected from halo, -CN, C 1-6 alkyl, C 2 _6alkenyl,
  • R 20a in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl;
  • R 20b in each occurrence is independently selected from C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 20c in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl;
  • R 30 in each occurrence is independently selected from halo, -CN, C 1-6 alkyl, C 2-6 alkenyl,
  • R 30* in each occurrence is independently selected from C 1-6 alky 1, carbocyclyl, heterocyclyl,
  • R 30a in each occurrence is independently selected from H, C 1-6 alky 1, carbocyclyl, and heterocyclyl;
  • R 30b in each occurrence is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2 _ 6 alkynyl, carbocyclyl, and heterocyclyl; and R 30c in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, and heterocyclyl.
  • R 40 in each occurrence is independently selected from halo, -CN, C 1-6 alkyl, C 2 _ 6 alkenyl,
  • R 40* in each occurrence is independently selected from C 1-6 alky 1, carbocyclyl, heterocyclyl,
  • R 40a in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl;
  • R 40b in each occurrence is independently selected from C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 40c in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, and heterocyclyl.
  • Ring A is 4- to 7-membered non-aromatic heterocyclyl, wherein said 4- to 7- membered non-aromatic heterocyclyl is optionally substituted on carbon with one or more R , and wherein any -NH- moiety of said 4- to 7-membered heterocyclyl is optionally substituted with R 2* ;
  • Ring B is 6-membered heteroaryl, wherein said 6-membered heteroaryl is substituted on carbon with one or more R 4 ;
  • X is selected from -O- and -NH-;
  • R 1 is selected from d_ 6 alkyl, 3- to 6-membered carbocyclyl, and 5- or 6-membered heterocyclyl, wherein said C 1-6 alkyl, 3- to 6-membered carbocyclyl, and 5- or 6-membered heterocyclyl are optionally substituted on carbon with one or more R ;
  • R 2 in each occurrence is independently selected from halo, -CN, C 1-6 alkyl, -OR 2a , -N(R 2a ) 2 ,
  • R 2* is C 1-6 alkyl
  • R 2a in each occurrence is independently selected from H and C 1-6 alkyl;
  • R 2b is C 1-6 alkyl;
  • R 3 is selected from C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with one or more
  • R 4 is halo
  • R 10 in each occurrence is independently selected from halo, 3- to 6-membered carbocyclyl , 5- or 6-membered heterocyclyl, and -OR 10a , wherein said 3- to 6-membered carbocyclyl and 5- or 6- membered heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R a ;
  • R 10a is selected from C 1-6 alkyl and 3- to 6-membered carbocyclyl
  • R 20 in each occurrence is independently selected from halo, -CN, 4- to 6-membered heterocyclyl, -OR 20a , -N(R 20a ) 2 , -C(O) 2 R 20a , -C(O)N(R 20a ) 2 , -N(R 20a )C(O) 2 R 20a , and -N(R 20a )S(O) 2 R 20b ;
  • R 20a in each occurrence is independently selected from H and C 1-6 alkyl;
  • R 20b is C 1-6 alkyl;
  • R 30 in each occurrence is independently selected from halo, -CN, -OR 30a , -C(O)N(R 30a )2, -S(O) 2 R 30b , and -S(O) 2 N(R 30a ) 2 ;
  • R 30a in each occurrence is independently selected from H and C 1-6 alkyl;
  • R 30b is C 1-6 alkyl;
  • R a in each occurrence is independently selected from halo and -OR m ; and R m is C 1-6 alkyl.
  • Ring A is selected from azetidinyl, morpholinyl, 1 ,4-oxazepanyl, piperazinyl, piperidinyl, and pyrrolidinyl, wherein said azetidinyl, morpholinyl, 1,4-oxazepanyl, piperazinyl, piperidinyl, and pyrrolidinyl are optionally substituted on carbon with one or more
  • Ring B is selected from pyridinyl and pyrimidinyl, wherein said pyridinyl and pyrimidinyl are optionally substituted with one or more R ;
  • X is selected from -O- and -NH-;
  • R 1 is selected from cyclopropyl ethyl , methyl, phenyl, and thiophenyl, wherein said cyclopropyl, ethyl, methyl, phenyl, and thiophenyl are optionally substituted on carbon with one or more R ;
  • R 2 is fluoro, -CN, methyl, ethyl, -N(R 2a ) 2 , -OR 2a , -C(O)N(R 2a ) 2 , -N(H)C(O)R 2b , and
  • R 2a in each occurrence is independently selected from H, tert-butyl, ethyl, and methyl;
  • R 2b is methyl
  • R 2* is methyl
  • R 3 is selected from methyl and ethyl, wherein said methyl and and ethyl are optionally substituted with one or more R 30 ;
  • R 4 is fluoro
  • R 10 in each occurrence is independently selected from fluoro, -OR 10a , cyclohexyl, imidazolyl, phenyl, and pyridinyl, wherein said cyclohexyl, imidazolyl, phenyl, and pyridinyl in each occurrence are optionally and independently substituted on carbon with one or more R a ;
  • R 10a in each occurrence is independently selected from methyl and phenyl;
  • R ,20a a in each occurrence is independently selected from H, fert-butoxy, ethyl, and methyl; and R 20b is methyl;
  • R 30 in each occurrence is independently selected from fluoro, -CN, and -OR 30a , -C(O)N(R 30a ) 2 , -S(O) 2 N(R 30a ) 2 , and -S(O) 2 Me;
  • R 30a is in each occurrence is independently selected from H, methyl, and ethyl; and R a in each occurrence is independently selected from fluoro and methoxy.
  • Ring A is heterocyclyl, wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 2 *;
  • Ring B is heterocyclyl, wherein said heterocyclyl is optionally substituted on carbon with one or more R 4 ;
  • X is selected from -O- and -NH-;
  • R 1 is C 1-6 alkyl
  • R 2* in each occurrence is independently selected from C 1-6 alkyl
  • R 3 is C 1-6 alkyl
  • R 4 is halo
  • Ring A is selected from morpholinyl and piperazinyl, wherein any -NH- moiety of said morpholinyl and piperazinyl is optionally substituted with R 2 *;
  • Ring B is selected from pyridinyl and pyrimidinyl, wherein said pyridinyl and pyrimidinyl are optionally substituted on carbon with one or more R 4 ;
  • X is selected from -O- and -NH-;
  • R 1 is methyl;
  • R 2* is methyl;
  • R 3 is methyl
  • R 4 is fluoro
  • Ring A is selected from morpholin-4-yl and 4-methylpiperazin-1-yl; Ring B is selected from 5-fluoropyridin-2-yl and 5-fluoropyrimidin-2-yl; X is selected from -O- and -NH-; R 1 is methyl; and R 3 is methyl.
  • Ring A is selected from 3-(acetylamino)azetidin-1-yl, 3-(acetylamino)pyrrolidin-lyl, 3-(amionmethyl)piperidin-1-yl, 3-aminopiperidin-1-yl,
  • Ring B is selected from 3,5-difluoropyridin-2-yl, 5-fluoropyridin-2-yl, and 5-fluoropyrimidin-2-yl;
  • X is selected from -O- and -NH-;
  • R 1 is selected from 2-cyclohexylethyl, cyclopropyl, 2-(2,4-difluorophenyl)ethyl, 2-(2,6-difluorophenyl)ethyl, 2-(3,4-difluorophenyl)ethyl , 2-(3,5-difluorophenyl)ethyl, 2-(3,5-dimethoxyphenyl)ethyl, 4-fluorophenyl, 2-(3-fluorophenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2-(1H-imidazol-2-yl)ethyl, 4-methoxyphenyl, methyl, 2-phenylethyl, phenyloxymethyl, 2-pyridin-4-ylethyl, and thiophen-2-yl; and
  • R 3 is selected from (aminocarbonyl)methyl, cyanomethyl, l,l-difluoro-2-hydroxyethyl, [(dimethylamino)carbonyl]methyl, (dimethylaminosulfonyl)methyl, ethoxymethyl, 1 -hydroxy ethyl, 2 ⁇ hydroxyethyl, 1-methoxy ethyl, methoxymethyl, [(methylamino)carbonyl] methyl, and (methylsulfonyl)methyl.
  • the compound of Formula (I) is a compound of Formula (Ia):
  • Ring A, Ring B, X, R 1 , and R 3 are as defined hereinabove.
  • the compounds of Formula (I) and Formula (Ia) are compounds of Formula (Ib):
  • Ring B, X, R 1 , and R 3 are as defined hereinabove, and wherein Ring C is nitrogen-containing 4- to 7-membered non-aromatic heterocyclyl, wherein said nitrogen- containing 4- to 7-membered non-aromatic heterocyclyl is optionally substituted on carbon with one or more R , and wherein any -NH- moiety of said nitrogen-containing 4- to 7-membered non-aromatic heterocyclyl is optionally substituted with R 2 *, wherein R 2 and R 2* are as defined hereinabove.
  • the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as illustrated by the Examples, each of which provides a further independent aspect of the invention.
  • the present invention provides a compound selected from:
  • Typical compounds of Formula (I) are believed to have utility for the treatment of myeloproliferative disorders, myelodysplastic syndrome and cancer by inhibiting the JAK tyrosine kinases, particularly the JAK2 family.
  • Methods of treatment target tyrosine kinase activity, particularly the JAK family activity and more particularly JAK2 activity, which is involved in a variety of myeloproliferative disorders, myelodysplastic syndrome and cancer related processes.
  • inhibitors of tyrosine kinase are expected to be active against myeloproliferative disorders such as chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and neoplastic disease such as carcinoma of the breast, ovary, lung, colon, prostate or other tissues, as well as leukemias, myelomas and lymphomas, tumors of the central and peripheral nervous system, and other tumor types such as melanoma, fibrosarcoma and osteosarcoma.
  • Tyrosine kinase inhibitors, particularly the JAK family inhibitors and more particularly JAK2 inhibitors are also expected to be useful for the treatment other proliferative diseases including but not limited to
  • the compounds of Formula (I) have been shown to inhibit tyrosine kinases, particularly the JAK family and more particularly JAK2, as determined by the JAK2 Assay described herein.
  • the compounds of Formula (I) should also be useful as standards and reagents in determining the ability of a potential pharmaceutical to inhibit tyrosine kinases, particularly the JAK family and more particularly JAK2. These would be provided in commercial kits comprising a compound of this invention.
  • JAK2 kinase activity may be determined by measuring the kinase's ability to phosphorylate synthetic tyrosine residues within a generic polypeptide substrate using an Amplified Luminescent Proximity Assay (Alphascreen) technology (PerkinElmer, 549 Albany Street, Boston, MA).
  • Alphascreen Amplified Luminescent Proximity Assay
  • JAK2 kinase activity a commercially available purified enzyme may be used.
  • the enzyme may be C-terminal His6-tagged, recombinant, human JAK2, amino acids 808-end, (Genbank Accession number NM 004972) expressed by baculovirus in Sf21 cells (Upstate Biotechnology MA).
  • ATP adenosine triphosphate
  • the kinase reaction may be stopped by the addition of 30 mM ethylenediaminetetraacetic acid (EDTA).
  • EDTA ethylenediaminetetraacetic acid
  • the reaction may be performed in 384 well microtitre plates and the reaction products may be detected with the addition of streptavidin coated Donor Beads and phosphotyrosine-specif ⁇ c antibodies coated Acceptor Beads using the EnVision Multilabel Plate Reader after an overnight incubation at room temperature.
  • Teween 20 is a registered trademark of ICI Americas, Inc.
  • the JAK inhibitory activity of the following examples was measured at the following IC50S.
  • the absence of a listed IC50 value for any particular example is not intended to imply that the particular compound does not possess JAK IC 50 activity.
  • ALK kinase activity was determined by measuring the kinase's ability to phosphorylate a tyrosine residue within a peptide substrate using a mobility shift assay on a Caliper LC3000 reader (Caliper, MA), which measures fluorescence of the phosphorylated and unphosphorylated substrate and calculates a ratiometric value to determine percent turnover.
  • ALK kinase activity a commercially available purified enzyme may be used.
  • the enzyme may be N-terminal GST-tagged, recombinant, human ALK, amino acids 1058-1620, (Genbank Accession number NP_004295) expressed in insect cells and activated in-vitro via autophosphorylation (Invitrogen CA).
  • a FAM labeled SRCtide substrate adenosine triphosphate (ATP), and MgCl 2
  • ATP adenosine triphosphate
  • MgCl 2 adenosine triphosphate
  • the kinase reaction may be stopped by the addition of 36 mM ethylenediaminetetraacetic acid (EDTA).
  • EDTA ethylenediaminetetraacetic acid
  • the reaction may be performed in 384 well microtitre plates and the reaction products may be detected using the Caliper LC3000 Reader.
  • the ALK inhibitory activity of the following examples was measured at the following IC50S.
  • the absence of a listed IC50 value for any particular example is not intended to imply that the particular compound does not possess ALK IC 50 activity.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use as a medicament.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of myeloproliferative disorders, myelodysplastic syndrome, and cancer, in a warm-blooded animal such as man.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of myeloproliferative disorders, myelodysplastic syndrome and cancers (solid and hematologic tumors), f ⁇ broproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acromegaly, acute and chronic inflammation, bone diseases, and ocular diseases with retinal vessel proliferation, in a warm-blooded animal such as man.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and cancers selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, mesothelioma, renal cancer, lymphoma
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the production of a JAK inhibitory effect.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the production of an ALK inhibitory effect.
  • a method for treating myeloproliferative disorders, myelodysplastic syndrome, and cancer comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • a method for treating myeloproliferative disorders, myelodysplastic syndrome, and cancers solid and hematologic tumors
  • f ⁇ broproliferative and differentiative disorders psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acromegaly, acute and chronic inflammation, bone diseases, and ocular diseases with retinal vessel proliferation, in a warm-blooded animal such as man
  • said method comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • a method for producing an anti-proliferative effect in a warm-blooded animal such as man comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • a method for producing a JAK inhibitory effect in a warm-blooded animal such as man comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • a method for producing an ALK inhibitory effect in a warm-blooded animal such as man comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • a method for treating cancer in a warm-blooded animal comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in treating myeloproliferative disorders, myelodysplastic syndrome, and cancer, in a warm-blooded animal such as man.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in treating myeloproliferative disorders, myelodysplastic syndrome, and cancers (solid and hematologic tumors), f ⁇ broproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acromegaly, acute and chronic inflammation, bone diseases, and ocular diseases with retinal vessel proliferation, in a warm-blooded animal such as man.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the production of an anti -proliferative effect, in a warm-blooded animal such as man.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the production of a JAK inhibitory effect in a warm-blooded animal such as man.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the production of an ALK inhibitory effect in a warm-blooded animal such as man.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of cancer in a warm-blooded animal such as man.
  • the treatment (or prophylaxis) of cancer may particularly refer to the treatment (or prophylaxis) of mesoblastic nephroma, mesothelioma, acute myeloblastic leukemia, acute lymphocytic leukemia, multiple myeloma, oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer including secretory breast cancer, colorectal cancer, prostate cancer including hormone refractory prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, renal cancer, lymphoma, thyroid cancer including papillary thyroid cancer, mesothelioma, leukaemia, tumors of the central and peripheral nervous system,
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixir
  • compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art.
  • compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.
  • Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl />-hydroxybenzoate; and anti-oxidants, such as ascorbic acid.
  • Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
  • Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions generally contain the active ingredient in finely powdered form or in the form of nano or micronized particles together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexito
  • the aqueous suspensions may also contain one or more preservatives such as ethyl or propyl p_-hydroxybenzoate; anti-oxidants such as ascorbic acid); coloring agents; flavoring agents; and/or sweetening agents such as sucrose, saccharine or aspartame.
  • preservatives such as ethyl or propyl p_-hydroxybenzoate
  • anti-oxidants such as ascorbic acid
  • coloring agents such as ascorbic acid
  • flavoring agents such as ascorbic acid
  • sweetening agents such as sucrose, saccharine or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as arachis oil, olive oil, sesame oil or coconut oil or in a mineral oil such as liquid paraffin.
  • the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavoring and coloring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these.
  • Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally- occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavoring and preservative agents.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavoring and/or coloring agent.
  • sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavoring and/or coloring agent.
  • compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above.
  • a sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.
  • Compositions for administration by inhalation may be in the form of a conventional pressurized aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets.
  • Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.
  • the amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 4 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient.
  • the size of the dose required for the therapeutic or prophylactic treatment of a particular disease state will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated.
  • a daily dose in the range of 1-50 mg/kg is employed. Accordingly, the optimum dosage may be determined by the practitioner who is treating any particular patient.
  • anti-cancer treatment may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
  • chemotherapy may include one or more of the following categories of anti -tumor agents: (i) antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines including 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea); antitumor antibiotics (for example anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin
  • cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5 ⁇ -reductase such as finasteride; (iii) agents which inhibit cancer cell invasion (for example metalloproteinase inhibitors such as marimastat and inhibitors of urokinase plasminogen activator receptor
  • inhibitors of growth factor function include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab [HerceptinTM] and the anti-erbbl antibody cetuximab [C225]) , farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as
  • N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, AZDl 839), N-(3-ethynylphenyl)-6,7-bis (2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033)
  • inhibitors of the platelet-derived growth factor family for example inhibitors of the hepatocyte growth factor family
  • PI3K phosphotidylinositol 3-kinase
  • MEK1/2 mitogen activated protein kinase
  • PBB/Akt protein kinase B
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [AvastinTM], compounds such as those disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds that work by other mechanisms (for example linomide, inhibitors of integrin ⁇ v ⁇ 3 function and angiostatin);
  • vascular endothelial growth factor for example the anti-vascular endothelial cell growth factor antibody bevacizumab [AvastinTM]
  • vastinTM anti-vascular endothelial cell growth factor antibody bevacizumab
  • compounds that work by other mechanisms for example linomide, inhibitors of integrin ⁇ v ⁇ 3 function and angiostatin
  • vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
  • antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy;
  • immunotherapy approaches including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine -transfected tumor cell lines and approaches using anti-idiotypic antibodies and approaches using the immunomodulatory drugs thalidomide and lenalidomide [Re
  • ALIMTA Cephalon's kinase inhibitors CEP-701 and CEP-2563, anti-Trk or anti-NGF monoclonal antibodies, targeted radiation therapy with 1311-metaiodobenzylguanidine (131I-MIBG), anti-G(D2) monoclonal antibody therapy with or without granulocyte- macrophage colony-stimulating factor (GM-CSF) following chemotherapy.
  • 131I-MIBG 1311-metaiodobenzylguanidine
  • GM-CSF granulocyte- macrophage colony-stimulating factor
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products employ the compounds of this invention, or pharmaceutically acceptable salts thereof, within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
  • compounds of Formula (I) and pharmaceutically acceptable salts thereof are also useful as pharmacological tools in the development and standardization of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of JAK2 in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
  • any of the alternate embodiments of the compounds of the invention described herein also apply.
  • the inhibition of JAK activity particularly refers to the inhibition of JAK2 activity.
  • the necessary starting materials for the procedures such as those described herein may be made by procedures which are selected from standard organic chemical techniques, techniques which are analogous to the synthesis of known, structurally similar compounds, or techniques which are analogous to the described procedure or the procedures described in the Examples. It is noted that many of the starting materials for synthetic methods as described herein are commercially available and/or widely reported in the scientific literature, or could be made from commercially available compounds using adaptations of processes reported in the scientific literature. The reader is further referred to Advanced Organic Chemistry, 5 X Edition, by Jerry March and Michael Smith, published by John Wiley & Sons 2001, for general guidance on reaction conditions and reagents.
  • F mula (H) and thereafter if necessary: i) converting a compound of Formula (I) into another compound of Formula (I); ii) removing any protecting groups; and/or iii) forming a pharmaceutically acceptable salt, wherein L in each occurrence may be the same or different, and is a leaving group as described hereinabove.
  • Process A - Compounds of Formula (A) and compounds of Formula (B) may be reacted together in the presence of a suitable solvent, examples of which include ketones such as acetone, alcohols such as ethanol and butanol, and aromatic hydrocarbons such as toluene and N-methyl pyrrolid- 2-one.
  • a suitable solvent examples of which include ketones such as acetone, alcohols such as ethanol and butanol, and aromatic hydrocarbons such as toluene and N-methyl pyrrolid- 2-one.
  • the reaction may advantageously occur in the presence of a suitable base, examples of which include inorganic bases such as potassium carbonate and cesium carbonate, and organic bases such as potassium tert-butoxide and sodium tert-butoxide.
  • the reaction may be advantageously performed at a temperature in a range from 0 C to reflux. Heating the reaction may be particularly advantageous.
  • compounds of Formula (A) and compounds of Formula (B) may be reacted together under standard Buchwald conditions (for example see J. Am. Chem. Soc, 118, 7215; J. Am. Chem. Soc, 119, 8451; J. Org. Chem., 62, 1568 and 6066), with a suitable base.
  • suitable bases include inorganic bases such as cesium carbonate, and organic bases such as potassium ⁇ -butoxide.
  • Such a reaction may advantageously occur in the presence of a palladium catalyst such as palladium acetate.
  • solvents suitable for such a reaction include toluene, benzene, dioxane, and xylene.
  • the -NH- moiety of the compound of Formula (B) may advantageously be protected with a suitable protecting group, examples of which include protecting groups such as tert-butoxycarbonyl.
  • Process B - Compounds of Formula (D) and compounds of Formula (C) may be reacted together under conditions similar to those described for the reaction of compounds of Formula (A) with compounds of Formula (B).
  • Process C- Compounds of Formula (F) and Ring A may be reacted together under conditions similar to those described for the reaction of compounds of Formula (A) with compounds of
  • L in each occurrence may be the same or different, and is a leaving group as described hereinabove.
  • Compounds of Formula (B) and compounds of Formula (E) may be reacted together in the presence of a suitable solvent, examples of which include ketones such as acetone, alcohols such as ethanol and butanol, and aromatic hydrocarbons such as toluene and N-methylpyrrolid-2-one.
  • a suitable solvent examples of which include ketones such as acetone, alcohols such as ethanol and butanol, and aromatic hydrocarbons such as toluene and N-methylpyrrolid-2-one.
  • the reaction advantageously will take place in the presence of a suitable base, examples of which include inorganic bases such as potassium carbonate and cesium carbonate, and organic bases such as potassium tert-butoxide and sodium tert-butoxide.
  • the reaction is advantageously performed at a temperature in a range from 0°C to reflux.
  • L in each occurrence may be the same or different, and is a leaving group as described hereinabove.
  • temperatures are given in degrees Celsius (°C); operations are carried out at room temperature or ambient temperature, that is, in a range of 18-25 °C;
  • yields are given for illustration only and are not necessarily those which can be obtained by diligent process development; preparations were repeated if more material was required;
  • NMR data when given, NMR data is in the form of delta values for major diagnostic protons, given in part per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz in DMSO-d ⁇ unless otherwise stated;
  • MeOD refers to CD 4 OD
  • CH 2 Cl 2 refers to CD 2 Cl 2 .
  • 1 H NMR peak corresponding to the pyrazole C-4' proton was not always obvious.
  • chemical symbols have their usual meanings;
  • ISCO refers to normal phase flash column chromatography using pre-packed silica gel cartridges (12 g, 40 g etc.), used according to the manufacturer's instructions, obtained from ISCO, Inc, 4700 Superior Street Lincoln, NE, USA.
  • Gilson chromatography refers to separation/purif ⁇ catio using a YMC-AQC 18 reverse phase HPLC Column with dimension 20 mm/100 and 50 mm/250 in H 2 O/MeCN with 0.1% TFA as mobile phase unless otherwise stated and used according to the manufacturer's instructions, obtained from Gilson, Inc. 3000 Parmenter Street, Middleton, WI 53562-0027, U.S.A.
  • AD (or AS or OJ or OD-) corresponds to the chiral column (see below), a number from 1-4 would correspond to mobile phase modifier, - number (corresponding to the % of mobile phase modifier).
  • AD-3-20 indicates Chiralpak AD with 20% of methanol, 0.4%dimethylethylamine used for chiral purification or e.e. determination
  • Parr Hydrogenator or Parr shaker type hydrogenators are systems for treating chemicals with hydrogen in the presence of a catalyst at pressures up to 5 atmospheres (60 psi) and temperatures to 80 °C.
  • H-Cube refers to the H-Cube continuous hydrogenation equipment manufactured by Thales Nanotechnology. (xxiii) the following abbreviations may have been used:
  • a 10 ml microwave vial was charged with 2-chloro-5-fluoropyrimidine (2.0 g, 15.09 mmol), Pd 2 (dba) 3 (0.549 g, 0.6 mmol), dppf (0.67 g, 1.21 mmol), zinc cyanide (1.15 g, 9.81 mmol), and zinc dust (0.237 mg, 3.62 mmol).
  • the flask was evacuated and backfilled with N 2 , and anhydrous dimethylacetamide.
  • the vial was mounted onto a Personal Chemistry microwave reactor and heated at 100 °C for 10 hours. The reaction mixture was diluted with EtOAc and then washed with brine three times. The organic layer was obtained and evaporated to dryness.
  • N- ⁇ (IS)- 1 -(5-Fluoropyridin-2-yl)ethyl1 acetamide To a solution of N-(l-(5-fluoropyridin-2-yl)vinyl)acetamide (Intermediate 8, 11.0 g, 61.1 mmol) in MeOH (120 ml) under N 2 was added (+)-1,2-bis((25,55)-2,5- diethylphospholano)benzene(cyclooctadiene)rhodium(I)trifluoromethanesulfonate (0.441 g, 0.611 mmol). The solution was transferred to a high pressure bomb and charged 150 psi H 2 .
  • the hydrochloride salt may be prepared by dissolving the title compound in MeOH and adding HCl/dioxane solution. Evaporation of the solvents gave the hydrochloride salt of the title product as a tan solid. While it is believed that the title product is in the form of a dihyrochloride salt, it is possible that it exists in the form of the monohydrochloride salt.
  • EtOAc extracts washed with brine and dried (MgSO 4 ).
  • the solvents were evaporated to a volume ( ⁇ 20ml) under reduced pressure (water bath ⁇ 30°C) and 10 ml of HCL in dioaxne (4N) weas added.
  • the mixture was stirred at room temperature for 30 minutes. Evaporation of the volatiles afforded l-(3,5-difluoropyridin-2-yl)-2-ethoxyethanamine hydrochloride as an off white solid.
  • N-(2-(fer?-butyldimethylsilyloxy)ethylidene)-2-methylpropane-2-sulf ⁇ namide To a suspension of rac-2-methylpropane-2-sulf ⁇ namide (3.10g, 26 mmol) and CuSO 4 (8.3g, 52 mmol) in 60 mL DCM, was added tert-butyldimethylsilyloxy acetaldehyde (5.Og, 26 mmol) at room temperature. The mixture was stirred at room temperature for 18 hours and then filtered through a Celite® pad followed by washing with DCM. The filtrate was concentrated in vacuo and then purified by column chromatography (20 to 40% EtOAc/ ⁇ -haxane) to give the title compound (6.59g, 92%) as a pale yellow oil.
  • the catalyst was filtered via Celite and the filtrate of l-(3,5-difluoropyridin-2-yl)-2-methoxyethanamine (0.4 M in ethyl acetate) (180 mL, 72.00 mmol) was treated with (R)-Mandelic acid (5.81 g, 38.16 mmol). Precipitation was observed almost instantaneously and the resulting mixture was allowed to stir overnight.
  • (R)-I- (3,5-difluoropyridin-2-yl)-2-methoxyethanamine (R)-mandelate salt was collected via filtration (8.5 g, 69.4 %).

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Abstract

The present invention relates to compounds of Formula (I) and to their salts, pharmaceutical compositions, methods of use, and methods for their preparation. These compounds provide a treatment for myeloproliferative disorders and cancer.

Description

Chemical Compounds 831
Field of the Invention
The present invention relates to novel compounds, their pharmaceutical compositions and methods of use. In addition, the present invention relates to therapeutic methods for the treatment and prevention of cancers and to the use of these compounds in the manufacture of medicaments for the treatment and prevention of myeloproliferative disorders and cancers.lson
Background of the Invention
The JAK (Janus-associated kinase)/STAT (signal transducers and activators of transcription) signalling pathway is involved in a variety of hyperproliferative and cancer related processes including cell-cycle progression, apoptosis, angiogenesis, invasion, metastasis and evasion of the immune system (Haura et al., Nature Clinical Practice Oncology, 2005, 2(6), 315-324; Verna et al., Cancer and Metastasis Reviews, 2003, 22, 423-434).
The JAK family consists of four non-receptor tyrosine kinases Tyk2, JAKl , JAK2, and JAK3 , which play a critical role in cytokine- and growth factor mediated signal transduction. Cytokine and/or growth factor binding to cell-surface receptor(s), promotes receptor dknerization and facilitates activation of receptor-associated JAK by autophosphorylation. Activated JAK phosphorylates the receptor, creating docking sites for SH2 domain-containing signalling proteins, in particular the STAT family of proteins (STATl , 2, 3, 4, 5a, 5b and 6). Receptor- bound STATs are themselves phosphorylated by JAKs, promoting their dissociation from the receptor, and subsequent dimerization and translocation to the nucleus. Once in the nucleus, the STATs bind DNA and cooperate with other transcription factors to regulate expression of a number of genes including genes which apoptosis inhibitors (e.g. BcI-XL, McI-I) and cell cycle regulators (e.g. Cyclin D1/D2, c-myc) (Haura et al., Nature Clinical Practice Oncology, 2005, 2(6), 315-324; Verna et al., Cancer and Metastasis Reviews, 2003, 22, 423-434).
Over the past decade, a considerable amount of scientific literature linking constitutive JAK and/or STAT signalling with hyperproliferative disorders and cancer has been published. Constitutive activation of the STAT family, in particular STAT3 and STAT5, has been detected in a wide range of cancers and hyperproliferative disorders (Haura et al, Nature Clinical Practice Oncology, 2005, 2(6), 315-324). Furthermore, aberrant activation of the JAK/STAT pathway provides an important proliferative and/or anti-apoptotic drive downstream of many kinases (e.g. Flt3, EGFR) whose constitutive activation have been implicated as key drivers in a variety of cancers and hyperproliferative disorders (Tibes et al., Annu Rev Pharmacol Toxicol 2550, 45, 357-384; Choudhary et al., International Journal of Hematology 2005, 82(2), 93-99; Sordella et al., Science 2004, 305, 1163-1167). In addition, impairment of negative regulatory proteins, such as the suppressors of cytokine signalling (SOCS) proteins, can also influence the activation status of the JAK/STAT signalling pathway in disease (JC Tan and Rabkin R, Pediatric Nephrology 2005, 20, 567-575).
Several mutated forms of JAK2 have been identified in a variety of disease settings. For example, translocations resulting in the fusion of the JAK2 kinase domain with an oligomerization domain, TEL- JAK2, Bcr-JAK2 and PCM1-JAK2, have been implicated in the pathogenesis of various hematologic malignancies (SD Turner and Alesander DR, Leukemia, 2006, 20, 572-582). More recently, a unique acquired mutation encoding a valine-to- phenylalanine (V617F) substitution in JAK2 was detected in a significant number of polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis patients and to a lesser extent in several other diseases. The mutant JAK2 protein is able to activate downstream signalling in the absence of cytokine stimulation, resulting in autonomous growth and/or hypersensitivity to cytokines and is believed to play a role in driving these diseases (MJ Percy and McMullin MF, Hematological Oncology 2005, 23(3-4), 91-93).
Another tyrosine kinase receptor is analplastic lymphoma kinase (ALK), a 200kd receptor tyrosine kinase encoded by the ALK gene on chromosome 2p23. ALK belongs to the insulin receptor superfamily. Normal expression of ALK is tightly controlled and limited to the testis, ganglion cells of the intestine and neural tissues. Recent data suggests that ALK is involved in neuronal cell differentiation and regeneration, synapse formation and muscle cell migration.
ALK was first identified in a chromosomal translocation associated with some anaplastic large cell lymphomas (ALCL). Approximately 50-60% of cases are associated with the t(2;2)(p23;q35) chromosomal translocation which generates a hybrid gene consisting of the intracellular domain of the ALK tyrosine kinase receptor juxtaposed with nucleophosmin (NPM), a nucleolar protein involved in shuttling ribonucleoproteins. The resulting fusion protein, NPM-ALK has constitutive kinase activity and transforms a variety of immortalized cell lines in vitro and supports tumor formation in vivo by controlling key cellular processes such as cell cycle progression, survival, cell migration and cell shaping (Chiarle et al., Nature Reviews Cancer, 8:11-23, 2008). Similarly, expression of NPM-ALK driven by a CD4 promoter in transgenic mice resulted in the development of aggressive lymphoma of multiple origins. Several signalling pathways have been implicated in the pathogenesis of NPM-ALK positive ALCLs. NPM-ALK has been shown to activate several members of the signal transducer and activator of transcription (STAT) family, including STAT3 and STAT5 as well as phospholipase C-γ and the PI3- kinase/AKT pathway.
Other ALK fusions partners have been reported in ALCL in addition to CD30-negative diffuse large cell lymphoma, albeit with lower frequency. ALK fusion proteins have also been detected in inflammatory myofϊbroblastic tumors, oesophageal squamous cell carcinomas and, more recently, in approximately 6% non small cell lung cancer (NSCLC) (Soda et al, Nature 448:561- 566, 2007). In NSCLC, a novel translocation was initially identified in which a small inversion within chromosome 2p results in formation of a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) and ALK genes. Expression of this fusion protein in mouse 3T3 fibroblasts results in generation of transformed foci in culture and tumors in mice. ALK inhibitors have also been reported to inhibit growth of some NSCLC cell containing an EML4-ALK protein fusion in vitro and in vivo (McDermott et al., Cancer Res. 68:3389-3395, 2008; Koivunen et al., AACR Annual Meeting 2008). Other fusion partners have also been reported or proposed in NSCLC (Rikova et al., Cell 131:1190-1203, 2007; Perner et al., Neoplasia 10:298-302, 2008).
Aberrant expression of ALK may represent an alternative mechanism of ALK activation that could contribute to oncogenesis. Aberrant deregulated expression and/or amplification of full length ALK has been documented in B cell NHL, in nervous system derived human cancer cell lines and primary tumors, including neuroblastoma, glioblastoma and retinoblastoma, cell lines derived from solid tumors of ectodermal origin, including melanoma and breast carcinoma and NSCLC (Chiarle et al, Nature Reviews Cancer, 8:11-23, 2008).
Summary of the Invention
The present invention provides compounds of Formula (I):
Figure imgf000005_0001
or pharmaceutically acceptable salts thereof.
It is expected that typical compounds of Formula (I) possess beneficial efficacious, metabolic, and/or pharmacodynamic properties.
Typical compounds of Formula (I) are believed to possess JAK kinase inhibitory activity and are accordingly useful for their anti-proliferation and/or pro-apoptotic activity and in methods of treatment of the human or animal body. The invention also relates to processes for the manufacture of said compound, or pharmaceutically acceptable salts thereof, to pharmaceutical compositions containing it and to its use in the manufacture of medicaments for use in the production of an anti-proliferation and/or pro-apoptotic effect in warm-blooded animals such as man. Also in accordance with the present invention the applicants provide methods of using said compound, or pharmaceutically acceptable salts thereof, in the treatment of myeloproliferative disorders, myelodysplastic syndrome and cancer. The properties of the compounds of Formula (I) are expected to be of value in the treatment of myeloproliferative disorders, myelodysplastic syndrome, and cancer by inhibiting the tyrosine kinases, particularly the JAK family and more particularly JAK2. Methods of treatment target tyrosine kinase activity, particularly the JAK family activity and more particularly JAK2 activity, which is involved in a variety of myeloproliferative disorders, myelodysplastic syndrome and cancer related processes. Thus, inhibitors of tyrosine kinases, particularly the JAK family and more particularly JAK2, are expected to be active against myeloproliferative disorders such as chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and neoplastic disease such as carcinoma of the breast, ovary, lung, colon, prostate or other tissues, as well as leukemias, myelomas and lymphomas, tumors of the central and peripheral nervous system, and other tumor types such as melanoma, fibrosarcoma and osteosarcoma. Tyrosine kinase inhibitors, particularly the JAK family inhibitors and more particularly JAK2 inhibitors are also expected to be useful for the treatment other proliferative diseases including autoimmune, inflammatory, neurological, and cardiovascular diseases.
Furthermore, the compounds of Formula (I), or pharmaceutically acceptable salts thereof, are expected to be of value in the treatment or prophylaxis of against myeloproliferative disorders selected from chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and cancers selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, mesothelioma, renal cancer, lymphoma and leukaemia; particularly myeloma, leukemia, ovarian cancer, breast cancer and prostate cancer.
Detailed Description of the Invention The present invention relates to compounds of Formula (I):
a (I)
Figure imgf000007_0001
or pharmaceutically acceptable salts thereof, wherein
Ring A is heterocyclyl, wherein said heterocyclyl is optionally substituted on carbon with one or more R2, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R2*; Ring B is selected from carbocyclyl and heterocyclyl, wherein said carbocyclyl and heterocyclyl are optionally substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R *; X is selected from -O-, -NH-, and -S-;
R1 is selected from H, halo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -ORla, -SRla, -N(Rla)2, -N(Rla)C(O)Rlb, -N(Rla)N(Rla)2, -NO2, -N(Rla)ORla, -ON(Rla)2, -C(O)H, -C(O)Rlb, -C(O)2R13, -C(O)N(Rla)2, -C(O)N(Rla)(ORla), -OC(O)N(Rla)2, -N(Rla)C(O)2Rla, -N(Rla)C(0)N(Rla)2, -OC(O)Rlb, -S(O)Rlb, -S(O)2Rlb, -S(O)2N(Rla)2, -N(Rla)S(O)2Rlb, -C(Rla)=N(Rla), and -C(Rla)=N(ORla), wherein said C1-6alkyl, C2_6alkenyl,
C2-6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more R10, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R10*; Rla in each occurrence is independently selected from H, Chalky 1, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R10, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R ;
Rlb in each occurrence is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C1-6alky!, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 10 and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 10* R2 is selected from halo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -OR2a, -SR2a, -N(R2a)2, -N(R2a)C(O)R2b, -N(R2a)N(R2a)2, -NO2, -N(R2a)OR2a, -ON(R2a)2, -C(O)H, -C(O)R2b, -C(O)2R2a, -C(O)N(R2a)2, -C(O)N(R2a)(OR2a) -OC(O)N(R2a)2, -N(R2a)C(O)2R2a, -N(R2a)C(O)N(R2a)2, -OC(O)R2b, -S(O)R2b, -S(O)2R2b, -S(O)2N(R2a)2,
-N(R2a)S(O)2R2b, -C(R2a)=N(R2a), and -C(R2a)=N(OR2a), wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more R20, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R20*; R2* in each occurrence is independently selected from C1-6alkyl, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R2b, -C(O)2R2c, -C(O)N(R2a)2, -S(O)R2b, -S(O)2R2b, -S(O)2N(R2a)2,
-C(R2a)=N(R2a), and -C(R2a)=N(OR2a), wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R20*; R2a in each occurrence is independently selected from H, C1-6alky 1, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R ;
R2b in each occurrence is selected from C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R20, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R20*; R2c in each occurrence is independently selected from C1-6alkyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R20*;
R3 is selected from H, halo, -CN, C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, heterocyclyl, -OR3a, -SR3a, -N(R3a)2, -N(R3a)C(O)R3b, -N(R3a)N(R3a)2, -NO2, -N(R3a)-OR3a, -O-N(R3a)2, -C(O)H, -C(O)R3b, -C(O)2R3a, -C(O)N(R3a)2, -C(O)N(R3a)(OR3a), -OC(O)N(R3a)2, -N(R3a)C(O)2R3, -N(R3a)C(O)N(R3a)2, -OC(O)R3b, -S(O)R3b, -S(O)2R3b, -S(O)2N(R3a)2, -N(R3a)S(O)2R3b, -C(R3a)=N(R3a), and -C(R3a)=N(OR3a), wherein said C1-6alkyl, C2_6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more R30, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R30*; R3a in each occurrence is independently selected from H, C1-6alkyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R30*;
R3b in each occurrence is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R30, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R30*; R4 is selected from halo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -OR4a, -SR4a, -N(R4a)2, -N(R4a)C(O)R4b, -N(R4a)N(R4a)2, -NO2, -N(R4a)-OR4a, -O-N(R4a)2, -C(O)H, -C(O)R4b, -C(O)2R4a, -C(O)N(R4a)2, -C(O)N(R4a)(OR4a) -OC(O)N(R4a)2, -N(R4a)C(O)2R4a, -N(R4a)C(O)N(R4a)2, -OC(O)R4b, -S(O)R4b, -S(O)2R4b, -S(O)2N(R4a)2, -N(R4a)S(O)2R4b, -C(R4a)=N(R4a), and -C(R4a)=N(OR4a), wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more R40, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R40*; R4* in each occurrence is independently selected from C1-6alky 1, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R4b, -C(O)2R4c, -C(O)N(R4a)2, -S(O)R4b, -S(O)2R4b, -S(O)2N(R4a)2, -C(R4a)=N(R4a), and -C(R4a)=N(OR4a), wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R40 and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R40* R4a in each occurrence is independently selected from H, C1-6alkyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R40*;
R4b in each occurrence is selected from C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R40, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R40*; R4c in each occurrence is independently selected from C1-6alkyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R40 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R40*
R10 in each occurrence is independently selected from halo, -CN, C1-6alkyl, C2-6alkenyl,
C2-6alkynyl, carbocyclyl, heterocyclyl, -OR10a, -SR10a, -N(R10a)2, -N(R10a)C(O)R10b, -N(R10a)N(R10a)2, -NO2, -N(R10a)-OR10a, -O-N(R10a)2, -C(O)H, -C(O)R10b, -C(O)2R10a,
-C(O)N(R10a)2, -C(O)N(R10a)(OR10a), -OC(O)N(R10a)2, -N(R10a)C(O)2R10a, -N(R10a)C(O)N(R10a)2, -OC(O)R10b, -S(O)R10b, -S(O)2R10b, -S(O)2N(R10a)2, -N(R10a)S(O)2R10b, -C(R10a)=N(R10a), and -C(R10a)=N(OR10a), wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more Ra, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with Ra*; R10* in each occurrence is independently selected from C1-6alkyl, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R10b, -C(O)2R10c, -C(O)N(R10a)2, -S(O)R10b, -S(O)2R10b, -S(O)2N(R10a)2, -C(R10a)=N(R10a), and -C(R10a)=N(OR10a), wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more Ra, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with Ra*; R10a in each occurrence is independently selected from H, C1-6alky 1, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more Ra, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with Ra*; R1Ob in each occurrence is independently selected from C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more Ra, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with Ra ; R1Oc in each occurrence is independently selected from C1-6alkyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more Ra, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with Ra*;
R20 in each occurrence is independently selected from halo, -CN, C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, heterocyclyl, -OR20a, -SR20a, -N(R20a)2, -N(R20a)C(O)R20b, -N(R20a)N(R20a)2, -NO2, -N(R20a)-OR20a, -O-N(R20a)2, -C(O)H, -C(O)R20b, -C(O)2R20a, -C(O)N(R20a)2, -C(O)N(R20a)(OR20a), -OC(O)N(R20a)2, -N(R20a)C(O)2R20a, -N(R20a)C(O)N(R20a)2, -OC(O)R20b, -S(O)R20b, -S(O)2R20b, -S(O)2N(R20a)2, -N(R20a)S(O)2R20b, -C(R20a)=N(R20a), and -C(R20a)=N(OR20a), wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R ; R20* in each occurrence is independently selected from C1-6alky 1, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R20b, -C(O)2R20c, -C(O)N(R20a)2, -S(O)R20b, -S(O)2R20b, -S(O)2N(R20a)2, -C(R20a)=N(R20a), and -C(R20a)=N(OR20a), wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more Rb, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with Rb*; R20a in each occurrence is independently selected from H, C1-6alkyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R ; R20b in each occurrence is independently selected from C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R ; R20c in each occurrence is independently selected from C1-6alkyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more Rb, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with Rb*;
R30 in each occurrence is independently selected from halo, -CN, C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, heterocyclyl, -OR30a, -SR30a, -N(R30a)2, -N(R30a)C(O)R30b, -N(R30a)N(R30a)2, -NO2, -N(R30a)-OR30a, -O-N(R30a)2, -C(O)H, -C(O)R30b, -C(O)2R30a, -C(O)N(R30a)2, -C(O)N(R30a)(OR30a), -OC(O)N(R30a)2, -N(R30a)C(O)2R30a, -N(R30a)C(O)N(R30a)2, -OC(O)R30b, -S(O)R30b, -S(O)2R30b, -S(O)2N(R30a)2, -N(R30a)S(O)2R30b, -C(R30a)=N(R30a), and -C(R30a)=N(OR30a), wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more Rc, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R0*; R30* in each occurrence is independently selected from C1-6alkyl, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R30b, -C(O)2R30c, -C(O)N(R30a)2, -S(O)R30b, -S(O)2R30b, -S(O)2N(R30a)2,
-C(R30a)=N(R30a), and -C(R30a)=N(OR30a), wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more Rc, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R0*; R30a in each occurrence is independently selected from H, C1-6alky 1, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more Rc, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with Rc ;
R30b in each occurrence is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more Rc, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R0*; R30c in each occurrence is independently selected from C1-6alkyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more Rc, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R0*;
R40 in each occurrence is independently selected from halo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -OR40a, -SR40a, -N(R40a)2, -N(R40a)C(O)R40b, -N(R40a)N(R40a)2, -NO2, -N(R40a)-OR40a, -O-N(R40a)2, -C(O)H, -C(O)R40b, -C(O)2R40a, -C(O)N(R40a)2, -C(O)N(R40a)(OR40a), -OC(O)N(R40a)2, -N(R40a)C(O)2R40a, -N(R40a)C(O)N(R40a)2, -OC(O)R40b, -S(O)R40b, -S(O)2R40b, -S(O)2N(R40a)2, -N(R40a)S(O)2R40b, -C(R40a)=N(R40a), and -C(R40a)=N(OR40a), wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R ; R40* in each occurrence is independently selected from C1-6alky 1, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R40b, -C(O)2R40c, -C(O)N(R40a)2, -S(O)R40b, -S(O)2R40b, -S(O)2N(R40a)2,
-C(R40a)=N(R40a), and -C(R40a)=N(OR40a), wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with Rd*; R40a in each occurrence is independently selected from H, C1-6alkyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more Rd, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with Rd*; R40b in each occurrence is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R ; R40c in each occurrence is independently selected from C1-6alkyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more Rd, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with Rd*; Ra, Rb, Rc, and Rd in each occurrence are independently selected from halo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -ORm, -SRm, -N(Rm)2, -N(Rm)C(O)R", -N(Rm)N(Rm)2, -NO2, -N(Rm)-0Rm, -0-N(Rm)2, -C(O)H, -C(O)R", -C(O)2R111, -C(0)N(Rm)2, -C(0)N(Rm)(0Rm), -0C(0)N(Rm)2, -N(Rm)C(O)2Rm, -N(Rm)C(0)N(Rm)2, -OC(O)R", -S(O)R", -S(O)2R", -S(O)2N(Rm)2, -N(Rm)S(O)2R", -C(Rm)=N(Rm), and -C(Rm)=N(0Rm); Ra*, Rb*, Rc*, and Rd*in each occurrence are independently selected from C1-6alkyl, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R", -C(O)2R0, -C(0)N(Rm)2, -S(O)R", -S(O)2R", -S(O)2N(Rm)2, -C(Rm)=N(Rm), and -C(Rm)=N(0Rm);
Rm in each occurrence is independently selected from H, C1-6alkyl, carbocyclyl, and heterocyclyl; R" in each occurrence is independently selected from C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl; and
R0 in each occurrence is independently selected from C1-6alkyl, carbocyclyl, and heterocyclyl.
In this specification the prefix Cx_y as used in terms such as Cx_yalkyl and the like (where x and y are integers) indicates the numerical range of carbon atoms that are present in the group; for example, C^alkyl includes Cialkyl (methyl), C2alkyl (ethyl), Csalkyl (propyl and isopropyl) and C4alkyl (butyl, 1-methylpropyl, 2-methylpropyl, and tert-butyl).
Alkyl - As used herein the term "alkyl" refers to both straight and branched chain saturated hydrocarbon radicals having the specified number of carbon atoms. For example, "C1-6alkyl" includes groups such as C1-salkyl, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, propyl, ri propyl, and hexyl. References to individual alkyl groups such as "propyl" are specific for the straight chain version only and references to individual branched chain alkyl groups such as 'isopropyl' are specific for the branched chain version only.
Alkenyl - As used herein, the term "alkenyl" refers to both straight and branched chain hydrocarbon radicals having the specified number of carbon atoms and containing at least one carbon-carbon double bond. For example, "C2-6alkenyl" includes groups such as C2-salkenyl, C2-4alkenyl, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, and 5-hexenyl.
Alkvnyl - As used herein, the term "alkynyl" refers to both straight and branched chain hydrocarbon radicals having the specified number of carbon atoms and containing at least one carbon-carbon triple bond. For example, "C2-6alkynyl" includes groups such as C2-salkynyl, C2-4alkynyl, ethynyl, 2-propynyl, 2-methyl-2-propynyl, 3-butynyl, 4-pentynyl, and 5-hexynyl.
Halo - As used herein, the term "halo" refers to fluoro, chloro, bromo and iodo. In one aspect, the term "halo" may refer to fluoro, chloro, and bromo. In another aspect, the term "halo" may refer to fluoro and chloro.
Carbocyclyl - As used herein, the term "carbocyclyl" refers to a saturated, partially saturated, or unsaturated, mono or bicyclic carbon ring that contains 3 to 12 ring atoms, of which one or more -CH2- groups may be optionally replaced with a corresponding number of -C(O)- groups.
Illustrative examples of "carbocyclyl" include adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, indanyl, naphthyl, oxocyclopentyl, 1-oxoindanyl, phenyl, and tetralinyl.
3- to 6-Membered Carbocyclyl - In one aspect, "carbocyclyl" may be "3- to 6-membered carbocyclyl." The term "3- to 6-membered carbocyclyl" refers to a saturated, partially saturated, or unsaturated monocyclic carbon ring containing 3 to 6 ring atoms, of which one or more -CH2- groups may be optionally replaced with a corresponding number of -C(O)- groups. Illustrative examples of "3- to 6-membered carbocyclyl" include cyclopropyl, cyclobutyl, cyclopentyl, oxocyclopentyl, cyclopentenyl, cyclohexyl, and phenyl. Heterocvclyl - As used herein, the term "heterocyclyl" refers to a saturated, partially saturated, or unsaturated, mono or bicyclic ring containing 4 to 12 ring atoms of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and which may, unless otherwise specified, be carbon or nitrogen linked, and of which a -CH2- group can optionally be replaced by a -C(O)-. Ring sulfur atoms may be optionally oxidized to form S-oxides. Ring nitrogen atoms may be optionally oxidized to form N-oxides. Illustrative examples of the term "heterocyclyl" include 1,3-benzodioxolyl, 3,5-dioxopiperidinyl, furanyl, imidazolyl, indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, oxazolyl, 2-oxopyrrolidinyl, oxo- 1,3-thiazolidinyl, piperazinyl, piperidyl, 2H-pyranyl, pyrazolyl, pyridinyl, pyrrolyl, pyrrolidinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 4-pyridonyl, quinolyl, tetrahydro furanyl, tetrahydropyranyl, thiazolyl, thiadiazolyl, thiazolidinyl, thiomorpholinyl, thiophenyl, pyridine -N-oxidyl and quinoline-N-oxidyl.
Non- Aromatic Ηeterocyclyl - In one aspect, "heterocyclyl" may be non-aromatic heterocyclyl, which refers to a saturated, or partially saturated mono or bicyclic non-aromatic ring containing 4 to 12 ring atoms of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and which may, unless otherwise specified, be carbon or nitrogen linked, and of which a -CH2- group can optionally be replaced by a -C(O)-. Ring sulfur atoms may be optionally oxidized to form S-oxides. Ring nitrogen atoms may be optionally oxidized to form N-oxides. Illustrative examples of the term "non-aromatic heterocyclyl" include dioxidotetrahydrothiophenyl,
2,4-dioxoimidazolidinyl, 3,5-dioxopiperidinyl, morpholinyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, oxoimidazolidinyl, 2-oxopyrrolidinyl, 2-oxotetrahydrofuranyl, oxo- 1,3 -thiazolidinyl, piperazinyl, piperidyl, 2H-pyranyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiomorpholinyl, and thiazolidinyl.
5- or 6-Membered Ηeterocvclyl - In one aspect, "heterocyclyl" may be 5- or 6-membered heterocyclyl, which refers to a saturated, partially saturated, or unsaturated, monocyclic ring containing 5 or 6 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and of which a -CΗ2- group may be optionally replaced by a -C(O)- group. Unless otherwise specified, "5- or 6-membered heterocyclyl" groups may be carbon or nitrogen linked. Ring nitrogen atoms may be optionally oxidized to form an N-oxide. Ring sulfur atoms may be optionally oxidized to form S-oxides. Illustrative examples of "5- or 6-membered heterocyclyl" include 3,5-dioxopiperidinyl, furanyl, imidazolyl, isothiazolyl, isoxazolyl, morpholinyl, oxazolyl, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, piperazinyl, piperidyl, 2H-pyranyl, pyrazolyl, pyridinyl, pyrrolyl, pyrrolidinyl, pyrrolidinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, 4-pyridonyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolyl, thiadiazolyl, thiazolidinyl, thiomorpholinyl, thiophenyl, and pyridine-N-oxidyl.
4- to 6- Membered Ηeterocvclyl - In one aspect, "heterocyclyl" and "5- or 6-membered heterocyclyl" may be 4- to 6-membered heterocyclyl. The term "4- to 6-membered heterocyclyl" refers to a saturated, partially saturated, or unsaturated, monocyclic ring containing 4 to 6 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and of which a -CH2- group may be optionally replaced by a -C(O)- group. Unless otherwise specified, "4- to 6-membered heterocyclyl" groups may be carbon or nitrogen linked. Ring nitrogen atoms may be optionally oxidized to form an N-oxide. Ring sulfur atoms may be optionally oxidized to form S-oxides. Illustrative examples of "4- to 6-membered heterocyclyl" include azetidin-1-yl, dioxidotetrahydrothiophenyl, 2,4-dioxoimidazolidinyl, 3,5-dioxopiperidinyl, furanyl, imidazolyl, isothiazolyl, isoxazolyl, morpholinyl, oxazolyl, oxetanyl, oxoimidazolidinyl, 3-oxo-1- piperazinyl, 2-oxopyrrolidinyl, 2-oxotetrahydrofuranyl, oxo- 1,3 -thiazolidinyl, piperazinyl, piperidyl, 2H-pyranyl, pyrazolyl, pyridinyl, pyrrolyl, pyrrolidinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, 4-pyridonyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolyl, 1,3,4- thiadiazolyl, thiazolidinyl, thiomorpholinyl, thiophenyl, 4H-1,2,4-triazolyl, and pyridine-N-oxidyl.
6-Membered Ηeterocvclyl - In one aspect, "heterocyclyl," "5- or 6-membered heterocyclyl," and "4- to 6-membered heterocyclyl" may be 6-membered heterocyclyl, which refers to a saturated, partially saturated, or unsaturated, monocyclic ring containing 6 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and of which a -CH2- group may be optionally replaced by a -C(O)- group. Unless otherwise specified, "6-membered heterocyclyl" groups may be carbon or nitrogen linked. Ring nitrogen atoms may be optionally oxidized to form an Ν-oxide. Ring sulfur atoms may be optionally oxidized to form S-oxides. Illustrative examples of "6-membered heterocyclyl" include 3,5-dioxopiperidinyl, morpholinyl, piperazinyl, piperidinyl, 2H-pyranyl, pyrazinyl, pyridazinyl, pyridinyl, and pyrimidinyl.
6-Membered Ηeteroaryl - In one aspect, "heterocyclyl," "5- or 6-membered heterocyclyl," "4- to 6-membered heterocyclyl," and "6-membered heterocyclyl" may be 6-membered heteroaryl. The term "6-membered heteroaryl" is intended to refer to a monocyclic, aromatic heterocyclyl ring containing 6 ring atoms. Unless otherwise specified, "6-membered heteroaryl" groups may be carbon or nitrogen linked. Ring nitrogen atoms may be optionally oxidized to form an N-oxide. Ring sulfur atoms may be optionally oxidized to form S-oxides. Illustrative examples of "6- membered heteroaryl" include pyrazinyl, pyridazinyl, pyrimidinyl, and pyridinyl.
4- to 7- Membered Non- Aromatic Ηeterocvclyl - In one aspect, "heterocyclyl" and "non- aromatic heterocyclyl" may be 4- to 7-membered non-aromatic heterocyclyl. The term "4- to 7- membered non-aromatic heterocyclyl" refers to a non-aromatic, monocyclic ring containing 4 to 7 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and of which a -CH2- group may be optionally replaced by a -C(O)- group. Unless otherwise specified, "4- to 7-membered non-aromatic heterocyclyl" groups may be carbon or nitrogen linked. Ring nitrogen atoms may be optionally oxidized to form an N-oxide. Ring sulfur atoms may be optionally oxidized to form S-oxides. Illustrative examples of "4- to 7-membered non-aromatic heterocyclyl" include azetidin-1-yl, dioxidotetrahydrothiophenyl, 2,4-dioxoimidazolidinyl, 3,5-dioxopiperidinyl, morpholinyl, oxetanyl, oxoimidazolidinyl, 3 -oxo-1 -piperazinyl, 2- oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-oxotetrahydrofuranyl, 1,4-oxazepan-4-yl, piperazinyl, piperidyl, 2H-pyranyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, , thiazolidinyl, and thiomorpholinyl.
For the purposes of Ring C, the term "nitrogen-containing 4- to 7-membered non-aromatic heterocvclyl" is intended to refer to a 4- to 7-membered non-aromatic heterocyclyl group having at least one ring nitrogen atom, said ring being bonded to the triazine ring via a nitrogen atom. In other aspects, Ring C may thus be nitrogen- containing 4- to 6- membered non-aromatic heterocyclyl, nitrogen-containing 5 or 6-membered non-aromatic heterocyclyl, and nitrogen- containing 6-membered non-aromatic heterocyclyl. 4- to 6- Membered Non- Aromatic Heterocvclyl - In one aspect, "heterocyclyl," "non-aromatic heterocyclyl," "4- to 7-membered non-aromatic heterocyclyl," and "4- to 6-membered heterocyclyl" may be 4- to 6-membered non-aromatic heterocyclyl. The term "4- to 6-membered non-aromatic heterocyclyl" refers to a non-aromatic, monocyclic ring containing 4 to 6 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and of which a -CH2- group may be optionally replaced by a -C(O)- group. Unless otherwise specified, "4- to 6-membered non-aromatic heterocyclyl" groups may be carbon or nitrogen linked. Ring nitrogen atoms may be optionally oxidized to form an N-oxide. Ring sulfur atoms may be optionally oxidized to form S-oxides. Illustrative examples of "4- to 6-membered non-aromatic heterocyclyl" include azetidin-1-yl, dioxidotetrahydrothiophenyl, 2,4-dioxoimidazolidinyl, 3,5-dioxopiperidinyl, morpholinyl, oxetanyl, oxoimidazolidinyl, 3-oxo-1-piperazinyl, 2- oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-oxotetrahydrofuranyl, piperazinyl, piperidyl, 2H- pyranyl, pyrrolidinyl, , tetrahydrofuranyl, tetrahydropyranyl, , thiazolidinyl, and thiomorpholinyl.
5 or 6-Membered Non- Aromatic Ηeterocvclyl - In one aspect, "heterocyclyl," "non-aromatic heterocyclyl," "5- or 6-membered heterocyclyl," "4- to 7-membered non-aromatic heterocyclyl," "4- to 6-membered heterocyclyl," and "4- to 6-membered non-aromatic heterocyclyl" may be 5 or 6-membered non-aromatic heterocyclyl. The term "5- or 6-membered non-aromatic heterocyclyl" is intended to refer to a saturated or partially saturated, monocyclic, non-aromatic heterocyclyl ring containing 5 or 6 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and which may, unless otherwise specified, be carbon or nitrogen linked, and of which a -CH2- group can optionally be replaced by a -C(O)-. Ring sulfur atoms may be optionally oxidized to form S-oxides. Ring nitrogen atoms may be optionally oxidized to form N-oxides. Illustrative examples of "5 or 6-membered non-aromatic heterocyclyl" include 3,5-dioxopiperidinyl, morpholinyl, 2-oxopyrrolidinyl, oxo- 1,3 -thiazolidinyl, piperazinyl, piperidyl, 2H-pyranyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiomorpholinyl, and thiazolidinyl.
6-Membered Non- Aromatic Ηeterocyclyl -In one aspect, "heterocyclyl," "non-aromatic heterocyclyl," "5- or 6-membered heterocyclyl," "4- to 7-membered non-aromatic heterocyclyl," "4- to 6-membered heterocyclyl," "4- to 6-membered non-aromatic heterocyclyl," and "5 or 6- membered non-aromatic heterocyclyl" may be 6-membered non-aromatic heterocyclyl. The term "6-membered non-aromatic heterocyclyl" is intended to refer to a saturated or partially saturated, monocyclic, non-aromatic heterocyclyl ring containing 6 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and which may, unless otherwise specified, be carbon or nitrogen linked, and of which a -CH2- group can optionally be replaced by a -C(O)-. Ring sulfur atoms may be optionally oxidized to form S-oxides. Ring nitrogen atoms may be optionally oxidized to form N-oxides. Illustrative examples of "6-membered non-aromatic heterocyclyl" include 3,5-dioxopiperidinyl, morpholinyl, piperazinyl, piperidyl, 2H-pyranyl, tetrahydropyranyl, and thiomorpholinyl.
Where a particular R group (e.g. Rla, R10, etc.) is present in a compound of Formula (I) more than once, it is intended that each selection for that R group is independent at each occurrence of any selection at any other occurrence. For example, the -N(R)2 group is intended to encompass: 1) those -N(R)2 groups in which both R substituents are the same, such as those in which both R substituents are, for example, C1-6alkyl; and 2) those -N(R)2 groups in which each R substituent is different, such as those in which one R substituent is, for example, Η, and the other R substituent is, for example, carbocyclyl.
Unless specifically stated, the bonding atom of a group may be any suitable atom of that group; for example, propyl includes prop-1-yl and prop-2-yl.
Effective Amount - As used herein, the phrase "effective amount" means an amount of a compound or composition which is sufficient enough to significantly and positively modify the symptoms and/or conditions to be treated (e.g., provide a positive clinical response). The effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically-acceptable excipient(s)/carrier(s) utilized, and like factors within the knowledge and expertise of the attending physician. In particular, an effective amount of a compound of Formula (I) for use in the treatment of cancer is an amount sufficient to symptomatically relieve in a warm-blooded animal such as man, the symptoms of cancer and myeloproliferative diseases, to slow the progression of cancer and myeloproliferative diseases, or to reduce in patients with symptoms of cancer and myeloproliferative diseases the risk of getting worse.
Leaving Group - As used herein, the phrase "leaving group" is intended to refer to groups readily displaceable by a nucleophile such as an amine nucleophile, and alcohol nucleophile, or a thiol nucleophile. Examples of suitable leaving groups include halo, such as chloro and bromo, and sulfonyloxy group, such as methanesulfonyloxy and toluene-4-sulfonyloxy.
Optionally substituted - As used herein, the phrase "optionally substituted," indicates that substitution is optional and therefore it is possible for the designated group to be either substituted or unsubstituted. In the event a substitution is desired, any number of hydrogens on the designated group may be replaced with a selection from the indicated substituents, provided that the normal valency of the atoms on a particular substituent is not exceeded, and that the substitution results in a stable compound.
In one aspect, when a particular group is designated as being optionally substituted with "one or more" substituents, the particular may be unsubstituted. In another aspect, the particular group may bear one substituent. In another aspect, the particular substituent may bear two substituents. In still another aspect, the particular group may bear three substituents. In yet another aspect, the particular group may bear four substituents. In a further aspect, the particular group may bear one or two substituents. In still a further aspect, the particular group may be unsubstituted, or may bear one or two substituents.
Pharmaceutically Acceptable - As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Protecting Group - As used herein, the term "protecting group" is intended to refer to those groups used to prevent selected reactive groups (such as carboxy, amino, hydroxy, and mercapto groups) from undergoing undesired reactions.
Illustrative examples of suitable protecting groups for a hydroxy group include acyl groups; alkanoyl groups such as acetyl; aroyl groups, such as benzoyl; silyl groups, such as trimethylsilyl; and arylmethyl groups, such as benzyl. The deprotection conditions for the above hydroxy protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively a silyl group such as trimethylsilyl may be removed, for example, by fluoride or by aqueous acid; or an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation in the presence of a catalyst such as palladium-on-carbon.
Illustrative examples of suitable protecting groups for an amino group include acyl groups; alkanoyl groups such as acetyl; alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl, and fert-butoxycarbonyl; arylmethoxycarbonyl groups, such as benzyloxycarbonyl; and aroyl groups, such benzoyl. The deprotection conditions for the above amino protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric, phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid, for example boron trichloride). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group, which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine or 2-hydroxyethylamine, or with hydrazine. Another suitable protecting group for an amine is, for example, a cyclic ether such as tetrahydrofuran, which may be removed by treatment with a suitable acid such as trifluoroacetic acid.
The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art, or they may be removed during a later reaction step or work-up.
With reference to substituent R for illustrative purposes, the following substituent definitions have the indicated meanings:
Figure imgf000022_0001
Figure imgf000023_0001
The compounds discussed herein in many instances were named and/or checked with ACD/Name by ACD/Labs®.
Compounds of Formula (I) may form stable pharmaceutically acceptable acid or base salts, and in such cases administration of a compound as a salt may be appropriate. Examples of acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate, camphorsulfonate, choline, citrate, cyclohexyl sulfamate, diethylenediamine, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethyl- sulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, maleate, methanesulfonate, meglumine, 2-naphthalenesulfonate, nitrate, oxalate, pamoate, persulfate, phenylacetate, phosphate, diphosphate, picrate, pivalate, propionate, quinate, salicylate, stearate, succinate, sulfamate, sulfanilate, sulfate, tartrate, tosylate (p-toluenesulfonate), trifluoroacetate, and undecanoate. Examples of base salts include ammonium salts; alkali metal salts such as sodium, lithium and potassium salts; alkaline earth metal salts such as aluminum, calcium and magnesium salts; salts with organic bases such as dicyclohexylamine salts and N-methyl-D-glucamine; and salts with amino acids such as arginine, lysine, ornithine, and so forth. Also, basic nitrogen-containing groups may be quaternized with such agents as: lower alkyl halides, such as methyl, ethyl, propyl, and butyl halides; dialkyl sulfates such as dimethyl, diethyl, dibutyl; diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl halides; arylalkyl halides such as benzyl bromide and others. Non-toxic physiologically-acceptable salts are preferred, although other salts may be useful, such as in isolating or purifying the product.
The salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion-exchange resin.
Some compounds of Formula (I) may have chiral centers and/or geometric isomeric centers (E- and Z- isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers. The invention further relates to any and all tautomeric forms of the compounds of Formula (I).
It is also to be understood that certain compounds of Formula (I) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms.
Additional embodiments of the invention are as follows. These additional embodiments relate to compounds of Formula (I) and pharmaceutically acceptable salts thereof. Such specific substituents may be used, where appropriate, with any of the definitions, claims or embodiments defined hereinbefore or hereinafter.
Ring A
In one aspect, Ring A is heterocyclyl, wherein said heterocyclyl is optionally substituted on carbon with one or more R2, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R2*;
R2 is selected from halo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -OR2a, -SR2a, -N(R2a)2, -N(R2a)C(O)R2b, -N(R2a)N(R2a)2, -NO2, -N(R2a)OR2a, -ON(R2a)2, -C(O)H, -C(O)R2b, -C(O)2R2a, -C(O)N(R2a)2, -C(O)N(R2a)(OR2a) -OC(O)N(R2a)2, -N(R2a)C(O)2R2a, -N(R2a)C(O)N(R2a)2, -OC(O)R2b, -S(O)R2b, -S(O)2R2b, -S(O)2N(R2a)2,
-N(R2a)S(O)2R2b, -C(R2a)=N(R2a), and -C(R2a)=N(OR2a), wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl may be optionally substituted on carbon with one or more R20, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R20*; R2* in each occurrence is independently selected from C1-6alky 1, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R2b, -C(O)2R2c, -C(O)N(R2a)2, -S(O)R2b, -S(O)2R2b, -S(O)2N(R2a)2,
-C(R2a)=N(R2a), and -C(R2a)=N(OR2a), wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R20*; R2a in each occurrence is independently selected from H, C1-6alky 1, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R20, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R20*;
R2b in each occurrence is selected from C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R20*; R2c in each occurrence is independently selected from C1-6alkyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R20, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R20*; R20 in each occurrence is independently selected from halo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -OR20a, -SR20a, -N(R20a)2, -N(R20a)C(O)R20b, -N(R20a)N(R20a)2, -NO2, -N(R20a)-OR20a, -O-N(R20a)2, -C(O)H, -C(O)R20b, -C(O)2R20a, -C(O)N(R20a)2, -C(O)N(R20a)(OR20a), -OC(O)N(R20a)2, -N(R20a)C(O)2R20a, -N(R20a)C(O)N(R20a)2, -OC(O)R20b, -S(O)R20b, -S(O)2R20b, -S(O)2N(R20a)2, -N(R20a)S(O)2R20b, -C(R20a)=N(R20a), and -C(R20a)=N(OR20a);
R20* in each occurrence is independently selected from C1-6alkyl, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R20b, -C(O)2R20c, -C(O)N(R20a)2, -S(O)R20b, -S(O)2R20b, -S(O)2N(R20a)2, -C(R20a)=N(R20a), and -C(R20a)=N(OR20a); R20a in each occurrence is independently selected from H, C1-6alkyl, carbocyclyl, and heterocyclyl;
R20b in each occurrence is independently selected from C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl; and
R20c in each occurrence is independently selected from C1-6alkyl, carbocyclyl, and heterocyclyl.
In another aspect, Ring A is 6-membered heterocyclyl, wherein said 6-membered heterocyclyl is optionally substituted on carbon with one or more R , and wherein any -NH- moiety of said 6- membered heterocyclyl is optionally substituted with R2*;
R2 is selected from halo, -CN, C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, heterocyclyl, -OR2a, -SR2a, -N(R2a)2, -N(R2a)C(O)R2b, -N(R2a)N(R2a)2, -NO2, -N(R2a)OR2a, -ON(R2a)2, -C(O)H, -C(O)R2b, -C(O)2R2a, -C(O)N(R2a)2, -C(O)N(R2a)(OR2a) -OC(O)N(R2a)2,
-N(R2a)C(O)2R2a, -N(R2a)C(O)N(R2a)2, -OC(O)R2b, -S(O)R2b, -S(O)2R2b, -S(O)2N(R2a)2, -N(R2a)S(O)2R2b, -C(R2a)=N(R2a), and -C(R2a)=N(OR2a), wherein said d_6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more R20, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R20*; R2* in each occurrence is independently selected from C1-6alkyl, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R2b, -C(O)2R2c, -C(O)N(R2a)2, -S(O)R2b, -S(O)2R2b, -S(O)2N(R2a)2, -C(R2a)=N(R2a), and -C(R2a)=N(OR2a), wherein said d_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R20, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R20*; R2a in each occurrence is independently selected from H, C1-6alkyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 20 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 20*
R2b in each occurrence is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R20*; R2c in each occurrence is independently selected from C1-6alkyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R20, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R20*;
R20 in each occurrence is independently selected from halo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -OR20a, -SR20a, -N(R20a)2, -N(R20a)C(O)R20b, -N(R20a)N(R20a)2, -NO2, -N(R20a)-OR20a, -O-N(R20a)2, -C(O)H, -C(O)R20b, -C(O)2R20a, -C(O)N(R20a)2, -C(O)N(R20a)(OR20a), -OC(O)N(R20a)2, -N(R20a)C(O)2R20a, -N(R20a)C(O)N(R20a)2, -OC(O)R20b, -S(O)R20b, -S(O)2R20b, -S(O)2N(R20a)2, -N(R20a)S(O)2R20b, -C(R20a)=N(R20a), and -C(R20a)=N(OR20a);
R20* in each occurrence is independently selected from C1-6alky 1, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R20b, -C(O)2R20c, -C(O)N(R20a)2, -S(O)R20b, -S(O)2R20b, -S(O)2N(R20a)2, -C(R20a)=N(R20a), and -C(R20a)=N(OR20a); R20a in each occurrence is independently selected from H, C1-6alkyl, carbocyclyl, and heterocyclyl;
R20b in each occurrence is independently selected from C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl; and
R20c in each occurrence is independently selected from C1-6alkyl, carbocyclyl, and heterocyclyl. In still another aspect, Ring A is 4- to 6-membered heterocyclyl, wherein said 4- to 6-membered heterocyclyl is optionally substituted on carbon with one or more R , and wherein any -NH- moiety of said 4- to 6-membered heterocyclyl is optionally substituted with R2*;
R2 in each occurrence is independently selected from halo, -CN, C1-6alkyl, -OR2a, -N(R2a)2,
-C(O)N(R2a)2, -N(R2a)C(O)R2b, and -N(R2a)C(O)2R2a, wherein said C1-6alkyl is optionally substituted with one or more R20;
R2* is C1-6alkyl;
R2a in each occurrence is independently selected from H and C1-6alkyl;
R2b is C1-6alkyl;
R20 in each occurrence is independently selected from halo, -CN, 4- to 6-membered heterocyclyl, -OR20a, -N(R20a)2, -C(O)2R20a, -C(O)N(R20a)2, -N(R20a)C(O)2R20a, and -N(R20a)S(O)2R20b;
R20a in each occurrence is independently selected from H and C1-6alkyl; and
R20b is C1-6alkyl.
In yet another aspect, Ring A is 4- to 7-membered non-aromatic heterocyclyl, wherein said 4- to 7-membered non-aromatic heterocyclyl is optionally substituted on carbon with one or more R , and wherein any -NH- moiety of said 4- to 7-membered heterocyclyl is optionally substituted with R2*;
R2 in each occurrence is independently selected from halo, -CN, C1-6alkyl, -OR2a, -N(R2a)2,
-C(O)N(R2a)2, -N(R2a)C(O)R2b, and -N(R2a)C(O)2R2a, wherein said C1-6alkyl is optionally substituted with one or more R20;
R2* is C1-6alkyl;
R2a in each occurrence is independently selected from H and C1-6alkyl;
R2b is C1-6alkyl;
R20 in each occurrence is independently selected from halo, -CN, 4- to 6-membered heterocyclyl, -OR20a, -N(R20a)2, -C(O)2R20a, -C(O)N(R20a)2, -N(R20a)C(O)2R20a, and -N(R20a)S(O)2R20b;
R20a in each occurrence is independently selected from H and C1-6alky 1; and
R20b is C1-6alkyl.
In a further aspect, Ring A is 4- to 6-membered non-aromatic heterocyclyl, wherein said 4- to 6- membered non-aromatic heterocyclyl is optionally substituted on carbon with one or more R2, and wherein any -NH- moiety of said 4- to 6-membered non-aromatic heterocyclyl is optionally substituted with R ;
R2 in each occurrence is independently selected from halo, -CN, C1-6alkyl, -OR2a, -N(R2a)2,
-C(O)N(R2a)2, -N(R2a)C(O)R2b, and -N(R2a)C(O)2R2a, wherein said C1-6alkyl is optionally substituted with one or more R20; R2* is C1-6alkyl;
R2a in each occurrence is independently selected from H and C1-6alkyl;
R2b is C1-6alkyl;
R20 in each occurrence is independently selected from halo, -CN, 4- to 6-membered heterocyclyl,
-OR20a, -N(R20a)2, -C(O)2R20a, -C(O)N(R20a)2, -N(R20a)C(O)2R20a , and -N(R20a)S(O)2R20b; R20a in each occurrence is independently selected from H and C1-6alkyl; and
R20b is C1-6alkyl.
In still a further aspect, Ring A is heterocyclyl, wherein any -NH- moiety of said heterocyclyl is optionally substituted with R2*; and R2* in each occurrence is independently selected from C1-6alkyl.
In yet a further aspect, Ring A is 5- or 6-membered heterocyclyl, wherein any -NH- moiety of said 5- or 6-membered heterocyclyl is optionally substituted with R2*; and R2* in each occurrence is independently selected from C1-6alkyl.
In one aspect, Ring A is 5- or 6-membered non-aromatic heterocyclyl, wherein any -NH- moiety of said 5- or 6-membered non-aromatic heterocyclyl is optionally substituted with R *; and R in each occurrence is independently selected from C1-6alkyl.
In another aspect, Ring A is selected from azetidinyl, morpholinyl, 1 ,4-oxazepanyl, piperazinyl, piperidinyl, and pyrrolidinyl, wherein said azetidinyl, morpholinyl, 1 ,4-oxazepanyl, piperazinyl, piperidinyl, and pyrrolidinyl are optionally substituted on carbon with one or more R , and wherein any -NH- moiety of said piperazinyl is optionally substituted with R2*; R' is halo, -CN, C1-6alkyl, -N(RZ3)2, -OR 2a ,
Figure imgf000030_0001
and j
Figure imgf000030_0002
wherein said C1-6alky 1 in each occurrence is optionally and independently substituted with one or more R20;
R2a in each occurrence is independently selected from H and C1-6alkyl;
R2b is C1-6alkyl; R2* is C1-6alkyl;
R20 in each occurrence is independently selected from halo, -CN, azetidinyl, -OR20a, -N(R20a)2,
-C(O)2R20a, -C(O)N(R20a)2, -N(H)C(O)2R203, and -N(H)S(O)2R20";
R20a in each occurrence is independently selected from H and C1-6alky 1; and
R20b is C1-6alkyl
In another aspect, Ring A is selected from azetidinyl, morpholinyl, 1 ,4-oxazepanyl, piperazinyl, piperidinyl, and pyrrolidinyl, wherein said azetidinyl, morpholinyl, 1 ,4-oxazepanyl, piperazinyl, piperidinyl, and pyrrolidinyl are optionally substituted on carbon with one or more R , and wherein any -NH- moiety of said piperazinyl is optionally substituted with R ; R2 is fluoro, -CN, methyl, ethyl, -N(R2a)2, -0R2a, -C(O)N(R2a)2, -N(H)C(O)R2b, and
-N(R2a)C(O)2R2a, wherein said methyl and ethyl in each occurrence is optionally and independently substituted with one or more R20;
R2a in each occurrence is independently selected from H, tert-butyl, ethyl, and methyl;
R2b is methyl; R2* is methyl;
R20 in each occurrence is independently selected from fluoro, -CN, azetidinyl, -OR20a, -N(R20a)2,
-C(O)2R203, -C(O)N(R20a)2, -N(H)C(O)2R203, and -N(H)S(O)2R20b;
R20a in each occurrence is independently selected from H, tert-butoxy, ethyl, and methyl; and
R20b is methyl.
In still another aspect, Ring A is selected from morpholinyl and piperazinyl, wherein any -NH- moiety of said morpholinyl and piperazinyl is optionally substituted with R *; and
R2* is independently selected from C1-6alky!.
In yet another aspect, Ring A is selected from morpholinyl and piperazinyl, wherein any -NH- moiety of said morpholinyl and piperazinyl is optionally substituted with R2*; and R2* is independently selected from methyl.
In a further aspect, Ring A is selected from 3-(acetylamino)azetidin-1-yl,
3 -(acetylamino)pyrrolidin- IyI, 3 -(amionmethyl)piperidin- 1 -yl, 3 -aminopiperidin- 1 -yl, 2-(azetidin-1-ylmethyl)morpholin-4-yl, 3-cyanoazetidin-1-yl, 2-(cyanomethyl)morpholin-4-yl, 3-(cyanomethyl)morpholin-4-yl, 2-(cyanomethyl)piperidin-1-yl, 3-cyanopiperidin-1-yl, 4-cyanopiperidin-1-yl, 2-[(diethylamino)methyl]morpholin-4-yl, 3,3-difluoroazetidin-1-yl, 2-(difluoromethyl)morpholin-4-yl, 3-(difluoromethyl)morpholin-4-yl, 3,3-difluropiperidin-1-yl, 4,4-difluoropiperidin- 1 -yl, 3 ,3 -difluoropyrrolidin- 1 -yl, 3 -(dimethylamino)azetidin- 1 -yl, 3-[(dimethylamino)carbonyl]methylmorpholin-4-yl, 3-[(dimethylamino)carbonyl]morpholin- 4-yl, 3 - [(dimethylamino)methyl]piperidin- 1 -yl, 3 -(dimethylamino)pyrrolidin- 1 -yl, 2,2-dimethylmorpholin-4-yl, 2,6-dimethylmorpholin-4-yl, 3,3-dimethylmorpholin-4-yl, 3-{[(ethoxycarbonyl)amino]methyl}morpholin-4-yl, 2-ethylmorpholin-4-yl, 3-ethylmorpholin- 4-yl, 3-ethyoxypyrrolidin-1-yl, 3-fluoroazetidin-1-yl, 3-fluropiperidin-1-yl, 4-fluoropiperidin-1-yl, 3-hydroxyazetidin-1-yl, 3-(2-hydroxyethyl)morpholin-4-yl, 2-(hydroxymethyl)azetidin- 1 -yl, 3 -hydroxy-3 -methylazetidin- 1 -yl, 2-(hydroxymethyl)morpholin-4-yl, 3-(hydroxymethyl)morpholin-4-yl, 3 -hydroxy-3 -methylpiperidin- 1 -yl, 4-hydroxy-4-methylpiperidin- 1 -yl, 2-(hydroxymethyl)piperidin- 1 -yl, 3 -hydroxypiperidin- 1 -yl, 4-hydroxypiperidin- 1 -yl, 3-methoxyazetidin-1-yl, 3-[(methoxycarbonyl)methyl]morpholin-4-yl, 2-(methoxymethyl)morpholin-4-yl, 3-(methoxymethyl)morpholin-4-yl, 3 -(methoxymethyl)piperidin- 1 -yl, 3 -methoxypiperidin- 1 -yl, 4-methoxypiperidin- 1 -yl, 3-(methylamino)azetidin- 1 -yl, 3-[(methylamino)carbonyl]morpholin-4-yl, 3-(methylamino)pyrrolidin- 1 -yl, 2-methylmorpholin-4-yl, 3-methylmorpholin-4-yl, 4-methyl-3-oxopiperazin- 1-yl, 3- {[(methylsulfonyl)amino]methyl}morpholin-4-yl, morpholin-4-yl, 4-methylpiperazin-1-yl, 1 ,4-oxazepan-4-yl, 3- { [(t-butoxycarbonyl)amino]methyl}piperidin- 1 -yl, and 3-[(?-butoxycarbonyl)amino]piperidin-1-yl.
In still a further aspect, Ring A is morpholin-4-yl. Ring B
In one aspect, Ring B is selected from carbocyclyl and heterocyclyl, wherein said carbocyclyl and heterocyclyl are optionally substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R *; R4 is selected from halo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -OR4a, -SR4a, -N(R4a)2, -N(R4a)C(O)R4b, -N(R4a)N(R4a)2, -NO2, -N(R4a)-OR4a, -O-N(R4a)2, -C(O)H, -C(O)R4b, -C(O)2R4a, -C(O)N(R4a)2, -C(O)N(R4a)(OR4a) -OC(O)N(R4a)2, -N(R4a)C(O)2R4a, -N(R4a)C(O)N(R4a)2, -OC(O)R4b, -S(O)R4b, -S(O)2R4b, -S(O)2N(R4a)2, -N(R4a)S(O)2R4b, -C(R4a)=N(R4a), and -C(R4a)=N(OR4a), wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more R40, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R40*; R4* in each occurrence is independently selected from d_6alkyl, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R4b, -C(O)2R4c, -C(O)N(R4a)2, -S(O)R4b, -S(O)2R4b, -S(O)2N(R4a)2, -C(R4a)=N(R4a), and -C(R4a)=N(OR4a), wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R40*; R4a in each occurrence is independently selected from H, C1-6alky 1, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R40, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R40*;
R4b in each occurrence is selected from C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R40*; R4c in each occurrence is independently selected from C1-6alky 1, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R40*; R40 in each occurrence is independently selected from halo, -CN, C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, heterocyclyl, -OR40a, -SR40a, -N(R40a)2, -N(R40a)C(O)R40b, -N(R40a)N(R40a)2, -NO2, -N(R40a)-OR40a, -O-N(R40a)2, -C(O)H, -C(O)R40b, -C(O)2R40a,
-C(O)N(R40a)2, -C(O)N(R40a)(OR40a), -OC(O)N(R40a)2, -N(R40a)C(O)2R40a, -N(R40a)C(O)N(R40a)2,
-OC(O)R40b, -S(O)R40b, -S(O)2R40b, -S(O)2N(R40a)2, -N(R40a)S(O)2R40b, -C(R40a)=N(R40a), and
-C(R40a)=N(OR40a);
R40* in each occurrence is independently selected from C1-6alky 1, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R40b, -C(O)2R40c, -C(O)N(R40a)2, -S(O)R40b, -S(O)2R40b, -S(O)2N(R40a)2,
-C(R40a)=N(R40a), and -C(R40a)=N(OR40a);
R40a in each occurrence is independently selected from H, C1-6alky 1, carbocyclyl, and heterocyclyl;
R40b in each occurrence is independently selected from C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl; and
R40c in each occurrence is independently selected from C1-6alkyl, carbocyclyl, and heterocyclyl.
In another aspect, Ring B is heterocyclyl, wherein said heterocyclyl is optionally substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R4 * ;
R4 is selected from halo, -CN, C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, heterocyclyl, -OR4a, -SR4a, -N(R4a)2, -N(R4a)C(O)R4b, -N(R4a)N(R4a)2, -NO2, -N(R4a)-OR4a, -O-N(R4a)2, -C(O)H, -C(O)R4b, -C(O)2R4a, -C(O)N(R4a)2, -C(O)N(R4a)(OR4a) -OC(O)N(R4a)2, -N(R4a)C(O)2R4a, -N(R4a)C(O)N(R4a)2, -OC(O)R4b, -S(O)R4b, -S(O)2R4b, -S(O)2N(R4a)2, -N(R4a)S(O)2R4b, -C(R4a)=N(R4a), and -C(R4a)=N(OR4a), wherein said C1-6alkyl, C2_6alkenyl,
C2_6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more R40, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R40*; R4* in each occurrence is independently selected from C1-6alky 1, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R4b, -C(O)2R4c, -C(O)N(R4a)2, -S(O)R4b, -S(O)2R4b, -S(O)2N(R4a)2, -C(R4a)=N(R4a), and -C(R4a)=N(OR4a), wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R40*; R4a in each occurrence is independently selected from H, C1-6alky!, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R40, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R40*;
R4b in each occurrence is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R40*; R4c in each occurrence is independently selected from C1-6alky 1, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R40*; R40 in each occurrence is independently selected from halo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -OR40a, -SR40a, -N(R40a)2, -N(R40a)C(O)R40b, -N(R40a)N(R40a)2, -NO2, -N(R40a)-OR40a, -O-N(R40a)2, -C(O)H, -C(O)R40b, -C(O)2R40a, -C(O)N(R40a)2, -C(O)N(R40a)(OR40a), -OC(O)N(R40a)2, -N(R40a)C(O)2R40a, -N(R40a)C(O)N(R40a)2, -OC(O)R40b, -S(O)R40b, -S(O)2R40b, -S(O)2N(R40a)2, -N(R40a)S(O)2R40b, -C(R40a)=N(R40a), and -C(R40a)=N(OR40a); R40* in each occurrence is independently selected from C1-6alky 1, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R40b, -C(O)2R40c, -C(O)N(R40a)2, -S(O)R40b, -S(O)2R40b, -S(O)2N(R40a)2, -C(R40a)=N(R40a), and -C(R40a)=N(OR40a);
R40a in each occurrence is independently selected from H, C1-6alkyl, carbocyclyl, and heterocyclyl; R40b in each occurrence is independently selected from C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl; and R40c in each occurrence is independently selected from C1-6alkyl, carbocyclyl, and heterocyclyl.
In still another aspect, Ring B is 6-membered heterocyclyl, wherein said 6-membered heterocyclyl is optionally substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R *;
R4 is selected from halo, -CN, C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, heterocyclyl, -OR4a, -SR4a, -N(R4a)2, -N(R4a)C(O)R4b, -N(R4a)N(R4a)2, -NO2, -N(R4a)-OR4a, -O-N(R4a)2, -C(O)H, -C(O)R4b, -C(O)2R4a, -C(O)N(R4a)2, -C(O)N(R4a)(OR4a) -OC(O)N(R4a)2, -N(R4a)C(O)2R4a, -N(R4a)C(O)N(R4a)2, -OC(O)R4b, -S(O)R4b, -S(O)2R4b, -S(O)2N(R4a)2, -N(R4a)S(O)2R , -C(R4a)=N(R4a), and -C(R4a)=N(0R4a), wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more R40, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R40*; R4* in each occurrence is independently selected from C1-6alky 1, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R4b, -C(O)2R4c, -C(O)N(R4a)2, -S(O)R4b, -S(O)2R4b, -S(O)2N(R4a)2, -C(R4a)=N(R4a), and -C(R4a)=N(OR4a), wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R40*; R4a in each occurrence is independently selected from H, C1-6alkyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R40, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R40*;
R4b in each occurrence is selected from d_6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R40*;
R4c in each occurrence is independently selected from C1-6alky 1, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R40, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R40*; R40 in each occurrence is independently selected from halo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -OR40a, -SR40a, -N(R40a)2, -N(R40a)C(O)R40b, -N(R40a)N(R40a)2, -NO2, -N(R40a)-OR40a, -O-N(R40a)2, -C(O)H, -C(O)R40b, -C(O)2R40a, -C(O)N(R40a)2, -C(O)N(R40a)(OR40a), -OC(O)N(R40a)2, -N(R40a)C(O)2R40a, -N(R40a)C(O)N(R40a)2, -OC(O)R40b, -S(O)R40b, -S(O)2R40b, -S(O)2N(R40a)2, -N(R40a)S(O)2R40b, -C(R40a)=N(R40a), and -C(R40a)=N(OR40a);
R40* in each occurrence is independently selected from C1-6alky 1, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R40b, -C(O)2R40c, -C(O)N(R40a)2, -S(O)R40b, -S(O)2R40b, -S(O)2N(R40a)2, -C(R40a)=N(R40a), and -C(R40a)=N(OR40a); R40a in each occurrence is independently selected from H, C1-6alkyl, carbocyclyl, and heterocyclyl; R40b in each occurrence is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl; and R40c in each occurrence is independently selected from C1-6alkyl, carbocyclyl, and heterocyclyl.
In yet another aspect, Ring B is heterocyclyl, wherein said heterocyclyl is optionally substituted oonn ccaarrbboonn λ with one or more R ; and R4 is halo.
In a further aspect, Ring B is 6-membered heterocyclyl, wherein said or 6-membered heterocyclyl is optionally substituted on carbon with one or more R4; and R4 is halo.
In still a further aspect, Ring B is 6-membered heteroaryl, wherein said 6-membered heteroaryl is substituted on carbon with at least one R4; and R4 is halo.
In yet a further aspect, Ring B is 6-membered heteroaryl, wherein said 6-membered heteroaryl is substituted on carbon with one or more R ; and R4 is halo.
In one aspect, Ring B is selected from pyridinyl and pyrimidinyl, wherein said pyridinyl and pyrimidinyl are optionally substituted on carbon with one or more R4; and R4 is halo.
In another aspect, Ring B is selected from pyridinyl and pyrimidinyl, wherein said pyridinyl and pyrimidinyl are optionally substituted with one or more R ; and R4 is fluoro.
In still another aspect, Ring B is pyridinyl, wherein said pyridinyl is optionally substituted on carbon with one or more R4; and R4 is halo. In yet another aspect, Ring B is pyrimidinyl, wherein said pyrimidinyl is optionally substituted on carbon with one or more R4; and R4 is halo.
In a further aspect, Ring B is selected from pyridin-2-yl and pyrimidin-2-yl, wherein said pyridin-2-yl and pyrimidin-2-yl are optionally substituted with one or more R ; and R4 is fluoro.
In still a further aspect, Ring B is selected from 3,5-difluoropyridin-2-yl, 5-fluoropyridin-2-yl, and 5-fluoropyrimidin-2-yl.
In yet a further aspect, Ring B is selected from 5-fluoropyridin-2-yl and 5-fluoropyrimidin-2-yl.
In one aspect, Ring B is 5-fluoropyridin-2-yl.
In another aspect, Ring B is 5-fluoropyrimidin-2-yl.
X
In one aspect, X is selected from -O- and -NH-.
In another aspect, X is -O-.
In still another aspect, X is -NH-.
R1
In one aspect, R1 is selected from H, halo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -ORla, -SRla, -N(Rla)2, -N(Rla)C(O)Rlb, -N(Rla)N(Rla)2, -NO2, -N(Rla)ORla, -ON(Rla)2, -C(O)H, -C(O)Rlb, -C(O)2R13, -C(O)N(Rla)2, -C(O)N(Rla)(ORla), -OC(O)N(Rla)2, -N(Rla)C(O)2Rla, -N(Rla)C(O)N(Rla)2, -OC(O)Rlb, -S(O)Rlb, -S(O)2Rlb, -S(O)2N(Rla)2, -N(Rla)S(O)2Rlb, -C(Rla)=N(Rla), and -C(Rla)=N(ORla), wherein said C1-6alkyl, C2_6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more R10, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R10*; Rla in each occurrence is independently selected from H, C1-6alkyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R10*;
Rlb in each occurrence is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R10, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R10*; R10 in each occurrence is independently selected from halo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -OR10a, -SR10a, -N(R10a)2, -N(R10a)C(O)R10b, -N(R10a)N(R10a)2, -NO2, -N(R10a)-OR10a, -O-N(R10a)2, -C(O)H, -C(O)R10b, -C(O)2R10a, -C(O)N(R10a)2, -C(O)N(R10a)(OR10a), -OC(O)N(R10a)2, -N(R10a)C(O)2R10a, -N(R10a)C(O)N(R10a)2, -OC(O)R10b, -S(O)R10b, -S(O)2R10b, -S(O)2N(R10a)2, -N(R10a)S(O)2R10b, -C(R10a)=N(R10a), and -C(R10a)=N(OR10a);
R10* in each occurrence is independently selected from C1-6alky 1, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R10b, -C(O)2R10c, -C(O)N(R10a)2, -S(O)R10b, -S(O)2R10b, -S(O)2N(R10a)2, -C(R10a)=N(R10a), and -C(R10a)=N(OR10a); R10a in each occurrence is independently selected from H, C1-6alkyl, carbocyclyl, and heterocyclyl;
R1Ob in each occurrence is independently selected from C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl; and
R1Oc in each occurrence is independently selected from C1-6alkyl, carbocyclyl, and heterocyclyl.
In another aspect, R1 is selected from C1-6alkyl, 3- to 6-membered carbocyclyl, and 5- or 6- membered heterocyclyl, wherein said C1-6alkyl, 3- to 6-membered carbocyclyl, and 5- or 6- membered heterocyclyl are optionally substituted on carbon with one or more R ; R10 in each occurrence is independently selected from halo, 3- to 6-membered carbocyclyl, 5- or 6-membered heterocyclyl, and -OR10a, wherein said 3- to 6-membered carbocyclyl and 5- or 6- membered heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more Ra;
R10a is selected from C1-6alkyl and 3- to 6-membered carbocyclyl;
Ra in each occurrence is independently selected from halo and -ORm; and
Rm is C1-6alkyl.
In still another aspect, R1 is selected from cyclopropyl, ethyl, methyl, phenyl, and thiophenyl, wherein said cyclopropyl, ethyl, methyl, phenyl, and thiophenyl are optionally substituted with one or more R10;
R10 in each occurrence is independently selected from fluoro, -OR10a, cyclohexyl, imidazolyl, phenyl, and pyridinyl, wherein said cyclohexyl, imidazolyl, phenyl, and pyridinyl in each occurrence are optionally and independently substituted on carbon with one or more Ra;
R10a in each occurrence is independently selected from methyl and phenyl; and
Ra in each occurrence is independently selected from fluoro and methoxy.
In yet another aspect, R is selected from 2-cyclohexylethyl, cyclopropyl,
2-(2,4-difluorophenyl)ethyl, 2-(2,6-difluorophenyl)ethyl, 2-(3 ,4-difluorophenyl)ethyl, 2-(3,5-difluorophenyl)ethyl, 2-(3,5-dimethoxyphenyl)ethyl, 4-fluorophenyl, 2-(3-fluorophenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2-(1H-imidazol-2-yl)ethyl, 4-methoxyphenyl, methyl, 2-phenylethyl, phenyloxymethyl, 2-pyridin-4-ylethyl, and thiophen-2-yl.
In a further aspect, R1 is C1-6alkyl.
In yet a further aspect, R1 is methyl.
R2
In one aspect, R3 is selected from Η, halo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -OR3a, -SR3a, -N(R3a)2, -N(R3a)C(O)R3b, -N(R3a)N(R3a)2, -NO2, -N(R3a)-OR3a, -O-N(R3a)2, -C(O)H, -C(O)R3b, -C(O)2R3a, -C(O)N(R3a)2, -C(O)N(R3a)(OR3a), -OC(O)N(R3a)2, -N(R3a)C(O)2R3, -N(R3a)C(O)N(R3a)2, -OC(O)R3b, -S(O)R3b, -S(O)2R3b, -S(O)2N(R3a)2, -N(R3a)S(O)2R3b, -C(R3a)=N(R3a), and -C(R3a)=N(OR3a), wherein said d_6alkyl, C2_6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more R30, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R30*; R3a in each occurrence is independently selected from H, C1-6alkyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R30*;
R3b in each occurrence is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R30, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R30*; R30 in each occurrence is independently selected from halo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -OR30a, -SR30a, -N(R30a)2, -N(R30a)C(O)R30b, -N(R30a)N(R30a)2, -NO2, -N(R30a)-OR30a, -O-N(R30a)2, -C(O)H, -C(O)R30b, -C(O)2R30a, -C(O)N(R30a)2, -C(O)N(R30a)(OR30a), -OC(O)N(R30a)2, -N(R30a)C(O)2R30a, -N(R30a)C(O)N(R30a)2, -OC(O)R30b, -S(O)R30b, -S(O)2R30b, -S(O)2N(R30a)2, -N(R30a)S(O)2R30b, -C(R30a)=N(R30a), and -C(R30a)=N(OR30a);
R30* in each occurrence is independently selected from C1-6alky 1, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R30b, -C(O)2R30c, -C(O)N(R30a)2, -S(O)R30b, -S(O)2R30b, -S(O)2N(R30a)2, -C(R30a)=N(R30a), and -C(R30a)=N(OR30a); R30a in each occurrence is independently selected from H, C1-6alkyl, carbocyclyl, and heterocyclyl;
R30b in each occurrence is independently selected from C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl; and
R30c in each occurrence is independently selected from C1-6alkyl, carbocyclyl, and heterocyclyl.
In another aspect, R3 is selected from C1-6alkyl, wherein said C1-6alkyl is optionally substituted with one or more R ;
R30 in each occurrence is independently selected from halo, -CN, -OR30a; -C(O)N(R30a)2,
-S(O)2R30b, and -S(O)2N(R30a)2;
R30a in each occurrence is independently selected from H and C1-6alkyl; and R30b is C1-6alkyl. In still another aspect, R3 is selected from methyl and ethyl, wherein said methyl and and ethyl are optionally substituted with one or more R30,
R30 in each occurrence is independently selected from fluoro, -CN, and -OR30a, -C(O)N(R30a)2, -S(O)2N(R30a)2, and -S(O)2Me; and R a is in each occurrence is independently selected from H, methyl, and ethyl.
In yet another aspect, R3 is C1-6alkyl.
In a further aspect, R3 is methyl.
In still a further aspect, R3 is selected from (aminocarbonyl)methyl, cyanomethyl, 1 , 1 -difluoro-2-hydroxyethyl, [(dimethylamino)carbonyl]methyl, (dimethylaminosulfonyl)methyl, ethoxymethyl, 1 -hydroxy ethyl, 2-hydroxy ethyl, 1-methoxy ethyl, methoxymethyl, methyl, [(methylamino)carbonyl] methyl, and (methylsulfonyl)methyl.
Ring A, Ring B, X, R1, and R-
In one aspect, Ring A is heterocyclyl, wherein said heterocyclyl is optionally substituted on carbon with one or more R2, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R2*; Ring B is heterocyclyl, wherein said heterocyclyl is optionally substituted on carbon with one or more R4, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R4*; X is selected from -O- and -NH-;
R1 is selected from H, halo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -ORla, -SRla, -N(Rla)2, -N(Rla)C(O)Rlb, -N(Rla)N(Rla)2, -NO2, -N(Rla)ORla, -0N(Rla)2, -C(O)H, -C(O)Rlb, -C(O)2R13, -C(O)N(Rla)2, -C(O)N(Rla)(ORla), -OC(O)N(Rla)2,
-N(Rla)C(O)2Rla, -N(Rla)C(O)N(Rla)2, -OC(O)Rlb, -S(O)Rlb, -S(O)2Rlb, -S(O)2N(Rla)2, -N(Rla)S(O)2Rlb, -C(Rla)=N(Rla), and -C(Rla)=N(ORla), wherein said C1-6alkyl, C2_6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more R10, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R10*; Rla in each occurrence is independently selected from H, C1-6alkyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 10 , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 10*
Rlb in each occurrence is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R10*; R2 is selected from halo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -OR2a, -SR2a, -N(R2a)2, -N(R2a)C(O)R2b, -N(R2a)N(R2a)2, -NO2, -N(R2a)OR2a, -ON(R2a)2, -C(O)H, -C(O)R2b, -C(O)2R23, -C(O)N(R2a)2, -C(O)N(R2a)(OR2a) -OC(O)N(R2a)2, -N(R2a)C(O)2R2a, -N(R2a)C(O)N(R2a)2, -OC(O)R2b, -S(O)R2b, -S(O)2R2b, -S(O)2N(R2a)2,
-N(R2a)S(O)2R2b, -C(R2a)=N(R2a), and -C(R2a)=N(OR2a), wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more R20, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R20*; R2* in each occurrence is independently selected from C1-6alky 1, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R2b, -C(O)2R2c, -C(O)N(R2a)2, -S(O)R2b, -S(O)2R2b, -S(O)2N(R2a)2,
-C(R2a)=N(R2a), and -C(R2a)=N(OR2a), wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R20*; R2a in each occurrence is independently selected from H, C1-6alky 1, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R20, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R20*;
R2b in each occurrence is selected from C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R20*; R2c in each occurrence is independently selected from C1-6alkyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R20, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R20*; R3 is selected from H, halo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -OR3a, -SR3a, -N(R3a)2, -N(R3a)C(O)R3b, -N(R3a)N(R3a)2, -NO2, -N(R3a)-OR3a, -O-N(R3a)2, -C(O)H, -C(O)R3b, -C(O)2R3a, -C(O)N(R3a)2, -C(O)N(R3a)(OR3a), -OC(O)N(R3a)2, -N(R3a)C(O)2R3, -N(R3a)C(O)N(R3a)2, -OC(O)R3b, -S(O)R3b, -S(O)2R3b, -S(O)2N(R3a)2, -N(R3a)S(O)2R3b, -C(R3a)=N(R3a), and -C(R3a)=N(OR3a), wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more R30, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R30*; R3a in each occurrence is independently selected from H, C1-6alky 1, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R30, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R30*;
R3b in each occurrence is selected from C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R30*; R4 is selected from halo, -CN, C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, heterocyclyl, -OR4a, -SR4a, -N(R4a)2, -N(R4a)C(O)R4b, -N(R4a)N(R4a)2, -NO2, -N(R4a)-OR4a, -O-N(R4a)2, -C(O)H, -C(O)R4b, -C(O)2R4a, -C(O)N(R4a)2, -C(O)N(R4a)(OR4a) -OC(O)N(R4a)2, -N(R4a)C(O)2R4a, -N(R4a)C(O)N(R4a)2, -OC(O)R4b, -S(O)R4b, -S(O)2R4b, -S(O)2N(R4a)2, -N(R4a)S(O)2R4b, -C(R4a)=N(R4a), and -C(R4a)=N(OR4a), wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more R40, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R40*; R4* in each occurrence is independently selected from C1-6alkyl, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R4b, -C(O)2R4c, -C(O)N(R4a)2, -S(O)R4b, -S(O)2R4b, -S(O)2N(R4a)2, -C(R4a)=N(R4a), and -C(R4a)=N(OR4a), wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R40*; R4a in each occurrence is independently selected from H, C1-6alky 1, carbocyclyl, and heterocyclyl, wherein said C1-6alky!, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R40, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R40*; R4b in each occurrence is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R40, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R40*;
R4c in each occurrence is independently selected from C1-6alkyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R40*;
R10 in each occurrence is independently selected from halo, -CN, C1-6alkyl, C2-6alkenyl,
C2-6alkynyl, carbocyclyl, heterocyclyl, -OR10a, -SR10a, -N(R10a)2, -N(R10a)C(O)R10b, -N(R10a)N(R10a)2, -NO2, -N(R10a)-OR10a, -O-N(R10a)2, -C(O)H, -C(O)R10b, -C(O)2R10a,
-C(O)N(R10a)2, -C(O)N(R10a)(OR10a), -OC(O)N(R10a)2, -N(R10a)C(O)2R10a, -N(R10a)C(O)N(R10a)2,
-OC(O)R10b, -S(O)R10b, -S(O)2R10b, -S(O)2N(R10a)2, -N(R10a)S(O)2R10b, -C(R10a)=N(R10a), and
-C(R10a)=N(OR10a);
R10* in each occurrence is independently selected from C1-6alky 1, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R10b, -C(O)2R10c, -C(O)N(R10a)2, -S(O)R10b, -S(O)2R10b, -S(O)2N(R10a)2,
-C(R10a)=N(R10a), and -C(R10a)=N(OR10a);
R10a in each occurrence is independently selected from H, C1-6alky 1, carbocyclyl, and heterocyclyl;
R1Ob in each occurrence is independently selected from C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl;
R1Oc in each occurrence is independently selected from H, C1-6alkyl, carbocyclyl, and heterocyclyl;
R20 in each occurrence is independently selected from halo, -CN, C1-6alkyl, C2_6alkenyl,
C2_6alkynyl, carbocyclyl, heterocyclyl, -OR20a, -SR20a, -N(R20a)2, -N(R20a)C(O)R20b, -N(R20a)N(R20a)2, -NO2, -N(R20a)-OR20a, -O-N(R20a)2, -C(O)H, -C(O)R20b, -C(O)2R20a,
-C(O)N(R20a)2, -C(O)N(R20a)(OR20a), -OC(O)N(R20a)2, -N(R20a)C(O)2R20a, -N(R20a)C(O)N(R20a)2,
-OC(O)R20b, -S(O)R20b, -S(O)2R20b, -S(O)2N(R20a)2, -N(R20a)S(O)2R20b, -C(R20a)=N(R20a), and
-C(R20a)=N(OR20a);
R20* in each occurrence is independently selected from C1-6alkyl, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R20b, -C(O)2R20c, -C(O)N(R20a)2, -S(O)R20b, -S(O)2R20b, -S(O)2N(R20a)2, -C(R20a)=N(R20a), and -C(R20a)=N(OR20a);
R20a in each occurrence is independently selected from H, C1-6alkyl, carbocyclyl, and heterocyclyl;
R20b in each occurrence is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl; R20c in each occurrence is independently selected from H, C1-6alkyl, carbocyclyl, and heterocyclyl;
R30 in each occurrence is independently selected from halo, -CN, C1-6alkyl, C2-6alkenyl,
C2-6alkynyl, carbocyclyl, heterocyclyl, -OR30a, -SR30a, -N(R30a)2, -N(R30a)C(O)R30b,
-N(R30a)N(R30a)2, -NO2, -N(R30a)-OR30a, -O-N(R30a)2, -C(O)H, -C(O)R30b, -C(O)2R30a, -C(O)N(R30a)2, -C(O)N(R30a)(OR30a), -OC(O)N(R30a)2, -N(R30a)C(O)2R30a, -N(R30a)C(O)N(R30a)2,
-OC(O)R30b, -S(O)R30b, -S(O)2R30b, -S(O)2N(R30a)2, -N(R30a)S(O)2R30b, -C(R30a)=N(R30a), and
-C(R30a)=N(OR30a);
R30* in each occurrence is independently selected from C1-6alky 1, carbocyclyl, heterocyclyl,
-C(O)H, -C(O)R30b, -C(O)2R30c, -C(O)N(R30a)2, -S(O)R30b, -S(O)2R30b, -S(O)2N(R30a)2, -C(R30a)=N(R30a), and -C(R30a)=N(OR30a);
R30a in each occurrence is independently selected from H, C1-6alky 1, carbocyclyl, and heterocyclyl;
R30b in each occurrence is independently selected from C1-6alkyl, C2-6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl; and R30c in each occurrence is independently selected from C1-6alkyl, carbocyclyl, and heterocyclyl.
R40 in each occurrence is independently selected from halo, -CN, C1-6alkyl, C2_6alkenyl,
C2_6alkynyl, carbocyclyl, heterocyclyl, -OR40a, -SR40a, -N(R40a)2, -N(R40a)C(O)R40b,
-N(R40a)N(R40a)2, -NO2, -N(R40a)-OR40a, -O-N(R40a)2, -C(O)H, -C(O)R40b, -C(O)2R40a,
-C(O)N(R40a)2, -C(O)N(R40a)(OR40a), -OC(O)N(R40a)2, -N(R40a)C(O)2R40a, -N(R40a)C(O)N(R40a)2, -OC(O)R40b, -S(O)R40b, -S(O)2R40b, -S(O)2N(R40a)2, -N(R40a)S(O)2R40b, -C(R40a)=N(R40a), and
-C(R40a)=N(OR40a);
R40* in each occurrence is independently selected from C1-6alky 1, carbocyclyl, heterocyclyl,
-C(O)H, -C(O)R40b, -C(O)2R40c, -C(O)N(R40a)2, -S(O)R40b, -S(O)2R40b, -S(O)2N(R40a)2,
-C(R40a)=N(R40a), and -C(R40a)=N(OR40a); R40a in each occurrence is independently selected from H, C1-6alkyl, carbocyclyl, and heterocyclyl;
R40b in each occurrence is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl; and
R40c in each occurrence is independently selected from C1-6alkyl, carbocyclyl, and heterocyclyl.
In another aspect, Ring A is 4- to 7-membered non-aromatic heterocyclyl, wherein said 4- to 7- membered non-aromatic heterocyclyl is optionally substituted on carbon with one or more R , and wherein any -NH- moiety of said 4- to 7-membered heterocyclyl is optionally substituted with R2*;
Ring B is 6-membered heteroaryl, wherein said 6-membered heteroaryl is substituted on carbon with one or more R4;
X is selected from -O- and -NH-;
R1 is selected from d_6alkyl, 3- to 6-membered carbocyclyl, and 5- or 6-membered heterocyclyl, wherein said C1-6alkyl, 3- to 6-membered carbocyclyl, and 5- or 6-membered heterocyclyl are optionally substituted on carbon with one or more R ; R2 in each occurrence is independently selected from halo, -CN, C1-6alkyl, -OR2a, -N(R2a)2,
-C(O)N(R2a)2, -N(R2a)C(O)R2b, and -N(R2a)C(O)2R2a, wherein said d_6alkyl is optionally substituted with one or more R20;
R2* is C1-6alkyl;
R2a in each occurrence is independently selected from H and C1-6alkyl; R2b is C1-6alkyl;
R3 is selected from C1-6alkyl, wherein said C1-6alkyl is optionally substituted with one or more
R30;
R4 is halo;
R10 in each occurrence is independently selected from halo, 3- to 6-membered carbocyclyl , 5- or 6-membered heterocyclyl, and -OR10a, wherein said 3- to 6-membered carbocyclyl and 5- or 6- membered heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more Ra;
R10a is selected from C1-6alkyl and 3- to 6-membered carbocyclyl;
R20 in each occurrence is independently selected from halo, -CN, 4- to 6-membered heterocyclyl, -OR20a, -N(R20a)2, -C(O)2R20a, -C(O)N(R20a)2, -N(R20a)C(O)2R20a, and -N(R20a)S(O)2R20b; R20a in each occurrence is independently selected from H and C1-6alkyl; R20b is C1-6alkyl;
R30 in each occurrence is independently selected from halo, -CN, -OR30a, -C(O)N(R30a)2, -S(O)2R30b, and -S(O)2N(R30a)2;
R30a in each occurrence is independently selected from H and C1-6alkyl; R30b is C1-6alkyl;
Ra in each occurrence is independently selected from halo and -ORm; and Rm is C1-6alkyl.
In still another aspect, Ring A is selected from azetidinyl, morpholinyl, 1 ,4-oxazepanyl, piperazinyl, piperidinyl, and pyrrolidinyl, wherein said azetidinyl, morpholinyl, 1,4-oxazepanyl, piperazinyl, piperidinyl, and pyrrolidinyl are optionally substituted on carbon with one or more
R2, and wherein any -NH- moiety of said piperazinyl is optionally substituted with R2*;
Ring B is selected from pyridinyl and pyrimidinyl, wherein said pyridinyl and pyrimidinyl are optionally substituted with one or more R ; X is selected from -O- and -NH-;
R1 is selected from cyclopropyl ethyl , methyl, phenyl, and thiophenyl, wherein said cyclopropyl, ethyl, methyl, phenyl, and thiophenyl are optionally substituted on carbon with one or more R ;
R2 is fluoro, -CN, methyl, ethyl, -N(R2a)2, -OR2a, -C(O)N(R2a)2, -N(H)C(O)R2b, and
-N(R2a)C(O)2R2a, wherein said methyl and ethyl in each occurrence is optionally and independently substituted with one or more R20;
R2a in each occurrence is independently selected from H, tert-butyl, ethyl, and methyl;
R2b is methyl;
R2* is methyl;
R3 is selected from methyl and ethyl, wherein said methyl and and ethyl are optionally substituted with one or more R30;
R4 is fluoro;
R10 in each occurrence is independently selected from fluoro, -OR10a, cyclohexyl, imidazolyl, phenyl, and pyridinyl, wherein said cyclohexyl, imidazolyl, phenyl, and pyridinyl in each occurrence are optionally and independently substituted on carbon with one or more Ra; R10a in each occurrence is independently selected from methyl and phenyl; R I20 iinn eeaacchh ooccccuurrrreennccee iiss iinnddeeppeennddeennttllyy sseelleecctteedd frfroomm fflluuoorroo,, --CCN^, a ■™ze*t;id-4;i~ny •'l, - <O^rR>20aa, - wN(Rr> 20aa λ)2,
> 20a /~i/i~v\-vτ/r» 20a\ AT/mn/nx τ-» 20a * ΛT/T I\C /Π\ r» 20b. -C(O)2R203, -C(O)N(R20a)2, -N(H)C(O)2R203, and -N(H)S(O)2R2
R ,20aa in each occurrence is independently selected from H, fert-butoxy, ethyl, and methyl; and R20b is methyl;
R30 in each occurrence is independently selected from fluoro, -CN, and -OR30a, -C(O)N(R30a)2 , -S(O)2N(R30a)2, and -S(O)2Me;
R30a is in each occurrence is independently selected from H, methyl, and ethyl; and Ra in each occurrence is independently selected from fluoro and methoxy.
In yet another aspect, Ring A is heterocyclyl, wherein any -NH- moiety of said heterocyclyl is optionally substituted with R2*;
Ring B is heterocyclyl, wherein said heterocyclyl is optionally substituted on carbon with one or more R4;
X is selected from -O- and -NH-;
R1 is C1-6alkyl; R2* in each occurrence is independently selected from C1-6alkyl;
R3 is C1-6alkyl; and
R4 is halo.
In a further aspect, Ring A is selected from morpholinyl and piperazinyl, wherein any -NH- moiety of said morpholinyl and piperazinyl is optionally substituted with R2*;
Ring B is selected from pyridinyl and pyrimidinyl, wherein said pyridinyl and pyrimidinyl are optionally substituted on carbon with one or more R4;
X is selected from -O- and -NH-;
R1 is methyl; R2* is methyl;
R3 is methyl; and
R4 is fluoro.
In yet a further aspect, Ring A is selected from morpholin-4-yl and 4-methylpiperazin-1-yl; Ring B is selected from 5-fluoropyridin-2-yl and 5-fluoropyrimidin-2-yl; X is selected from -O- and -NH-; R1 is methyl; and R3 is methyl.
In one aspect, Ring A is selected from 3-(acetylamino)azetidin-1-yl, 3-(acetylamino)pyrrolidin-lyl, 3-(amionmethyl)piperidin-1-yl, 3-aminopiperidin-1-yl,
2-(azetidin-1-ylmethyl)morpholin-4-yl, 3-cyanoazetidin-1-yl, 2-(cyanomethyl)morpholin-4-yl, 3-(cyanomethyl)morpholin-4-yl, 2-(cyanomethyl)piperidin-1-yl, 3-cyanopiperidin-1-yl, 4-cyanopiperidin- 1-yl, 2-[(diethylamino)methyl]morpholin-4-yl, 3 ,3-difluoroazetidin- 1 -y, 2-(difluoromethyl)morpholin-4-yl, 3-(difluoromethyl)morpholin-4-yl, 3,3-difluropiperidin-1-yl , 4,4-difluoropiperidin-1-yl, 3,3-difluoropyrrolidin-1-yl, 3-(dimethylamino)azetidin-1-yl, 3-[(dimethylamino)carbonyl]methylmorpholin-4-yl,
3-[(dimethylamino)carbonyl]morpholin-4-yl, 3-[(dimethylamino)methyl]piperidin-1-yl, 3-(dimethylamino)pyrrolidin-1-yl, 2,2-dimethylmorpholin-4-yl, 2,6-dimethylmorpholin-4-yl, 3,3-dimethylmorpholin-4-yl, 3- {[(ethoxycarbonyl)amino]methyl}morpholin-4-yl, 2- ethylmorpholin-4-yl, 3-ethylmorpholin-4-yl, 3-ethyoxypyrrolidin-1-yl, 3-fluoroazetidin-1-yl, 3-fluropiperidin-1-yl, 4-fluoropiperidin-1-yl, 3-hydroxyazetidin-1-yl, 3-(2-hydroxyethyl)morpholin-4-yl, 2-(hydroxymethyl)azeti din- 1-yl, 3-hydroxy-3-methylazetidin- 1 -yl, 2-(hydroxymethyl)morpholin-4-yl, 3-(hydroxymethyl)morpholin-4-yl, 3-hydroxy-3-methylpiperidin-1-yl, 4-hydroxy-4-methylpiperi din- 1-yl, 2-(hydroxymethyl)piperidin-1-yl, 3-hydroxypiperidin-1-yl, 4-hydroxypiperidin-1-yl, 3-methoxyazetidin-1-yl, 3-[(methoxycarbonyl)methyl]morpholin-4-yl, 2-(methoxymethyl)morpholin-4-yl, 3-(methoxymethyl)morpholin-4-yl, 3 -(methoxymethyl)piperidin- 1 -yl, 3 -methoxypiperidin- 1 -yl, 4-methoxypiperidin- 1 -yl, 3-(methylamino)azetidin- 1 -yl, 3-[(methylamino)carbonyl]morpholin-4-yl, 3-(methylamino)pyrrolidin-1-yl, 2-methylmorpholin-4-yl, 3-methylmorpholin-4-yl,
4-methyl-3-oxopiperazin- 1-yl, 3- {[(methylsulfonyl)amino]methyl}morpholin-4-yl, morpholin- 4-yl, 4-methylpiperazin-1-yl, 1,4-oxazepan-4-yl, 3-{[(t- butoxycarbonyl)amino]methyl}piperidin- 1 -yl, and 3-[(Y-butoxycarbonyl)amino]piperidin- 1 -yl; Ring B is selected from 3,5-difluoropyridin-2-yl, 5-fluoropyridin-2-yl, and 5-fluoropyrimidin-2-yl; X is selected from -O- and -NH-;
R1 is selected from 2-cyclohexylethyl, cyclopropyl, 2-(2,4-difluorophenyl)ethyl, 2-(2,6-difluorophenyl)ethyl, 2-(3,4-difluorophenyl)ethyl , 2-(3,5-difluorophenyl)ethyl, 2-(3,5-dimethoxyphenyl)ethyl, 4-fluorophenyl, 2-(3-fluorophenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2-(1H-imidazol-2-yl)ethyl, 4-methoxyphenyl, methyl, 2-phenylethyl, phenyloxymethyl, 2-pyridin-4-ylethyl, and thiophen-2-yl; and
R3 is selected from (aminocarbonyl)methyl, cyanomethyl, l,l-difluoro-2-hydroxyethyl, [(dimethylamino)carbonyl]methyl, (dimethylaminosulfonyl)methyl, ethoxymethyl, 1 -hydroxy ethyl, 2~hydroxyethyl, 1-methoxy ethyl, methoxymethyl, [(methylamino)carbonyl] methyl, and (methylsulfonyl)methyl.
In another aspect, the compound of Formula (I) is a compound of Formula (Ia):
Formula (Ia)
or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, X, R1, and R3 are as defined hereinabove.
In still another aspect, the compounds of Formula (I) and Formula (Ia) are compounds of Formula (Ib):
Figure imgf000051_0001
Formula (Ib) or pharmaceutically acceptable salts thereof, wherein Ring B, X, R1, and R3 are as defined hereinabove, and wherein Ring C is nitrogen-containing 4- to 7-membered non-aromatic heterocyclyl, wherein said nitrogen- containing 4- to 7-membered non-aromatic heterocyclyl is optionally substituted on carbon with one or more R , and wherein any -NH- moiety of said nitrogen-containing 4- to 7-membered non-aromatic heterocyclyl is optionally substituted with R2*, wherein R2 and R2* are as defined hereinabove.
In yet a further aspect, the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as illustrated by the Examples, each of which provides a further independent aspect of the invention.
In one aspect, the present invention provides a compound selected from:
4-[(I1S)- 1 -(5-fluoropyridin-2-yl)ethoxy]-N-(5-methyl- 1H-pyrazol-3-yl)-6-morpholin-4-yl- 1 ,3 ,5- triazin-2-amine;
4-[(IR)- 1 -(5-fluoropyridin-2-yl)ethoxy]-N-(5-methyl- 1H-pyrazol-3-yl)-6-morpholin-4-yl- 1 ,3 ,5- triazin-2-amine;
4-[(l.S)-1-(5-fluoropyrimidin-2-yl)ethoxy]-N-(5-methyl-1H-pyrazol-3-yl)-6-morpholin-4-yl-
1 ,3 ,5-triazin-2-amine; 4-[(li?)-1-(5-fluoropyrimidin-2-yl)ethoxy]-N-(5-methyl-1H-pyrazol-3-yl)-6-morpholin-4-yl-
1 ,3 ,5-triazin-2-amine;
(2i?)-2-(5-fluoropyridin-2-yl)-N,N-dimethyl-2-({4-[(5-methyl-1H-pyrazol-3-yl)amino]-6- morpholin-4-yl- 1 ,3 ,5-triazin-2-yl} amino)ethanesulfonamide; (21Sl)-2-(5-fluoropyridin-2-yl)-N,N-dimethyl-2-({4-[(5-methyl-1H-pyrazol-3-yl)amino]-6- morpholin-4-yl- 1 ,3 ,5-triazin-2-yl} amino)ethanesulfonamide;
(3S)- 1 -(4- { [(IS)- 1 -(5-fluoropyrimidin-2-yl)ethyl]amino}-6-[(5-methyl- 1H-pyrazol-3-yl)amino]-
1,3,5-triazin-2-yl)piperidine-3-carbonitrile;
(3R)- 1 -(4- { [(IS)- 1 -(5-fluoropyrimidin-2-yl)ethyl]amino}-6-[(5-methyl- 1H-pyrazol-3-yl)amino]- 1,3,5-triazin-2-yl)piperidine-3-carbonitrile;
N-[(l1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-6-[(31S)-3-methoxypiperidin-1-yl]-N!-(5-methyl-1H- pyrazol-3-yl)- 1 ,3 ,5-triazine-2,4-diamine;
N-[(15)-1-(5-fluoropyrimidin-2-yl)ethyl]-6-[(3i?)-3-methoxypiperidin-1-yl]-N'-(5-methyl-1H- pyrazol-3-yl)- 1 ,3 ,5-triazine-2,4-diamine; (3i?)-1-(4-{[(l1Sl)-1-(5-fluoropyrimidin-2-yl)ethyl]amino}-6-[(5-methyl-1H-pyrazol-3-yl)amino]-
1 ,3 ,5-triazin-2-yl)-3 -methylpiperidin-3 -ol;
(3S)- 1 -(4- { [(IS)- 1 -(5-fluoropyrimidin-2-yl)ethyl]amino}-6-[(5-methyl- 1H-pyrazol-3-yl)amino]-
1 ,3 ,5-triazin-2-yl)-3 -methylpiperidin-3 -ol;
N-[(l1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-6-[(31S)-3-(methoxymethyl)piperidin-1-yl]-N'-(5- methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine-2,4-diamine;
N-[(l1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-6-[(3i?)-3-(methoxymethyl)piperidin-1-yl]-N'-(5- methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine-2,4-diamine;
6-{(2i?)-2-[(diethylamino)methyl]morpholin-4-yl}-N-[(l1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N!-
(5-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine-2,4-diamine; 6-{(21S)-2-[(diethylamino)methyl]morpholin-4-yl}-N-[(l1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N'-
(5-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine-2,4-diamine;
N-[(li?)-1-(3,5-difluoropyridin-2-yl)-2-methoxyethyl]-6-[(31S)-3-fluoropiperidin-1-yl]-N!-(5- methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine-2,4-diamine;
N-[(li?)-1-(3,5-difluoropyridin-2-yl)-2-methoxyethyl]-6-[(3i?)-3-fluoropiperidin-1-yl]-N'-(5- methyl- 1H-pyrazol-3-yl)- 1 ,3 ,5-triazine-2,4-diamine;
N-[(li?)-1-(3,5-difluoropyridin-2-yl)-2-methoxyethyl]-6-[(2i?)-2-ethylmorpholin-4-yl]-N'-(5- methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine-2,4-diamine;
N-[(li?)-1-(3,5-difluoropyridin-2-yl)-2-methoxyethyl]-6-[(21S)-2-ethylmorpholin-4-yl]-N'-(5- methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine-2,4-diamine; N-[(li?)-1-(3,5-difluoropyridin-2-yl)-2-methoxyethyl]-6-[(2i?)-2-methylmorpholin-4-yl]-N!-(5- methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine-2,4-diamine;
N-[(li?)-1-(3,5-difluoropyridin-2-yl)-2-methoxyethyl]-6-[(21S)-2-methylmorpholin-4-yl]-N!-(5- methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine-2,4-diamine;
N-[(l1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-6-[(21S)-2-methylmorpholin-4-yl]-N'-(5-methyl-1H- pyrazol-3-yl)- 1 ,3 ,5-triazine-2,4-diamine;
N-[(l1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-6-[(2i?)-2-methylmorpholin-4-yl]-N'-(5-methyl-1H- pyrazol-3-yl)- 1 ,3 ,5-triazine-2,4-diamine;
[(2i?)-4-(4- { [(IS)- 1 -(5-fluoropyrimidin-2-yl)ethyl]amino} -6- [(5 -methyl- 1H-pyrazol-3-yl)amino]-
1 ,3 ,5-triazin-2-yl)morpholin-2-yl]methanol; [(2,S<)-4-(4-{[(l1S)-1-(5-fluoropyrimidin-2-yl)ethyl]amino}-6-[(5-methyl-1H-pyrazol-3-yl)amino]-
1 ,3 ,5-triazin-2-yl)morpholin-2-yl]methanol;
6-[(21S)-2-ethylmorpholin-4-yl]-N-[(l1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N'-(5-methyl-1H- pyrazol-3-yl)- 1 ,3 ,5-triazine-2,4-diamine;
6-[(2i?)-2-ethylmorpholin-4-yl]-N-[(l1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N'-(5-methyl-1H- pyrazol-3-yl)- 1 ,3 ,5-triazine-2,4-diamine;
N-[(l1S)-1-(3,5-difluoropyridin-2-yl)ethyl]-N'-(5-methyl-1H-pyrazol-3-yl)-6-morpholin-4-yl-
1 ,3 ,5-triazine-2,4-diamine;
N-[(li?)-1-(3,5-difluoropyridin-2-yl)ethyl]-N!-(5-methyl-1H-pyrazol-3-yl)-6-morpholin-4-yl-
1 ,3 ,5-triazine-2,4-diamine; [(3i?)-4-(4-{[(l1S')-1-(3,5-difluoropyridin-2-yl)ethyl]amino}-6-[(5-methyl-1H-pyrazol-3- yl)amino]- 1 ,3 ,5-triazin-2-yl)morpholin-3 -yljmethanol;
[(3i?)-4-(4-{[(li?)-1-(3,5-difluoropyridin-2-yl)ethyl]amino}-6-[(5-methyl-1H-pyrazol-3- yl)amino]- 1 ,3 ,5-triazin-2-yl)morpholin-3 -yljmethanol;
N-[(l1S)-1-(3,5-difluoropyridin-2-yl)ethyl]-6-(3-fluoroazetidin-1-yl)-N!-(5-methyl-1H-pyrazol-3- yl)-1,3,5-triazine-2,4-diamine;
N-[(li?)-1-(3,5-difluoropyridin-2-yl)ethyl]-6-(3-fluoroazetidin-1-yl)-N'-(5-methyl-1H-pyrazol-3- yl)-1,3,5-triazine-2,4-diamine; l-(4-{[(l1S)-1-(3,5-difluoropyridin-2-yl)ethyl]amino}-6-[(5-methyl-1H-pyrazol-3-yl)amino]-
1 ,3 ,5-triazin-2-yl)-4-methylpiperidin-4-ol; l-(4-{[(li?)-1-(3,5-difluoropyridin-2-yl)ethyl]amino}-6-[(5-methyl-1H-pyrazol-3-yl)amino]-
1 ,3 ,5-triazin-2-yl)-4-methylpiperidin-4-ol;
N-[(l1S)-1-(3,5-difluoropyridin-2-yl)ethyl]-6-(4-methoxypiperidin-1-yl)-N!-(5-methyl-1H- pyrazol-3-yl)- 1 ,3 ,5-triazine-2,4-diamine;
N-[(li?)-1-(3,5-difluoropyridin-2-yl)ethyl]-6-(4-methoxypiperidin-1-yl)-N'-(5-methyl-1H- pyrazol-3-yl)- 1 ,3 ,5-triazine-2,4-diamine; l-(4-{[(l1S)-1-(3,5-difluoropyridin-2-yl)ethyl]amino}-6-[(5-methyl-1H-pyrazol-3-yl)amino]-
1 ,3 ,5-triazin-2-yl)piperidine-4-carbonitrile; l-(4-{[(li?)-1-(3,5-difluoropyridin-2-yl)ethyl]amino}-6-[(5-methyl-1H-pyrazol-3-yl)amino]-
1 ,3 ,5-triazin-2-yl)piperidine-4-carbonitrile; N-[(l1S)-1-(3,5-difluoropyridin-2-yl)ethyl]-6-(4-fluoropiperidin-1-yl)-N!-(5-methyl-1H-pyrazol-3- yl)-1,3,5-triazine-2,4-diamine;
N-[(li?)-1-(3,5-difluoropyridin-2-yl)ethyl]-6-(4-fluoropiperidin-1-yl)-N!-(5-methyl-1H-pyrazol-3- yl)-1,3,5-triazine-2,4-diamine;
6-(4,4-difluoropiperidin-1-yl)-N-[(l1S<)-1-(3,5-difluoropyridin-2-yl)ethyl]-N'-(5-methyl-1H- pyrazol-3-yl)- 1 ,3 ,5-triazine-2,4-diamine;
6-(4,4-difluoropiperidin-1-yl)-N-[(li?)-1-(3,5-difluoropyridin-2-yl)ethyl]-N'-(5-methyl-1H- pyrazol-3-yl)- 1 ,3 ,5-triazine-2,4-diamine;
N-[(l1S)-1-(3,5-difluoropyridin-2-yl)ethyl]-6-(3-methoxyazetidin-1-yl)-N!-(5-methyl-1H-pyrazol-
3-yl)-1,3,5-triazine-2,4-diamine; N-[(li?)-1-(3,5-difluoropyridin-2-yl)ethyl]-6-(3-methoxyazetidin-1-yl)-N!-(5-methyl-1H-pyrazol-
3-yl)-1,3,5-triazine-2,4-diamine;
N-[(li?)-1-(3,5-difluoropyridin-2-yl)-2-methoxyethyl]-6-(3-fluoroazetidin-1-yl)-N!-(5-methyl-1H- pyrazol-3-yl)- 1 ,3 ,5-triazine-2,4-diamine;
N-[(l1S)-1-(3,5-difluoropyridin-2-yl)-2-methoxyethyl]-6-(3-fluoroazetidin-1-yl)-N!-(5-methyl-1H- pyrazol-3-yl)- 1 ,3 ,5-triazine-2,4-diamine;
N-[(li?)-1-(3,5-difluoropyridin-2-yl)-2-methoxyethyl]-6-(4-methoxypiperidin-1-yl)-N!-(5-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine-2,4-diamine;
N-[(l1S)-1-(3,5-difluoropyridin-2-yl)-2-methoxyethyl]-6-(4-methoxypiperidin- ^yI)-TV-(S-HIeUIyI- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine-2,4-diamine; N-[(li?)-1-(3,5-difluoropyridin-2-yl)-2-methoxyethyl]-6-(3-methoxyazetidin- l-yrj-NXS-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine-2,4-diamine;
N-[(l1S)-1-(3,5-difluoropyridin-2-yl)-2-methoxyethyl]-6-(3-methoxyazetidin- ^yI)-TV-(S-HIeUIyI- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine-2,4-diamine;
N-[(li?)-1-(3,5-difluoropyridin-2-yl)-2-methoxyethyl]-N'-(5-methyl-1H-pyrazol-3-yl)-6- morpholin-4-yl-1,3,5-triazine-2,4-diamine;
N-[(l1S)-1-(3,5-difluoropyridin-2-yl)-2-methoxyethyl]-N!-(5-methyl-1H-pyrazol-3-yl)-6- morpholin-4-yl-1,3,5-triazine-2,4-diamine;
N-[(li?)-1-(3,5-difluoropyridin-2-yl)-2-ethoxyethyl]-Nl-(5-methyl-1H-pyrazol-3-yl)-6-morpholin-
4-yl-1,3,5-triazine-2,4-diamine; N-[(l1S)-1-(3,5-difluoropyridin-2-yl)-2-ethoxyethyl]-N'-(5-methyl-1H-pyrazol-3-yl)-6-morpholin-
4-yl-1,3,5-triazine-2,4-diamine;
N-[(li?)-2-ethoxy-1-(5-fluoropyridin-2-yl)ethyl]-N'-(5-methyl-1H-pyrazol-3-yl)-6-morpholin-4- yl- 1 ,3 ,5-triazine-2,4-diamine;
N-[(l1S)-2-ethoxy-1-(5-fluoropyridin-2-yl)ethyl]-N!-(5-methyl-1H-pyrazol-3-yl)-6-morpholin-4- yl- 1 ,3 ,5-triazine-2,4-diamine;
4-[(li?)-1-(3,5-difluoropyridin-2-yl)-2-methoxyethoxy]-N-(5-methyl-1H-pyrazol-3-yl)-6- morpholin-4-yl-1,3,5-triazin-2-amine;
4-[(l1S)-1-(3,5-difluoropyridin-2-yl)-2-methoxyethoxy]-N-(5-methyl-1H-pyrazol-3-yl)-6- morpholin-4-yl-1,3,5-triazin-2-amine; (31Sl)-3-(5-fluoropyridin-2-yl)-3-({4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-morpholin-4-yl-1,3,5- triazin-2-yl} amino)propanamide;
(3i?)-3-(5-fluoropyridin-2-yl)-3-({4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-morpholin-4-yl- 1,3,5- triazin-2-yl} amino)propanamide;
6-[(31S)-3-ethylmorpholin-4-yl]-N-[(l1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N!-(5-methyl-1H- pyrazol-3-yl)- 1 ,3 ,5-triazine-2,4-diamine;
6-[(3i?)-3-ethylmorpholin-4-yl]-N-[(l1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N'-(5-methyl-1H- pyrazol-3-yl)- 1 ,3 ,5-triazine-2,4-diamine;
N-[(li?)-1-(5-fluoropyrimidin-2-yl)-2-methoxyethyl]-N!-(5-methyl-1H-pyrazol-3-yl)-6- morpholin-4-yl-1,3,5-triazine-2,4-diamine; N-tCl^-1-CS-fluoropyrimidin-1-y^-1-methoxyethyy-N'-CS-methyl-1H-pyrazol-S-yO-β- morpholin-4-yl-1,3,5-triazine-2,4-diamine;
4-[(li?)-1-(5-fluoropyridin-2-yl)-2-methoxyethoxy]-N-(5-methyl-1H-pyrazol-3-yl)-6-morpholin-
4-yl-1,3,5-triazin-2-amine;
4-[(l1S)-1-(5-fluoropyridin-2-yl)-2-methoxyethoxy]-N-(5-methyl-1H-pyrazol-3-yl)-6-morpholin- 4-yl-1,3,5-triazin-2-amine;
(31Sl)-3-(5-fluoropyridin-2-yl)-N-methyl-3-({4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-morpholin-
4-yl-1,3,5-triazin-2-yl}amino)propanamide;
(3i?)-3-(5-fluoropyridin-2-yl)-N-methyl-3-({4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-morpholin-
4-yl-1,3,5-triazin-2-yl}amino)propanamide; (31S<)-3-(5-fluoropyridin-2-yl)-3-({4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-morpholin-4-yl-1,3,5- triazin-2 -yl } amino)propanenitrile ;
(3i?)-3-(5-fluoropyridin-2-yl)-3-({4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-morpholin-4-yl-1,3,5- triazin-2 -yl } amino)propanenitrile ;
4-[(li?)-1-(5-fluoropyrimidin-2-yl)-2-methoxyethoxy]-N-(5-methyl-1H-pyrazol-3-yl)-6- morpholin-4-yl-1,3,5-triazin-2-amine;
4-[(l1S)-1-(5-fluoropyrimidin-2-yl)-2-methoxyethoxy]-N-(5-methyl-1H-pyrazol-3-yl)-6- morpholin-4-yl- 1,3,5-triazin-2-amine;
(31Sl)-3-(5-fluoropyridin-2-yl)-N,N-dimethyl-3-({4-[(5-methyl-1H-pyrazol-3-yl)amino]-6- morpholin-4-yl- 1 ,3 ,5-triazin-2-yl} amino)propanamide; (3i?)-3-(5-fluoropyridin-2-yl)-N,N-dimethyl-3-({4-[(5-methyl-1H-pyrazol-3-yl)amino]-6- morpholin-4-yl- 1 ,3 ,5-triazin-2-yl} amino)propanamide;
(31Sl)-3-(5-fluoropyridin-2-yl)-3-({4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-morpholin-4-yl- 1,3,5- triazin-2 -yl } amino)propan- 1 -ol;
(3i?)-3-(5-fluoropyridin-2-yl)-3-({4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-morpholin-4-yl-1,3,5- triazin-2-yl}amino)propan-1-ol;
N-[(li?)-1-(5-fluoropyridin-2-yl)-2-(methylsulfonyl)ethyl]-N!-(5-methyl-1H-pyrazol-3-yl)-6- morpholin-4-yl- 1, 3, 5-triazine-2,4-diamine;
N-[(15)-1-(5-fluoropyridin-2-yl)-2-(methylsulfonyl)ethyl]-N'-(5-methyl-1H-pyrazol-3-yl)-6- morpholin-4-yl- 1, 3, 5-triazine-2,4-diamine; 4-{[(li?,21Sl)-1-(5-fluoropyridin-2-yl)-2-methoxypropyl]oxy}-N-(5-methyl-1H-pyrazol-3-yl)-6- morpholin-4-yl-1,3,5-triazin-2-amine;
4-{[(l1S<,21S)-1-(5-fluoropyridin-2-yl)-2-methoxypropyl]oxy}-N-(5-methyl-1H-pyrazol-3-yl)-6- morpholin-4-yl-1,3,5-triazin-2-amine;
6-{(31S)-3-[(dimethylamino)methyl]piperidin-1-yl}-N-[(l1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N'- (5-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine-2,4-diamine;
6-{(3i?)-3-[(dimethylamino)methyl]piperidin-1-yl}-N-[(l1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N!-
(5-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine-2,4-diamine; tert-butyl [(3R)- 1 -(4- { [(IS)- 1 -(5-fluoropyrimidin-2-yl)ethyl]amino}-6-[(5-methyl- 1H-pyrazol-3- yl)amino]- 1 ,3 ,5-triazin-2-yl)piperidin-3 -yljmethylcarbamate; tert-butyl [(3i?)-1-(4-{[(li?)-1-(5-fluoropyrimidin-2-yl)ethyl]amino}-6-[(5-methyl-1H-pyrazol-3- yl)amino]- 1 ,3 ,5-triazin-2-yl)piperidin-3 -yljmethylcarbamate;
4-[(l1S)-1-(3,5-difluoropyridin-2-yl)ethoxy]-N-(5-methyl-1H-pyrazol-3-yl)-6-morpholin-4-yl-
1 ,3 ,5-triazin-2-amine;
4-[(li?)-1-(3,5-difluoropyridin-2-yl)ethoxy]-N-(5-methyl-1H-pyrazol-3-yl)-6-morpholin-4-yl- 1,3,5-triazin-2-amine;
6-[(31S)-3-fluoropiperidin-1-yl]-N-[(l1S')-1-(5-fluoropyrimidin-2-yl)ethyl]-N'-(5-methyl-1H- pyrazol-3-yl)- 1 ,3 ,5-triazine-2,4-diamine;
6-[(3i?)-3-fluoropiperidin-1-yl]-N-[(l1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N'-(5-methyl-1H- pyrazol-3-yl)- 1 ,3 ,5-triazine-2,4-diamine; N-[(li?)-1-(3,5-difluoropyridin-2-yl)-2-methoxyethyl]-6-[(21S)-2-(methoxymethyl)morpholin-4- yl]-Λ/I-(5-methyl- 1H-pyrazol-3-yl)- 1 ,3 ,5-triazine-2,4-diamine; and
N-[(li?)-1-(3,5-difluoropyridin-2-yl)-2-methoxyethyl]-6-[(2i?)-2-(methoxymethyl)morpholin-4- yl]-N!-(5-methyl-1H-pyrazol-3-yl)-1,3,5-triazine-2,4-diamine(137), or a pharmaceutically acceptable salt thereof.
Utility
Typical compounds of Formula (I) are believed to have utility for the treatment of myeloproliferative disorders, myelodysplastic syndrome and cancer by inhibiting the JAK tyrosine kinases, particularly the JAK2 family. Methods of treatment target tyrosine kinase activity, particularly the JAK family activity and more particularly JAK2 activity, which is involved in a variety of myeloproliferative disorders, myelodysplastic syndrome and cancer related processes. Thus, inhibitors of tyrosine kinase, particularly the JAK family and more particularly JAK2, are expected to be active against myeloproliferative disorders such as chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and neoplastic disease such as carcinoma of the breast, ovary, lung, colon, prostate or other tissues, as well as leukemias, myelomas and lymphomas, tumors of the central and peripheral nervous system, and other tumor types such as melanoma, fibrosarcoma and osteosarcoma. Tyrosine kinase inhibitors, particularly the JAK family inhibitors and more particularly JAK2 inhibitors are also expected to be useful for the treatment other proliferative diseases including but not limited to autoimmune, inflammatory, neurological, and cardiovascular diseases.
The compounds of Formula (I) have been shown to inhibit tyrosine kinases, particularly the JAK family and more particularly JAK2, as determined by the JAK2 Assay described herein.
The compounds of Formula (I) should also be useful as standards and reagents in determining the ability of a potential pharmaceutical to inhibit tyrosine kinases, particularly the JAK family and more particularly JAK2. These would be provided in commercial kits comprising a compound of this invention.
JAK2 kinase activity may be determined by measuring the kinase's ability to phosphorylate synthetic tyrosine residues within a generic polypeptide substrate using an Amplified Luminescent Proximity Assay (Alphascreen) technology (PerkinElmer, 549 Albany Street, Boston, MA).
To measure JAK2 kinase activity, a commercially available purified enzyme may be used. The enzyme may be C-terminal His6-tagged, recombinant, human JAK2, amino acids 808-end, (Genbank Accession number NM 004972) expressed by baculovirus in Sf21 cells (Upstate Biotechnology MA). After incubation of the kinase with a biotinylated substrate and adenosine triphosphate (ATP) for 60 minutes at room temperature, the kinase reaction may be stopped by the addition of 30 mM ethylenediaminetetraacetic acid (EDTA). The reaction may be performed in 384 well microtitre plates and the reaction products may be detected with the addition of streptavidin coated Donor Beads and phosphotyrosine-specifϊc antibodies coated Acceptor Beads using the EnVision Multilabel Plate Reader after an overnight incubation at room temperature. "Tween 20" is a registered trademark of ICI Americas, Inc.
Figure imgf000059_0001
Although the pharmacological properties of the compounds of the Formula (I) may vary with structural change, typical compounds of the Formula (I) are believed to possess JAK inhibitory activity at IC50 concentrations (concentrations to achieve 50% inhibition) or doses at a level below 10 μM.
When tested in an in- vitro assay based on the one described above, the JAK inhibitory activity of the following examples was measured at the following IC50S. The absence of a listed IC50 value for any particular example is not intended to imply that the particular compound does not possess JAK IC50 activity.
Examples 1 to 10
Figure imgf000060_0001
Examples 11 to 20
Examples 21 to 30
Figure imgf000060_0002
Examples 31 to 40
Figure imgf000061_0001
Examples 41 to 50
Examples 51 to 60
Figure imgf000062_0001
Examples 61 to 70
Figure imgf000063_0001
Figure imgf000064_0001
Examples 71 to 80
Examples 81 to 90
Figure imgf000064_0002
Example 91 to 100
Examples
Figure imgf000065_0001
Examples 111 to 120
Figure imgf000066_0001
Examples 121 to 130
Examples 131 to 140
Figure imgf000067_0001
Examples 141 to 145
Figure imgf000068_0001
The compounds of Formula (I) have also been shown to inhibit ALK kinases. ALK kinase activity was determined by measuring the kinase's ability to phosphorylate a tyrosine residue within a peptide substrate using a mobility shift assay on a Caliper LC3000 reader (Caliper, MA), which measures fluorescence of the phosphorylated and unphosphorylated substrate and calculates a ratiometric value to determine percent turnover.
To measure ALK kinase activity, a commercially available purified enzyme may be used. The enzyme may be N-terminal GST-tagged, recombinant, human ALK, amino acids 1058-1620, (Genbank Accession number NP_004295) expressed in insect cells and activated in-vitro via autophosphorylation (Invitrogen CA). After incubation of the kinase with a FAM labeled SRCtide substrate, adenosine triphosphate (ATP), and MgCl2 for 90 minutes at room temperature, the kinase reaction may be stopped by the addition of 36 mM ethylenediaminetetraacetic acid (EDTA). The reaction may be performed in 384 well microtitre plates and the reaction products may be detected using the Caliper LC3000 Reader.
Figure imgf000069_0001
When tested in an in-vitro assay based on the one described above, the ALK inhibitory activity of the following examples was measured at the following IC50S. The absence of a listed IC50 value for any particular example is not intended to imply that the particular compound does not possess ALK IC50 activity.
Figure imgf000069_0002
Thus, in one aspect, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament.
In another aspect, there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of myeloproliferative disorders, myelodysplastic syndrome, and cancer, in a warm-blooded animal such as man.
In still another aspect, there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of myeloproliferative disorders, myelodysplastic syndrome and cancers (solid and hematologic tumors), fϊbroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acromegaly, acute and chronic inflammation, bone diseases, and ocular diseases with retinal vessel proliferation, in a warm-blooded animal such as man.
In yet another aspect, there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and cancers selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, mesothelioma, renal cancer, lymphoma and leukaemia, in a warm-blooded animal such as man.
In a further aspect, there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the production of an anti-proliferative effect, in a warm-blooded animal such as man.
In still a further aspect, there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the production of a JAK inhibitory effect. In yet a further aspect, there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the production of an ALK inhibitory effect.
In one aspect, there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.
In another aspect, there is provided a method for treating myeloproliferative disorders, myelodysplastic syndrome, and cancer, in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
In still another aspect, there is provided a method for treating myeloproliferative disorders, myelodysplastic syndrome, and cancers (solid and hematologic tumors), fϊbroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acromegaly, acute and chronic inflammation, bone diseases, and ocular diseases with retinal vessel proliferation, in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
In yet another aspect, there is provided a method for treating chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and cancers selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, mesothelioma, renal cancer, lymphoma and leukaemia, in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of compound of Formula (I), or a pharmaceutically acceptable salt thereof.
In a further aspect, there is provided a method for producing an anti-proliferative effect in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
In still a further aspect, there is provided a method for producing a JAK inhibitory effect in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
In yet a further aspect, there is provided a method for producing an ALK inhibitory effect in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
In one aspect, there is provided a method for treating cancer in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
In another aspect, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating myeloproliferative disorders, myelodysplastic syndrome, and cancer, in a warm-blooded animal such as man.
In still another aspect, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating myeloproliferative disorders, myelodysplastic syndrome, and cancers (solid and hematologic tumors), fϊbroproliferative and differentiative disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, acromegaly, acute and chronic inflammation, bone diseases, and ocular diseases with retinal vessel proliferation, in a warm-blooded animal such as man.
In yet another aspect, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treating chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and cancers selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, mesothelioma, renal cancer, lymphoma and leukaemia, in a warm-blooded animal such as man.
In a further aspect, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the production of an anti -proliferative effect, in a warm-blooded animal such as man.
In still a further aspect, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the production of a JAK inhibitory effect in a warm-blooded animal such as man.
In yet a further aspect, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the production of an ALK inhibitory effect in a warm-blooded animal such as man.
In one aspect, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in a warm-blooded animal such as man.
In another aspect, where reference is made to the treatment (or prophylaxis) of cancer, it may particularly refer to the treatment (or prophylaxis) of mesoblastic nephroma, mesothelioma, acute myeloblastic leukemia, acute lymphocytic leukemia, multiple myeloma, oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer including secretory breast cancer, colorectal cancer, prostate cancer including hormone refractory prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, renal cancer, lymphoma, thyroid cancer including papillary thyroid cancer, mesothelioma, leukaemia, tumors of the central and peripheral nervous system, melanoma, fibrosarcoma including congenital fibrosarcoma and osteosarcoma. More particularly it refers to prostate cancer. In addition, more particularly it refers to SCLC, NSCLC, colorectal cancer, ovarian cancer and / or breast cancer. In a further aspect it may refer to hormone refractory prostate cancer.
In still another aspect, there is provided a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
In yet another aspect, there is provided a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.
Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl />-hydroxybenzoate; and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions generally contain the active ingredient in finely powdered form or in the form of nano or micronized particles together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives such as ethyl or propyl p_-hydroxybenzoate; anti-oxidants such as ascorbic acid); coloring agents; flavoring agents; and/or sweetening agents such as sucrose, saccharine or aspartame.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as arachis oil, olive oil, sesame oil or coconut oil or in a mineral oil such as liquid paraffin. The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally- occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavoring and preservative agents.
Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavoring and/or coloring agent.
The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol. Compositions for administration by inhalation may be in the form of a conventional pressurized aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.
For further information on formulation the reader is referred to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.
The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 4 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.
As stated above the size of the dose required for the therapeutic or prophylactic treatment of a particular disease state will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated. Preferably a daily dose in the range of 1-50 mg/kg is employed. Accordingly, the optimum dosage may be determined by the practitioner who is treating any particular patient.
The anti-cancer treatment defined herein may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti -tumor agents: (i) antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines including 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea); antitumor antibiotics (for example anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids such as vincristine, vinblastine, vindesine and vinorelbine and taxoids such as taxol and taxotere); and topoisomerase inhibitors (for example epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan and camptothecin); and proteosome inhibitors (for example bortezomib [Velcade®]); and the agent anegrilide [Agrylin®]; and the agent alpha-interferon;
(ii) cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5α-reductase such as finasteride; (iii) agents which inhibit cancer cell invasion (for example metalloproteinase inhibitors such as marimastat and inhibitors of urokinase plasminogen activator receptor function);
(iv) inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab [Herceptin™] and the anti-erbbl antibody cetuximab [C225]) , farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as
N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, AZDl 839), N-(3-ethynylphenyl)-6,7-bis (2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033)), for example inhibitors of the platelet-derived growth factor family and for example inhibitors of the hepatocyte growth factor family, for example inhibitors or phosphotidylinositol 3-kinase (PI3K) and for example inhibitors of mitogen activated protein kinase (MEK1/2) and for example inhibitors of protein kinase B (PKB/Akt), for example inhibitors of Src tyrosine kinase family and/or Abelson (AbI) tyrosine kinase family such as AZD0530 and dasatinib (BMS-354825) and imatinib mesylate
(Gleevec™); and any agents that modify STAT signalling;
(v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [Avastin™], compounds such as those disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds that work by other mechanisms (for example linomide, inhibitors of integrin αvβ3 function and angiostatin);
(vi) vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
(vii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
(viii) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; (ix) immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine -transfected tumor cell lines and approaches using anti-idiotypic antibodies and approaches using the immunomodulatory drugs thalidomide and lenalidomide [Revlimid®]; and (x) other treatment regimes including: dexamethasone, proteasome inhibitors (including bortezomib), isotretinoin (13-cis retinoic acid), thalidomide, revemid, Rituxamab,
ALIMTA, Cephalon's kinase inhibitors CEP-701 and CEP-2563, anti-Trk or anti-NGF monoclonal antibodies, targeted radiation therapy with 1311-metaiodobenzylguanidine (131I-MIBG), anti-G(D2) monoclonal antibody therapy with or without granulocyte- macrophage colony-stimulating factor (GM-CSF) following chemotherapy.
Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention, or pharmaceutically acceptable salts thereof, within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
In addition to its use in therapeutic medicine, compounds of Formula (I) and pharmaceutically acceptable salts thereof are also useful as pharmacological tools in the development and standardization of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of JAK2 in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
In any of the above-mentioned pharmaceutical composition, process, method, use, medicament, and manufacturing features of the instant invention, any of the alternate embodiments of the compounds of the invention described herein also apply.
In one aspect, the inhibition of JAK activity particularly refers to the inhibition of JAK2 activity.
Process If not commercially available, the necessary starting materials for the procedures such as those described herein may be made by procedures which are selected from standard organic chemical techniques, techniques which are analogous to the synthesis of known, structurally similar compounds, or techniques which are analogous to the described procedure or the procedures described in the Examples. It is noted that many of the starting materials for synthetic methods as described herein are commercially available and/or widely reported in the scientific literature, or could be made from commercially available compounds using adaptations of processes reported in the scientific literature. The reader is further referred to Advanced Organic Chemistry, 5X Edition, by Jerry March and Michael Smith, published by John Wiley & Sons 2001, for general guidance on reaction conditions and reagents.
It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in compounds. The instances where protection is necessary or desirable are known to those skilled in the art, as are suitable methods for such protection. Conventional protecting groups may be used in accordance with standard practice (for illustration see T.W. Greene, Protective Groups in Organic Synthesis, published by John Wiley and Sons, 1991) and as described hereinabove.
Compounds of Formula (I), Formula (Ia), and Formula (Ib) may be prepared in a variety of ways. The Processes and Scheme shown below illustrate some methods for synthesizing compounds of Formula (I), Formula (Ia), and Formula (Ib) (wherein Ring A, Ring B, Ring C, X, R1, and R3 unless otherwise defined, are as defined hereinabove). Where a particular solvent or reagent is shown in a Scheme or referred to in the accompanying text, it is to be understood that the chemist of ordinary skill in the art will be able to modify that solvent or reagent as necessary. The Processes and Scheme are not intended to present an exhaustive list of methods for preparing the compounds of Formula (I), Formula (Ia), and Formula (Ib); rather, additional techniques of which the skilled chemist is aware may be also be used for the compounds' synthesis. The claims are not intended to be limited to the structures shown in the Processes and Schemes.
The skilled chemist will be able to use and adapt the information contained and referenced within the above references, and accompanying Examples therein and also the Examples and Schemes herein, to obtain necessary starting materials and products.
1) Process A - reacting a compound of Formula (A):
Figure imgf000082_0001
ormula (A) with a compound of Formula (B):
Figure imgf000082_0002
Formula (B); or
2) Process B - reacting a compound of Formula (C):
Figure imgf000082_0003
Formula (C) with a compound of Formula (D):
Formula (D);
Figure imgf000082_0004
3) Process C - reacting a compound of Formula (F) with Ring A: mula (F) with a compound of Formula (H):
F mula (H)
Figure imgf000083_0001
and thereafter if necessary: i) converting a compound of Formula (I) into another compound of Formula (I); ii) removing any protecting groups; and/or iii) forming a pharmaceutically acceptable salt, wherein L in each occurrence may be the same or different, and is a leaving group as described hereinabove.
For each of Processes A and B, it is to be understood that protecting groups may be used as necessary. Leaving groups suitable for use in Processes A and B include halo groups such as chloro. The Processes are discussed in more detail below.
Process A - Compounds of Formula (A) and compounds of Formula (B) may be reacted together in the presence of a suitable solvent, examples of which include ketones such as acetone, alcohols such as ethanol and butanol, and aromatic hydrocarbons such as toluene and N-methyl pyrrolid- 2-one. The reaction may advantageously occur in the presence of a suitable base, examples of which include inorganic bases such as potassium carbonate and cesium carbonate, and organic bases such as potassium tert-butoxide and sodium tert-butoxide. The reaction may be advantageously performed at a temperature in a range from 0 C to reflux. Heating the reaction may be particularly advantageous.
In another aspect, compounds of Formula (A) and compounds of Formula (B) may be reacted together under standard Buchwald conditions (for example see J. Am. Chem. Soc, 118, 7215; J. Am. Chem. Soc, 119, 8451; J. Org. Chem., 62, 1568 and 6066), with a suitable base. Examples of suitable bases include inorganic bases such as cesium carbonate, and organic bases such as potassium ϊ-butoxide. Such a reaction may advantageously occur in the presence of a palladium catalyst such as palladium acetate. Examples of solvents suitable for such a reaction include toluene, benzene, dioxane, and xylene. The -NH- moiety of the compound of Formula (B) may advantageously be protected with a suitable protecting group, examples of which include protecting groups such as tert-butoxycarbonyl.
Process B - Compounds of Formula (D) and compounds of Formula (C) may be reacted together under conditions similar to those described for the reaction of compounds of Formula (A) with compounds of Formula (B).
Process C- Compounds of Formula (F) and Ring A may be reacted together under conditions similar to those described for the reaction of compounds of Formula (A) with compounds of
Formula (B).
Compounds of Formula (A) may be prepared according to Scheme 1:
Scheme 1
ula (D) Formula (E)
Figure imgf000085_0001
mula (A) wherein L in each occurrence may be the same or different, and is a leaving group as described hereinabove.
Compounds of Formula (D) and compounds of Formula (E) may be reacted together under conditions similar to those described for the reaction of compounds of Formula (A) with compounds of Formula (B).
Compounds of Formula (C) may be prepared according to Scheme 2:
Scheme 2
Form Formula (B) Formula (C)
Figure imgf000085_0002
wherein L in each occurrence may be the same or different, and is a leaving group as described hereinabove.
Compounds of Formula (B) and compounds of Formula (E) may be reacted together in the presence of a suitable solvent, examples of which include ketones such as acetone, alcohols such as ethanol and butanol, and aromatic hydrocarbons such as toluene and N-methylpyrrolid-2-one. The reaction advantageously will take place in the presence of a suitable base, examples of which include inorganic bases such as potassium carbonate and cesium carbonate, and organic bases such as potassium tert-butoxide and sodium tert-butoxide. The reaction is advantageously performed at a temperature in a range from 0°C to reflux.
Compounds of Formula (F) may be prepared according to Scheme 3:
Scheme 3
F (D) mula (F)
Figure imgf000086_0001
wherein L in each occurrence may be the same or different, and is a leaving group as described hereinabove.
Compounds of Formula (D) and compounds of Formula (G) may be reacted together under conditions similar to those described for the reaction of compounds of Formula (A) with compounds of Formula (B).
Examples The invention will now be further described with reference to the following illustrative examples in which, unless stated otherwise:
(i) temperatures are given in degrees Celsius (°C); operations are carried out at room temperature or ambient temperature, that is, in a range of 18-25 °C;
(ii) organic solutions were dried over anhydrous magnesium sulfate unless other wise stated; evaporation of organic solvent was carried out using a rotary evaporator under reduced pressure (4.5 - 30 mmHg) with a bath temperature of up to 60 °C; (iii) chromatography means flash chromatography on silica gel; thin layer chromatography (TLC) was carried out on silica gel plates;
(iv) in general, the course of reactions was followed by TLC or liquid chromatography/mass spectroscopy (LC/MS) and reaction times are given for illustration only;
(v) final products have satisfactory proton nuclear magnetic resonance (NMR) spectra and/or mass spectra data;
(vi) yields are given for illustration only and are not necessarily those which can be obtained by diligent process development; preparations were repeated if more material was required;
(vii) when given, NMR data is in the form of delta values for major diagnostic protons, given in part per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz in DMSO-dβ unless otherwise stated; For NMR, MeOD refers to CD4OD, CH2Cl2 refers to CD2Cl2. With regard to both the Intermediates and Examples, in many instances the 1H NMR peak corresponding to the pyrazole C-4' proton was not always obvious. (viii) chemical symbols have their usual meanings;
(ix) solvent ratio was given in volume : volume (v/v) terms.
(x) "ISCO" refers to normal phase flash column chromatography using pre-packed silica gel cartridges (12 g, 40 g etc.), used according to the manufacturer's instructions, obtained from ISCO, Inc, 4700 Superior Street Lincoln, NE, USA. (xi) "Gilson chromatography" refers to separation/purifϊcatio using a YMC-AQC 18 reverse phase HPLC Column with dimension 20 mm/100 and 50 mm/250 in H2O/MeCN with 0.1% TFA as mobile phase unless otherwise stated and used according to the manufacturer's instructions, obtained from Gilson, Inc. 3000 Parmenter Street, Middleton, WI 53562-0027, U.S.A. (xii) "Biotage" refers to normal phase flash column chromatography using pre-packed silica gel cartridges (12g, 4Og, 80 g etc.), used according to the manufacturer's instructions, obtained from Biotage Inc, 1725 Discovery Drive Charlotteville, Virginia 22911, USA. (xiii) "SFC (super critical fluid chromatography)" refers to Analytical SFC (ASC- 1000
Analytical SFC System with Diode Array Detector) and/or Preparative SFC (APS- 1000 AutoPrep Preparative SFC), used according to the manufacturer's instruction, obtained from SFC Mettler Toledo AutoChem, Inc. 7075 Samuel Morse Drive Columbia MD 21046, U.S.A. (xiv) Conditions (A) for Preparative SFC: Oven 40°C, Flow: 60ml/min, Outlet Pressure:
100 bar, Wavelength: 254nm and/or 220 nm unless otherwise specified (xv) Conditions (B) for Analytical SFC for chiral determination: Oven 35°C, Flow:
5ml/min, Outlet Pressure: 120 bar, Wavelength for e.e. determination: 254nm and/or 220 nm unless otherwise stated, (xvi) Column and solvent conditions: AD (or AS or OJ or OD-) corresponds to the chiral column (see below), a number from 1-4 would correspond to mobile phase modifier, - number (corresponding to the % of mobile phase modifier). For instance: AD-3-20 indicates Chiralpak AD with 20% of methanol, 0.4%dimethylethylamine used for chiral purification or e.e. determination (xvii) For mobile phase modifier: l=Methanol, 2=isopropanol, 3=methanol,
0.4%dimethylethylamine and 4=isopropanol, 0.4%dimethylethylamine (xviii) Chiralcel® OJ and OD or Chiralpak® AS, IA and AD columns are used according to the manufacturers instruction obtained from Chiral Technologies,Inc. 800 NorthFivePointsRoad WestChester, PA19380, USA (xix) Enantiomeric excess for each individual enantiomer (e.e.): > % calculated using area percent at 220 nm or 254nm (xx) After chiral purification, all Examples have e.e. >98% unless otherwise stated,
(xxi) Parr Hydrogenator or Parr shaker type hydrogenators are systems for treating chemicals with hydrogen in the presence of a catalyst at pressures up to 5 atmospheres (60 psi) and temperatures to 80 °C.
(xxii) "H-Cube" refers to the H-Cube continuous hydrogenation equipment manufactured by Thales Nanotechnology. (xxiii) the following abbreviations may have been used:
BINAP 2,2'-bis(diphenylphosphino)- 1 , 1 '-binapthyl
BoC2O tert-butyloxycarbonyl anhydride
DAST Diethylaminosulfur trifluoride
DCM dichloromethane
DIPEA N, N-diisopropylethylamine
DMAc N,N-dimethylacetamide
DMF N,N-dimethylformamide dppf 1 , 1 '-bis(diphenylphosphino)ferrocene
DMAP 4-dimethylaminopyridine
DMSO dimethylsulfoxide
EtOAc ethyl acetate
Et2O diethyl ether
GC gas chromatography
HATU O-(7-Azabenzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
HPLC high-performance liquid chromatography hr hours
LDA Lithium diisopropylamide mins minutes
NMP N-methylpyrrolidone o/n overnight
Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0)
/PrOH z'-propanol rac. rracemic
SEM l-((2-(trimethylsilyl)ethoxy)methyl
TBME tert-butylmethyl ether
TEA triethylamine
TFA trifluoroacetic acid
TFAA trifluoroacetic anhydride
THF tetrahydrofuran TMS trimethyl silyl
Tosyl, Ts para-toluenesulfonyl
Xantphos 9 ,9 -Dimethyl-4 ,5 -bis(diphenylphosphino)xanthene
Intermediate 1
S-Fluoropyrimidine^-carbonitrile
A 10 ml microwave vial was charged with 2-chloro-5-fluoropyrimidine (2.0 g, 15.09 mmol), Pd2(dba)3 (0.549 g, 0.6 mmol), dppf (0.67 g, 1.21 mmol), zinc cyanide (1.15 g, 9.81 mmol), and zinc dust (0.237 mg, 3.62 mmol). The flask was evacuated and backfilled with N2, and anhydrous dimethylacetamide. The vial was mounted onto a Personal Chemistry microwave reactor and heated at 100 °C for 10 hours. The reaction mixture was diluted with EtOAc and then washed with brine three times. The organic layer was obtained and evaporated to dryness. The dried residue was purified by silica gel chromatography (By ISCO Combiflash with gradient EtOAc and hexanes) to afford the title compound as a creamy solid (1.50 g, 80%). GC-MS: 123 [M]. 1H NMR (CDCl3) δ: 8.80 (s, 2H).
Intermediate 2
N-( 1 -(5-Fluoropyrimidin-2-yl)vinyl)acetamide
5-Fluoropyrimidine-2-carbonitrile (Intermediate 1, 1.0 g, 8.1 mmol) in THF (10 ml) was added to a solution of MeMgBr (3.3 ml, 9.75 mmol) in ether drop wise at 0 °C. After addition, the reaction was warmed to room temperature, stirred at room temperature for 1 hour and then diluted with DCM (10 ml). Acetic anhydride (1.23 ml, 13.0 mmol) was added in one portion. The reaction was stirred at room temperature for 1 hour and 40 °C for 1 hour. Saturated sodium bicarbonate solution (10 ml) was added and extracted with EtOAc (2x20 ml). The combined organic was dried over sodium sulfate. After removal of solvent, the resulted residue was purified by column chromatography (hexane-EtOAc = 2.5 : 1) to give the title compound as a white solid
(0.38 g, 26%).
1H NMR (400 MHz) δ: 9.34 (s, 1H), 8.95 (s, 2H), 6.25 (s, 1H), 6.03 (s, 1H), 2.11 (s, 3H).
LC-MS: 182 [M+H]+. Intermediate 3
N-fd^-1-fS-Fluoropyrimidin-1-vDethyllacetamide
To a solution of N-(l-(5-Fluoropyrimidin-2-yl)vinyl)acetamide (Intermediate 2, 0.10 g, 0.55 mmol) in MeOH (5 ml) under N2 was added (+)-1,2-bis((25l, 5S)-2,5- diethylphospholano)benzene (cyclooctadiene)rhodium(I)trifluoromethanesulfonate (0.04 g, 0.0055 mmol). The solution was transferred to a high pressure bomb and charged with 150 psi
H2. The reaction was stirred at room temperature for 4 hours. The solvent was removed and the resulted residue was purified by column chromatography (EtOAc) to give the title compound as a white solid (0.096 g, 95%).
1H NMR (400 MHz) δ: 8.84 (d, 2H), 8.34 (d, 1H), 5.00 (m, 1H), 1.84 (s, 3H), 1.37 (d, 3H). LC-MS: 184 [M+H]+.
Enantiomeric excess determined by SFC (Chiralpak IA; 95:5 CO2MeOH), >99% e.e.
Intermediate 4 tert-Butyl [(15Vl-(5-fluoropyrimidin-2-yl)ethyl-|carbamate N-[(1S> l-(5-Fluoropyrimidin-2-yl)ethyl]acetamide (Intermediate 3, 0.20 g, 1.09 mmol), DMAP (0.027 g, 0.22 mmol) and BoC2O (0.60 g, 2.73 mmol) in THF (10 ml) was stirred at 50 °C for 40 hours. After cooling to room temperature, lithium hydroxide monohydrate (0.094 g, 2.24 mmol) and water (10 ml) was added. The reaction was stirred at room temperature for 9 hours. Ether (30 ml) was added, organic layer was separated, washed with brine (20 ml) and dried over sodium sulfate. After removal of solvent, the resulted residue was purified by column chromatography (Hex-EtOAc=5:l) to give the title compound as a pale yellow oil (0.21 g, 80%). 1H NMR (400 MHz) δ: 8.84 (s, 2H), 7.24 (d, 1H), 4.74 (m, 1H), 1.35 (s, 12H). LC-MS: 242 [M+H]+.
Intermediate 5
( IS)- 1 -(5-Fluoropyrimidin-2-yl)ethanamine hydrochloride
To a solution of tert-butyl [(l.S)-1-(5-fluoropyrimidin-2-yl)ethyl]carbamate (Intermediate 4, 0.21 g, 0.87 mmol) in DCM (5 ml) was added HCl (1.3 ml, 5.2 mmol) in dioxane. The reaction was stirred at room temperature for 3 hours. The solvent was removed to give the title compound as a white solid (quantitative). LC-MS: 142 [M+H]+.
Intermediate 6 tert-Butyl S-amino-S-methyl-1H-pyrazole-1-carboxylate
To a solution of 5-methyl-1H-pyrazol-3-amine (2.48 g, 17.6 mmol) in DCM (70 ml) was added BoC2O (4.0 g, 18.5 mmol) followed by a 4.5 M solution of KOΗ (31 ml, 140.8 mmol) at 0°C. The resulting mixture was stirred at ambient temperature overnight, diluted with more DCM. The combined organic layers dried (MgSO4) and evaporated to give a yellow oil. Purification by column chromatography (Biotage, 20%->30% EtOAc/hexanes) afforded the title compound as a white solid. LC-MS: 198 [M+Η]+.
Intermediate 7
5-Fluoropyridine-2-carbonitrile
A mixture of 2-bromo-5-fluoropyridine (93.0 g, 528 mmol), Zn dust (8.29 g, 127 mmol), zinc cyanide (40.3 g, 343 mmol), dppf (11.7 g, 21.1 mmol) and Pd2dba3 (9.68 g, 10.6 mmol) in anhydrous DMA (300 ml) were heated at 95 °C for 3 hours. After cooling to room temperature, brine (100 ml) and ether (500 ml) was added. The solid formed was removed by filtration and washed with ether (300 ml). The organic layer was separated, washed with brine (200 ml) and dried over sodium sulfate, and concentrated. After removal of solvent, the resulted residue was purified by column chromatography (hexane-DCM = 1 : 1) to give the title compound as a white solid (49 g, 72%). 1H NMR (400 MHz) δ: 8.82 (d, 1H), 8.21 (dd, 1H), 8.05 (dd, 1H).
Intermediate 8 N-( 1 -(5-Fluoropyridin-2-yl)vinyl)acetamide
A solution of MeMgBr (170.3 ml, 510.98 mmol) in ether was diluted with 170 ml of anhydrous THF and cooled to 0 °C. 5-Fluoropyridine-2-carbonitrile (Intermediate 7, 53.6 g, 425.82 mmol) in THF (170 ml) was added dropwise. The reaction was stirred at 0 °C for 30 minutes, then diluted with DCM (170 ml). Acetic anhydride (48.3 ml, 510.98 mmol) in DCM (100 ml) was added drop-wise at 0 °C. After addition, the reaction was warmed to room temperature and stirred at room temperature for 8 hours. Saturated sodium bicarbonate solution (50 ml) was added and extracted with EtOAc (2 x 200 ml). The combined organic was dried over sodium sulfate. After removal of solvent, the resulted residue was purified by column chromatography (hexane-EtOAc = 2.5 : 1) to give the title compound as a white solid (26.6 g, 35%). 1H NMR (400 MHz) δ: 9.37 (s, 1H), 8.57 (d, 1H), 7.81 (m, 2H), 6.01 (s, 1H), 5.52 (s, 1H), 2.08 (s, 3H).
LC-MS: 181 [M+H]+.
Intermediate 9
N-\(IS)- 1 -(5-Fluoropyridin-2-yl)ethyl1 acetamide To a solution of N-(l-(5-fluoropyridin-2-yl)vinyl)acetamide (Intermediate 8, 11.0 g, 61.1 mmol) in MeOH (120 ml) under N2 was added (+)-1,2-bis((25,55)-2,5- diethylphospholano)benzene(cyclooctadiene)rhodium(I)trifluoromethanesulfonate (0.441 g, 0.611 mmol). The solution was transferred to a high pressure bomb and charged 150 psi H2. The reaction was stirred at room temperature and maintained at a pressure between 120-150 psi for 7 hours. The solvent was removed and the resulted residue was purified by column chromatography (EtOAc) to give the title compound as a white solid (9.8 g, 88%). 1H NMR (400 MHz) δ: 8.49 (d, J= 2.4 Hz, 1H), 8.32 (d, J= 7.6 Hz, 1H), 7.66 (m, 1H), 7.39 (dd, J= 4.4 and 8.8 Hz, 1H), 4.95 (m, 1H), 1.85 (s, 3H), 1.34 (d, J= 7.2 Hz, 3H). LC-MS: 183 [M+H]+. Enantiomeric excess determined by HPLC (Chiralpak IA; 70:30 CO2MeOH), 95.3% e.e.
Intermediate 10 tert-Butyl [( 1 S)- 1 -(5-fluoropyridin-2-yl)ethyll carbamate
A solution of N-[(15)-1-(5-fluoropyridin-2-yl)ethyl]acetamide (Intermediate 9, 11.0 g, 60.37 mmol), DMAP (1.48 g, 12.07 mmol) and di-fert-butyl-dicarbonate (26.35 g, 120.7 mmol) in THF (100 ml) was stirred at 50 °C for 20 hours. After cooling to room temperature, lithium hydroxide monohydrate (5.19 g, 123.8 mmol) and water (100 ml) were added. The reaction was stirred at room temperature for 5 hours and diluted with ether (200 ml). The organic layer was separated, washed with brine (100 ml), and dried over sodium sulfate. After removal of solvent, the resulted residue was purified by column chromatography (hexane-EtOAc = 5: 1) to give the title compound as a pale yellow oil (13.6 g, 94%).
1H NMR (400 MHz) δ: 8.46 (d, 1H), 7.69 (m, 1H), 7.35-7.41 (m, 2H), 4.67 (m, 1H), 1.37 (s, 9H), 1.32 (d, 3H). LC-MS: 241 [M+H]+.
Intermediate 11
T(ISV l-(5-Fluoropyridin-2-yl)ethyl-|amine dihydrochloride
To a solution of tert-butyl [(l1S)-1-(5-fluoropyridin-2-yl)ethyl]carbamate (Intermediate 10, 12.8 g, 53.3 mmol) in DCM (100 ml) was added HCl/dioxane solution (107 ml, 4 N, 428 mmol). The reaction was stirred at room temperature for 3 hours. The solvent was removed and 50 ml of saturated sodium bicarbonate was added. The resulting aqueous solution was extracted with ether
(6 x 400 ml), dried over sodium sulfate and concentrated to give the title compound (7.30 g,
98%) as pale yellow oil.
1H NMR (400 MHz) δ: 8.44 (d, 1H), 7.66 (m, 1H), 7.53 (m, 1H), 4.01 (q, 1H), 1.94 (b, 2H), 1.26
(d, 3H). LC-MS: 141 [M+H]+.
The hydrochloride salt may be prepared by dissolving the title compound in MeOH and adding HCl/dioxane solution. Evaporation of the solvents gave the hydrochloride salt of the title product as a tan solid. While it is believed that the title product is in the form of a dihyrochloride salt, it is possible that it exists in the form of the monohydrochloride salt.
Intermediate 12
1 -(5-Fluoropyridin-2-yl)ethanol
To a solution of 5-fluoropyridine-2-carbaldehyde (2.5 g) in Et2θ (50 ml) at 0°C was added drop- wise a solution of MeMgBr (8 ml, 3.0M in Et2θ). The resulting solution was stirred at this temperature for 30 minutes and then it was allowed to warm to ambient temperature over 1 hour.
The mixture was quenched with a solution of saturated NH4Cl^q) and extracted with Et2θ. The organic extracts dried and evaporation gave the title compound (2.6 g).
1H NMR δ 8.43 (s, 1H), 7.69 (m, 1H), 7.55 (m, 1H), 5.40 (d, 1H), 4.71 (m, 1H), 1.33 (d, 3H). Intermediate 13 l-(5-Fluoropyrimidin-2-yr)ethanone
To a solution of 5-fluoropyrimidine-2-carbonitrile (Intermediate 1, 2.5 g) in Et2O (50 ml) at 0°C was added drop-wise a solution of MeMgBr (12 ml, 3.0M in Et2O). The resulting solution was stirred at this temperature for 30 minutes and then it was allowed to warm to ambient temperature overnight. The mixture was quenched with a solution of saturated NH4Cl(aq) and extracted with Et2O. The organic extracts dried and evaporation gave a colored residue. Purification by column chromatography (ISCO, 3% MeOH/DCM) to afford the title compound (800 mg). 1H NMR (CDCl3) δ 8.75 (s, 2H), 2.77 (s, 3H).
Intermediate 14 l-(5-Fluoropyrimidin-2-yl)ethanol
To a solution of l-(5-fluoropyrimidin-2-yl)ethanone (Intermediate 13, 800 mg) in MeOH (40 ml) at 0°C was added portion-wise NaBH4 (12 ml, 3.0M in Et2O). The resulting solution was stirred at room temperature for 30 minutes. The solvent was evaporated and the residue was partitioned between H2O and DCM. The organic layer was washed with saturated NH4Cl(aq) solution, H2O and brine. The organic extracts dried and evaporation gave the tile compound (330 mg).
1H NMR (CDCl3) δ 8.59 (s, 2H), 4.96 (m, 1H), 3.79 (br s, 1H), 1.54 (d, 3H).
Intermediate 15
4-Chloro-N-(5-methyl- 1H-pyrazol-3-yl)-6-morpholino- 1 ,3 ,5-triazin-2-amine In a 100 mL round-bottomed flask were added 4,6-dichloro-N-(5-methyl-1H-pyrazol-3-yl)-1,3,5- triazin-2-amine (Intermediate 18, 2 g, 8.16 mmol), Et3N (1.137 ml, 8.16 mmol), and morpholine (0.711 ml, 8.16 mmol) in ethanol (40.8 ml) to give a yellow suspension. The suspension was stirred for 1 hour at 0 °C whereupon diethyl ether was added. The precipitated solid was filtered and washed with a mixture of EtOAc/diethyl ether (1/1 v/v). The combined filtrates were evaporated under reduced pressure to give an orange oil. Purification by column chromatography (ISCO, 50% EtOAc/hexanes) gave the title compound as a white solid. LC-MS: 296 [M+Η]+. Intermediate 16
CSV6-Chloro-N--f 1 -f S-fluoropyridin-1-yltethylVA^-f 5-methyl- 1H-pyrazol-3 -ylV 1.3.5-triazine-
2,4-diamine
In a 500 mL round-bottomed flask was added 4,6-dichloro-N-(5-methyl-1H-pyrazol-3-yl)-1,3,5- triazin-2-amine (Intermediate 18, 5 g, 20.40 mmol), [(l1Sl)-1-(5-Fluoropyridin-2-yl)ethyl]amine dihydrochloride (Intermediate 11, 4.35 g, 20.40 mmol) and N-ethyl-N-isopropylpropan-2-amine
(7.91 g, 61.21 mmol) in ethanol (51.0 ml) to give a yellow solution. The resulting mixture was stirred at ambient temperature for 24 hours. Evaporation gave the title compound that was used in the next step without any further purification.
LC-MS: 349 [M+Η]+.
Intermediate 17
CSy6-Chloro-N2-( 1 -(5-fluoropyrimidin-2-vDethyl)-Ni-(5-methyl- 1H-pyrazol-3 -vP)- 1 ,3 ,5-triazine-
2,4-diamine
Following a procedure analogous to the one described for the synthesis of Intermediate 16, the title compound was synthesized from 4,6-dichloro-N-(5-methyl-1H-pyrazol-3-yl)-1,3,5-triazin-2- amine (Intermediate 18) and (5)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride
(Intermediate 5). Purification by column chromatography (ISCO, EtOAc-hexanes
50%->EtOAc 100%) gave the title compound as white foam.
LC-MS: 350 [M+Η]+.
Intermediate 18
4,6-Dichloro-N-(5 -methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazin-2-amine
To a solution of 2,4,6-trichloro-1,3,5-triazine (5 g, 27.11 mmol) in EtOH (90 ml) at 0°C was added 5-methyl-1H-pyrazol-3-amine (2.63 g, 27.11 mmol) and Et3N (7.56 ml, 54.23 mmol). The resulting solution was stirred at room temperature overnight. The mixture was triturated with
Et2θ and the title compound was collected via filtration as an off white solid (4.5 g).
LC-MS: 245 [M+Η]+.
Intermediate 19 4-(4-Chloro-6-(l-(5-fluoropyrimidin-2-yl)ethoxy)-1,3,5-triazin-2-yl)morpholine To a microwave tube was added l-(5-fluoropyrimidin-2-yl)ethanol (Intermediate 14, 290 mg, 2.04 mmol), 3 mL t-BuOH and sodium tert-butoxide (196 mg, 2.04 mmol) and the resulting solution was stirred at room temperature for 1 hour under inert atmosphere. The above solution was added to a solution of 4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine (Intermediate 20, 600 mg, 2.55 mmol) in 1 mL t-BuOH / 0.5 mL THF at 0°C over 10 minutes. The resulting reaction mixture was stirred at room temperature overnight. The reaction was filtered under reduced pressure and the collected filtrate was evaporated under reduced pressure to give a colored residue. Purification by column chromatography (ISCO, 50% EtOAc/hexanes) gave 530 mg of the title compound. LC-MS: 341 [M+H]+.
Intermediate 20
4-(4,6-Dichloro-1,3,5-triazin-2-yl)morphorine
In a 500 ml round-bottom flask was added 2,4,6-trichloro-1,3,5-triazine (10.77 g, 58.40 mmol) and DIPEA (20.40 ml, 116.80 mmol) in 200 mL EtOH to give a white emulsion. The solution was cooled to -40°C and morpholine (5.11 ml, 58.40 mmol) in 25 mL EtOH was added slowly at -40°C. The resulting mixture was allowed to warm up to ambient temperature overnight. Evaporation of the volatiles under reduced pressure, gave a residue that was purified by column chromatography (ISCO, 0->10% MeOH in DCM) to afford the title compound as a white solid (6.6 g). LC-MS: 236 [M+H]+.
Intermediate 21
N-[(5-Fluoropyridin-2-yl)methylenel-2-methylpropane-2-sulfϊnamide 5-Fluoro-2-formylpyridine (5g, 40mmol), racemic tert-butyl sulfanamide (9.7g, 80mmol) were dissolved in DCM (10OmL) and CuSO4 (12.8g, 80mmol) was added. The reaction mixture was stirred overnight at room temperature under nitrogen atmosphere. After completion of the reaction as indicated by TLC, the reaction mixture was filtered through Celite® and washed with DCM. The filtrate was evaporated in vacuo to obtain a light yellow oil, which was purified by column chromatography (Hexane/EtOAc = 80:20) to provide the title compound (7.2g, 82%) as a white solid. LC-MS: 229 [M+H]4
Intermediate 22
2-Amino-2-(5-fluoropyridin-2-yl)-N,N-dimethylethanesulfonamide hydrochloride
To a solution of a N,N-dimethy Sulfonamide in 2 mL of anhydrous THF, was slowly added 1.8M of LDA at -78°C. After being stirred for 30 minutes at -78°C, a solution of N-[(5- fluoropyridin-2-yl)methylene]-2-methylpropane-2-sulfϊnamide (Intermediate 21) in 1 mL of anhydrous THF was slowly added into the reaction mixture and stirred additional 2 hours at the same temperature. The reaction was quenched with saturated ammonium chloride solution, extracted with EtOAc, and then dried (NaiSCU). The collected organic layer was concentrated in vacuo to provide a brown oil. This oil was re-dissolved in EtOAc (10 mL) and was slowly added 4M HCl in dioxane at room temperature. The reaction mixture was turned to cloudy solution and then the brown solids were precipitated out. After 2 hours at room temperature, diethyl ether was added for completion of precipitation of the desired product. The resulting solid was collected by filtration, washed with diethyl ether, and dried under high vacuum to give the title compound as off-white powder.
1H NMR (500 MHz) δ ppm 2.67 (s, 6 H) 3.75 (dd, 1H) 3.84 (dd, 1H) 4.79 (m, 1 H) 7.70-7.72 (m, 1H) 7.83-7.85 (m, 1H) 8.69 (s, 1H) 8.89 (br.s., 2H).
Intermediate 23 2-(4-Chloro-6-(5-methyl-1H-pyrazol-3-ylamino)-1,3.5-triazin-2-ylamino)-2-(5-fluoropyridin-2- yl)-N,N-dimethylethanesulfonamide
In a 250 mL round-bottomed flask was added 4,6-dichloro-N-(5-methyl-1H-pyrazol-3-yl)-1,3,5- triazin-2-amine (Intermediate 18, 1 g, 4.08 mmol) and 2-amino-2-(5-fluoropyridin-2-yl)-N,N- dimethylethanesulfonamide hydrochloride (Intermediate 22, 1.158 g, 4.08 mmol) in ethanol (13.60 ml) to give a white suspension. The mixture was cooled to 0°C and DIPEA (2.138 ml,
12.24 mmol) was added via syringe with caution (exothermic reaction). After the evolution of gas (white cloud) ceased, the resulting mixture was stirred at 25 °C for 16 hours. Evaporation of the volatiles gave a yellow residue. Purification by column chromatography (50%EtOAc/hexanes -> 100% EtOAc) gave the title compound as an off white solid (1.5Ig). LC-MS: 456, 457 [M+Η]. Intermediate 24
(i?)-N-(Pyrrolidin-3-vP)acetamide hydrochloride
To a solution of (R)-tert-butyl S-acetamidopyrrolidine-1-carboxylate (1 g, 4.38 mmol) in MeOH (-15 ml) at 25 °C was added with caution a solution of HCl (2.190 mL, 8.76 mmol) in dioxane (4N). The resulting mixture was stirred at this temperature for 1 hour. Evaporation of the volatiles under reduced pressure gave the title product.
Intermediate 25
(i?)-Piperidin-2-ylmethanol hydrochloride To a solution of (R)-tert-buty\ 2-(hydroxymethyl)piperidine-1-carboxylate (Ig, 4.64 mmol) in MeOH (15.48 ml) at 25 °C was added with caution a solution of HCl (1.161 ml, 4.64 mmol) in dioxane (4N). The resulting mixture was stirred at this temperature for 1 hour. Evaporation of the volatiles under reduced pressure gave the title product as a white sticky solid 1H NMR (300 MHz, MeOD) δ ppm 1.40 - 2.09 (m, 6 H) 2.98 (t, 1 H) 3.10 - 3.22 (m, 1 H) 3.30 - 3.42 (m, 1 H) 3.50 - 3.63 (m, 1 H) 3.76 (dd, , 1 H).
Intermediate 26
(i?)-Azetidin-2-ylmethanol hydrochloride
(R)-tert-Buty\ 2-(hydroxymethyl)azetidine-1-carboxylate was reacted using a procedure similar to the one described for the synthesis of Intermediate 25, providing the title product.
Intermediate 27
CSVPiperidin-2-ylmethanol hydrochloride
To a solution of (S)-tert-butyl 2-(hydroxymethyl)piperidine-1-carboxylate (500 mg, 2.32 mmol) in MeOH (~8 ml) at 25 °C was added with caution a solution of HCl (1161 μl, 4.64 mmol) in dioxane (4N). The resulting mixture was stirred at this temperature for 1 hour. Evaporation of the volatiles under reduced pressure gave the title product.
Intermediate 28 3-Methylazetidin-3-ol hydrochloride tert-Butyl S-hydroxy-S-methylazetidine-1-carboxylate (200 mg, 1.07 mmol) was dissolved in MeOH (1.068 mL) at 0°C and HCl 4M in dioxane (0.801 mL, 3.20 mmol) was added. The reaction was then stirred at 0°C for 2 hours and then at 25 °C for 1 hour. The reaction mixture was then concentrated in vacuo providing the title product as a yellow oil (132 mg). 1H NMR (300 MHz, DICHLOROMETHANE-J2) δ ppm 3.64 (s, 2 H) 3.42 (s, 2 H) 1.42 (s, 3 H).
Intermediate 29
3-Fluoroazetidine hydrochloride l-Benzhydryl-3-fluoroazetidine hydrochloride (200 mg, 0.72 mmol) was dissolved in MeOH (50 mL) and processed through the "H-Cube" (10 barr, flow rate ~lml/min, 25°C, using a 20 wt% Pd/Carbon cartridge). Concentration in vacuo gave a white solid (187 mg). This material was dissolved in dioxane (2 mL) at 0° and HCl 4M in Dioxane (0.540 mL, 2.16 mmol) was added. The reaction was then stirred at 25°C. After 1 hour, the reaction mixture was concentrated in vacuo providing the title compound as a clear semi-solid (181 mg).
Intermediate 30 tert-Butyl 4-hvdroxy-4-methylpiperidine- 1 -carboxylate
Methylmagnesium bromide (1.795 g, 15.06 mmol) (3M solution in ether) was cooled in a dry-ice bath, tert-butyl 4-oxopiperidine-l -carboxylate (3.00 g, 15.06 mmol) in THF was added to the reaction mixture drop-wise. The reaction was stirred at -78°C for 1 hour, and quenched with saturated NH4Cl solution at the same temperature. Ethyl acetate was added, and the organic phase separated, dried over MgSO4 and concentrated under reduced pressure. Purification by ISCO (80 g column, 35%->65% EtOAc/hexanes) afforded 1.86 g of the title compound. 1H NMR (300 MHz, DICHLOROMETHANE-J2) δ ppm 1.15 (s, 3 H) 1.35 (s, 9 H) 1.37 - 1.46 (m, 4 H) 2.92 - 3.24 (m, 2 H) 3.46 - 3.66 (m, 2 H).
Intermediate 31
4-Methylpiperidin-4-ol hydrochloride tert-Butyl 4-hydroxy-4-methylpiperidine- 1 -carboxylate (Intermediate 30, 1.82 g, 8.45 mmol) in methanol (10 ml) was cooled to 0°C. HCl (7 ml, 4N in dioxane) was added to the reaction. Ice- bath was removed, and the reaction was stirred at room temp, for 2 hours. Solvent was removed under reduced pressure to afford 1.26 g product of the title compound.
1H NMR (300 MHz, Dichloromethane-^) δ ppm 0.66 - 0.93 (m, 2 H) 1.08 - 1.32 (m, 4 H) 1.64 - 1.74 (m, 1 H) 1.87 - 2.08 (m, 2 H) 3.06 - 3.31 (m, 2 H).
Intermediate 32 Piperidine-4-carbonitrile hydrochloride tert-Butyl 4-cyanopiperidine- 1 -carboxylate (2.100 g, 9.99 mmol) in methanol (15 ml) was added with HCl in z'-PrOH (3 ml, 5-6N solution). The reaction was stirred at room temperature overnight. Solvent was removed to get 1.56 g of the title compound. The material was directly used for the next step reaction without further purification. 1H NMR (300 MHz, MeOD) δ ppm 1.82 - 2.03 (m, 2 H) 2.04 - 2.21 (m, 2 H) 3.00 - 3.15 (m, 3 H) 3.17 - 3.32 (m, 2 H).
Intermediate 33 tert-Butyl 3 -hydroxy-3 -methylpiperidine- 1 -carboxylate To methylmagnesium bromide (IM in butyl ether, 12.5 mL) at -78 °C was added a solution of tert-butyl 3 -oxopiperidine-1 -carboxylate (586 mgs, 2.94 mmol) in THF (5 mL). The reaction mixture was allowed to stir at -78 °C for 2-3 hours, followed by quenching the reaction mixture at -78 °C with saturated NH4Cl solution dropwise. The reaction mixture was then warmed to ambient temperature and extracted with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated to afford a crude residue which was purified directly on an ISCO system (100% hexanes to 100% ethyl acetate) to afford the title compound. The material (0.488 g) was taken on directly into the next step.
Intermediate 34 3-Methylpiperidin-3-ol
To tert-butyl 3-hydroxy-3-methylpiperidine-1-carboxylate (Intermediate 33, 0.488 g, 2.27 mmol) in 5 mL methanol was added 2N HCl in ether solution (10 mL). The reaction was stirred at room temperature for one hour. The reaction mixture was then concentrated under reduced pressure and dried under high vacuum to afford the title compound. Intermediate 35
(i?VN,N-Dimethylmorpholine-3-carboxamide
To (i?)-4-(tert-butoxycarbonyl)morpholine-3-carboxylic acid (0.25 g, 1.08 mmol) in DMF (5 mL) was added dimethylamine (1.62 mL, 3.24 mmol), DIPEA (0.566 mL, 3.24 mmol), and HATU (0.452 g, 1.19 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was extracted with saturated NH4Cl solution and ethyl acetate. The organic layers were collected, dried over MgSO4, filtered, and concentrated to afford a crude residue which was purified on an ISCO system (100% hexanes to 100% ethyl acetate). The desired fractions were collected and dissolved in methanol to which was added 10 mL 2N HCl in diethyl ether solution. The reaction mixture was stirred at room temperature for 2 hours followed by concentration of the reaction mixture to afford the title compound which was used directly in the next step.
Intermediate 36
(i?)-N,N-Dimethyl-2-(morpholin-3-yl)acetamide To (i?)-2-(4-(tert-butoxycarbonyl)morpholin-3-yl)acetic acid (0.35 g, 1.43 mmol) in DMF (5 mL) was added dimethylamine (2.14 mL, 4.28 mmol), DIPEA (0.498 mL, 2.85 mmol), and HATU (0.597 g, 1.57 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was extracted with saturated NH4Cl solution and ethyl acetate. The organic layers were collected, dried over MgSO4, filtered, and concentrated to afford a crude residue which was purified on an ISCO system (100% hexanes to 100% ethyl acetate). The desired fractions were collected and dissolved in methanol to which was added 10 mL 2N HCl in diethyl ether solution. The reaction mixture was stirred at room temperature for 2 hours followed by concentration of the reaction mixture to afford the title compound, which was used directly in the next step.
Intermediate 37
(i?)-N-Methylmorpholine-3-carboxamide
To (i?)-4-(fert-butoxycarbonyl)morpholine-3-carboxylic acid (0.431 g, 1.86 mmol) in DMF (5 mL) was added methanamine (2.80 mL, 5.59 mmol), DIPEA (0.651 mL, 3.73 mmol), and HATU (0.780 g, 2.05 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was extracted with saturated NH4Cl solution and ethyl acetate. The organic layers were collected, dried over MgSO4, filtered, and concentrated to afford a crude residue which was purified on an ISCO system (100% hexanes to 100% ethyl acetate). The desired fractions were collected and dissolved in methanol to which was added 10 mL 2N HCl in diethyl ether solution. The reaction mixture was stirred at room temperature for 2 hours followed by concentration of the reaction mixture to afford the title compound which was used directly in the next step.
Intermediate 38
(yi-β-Chloro-N^fS-cvclopropyl-1H-pyrazol-S-vD-Λ^-d-fS-fluoropyrimidin-1-vDethvD-U.S- triazine-2,4-diamine
4,6-Dichloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-1,3,5-triazin-2-amine (Intermediate 54) and (15)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Intermediate 5) were reacted using a procedure similar to the one described for the synthesis of Intermediate 17, providing the title compound. LC-MS: 376 [M+Η]+.
Intermediate 39
2-(Piperidin-2-yl)acetonitrile hydrochloride tert-Butyl 2-(hydroxymethyl)piperidine-1-carboxylate (400 mg, 1.86 mmol) was dissolved in DCM (3 ml) and Et3N (0.518 mL, 3.72 mmol) was added to it. The mixture was cooled to O°C whereupon Ts-Cl (531 mg, 2.79 mmol) in DCM (3 ml) was added drop-wise at O°C. The reaction mixture was stirred at ambient temperature overnight. Diluted with DCM and the organic phase washed with H2O (2x), dried and evaporated under reduced pressure gave an oil. The oil was dissolved in DMSO (5 mL) and NaCN (273 mg, 5.57 mmol) was added. The reaction mixture was heated at 8O°C over 48 hours. Phases were separated between EtOAc/EkO. The organic layer was washed with H2O (2x), dried and evaporated under reduced pressure gave an oil. The oil was dissolved in MeOH (3 mL) and HCl (2M in ether , 4 mL, 8.00 mmol) was added. The reaction was allowed to stir for 2 hours at room temperature and evaporation in vacuo gave the title product. Intermediate 40
6-Chloro-N2-( 1 -(3 J-difluoropyridin-1-yltethylVA^-f 5-methyl- 1H-pyrazol-3 -ylV 1.3.5-triazine-
2,4-diamine
4,6-Dichloro-N-(5-methyl-1H-pyrazol-3-yl)-1,3,5-triazin-2-amine (Intermediate 18, 1.409 g, 5.75 mmol) and l-(3,5-difluoropyridin-2-yl)ethanamine (Intermediate 105, 1 g, 6.32 mmol) were dissolved in ethanol (16.42 ml) and TEA (1.602 ml, 11.50 mmol) was added. The reaction was then stirred overnight at 25°C. The reaction mixture was concentrated in vacuo leaving an off-white solid (4.649 g). This material was purified by ISCO (0-10% MeOΗ/DCM). The title compound was collected as a yellow solid (2.195 g). LC-MS: 367 [M+Η]+.
Intermediate 41
6-Chloro-N2-(l-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)-Ni-(5-methyl-1H-pyrazol-3-yl)- 1 ,3 ,5-triazine-2,4-diamine 4,6-Dichloro-N-(5-methyl-1H-pyrazol-3-yl)-1,3,5-triazin-2-amine (Intermediate 18, 550 mg, 2.24 mmol) and l-(3,5-difluoropyridin-2-yl)-2-methoxyethanamine (Intermediate 102, 422 mg, 2.24 mmol) were dissolved in ethanol (6.407 mL) at 0°C and TEA (0.938 mL, 6.73 mmol) was added. The reaction was then stirred overnight at 25°C. The reaction mixture was then concentrated in vacuo leaving a yellow solid (810 mg). This material was purified by ISCO (0- 10% MeOΗ/DCM). Concentration of the fractions in vacuo provided the title compound as a white solid (653 mg). LC-MS: 397 [M+Η]+.
Intermediate 42 (i?)-6-Chloro-N2-(l-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)-Ni-(5-methyl-1H-pyrazol-3-yl)- 1 ,3 ,5-triazine-2,4-diamine
4,6-Dichloro-N-(5-methyl-1H-pyrazol-3-yl)-1,3,5-triazin-2-amine (Intermediate 18, 1.964 g, 8.01 mmol) and (R)-1-(3,5-difluoropyridin-2-yl)-2-methoxyethanaminium (R)-mandelic acid salt (Intermediate 95, 3.0 g, 8.82 mmol) were dissolved in ethanol (22.90 ml) and TEA (4.47 ml, 32.06 mmol) was added. The reaction was then stirred overnight at 25°C. The reaction mixture was then concentrated in vacuo leaving a pale yellow semi-solid (7.120 g). This material was then purified by ISCO (50% EtOAc/Hex, 10 min, 60%EtOAc/Hex, 20 min, 70% EtOAc/Hex, 10 min) in ~1.5 g batches. Concentration of the fractions in vacuo provided the title compound as a white solid (2.024 g), with a 64% yield
1H NMR (300 MHz, MeOD) δppm 8.38 (s, 1 H) 7.58 (td, 1 H) 6.22 - 6.55 (m, 1 H) 5.71 (t,l H) 3.63 - 3.95 (m, 2 H) 3.35 (s, 3 H) 2.26 (br. s., 3 H). LC-MS: 397 [M+H]+.
Intermediate 43
^)-fer?-Butyl-3-(methylsulfonamidomethyl)morpholine-4-carboxylate In a 10 mL vial, methanesulfonyl chloride (0.170 ml, 2.20 mmol) and (R)-tert-butyl 3-
(aminomethyl)morpholine-4-carboxylate (0.396 g, 1.83 mmol) were combined in THF (3.66 ml) to give a colorless solution. The reaction was stirred at 23 °C for 30 minutes and was poured into 10 % aqueous K2HPO4 (20 ml), and rinsed with EtOAc (2 x 20 ml). The organic fractions were combined and rinsed with brine (20 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to yield the title compound as an orange oil.
Intermediate 44
(i?)-N-(Morpholin-3 -ylmethvDmethanesulfonamide hydrochloride
(R)-tert-Buty\ 3-(methylsulfonamidomethyl)morpholine-4-carboxylate (Intermediate 43, 539 mg, 1.83 mmol) was dissolved in MeOH (1.831 mL) and HCl 4M in Dioxane (1.831 mL, 7.32 mmol) was added. The reaction was then stirred at 25°C. After 2 hours, the reaction mixture was concentrated in vacuo leaving the title compound as an orange solid (407 mg).
Intermediate 45 (RYtert- Butyl 3-((ethoxycarbonylamino)methyl)morpholine-4-carboxylate
In a 10 mL vial, ethyl chloroformate (0.330 ml, 3.36 mmol) and (R)-tert-buty\ 3- (aminomethyl)morpholine-4-carboxylate (0.605 g, 2.80 mmol) were combined in THF (5.59 ml) to give a colorless solution. The reaction was stirred at 23 °C for 30 minutes and was poured into 10 % aqueous K2HPO4 (20 ml), and rinsed with EtOAc (2 x 20 ml). The organic fractions were combined and rinsed with brine (20 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to yield the title compound as an orange oil.
Intermediate 46
Ethyl r(3iO-morpholin-3-ylmethyll carbamate hydrochloride
(R)-tert-Butyl 3-((ethoxycarbonylamino)methyl)morpholine-4-carboxylate (Intermediate 45, 807 mg, 2.80 mmol) was dissolved in MeOH (2.799 mL) and HCl 4M in Dioxane (2.80 mL, 11.20 mmol) was added. The reaction was then stirred at 25°C. After 2 hours, the reaction mixture was concentrated in vacuo leaving the title compound as an off-white, sticky solid (445 mg).
Intermediate 47
(i?)-(4-(4-Methoxybenzyl)morpholin-3-yl)methanol
To a solution of (i?)-morpholin-3-ylmethanol hydrochloride (1.7g, l lmmol) dissolved in DMF (3OmL) was added K2CO3 (3.82g, 27mmol) followed by l-(bromomethyl)-4-methoxybenzene (2.33g, 11.6mmol) with vigorous stirring at room temperature. The mixture was stirred at ambient temperature overnight. The mixture was diluted with EtOAc and the organic phase was washed with H2O and dried. Purification by ISCO (CH2CyCH3OHZNH4OHiIOOZO -> 100Z3Z0.3). gave the title compound (2.65g).
1H NMR (CH2Cl2) δ 7.21 (d, 2H), 6.87(d, 2H), 4.04(d, 1H), 3.88 (dd, 1H), 3.78 (s, 3H), 3.70 (m, 1H), 3.60 (m, 1H), 3.47 (m, 2H), 3.19 (s, 1H), 1.87 (d, 1H), 2.67 (m, 1H), 2.51 (m, 2H), 2.26 (m, 1H).
LC-MS: 238 [M+H]+.
Intermediate 48
(5)-(4-(4-Methoxybenzyl)morpholin-3-yl)methyl 4-methylbenzenesulfonate (i?)-(4-(4-Methoxybenzyl)morpholin-3-yl)methanol (Intermediate 47, 1.7g, 7.16 mmol) in DCM (20 mL) was treated with Et3N (3.99 mL, 28.66 mmol) and the resulting solution was stirred at
O°C. 4-methylbenzene-1-sulfonyl chloride (2.73 g, 14.33 mmol) was added portion-wise and the mixture was allowed to stir at room temperature for 1 hour. The reaction mixture was partitioned between H2O and CH2Cl2. The organic phase was separated and dried over Na2SO4 and evaporation of the volatiles under reduced pressure gave the title compound. Intermediate 49
(i?)-4-(4-Methoxybenzyl)-3-(methoxymethyl)morpholine
To a solution of (5)-(4-(4-methoxybenzyl)morpholin-3-yl)methyl 4-methylbenzenesulfonate
(Intermediate 48, 1.2g, 3.07 mmol) in anhydrous CH3OH (1OmL) was added powder NaOCH3 (0.497 g, 9.20 mmol). The reaction mixture was stirred at room temperature for 1 hour and consequently heated at 8O°C for 4 hours. Partition between CH2CI2 and H2O and the combined organic phase was concentrated under reduced pressure. Purification by ISCO (hexanes/Et2θ with 1% Et3N= 100/0^ 100/20) gave the title compound (0.380 g, 49.3 %). 1H NMR (CD2Cl2) δ 7.27 (d, 2H), 6.87 (d, 2H), 4.01 (d, 1H), 3.78 (s, 3H), 3.62 (m, 2H), 3.44 (m, 3H), 3.32 (s, 3H), 3.26 (d, 1H), 2.62 (m, 2H), 2.19 (m, 1H). LC-MS: 252 [M+H]+.
Intermediate 50
(R)-3 -(Methoxymethyl)morpholine hydrochloride The solution of (i?)-4-(4-methoxybenzyl)-3-(methoxymethyl)morpholine (Intermediate 49, 440mg, 1.75 mmol) in CH3OH (5mL) was degassed and Pd(OH)2 on C (20% w, 40mg) was added. The resulting mixture was subjected to a hydrogen atmosphere and stirred for 48 hours. The catalyst was filtered via Celite and the resulting filtrate was treated with HCl. After stirring for 30 minutes, evaporation of the volatiles under reduced pressure gave the title compound.
Intermediate 51
(5)-4-(4-Methoxybenzyl)morpholine-3-carbaldehvde
A DMSO (1.669 mL, 23.52 mmol) solution in DCM (8mL) was cooled at -78°C and oxalyl chloride (1.029 mL, 11.76 mmol) in DCM (2mL) was added drop-wise. The mixture was stirred at -78°C for 15 minutes whereupon a solution of (i?)-(4-(4-methoxybenzyl)morpholin-3- yl)methanol (Intermediate 47, 0.93g, 3.92 mmol) in CH2Cl2 (2mL) was added in 30min. The resulting mixture was stirred at -78°C for 16 hours and Et3N (6.56 mL, 47.03 mmol) was added drop wise at -78°C. The resulting mixture was warmed to r.t over 30 mins. The mixture was partitioned between CH2Cl2 and saturated aq. NaHCO3 solution. The organic phase was separated and removal of the volatiles under reduced pressure gave the title compound.
Intermediate 52
(5)-3-(Difluoromethyl)-4-(4-methoxybenzyl)morpholine (.S)-4-(4-Methoxybenzyl)morpholine-3-carbaldehyde (Intermediate 51, 0.922 g, 3.92mmol) in CH2Cl2 (12mL) was cooled to O°C and DAST was added drop-wise at 0-5°C. The reaction mixture was stirred at room temperature overnight. The mixture was partitioned between DCM/saturated aqueous NaHCO3 solution. The organic layer washed with H2O, dried and evaporation of the volatiles under reduced pressure gave a residue. Purification by ISCO (Hexanes/EtOAc with 1% Et3N= 100/0 -» 100/30 gave the title compound (280mg). LC-MS: 258 [M+H]+.
Intermediate 53
(S)S -(DifluoromethvDmorpholine hydrochloride
A solution of fS/)-3-(difluoromethyl)-4-(4-methoxybenzyl)morpholine (Intermediate 52, 257mg, 1.00 mmol) in CH3OH (5mL) was degassed and Pd(OH)2 on C (20% w, 50mg) was added. The resulting mixture was subjected to a hydrogen atmosphere and stirred for 48 hours. The catalyst was filtered via Celite and the resulting filtrate was treated with HCl. After stirring for 30 minutes, evaporation of the volatiles under reduced pressure gave the title compound.
Intermediate 54
4,6-Dichloro-N-(5-cvclopropyl- 1H-pyrazol-3-ylV 1 ,3 ,5-triazin-2-amine
S-Cyclopropyl-1H-pyrazol-S-amine (200 mg, 1.63 mmol) was dissolved in ethanol (4.648 mL) and cooled to 0°C. 2,4,6-trichloro-1,3,5-triazine (300 mg, 1.63 mmol) and TEA (0.453 mL, 3.25 mmol) were then added slowly. The reaction was then stirred overnight at 25°C. The reaction mixture was cooled to 0°C and filtered. A pale yellow solid (136 mg) was collected. The filtrate was also concentrated in vacuo and purified by ISCO (15-50% EtOAc/Ηex). Concentration of the fractions in vacuo provided the title compound a pale peach solid (48 mg). LC-MS: 272 [M+Η]+.
Intermediate 55 ^j-β-Chloro-N-rS-cvclopropyl-1H-pyrazol-S-vD-Λ^-d-O.S-difluoropyridin-1-vD-1- methoxyethylM,3.5-triazine-2,4-diamine
4,6-Dichloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-1,3,5-triazin-2-amine (Intermediate 54, 184 mg, 0.68 mmol) and (R)-1-(3,5-difluoropyridin-2-yl)-2-methoxyethanaminium (R)-mandelic acid salt (Intermediate 95, 254 mg, 0.75 mmol) were dissolved in ethanol (1.939 mL) and TEA (0.378 mL, 2.71 mmol) was added. The reaction was then stirred overnight at 25°C. The reaction mixture was then concentrated in vacuo leaving a pale yellow semi-solid (641 mg). This material was purified by ISCO (50%EtOAc/Ηex, 10 min, 60%EtO Ac/Hex, 20 min, 70% EtO Ac/Hex, 10 min). Concentration of the fractions in vacuo provided the title compound as a white solid (201 mg). LC-MS: 423 [M+H]+.
Intermediate 56 l-(3,5-Difluoro-4-(trimethylsilyl)pyridin-2-yl)-2-ethoxyethanone
To a solution of 3,5-difluoropyridine (2.99 g, 25.98 mmol) in tetrahydrofuran (87 ml) was added LDA (14.43 ml, 25.98 mmol) at -78 °C. The resulting mixture was stirred for 1 hour at this temperature whereupon TMS-Cl (3.32 ml, 25.98 mmol) was added. Additional LDA (14.43 ml, 25.98 mmol) was added and the mixture was stirred at -78 °C for 1 hour whereupon ethyl 2- ethoxyacetate (3.54 ml, 25.98 mmol) was added in one portion.The mixture was allowed to warm to room temperature over 30 minutes whereupon NH4CI (sat) was added. The mixture was diluted with EtOAc and the organic phase was washed with H2O, brine and dried. Evaporated under reduced pressure gave a colored oil. Purification by column chromatography (10%-30%
EtOAc/hexanes) gave the title compound as an oil that upon standing to air solidified to a tan solid (5.3g).
LC-MS: 274 [M+H]+.
Intermediate 57 l-(3,5-Difluoropyridin-2-yl)-2-ethoxyethanone l-(3,5-Difluoro-4-(trimethylsilyl)pyridin-2-yl)-2-ethoxyethanone (Intermediate 56, 2.11 g, 7.72 mmol) was dissolved in HCl (20 mL, 100.00 mmol) (5N) and the resulting mixture was heated to 60 °C for 2 hours. The mixture was allowed to cool to room temperature whereupon aqueous NaHCθ3(sat) was added slowly until pH~8. The aqueous phase was extracted with EtOAc (3x), dried (MgSO4) and evaporation of the volatiles under reduced pressure afforded l-(3,5- difluoropyridin-2-yl)-2-ethoxyethanone as yellow oil (1.2 g) that was used in the subsequent step without any further purification. LC-MS: 200 [M-H]+.
Intermediate 58 l-(3,5-Difluoropyridin-2-yl)-2-ethoxyethanone oxime
To a solution of l-(3,5-difluoropyridin-2-yl)-2-ethoxyethanone (Intermediate 57, 1.5 g, 7.46 mmol) in ethanol (37.3 ml) was added hydroxylamine hydrochloride (0.518 g, 7.46 mmol) followed by Et3N (1.039 ml, 7.46 mmol). The resulting colored solution was stirred at 25 °C overnight. The volatiles were evaporated under reduced pressure and the residue obtained was re- dissolved in EtOAc. The organic layer was washed with H2O, brine and dried. Purification by ISCO (10%-30% EtOAc/hexanes) provided l-(3,5-difluoropyridin-2-yl)-2-ethoxyethanone oxime as a yellow solid. The title compound was triturated with Et2θ and filtered to give a granular white solid.
1H NMR (300 MHz, MeOD) δ ppm 1.06 (t, 3 H) 3.49 (q, J=7.03 Hz, 2 H) 4.44 (s, 1 H) 4.74 (s, 2 H) 7.56 - 7.73 (m, 1 H) 8.30 - 8.52 (m, 1 H).
Intermediate 59 1 -(3 ,5-Difluoropyridin-2-yl)-2-ethoxyethanamine hydrochloride
To a suspension of (Z)-1-(3,5-difluoropyridin-2-yl)-2-ethoxyethanone oxime (Intermediate 58, 460 mg, 2.13 mmol) in water were added ammonium hydroxide (829 μl, 21.28 mmol) and ammonium acetate (197 mg, 2.55 mmol) in one portion. The mixture was heated to 65 °C and zinc (557 mg, 8.51 mmol) was added in one portion. The mixture was allowed to stir at this temperature for 3 hours, whereupon it was filtered via Celite and washed with EtOAc. The
EtOAc extracts washed with brine and dried (MgSO4). The solvents were evaporated to a volume (~20ml) under reduced pressure (water bath<30°C) and 10 ml of HCL in dioaxne (4N) weas added. The mixture was stirred at room temperature for 30 minutes. Evaporation of the volatiles afforded l-(3,5-difluoropyridin-2-yl)-2-ethoxyethanamine hydrochloride as an off white solid. 1H NMR (300 MHz, MeOD) δ ppm 1.23 (t, 3 H) 3.50 - 3.68 (m, 2 H) 3.72 - 3.93 (m, 2 H) 4.82 - 4.94 (m, 1 H) 7.65 - 7.86 (m, 1 H) 8.45 - 8.53 (m, 1 H).
Intermediate 60
6-Chloro-N2-( 1 -(3.5-difluoropyridin-2-ylV2-ethoxyethylVA^-(5-methyl- 1H-pyrazol-3 -vD- 1,3,5- triazine-2,4-diamine To a solution of 4,6-dichloro-N-(5-methyl-1H-pyrazol-3-yl)-1,3,5-triazin-2-amine (Intermediate 18, 0.522 g, 2.13 mmol) in ethanol (7.10 ml) at 25 °C, was added l-(3,5-difluoropyridin-2-yl)-2- ethoxyethanamine hydrochloride (Intermediate 59, 0.508 g, 2.13 mmol) and DIPEA (1.116 ml, 6.39 mmol). The resulting mixture was stirred at ambient temperature for 12 hours. The volatiles were removed under reduced pressure and the residue was purified by ISCO (50%EtOAc/hexanes-> 100% EtOAc) to give the title compoound as a white solid. LC-MS: 411 [M+Η]+.
Intermediate 61
Ethyl 3-[(fer?-butylsulfϊnyl)aminol-3-(5-fluoropyridin-2-yl)propanoate To a stirred solution of LDA (26.7mL of 2M solution, 53.4 mmol) in anhydrous TBME (15OmL) was added drop-wise a solution of EtOAc (4.47g, 50.9 mmol) in TBME (2OmL) at -78°C under nitrogen atmosphere. After stirring for 30 min, to this was added drop-wise a solution of N-[(5- fluoropyridin-2-yl)methylene]-2-methylpropane-2-sulfinamide (Intermediate 21, 5.8g, 25.43mmol) in TBME (3OmL). After stirring for 2 hours at -78°C (completion of the reaction as indicated by TLC), reaction mixture was quenched by saturated ammonium chloride and warmed to room temperature. The organic layer was separated and the aqueous layer was extracted with EtOAc (2x). The combined organic layer was dried (Na2SU4), and evaporated to provide the title compound (5.2g, 68%) as a mixture of diastereomers (higher Rf is major, lower Rf is minor), after purification by column chromatography (Hexane: EtOAc = 50:50). LC-MS: 317 [M+H]+.
Intermediate 62
N-(2-Cvano-1-(5-fluoropyridin-2-yl)ethyl)-2-methylpropane-2-sulfϊnamide N-[(liT)-(5-Fluoropyridin-2-yl)methylene]-2-methylpropane-2-sulfinamide (Intermediate 21) and acetonitrile were reacted using a procedure similar to the one described for the synthesis of Intermediate 61, providing the title compound. LC-MS: 270 [M+H]+.
Intermediate 63
3-Amino-3-(5-fluoropyridin-2-yl)propanenitrile hydrochloride N-(2-cyano-1-(5-fluoropyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (Intermediate 62) was reacted using a procedure similar to the one described for the synthesis of Intermediate 75, providing the title compound. LC-MS: 219 [M+H] +.
Intermediate 64
(.SVN-fPyrrolidin-S-vDacetamide hydrochloride
To a solution of (S)-tert-butyl S-acetamidopyrrolidine-1-carboxylate (1 g, 4.38 mmol) in MeOH (15 ml) at 25 °C was added with caution a solution of HCl (2.190 mL, 8.76 mmol) in dioxane (4N). The resulting mixture was stirred at this temperature for 1 hour. Evaporation of the volatiles under reduced pressure gave the title product.
Intermediate 66
N-(l-(5-Fluoropyridin-2-yl)-2-(methylsulfonyl)ethyl)-2-methylpropane-2-sulfϊnamide N-[(liT)-(5-Fluoropyridin-2-yl)methylene]-2-methylpropane-2-sulfϊnamide (Intermediate 21) and dimethylsulfone were reacted using a procedure similar to the one described for the synthesis of Intermediate 61, providing the title compound. LC-MS: 323 [M+H]+.
Intermediate 67 l-(5-Fluoropyridin-2-yl)-2-(methylsulfonyl)ethanamine hydrochloride
N-(l-(5-Fluoropyridin-2-yl)-2-(methylsulfonyl)ethyl)-2-methylpropane-2-sulfϊnamide (Intermediate 66) was reacted using a procedure similar to the one described for the synthesis of Intermediate 75, providing the title compound. LC-MS: 219 [M+H]+. Intermediate 68
S-d.l-Dimethylethylsulfinamidol-S-fS-fluoropyridin-1-vDpropanamide The title compound was obtained as a by-product of the synthesis of N-(2-cyano-1-(5- fluoropyridin-2-yl)ethyl)-2-methylpropane-2-sulfϊnamide (Intermediate 62). LC-MS: 287 [M+H] +.
Intermediate 69
3 -Amino-3 -(5 -fluoropyridin-2-vP)propanamide hydrochloride
3-(l,l-Dimethylethylsulfϊnamido)-3-(5-fluoropyridin-2-yl)propanamide (Intermediate 68) was reacted using a procedure similar to the one described for the synthesis of Intermediate 75, providing the title compound. LC-MS: 183 [M+H] +.
Intermediate 70
Ethyl 3-r(fer?-butylsulfϊnyl)aminol-2,2-difluoro-3-(5-fluoropyridin-2-yl)propanoate To a suspension of zinc metal (0.856, 13.14mmol) in anhydrous, degassed THF(14mL) was added ethyl 2-bromo-2,2-difluoroacetate (2.67g, 13.14mmol). The mixture was warmed to 30°C, resulting in a vigorous exothermic reaction. 30 minutes later, the oil bath was removed and additional ethyl 2-bromo-2,2-difluoroacetate(0.5mL) was added to consume the remaining zinc. After cooling to room temperature N-((5-fluoropyridin-2-yl)methylene)-2-methylpropane-2- sulfanamide (Intermediate 21, Ig, 4.38mmol) in THF was added. The reaction was stirred at room temperature for 18 hours. Partitioned between EtOAc and saturated aqueous ammonium chloride. The organic phase was washed with H2O, dried and evaporated under reduced pressure gave the crude product. The crude product was purified by ISCO (EtOAc/Hexane 0-90%) to give the title compound (1.16g). LC-MS: 353 [M+H]+.
Intermediate 71
3-Amino-2,2-difluoro-3-(5-fluoropyridin-2-yl)propan-1-ol hydrochloride To a THF(18mL) solution of ethyl 3-(l,l-dimethylethylsulfϊnamido)-2,2-difluoro-3-(5- fluoropyridin-2-yl)propanoate (Intermediate 70, 1.159 g, 3.29 mmol) was added lithium borohydride (1.810 mL, 3.62 mmol) at 0°C. The solution was warmed up slowly over 3 hours, partitioned between EtOAc and saturated aqueous ammonium chloride. The organic phase was washed with H2O, dried and evaporated under reduced pressure gave the crude product. Crude product was purified by ISCO (EtOAc/hexane 50%) to give N-(2,2-difluoro-1-(5-fluoropyridin- 2-yl)-3-hydroxypropyl)-2-methylpropane-2-sulfinamide. This compound was re-dissolved in ethyl acetate followed by the addition of then 4N HCl in dioxane. The resulting solution was stirred for 1 hour and evaporation of the volatiles under reduced pressure gave the title compound (0.47Og).
Intermediate 72 3-r(fer?-Butylsulfinyl)aminol-3-(5-fluoropyridin-2-yl)propanoic acid
To a stirred solution of ethyl 3-[(tert-butylsulfϊnyl)amino]-3-(5-fluoropyridin-2-yl)propanoate (Intermediate 61, 1.2g, 3.8mmol ) in MeOH (8mL) and THF (8mL) was added a solution of LiOH (480mg, 20mmol) in H2O (4mL). After 2 hours stirring at room temperature (completion of the reaction as indicated by TLC), reaction mixture was acidified with IM citric acid and extracted with EtOAc (3X). The combined organic layers were dried (Na2SO4), and evaporated to obtain the title compound (910mg, 84%) as a thick oil. LC-MS: 289 [M+H]+.
Intermediate 73 3-r(fer?-Butylsulfϊnyl)aminol-3-(5-fluoropyridin-2-yl)-N-methylpropanamide
To a stirred solution of 3-[(tert-butylsulfϊnyl)amino]-3-(5-fluoropyridin-2-yl)propanoic acid (Intermediate 72, 900mg, 3.12mmol), MeNH2- HCl (631mg, 9.36mmol) and HATU (2.37g, 6.24mmol) in anhydrous DMF (3OmL) was added DIPEA (5.13mL, 30mmol). The reaction mixture was stirred overnight at room temperature under nitrogen atmosphere. After completion of the reaction as indicated by TLC, the reaction mixture was diluted with EtOAc, washed with H2O, saturated NaHCOs(aq), and brine. The organic layer was dried (Na2SO4), and evaporated to obtain a residue (320mg). Purification by column chromatography (DCM /MeOH = 90:10) afforded the title compound (280mg, 29%) as a white solid. LC-MS: 302 [M+H]+. Intermediate 74
S-d.l-Dimethylethylsulfinamidol-S-fS-fluoropyridin-1-vD-N.N-dimethylpropanamide 3-[(tert-butylsulfinyl)amino]-3-(5-fluoropyridin-2-yl)propanoic acid (Intermediate 72) and Me2NH- HCl were reacted using a procedure similar to the one described for the synthesis of Intermediate 73, providing the title compound. LC-MS: 316 [M+H]+.
Intermediate 75
3-Amino-3-(5-fluoropyridin-2-yl)-N-methylpropanamide hydrochloride
To a stirred solution of 3-[(tert-butylsulfϊnyl)amino]-3-(5-fluoropyridin-2-yl)-N- methylpropanamide (Intermediate 73, 280mg, 0.73mmol ) in EtOAc (1OmL ) was added 4M HCl (2M in dioxane) under nitrogen atmosphere. The reaction mixture was stirred for 2 hours at room temperature to obtain a precipitate. The reaction mixture was diluted with TBME (1OmL) and the precipitate was filtered, washed with TBME (10ml) and dried overnight to obtain the title compound hydrochloride salt (175mg, 95%) as a tan solid. 1H NMR (500 MHz) δ: 2.48 (s, 3H), 2.85-2.77 (m, 2H), 4.71-4.70 (m, 1H), 7.58 (dd, 1H), 7.76 (ddd, 1H), 8.14 (d, 1H), 8.59 (s, 1H). LC-MS: 198 [M+H] +.
Intermediate 76 3-(lJ-Dimethylethylsulfϊnamido)-3-(5-fluoropyridin-2-yl)-N,N-dimethylpropanamide hydrochloride
3-(l,l-Dimethylethylsulfϊnamido)-3-(5-fluoropyridin-2-yl)-N,N-dimethylpropanamide
(Intermediate 74) was reacted using a procedure similar to the one described for the synthesis of Intermediate 75, providing the title compound. LC-MS: 212 [M+H] +.
Intermediate 77
N-(2-(fer?-butyldimethylsilyloxy)ethylidene)-2-methylpropane-2-sulfϊnamide To a suspension of rac-2-methylpropane-2-sulfϊnamide (3.10g, 26 mmol) and CuSO4 (8.3g, 52 mmol) in 60 mL DCM, was added tert-butyldimethylsilyloxy acetaldehyde (5.Og, 26 mmol) at room temperature. The mixture was stirred at room temperature for 18 hours and then filtered through a Celite® pad followed by washing with DCM. The filtrate was concentrated in vacuo and then purified by column chromatography (20 to 40% EtOAc/π-haxane) to give the title compound (6.59g, 92%) as a pale yellow oil.
Intermediate 78
N-(2-(fer?-Butyldimethylsilyloxy)-1-(5-fluoropyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide To a solution of 2-bromo-5-fluoropyridine (5.2g, 29 mmol) in 80 mL of anhydrous MTBE was slowly added 1.7M solution of LDA in pentane (21 mL, 36 mmol) at -78°C. After being stirred for 30 minutes at -78°C, a solution of N-(2-(tert-butyldimethylsilyloxy)ethylidene)-2- methylpropane-2-sulfϊnamide (Intermediate 77, 6.59 g, 24 mmol) in 15 mL of anhydrous MTBE was slowly added into the reaction mixture and stirred additional 2 hours at the same temperature. The reaction was quenched with saturated NH4Cl (aq) solution, extracted with EtOAc, dried over anhydrous Na2SO4. The collected organic layer was concentrated in vacuo and then purified by column chromatography (30% EtOAc/hexanes) to give the title compound (8.0g, 90%) as a viscous oil. LC-MS: 375 [M+H]+.
Intermediate 79 tert-Butyl [l-(5-fluoropyridin-2-yl)-2-hvdroxyethyl-|carbamate
To a solution of N-(2-(tert-butyldimethylsilyloxy)-1-(5-fluoropyridin-2-yl)ethyl)-2- methylpropane-2-sulfϊnamide (Intermediate 78, 1.59g, 6 mmol) in 50 mL of EtOAc, was slowly added a 4M solution of HCl in dioxane (4.6 mL) at room temperature. The reaction mixture was turned into a cloudy solution and then white solid started to precipitate out. After 2 hours at room temperature, diethyl ether (5OmL) was added for complete precipitation of a desired product. After being stood for 30 minutes at room temperature, the resulting liquid portion was removed by decantation. The remaining solid portion was dried under vacuum, and used to next step. The solid was added into 2OmL of water, 4OmL of THF and 4.8mL of 5N-NaOH followed by BoC2O (1.7g) at room temperature. After being stirred at room temperature for 2 hours, the reaction was extracted with EtOAc, dried over anhydrous Na2SO4. The collected organic layer was concentrated in vacuo and then purified by column chromatography (40% EtOAc/hexanes) to give the title compound (1.29g, 84%) as a pale yellow oil. LC-MS: 257 [M+H]
Intermediate 80
1 -(5-Fluoropyridin-2-yl)-2-methoxyethanamine hydrochloride
To a solution of a tert-butyl [l-(5-fluoropyridin-2-yl)-2-hydroxyethyl]carbamate (Intermediate 79, 1.27, 5 mmol) in 18 mL of anhydrous THF, was slowly added 20% potassium- ϊ-butoxide solution in THF at -15°C. After being stirred for 20 minutes at the same temperature, was added 0.32 mL of MeI, and then allowed to warm up to room temperature. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with EtOAc, dried over anhydrous Na2SO4. The collected organic layer was concentrated in vacuo and then purified by column chromatography (20-30% EtOAc/hexanes) to give fert-butyl [l-(5-fluoropyridin-2-yl)-2- methoxy ethyl] carbamate (0.58g, 45%) as viscous oil. The resulting oil was dissolved in EtOAc (1OmL) and treated with 4M HCl in dioxane. After 2 hours at room temperature, diethyl ether (2OmL) was added for completion of precipitation of a desired product. After standing for 30 minutes at room temperature, the resulting liquid portion was removed by decantation. The remaining solid portion was dried under vacuum to give a highly moisture sensitive title compound (267 mg, 72% as mono hydrochloride salt) as colorless solid
1H NMR (500 MHz) δ 3.23 (s, 3H), 3.69 (d, 2H), 4.55 (m, 1H), 7.67 (m, 1H), 7.82 (m, 1H) 8.59 (d, 1H) 8.65 (br, 2H). LC-MS: 171 [M+H] +.
Intermediate 81
N-ri-(5-Fluoropyridin-2-yl)-3-hvdroxypropyl1-2-methylpropane-2-sulfϊnamide
Ethyl 3-[(fert-butylsulfϊnyl)amino]-3-(5-fluoropyridin-2-yl)propanoate (Intermediate 61, 1.6g,
5.06mmol) was dissolved in THF (4OmL) and cooled to O°C. To this solution was added LiBH4 (318mg, 15mmol) in small portions under nitrogen atmosphere. After stirring at room temperature overnight (completion of the reaction as indicated by TLC), the reaction mixture was quenched with methanol at O°C and treated with saturated NH4Cl (aq) solution (5 mL). Organic solvent was removed in vacuo and extracted with EtOAc (2x). The combined organic layers were dried (Na2SO4) and purified by column chromatography (EtOAc/MeOH = 98:2) to give the title compound (920mg, 66%). LC-MS: 275 [M+H]
Intermediate 82
3-Amino-3-(5-fluoropyridin-2-yl)propan-1-ol hydrochloride salt
N-[l-(5-Fluoropyridin-2-yl)-3-hydroxypropyl]-2-methylpropane-2-sulfinamide (Intermediate 81, 920mg, 3.35mmol) was dissolved in EtOAc (2OmL). To solution was added 4N HCl
(5mL/dioxane) under nitrogen atmosphere. The reaction mixture was stirred for 2 hours at room temperature to give a precipitate. The reaction mixture was diluted with TBME (2OmL) and the precipitate was filtered, washed with TBME (10ml) and dried to provide the title compound
(560mg, 81%) as a white solid. 1H NMR (SOO MHZ) O 1.88-1.94 (m, 1H), 2.01-2.05 (m, 1H), 3.23-3.25 (m, 1H), 3.36-3.39 (m,
1H), 4.46 (m, 1H), 7.63 (dd, 1H), 7.80 (ddd, 1H), 8.59 (d, 1H), 8.60 (br. s, 2H).
LC-MS: 171 [M+H] +.
Intermediate 83 (2S)- 1 -(5-Fluoropyridin-2-yl)-2-methoxypropan- 1 -ol
In a 200 mL round-bottomed flask was added 2-bromo-5-fluoropyridine (5 g, 28.41 mmol), in diethyl ether (95 ml) to give a colorless solution. The resulting mixture was cooled to -78 °C and the mixture was treated with a solution of ^-BuLi (33.4 ml, 56.82 mmol) over 20 minutes. The resulting dark mixture was stirred at this temperature for 20 minutes whereupon a solution of Ethyl (S)-(-)-2-methoxypropionate (3.75 g, 28.41 mmol) in Et20 (20 ml) was added to the solution. The resulting yellow solution stirred at -78 °C for 2 hours, whereupon it was slowly quenched by the addition of sat. NH4Cl (aq.) while vigourously stirring the mixture. The mixture was partitioned between EtOAc and H2O. The organic phase washed with brine and dried. Evaporation gave a dark oil. Purification by column chromatography (10%->40% EtOAc/hexanes) gave f2^-1-(5-fluoropyridin-2-yl)-2-methoxypropan-1-one as a colored solid. LC-MS: 184 [M+H]+. fS/)-1-(5-Fluoropyridin-2-yl)-2-methoxypropan-1-one and NaBH4 were reacted using a procedure similar to the one described for the synthesis of Intermediate 85, providing the title compound. LC-MS: 186 [M+H]+ Intermediate 84 β>,)-2-(fert-Butyldimethylsilyloxy)- 1 -(5-fluoropyridin-2-yr)propan- 1 -one In a 200 mL round-bottomed flask was added 2-bromo-5-fluoropyridine (5 g, 28.41 mmol) in diethyl ether (95 ml) to give a colorless solution. The resulting mixture was cooled to -78 °C and the mixture was treated with a solution of ^-BuLi (33.4 ml, 56.82 mmol) over 20 minutes. The resulting dark mixture was stirred at this temperature for 20 minutes whereupon a solution of ethyl (S)-(-)-2-(fert-butyldimethylsilyl-oxy)propionate (7.55 ml, 28.41 mmol) in Et2O (20 ml) was added to the solution. The resulting yellow solution stirred at -78 °C for 2 hours, whereupon it was slowly quenched by the addition of sat. NH Cl (aq.) while vigourously stirring the mixture.
The mixture was partitioned between EtOAc and H2O. The organic phase washed with brine and dried. Evaporation gave a dark oil. Purification by column chromatography (5%->30% EtOAc/hexanes) gave the title compound as an oil. LC-MS: 284 [M+H] +
Intermediate 85
25'-2-(fer?-Butyldimethylsilyloxy)- 1 -(5-fluoropyridin-2-yl)propan- 1 -ol fS/)-2-(tert-Butyldimethylsilyloxy)-1-(5-fluoropyridin-2-yl)propan-1-one (Intermediate 84, 500 mg, 1.76 mmol) was dissolved in MeOH (8.821 mL) and cooled to 0°C. NaBH4 (66.7 mg, 1.76 mmol) was then added and the reaction was stirred at 25°C for 30 minutes. The reaction mixture was concentrated in vacuo leaving a yellow oil. This material was dissolved in EtOAc, washed with NH4CI and dried with Na2SO4. Concentration in vacuo gave a yellow oil (410 mg). This material was purified by ISCO (5-30% EtOAc/Hex). Concentration of the fractions in vacuo provided the title compound as a mixture of two diastereomers : Intermediate 85(a) as a clear oil (64 mg) and Intermediate 85(b) as a clear oil (27 mg). The stereochemistry of these two materials was not assigned.
Intermediate 86
2-Ethoxy- 1 -(5-fluoropyridin-2-yl)ethanone
In a 200 mL round-bottomed flask was added 2-bromo-5-fluoropyridine (2 g, 11.36 mmol) in Et2O (37.9 ml) to give a colorless solution. The resulting mixture was cooled to -78 °C and the mixture was treated with a solution of tBuLi (13.37 ml, 22.73 mmol) over 20 minutes. The resulting dark mixture was stirred at this temperature for 20 minutes whereupon a solution of ethyl ethoxyacetate (1.540 ml, 11.36 mmol) in Et2θ (20 ml) was added to the solution. The resulting yellow solution stirred at -78 °C for 2 hours, whereupon it was slowly quenched by the addition of sat. NH Cl (aq.) while vigourously stirring the mixture. The mixture was partitioned between EtOAc and H O. The organic phase washed with brine and dried.
Evaporation gave a dark oil. Purification by column chromatography (5%-30% EtOAc/hexanes) gave the title compound as an oil. LC-MS: 184 [M+H]+.
Intermediate 87
2-Ethoxy- 1 -(5-fluoropyridin-2-yP)ethanol A solution of 2-ethoxy-1-(5-fluoropyridin-2-yl)ethanone (Intermediate 86, 533 mg, 2.91 mmol) in MeOH (7274 μl) and water (7274 μl) at 25 °C was added portion-wise NaBH4 (110 mg, 2.91 mmol). The resulting mixture was stirred at this temperature for 3 hours whereupon the volatiles were removed under reduced pressure. The residue obtained was diluted with EtOAc and the organic phase was washed with brine and dried. Evaporated under reduced pressure gave the title compound as an oil. LC-MS: 186 [M+H]+.
Intermediate 88
2-(l-Azido-2-ethoxyethyl)-5-fluoropyridine To a solution of 2-ethoxy-1-(5-fluoropyridin-2-yl)ethanol (Intermediate 87, 0.539 g, 2.91 mmol) in DCM (2.91 ml) was added Et3N (0.406 ml, 2.91 mmol) and methanesulfonyl chloride (0.227 ml, 2.91 mmol) at 0°C. The resulting mixture was allowed to stir at ambient temperature for 2 hours whereupon it was partitioned between EtOAc and H2O. The organic phase was dried and evaporated under reduced pressure gave the corresponding methyl sulfonate, which was used in the subsequent step without any further purification. The sulfonate was dissolved in DMF (2.91 ml) and sodium azide (0.246 g, 3.78 mmol) was added. The mixture was heated to 6O°C for 4 hours. The mixture was allowed to cool to room temperature and it was partitioned between EtOAc and H2O. The organic phase was dried and evaporated under reduced pressure (not to dryness due to the potential explosive behavior of the azide) gave the title compound as an oil that was used in the next step without any further purification. LC-MS: 211 [M+H]4
Intermediate 89
2-Ethoxy- 1 -(5-fruoropyridin-2-yl)ethanamine
To a solution of 2-(l-azido-2-ethoxyethyl)-5-fluoropyridine (Intermediate 88, 0.612 g, 2.91 mmol) in tetrahydrofuran (7.28 ml) and water (7.28 ml) was added PS(polymer supported)- triphenylphosphine (3.82 g, 14.55 mmol). The resulting slurry was heated to 60 °C for 6 hours.
The mixture was filtered to remove the PS(polymer supported) triphenyl phosphine and oxide and subsequent evaporation of the volatiles under reduced pressure gave 2-ethoxy-1-(5- fluoropyridin-2-yl)ethanamine 212 mg as a yellow oil. The product was used in a subsequent step without any further purification.
LC-MS: 185 [M+H]+.
Intermediate 90
6-Chloro-N2-(2-ethoxy-1-(5-fluoropyridin-2-yl)ethyl)-Ni-(5-methyl-1H-pyrazol-3-yl)-1,3,5- triazine-2,4-diamine
To a solution of 4,6-dichloro-N-(5-methyl-1H-pyrazol-3-yl)-1,3,5-triazin-2-amine (Intermediate 18, 282 mg, 1.15 mmol) in ethanol (3836 μl) were added 2-ethoxy-1-(5-fluoropyridin-2- yl)ethanamine (Intermediate 89, 212 mg, 1.15 mmol) and Et3N (481 μl, 3.45 mmol). The resulting pale yellow solution was stirred at 25 °C overnight. Evaporation of the volatiles under reduced pressure gave a yellow residue. Purification by column chromatography (70% -> 100% EtOAc/hexanes) gave the title compound as an off-white solid. LC-MS: 393 [M+Η]+.
Intermediate 91 l-(5-Fruoropyrimidin-2-yl)-2-methoxyethanol
In a 100 mL round-bottomed flask was added 5-fluoro-2-(oxiran-2-yl)pyrimidine (Intermediate 110, 200 mg, 1.43 mmol) and rac-Co(II)-salen OTs (111 mg, 0.14 mmol)-prepared from the addition of />-TsOH in a solution of (S),(S)- and (R,R)-Co-salen in MeOH for 1 hour in the open air and subsequent evaporation of the volatiles (final product is green while sm is orange)- in MeOH (7137 μl) to give a green solution. The mixture was stirred at 25 °C for 7 days. The volatiles were evaporated and the residue was purified by column chromatography (ISCO, 30%EtOAc/hexanes->90% EtOAc/hexanes) to give the title compound as a dark oil. 1H NMR (300 MHz, Chloroform-D) δ ppm 3.38 (s, 3 H) 3.74 - 3.87 (m, 2 H) 4.01 (s, 1 H) 4.82 - 5.35 (m, 1 H) 8.63 (s, 2 H)
Intermediate 92
^)-6-Chloro-N2-( 1 -(3 ,5 -difluoropyridin-2-yl)ethyl)-Ni-(5 -methyl- 1H-pyrazol-3 -vD- 1,3,5- triazine-2,4-diamine
DIPEA (1.875 ml, 10.74 mmol) was added to a solution of 4,6-dichloro-N-(5-methyl-1H-pyrazol-
3-yl)-1,3,5-triazin-2-amine (Intermediate 18, 877 mg, 3.58 mmol) and (S)-1-(3,5- difluoropyridin-2-yl)ethanamine (7?)-mandelic acid salt (Intermediate 106, 127 mg, 0.41 mmol) in ethanol (15 ml). The reaction mixture was stirred for 24 hours at room temperature. The reaction was filtered to remove solid and the remaining solution was concentrated under reduced pressure leaving a yellow residue. This material was purified by ISCO (0-5% MeOΗ/DCM) to provide 380 mg of the title compound. 1H NMR (400 MHz, MeOD) δ ppm 8.32 - 8.40 (m, 1 H) 7.54 - 7.62 (m, 1 H) 5.47 - 5.58 (m, 1
H) 2.29 (d, 3 H) 1.55 (s, 3 H).
LC-MS: 367 [M+H]+.
Intermediate 93 l-(3,5-Difluoropyridin-2-yl)-2-methoxyethanone
3,5-Difluoropyridine (5.0 g, 43.45 mmol) in THF was cooled to -72°C (external -80°C). LDA (23.9 mL, 1.1 eq.) was added drop-wise so that the internal temp did not increase more than 3°C during addition. The reaction turned into a deep brownish, thick phase. The reaction was stirred for 30 mins. TMS-Cl (43.4 mL, 43.45 mmol) was added drop-wise in a relatively fast fashion. The reaction became a clear and light yellow solution. LDA (23.9 mL, 1.1 eq.) was added drop- wise, and the reaction was allowed to stir for 2 hours. Methyl 2-methoxyacetate (5.59 mL, 56.48 mmol) was added quickly through a syringe. The reaction was quenched at -78°C by adding 20 ml of saturated NH4Cl solution. Evaporation of the organic extracts under reduced pressure gave a colored residue. Purification by ISCO (0-25% EtOAc/hexanes), gave the title compound (3 g). LC-MS: 188 [M+H]+ Intermediate 94
1 -(3 ,5-Difruoropyridin-2-yl)-2-methoxyethanone oxime l-(3,5-Difluoropyridin-2-yl)-2-methoxyethanone (Intermediate 93) was dissolved in ethanol (255 ml, 10 vol). Hydroxylamine hydrochloride (14.22 g, 204.61 mmol) was added, followed by drop-wise by triethylamine (28.5 ml, 204.61 mmol). The resulting colored mixture was heated to 50° C for 2 hours. The volatiles were evaporated under reduced pressure and the residue left was partitioned between water (255 ml) and ethyl acetate (255 ml). The separated aqueous layer was further extracted into 2 x ethyl acetate (255 ml). The combined organic extracts washed with water (255 ml), saturated brine (255 ml), dried over MgSO4, filtered and concentrated in vacuo to give 42g of a brown oil. Purification by column chromatography (25-40% EtOAc in isohexanes) gave 32g of the title compound as yellow oily solid (-3:1 mixture of isomers). Trituration in MTBE to gave the title compound (12.3 g, 60.84 mmol, 44.6 %, single isomer) as a white solid. The liquor was evaporated under reduced pressure and the residue was re-columned using the previous conditions followed by trituration with EtOAc/isohexanes to give additional l-(3,5- difluoropyridin-2-yl)-2-methoxyethanone oxime (7.2 g, 35.62 mmol, 26.1 %). LC-MS: 203 [M+H]+.
Intermediate 95
^M-(3,5-Difluoropyridin-2-yl)-2-methoxyethanamine, fR,)-mandelic acid salt l-(3,5-Difluoropyridin-2-yl)-2-methoxyethanone oxime (Intermediate 94) was dissolved in EtOAc (0.4M) and was subsequently subjected to catalytic hydrogenation (Pd/C) in a Parr Hydrogenator (Pressure 5 bar at 40°C) for 1 hour. The catalyst was filtered via Celite and the filtrate of l-(3,5-difluoropyridin-2-yl)-2-methoxyethanamine (0.4 M in ethyl acetate) (180 mL, 72.00 mmol) was treated with (R)-Mandelic acid (5.81 g, 38.16 mmol). Precipitation was observed almost instantaneously and the resulting mixture was allowed to stir overnight. (R)-I- (3,5-difluoropyridin-2-yl)-2-methoxyethanamine (R)-mandelate salt was collected via filtration (8.5 g, 69.4 %). The other enantiomer (S)-1-(3,5-difluoropyridin-2-yl)-2-methoxyethanamine (R)-mandelic acid salt was recovered after evaporation of the mother liquor. 1H NMR (400 MHz) δ ppm 8.6 (s, 1H) 8.01 (m, 1H) 7.41 (t, 2H) 7.36 (t, 2H) 7.19 (m ,1H) 4.81 (s, 1H) 4.50 (m, 1H) 3.57 (d, 2H) 3.23 (s, 3H). LC-MS: 188 [M-H]+
Intermediate 96
3,5-Difluoro-2-hvdrazinylpyridine
In a 250 mL round-bottomed flask was added hydrazine monohydrate (17.69 mL, 563.61 mmol) and 2,3,5-trifluoropyridine (25.0 g, 187.87 mmol) in THF (150 mL) to give a colorless solution. The reaction was heated over 72 h at 50 °C. Concentration removed THF, and EtOAc (80 mL) was added. Filtration afforded the first crop of product as a solid which was washed with water (50 mL). The aqueous layer was extracted with EtOAc (3 x 30 mL). Concentration of the organic layer afforded the second crop of the product. The crude product was loaded into silica gel chromatography and eluted with EtOAc/hexane (30%). The collected fractions were concentrated to give the product (23.0 g, 84% yield). 1H NMR δ 4.09 (s, 2 H), 7.62 (ddd, 1 H), 7.75 (s, 1 H), 7.96 (d, 1 H).
Intermediate 97 2-Bromo-3,5-difruoropyridine
In a 500 mL round-bottomed flask was added 3,5-difluoro-2-hydrazinylpyridine (Intermediate 96, 16.0 g, 110.26 mmol) in CHCI3 (158 ml) to give a brown suspension. The reaction was heated to 40 °C, and bromine (14.20 ml, 275.65 mmol) was added drop-wise over 15 minutes. The reaction mixture was refluxed at 60 °C for 1 hour. After cooling down to room temperature, the flask was placed in a ice bath, and sat. NaHCO3 was added very slowly to quench the reaction. Partition, extraction with DCM (2 X 80 mL), drying (Na2SU4), and concentration gave the crude product. The crude product was added to a silica gel column and was eluted with EtOAc/hexane (0-20%). Collected fractions were concentrated to give the product (12.0 g, 56% yield). 1H NMR O 8.18 (td, I H), 8.46 (d, I H).
Intermediate 98
2-Bromo-3,5-difluoro-4-(trimethylsilyl)pyridine
In a 250 mL round-bottomed flask was added 2-bromo-3,5-difluoropyridine (Intermediate 97, 5.35 g, 27.58 mmol) in THF (55.2 ml) to give a yellow solution. The solution was cooled to -78 °C and LDA (22.98 ml, 41.37 mmol) was added. The solution turned dark immediately, and after stirring at room temperature for 10 min, chlorotrimethylsilane (3.66 ml, 28.96 mmol) was added. After 0.5 h, sat. NH4Cl was added to quench the reaction. Partition, extraction with EtOAc (2 X 30 mL), drying (Na2SO4), and concentration gave the crude product. The crude product was added to a silica gel column and was eluted with EtOAc/hexane (0-20%). Collected fractions were concentrated to give the product (5.90 g, 80% yield). 1H NMR δ 0.40 (s, 9 H), 8.34 (s, 1 H).
Intermediate 99
N-(2-(fer?-Butyldimethylsilyloxy)-1-(3,5-difluoro-4-(trimethylsilyl)pyridin-2-yl)ethyl)-2- methylpropane-2-sulfinamide
In a 250 mL round-bottomed flask was 2-bromo-3,5-difluoro-4-(trimethylsilyl)pyridine (Intermediate 98, 5.9 g, 22.17 mmol) in THF (36.9 ml) to give a yellow solution. The solution was cooled to -78 °C, and H-BuLi (13.85 ml, 22.17 mmol) was added. After stirring at that temperature for 10 min, N-(2-(tert-butyldimethylsilyloxy)ethylidene)-2-methylpropane-2- sulfinamide (Intermediate 77, 7.38 g, 26.60 mmol) was added. The reaction was stirred for another 20 min, and sat. NH4Cl (40 mL) was added to quench the reaction. Warming up to room temperature, partition, extraction with EtOAc (2 X 20 mL), drying (Na2SO4), and concentration gave the crude product. The crude product was added to a silica gel column and was eluted with EtOAC/hexane (0-60%). Collected fractions were concentrated to give the product (5.0 g, 48.5% yield).
1H NMR δ -0.17 (s, 3 H), -0.06 (s, 3 H), 0.37 (s, 9 H), 0.71 (s, 9 H), 1.05 (s, 9 H), 3.92 (m, 2 H), 4.67 (m, 1 H), 5.50 (d, J= 7.91 Hz, 1 H), 8.44 (s, 1 H).
Intermediate 99 can also be prepared by the following procedure:
In a 500 mL round-bottomed flask was added 3,5-difluoropyridine (4.22 g, 36.67 mmol) in tetrahydrofuran (147 ml) to give a colorless solution. The solution was cooled to -78 °C before LDA (20.37 ml, 36.67 mmol) was added. After kept at -78 °C for 10 min, chlorotrimethylsilane (4.64 ml, 36.67 mmol) was added slowly. The reaction mixture was kept at -78 °C for another 10 min, LDA (50.9 ml, 91.67 mmol) was slowly added and the mixture was allowed to stir for 0.5 h before N-(2-(fer^butyldimethylsilyloxy)ethylidene)-2-methylpropane-2-sulfinamide
(Intermediate 77, 10.18 g, 36.67 mmol) was added in THF (20 mL). Sat. NH4Cl (80 mL) was added to quench the reaction after 0.5 hours. Partition, extraction with EtOAc (2 X 50 mL), drying (Na2SO4), and concentration gave the crude product. The crude product was added to a silica gel column and was eluted with EtOAc/hexanes (0-40%). Collected fractions were concentrated to give the product at 41.1 % yield.
Intermediate 100 tert-Butyl l-(3,5-difluoropyridin-2-yl)-2-hvdroxyethylcarbamate
In a 200 mL round-bottomed flask was N-(2-(fert-butyldimethylsilyloxy)-1-(3,5-difluoro-4- (trimethylsilyl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (Intermediate 99, 5.0 g,
10.76 mmol) in methanol (45 ml) to give a brown solution. Cool the solution to 0 °C, and HCl (4 M in dioxane) (10.76 ml, 43.03 mmol) was added. The reaction was stirred at 0 °C for 1 hour. The solution was concentrated in a 250 mL of round-bottomed flask to give a residue (2.65 g). To the residue was added water (35 mL) to give a yellow solution. The reaction mixture was diluted with THF (70 mL). At room temperature, BoC2O (3.00 mL, 12.91 mmol) and NaOH
(8.61 mL, 5 M aq solution) were added. The reaction was allowed to stir at room temperature for 1 hour. Extraction with EtOAc (2 x 40 mL), drying (Na2SO4), and concentration gave the crude product. The crude product was loaded into a silica gel chromatography and eluted with EtOAc/hexane (20-80%). Collected fractions were concentrated to give the product (1.80 g, 61% yield).
LC-MS (M + Na) = 297.
Intermediate 101 fert-Butyl l-(3,5-difluoropyridin-2-yl)-2-methoxyethylcarbamate In a 200 mL round-bottomed flask was tert-butyl l-(3,5-difluoropyridin-2-yl)-2- hydroxyethylcarbamate (Intermediate 100, 1.80 g, 6.60 mmol) in THF (25 mL) to give a brown solution. The solution was cooled to -15 °C using NaCl-ice bath. Potassium tert-butoxide (1.481 g, 13.2 mmol) was added. The reaction was kept at that temp and after 20 min, iodomethane (0.413 mL, 6.6 mmol) was added. The reaction was stirred at that temp for 1.5 hours. TLC monitor showed a little starting material left, additional 0.3 g of KOt-Bu was added, followed by 0.05 mL of iodomethane. After another 10 min, sat. NH4Cl was added to work up the reaction. Partition, extraction (EtOAc, 2x 15 mL), drying (Na2SO4), and concentration gave the crude product. The crude product was added to a silica gel column and was eluted with EtOAC/hexane (0-40%). Collected fractions were concentrated to give the product (1.0 g, 53%). 1H NMR δ 1.34 (s, 9 H), 3.21 (s, 3 H), 3.57 (d, 2 H), 5.06 (d, 1 H), 7.28 (d, 1 H), 7.90 (m, 1 H), 8.49 (m, 1 H).
Intermediate 102
1 -(3 ,5-Difluoropyridin-2-yl)-2-methoxyethanamine hydrochloride
In a 100 mL round-bottomed flask was tert-butyl l-(3,5-difluoropyridin-2-yl)-2- methoxyethylcarbamate (Intermediate 101, 1.10 g, 3.82 mmol) in MeOH (5.0 mL) to give a colorless solution. To the solution at room temperature HCl in dioxane (1.908 mL, 7.63 mmol) was added. The reaction was stirred at room temperature for 2 hours. Concentration removed MeOH, and to the residue was added dry ether (10 mL). Decanting removed ether, and concentration gave the product as a solid (0.7 g, 97%). 1H NMR δ 3.29 (s, 3 H), 3.72 (m, 2 H), 4.83 (s, 1 H), 8.13 (m, 1 H), 8.65 (m, 3 H).
Intermediate 103 l-(3,5-Difruoropyridin-2-yl)ethanone
A solution of methylmagnesium bromide (36.8 ml, 117.78 mmol) in THF (50ml) was stirred under N2 and cooled to -78°C. 3,5-difluoropicolinonitrile (15.0 g, 107.07 mmol) in THF (50 ml) was added drop wise with an addition funnel at such a rate that the internal temp, was kept below -4°C. After the addition was complete, the reaction was poured into a IM HCl (100 ml, chilled in an ice bath). The reaction was stirred at 0°C for 30 mins and room temperature for 30 mins. To this solution 150 ml of EtOAc was added to extract product. The aquous phase was neutralized to pH9 with NaHCO3 and extracted with EtOAc (2 X 20 ml). The organic layers were combined and the volatiles were removed under reduced pressure. Purification by ISCO (0-10% EtOAc- hexanes) gave the title compound as light yellow oil. LC-MS: 158 [M+H] +.
Intermediate 104 1 -(3 ,5-Difluoropyridin-2-yl)ethanone oxime
To a solution of l-(3,5-difluoropyridin-2-yl)ethanone (Intermediate 103, 12.91 g, 82.17 mmol) in ethanol (164 ml) was added hydroxylamine hydrochloride (8.56 g, 123.25 mmol) followed by Et3N (17.18 ml, 123.25 mmol) and the resulting mixture was stirred overnight at room temperature The volatiles were removed under reduced pressure and the resulting residue was partitioned between EtOAc/H2θ. The organic extracts washed with brine and dried. Orange yellow solid was obtained and purification by ISCO (10%EtOAc/hexanes->25% EtOAc/hexanes) gave l-(3,5-difluoropyridin-2-yl)ethanone oxime (9.73 g, 68.8 %) as yellow solid. 1H NMR (300 MHz, DMSO-J6) δ ppm 2.19 (s, 3 H) 7.98 (ddd, J=I 0.97, 8.81, 2.26 Hz, 1 H) 8.55 (d, J=2.26 Hz, 1 H) 11.70 (s, 1 H). LC-MS: 173 [M+H] +.
Intermediate 105
1 -(3 ,5-Difluoropyridin-2-yl)ethanamine l-(3,5-Difluoropyridin-2-yl)ethanone oxime (Intermediate 104, 9.73 g, 56.53 mmol) was added to water (113 ml) to form a suspension. Ammonium hydroxide (22.01 ml, 565.26 mmol) was added to the above solution, followed by ammonium acetate (5.23 g, 67.83 mmol). The mixture was heated at 50°C and subsequently zinc (14.79 g, 226.11 mmol) was added portion wise while maintain the internal temperature below 65°C. After the addition was complete, the reaction was stirred at 50°C for 3 hr. Solid NaCl and EtOAc was added to quench the reaction, stirred for 1 hour at room temperature, was then filtered through celite pad and rinsed with EtOAc. The organic layer was washed with 5 ml 2.5% NaOH (aq.) then 10 ml NH4OH. The organic layer was then washed with brine and dried with Na2SO4. The organic layer was concentrated down under reduced pressure to obtain the title compound as light yellow oil. 1H NMR (400 MHz, MeOD) δ ppm 1.62 (d, J=6.82 Hz, 3 H) 4.86 (q, J=6.82 Hz, 1 H) 7.75 (ddd, J=IOA l, 8.34, 2.27 Hz, 1 H) 8.49 (d, J=2.27 Hz, 1 H).
Intermediate 106 fffM-(3,5-Difluoropyridin-2-yl)ethanamine (R)-mandelic acid salt
Figure imgf000129_0001
l-(3,5-Difluoropyridin-2-yl)ethanone oxime (Intermediate 104, 9.73 g, 56.53 mmol) was added to water (113 ml) to form a suspension. Ammonium hydroxide (22.01 ml, 565.26 mmol) was added to the above solution, followed by ammonium acetate (5.23 g, 67.83 mmol). The mixture was heated at 50°C and subsequently zinc (14.79 g, 226.11 mmol) was added portion wise while maintain the internal temperature below 65°C. After the addition was complete, the reaction was stirred at 50°C for 3 hr. Solid NaCl and EtOAc was added to quench the reaction, stirred for 1 hour at room temperature, was then filtered through celite pad and rinsed with EtOAc. The organic layer was washed with 5 ml 2.5% NaOH (aq.) then 10 ml NH4OH. The organic layer was then washed with brine and dried with Na2SO4. The organic layer was concentrated down under reduced pressure to obtain the title compound as light yellow oil.
1H NMR (400 MHz, MeOD) δ ppm 1.62 (d, J=6.82 Hz, 3 H) 4.86 (q, J=6.82 Hz, 1 H) 7.75 (ddd, ./=10.11, 8.34, 2.27 Hz, 1 H) 8.49 (d, J=2.27 Hz, 1 H).
l-(3,5-Difluoropyridin-2-yl)ethanamine (0.83 g, 5.25 mmol) and (7?)-2-hydroxy-2-phenylacetic acid (0.399 g, 2.62 mmol) in ethyl acetate (10 mL) was heated to 50 °C. Solid formed after heating for a few minutes and even after addition of additional 5 mL EtOAc reaction did not go into solution. Continued to stir reaction for 1 hour at 50 °C. After 1 hour, the reaction mixture was cooled to ambient temperature. The solid was collected via gravity filtration (no vacuum) washing with ethyl acetate until orange color disappeared. The solid (265 mg) was identified as the title compound (Crompak CR+, 0.4xl5cm, 98:2:0.1 H2O:MeOH:TFA, flow lml/min, e.e
>98% as HCl salt. Procedure for e.e. determination: 5-10 mgs of the (R)-mandelic acid salt was treated with a few drops of 2N HCl in ether and concentrated, followed by adding EtOAc to this residue. The resulting white solid (HCl salt) was filtered and was utilized for e.e determination.
Elution time: First Eluting Compound: 3.19 minutes; Second Eluting Compound: 4.46 minutes (title product).
1H NMR (300 MHz) δ ppm 1.6 (d,3 H) 4.4-4.6 (m, 2 H) 7.5-7.8 (m, 5H) 8.0 (m, 1 H), 8.4 (br.s., 1H). Intermediate 107 l-(3,5-Difluoropyridin-2-yr)ethanol
In a 250 mL round-bottomed flask, l-(3,5-difluoropyridin-2-yl)ethanone (Intermediate 103, 1.0 g, 6.36 mmol) was dissolved in MeOH (30 ml) to give a colorless solution. Cooled to -10 °C (ice in MeOH) and sodium borohydride (0.060 g, 1.59 mmol) was added to the above solution at - 10°C. The reaction was stirred for 30 minutes. Concentration under reduced pressure removed MeOH, and to the residue was added sat. NaHCO3, and extracted with EtOAc. The crude product was added to a silica gel column and was eluted with EtOAc/DCM (20-50%). The title compound was obtained as colorless oil (600 mg). LC-MS: 160 [M+H]+.
Intermediate 108 l-(3,5-Difluoropyridin-2-yl)-2-methoxyethanol l-(3,5-Difluoropyridin-2-yl)-2-methoxyethanone (Intermediate 93, 2.78 g, 14.85 mmol) in MeOH was cooled to -72°C. NaBH4 was added portion wise. The reaction was complete almost instantly after the addition OfNaBH4 (monitored by TLC 25% EtOAc/hexanes). NH4Cl solution (Ig in 2 ml H2O) was added to quench the reaction. Solvent was removed under reduced pressure and the residue was partitioned between DCM and H2O. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford a yellow oil. ISCO purification (25% EtOAc/Hexanes) gave the title compound (2.0 g). LC-MS: 190 [M+H]+.
Intermediate 109
5 -F luoro-2 - vinylpyrimidine To a stirred solution of potassium vinyltrifluoroborate (9.80 g, 73.19 mmol), 2-chloro-5- fluoropyrimidine (9.32 mL, 73.19 mmol), PPh3 (2.304 g, 8.78 mmol), and Cs2CO3 (71.5 g, 219.58 mmol) in THF (144 mL) and water (16 mL) was added PdCl2 (0.519 g, 2.93 mmol) in one portion. The reaction mixture was heated to 85 °C for 48 hours. After cooling, the reaction mixture was filtered through a pad of celite with the aid of DCM (10OmL). The solids that remained in the flask were triturated with DCM and filtered. The resulting filtrate was carefully concentrated to give 5-fluoro-2-vinylpyrimidine as a heterogeneous brown oil, which was used directly in the next step.
1H NMR (400 MHz, CDCl3) δ 5.70 (d, 1 H) 6.53 (dd, 1 H) 6.86 (dd, 1 H) 8.55 (s, 2 H). LC-MS: [M+H]+ = 124.36.
Intermediate 110
5-Fluoro-2-(oxiran-2-yl)pyrimidine
To a stirred solution of 5-fluoro-2-vinylpyrimidine (Intermediate 109, 9.06 g, 73 mmol), fS,.S^- (+)-N,N'-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamino-manganese(III) chloride (0.927 g, 1.46 mmol), and 4-Phenylpropyl pyridine N-oxide (1.246 g, 5.84 mmol), and sodium phosphate, dibasic (1.036 g, 7.30 mmol) in water (76 ml) and DCM (106 ml) was added NaOCl solution 5.65-6% (380 ml, 255.50 mmol) in one portion. The reaction mixture was stirred for 48 hours. The reaction was filtered through a pad of celite with the aid of DCM. The aqueous layer was extracted with DCM. The combined organic extracts were dried (Na2SO4) and concentrated. Purification via ISCO chromatography (0% to 10% to 20% EtOAc-hexanes, DCM load, SiO2) gave 5-fluoro-2-(oxiran-2-yl)pyrimidine (2.80 g, 27.4 %) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 3.20 (ddd, 2 H) 4.12 (dd, 1 H) 8.58 (s, 2 H). LC-MS: 140.61 [M+H]+.
Intermediate 111 2-Azido-1-(5-fluoropyrimidin-2-vP)ethanol
To a stirred solution of 5-fluoro-2-(oxiran-2-yl)pyrimidine (Intermediate 110, 2.8 g, 19.98 mmol) and ammonium chloride (1.817 g, 33.97 mmol) in MeOH (200 mL) was added NaN3 (3.25 g, 49.96 mmol) in one portion. The reaction mixture was heated to 50 °C for 8 hours. After cooling, the MeOH was removed via rotary evaporation and the resulting solids were partitioned between EtOAc and brine. The aqueous phase was extracted with EtOAc and the combined organic layers were dried (Na2SO4) and concentrated. Purification via ISCO chromatography (0% to 23% to 50% EtOAc-hexanes, DCM load, SiO2) gave 2-azido-2-(5- fluoropyrimidin-2-yl)ethanol (0.500 g, 13.66 %) and 2-azido-1-(5-fluoropyrimidin-2-yl)ethanol (1.600 g, 43.7 %) as yellow oils. 1H NMR (400 MHz, CDCl3) δ 3.02 (t, 1 H) 4.07 (t, 2 H) 4.74 (t, 1 H) 8.64 (s, 2 H). LC-MS: [M-N2-H] = 154.42.
Intermediate 112
2-(l-Azido-2-methoxyethyl)-5-fluoropyrimidine
To a stirred solution of 2-azido-2-(5-fluoropyrimidin-2-yl)ethanol (Intermediate 111, 360 mg, 1.97 mmol) and proton-sponge (1,8-Bis-(dimethylamino)-naphthalene, 421 mg, 1.97 mmol) in DCM (19 ml) at 0 °C was added trimethyloxonium tetrafluoroborate (291 mg, 1.97 mmol) in one portion. The reaction was monitored by TLC. The reaction proceeded to 60% conversion, then stalled. Additional Proton-sponge (1,8-Bis-(dimethylamino)-naphthalene, 211 mg, 0.98 mmol) and Trimethyloxonium tetrafluoroborate (116 mg, 0.79 mmol) were added. The reaction reached 85% conversion. Water was added and the reaction mixture was partitioned between EtOAc and 0.5 M (aq) CuSO4 to give a partial emulsion. This biphasic mixture was filtered though a fritted funnel with the aid of EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organics were dried (Na2SO4) and concetrated. Purification via ISCO chromatography (0% to 10% to 20% EtOAc-hexanes, DCM load, SiO2) gave 2-(l-azido-2- methoxyethyl)-5-fluoropyrimidine (243 mg, 62.7 %) as a colorless oil.
1H NMR (400 MHz, CDCl3) δ 3.41 (s, 3 H) 3.85 - 3.94 (m, 2 H) 4.80 (dd, 1 H) 8.62 (s, 2 H). LC-MS: 198.01 [M+H]+.
Intermediate 113 1 -(5-Fluoropyrimidin-2-yl)-2-methoxyethanamine hydrochloride
To a stirred solution of 2-(l-azido-2-methoxyethyl)-5-fluoropyrimidine (Intermediate 112, 243 mg, 1.23 mmol) in THF (10.6 mL) and water (1.767 mL) was added 4-diphenylphosphino polystyrene resin (998 mg, 1.85 mmol) in one portion. The reaction mixture was heated to 65 °C for 2 hours. After cooling, the reaction mixture was filtered with the aid of EtOAc and concentrated to give l-(5-fluoropyrimidin-2-yl)-2-methoxyethanamine (196 mg, 93 %) as a yellow oil which was used without further purification.
1H NMR (400 MHz, CDCl3) δ 3.35 (s, 3 H) 3.64 (dd, 1 H) 3.76 (dd, 1 H) 4.34 (dd, 1 H) 8.57 (s, 2 H). LC-MS: 171.82 [M+H]+. The hydrochloride salt was prepared by the addition of 4N HCl in dioxane to a methanolic solution of the amine followed by evaporation of the solvents to dryness.
Intermediate 114
N-(2-(fer?-Butyldimethylsilyloxy)-1-(5-fluoropyridin-2-yl)ethyl)-2-methylpropane-2-sulfϊnamide To a solution of 2-bromo-5-fluoropyridine (5.2g, 29 mmol) in 80 mL of anhydrous MTBE was slowly added 1.7M solution of LDA in pentane (21 mL, 36 mmol) at -78°C. After being stirred for 30 minutes at -78°C, a solution of N-(2-(Yert-butyldimethylsilyloxy)ethylidene)-2- methylpropane-2-sulfϊnamide (Intermediate 77, 6.59 g, 24 mmol) in 15 mL of anhydrous MTBE was slowly added into the reaction mixture and stirred additional 2 hours at the same temperature. The reaction was quenched with saturated NH4Cl (aq) solution, extracted with EtOAc, dried over anhydrous Na2SO4. The collected organic layer was concentrated in vacuo and then purified by column chromatography (30% EtOAc/hexanes) to give the title compound (8.Og, 90%) as a viscous oil. LC-MS: 375 [M+H]+.
Intermediate 115 tert-Butyl [l-(5-fluoropyridin-2-yl)-2-hvdroxyethyl-|carbamate
To a solution of N-(2-(tert-butyldimethylsilyloxy)-1-(5-fluoropyridin-2-yl)ethyl)-2- methylpropane-2-sulfϊnamide (Intermediate 114, 1.59g, 6 mmol) in 50 mL of EtOAc, was slowly added a 4M solution of HCl in dioxane (4.6 mL) at room temperature. The reaction mixture was turned into a cloudy solution and then white solid started to precipitate out. After stirring 2 hours at room temperature, diethyl ether (5OmL) was added for complete precipitation of a desired product. After being stood for 30 minutes at room temperature, the resulting liquid portion was removed by decantation. The remaining solid portion was dried under vacuum, and used to next step. The solid was added into 2OmL of water, 4OmL of THF and 4.8mL of 5N- NaOH followed by BOC2O (1.7g) at room temperature. After being stirred at room temperature for 2 hours, the reaction was extracted with EtOAc, dried over anhydrous Na2SO4. The collected organic layer was concentrated in vacuo and then purified by column chromatography (40% EtOAc/hexanes) to give the title compound (1.29g, 84%) as a pale yellow oil. LC-MS: 257 [M+H]+.
Intermediate 116 1 -(5-Fluoropyridin-2-yl)-2-methoxyethanamine hydrochloride
To a solution of a tert-butyl [l-(5-fluoropyridin-2-yl)-2-hydroxyethyl]carbamate (Intermediate 115, 1.27g, 5 mmol) in 18 mL of anhydrous THF, was slowly added 20% potassium-?-butoxide solution in THF at -15°C. After being stirred for 20 minutes at the same temperature, was added 0.32 mL of MeI, and then allowed to warm up to room temperature. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with EtOAc, dried over anhydrous Na2SU4. The collected organic layer was concentrated in vacuo and then purified by column chromatography (20-30% EtOAc/hexanes) to give fert-butyl [l-(5-fluoropyridin-2-yl)-2- methoxy ethyl] carbamate (0.58g, 45%) as viscous oil. The resulting oil was dissolved in EtOAc (1OmL) and treated with 4M HCl in dioxane. After 2 stirring hours at room temperature, diethyl ether (2OmL) was added for completion of precipitation of a desired product. After standing for 30 minutes at room temperature, the resulting liquid portion was removed by decantation. The remaining solid portion was dried under vacuum to give a highly moisture sensitive title compound (267 mg, 72% as mono hydrochloride salt) as colorless solid. 1H NMR (500 MHz) δ 3.23 (s, 3H), 3.69 (d, 2H), 4.55 (m, 1H), 7.67 (m, 1H), 7.82 (m, 1H) 8.59 (d, 1H) 8.65 (br. s, 2H). LC-MS: 171 [M+H]+.
Intermediate 117
3-(4-Chloro-6-(3-methyl-1H-pyrazol-5-ylamino)-1,3.5-triazin-2-ylamino)-2,2-difluoro-3-(5- fluoropyridin-2-yl)propan- 1 -ol
3-Amino-2,2-difluoro-3-(5-fluoropyridin-2-yl)propan-1-ol hydrochloride (Intermediate 71, 273 mg, 1.54 mmol) and 4,6-dichloro-N-(5-methyl-1H-pyrazol-3-yl)-1,3,5-triazin-2-amine (Intermediate 18, 500 mg, 1.54 mmol) were reacted using a procedure similar to the one described for the synthesis of Intermediate 17, providing the title compound. LC-MS: 415 [M+Η]+.
Intermediate 118
3-(4-Chloro-6-(3-methyl-1H-pyrazol-5-ylamino)-1,3,5-triazin-2-ylamino)-3-(5-fluoropyridin-2- vDpropanamide 3-Amino-3-(5-fluoropyridin-2-yl)propanamide (Intermediate 69, 273 mg, 1.54 mmol) and 4,6- dichloro-N-(5-methyl-1H-pyrazol-3-yl)-1,3,5-triazin-2-amine (Intermediate 18, 500 mg, 1.54 mmol) were reacted using a procedure similar to the one described for the synthesis of Intermediate 17, providing the title compound. LC-MS: 392 [M+Η]+.
Intermediate 119
(6-Chloro-N--( 1 -(S-fluoropyrimidin^-vD^-methoxyethylVA^-π -methyl- 1H-pyrazol-5-vD- 1,3,5- triazine-2.4-diamine l-(5-Fluoropyrimidin-2-yl)-2-methoxyethanamine (Intermediate 113) and 4,6-dichloro-N-(5- methyl-1H-pyrazol-3-yl)-1,3,5-triazin-2-amine (Intermediate 18) were reacted using a procedure similar to the one described for the synthesis of Intermediate 17, providing the title compound. LC-MS: 380 [M+Η]+.
Intermediate 120
3-(4-Chloro-6-(3-methyl-1H-pyrazol-5-ylamino)-1,3,5-triazin-2-ylamino)-3-(5-fluoropyridin-2- vD-N-methylpropanamide
3-Amino-3-(5-fluoropyridin-2-yl)-N-methylpropanamide hydrochloride (Intermediate 75, 273 mg, 1.54 mmol) and 4,6-dichloro-N-(5-methyl-1H-pyrazol-3-yl)-1,3,5-triazin-2-amine (Intermediate 18, 500 mg, 1.54 mmol) were reacted using a procedure similar to the one described for the synthesis of Intermediate 17, providing the title compound. LC-MS: 406 [M+Η]+.
Intermediate 121
3-(4-Chloro-6-(3-methyl-1H-pyrazol-5-ylamino)-1,3,5-triazin-2-ylamino)-3-(5-fluoropyridin-2- vDpropanenitrile 3-Amino-3-(5-fluoropyridin-2-yl)propanenitrile hydrochloride (Intermediate 63, 273 mg, 1.54 mmol) and 4,6-dichloro-N-(5-methyl-1H-pyrazol-3-yl)-1,3,5-triazin-2-amine (Intermediate 18,
500 mg, 1.54 mmol) were reacted using a procedure similar to the one described for the synthesis of Intermediate 17, providing the title compound.
LC-MS: 374 [M+Η]+. Intermediate 122
3-(4-Chloro-6-(3-methyl-1H-pyrazol-5-ylaminoN)-1,3.5-triazin-2-ylaminoN)-3-(5-fluoropyridin-2- vD-N-N-dimethylpropanamide
3-Amino-3-(5-fluoropyridin-2-yl)-N,N-dimethylpropanamide hydrochloride (Intermediate 76) and 4,6-dichloro-N-(5-methyl-1H-pyrazol-3-yl)-1,3,5-triazin-2-amine (Intermediate 18) were reacted using a procedure similar to the one described for the synthesis of Intermediate 17, providing the title compound. LC-MS: 420 [M+Η]+.
Intermediate 124 6-Chloro-N-r5-(2-cvclohexylethyl)-1H-pyrazol-3-yl1-N'-r(l»y)-1-(5-fluoropyrimidin-2-yl)ethyl1- 1 ,3 ,5-triazine-2,4-diamine fS/)-1-(5-Fluoropyrimidin-2-yl)ethanamine hydrochloride (Intermediate 5, 208 mg, 1.17 mmol) and 4,6-dichloro-N-(3-(2-cyclohexylethyl)-1H-pyrazol-5-yl)-1,3,5-triazin-2-amine (Intermediate 155, 400 mg, 1.17 mmol) were reacted using a procedure similar to the one described for the synthesis of Intermediate 17, providing the title compound.
1H NMR (300 MHz, MeOD) δ ppm 8.72 (s, 2 H) 5.34 (q, 1 H) 2.66 (t 2H) 0.92-1.89 (m, 16 H). LC-MS: 447 [M+H]+.
Intermediate 125 6-Chloro-N-r(l»y)-1-(5-fluoropyrimidin-2-yl)ethyl1-N>-r5-(4-methoxyphenyl)-1H-pyrazol-3-yl1-
1 ,3 ,5-triazine-2,4-diamine fS/)-1-(5-Fluoropyrimidin-2-yl)ethanamine hydrochloride (Intermediate 5, 263 mg, 1.48 mmol) and 4,6-dichloro-N-(3 -(4-methoxyphenyl)- 1H-pyrazol-5-yl)- 1 ,3 ,5-triazin-2-amine
(Intermediate 156, 500 mg, 1.48 mmol) were reacted using a procedure similar to the one described for the synthesis of Intermediate 17, providing the title compound
1H NMR (300 MHz, MeOD) δ ppm 8.73 (s, 2 H) 7.75(d, 2H) 7.06(d, 2H) 5.38(q, 1H) 3.87(s, 3H)
1.63(d, 3H).
LC-MS: 442 [M+H]+.
Intermediate 126 3-(4-Chloro-6-(3-methyl-1H-pyrazol-5-ylamino)-1,3,5-triazin-2-ylamino)-3-(5-fluoropyridin-2- vDpropan-1-ol
3-Amino-3-(5-fluoropyridin-2-yl)propan-1-ol hydrochloride (Intermediate 82) and 4,6-dichloro- N-(5-methyl-1H-pyrazol-3-yl)-1,3,5-triazin-2-amine (Intermediate 18) were reacted using a procedure similar to the one described for the synthesis of Intermediate 17, providing the title compound.
LC-MS: 379 [M+Η]+.
Intermediate 127
6-Chloro-N2-(l-(5-fluoropyridin-2-yl)-2-(methylsulfonyl)ethyl)-Ni-(3-methyl-1H-pyrazol-5-yl)- 1 ,3 ,5-triazine-2,4-diamine l-(5-Fluoropyridin-2-yl)-2-(methylsulfonyl)ethanamine hydrochloride (Intermediate 67) and 4,6-dichloro-N-(5-methyl-1H-pyrazol-3-yl)-1,3,5-triazin-2-amine (Intermediate 18) were reacted using a procedure similar to the one described for the synthesis of Intermediate 17, providing the title compound. LC-MS: 427 [M+Η]+.
Intermediate 128
6-Chloro-N-r5-(4-fluorophenyl)-1H-pyrazol-3-yl1-N'-r(l»y)-1-(5-fluoropyrimidin-2-yl)ethyl1-
1 ,3 ,5-triazine-2,4-diamine fS/)-1-(5-Fluoropyrimidin-2-yl)ethanamine hydrochloride (Intermediate 5, 273 mg, 1.54 mmol) and 4,6-dichloro-N-(3-(4-fluorophenyl)-1H-pyrazol-5-yl)-1,3,5-triazin-2-amine (Intermediate
154, 500 mg, 1.54 mmol) were reacted using a procedure similar to the one described for the synthesis of Intermediate 17, providing the title compound.
1H NMR (300 MHz, MeOD) δ ppm 8.74 (s, 2 H) 7.85(m, 2H) 7.20(m, 2H) 5.37(q, 1H) 1.63(d, 3H).
LC-MS: 430 [M+H]+.
Intermediate 129
6-Chloro-N-rα,SV I -(5-fluoropyrimidin-2-vnethyll-N'-(5-thien-2-yl- 1H-pyrazol-3-yr)- 1.3.5- triazine-2,4-diamine β)-1-(5-Fluoropyrimidin-2-yl)ethanamine hydrochloride (Intermediate 5, 227 mg, 1.28 mmol) and 4,6-dichloro-N-(3-(thiophen-2-yl)-1H-pyrazol-5-yl)-1,3,5-triazin-2-amine (Intermediate 157, 400 mg, 1.28 mmol) were reacted using a procedure similar to the one described for the synthesis of Intermediate 17, providing the title compound
1H NMR (300 MHz, MeOD) δ ppm 8.74 (s, 2 H) 7.33-7.57(m, 2H) 7.1 l(m, 1H) C-4' proton of pyrazole not obvious 5.37(q, 1H) 1.63(d, 3H). LC-MS: 418 [M+H]+.
Intermediate 130
2-(DifruoromethyP)morpholine tert-Butyl 2-formylmorpholine-4-carboxylate (383 mg, 1.78 mmol) in DCM (20 mL) was added in a two neck flask with cold water condenser at O°C was treated with DAST (Diethylaminosulfur trifluoride, 0.564 mL, 4.27 mmol) at such a rate that the internal temperature did not exceed above 0-5°C. The mixture was allowed to warm overnight to room temperature. The phases were separated between DCM and saturated aqueous NaHCO3. The organic layer was washed with H2O, dried and evaporation of the volatiles under reduced pressure gave tert- butyl 2-(difluoromethyl)morpholine-4-carboxylate (-420 mg). 1H NMR (δ) (MeOD): 5.76(m, 1H), 3.79 (m, 3H), 3.47 (m, 2H), 2.96 (m, 2H), 1.41 (s, 9H).
tert-Butyl 2-(difluoromethyl)morpholine-4-carboxylate was dissolved in MeOH (3 mL) and HCl (2N in ether, 5 ml, 10.00 mmol) was added. The resulting reaction mixture was stirred at room temperature for 2 hours and evaporation of the volatiles under reduced pressure gave the title compound.
Intermediate 131 N--(l-(5-Fluoropyridin-2-yl)-2-methoxyethyl)-Λ^-(5-methyl-1H-pyrazol-3-yl)-6-morpholino- 1 ,3 ,5-triazine-2,4-diamine l-(5-Fluoropyridin-2-yl)-2-methoxyethanamine hydrochloride (Intermediate 116) and 4,6- dichloro-N-(5-methyl-1H-pyrazol-3-yl)-1,3,5-triazin-2-amine (Intermediate 18) were reacted using a procedure similar to the one described for the synthesis of Intermediate 17, providing the title compound. LC-MS: 379 [M+H]+.
Intermediate 132 β>,)-4-Chloro-N-( 1 -(5-fluoropyrimidin-2-yl)ethyl)-6-morpholino- 1 ,3 ,5-triazin-2-amine 2,4,6-Trichloro-1,3,5-triazine (3.69 g, 20 mmol) in ethanol (80 ml) was cooled to -78°C. In a separate flask, fS/)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Intermediate 5, 3.55 g, 20.00 mmol) in ethanol (20 ml) was treated with DIPEA (6.99 ml, 40.00 mmol)and the resulting mixture was stirred for 30 mins whereupon it was added drop-wise to a flask containing 2,4,6- trichloro-1,3,5-triazine (3.69 g, 20 mmol) in ethanol (80 ml) pre-cooled to -78°C. The reaction was stirred at -78°C for 2 hours. LC-MS indicated complete and clean conversion. The reaction mixture was re-cooled to -78°C, morpholine (1.742 ml, 20.00 mmol) and DIPEA (3.49 ml, 20.00 mmol) in ethanol (10 ml) was added drop-wise via syringe. The reaction was stirred at -78°C for 2 hours and subsequently at room temperature overnight. The volatiles were removed under reduced pressure and the residue was partitioned between CH2Cb and H2O. The organic phase was dried and concentrated in vacuo to yield the title compound. LC-MS: 340 [M+H]+.
Intermediate 133
2-(Methoxymethyl)morpholine hydrochloride To a solution of tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (300 mg, 1.38 mmol) in dry DMF ( 4 mL) was added 60% sodium hydride (83 mg, 2.07 mmol) at 0 °C under nitrogen and the suspension was stirred at room temperature for 30 minutes. Iodomethane (294 mg, 2.07 mmol) was added to the reaction mixture at 0 °C and stirred over night at room temperature. Solvent was removed in vacuo, the residue was dissolved in DCM (20 mL), washed with water (10 mL) and dried over Na2SC>4. Evaporation of the volatiles under reduced pressure gave a residue, which was dissolved in methanol (3ml) and 4M HCl in dioxane (0.8ml) was subsequently added. The resulting mixture was stirred for 2 h at room temperature and evaporation of the volatiles under reduced pressure gave the title compound. 1H NMR (300 MHz, MeOD) δ ppm 4.72 (d, J=I 1.11 Hz, 2 H), 4.58 (t, J=I 1.87 Hz, 1 H), 4.17 (m, 2 H), 4.05 (s, 3 H), 3.94 (m, 2 H), 3.72 (t, J=9.70 Hz, 1 H), 3.56 (q, J=10.86 Hz, 1 H).
Intermediate 134
2-(Azetidin- 1 -ylmethyl)morpholine hydrochloride
Sodium triacetoxyborohydride (551 mg, 2.52 mmol) was added to a solution of tert-butyl 2- formylmorpholine-4-carboxylate (181 mg, 0.84 mmol) and azetidine (57.6 mg, 1.01 mmol) in 1,2-dichloroethane (3 mL) at room temperature. The mixture were stirred for 24 hours at room temperature, quenched with saturated aq. ammonium chloride, extracted with DCM and dried over Na2SC>4. Evaporation of the volatiles under reduced pressure gave a colorless solid, which was dissolved in methanol (3ml) and 4M HCl in dioxane (0.8ml) was added. The resulting mixture was stirred for 2 h at room temperature, evaporated to give the title compound
1H NMR (300 MHz, MeOD) δ ppm 4.21 (m, 4 H), 3.96 (t, J=I 1.87 Hz, 1 H), 3.67 (m, 2 H), 3.43 (br. s., 1 H), 3.33 (d, J=1.32 Hz, 2 H), 3.23 (d, J=12.06 Hz, 1 H), 3.05 (br. s., 1 H), 2.64 (d, J=7.91 Hz, 1 H), 2.45 (br. s., 1H), 1.39 (m, 1 H)
Intermediate 135
2-(Morpholin-2-yl)acetonitrile hydrochloride
Potassium cyanide (158 mg, 2.42 mmol) was added to solution of tert-butyl 2-
(tosyloxymethyl)morpholine-4-carboxylate (300 mg, 0.81 mmol) in EtOH (5 mL), the mixture was stirred for 2 days at 8O°C, then cooled to room temperature and filtered off through Celite. Evaporation of the volatiles under reduced pressure gave a colorless solid, which was dissolved in methanol (3ml) and 4M HCl in dioxane (0.8ml) was added. The resulting mixture was stirred for 2 h at room temperature, evaporated to give the title compound.
1H NMR (300 MHz, CDCl3) δ ppm 4.07 (m, 1 H), 3.85 (m, 3 H), 3.61 (m, 2 H), 3.41 (m, 2 H),
2.90 (t, J=I 1.40 Hz, 1 H), 2.67 (m, 1 H).
Intermediate 136
^)-2-(4-(3,4-Dimethoxybenzyl)morpholin-3-yl)acetonitrile fS/)-(4-(3,4-Dimethoxybenzyl)morpholin-3-yl)methyl 4-methylbenzenesulfonate (Intermediate
138, 1.657 g, 3.93 mmol) and NaCN (0.636 g, 12.97 mmol) were reacted using a procedure similar to the one described for the synthesis of Intermediate 135, providing the title compound.
1H NMR (CD2Cl2) δ 6.94 (s, 1H), 6.82 (m, 2H), 3.83 (s, 3H), 3.82 (m, 1H), 3.80 (s, 3H), 3.75 (d,
1H), 3.66 (m, 3H), 3.34 (d, 1H), 2.86 (m, 1H), 2.80 (dd, 1H), 2.64 (m, 1H), 2.54 (dd, 1H), 2.34
(m, 1H).
LC-MS: 277 [M+H]+.
Intermediate 137
^)-2-(Morpholin-3-yl)acetonitrile, TFA salt
((^)-2-(4-(3,4-Dimethoxybenzyl)morpholin-3-yl)acetonitrile (Intermediate 136) was reacted using a procedure similar to the one described for the synthesis of Intermediate 50, providing the title compound.
Intermediate 138 fer?-Butyl 2-(tosyloxymethylN)morpholine-4-carboxylate
To a solution of tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (Intermediate 134, lOOmg, 0.46 mmol) in 3mL DCM was added TsCl and DMAP. After cooled to O°C, TEA was added and the mixture was allowed to room temperature over night before being put into 20 mL of water and 2 mL saturated potassium carbonate. Extraction with DCM (3xl0mL), drying and subsequent evaporation of the volatiles under reduced pressure gave a residue. Purification on silica gel eluting with EtOAc/Hexane (1/2 v/v) afforded the title compound (131 mg, 77 %) 1H NMR (300 MHz, Chloroform-d) δ ppm 7.71 (m, J=8.29 Hz, 2 H), 7.27 (m, J=8.10 Hz, 2 H), 3.93 (m, 2 H), 3.74 (dd, J=I 1.21, 2.54 Hz, 3 H), 3.52 (m, J=10.24, 4.97, 2.54, 2.40 Hz, 1 H), 3.37 (td, J=I 1.59, 2.64 Hz, 1 H), 2.81 (t, J=I LI l Hz, 1 H), 2.58 (br. s., 1 H), 2.37 (s, 3 H), 1.37 (s, 9
H).
LC-MS: 272.2 [M+H]+.
Intermediate 139
6-Chloro-N-r(l»y)-1-(5-fluoropyrimidin-2-yl)ethyl1-N>-r5-(phenoxymethyl)-1H-pyrazol-3-yl1- 1 ,3 ,5-triazine-2,4-diamine fS/)-1-(5-Fluoropyrimidin-2-yl)ethanamine hydrochloride (Intermediate 5, 263 mg, 1.48 mmol) and 4,6-dichloro-N-(3-(phenoxymethyl)-1H-pyrazol-5-yl)-1,3,5-triazin-2-amine (Intermediate 178, 500 mg, 1.48 mmol) were reacted using a procedure similar to the one described for the synthesis of Intermediate 17, providing the title compound
1H NMR (300 MHz, MeOD) δ ppm 8.73 (s, 2 H) 7.32(d, 2H) 6.92-7.1 l(m, 3H) 5.31(q, 1H) 5.10(s, 2H) 1.62(d, 3H). LC-MS: 442 [M+H]+.
Intermediates 140 to 147 were prepared from the indicated starting material using a procedure similar to the one described for the synthesis of Intermediate 17.
Intermediate 140 ^)-6-Chloro-N2-( 1 -(5-fluoropyrimidin-2-yl)ethyl)-Ni-(5-phenethyl- 1H-pyrazol-3 -yl)- 1,3,5- triazine-2,4-diamine
Starting material: 4,6-Dichloro-N-(5-phenethyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazin-2-amine
(Intermediate 148) and fS/)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Intermediate
5). LC-MS: 440 [M+Η]+.
Intermediate 141
^)-6-Chloro-N2-(5-(4-fluorophenethyl)-1H-pyrazol-3-yl)-NA-(l-(5-fluoropyrimidin-2-yl)ethyl)- 1 ,3 ,5-triazine-2,4-diamine Starting material: 4,6-Dichloro-N-(5-(4-fluorophenethyl)-1H-pyrazol-3-yl)-1,3,5-triazin-2-amine (Intermediate 149) and fS/)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Intermediate
5).
LC-MS: 458 [M+Η]+.
Intermediate 142
^)-6-Chloro-N2-(5-(3-fluorophenethyl)-1H-pyrazol-3-yl)-NA-(l-(5-fluoropyrimidin-2-yl)ethyl)- 1 ,3 ,5-triazine-2,4-diamine
Starting Material: 4,6-Dichloro-N-(5-(3-fluorophenethyl)- 1H-pyrazol-3-yl)- 1 ,3 ,5-triazin-2-amine (Intermediate 150) and fS/)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Intermediate 5). LC-MS: 458[M+H]+.
Intermediate 143
(S)-6-Chloro-N2 -(5-(3,5-difluorophenethyl)-1H-pyrazol-3-yl)-N4-(1-(5-fluoropyrimidin-2- yl)ethyl)-1,3,5-triazine-2,,4-diamine Starting material: 4,6-Dichloro-N-(5-(3,5-difluorophenethyl)-1H-pyrazol-3-yl)-1,3,5-triazin-2- amine (Intermediate 151) and (S)-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Intermediate 5). LC-MS: 476 [M+Η]+.
Intermediate 144
(S)-6-Chloro-N2 -(5-(2,4-difluorophenethyl)-1H-pyrazol-3-yl)-N4-(1-(5-fluoropyrimidin-2- y1)ethyl)-1,3,5-triazine-2,4-diamine
Starting material: 4,6-Dichloro-N-(5-(2,4-difluorophenethyl)- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazin-2- amine (Intermediate 152) and (S) -1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Intermediate 5).
LC-MS: 476 [M+Η]+.
Intermediate 145
(S) -6-Chloro-N2-(3 -(3 ,4-difluorophenethyl)- 1H-pyrazol-5-yl)-N4-( 1 -(5-fluoropyrimidin-2- yl)ethyl)-1,3,5-triazine-2,4-diamine
Starting material: 4,6-Dichloro-N-(3-(3 ,4-difluorophenethyl)- 1H-pyrazol-5-yl)- 1,3, 5-triazin-2- amine (Intermediate 153) and (S) -1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride
(Intermediate 5).
LC-MS: 476 [M+Η]+.
Intermediate 146
6-Chloro-N-(3-r2-(2.6-difluorophenyl)ethyl1-1H-pyrazol-5-vU-N'-[(1S)-1-(5-fluoropyrimidin-2- yl)ethyll-1,3,5-triazine-2,4-diamine
Starting material: 4,6-Dichloro-N- {3-[2-(2,6-difluorophenyl)ethyl]- 1H-pyrazol-5-yl} - 1 ,3 ,5- triazin-2-amine (Intermediate 158) and (S) -1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Intermediate 5). LC-MS: 476 [M+H]+.
Intermediate 147
^-β-Chloro-N^fS-OΛ-dimethoxyphenethvD-1H-pyrazol-S-vD-Λ^-d-fS-fluoropyrimidin-1- yl)ethyl)-1,3,5-triazine-2,,4-diamine
Starting material: 4,6-Dichloro-N-(5-(3 ,4-dimethoxyphenethyl)- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazin-2- amine (Intermediate 159) and fSM-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride
(Intermediate 5).
LC-MS: 500 [M+Η]+.
Intermediates 148 to 157 were prepared from the indicated starting materials using a procedure similar to the one described for the synthesis of Intermediate 18.
Intermediate 148 4,6-Dichloro-N-(5-phenethyl- 1H-pyrazol-3-vP)- 1 ,3 ,5-triazin-2-amine
Starting material: 5-Phenethyl-1H-pyrazo 1-3 -amine (Intermediate 162) and 2,4,6-trichloro-1,3,5- triazine.
LC-MS: 336 [M+Η]+.
Intermediatel49
4,6-Dichloro-N-(5-(4-fluorophenethyl)- 1H-pyrazol-3-vP)- 1 ,3 ,5-triazin-2-amine
Starting material: 5-(4-Fluorophenethyl)-1H-pyrazol-3-amine (Intermediate 163) and 2,4,6- trichloro- 1 ,3 ,5-triazine.
LC-MS: 354 [M+Η]+.
Intermediate 150
4,6-Dichloro-N-(5-(3-fluorophenethyl)-1H-pyrazol-3-yl)-1,3.5-triazin-2-amine
Starting material: 5-(3-Fluorophenethyl)-1H-pyrazol-3-amine (Intermediate 164) and 2,4,6- trichloro- 1 ,3 ,5-triazine. LC-MS: 354 [M+Η]+. Intermediate 151
4,6-Dichloro-N-(5-(3,5-difluorophenethylN)- 1H-pyrazol-3-yl)- 1 ,3 ,5-triazin-2-amine Starting material: 5-(3,5-Difluorophenethyl)-1H-pyrazol-3-amine (Intermediate 165) and 2,4,6- trichloro- 1 ,3 ,5-triazine. LC-MS: 372 [M+Η]+.
Intermediate 152
4,6-Dichloro-N-(5-(2,4-difluorophenethyl)- 1H-pyrazol-3-ylV 1 ,3 ,5-triazin-2-amine Starting material: 5-(2,4-Difluorophenethyl)-1H-pyrazol-3-amine (Intermediate 166) and 2,4,6- trichloro- 1,3 ,5-triazine. LC-MS: 372 [M+Η]+.
Intermediate 153
4,6-Dichloro-N-(3-(3,4-difluorophenethyl)-1H-pyrazol-5-yl)-1,3,5-triazin-2-amine Starting material: 3-(3,4-Difluorophenethyl)-1H-pyrazol-5-amine (Intermediate 167) and 2,4,6- trichloro- 1 ,3 ,5-triazine. LC-MS: 372 [M+Η]+.
Intermediate 154 4,6-Dichloro-N-(5-(4-fluorophenyl)- 1H-pyrazol-3-yl)- 1 ,3 ,5-triazin-2-amine
Starting material: 5-(4-Fluorophenyl)-1H-pyrazo 1-3 -amine and 2,4,6-trichloro- 1,3 ,5-triazine. LC-MS: 326 [M+Η]+.
Intermediate 155 4,6-Dichloro-N-(5-(2-cvclohexylethyl)- 1H-pyrazol-3-ylV 1 ,3 ,5-triazin-2-amine
Starting material: 5-(2-Cyclohexylethyl)-1H-pyrazol-3-amine and 2,4,6-trichloro- 1,3 ,5-triazine. LC-MS: 342 [M+Η]+.
Intermediate 156 4,6-Dichloro-N-(5-(4-methoxyphenyl)- 1H-pyrazol-3-yl)- 1 ,3 ,5-triazin-2-amine Starting material: 5-(4-Methoxyphenyl)- 1H-pyrazol-3 -amine and 2,4,6-trichloro- 1 ,3 ,5-triazine. LC-MS: 338 [M+Η]+.
Intermediate 157
4,6-Dichloro-N-(5-(thiophen-2-yl)- 1H-pyrazol-3-ylV 1 ,3 ,5-triazin-2-amine Starting material: 5-(Thiophen-2-yl)-1H-pyrazo 1-3 -amine and 2,4,6-trichloro-1,3,5-triazine. LC-MS: 314 [M+Η]+.
Intermediate 158
4,6-Dichloro-N- {3-[2-(2,,6-difluorophenyl)ethyl-|- 1H-pyrazol-5-vU - 1 ,3 ,5-triazin-2-amine Starting material: 3-[2-(2,6-Difluorophenyl)ethyl]-1H-pyrazol-5-amine (Intermediate 169) and 2,4,6-trichloro- 1 ,3 ,5-triazine. LC-MS: 372 [M+Η]+.
Intermediate 159 4,6-Dichloro-N-(5-(3,4-dimethoxyphenethylN)- 1H-pyrazol-3-vP)- 1 ,3 ,5-triazin-2-amine
Starting material: 5-(3,4-Dimethoxyphenethyl)-1H-pyrazol-3-amine (Intermediate 170) and 2,4,6-trichloro- 1 ,3 ,5-triazine. LC-MS: 396 [M+Η]+.
Intermediate 160
3-Oxo-4-phenoxybutanenitrile
Acetonitrile (1.998 ml, 38.26 mmol) was dissolved in dried dioxane (50 mL) followed by the addition of NaH (1.808 g, 41.45 mmol). The resulting reaction mixture was stirred at room temperature for 0.5 hours. Ethyl 2-phenoxyacetate (5 ml, 31.88 mmol) was added and the resulting solution was heated at 85°C for 24 hours. The solution was evaporated, separated between ethyl acetate and water. The water layer was acidified by 2N HCl, then extracted with EtOAc (2x) and the combined organic layers dried. Evaporation of the volatiles under reduced pressure gave the title compound (0.88g).
Intermediate 161 3-(Phenoxymethyl)-1H-pyrazol-5-amine
3-Oxo-4-phenoxybutanenitrile (Intermediate 156, 0.88 g, 5.02 mmol) was dissolved in ethanol (10 mL) and hydrazine (0.189 mL, 6.03 mmol) was added. The reaction mixture was stirred at room temperature for 10 minutes and then heated at 85°C for 48 hours. The volatiles were evaporated under reduced pressure to give a residue that was purified by ISCO (MeOΗ/DCM 0-M5%) to give the title compound (0.565g). LC-MS: 190 [M+Η]+.
Intermediates 162 to 170 were prepared from the indicated starting material using a procedure similar to the one described for Intermediate 161.
Intermediate 162
5-Phenethyl- 1H-pyrazol-3 -amine
Starting material: 3-Oxo-5-phenylpentanenitrile and hydrazine.
LC-MS: 188 [M+Η]+.
Intermediate 163
5-(4-Fluorophenethyl)- 1H-pyrazol-3 -amine
Starting material: 5-(4-Fluorophenyl)-3-oxopentanenitrile and hydrazine.
LC-MS: 206 [M+Η]+.
Intermediate 164
5-(3-FluorophenethylV1H-pyrazol-3-amine
Starting material: 5-(3-Fluorophenyl)-3-oxopentanenitrile and hydrazine.
LC-MS: 206 [M+Η]+.
Intermediate 165
5-(3.S-DifluorophenethylV 1H-pyrazol-3 -amine
Starting material: 5-(3,5-Difluorophenyl)-3-oxopentanenitrile and hydrazine.
LC-MS: 224 [M+Η]+. Intermediate 166
5-(2,4-Difluorophenethyr)- 1H-ρyrazol-3 -amine
Starting material: 5-(2,4-Difluorophenyl)-3-oxopentanenitrile and hydrazine.
LC-MS: 224 [M+Η]+.
Intermediate 167
3-(3,4-DifluorophenethylV1H-pyrazol-5-amine
Starting material: 3-(3,4-Difluorophenyl)-3-oxopentanenitrile and hydrazine.
LC-MS: 224 [M+Η]+.
Intermediate 168
3-(2-(Pyridin-4-ylN)ethylN)-1H-pyrazol-5-amine
Starting material: 3-Oxo-5-(pyridin-4-yl)pentanenitrile and hydrazine.
LC-MS: 189 [M+Η]+.
Intermediate 169
3-[2-(2,6-DJfIuOrOPhBnVDeAyIl- 1H-pyrazol-5-amine
Starting material: 5-(2,6-Difluorophenyl)-3-oxopentanenitrile and hydrazine.
LC-MS: 224 [M+Η]+.
Intermediate 170
5-(3,4-DimethoxyphenethylMH-pyrazol-3-amine
Starting material: 5-(3,4-Dimethoxyphenyl)-3-oxopentanenitrile and hydrazine. LC-MS: 248 [M+Η]+.
The corresponding nitriles were prepared according to procedures similar to those described in PCT Publication No. WO 2008001070.
Intermediate 171
6-Chloro-N-r(iy)-1-(5-fluoropyrimidin-2-yl)ethyll-N'-{3-r2-(l-{r2-
(trimethylsilyl)ethoxylmethvU-1H-imidazol-2-yl)ethyll-1H-pyrazol-5-vU-1,3,5-triazine-2,4- diamine 4,6-Dichloro-N-{3-[2-(l-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)ethyl]-1H- pyrazol-5-yl}-1,3,5-triazin-2-amine (Intermediate 172) and (S)-1-(5-fluoropyrimidin-2- yl)ethanamine hydrochloride (Intermediate 5) were reacted using a procedure similar to the one described for the synthesis of Intermediate 17, providing the title compound.
LCMS: 561 [M+Η]+.
Intermediate 172
4,6-Dichloro-N-{3-[2-(l-{[2-(trimethylsilyl)ethoxylmethvU-1H-imidazol-2-yl)ethyll-1H- pyrazol-5-vU -1,3 ,5-triazin-2-amine
3-(2-(l-((2-(Trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)ethyl)-1H-pyrazol-5-amine (Intermediate 173) and 2,4,6-trichloro-1,3,5-triazine were reacted using a procedure similar to the one described for the synthesis of Intermediate 18, providing the title compound.
LCMS: 456 [M+Η]+.
Intermediate 173 3-(2-(l-((2-(Trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)ethyl)-1H-pyrazol-5-amine
3-Oxo-5-(l-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pentanenitrile (Intermediate 174, 2.95 g, 10.05 mmol) was dissolved in ethanol (50 mL) and hydrazine (0.338 g, 10.56mmol) was added. The reaction mixture was heated at 85°C for 3 hours. The solvent was evaporated under reduced pressure to give a residue. Column purification by ISCO gave the title compound (3.0g) as an oil.
LCMS: 308 [M+Η]+.
Intermediate 174
3-Oxo-5-(l-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pentanenitrile Acetonitrile (1.197 mL, 22.92 mmol) was dissolved in dried dioxane (100 mL) whereupon sodium hydride (1.Og, 22.92mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. Ethyl 3-(l-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2- yl)propanoate (Intermediate 175, 5.7 g, 19.10 mmol) was added, the resulted solution was heated at 85°C for 3 hours. The solution was evaporated, separated between ethyl acetate and water. The water layer was acidified by 2N HCl, and extracted by ethyl acetate. The organic layer was evaporated to give the title compound that was used in the next step without any further purification LCMS: 294 [M+H]+.
Intermediate 175 Ethyl 3 -( 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1H-imidazol-2-yl)propanoate
(iT)-Ethyl 3-(l-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)acrylate (Intermediate 176, 5.995 g, 20.22 mmol) was dissolved t in EtOAc (100 mL) and charged with palladium on carbon (1.2 g, 1.13 mmol). The reaction mixture was stirred overnight under hydrogen atmosphere. Filtration of the catalyst through Celite, followed by evaporation of the volatiles under reduced pressure gave the title compound (5.7g). LCMS: 299 [M+Η]+
Intermediate 176
(E)-Ethyl 3-(l-((2-(trimethylsilvDethoxy)methylV1H-imidazol-2-vDacrylate Ethyl (triphenylphosphoranylidene)acetate (9.01g, 25.85mmol) and l-((2-
(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carbaldehyde (Intermediate 177, 5.319 g, 23.50 mmol) were dissolved in TΗF (100 mL) and the resulting solution was stirred overnight. The volatiles were evaporated under reduced pressure. Ethyl acetate/hexane(100 ml, 5%) was added to the crude oil and a white solid was precipitated, filtered and the filtrate was evaporated under reduced pressure. Purification by column chromatography (ISCO) afforded the title compound
6.Og).
1H NMR (300 MHz, DMSO) δ ppm 7.64 (d, 1 H) 7.60 (s, 1H) 7.17 (s, 1H) 6.67 (d, 1H) 5.58 (s, 2
H) 4.26 (q, 2H) 3.54 (t, 2H) 1.32 (t, 3H) 0.90 (t, 2 H) 0.0 (s, 9 H).
LCMS: 297 [M+H]+.
Intermediate 177 l-((2-(Trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carbaldehvde 1H-Imidazole-2-carbaldehyde (5 g, 52.04 mmol) was dissolved in TΗF (200 mL) and sodium hydride (2.384 g, 54.64 mmol) was added. The resulting reaction mixture was stirred at room temperature for 0.5 hours, and thereafter 40 mL DMF was added. The resulting solution was stirred for 1 hour, whereupon it became clear solution, and SEM-Cl (10.15 mL, 57.24 mmol) was added. The reaction mixture was stirred for 15minutes and the volatiles were subsequently evaporated under reduced pressure. Purification by ISCO yielded the title compound (5.32g) 1H NMR (300 MHz, CDC13) δ ppm 9.86 (s, 1 H) 7.39 (s, 1H) 7.36 (s, 1H) 5.81 (s, 2 H) 3.58 (t, 2H) 0.946 (t, 2 H) 0.0 (s, 9 H). LCMS: 227 [M+H]+.
Intermediate 178
4,6-Dichloro-N-(3 -(phenoxymethyl)- 1H-pyrazol-5-vP)- 1 ,3 ,5-triazin-2-amine 3-(Phenoxymethyl)-1H-pyrazol-5-amine (Intermediate 161) and and 2,4,6-trichloro-1,3,5- triazine were reacted using a procedure similar to the one described for the synthesis of Intermediate 15, providing the title compound. LC-MS: 338 [M+Η]+.
Example 1 (y)-N2-(l-(5-Fluoropyridin-2-yl)ethyl)-Ni-(5-methyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1- vD- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000151_0001
In a 50 mL round-bottomed flask was added fS/)-6-chloro-N2-(l-(5-fluoropyridin-2-yl)ethyl)-Λ/4- (5-methyl-1H-pyrazol-3-yl)-1,3,5-triazine-2,4-diamine (Intermediate 16, 0.338 g, 0.97 mmol) in n-BuOΗ (3.23 ml) to give a yellow solution. 1-Methylpiperazine (0.486 g, 4.85 mmol) was then added and the resulting solution was heated to reflux for 30 minutes. Evaporation of the volatiles under reduced pressure gave an orange oil. Purification by Gilson chromatography chromatography (5%->95% MeCN/Η2θ with 0.1% formic acid) gave the title compound (elution time t=8 min, 52 mg as a free base after removal of formic acid with sat. aqueous NaHCO3 solution).
1H NMR (300 MHz, MeOD) δ 1.40 (d, 3 H) 2.15 (s, 3 H) 2.40 (s, 3H) 2.50 - 2.72 (m, 4 H) 3.72 (m, 4 H) 4.96 - 5.14 (m, 1 H) 5.83 - 6.02 (m, 1 H) 7.37 (dd, 1 H) 7.42 - 7.52 (m, 1 H) 8.23 - 8.40 (m, 2 H). LC-MS: 413 [M+H]+.
Example 2
(S)-Nz-( 1 -(5-Fluoropyrimidin-2-yl)ethyl)-Ni-(5-methyl- 1H-pyrazol-3 -yl)-6-morpholino- 1,3,5- triazine-2,4-diamine
Figure imgf000152_0001
In a 250 mL round-bottomed flask was added fS/)-6-chloro-N2-(l-(5-fluoropyrimidin-2-yl)ethyl)- Λ/4-(5-methyl-1H-pyrazol-3-yl)-1,3,5-triazine-2,4-diamine (Intermediate 17, 300 mg) and morpholine (1.385 ml, 15.90 mmol) in EtOH to give a yellow solution. The mixture was stirred overnight at room temperature. Evaporation of the volatiles under reduced pressure gave an orange residue. The residue was purified via Gilson chromatography (5%->95% MeCN/Η2θ with 0.1%HCOOH, 40 minutes, collection at t=7.5 minutes) to afford the title compound as a tan solid. Acid free compound was obtained after dissolving the salt in EtOAc, washing the organic layer with sat. aqueous NaHCO3, drying and subsequent evaporation of the volatiles under reduced pressure. 1H NMR (300 MHz, MeOD) δ ppm 1.58 (d, 3 H) 2.25 (s, 3 H) 3.47 - 3.95 (m, 8 H) 5.11 - 5.45 (m, 1 H) 5.98 - 6.22 (m, 1 H) 8.71 (s, 2 H). LC-MS: 401 [M+H]+.
Example 3 (S)-Nz-(l -(5-Fluoropyridin-2-vDethyl>A^-(5-methyl- 1H-pyrazol-3-yl)-6-morpholino- 1 ,3 ,5- triazine-2,4-diamine
Figure imgf000153_0001
A solution of fS/)-6-chloro-N2-(l-(5-fluoropyridin-2-yl)ethyl)-Λ/4-(5-methyl-1H-pyrazol-3-yl)-
1,3,5-triazine-2,4-diamine (Intermediate 16, 550 mg, 1.58 mmol) in morpholine (4122 μl, 47.31 mmol) was stirred overnight at room temperature. The volatiles were evaporated to give an orange oil. Purification by column chromatography (70%EtOAc-hexanes to 100%EtOAc with
0.2% TEA) afforded the title compound (625.5 mg) as a white solid.
1H NMR (300 MHz) δ 1.49 (d, 3 H) 2.27 (s, 3 H) 3.51 - 3.89 (m, 8 H) 5.05 - 5.33 (m, 1 H) 5.91
(s, 1 H) 7.55 (dd, 1 H) 7.65 - 7.96 (m, 1 H) 8.55 (d, 1 H). LC-MS: 400 [M+H]+.
Example 4
4-(l-(5-Fluoropyridin-2-yl)ethoxy)-N-(5-methyl-1H-pyrazol-3-yl)-6-morpholino-1,3.5-triazin-2- amine
Figure imgf000153_0002
In a 100 mL round-bottomed flask was added l-(5-fluoropyridin-2-yl)ethanol (Intermediate 12, 251 mg, 1.78 mmol) and sodium tert-butoxide (341 mg, 3.55 mmol) in t-BuOH (5918 μl) to give a tan solution. The mixture was stirred for 1 hour whereupon 4-chloro-N-(5 -methyl- 1H-pyrazol- 3-yl)-6-morpholino-1,3,5-triazin-2-amine (Intermediate 15, 350 mg, 1.18 mmol) was added. The resulting red mixture was stirred at ambient temperature for 48 hours. Evaporation of the volatiles and purification by Gilson chromatography (5%->95% MeCN/Η2O, 15 minute run, elution time -6.5 min) gave the title compound as a mixture of enantiomers. 1H NMR (300 MHz, MeOD) δ 1.72 (d, 3 H) 2.38 (s, 3 H) 3.63 - 3.87 (m, 8 H) 6.07 (s, 1H) 6.18 (q, 1 H) 7.50 - 7.79 (m, 2 H) 8.46 (d, 1 H). LC-MS: 400 [M+H].
Column and solvent conditions The title compound was chirally purified using Chiral HPLC.
Column: Chirapak AD
Dimensions: 250 x 20mm, lOμ
Mobile phase: 80% Hexane, 20% 1:1 ethanohmethanol, 0.1% diethylamine (v/v/v)
Flow rate (ml/min): 20 Detection (nm): 254
Example 4(a), First Eluting Compound
1H NMR (300 MHz, MeOD) δ 1.72 (d, 3 H) 2.38 (s, 3 H) 3.63 - 3.87 (m, 8 H) 6.07 (s, 1 6.18 (q, 1 H) 7.50 - 7.79 (m, 2 H) 8.46 (d, 1 H).
Example 4(b), Second Eluting Compound
1H NMR (300 MHz, MeOD) δ 1.72 (d, 3 H) 2.38 (s, 3 H) 3.63 - 3.87 (m, 8 H) 6.07 (s, 1 6.18 (q,
1 H) 7.50 - 7.79 (m, 2 H) 8.46 (d, 1 H).
Example 5
(5)-4-(l-(5-Fluoropyrimidin-2-yl)ethoxy)-N-(5-methyl-1H-pyrazol-3-yl)-6-morpholino-1,3,5- triazin-2-amine
Figure imgf000155_0001
In a microwave vessel, 4-(4-chloro-6-(l-(5-fluoropyrimidin-2-yl)ethoxy)-1,3,5-triazin-2- yl)morpholine (Intermediate 19, 253 mg, 0.74 mmol), tert-butyl 3 -amino-5 -methyl- IH- pyrazole-1-carboxylate (Intermediate 6, 220 mg, 1.11 mmol), BINAP (46.2 mg), Cs2CO3 (605 mg) and Pd2(dba)3 (34.0 mg) were added followed by dioxane (2 ml) and the resulting mixture was purged with Argon for 20 minutes. The reaction mixture was heated to 100°C for 4 hours whereupon MeOH was added and the resulting mixture was stirred at room temperature for 3 hours. The mixture was filtered and washed several times with DCM. Evaporation of the volatiles under reduced pressure gave a dark brown residue. Purification by column chromatography (ISCO 3% MeOH, 0.3% NH4OH in DCM) gave the title compound as a light yellow powder. LC-MS: 402 [M+H]+.
Column and solvent conditions
The title compound was chirally purified using conditions (A) and OD-4-20 (with 0.1% dimethylethylamine) Column particle size (μ): 5
Column dimensions (mm): 21x250
Post purification purity check
The sample purity was checked using conditions (B) and AD-4-20.
Example 5(a), First Eluting Compound
1H NMR (400 MHz, MeOD) δ ppm 8.69 (s, 2 H) 6.23 (s, 1H) 6.02 (q, J=6.57 Hz, 1 H) 3.61 (m, 8
H) 2.24 (s, 3 H) 1.67 (d, J=6.82 Hz, 3 H).
The first eluting compound had a retention time of 2.06 minutes. Example 5(b), Second Eluting Compound
1H NMR (400 MHz, MeOD) δ ppm 8.69 (s, 2 H) 6.23 (s, 1H) 6.02 (q, J=6.57 Hz, 1 H) 3.64 (m, 8 H) 2.24 (s, 3 H) 1.68 (d, J=6.57 Hz, 3 H).
The second eluting compound had a retention time of 2.91 minutes.
Example 6
6-(R)-3-(Dimethylamino)pyrrolidin-1-yl)-N2-(S)-1-(5-fluoropyrimidin-2-yl)ethyl)-N4-(5- methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000156_0001
(R)- 6-Chloro-N2-( 1 -(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine-
2,4-diamine (Intermediate 17) and (R)-N,N-dimethylpyrrolidin-3-amine were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound.
1H NMR (300 MHz, MeOD) δ ppm 1.30 (d, J=6.59 Hz, 3 H) 1.58 (s, 3 H) 1.72 - 1.98 (m, 1 H) 2.12 - 2.45 (m, 10 H) 2.75 - 2.95 (m, 1 H) 3.72 - 3.99 (m, 1 H) 5.15 - 5.42 (m, 1 H) 5.53 - 5.75
(m, I H) 8.71 (s, 2 H).
LC-MS: 428 [M+H]+.
Example 7 2-(5-Fluoropyridin-2-yl)-N, N-dimethyl-2-(4-(5-methyl-1H-pyrazol-3-ylamino)-6-morpholino- 1.3.5-triazin-2-ylamino)ethanesulfonamide
Figure imgf000157_0001
In a 250 mL round-bottomed flask was added 2-(4-chloro-6-(5-methyl-1H-pyrazol-3-ylamino)-
1 ,3 ,5-triazin-2-ylamino)-2-(5-fluoropyridin-2-yl)-N,N-dimethylethanesulfonamide (Intermediate
23, 1.5 g, 3.29 mmol) and morpholine (1.720 ml, 19.74 mmol) in EtOH (3.29 ml) to give a yellow solution. The resulting mixture was stirred at 25 °C for 1 hour. Evaporation of the volatiles under reduced pressure gave an oil. Purification by column chromatography (ISCO,
5%MeOΗ/DCM) gave the title compound as a mixture of enantiomers.
1H NMR (300 MHz, MeOD) δ ppm 2.25 (s, 3 H) 2.81 (s, 6 H) 2.82 - 2.89 (m, 2 H) 3.53 - 3.87
(m, 8 H) 5.73 (t, J=6.41 Hz, 1 H) 6.38 (s, 1 H) 7.29 - 7.79 (m, 2 H) 8.47 (s, 1 H).
LC-MS: 507 [M+H]+.
Column and solvent conditions
The title compound was chirally purified using conditions (A) and OD-4-20.
Column particle size (μ): 5
Column dimensions (mm): 21x250
Post purification purity check
The sample purity was checked using conditions (B) and OD-4-20.
Column dimensions (mm): 100 x 4.6
Column particle size (μ): 5
Example 7(a), First Eluting Compund
1H NMR (300 MHz, MeOD) δ ppm 2.14 (s, 3 H) 2.71 (s, 6 H) 3.43 - 3.80 (m, 10 H) 5.48 - 5.68
(m, 1 H) 5.99 (s, 1 H) 7.11 - 7.72 (m, 2 H) 8.37 (s, 2 H).
The first eluting compound had a retention titme of 20.5 minutes. Example 7(b), Second Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 2.14 (s, 3 H) 2.71 (s, 6 H) 3.42 - 3.67 (m, 10 H) 5.45 - 5.65 (m, 1 H) 5.99 (s, 1 H) 7.18 - 7.68 (m, 2 H) 8.37 (d, J=1.70 Hz, 1 H). The second eluting compound had a retention time of 24.1 minutes.
Example 8
6-((S)-3-(Dimethylamino)pyrrolidin-1-yl)-N2-((y)-1-(5-fluoropyrimidin-2-yl)ethyl)-Ni-(5- methyl- 1H-pyrazol-3 -vD- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000158_0001
(R)- 6-Chloro-N2-( 1 -(S-fluoropyrimidin^-yrjethy^-Λ^S-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine-
2,4-diamine (Intermediate 17) and (S)-N,N-dimethylpyrrolidin-3-amine were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound.
1H NMR (300 MHz, MeOD) δ ppm 1.25 (d, J=6.41 Hz, 3 H) 1.58 (s, 3 H) 1.75 - 1.89 (m, 1 H) 2.22 - 2.28 (m, 1 H) 2.33 (s, 6 H) 2.72 - 2.92 (m, 1 H) 3.40 - 3.59 (m, 1 H) 3.66 - 4.13 (m, 2 H)
5.17 - 5.44 (m, 1 H) 5.50 - 5.82 (m, 1 H) 6.45 (s, 1 H) 8.71 (s, 2 H).
LC-MS: 428 [M+H]+.
Example 9 N-( 1 -(4-((S)- 1 -(5-Fluoropyrimidin-2-yl)ethylamino)-6-(5-methyl- 1H-pyrazol-3 -ylaminoV 1,3,5- triazin-2-yl)pyrrolidin-3-yl)acetamide
Figure imgf000159_0001
(R)- 6-Chloro-N2-( 1 -(S-fluoropyrimidin^-yrjethy^-Λ^S-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 17) andN-(pyrrolidin-3-yl)acetamide were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of diastereomers. 1H NMR (300 MHz, MeOD) δ ppm 1.37 (d, J=6.59 Hz, 3 H) 1.58 (s, 3 H) 1.96 (s, 3 H) 3.44 - 3.89 (m, 4 H) 4.23 - 4.50 (m, 1 H) 5.22 - 5.41 (m, 1 H) 5.50 - 5.82 (m, 1 H) 8.71 (s, 2 H). LC-MS: 442 [M+H]+.
Example 10 N2-((,y)-1-(5-Fluoropyrimidin-2-yl)ethyl)-Ni-(5-methyl-1H-pyrazol-3-yl)-6-((i?)-3- (methylamino)pyrrolidin- 1 -vD- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000159_0002
(S>6-Chloro-N2-( 1 -(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 17) and (7^)-N-methylpyrro Ii din-3 -amine were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound. 1H NMR (SOO MHz5 MeOD) S pPm LSS (Cl5 S H) 1.74 - 1.93 (m, 1 H) 2.18 - 2.26 (m, 4 H) 2.41 (s, 3 H) 3.11 - 3.32 (m, 2 H) 3.46 - 3.89 (m, 2 H) 5.22 - 5.44 (m, 1 H) 5.50 - 5.74 (m, 1 H) 6.45 (s, I H) 8.71 (s, 2 H). LC-MS: 414 [M+H]+.
Example 11
6-(3-Ethoxypyrrolidin-1-yl)-N--((S)-1-(5-fluoropyrimidin-2-yl)ethyl)-Λ^-(5-methyl-1H-pyrazol- 3-ylVL3,5-triazine-2,4-diamine
To a solution of fS/)-6-chloro-N2-(l-(5-fluoropyrimidin-2-yl)ethyl)-Λ/4-(5-methyl-1H-pyrazol-3- yl)-1,3,5-triazine-2,4-diamine (Intermediate 17, 100 mg, 0.29 mmol) in EtOH (572 μl) was added 3-ethoxypyrrolidine hydrochloride (43.4 mg, 0.29 mmol) and DIPEA (49.9 μl, 0.29 mmol). The resulting mixture was stirred at 25 °C for 16 hours. Evaporation of the volatiles under reduced pressure gave a yellow residue. Purification by column chromatography (ISCO, 5%-10%MeOΗ/DCM) gave the title compound as a mixture of diastereomers (87 mg, 71.0 %). 1H NMR (300 MHz, MeOD) δ ppm 0.98 - 1.14 (m, 2 H) 1.21 - 1.33 (m, 3 H) 1.46 (t, J=6.97 Hz, 3 H) 1.79 - 1.99 (m, 2 H) 2.14 (s, 3 H) 3.34 - 3.54 (m, 4 H) 3.87 - 4.20 (m, 1 H) 4.99 - 5.35 (m, 1 H) 5.96 (s, 1 H) 8.62 (s, 2 H). LC-MS: 429 [M+H]+
Example 12
(S)-N-( 1 -(4-( 1 -(5-Fluoropyrimidin-2-yl)ethylamino)-6-(5-methyl- 1H-pyrazol-3 -ylaminoV L3 ,5- triazin-2-yl)azetidin-3-yl)acetamide
Figure imgf000161_0001
(S)-6-Chloro-N2-( 1 -(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine-
2,4-diamine (Intermediate 17) and N-(azetidin-3-yl)acetamide were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound. 1H NMR (300 MHz, MeOD) δ ppm 1.36 - 1.53 (m, 3 H) 1.86 (s, 3 H) 2.14 (s, 3 H) 3.68 - 3.96 (m, 2 H) 4.09 - 4.35 (m, 2 H) 4.40 - 4.61 (m, 1 H) 5.08 - 5.37 (m, 1 H) 6.12 (s, J=6.00 Hz, 1 H) 8.61 (s, 2 H). LC-MS: 428 [M+H]+.
Example 13 N-((S))- 1 -(4-((S)- 1 -(5-Fluoropyrimidin-2-yl)ethylaminoV6-(5-methyl- 1H-pyrazol-3-ylamino)- 1,3.5-triazin-2-yl)pyrrolidin-3-yl)acetamide
Figure imgf000161_0002
(S)-6-Chloro-N2-( 1 -(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 17) and (S)-N-(pyrrolidin-3-yl)acetamide hydrochloride (Intermediate 64) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound.
1H ΝMR (300 MHz, MeOD) δ ppm 1.46 (d, 3 H) 1.83 (s, 3 H) 2.14 (s, 3 H) 3.27 - 3.79 (m, 4 H) 4.14 . 4.44 (m, 1 H) 5.05 - 5.44 (m, 1 H) 5.90 - 6.45 (m, 1 H) 8.60 (s, 2 H). LC-MS: 442 [M+H]4
Example 14
N-((R)- 1 -(4-((S)- 1 -(5-Fluoropyrimidin-2-yl)ethylaminoV6-(5-methyl- 1H-pyrazol-3-ylamino)- 1,3,5-triazin-2-yl)pyrrolidin-3-yl)acetamide
Figure imgf000162_0002
(S)-6-Chloro-N2-( 1 -(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine-
2,4-diamine (Intermediate 17) and (R)-N-(pyrrolidin-3-yl)acetamide (Intermediate 24) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound. 1H NMR (300 MHz, MeOD) δ ppm 1.46 (d, 3 H) 1.83 (s, 3 H) 2.14 (s, 3 H) 3.27 - 3.79 (m, 4 H) 4.14 - 4.44 (m, 1 H) 5.05 - 5.44 (m, 1 H) 5.90 - 6.45 (m, 1 H) 8.60 (s, 2 H). LC-MS: 442 [M+H]+.
Example 15 ((R)- 1 -(4-(CS)- 1 -(5-Fluoropyrimidin-2-yl)ethylamino)-6-(5-methyl- 1H-pyrazol-3-ylamino)- 1,3,5- triazin-2-yl)piperidin-2-yl)methanol
Figure imgf000162_0001
(S)6-Chloro-N2-( 1 -(5-fluoropyrimi n-2-yl)ethyl)-N4-(5-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 17) and (R)-piperidin-2-ylmethanol hydrochloride (Intermediate 25) were reacted using a procedure similar to the one described for the synthesis of Example 62, providing the title compound.
1H NMR (300 MHz, MeOD) δ ppm 1.45 (d, J=6.78 Hz, 10 H) 1.45 - 1.73 (m, 5 H) 1.67 - 1.83 (m, 1 H) 2.13 (s, 3 H) 2.53 - 2.81 (m, 1 H) 3.37 - 3.85 (m, 2 H) 4.22 - 4.63 (m, 1 H) 4.64 - 4.77 (m, 1 H) 5.01 - 5.30 (m, 1 H) 6.20 (s, 1 H) 8.59 (s, 2 H). LC-MS: 429 [M+H]+.
Example 16
((R)- 1 -(4-((S)- 1 -(5-Fluoropyrimidin-2-yl)ethylamino)-6-(5-methyl- 1H-pyrazol-3-ylamino)- 1 ,3 ,5- triazin-2-yl)azetidin-2-vP)methanol
Figure imgf000163_0001
(S>6-Chloro-N2-( 1 -(S-fluoropyrimidin^-yrjethy^-Λ^S-methyl- 1H-pyrazol-3 -yl> 1 ,3 ,5-triazine-
2,4-diamine (Intermediate 17) and (7?)-azetidin-2-ylmethanol hydrochloride (Intermediate 26) were reacted using a procedure similar to the one described for the synthesis of Example 62, providing the title compound.
1H NMR (300 MHz, MeOD) δ ppm 1.46 (d, J=6.41 Hz, 3 H) 1.95 - 2.37 (m, 2 H) 2.13 (s, 3 H)
3.53 - 3.75 (m, 2 H) 3.74 - 3.91 (m, 2 H) 4.13 - 4.49 (m, 1 H) 5.05 - 5.22 (m, 1 H) 5.88 (s, 1 H)
8.60 (s, 2 H).
LC-MS: 40 [M+H]+.
Example 17
((S)- 1 -(4-((S)- 1 -(5-Fluoropyrimidin-2-yl)ethylamino)-6-(5-methyl- 1H-pyrazol-3-ylamino)- 1 ,3 ,5- triazin-2-yl)piperidin-2-yl)methanol
Figure imgf000164_0001
(S)-6-Chloro-N2-( 1 -(S-fluoropyrimidin^-yrjethy^-Λ^S-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine-
2,4-diamine (Intermediate 17) and (2^-piperidin-2-ylmethanol hydrochloride (Intermediate 27) were reacted using a procedure similar to the one described for the synthesis of Example 62, providing the title compound. 1H NMR (300 MHz, MeOD) δ pPm 1.17- 1.30 (m, 2 H) 1.45 (d, J=6.97 Hz, 3 H) 1.48 - 1.62 (m, 4 H) 1.68 - 1.93 (m, 1 H) 2.13 (s, 3 H) 2.52 - 2.84 (m, 1 H) 3.51 - 3.78 (m, 2 H) 4.26 - 4.62 (m, 1 H) 5.04 - 5.29 (m, 1 H) 5.36 - 6.34 (m, 1 H) 8.60 (s, 2 H). LC-MS: 429 [M+H]+.
Example 18
(S)-6-(3-(Dimethvlamino)azetidin-1-vl)-N2-(l-(5-fluoropvrimidin-2-vl)ethvl)-N4-(5-methyl-1H- pyrazol-3-vlV 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000164_0002
(S)-6-Chloro-N2-( 1 -(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 17) and N,N-dimethylazetidin-3 -amine, 2ΗC1 were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound. 1H NMR (300 MHz, MeOD) δ ppm 1.56 (t, 3 H) 2.26 (s, 3 H) 2.33 (s, 6 H) 3.79 - 3.99 (m, 2 H) 4.03 - 4.31 (m, 2 H) 4.81 - 4.88 (m, 1 H) 5.16 - 5.43 (m, 1 H) 6.12 (s, 1 H) 8.73 (s, 2 H). LC-MS: 414 [M+H]+.
Example 19 (,y)-N2-(l-(5-Fluoropyrimidin-2-yl)ethyl)-Ni-(5-methyl-1H-pyrazol-3-yl)-6-(3- (methylamino)azetidin-1-yl)-1,3,5-triazine-2,4-diamine hydrochloride
Figure imgf000165_0001
To a solution of fS/)-6-chloro-N2-(l-(5-fluoropyrimidin-2-yl)ethyl)-Λ/4-(5-methyl-1H-pyrazol-3- yl)-1,3,5-triazine-2,4-diamine (Intermediate 17, 100 mg, 0.29 mmol) in EtOH (953 μl) was added tert-butyl azetidin-3-yl(methyl)carbamate (53.3 mg, 0.29 mmol) and Et3N (120 μl, 0.86 mmol). The resulting mixture was stirred at 25 °C for 16 hours. Evaporation of the volatiles under reduced pressure gave a yellow residue. Purification by column chromatography (ISCO, 5%-10%MeOΗ/DCM) gave the intermediate Boc product as a white solid. The Boc product was dissolved in MeOH (1 ml) and was cooled to 0°C. A solution of HCl in dioxane (4N, ImI) was added. The mixture was warmed up to room temperature and stirred for 30 minutes. Evaporation of the volatiles gave the title product (20.00 mg, 17.51 %). The free base was obtained by dissolving the solid in EtOAc and washing the organic layer (2x) with saturated aq. NaHCO3. 1H NMR (300 MHz, MeOD) δ ppm 1.45 (d, 3 H) 2.14 (s, 3 H) 2.29 (s, 3 H) 3.52 - 3.93 (m, 2 H) 3.93 - 4.24 (m, 2 H) 4.73 - 4.80 (m, 1 H) 5.03 - 5.40 (m, 1 H) 8.61 (s, 2 H). LC-MS: 400 [M+H]+.
Example 20
6SV 6-(3.3 -Difluoroazetidin- 1 -γϊ)-Nλ-( 1 -(5-fluoropyrimidin-2-yl)ethyl)-Ni-(5-methyl- 1H-pyrazol- 3-ylV1,3,5-triazine-2,,4-diamine
Figure imgf000166_0001
(R)- 6-Chloro-N2-( 1 -(S-fluoropyrimidin^-yrjethy^-Λ^S-methyl- 1H-pyrazol-3 -yl> 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 17, 200 mg, 0.57 mmol) and 3,3-difluoroazetidine hydrochloride (81 mg, 0.63 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound.
1H NMR (300 MHz, MeOD) δ ppm 8.71 (s, 2 H) 6.07 (br. s., 1 H) 5.29 (q, 1 H) 3.98 - 4.55 (m, 4 H) 2.25 (s, 3 H) 1.57 (d, 3 H). LC-MS: 407 [M+H]+.
Example 21 fS)-6-(3 ,3 -Difluoropyrrolidin- 1 -γϊ)-Nz-( 1 -(5-fluoropyrimidin-2-yl)ethyl)-Ni-(5-methyl- IH- pyrazol-3-ylV 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000166_0002
(S>6-Chloro-N2-( 1 -(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl- 1H-pyrazol-3 -yl> 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 17, 200 mg, 0.57 mmol) and 3,3-difluoropyrrolidine hydrochloride (90 mg, 0.63 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound. 1H NMR (300 MHz, MeOD) δ ppm 8.71 (s, 1 H) 6.04 (br. s., 1 H) 5.29 (q, 1 H) 3.59 - 4.03 (m, 4 H) 2.30 - 2.58 (m, 2 H) 2.25 (s, 3 H) 1.57 (d, 3 H). LC-MS: 421 [M+H]+.
Example 22 (S)- 1 -(4-( l-(5-Fluoropyrimidin-2-yl)ethylamino)-6-(5-methyl- 1H-pyrazol-3-ylamino)- 1 ,3 ,5- triazin-2-yl)azetidin-3-ol
Figure imgf000167_0001
(S)-6-Chloro-N2-( 1 -(5-fluoropyrimidin-2-yl)-N4-(5-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine-
2,4-diamine (Intermediate 17, 200 mg, 0.57 mmol) and azetidin-3-ol hydrochloride (68.9 mg, 0.63 mmol) were reacted using a procedure similar to the one described for the synthesis of
Example 11, providing the title compound.
1H NMR (300 MHz, MeOD) δ ppm 8.71 (s, 2 H) 5.98 (br. s., 1 H) 5.29 (q, 1 H) 4.60 (br. s., 1 H)
4.28 (br. s., 2 H) 3.84 (br. s., 2 H) 2.26 (s, 3 H) 1.57 (d, 3 H).
LC-MS: 387 [M+H]+.
Example 23
N2-((S)-1-(5.Fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl-1H-pyrazol-3-yl)-6-((S)-3- methylmorpholino)-1,3,5-triazine-2,4-diamine
Figure imgf000168_0001
fS>6-Chloro-N2-( 1 -(S-fluoropyrimidin^-yrjethy^-Λ^S-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 17, 200 mg, 0.57 mmol) and (S)-3-methylmorpholine (63.6 mg, 0.63 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 62, providing the title compound. 1H NMR (300 MHz, MeOD) δ ppm 8.70 (s, 2 H) 5.76 (br. s., 1 H) 4.98 - 5.40 (m, 1 H) 4.40 -
4.76 (m, 1 H) 4.03 - 4.39 (m, 1 H) 3.86 (d, 1 H) 3.51 - 3.78 (m, 2 H) 2.94 - 3.23 (m, 1 H) 2.24 (s, 3 H) 1.55 (d, 3 H) 1.32 (br. s., 2 H) 0.95 (br. s., 2 H). LC-MS: 415 [M+H]+.
Example 24
(S)- 1 -(4-( l-(5-Fluoropyrimidin-2-yl)ethylamino)-6-(5-methyl- 1H-pyrazol-3-ylamino)- 1 ,3 ,5- triazin-2-ylV3-methylazetidin-3-ol
Figure imgf000168_0002
(S>6-Chloro-N2-( 1 -(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 17, 340 mg, 0.97 mmol) and 3-methylazetidin-3-ol hydrochloride (Intermediate 28, 132 mg, 1.07 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound. 1H NMR (300 MHz, MeOD) δ ppm 8.71 (s, 2 H) 6.15 (br. s., 1 H) 5.28 (m, 1 H) 3.73 - 4.04 (m, 4 H) 2.24 (s, 3 H) 1.36 - 1.71 (m, 6 H). LC-MS: 401[M+H]+.
Example 25 (S)- 1 -(4-( l-(5-Fluoropyrimidin-2-yl)ethylamino)-6-(5-methyl- 1H-pyrazol-3-ylamino)- 1 ,3 ,5- triazin-2-yl)azetidine-3-carbonitrile
Figure imgf000169_0001
fS>6-Chloro-N2-( 1 -(S-fluoropyrimidin^-y^ethy^-Λ^S-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine-
2,4-diamine (Intermediate 17, 200 mg, 0.57 mmol) and azetidine-3-carbonitrile hydrochloride (74.6 mg, 0.63 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound.
1H NMR (300 MHz, MeOD) δ ppm 8.70 (s, 2 H) 6.19 - 6.61 (m, 1 H) 5.59 (m, 1H) 5.28 (m, 1 H)
3.87 - 4.52 (m, 2 H) 3.60 - 3.86 (m, 2 H) 2.24 (d, 3 H) 1.55 (d, 3 H).
LC-MS: 396 [M+H]+.
Example 26
(5)-6-(3-Fluoroazetidin-1-yl)-N--(l-(5-fluoropyrimidin-2-yl)ethyl)-Λ^-(5-methyl-1H-pyrazol-3- vD- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000170_0001
fS>6-Chloro-N2-( 1 -(S-fluoropyrimidin^-yrjethy^-Λ^S-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 17, 228 mg, 0.65 mmol) and 3-fluoroazetidine hydrochloride (Intermediate 29, 80 mg, 0.72 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound. 1H NMR (300 MHz, MeOD) δ ppm 8.70 (s, 2 H) 6.16 (br. s., 1 H) 5.47 (m, 1 H) 5.27 (m, 1 H) 3.69 - 4.57 (m, 4 H) 2.24 (s, 3 H) 1.56 (d, 3 H). LC-MS: 389 [M+H]+.
Example 27 (y)-6-(4.4-Difluoropiperidin-1-yl)-N2-(l-(5-fluoropyrimidin-2-yl)ethyl)-Ni-(5-methyl-1H- pyrazol-3-ylV 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000170_0002
(S>6-Chloro-N2-( 1 -(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 17, 200 mg, 0.57 mmol) and 4,4-difluoropiperidine hydrochloride (99 mg, 0.63 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound. 1H NMR (300 MHz, MeOD) δ ppm 8.70 (s, 2 H) 6.05 (br. s., 1 H) 5.12 - 5.41 (m, 1 H) 3.82 (d, 4 H) 2.26 (s, 3 H) 1.98 (m, 4 H) 1.52 (d, 3 H). LC-MS: 435 [M+H]+
Example 28
(S)- 1 -(4-( l-(5-Fluoropyrimidin-2-yl)ethylamino)-6-(5-methyl- 1H-pyrazol-3-ylamino)- 1 ,3 ,5- triazin-2-yl)piperidin-4-ol
Figure imgf000171_0001
(S)-6-Chloro-N2-( 1 -(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine-
2,4-diamine (Intermediate 17, 200 mg, 0.57 mmol) and piperidin-4-ol (63.6 mg, 0.63 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound.
1H NMR (300 MHz, MeOD) δ ppm 8.69 (s, 2 H) 6.03 (br. s., 1 H) 5.06 - 5.41 (m, 1 H) 4.03 -
4.54 (m, 2 H) 3.79 (m, 1 H) 2.90 - 3.26 (m, 2 H) 2.25 (s, 3 H) 1.78 (m, 2 H) 1.56 (d, 3 H) 1.34
(m, 2 H).
LC-MS: 415 [M+H]+.
Example 29
(S)-6-(4-Fluoropiperidin-1-yl)-N--(l-(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl-1H-pyrazol-3- yl)- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000172_0001
fS>6-Chloro-N2-( 1 -(S-fluoropyrimidin^-yrjethy^-Λ^S-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine- 2,4-diamine (200 mg, 0.57 mmol) (Intermediate 17) and 4-fluoropiperidine hydrochloride (88 mg, 0.63 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound. 1H NMR (300 MHz, MeOD) δ ppm 8.69 (s, 2 H) 6.06 (br. s., 1 H) 5.09 - 5.40 (m, 1 H) 4.70 (m, 1 H) 3.46 - 4.10 (m, 4 H) 2.23 (s, 3 H) 1.61 - 2.02 (m, 4 H) 1.55 (d, 3 H). LC-MS: 417 [M+H]+.
Example 30 (S)-N~-( 1 -(5-Fluoropyrimidin-2-yl)ethylV6-(3 -methoxyazetidin- 1 -yP)-A^-(5 -methyl- 1H-pyrazol- 3-ylV1,3,5-triazine-2,4-diamine
Figure imgf000172_0002
(S>6-Chloro-N2-( 1 -(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 17, 200 mg, 0.57 mmol) and 3-methoxyazetidine hydrochloride (78 mg, 0.63 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound.
1H NMR (300 MHz, Chloroform-t/) δ ppm 8.56 (br. s., 2 H) 5.55 - 6.61 (m, 1 H) 5.39 (br.s, 1 H) 4.26 (m, 3 H) 3.98 (m, 2 H) 3.32 (s, 3 H) 2.29 (br. s., 3 H) 1.57 (d, 3 H). LC-MS: 401 [M+H]+.
Example 31
(S)- 1 -(4-( l-(5-Fluoropyrimidin-2-yl)ethylamino)-6-(5-methyl- 1H-pyrazol-3-ylamino)- 1 ,3 ,5- triazin-2-yl)-4-methylpiperidin-4-ol
Figure imgf000173_0001
fS>6-Chloro-N2-( 1 -(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine- 2,4-diamine (200 mg, 0.57 mmol) (Intermediate 17) and 4-methylpiperidin-4-ol hydrochloride (Intermediate 31, 95 mg, 0.63 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound.
1H NMR (SOO MHZ, MeOD) δ ppm 8.69 (s, 2 H) 6.18 (br. s., I H) 5.21 (m, 1 H) 3.81 - 4.38 (m, 2 H) 3.34 - 3.53 (m, 1 H) 2.23 (s, 3 H) 1.35 - 1.69 (m, 7 H) 1.13 - 1.29 (m, 4 H). LC-MS: 429 [M+Hf.
Example 32
(S)-N~-( 1 -(5-Fluoropyrimidin-2-yl)ethyl)-6-(4-methoxypiperidin- 1 -vP)-A^-(5 -methyl- 1H-pyrazol- 3-yl)-1,3.5-triazine-2,4-diamine
Figure imgf000174_0001
fS>6-Chloro-N2-( 1 -(S-fluoropyrimidin^-yrjethy^-Λ^S-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine- 2,4-diamine (200 mg, 0.57 mmol) (Intermediate 17) and 4-methoxypiperidine hydrochloride (95 mg, 0.63 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound. 1H NMR (300 MHz, MeOD) δ ppm 8.69 (s, 2 H) 6.05 (br. s., 1 H) 5.20 (m, 1 H) 3.89 - 4.41 (m, 2 H) 3.43 (m 1 H) 3.35 (s, 3 H) 3.09 - 3.27 (m, 1 H) 2.23 (s, 3 H) 1.77 (m, 2 H) 1.55 (d, 3 H) 1.37 (m, 2 H). LC-MS: 429 [M+H]+.
Example 33
(S)-A-(A-J l-(5-Fluoropyrimidin-2-yl)ethylamino)-6-(5-methyl- 1H-pyrazol-3-ylamino)- 1 ,3 ,5- triazin-2-vD- 1 -methylpiperazin-2-one
Figure imgf000174_0002
(S>6-Chloro-N2-( 1 -(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 17, 200 mg, 0.57 mmol) and l-methylpiperazin-2-one hydrochloride (95 mg, 0.63 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound.
1H NMR (300 MHz, MeOD) δ ppm 8.69 (br. s., 2 H) 6.11 (br. s., 1 H) 5.12 - 5.39 (m, 1 H) 4.07 - 4.48 (m, 2 H) 3.69 - 4.06 (m, 2 H) 3.41 (m, 1 H) 2.96 (br. s., 3 H) 2.24 (s, 3 H) 1.56 (d, 3 H). LC-MS: 428 [M+H]+.
Example 34
(S)- 1 -(4-( l-(5-Fluoropyrimidin-2-yl)ethylamino)-6-(5-methyl- 1H-pyrazol-3-ylamino)- 1 ,3 ,5- triazin-2-yl)piperidine-4-carbonitrile
Figure imgf000175_0001
(S>6-Chloro-N2-( 1 -(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl- 1H-pyrazol-3 -yl> 1 ,3 ,5-triazine-
2,4-diamine (Intermediate 17, 200 mg, 0.57 mmol) and piperidine-4-carbonitrile hydrochloride (Intermediate 32, 92 mg, 0.63 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound. 1H NMR (300 MHz, MeOD) δ ppm 8.69 (s, 2 H) 6.06 (br. s., 1 H) 5.10 - 5.42 (m, 1 H) 3.78 - 4.35 (m, 2 H) 3.35 - 3.63 (m, 2 H) 2.97 (m, 1 H) 2.24 (s, 3 H) 1.61 - 1.99 (m, 4 H) 1.55 (d, 3 H). LC-MS: 424 [M+H]+.
Example 35 1 -(4-((S)- 1 -(5-Fluoropyrimidin-2-yl)ethylamino)-6-(5-methyl- 1H-pyrazol-3-ylamino)- 1,3,5- triazin-2-yl)piperidine-3-carbonitrile
Figure imgf000176_0001
fS>6-Chloro-N2-( 1 -(S-fluoropyrimidin^-yrjethy^-Λ^S-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 17) and piperidine-3-carbonitrile were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of diastereomers. 1H NMR δ ppm 8.69 (m, 2H), 6.33 (m, 1H), 5.19 (m, 1H), 4.10 (m, 1H), 3.88 (m, 3H), 2.84 (m, 1H), 2.26 (m, 3H), 1.95 (m, 2H), 1.53 (m, 5H). LC-MS: 424 [M+H]+.
Column and solvent conditions The two diastereomers were separated using conditions (A) and AS-3-25. Column particle size (μ): 5 Column dimensions (mm): 21x250
Post purification purity check The sample purity was checked using conditions (B) and AD-3-25. Column dimensions: 4.6 x 250 mm, 10 μm Flow: 3 mL/min
Example 35(a), First Eluting Compound 1H NMR δ ppm 8.66 (m, 2H), 6.35 (m, 1H), 5.19 (m, 1H), 4.08 (m, 1H), 3.88 (m, 3H), 2.83 (m, 1H), 2.23 (m, 3H), 1.93 (m, 2H), 1.55 (m, 5H). LC-MS: 424 [M+H]+. The first eluting compound had a retention time of 8.59 minutes. Example 35(b), Second Eluting Compound
1H NMR δ ppm 8.70 (s, 2H), 5.99 (m, 1H), 5.23 (m, 1H), 4.08 (m, 1H), 3.90 (m, 3H), 2.85 (m, 1H), 2.24 (s, 3H), 1.98 (m, 3H), 1.56 (d, 4H). LC-MS: 424 [M+H]+. The second eluting compound had a retention time of 11.21 minutes.
Example 36
N--((S)- 1 -(5-Fluoropyrimidin-2-yl)ethyl)-6-(3 -methoxypiperi din- l-yl)-Λ^-(5 -methyl- 1H-pyrazol- 3-yl)-1,3.5-triazine-2,4-diamine
Figure imgf000177_0001
fS>6-Chloro-N2-( 1 -(S-fluoropyrimidin^-yrjethy^-Λ^S-methyl- 1H-pyrazol-3 -yl> 1 ,3 ,5-triazine-
2,4-diamine (Intermediate 17) and 3-methoxypiperidine were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of diastereomers 1H NMR δ ppm 8.68 (s, 2Η), 6.35 (br s, 1H), 5.21 (m, 1H), 4.11 (m, 1H), 3.87 (m, 1H), 3.36 (m, 6H), 2.22 (m, 3H), 1.94 (m, 1H), 1.72 (m, 1H), 1.55 (m, 4H), 1.39 (m, 1H).
LC-MS: 429 [M+Hf +.
Column and solvent conditions The two diastereomers were separated using conditions (A) and OJ-3-10. Column particle size (μ): 5 Column dimensions (mm): 21x250 Post purification purity check
The sample purity was checked using conditions (B) and OJ-3-15.
Column dimensions: 4.6 x 250 mm, 10 μm
Flow: 3 mL/min
Detection: 220 nm
Example 36(a), First Eluting Compound
1H NMR δ ppm 8.68 (s, 2H), 6.35 (br s, 1H), 5.21 (m, 1H), 3.90 (m, 2H), 3.36 (m, 6H), 2.22 (m,
3H), 1.94 (m, 1H), 1.55 (m, 5H), 1.40 (m, 1H).
LC-MS: 429 [M+H]+. The first eluting compound had a retention time of 5.07 minutes.
Example 36(b), Second Eluting Compound
1H NMR δ ppm 8.68 (s, 2H), 6.33 (br s, 1H), 5.23 (m, 1H), 4.13 (m, 1H), 3.80 (m, 1H), 3.36 (m, 6H), 2.22 (m, 3H), 1.93 (m, 1H), 1.69 (m, 1H), 1.55 (m, 5H). LC-MS: 429 [M+H]+.
The second eluting compound had a retention time of 6.57 minutes..
Example 37
1 -(4-((S)- 1 -(5-Fluoropyrimidin-2-yl)ethylamino)-6-(5-methyl- 1H-pyrazol-3-ylamino)- 1,3.5- triazin-2-yl)-3-methylpiperidin-3-ol
Figure imgf000178_0001
(S)-6-Chloro-N2-(l-(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl-1H-pyrazol-3-yl)-1,3,5-triazine- 2,4-diamine (Intermediate 17) and 3-methylpiperidin-3-ol (Intermediate 34) were reacted usin^ a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of diastereomers.
1H NMR O ppm 8.69 (s, 2H), 6.02 (m, 1H), 5.25 (m, 1H), 3.80 (m, 1H), 3.64 (m, 1H), 3.51 (m, 2H), 2.23 (s, 3H), 1.63 (m, 4H), 1.54 (m, 3H), 1.15 (m, 3H). LC-MS: 429 [M+H]+.
Column and solvent conditions
The two diastereomers were separated using conditions (A) and AD-3-20. Column particle size (μ): 5 Column dimensions (mm): 21x250
Post purification purity check:
The sample purity was checked using conditions (B) and AD-3-20. Column dimensions: 4.6 x 100 mm, 10 μm Flow: 3 mL/min
Detection: 254 nm
Example 37(a), First Eluting Compound
1H NMR O ppm 8.68 (s, 2H), 6.38 (m, 1H), 5.24 (m, 1H), 3.80 (m, 1H), 3.64 (m, 1H), 3.51 (m, 2H), 2.24 (m, 3H), 1.63 (m, 4H), 1.54 (m, 3H), 1.15 (m, 3H). LC-MS: 429 [M+H]+. The first eluting compound had a retention time of 2.13 minutes.
Example 37(b), Second Eluting Compound 1H NMR δ ppm 8.68 (s, 2H), 6.35 (m, 1H), 5.24 (m, 1H), 3.86 (m, 1H), 3.69 (m, 1H), 3.50 (m, 2H), 2.25 (m, 3H), 1.61 (m, 4H), 1.55 (m, 3H), 1.15 (m, 3H). LC-MS: 429 [M+H]+. The second eluting compound had a retention time of 3.18 minutes.
Example 38 tert-Butyl (R)- 1 -(4-((S)- 1 -(5-fluoropyrimidin-2-yl)ethylamino)-6-(5-methyl- 1H-pyrazol-3- ylaminoV 1 ,3 ,5-triazin-2-yr)piperidin-3-ylcarbamate
Figure imgf000180_0001
fS>6-Chloro-N2-( 1 -(S-fluoropyrimidin^-yrjethy^-Λ^S-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 17) and (R)-tert-butyl piperidin-3-ylcarbamate were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound.
1H NMR δ ppm 8.67 (m, 2H), 6.40 (m, 1H), 5.24 (m, 1H), 4.31 (m, 2H), 2.97 (m, 2H), 2.25 (m,
3H), 1.94 (m, 1H), 1.44 (m, 16H). LC-MS: 514 [M+H]+.
Example 39
6-((R)-3 -Aminopiperidin- 1 -γϊ)-Nz-((S)- 1 -(5-fluoropyrimidin-2-yl)ethyl)-Ni-(5-methyl- IH- Pyrazol-3-yl)-1,3,5-triazine-2,4-diamine, hydrochloride salt
Figure imgf000180_0002
tert-Butyl (R)- 1 -(4-((S)- 1 -(5-fluoropyrimidin-2-yl)ethylamino)-6-(5-methyl- 1H-pyrazol-3- ylamino)-1,3,5-triazin-2-yl)piperidin-3-ylcarbamate (Example 38) was dissolved in methanol and treated with 10 mL of 2N HCl in diethyl ether solution. The reaction mixture was stirred for four hours, concentrated under reduced pressured and dried in a vacuum oven at 50 °C to afford the title compound.
1H NMR δ ppm 8.76 (m, 2H), 5.88 (m, 1H), 5.34 (m, 1H), 4.23 (m, 1H), 3.96 (m, 1H), 3.65 (m, 2H), 2.39 (m, 1H), 2.32 (m, 3H), 2.11 (m, 1H), 1.63 (m, 6H). LC-MS: 414 [M+H]+.
Example 40 tert-Butyl (S)- 1 -(4-((S)- 1 -(5-fluoropyrimidin-2-yl)ethylamino)-6-(5-methyl- 1H-pyrazol-3- ylaminoV 1 ,3 ,5-triazin-2-yl)piperidin-3-ylcarbamate
Figure imgf000181_0001
(S)-6-Chloro-N2-( 1 -(S-fluoropyrimidin-2-yl)-N4-(5- methyl- 1H-pyrazol-3 -yl> 1 ,3 ,5-triazine-
2,4-diamine (Intermediate 17) and (S)-tert-buty\ piperidin-3-ylcarbamate were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound.
1H NMR δ ppm 8.67 (m, 2H), 6.39 (m, 1H), 5.22 (m, 1H), 4.31 (m, 2H), 2.91 (m, 2H), 2.23 (m, 3H), 1.90 (m, 1H), 1.55 (m, 7H), 1.43 (m, 9H).
LC-MS: 514 [M+H]+.
Example 41
6-((S)-3 -Aminopiperidin- 1 -γϊ)-N2-((S)- 1 -(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl- IH- pyrazol-3-yl)-1,3,5-triazine-2,4-diamine, hydrochloride salt
Figure imgf000182_0001
tert-Butyl (S)- 1 -(4-((S)- 1 -(5-fluoropyrimidin-2-yl)ethylamino)-6-(5-methyl- 1H-pyrazol-3- ylamino)-1,3,5-triazin-2-yl)piperidin-3-ylcarbamate (Example 40) was dissolved in methanol and treated with 10 mL 2N HCl in diethyl ether solution. The reaction mixture was stirred for four hours, concentrated under reduced pressured and dried in a vacuum oven at 50 °C to afford the title product.
1H NMR O ppm 8.76 (m, 2H), 5.91 (m, 1H), 5.30 (m, 1H), 4.42 (m, 1H), 3.95 (m, 1H), 3.58 (m,
2H), 2.33 (m, 3H), 2.17 (m, 1H), 1.87 (m, 1H), 1.64 (m, 5H), 1.39 (m, 1H).
LC-MS: 414 [M+H]+.
Example 42
(R)- 1 -(4-((S)- 1 -(5-Fluoropyrimidin-2-yl)ethylamino)-6-(5-methyl- 1H-pyrazol-3 -ylaminoV 1,3,5- triazin-2-yl)piperidin-3 -ol
Figure imgf000182_0002
(S>6-Chloro-N2-( 1 -(S-fluoropyrimidin^-yrjethy^-Λ^S-methyl- 1H-pyrazol-3 -yl> 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 17) and (R)-piperidin-3-ol were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound. 1H NMR δ ppm 8.68 (s, 2H), 6.35 (m, 1H), 5.23 (m, 1H), 4.26 (m, 2H), 3.54 (m, 1H), 2.96 (m, 2H), 2.23 (m, 3H), 1.95 (m, 1H), 1.54 (m, 3H), 1.43 (m, 3H). LC-MS: 415 [M+H]+.
Example 43
(S)- 1 -(4-((S)- 1 -(5-Fluoropyrimidin-2-yl)ethylamino)-6-(5-methyl- 1H-pyrazol-3 -ylaminoV 1,3,5- triazin-2-yl)piperidin-3 -ol
Figure imgf000183_0001
(S>6-Chloro-N2-( 1 -(S-fluoropyrimidin^-y^ethy^-N^S-methyl- 1H-pyrazol-3 -yl> 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 17) and (2^-piperidin-3-ol were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound. 1H NMR δ ppm 8.68 (s, 2H), 6.34 (m, 1H), 5.23 (m, 1H), 4.38 (m, 1H), 4.22 (m, 2H), 3.53 (m, 1H), 2.93 (m, 2H), 2.23 (m, 3H), 1.98 (m, 1H), 1.72 (m, 1H), 1.55 (m, 3H), 1.45 (m, 1H). LC-MS: 415 [M+H]+.
Example 44
N--((S)- 1 -(5-Fluoropyrimidin-2-yl)ethyl)-6-(3-(methoxymethyl)piperidin- l-yP)-A^-(5-methyl- IH- pyrazol-3-vP)- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000184_0001
(S>6-Chloro-N2-( 1 -(S-fluoropyrimidin^-yrjethy^-N^S-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine-
2,4-diamine (Intermediate 17) and 3-(methoxymethyl)piperidine were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of diastereomers 1H NMR δ ppm 8.68 (m, 2H), 6.39 (m, 1H), 5.22 (m, 1H), 4.62 (m, 1H), 4.42 (m, 1H), 3.23 (m, 5H), 2.87 (m, 1H), 2.69 (m, 1H), 2.22 (m, 3H), 1.76 (m, 3H), 1.54 (m, 3H), 1.29 (m, 2H). LC-MS: 443 [M+H]+.
Column and solvent conditions The two diastereomers were separated using conditions (A) and OD-3-15. Column particle size (μ): 5 Column dimensions (mm): 21x250
Post purification purity check: The sample purity was checked using conditions (B) and AD-4-25. Column dimensions: 4.6 x 100 mm, 10 μm Detection: 254 nm
Example 44(a), First Eluting Compound 1H NMR (δ) 8.69 (m, 2H), 6.36 (m, 1H), 5.22 (m, 1H), 4.48 (m, 1H), 4.27 (m, 1H), 3.25 (m, 5H), 2.89 (m, 1H), 2.65 (m, 1H), 2.22 (m, 3H), 1.75 (m, 3H), 1.55 (m, 3H), 1.27 (m, 2H). LC-MS: 443 [M+H]+. The first eluting compound had a retention time of 2.21 minutes. Example 44(b), Second Eluting Compound
1H NMR (δ) 8.68 (m, 2H), 6.36 (m, 1H), 5.23 (m, 1H), 4.45 (m, 2H), 3.23 (m, 5H), 2.89 (m, 1H), 2.72 (m, 1H), 2.22 (m, 3H), 1.79 (m, 3H), 1.54 (m, 3H), 1.28 (m, 2H). LC-MS: 443 [M+H]+. The second eluting compound had a retention time of 3.07 minutes.
Example 45
6-(2-((Diethylamino)methyl)morpholino)-N--((5f)-1-(5-fluoropyrimidin-2-yl)ethyl)-Λ^-(5-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000185_0001
fS>6-Chloro-N2-( 1 -(S-fluoropyrimidin^-yrjethy^-Λ^S-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 17) and N-ethyl-N-(morpholin-2-ylmethyl)ethanamine were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of diastereomers.
1H NMR δ ppm 8.69 (m, 2H), 6.35 (m, 1H), 5.24 (m, 1H), 4.49 (m, 2H), 3.90 (m, 1H), 3.54 (m, 2H), 2.89 (m, 1H), 2.67 (m, 7H), 2.23 (m, 3H), 1.55 (m, 3H), 1.07 (m, 6H). LC-MS: 486 [M+H]+.
Column and solvent conditions
The two diastereomers were separated using conditions (A) and AS-3-30. Column particle size (μ): 5 Column dimensions (mm): 21x250 Post purification purity check:
The sample purity was checked using conditions (B) and AS-3-30.
Column dimensions: 4.6 x 100 mm, 10 μm
Detection: 220 nm
Example 45(a), First Eluting Compound
1H NMR δ ppm 8.68 (m, 2H), 6.35 (m, 1H), 5.23 (m, 1H), 4.49 (m, 2H), 3.87 (m, 1H), 3.50 (m,
2H), 2.90 (m, 1H), 2.61 (m, 7H), 2.23 (m, 3H), 1.55 (m, 3H), 1.06 (m, 6H).
LC-MS: 486 [M+H]+. The first eluting compound had a retention time of 0.64 minutes.
Example 45(b), Second Eluting Compound
1H NMR (δ) 8.69 (m, 2H), 6.34 (m, 1H), 5.25 (m, 1H), 4.44 (m, 2H), 3.89 (m, 1H), 3.49 (m, 2H), 2.92 (m, 1H), 2.62 (m, 7H), 2.23 (m, 3H), 1.55 (m, 3H), 1.05 (m, 6H). LC-MS: 486 [M+H]+.
The second eluting compound had a retention time of 1.11 minutes.
Example 46
(R)-A-(A-J(S)- 1 -(5-Fluoropyrimidin-2-yl)ethylamino)-6-(5-methyl- 1H-pyrazol-3 -ylaminoV 1,3.5- triazin-2-yl)-N,N-dimethylmorpholine-3-carboxamide
Figure imgf000186_0001
(S>6-Chloro-N2-( 1 -(S-fluoropyrimidin^-yrjethy^-Λ^S-methyl- 1H-pyrazol-3 -yl> 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 17) and (7?)-N,N-dimethylmorpholine-3-carboxamide (Intermediate 35) were reacted using a procedure similar to the one described for the synthesis of Example 62, providing the title compound.
1H NMR δ ppm 8.69 (m, 2H), 6.29 (m, 1H), 5.34 (m, 1H), 4.25 (m, 1H), 4.15 (m, 2H), 3.93 (m, 1H), 3.78-3.53 (m, 3H), 3.11 (m, 3H), 2.91 (m, 3H), 2.23 (m, 3H), 1.54 (m, 3H). LC-MS: 472 [M+H]+.
Example 47
2-((R)-4-(4-((S)- 1 -(5-Fluoropyrimidin-2-yl)ethylamino)-6-(5-methyl- 1H-pyrazol-3-ylamino)-
1 ,3 ,5-triazin-2-yl)morpholin-3-yl)-NJV-dimethylacetamide
Figure imgf000187_0001
(S>6-Chloro-N2-( 1 -(S-fluoropyrimidin^-y^ethy^-Λ^S-methyl- 1H-pyrazol-3 -yl> 1 ,3 ,5-triazine-
2,4-diamine (Intermediate 17) and (7^)-N,N-dimethyl-2-(morpholin-3-yl)acetamide (Intermediate 36) were reacted using a procedure similar to the one described for the synthesis of Example 62, providing the title compound. 1H NMR δ ppm 8.68 (m, 2H), 6.32 (m, 1H), 5.22 (m, 1H), 4.92 (m, 1H), 4.34 (m, 1H), 3.87 (m, 3H), 3.60 (m, 1H), 3.46 (m, 1H), 3.08 (m, 4H), 2.87 (m, 3H), 2.52 (m, 1H), 2.22 (m, 3H), 1.54 (m, 3H). LC-MS: 486 [M+H]+.
Example 48 (R)-4-(4-((S)- 1 -(5-Fluoropyrimidin-2-yl)ethylamino)-6-(5-methyl- 1H-pyrazol-3 -ylaminoV 1,3,5- triazin-2-yl)-N-methylmorpholine-3-carboxamide
Figure imgf000188_0001
(S)-6-Chloro-N2-( 1 -(S-fluoropyrimidin-2-yl)ethyl)-N4-5-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 17) and (T^-N- methylmorpholine-3-carboxamide (Intermediate 37) were reacted using a procedure similar to the one described for the synthesis of Example 62, providing the title compound.
1H NMR δ ppm 8.64 (m, 2H), 6.34 (m, 1H), 5.29 (m, 1H), 5.03 (m, 1H), 4.43 (m, 2H), 3.80 (m, 1H), 3.53 (m, 2H), 2.73 (m, 2H), 2.57 (m, 2H), 2.24 (m, 3H), 1.53 (m, 3H). LC-MS: 458 [M+H]+.
Example 49 (R)-6-(3.3-Difluoropiperidin-1-yl)-N2-(l-(3.5-difluoropyridin-2-yl)-2-methoxyethyl)-N4-(5- methyl- 1H-pyrazol-3 -yP)- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000188_0002
(R)-6-Chloro-N2-(l-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)-N4-(5-methyl-1H-pyrazol-3-yl)- 1,3,5-triazine-2,4-diamine (Intermediate 42) and 3,3-difluoropiperidine hydrochloride were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound. 1H NMR δ ppm 8.34 (m, 1H), 7.54 (m, 1H), 6.01 (m, 1H), 5.62 (m, 1H), 4.01 (m, 2H), 3.79 (m, 4H), 3.35 (m, 3H), 2.23 (s, 3H), 2.04 (m, 2H), 1.71 (m, 2H). LC-MS: 482 [M+H]+.
Example 50 (R)- N2-(l-(3,5-Difluoropyridin-2-yl)-2-methoxyethyl)-6-(2,2-dimethylmorpholino)-N4-(5- methyl- 1H-pyrazol-3 -yP)- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000189_0001
(R)-6-Chloro-N2-(1-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)-N4(5-methyl-1H-pyrazol-3-yl)-
1,3,5-triazine-2,4-diamine (Intermediate 42) and 2,2-dimethylmorpholine hydrochloride were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound.
1H NMR δ ppm 8.35 (s, 1H), 7.59 (m, 1H), 6.36 (br s, 1H), 5.63 (m, 1H), 3.71 (m, 8H), 3.34 (m,
3H), 2.26 (br s, 3H), 1.19 (m, 6H).
LC-MS: 476 [M+H]+.
Example 51
N2-((R)-1-(3,5-Difluoropyridin-2-yl)-2-methoxyethyl)-6-(3-fluoropiperidin-1-yl)-N4-(5-methyl-
1H-pyrazol-3 -yP)- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000190_0001
(Tϊ^β-Chloro-Λ^-Cl-CS^-difluoropyridin-1-y^-1-methoxyethy^-V-CS-methyl-1H-pyrazol-S-yl)-
1,3,5-triazine-2,4-diamine (Intermediate 42) and 3-fluoropiperidine hydrochloride were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of diastereomers.
Column and solvent conditions
The two diastereomers were separated using conditions (A) and AS-3-20.
Column particle size (μ): 5
Column dimensions (mm): 21x250
Post purification purity check:
The sample purity was checked using conditions (B) and AS-3-15.
Column dimensions: 4.6 x 100 mm, 10 μm
Detection: 254 nm
Example 5Ka), First Eluting Compound
1H NMR (O) 8.35 (m, 1H), 7.54 (m, 1H), 6.37 (m, 1H), 5.65 (m, 1H), 3.81 (m, 6H), 3.61 (m, 1H),
3.31 (m, 3H), 2.25 (m, 3H), 1.87 (m, 3H), 1.53 (m, 1H).
LC-MS: 464 [M+H]+. The first eluting compound had a retention time of 1.75 minutes.
Example 5 Kb), Second Eluting Compound
1H NMR (δ) 8.34 (m, 1H), 7.53 (m, 1H), 6.36 (m, 1H), 5.63 (m, 1H), 4.50 (m, 1H), 3.78 (m, 5H),
3.58 (m, 1H), 3.35 (m, 3H), 2.26 (m, 3H), 1.88 (m, 3H), 1.48 (m, 1H). LC-MS: 464 [M+H]+.
The second eluting compound had a retention time of 2.50 minutes.
Example 52
(R)- 1 -(4-((R)- 1 -(3,5-Difluoropyridin-2-vD-2-methoxyethylaminoV6-(5-methyl- 1H-pyrazol-3- ylamino)- 1 ,3 ,5-triazin-2-yl)piperidin-3 -ol
Figure imgf000191_0001
(7?>6-Chloro-N2-(l-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)-N4-(5-methyl-1H-pyrazol-3-yl)-
1,3,5-triazine-2,4-diamine (Intermediate 42) and fi?)-piperidin-3-ol hydrochloride were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound.
1H NMR (δ) 8.35 (s, 1H), 7.54 (m, 1H), 6.09 (br s, 1H), 5.67 (m, 1H), 4.39 (m, 1H), 4.23 (m,
1H), 3.77 (m, 2H), 3.34 (s, 3H), 3.07 (m, 3H), 2.23 (s, 3H), 1.99 (m, 1H), 1.76 (m, 1H), 1.46 (m,
2H).
LC-MS: 462 [M+H]+.
Example 53
N2-((i?)-1-(3,5-Difluoropyridin-2-yl)-2-methoxyethyl)-6-(2-ethylmorpholino)-NA-(5-methyl-1H- pyrazol-3-vP)- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000192_0001
(TJj-o-Chloro-A^-Cl-CS^-difluoropyridin-1-y^-1-methoxyethy^-V-CS-methyl-1H-pyrazol-S-yl)-
1,3,5-triazine-2,4-diamine (Intermediate 42) and 2-ethylmorpholine were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of diastereomers.
Column and solvent conditions
The two diastereomers were separated using conditions (A) and OJ-3-10.
Column particle size (μ): 5
Column dimensions (mm): 21x250
Post purification purity check:
The sample purity was checked using conditions (B) and AD-4-10.
Column dimensions: 4.6 x 100 mm, 10 μm
Detection: 254 nm
Example 53 (a). First Eluting Compound
1H NMR (δ) 8.35 (s, 1H), 7.54 (m, 1H), 6.35 (br s, 1H), 5.65 (m, 1H), 4.51 (m, 2H), 3.89 (m,
2H), 3.76 (m, 2H), 3.52 (m, 1H), 3.33 (m, 3H), 2.93 (m, 1H), 2.61 (m, 1H), 2.25 (m, 3H), 1.53
(m, 2H), 0.98 (t, 3H). LC-MS: 476 [M+H]+.
The first eluting compound had a retention time of 17.77 minutes.
Example 53(b), Second Eluting Compound 1H NMR (δ) 8.35 (s, 1H), 7.55 (m, 1H), 6.36 (m, 1H), 5.66 (m, 1H), 4.50 (m, 2H), 3.88 (m, 2H), 3.76 (m, 3H), 3.34 (m, 3H), 2.95 (m, 1H), 2.61 (m, 1H), 2.25 (m, 3H), 1.52 (m, 2H), 0.98 (t, 3H). LC-MS: 476 [M+H]+. The second eluting compound had a retention time of 22.55 minutes.
Example 54
^)-N2-(3-(2-(1H-Imidazol-2-yl)ethyl)-1H-pyrazol-5-yl)-Ni-(l-(5-fiuoropyrimidin-2-yl)ethyl)-6- morpholino-l,,3,5-triazine-2,4-diamine
Figure imgf000193_0001
o-Chloro-N-Kl^-1-CS-fluoropyrimidin^-y^ethyll-TV-IS-P-Cl-IP-
(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)ethyl]-1H-pyrazol-5-yl}-1,3,5-triazine-2,4- diamine (Intermediate 171) and morpholine were reacted using a procedure similar to the one described for the synthesis of Example 11, providing fS/)-N2-(l-(5-fluoropyrimidin-2-yl)ethyl)-6- morpholino-Λ/4-(3-(2-(l-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)ethyl)-1H-pyrazol- 5-yl)- 1 ,3 ,5-triazine-2,4-diamine. (S)-N2 -{\ -(5-fluoropyrimidin-2-yl)ethyl)-6-morpholino-Λ/4-(3- (2-( 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1H-imidazol-2-yl)ethyl)- 1H-pyrazol-5-yl)- 1,3,5- triazine-2,4-diamine was dissolved in DCM. TFA and water was added to the solution and reaction was stirred for 2 hours. Concentration of reaction was followed by purification gave the title compound.
1H NMR (300 MHz, MeOD) δ ppm 8.75 (s, 2 H) 7.49 (s, 2H) 5.31 (q, 1 H) 3.59-3.86 (m, 8H) 3.08-3.26 (m, 4 H) 1.63 (d, 3 H). LCMS: 481 [M+H]+. Example 55
N--((R)-1-(3.5-Difluoropyridin-2-yl)-2-methoxyethyl)-N4-(5-methyl-1H-pyrazol-3-yl)-6-(2- methylmorpholinoM,3.5-triazine-2,4-diamine
Figure imgf000194_0001
(R)-6-Chloro-N2-(1-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)-N4-(5-methyl-1H-pyrazol-3-yl)- 1,3,5-triazine-2,4-diamine (Intermediate 42) and 2-methylmorpholine were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of diastereomers.
Column and solvent conditions The two diastereomers were separated using conditions (A) and OJ-3-15. Column particle size (μ): 5 Column dimensions (mm): 21x250
Post purification purity check The sample purity was checked using conditions (B) and OJ-3-10.
Column dimensions: 4.6 x 100 mm, 10 μm
Detection: 254 nm
Flow: 5 mL/min
Detection: 220 nm
Example 55(a), First Eluting Compound
1H NMR (δ) 8.35 (s, 1H), 7.55 (m, 1H), 6.36 (m, 1H), 5.63 (m, 1H), 4.49 (m, 2H), 3.88 (m, 2H),
3.76 (m, 2H), 3.52 (m, 1H), 3.33 (m, 3H), 2.92 (m, 1H), 2.58 (m, 1H), 2.26 (m, 3H), 1.17 (d, 3H).
LC-MS: 462 [M+H]+. The first eluting compound had a retention time of 1..64 minutes.
Example 55(b), Second Eluting Compound
1H NMR (δ) 8.34 (s, 1H), 7.55 (m, 1H), 6.35 (m, 1H), 5.64 (m, 1H), 4.48 (m, 2H), 3.85 (m, 4H), 3.50 (m, 1H), 3.34 (m, 3H), 2.93 (m, 1H), 2.56 (m, 1H), 2.25 (m, 3H), 1.17 (d, 3H). LC-MS: 462 [M+H]+.
The second eluting compound had a retention time of 3.24 minutes.
Example 56
(5f)-N--(5-Cvclopropyl-1H-pyrazol-3-yl)-Λ^-(l-(5-fluoropyrimidin-2-yl)ethyl)-6-morpholino- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000195_0001
(S>6-Chloro-N2-(5-cyclopropyl- 1H-pyrazol-3 -yl)-N4-( 1 -(5-fluoropyrimidin-2-yl)ethyl)- 1,3,5- triazine-2,4-diamine (Intermediate 38) and morpholine were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound. 1H (300 MHz, MeOD) δ ppm 8.60 (s, 2H), 5.13-5.15 (m, 1H), 3.48-3.61 (m, 8H), 3.25 (s, 1H), 1.75-1.82 (m, 1H), 1.46 (d, 3H), 0.83-0.88 (m, 2H), 0.62 (bs, 2H). LC-MS: 427 [M+H]+.
Example 57 N2-((,y)-1-(5-Fluoropyrimidin-2-vnethvn-Ni-(5-methyl-1H-pyrazol-3-vn-6-(2- methylmorpholino)-1,3.5-triazine-2,4-diamine
Figure imgf000196_0001
(S>6-Chloro-N2-( 1 -(5-fluoropyrimidin-2-yl)ethyl)-Λ^-(5-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine-
2,4-diamine (Intermediate 17) and 2-methylmorpholine were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of diastereomers. 1H NMR (δ) 8.71 (s, 2H), 6.37 (m, 1H), 5.24 (m, 1H), 4.38 (m, 2H), 3.86 (m, 1H), 3.49 (m, 2H), 2.92 (m, 1H), 2.57 (m, 1H), 2.27 (m, 3H), 1.56 (m, 3H), 1.17 (m, 3H). LC-MS: 415 [M+H]+.
Column and solvent conditions The two diastereomers were separated using conditions (A) and OJ-3-40. Column particle size (μ): 5 Column dimensions (mm): 21x250
Example 57(a), First Eluting Compound 1H NMR (O) 8.69 (s, 2H), 6.19 (m, 1H), 5.21 (m, 1H), 4.38 (m, 2H), 3.85 (m, 1H), 3.47 (m, 2H), 2.89 (m, 1H), 2.51 (m, 1H), 2.22(s, 3H), 1.54 (m, 3H), 1.17 (m, 3H). LC-MS: 415 [M+H]+.
Example 57(b), Second Eluting Compound 1H NMR (δ) 8.69 (s, 2H), 6.03 (m, 1H), 5.21 (m, 1H), 4.36 (m, 2H), 3.84 (m, 1H), 3.48(m, 2H), 2.89 (m, 1H), 2.56 (m, 1H), 2.23(s, 3H), 1.55(m, 3H), 1.15 (d, 3H). LC-MS: 415 [M+H]4
Example 58
(4-(4-((S)- 1 -(5-Fluoropyrimidin-2-yl)ethylamino)-6-(5-methyl- 1H-pyrazol-3-ylamino)- 1 ,3 ,5- triazin-2-yl)morpholin-2-yl)methanol
Figure imgf000197_0001
fS>6-Chloro-N2-( 1 -(S-fluoropyrimidin^-yrjethy^-Λ^S-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine-
2,4-diamine (Intermediate 17) and morpholin-2-ylmethanol were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of diastereomers. 1H NMR (δ) 8.71 (s, 2H), 6.26 (bs, 1H), 5.25 (m, 1H), 4.46 (m, 2H), 3.93 (m, 1H), 3.57 (m, 4H), 2.72-2.92 (m, 2H), 2.25 (m, 3H), 1.57 (m, 3H). LC-MS: 431, 432 [M+H]+.
The two diastereomers were separated using conditions (A) and OJ-3-30. Column particle size (μ): 5
Column dimensions (mm): 21x250
Example 58(a), First Eluting Compound
1H NMR (δ) 8.68 (s, 2H), 6.26 (bs, 1H), 5.23(m, 1H), 4.48 (m, 2H), 3.90 (m, 1H), 3.55(m, 4H), 2.81 (m, 2H), 2.51 (m, 1H), 2.23(s, 3H), 1.54 (m, 3H). LC-MS: 431[M+H]+. Example 58(b), Second Eluting Compound
1H NMR (δ) 8.68 (s, 2H), 6.06 (bs, 1H), 5.23(m, 1H), 4.44 (m, 2H), 3.89 (m, 1H), 3.56(m, 4H),
2.84 (m, 2H), 2.51 (m, 1H), 2.23(s, 3H), 1.54 (m, 3H).
LC-MS: 431 [M+H]+.
Example 59
6-(2-Ethylmorpholino)-N--((5)-1-(5-fluoropyrimidin-2-yl)ethyl)-Λ^-(5-methyl-1H-pyrazol-3-yl)- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000198_0001
fS>6-Chloro-N2-( 1 -(S-fluoropyrimidin^-yrjethy^-Λ^S-methyl- 1H-pyrazol-3 -yl> 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 17) and 2-ethylmorpholine were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of diastereomers. 1H NMR (δ) 8.68 (m, 2H), 6.33 (m, 1H), 5.21 (m, 1H), 4.42 (m, 2H), 3.86 (m, 1H),3.48 (m, 1H), 2.91 (m, 2H), 2.58 (m, 1H), 2.27 (m, 3H), 1.53 (m, 5H), 0.97 (m, 3H). LC-MS: 429 [M+H]+.
The mixture of diastereomers was separated using Chiral HPLC. Column: Chirapak AD Dimensions: 250 x 20mm, lOμ
Mobile phase: 90% Hexane, 10% isopropanol, 0.1% diethylamine (v/v/v)
Flow rate (ml/min): 20 Detection (nm): 220
Example 59(a), First Eluting Compound
1H NMR (δ) 8.71 (s, 2H), 6.35 (bs, 1H), 5.24 (m, 1H), 4.43 (m, 2H), 3.89(m, 1H),3.47 (m, 1H), 2.93 (m, 2H), 2.56 (m, 1H), 2.26 (m, 3H), 1.56 (m, 5H), 0.99 (t, 3H). LC-MS: 429 [M+H]+.
Example 59(b), Second Eluting Compound
1H NMR (δ) 8.68 (s, 2H), 6.29 (bs, 1H), 5.21 (m, 1H), 4.43 (m, 2H), 3.85(m, 1H),3.49 (m, 1H), 2.90 (m, 2H), 2.58 (m, 1H), 2.22 (s, 3H), 1.54 (m, 5H), 0.97 (t, 3H). LC-MS: 429 [M+H]+.
Example 60
2-( 1 -(4-((S)- 1 -(5-Fluoropyrimidin-2-yl)ethylamino)-6-(5-methyl- 1H-pyrazol-3 -ylaminoV 1,3,5- triazin-2-yl)piperidin-2-yl)acetonitrile
Figure imgf000199_0001
fS>6-Chloro-N2-( 1 -(S-fluoropyrimidin^-y^ethy^-N^S-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 17) and 2-(piperidin-2-yl)acetonitrile (Intermediate 39) were reacted using a procedure similar to the one described for the synthesis of Example 62, providing the title compound as a mixture of diastereomers. 1H NMR (δ) 8.69 (s, 2H), 6.03 (m, 1H), 5.23 (m, 1H), 4.57 (m, 1H), 2.78 (m, 3H), 2.23 (s, 3H), 1.92 (m, 1H), 1.81 (m, 1H), 1.66 (m 4H), 1.56 (m, 3H), 1.40 (m, 1H). LC-MS: 438 [M+H]+. Example 61
Nz-( 1 -(3.5 -Difluoropyridin-2-yr)ethylV./V1-f 5 -methyl- 1H-pyrazol-3 -ylV 6-morpholino- 1.3.5- triazine-2.4-diamine
Figure imgf000200_0001
6-Chloro-N2-( 1 -(3 ^-difluoropyridin^-y^ethyrj-Λ^S-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 40, 1.092 g, 2.98 mmol) was dissolved in ethanol (3.91 ml) and morpholine (9.08 ml, 104.21 mmol) was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was then concentrated in vacuo leaving a yellow semi-solid (3.143 g). This material was purified by ISCO (0-15% MeOΗ/DCM). The title compound, a mixture of enantiomers, was collected as a yellow solid (1.240 g) with a 99% yield.
1H NMR (300 MHz, MeOD) δ ppm 8.33 (s, 1 H) 7.41 - 7.66 (m, 1 H) 6.34 (br. s., 1 H) 5.29 - 5.74 (m, 1 H) 3.49 - 3.87 (m, 8 H) 2.23 (d, 3 H) 1.51 (br. s., 3 H). LC-MS: 418 [M+H]+.
Column and solvent conditions
The title compound was chirally purified using conditions (A) and AD-3-20.
Column particle size (μ): 5
Column dimensions (mm): 21x250
Detection: 220 nm
Post purification purity check:
The sample purity was checked using conditions (B) and OJ-3-20.
Column dimensions: 4.6 x 100 mm Detection: 220 nm
Example 6Ka), First Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.33 (s, 1 H) 7.41 - 7.66 (m, 1 H) 6.34 (br. s., 1 H) 5.29 - 5.74 (m, 1 H) 3.49 - 3.87 (m, 8 H) 2.23 (d, 3 H) 1.51 (br. s., 3 H) LC-MS: 418 [M+H]+.
The first eluting compound had a retention time of 0.58 minutes.
Example 6Kb), Second Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.33 (d, 1 H) 7.40 - 7.65 (m, 1 H) 6.34 (br. s., 0.5 H) 5.59 (br. s., 0.5 H) 5.38 - 5.49 (m, 1 H) 3.48 - 3.84 (m, 8 H) 2.09 - 2.38 (m, 3 H) 1.50 (d, 3 H) LC-MS: 418 [M+H]+. The second eluting compound had a retention time of 1.17 minutes.
Example 62 ((K)-A-(A-(I -(3 ,5-Difluoropyridin-2-yl)ethylamino)-6-(5-methyl- 1H-pyrazol-3-ylamino)- 1,3,5- triazin-2-yl)morpholin-3-yl)methanol
Figure imgf000201_0001
6-Chloro-N2-( 1 -(3 ,5-difluoropyridin-2-yl)ethyl)-N4-(5-methyl- 1H-pyrazol-3 -yl> 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 40, 200 mg, 0.55 mmol) and (^-morpholin-3-ylmethanol hydrochloride (92 mg, 0.60 mmol) were dissolved in BuOH (2 mL) and DIPEA (0.286 mL, 1.64 mmol) was added. The reaction was then heated at 100°C overnight. The reaction mixture was then concentrated in vacuo leaving a yellow oil. This material was then separated between EtOAc and water and the organics were concentrated in vacuo leaving a pale yellow solid (240 mg). This material was purified by ISCO (2-15% MeOH/DCM). Concentration of the fractions in vacuo provided the title compound, a mixture of diastereomers, as an off- white solid (209 mg). 1H NMR (300 MHz, MeOD) δ ppm 8.32 (s, 1 H) 7.54 (t, 1 H) 6.36 (br. s., 1 H) 5.32 - 5.76 (m, 1 H) 4.55 (br. s., 1 H) 4.35 (d, 1 H) 4.08 (d, 1 H) 3.88 (d, 2 H) 3.37 - 3.72 (m, 3 H) 2.98 - 3.22 (m, 1 H) 2.25 (br. s., 3 H) 1.50 (d, 3 H). LC-MS: 448 [M+H]+.
Column and solvent conditions
The two diastereomers were purified using conditions (A) and AD-3-30. Column particle size (μ): 5 Column dimensions (mm): 21x250
Post purification purity check:
The sample purity was checked using conditions (B) and AD-3-30. Column dimensions: 4.6 x 100 mm Detection: 254 nm
Example 62(a), First Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.32 (s, 1 H) 7.54 (t, 1 H) 6.36 (br. s., 1 H) 5.32 - 5.76 (m, 1 H) 4.55 (br. s., 1 H) 4.35 (d, 1 H) 4.08 (d, 1 H) 3.88 (d, 2 H) 3.37 - 3.72 (m, 3 H) 2.98 - 3.22 (m, 1 H) 2.25 (br. s., 3 H) 1.50 (d, 3 H). LC-MS: 448 [M+H]+. The first eluting compound had a retention time of 1.23 minutes.
Example 62(b), Second Eluting Compound 1H NMR (300 MHz, MeOD) δ ppm 8.32 (s, 1 H) 7.54 (t, 1 H) 6.36 (br. s., 1 H) 5.32 - 5.76 (m, 1
H) 4.55 (br. s., 1 H) 4.35 (d, 1 H) 4.08 (d, 1 H) 3.88 (d, 2 H) 3.37 - 3.72 (m, 3 H) 2.98 - 3.22 (m,
1 H) 2.25 (br. s., 3 H) 1.50 (d, 3 H).
LC-MS: 448 [M+H]+.
The second eluting compound had a retention time of 1.89 minutes. Example 63
N--(l-(3.5-Difluoropyridin-2-yl)ethyl)-6-(3-fluoroazetidin-1-yl)-Ni-(5-methyl-1H-pyrazol-3-yl)-
Figure imgf000203_0001
6-Chloro-N2-( 1 -(3 ^-difluoropyridin^-y^ethyrj-Λ^S-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 40, 136 mg, 0.37 mmol) and 3-fluoroazetidine hydrochloride
(Intermediate 29, 45.5 mg, 0.41 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of enantiomers.
1H NMR (300 MHz, MeOD) δ ppm 8.33 (br. s., 1 H) 7.41 - 7.69 (m, 1 H) 6.22 (br. s., 1 H) 5.47 (m, 1H) 5.28 (m, 1 H) 3.84 - 4.53 (m, 4 H) 2.23 (br. s., 3 H) 1.50 (d, 3 H).
LC-MS: 406 [M+H]+.
Column and solvent conditions
The two enantiomers were purified using Chiral HPLC. Column: Chirapak IA
Dimensions: 250 x 20mm, 5μ
Mobile phase: 90% Hexane, 10% 1:1 ethanohmethanol, 0.1% diethylamine (v/v/v)
Flow rate (ml/min): 20
Detection (nm): 220
Post purification purity check:
Post purification purity check
Sample purity was checked with a Chiralpak IA.
Column dimensions: 4.6 x 250 mm Mobile phase: 90 :10 :0.1 Hexanes :Ethanol/Methanol (1 :1) : Diethylamine Flow: 1 mL/min Detection: 220 nm
First Eluting Compound, Example 63 (a) 1H NMR (300 MHz, MeOD) δ ppm 8.33 (br. s., 1 H) 7.41 - 7.69 (m, 1 H) 6.22 (br. s., 1 H) 5.47 (m, 1H) 5.28 (m, 1 H) 3.84 - 4.53 (m, 4 H) 2.23 (br. s., 3 H) 1.50 (d, 3 H). LC-MS: 406 [M+H]+. The first eluting compound had a retention time of 16.99 minutes.
Second Eluting Compound, Example 63 (b)
1H NMR (300 MHz, MeOD) δ ppm 8.33 (br. s., 1 H) 7.41 - 7.69 (m, 1 H) 6.22 (br. s., 1 H) 5.47
(m, 1H) 5.28 (m, 1 H) 3.84 - 4.53 (m, 4 H) 2.23 (br. s., 3 H) 1.50 (d, 3 H).
LC-MS: 406 [M+H]+.
The second eluting compound had a retention time of 20.61 minutes.
Example 64 l-(4-(l-(3,5-Difluoropyridin-2-ylN)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-1,3,5-triazin-
2-yl)-4-methylpiperidin-4-ol
Figure imgf000204_0001
6-Chloro-N2-( 1 -(3 ,5-difluoropyridin-2-yl)ethyl)-N4-(5-methyl- 1H-pyrazol-3 -yl> 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 40, 200 mg, 0.55 mmol) and 4-methylpiperidin-4-ol hydrochloride (Intermediate 31, 91 mg, 0.60 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of enantiomers.
1H NMR (SOO MHz5 MeOD) S pPm SJl (S, 1 H) 7.41 - 7.67 (m, 1 H) 6.34 (br. s., 1 H) 5.15 - 5.93 (m, 1 H) 4.15 (m, 2 H) 3.35 (m, 2 H) 2.23 (m, 4 H) 1.50 (d, 7 H) 1.22 (br. s., 3 H) LC-MS: 446 [M+H]+.
Column and solvent conditions
The two enantiomers were purified using conditions (A) and OJ-3-20. Column particle size (μ): 5 Column dimensions (mm): 21x250
Post purification purity check:
The sample purity was checked using conditions (B) and OJ-3-20. Flow: 3 mL/min
Detection: 220 nm
Example 64(a), First Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.32 (s, 1 H) 7.41 - 7.67 (m, 1 H) 6.34 (br. s., 1 H) 5.15 -
5.93 (m, 1 H) 4.15 (m, 2 H) 3.35 (m, 2 H) 2.23 (m, 4 H) 1.50 (d, 7 H) 1.22 (br. s., 3 H)
LC-MS: 446 [M+H]+.
The first eluting compound had a retention time of 2.0 minutes.
Example 64(b), Second Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.32 (s, 1 H) 7.41 - 7.67 (m, 1 H) 6.34 (br. s., 1 H) 5.15 -
5.93 (m, 1 H) 4.15 (m, 2 H) 3.35 (m, 2 H) 2.23 (m, 4 H) 1.50 (d, 7 H) 1.22 (br. s., 3 H)
LC-MS: 446 [M+H]+. The second eluting compound had a retention time of 4.19 minutes.
Example 65
N2-(l-(3,5-Difluoropyridin-2-yl)ethyl)-6-(4-methoxypiperidin-1-yl)-Ni-(5-methyl-1H-pyrazol-3- vD- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000206_0001
6-Chloro-N2-( 1 -(3 ^-difluoropyridin^-y^ethyrj-N^S-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine-
2,4-diamine (Intermediate 40, 200 mg, 0.55 mmol) and 4-methoxypiperidine hydrochloride (91 mg, 0.60 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of enantiomers. 1H NMR (300 MHz, MeOD) δ ppm 8.32 (s, 1 H) 7.42 - 7.69 (m, 1 H) 6.35 (br. s., 1 H) 5.30 -
5.83 (m, 1 H) 4.17 (m, 3 H) 3.47 (m, 1 H) 3.36 (s, 3 H) 2.24 (br. s., 3 H) 1.86 (m, 2 H) 1.05 - 1.69
(m, 6 H).
LC-MS: 446 [M+H]+.
Column and solvent conditions
The two enantiomers were purified using conditions (A) and OJ-3-20. Column particle size (μ): 5 Column dimensions (mm): 21x250
Post purification purity check:
The sample purity was checked using conditions (B) and OJ-3-20. Flow: 3 mL/min
Detection: 220 nm
Example 65(a), First Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.32 (s, 1 H) 7.42 - 7.69 (m, 1 H) 6.35 (br. s., 1 H) 5.30 - 5.83 (m, 1 H) 4.17 (m, 3 H) 3.47 (m, 1 H) 3.36 (s, 3 H) 2.24 (br. s., 3 H) 1.86 (m, 2 H) 1.05 - 1.69 (m, 6 H). LC-MS: 446 [M+H]+.
The first eluting compound had a retention time of 2.15 minutes.
Example 65(b), Second Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.32 (s, 1 H) 7.42 - 7.69 (m, 1 H) 6.35 (br. s., 1 H) 5.30 - 5.83 (m, 1 H) 4.17 (m, 3 H) 3.47 (m, 1 H) 3.36 (s, 3 H) 2.24 (br. s., 3 H) 1.86 (m, 2 H) 1.05 - 1.69 (m, 6 H).
LC-MS: 446 [M+H]+. The second eluting compound had a retention time of 4.46 minutes.
Example 66 l-(4-(l-(3,5-Difluoropyridin-2-yl)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-1,3,5-triazin- 2-yl)piperidine-4-carbonitrile
Figure imgf000207_0001
6-Chloro-N2-( 1 -(3 ,5-difluoropyridin-2-yl)ethyl)-N4-(5-methyl- 1H-pyrazol-3 -yl> 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 40, 200 mg, 0.55 mmol) and piperidine-4-carbonitrile hydrochloride
(Intermediate 32, 88 mg, 0.60 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of enantiomers.
1H NMR (300 MHz, MeOD) δ ppm 8.33 (s, 1 H) 7.55 (ddd, 1 H) 6.34 (br. s., 1 H) 5.25 - 5.78 (m, 1 H) 4.07 (m, 2 H) 3.52 (m, 2 H) 3.06 (m 1 H) 2.24 (m, 3 H) 1.57 - 2.06 (m, 4 H) 1.51 (d, 3 H).
LC-MS: 441 [M+H]+. Column and solvent conditions
The two enantiomers were purified using conditions (A) and OJ-3-15. Column particle size (μ): 5 Column dimensions (mm): 21x250
Post purification purity check:
The sample purity was checked using conditions (B) and OJ-3-20.
Column dimensions: 4.6 x 250 mm
Flow: 3 mL/min
Detection: 220 nm
Example 66(a), First Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.33 (s, 1 H) 7.55 (ddd, 1 H) 6.34 (br. s., 1 H) 5.25 - 5.78 (m,
1 H) 4.07 (m, 2 H) 3.52 (m, 2 H) 3.06 (m 1 H) 2.24 (m, 3 H) 1.57 - 2.06 (m, 4 H) 1.51 (d, 3 H).
LC-MS: 441 [M+H]+. The first eluting compound had a retention time of 2.60 minutes.
Example 66(b), Second Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.33 (s, 1 H) 7.55 (ddd, 1 H) 6.34 (br. s., 1 H) 5.25 - 5.78 (m, 1 H) 4.07 (m, 2 H) 3.52 (m, 2 H) 3.06 (m 1 H) 2.24 (m, 3 H) 1.57 - 2.06 (m, 4 H) 1.51 (d, 3 H). LC-MS: 441 [M+H]+.
The second eluting compound had a retention time of 3.61 minutes.
Example 67
N--(l-(3,5-Difluoropyridin-2-yl)ethyl)-6-(4-fluoropiperidin-1-yl)-NA-(5-methyl-1H-pyrazol-3-yl)- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000209_0001
6-Chloro-N2-( 1 -(3 ^-difluoropyridin^-y^ethyrj-Λ^S-methyl- 1H-pyrazol-3 -yl> 1 ,3 ,5-triazine-
2,4-diamine (Intermediate 40, 200 mg, 0.55 mmol) and 4-fluoropiperidine hydrochloride (84 mg, 0.60 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of enantiomers. 1H NMR (300 MHz, MeOD) δ ppm 8.32 (s, 1 H) 7.38 - 7.69 (m, 1 H) 6.35 (br. s., 1 H) 5.31 -
5.75 (m, 1 H) 4.73 (m, 1 H) 3.60 - 4.05 (m, 4 H) 2.07 - 2.42 (m, 3 H) 1.58 - 2.05 (m, 4 H) 1.52 (d,
3 H).
LC-MS: 434 [M+H]+.
Column and solvent conditions
The two enantiomers were purified using conditions (A) and OJ-3-20. Column particle size (μ): 5 Column dimensions (mm): 21x250
Post purification purity check:
The sample purity was checked using conditions (B) and OJ-3-20.
Column dimensions: 4.6 x 250 mm
Flow: 3 mL/min
Detection: 220 nm
Example 67(a), First Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.32 (s, 1 H) 7.38 - 7.69 (m, 1 H) 6.35 (br. s., 1 H) 5.31 -
5.75 (m, 1 H) 4.73 (m, 1 H) 3.60 - 4.05 (m, 4 H) 2.07 - 2.42 (m, 3 H) 1.58 - 2.05 (m, 4 H) 1.52 (d, 3 H).
LC-MS: 434 [M+H]+.
The first eluting compound had a retention time of 2.19 minutes.
Example 67(b), Second Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.32 (s, 1 H) 7.38 - 7.69 (m, 1 H) 6.35 (br. s., 1 H) 5.31 -
5.75 (m, 1 H) 4.73 (m, 1 H) 3.60 - 4.05 (m, 4 H) 2.07 - 2.42 (m, 3 H) 1.58 - 2.05 (m, 4 H) 1.52 (d,
3 H).
LC-MS: 434 [M+H]+.
The second eluting compound had a retention time of 3.97 minutes.
Example 68
6-(4,4-Difluoropiperidin-1-yl)-N2-(l-(3,5-difluoropyridin-2-yl)ethyl)-Ni-(5-methyl-1H-pyrazol- 3-yl)-1,3.5-triazine-2,4-diamine
Figure imgf000210_0001
6-Chloro-N2-( 1 -(3 ^-difluoropyridin^-y^ethyrj-Λ^S-methyl- 1H-pyrazol-3 -yl> 1 ,3 ,5-triazine-
2,4-diamine (Intermediate 40, 200 mg, 0.55 mmol) and 4,4-difluoropiperidine hydrochloride (95 mg, 0.60 mmol) were reacted using a procedure similar to the one described for the synthesis of
Example 11, providing the title compound as a mixture of enantiomers.
1H NMR (300 MHz, MeOD) δ ppm 8.33 (s, 1 H) 7.55 (ddd, 1 H) 6.34 (br. s., 1 H) 5.25 - 5.82
(m, 1 H) 3.87 (br. s., 4 H) 2.24 (br. s., 3 H) 1.68 - 2.08 (m, 4 H) 1.51 (d, 3 H).
LC-MS: 452 [M+H]+. Column and solvent conditions
The two enantiomers were purified using conditions (A) and OJ-3-15. Column particle size (μ): 5 Column dimensions (mm): 21x250
Post purification purity check:
The sample purity was checked using conditions (B) and OJ-3-20.
Column dimensions: 4.6 x 250 mm
Flow: 3 mL/min
Detection: 220 nm
Example 68(a), First Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.33 (s, 1 H) 7.55 (ddd, 1 H) 6.34 (br. s., 1 H) 5.25 - 5.82
(m, 1 H) 3.87 (br. s., 4 H) 2.24 (br. s., 3 H) 1.68 - 2.08 (m, 4 H) 1.51 (d, 3 H).
LC-MS: 452 [M+H]+. The first eluting compound had a retention time of 1.99 minutes.
Example 68(b), Second Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.33 (s, 1 H) 7.55 (ddd, 1 H) 6.34 (br. s., 1 H) 5.25 - 5.82 (m, 1 H) 3.87 (br. s., 4 H) 2.24 (br. s., 3 H) 1.68 - 2.08 (m, 4 H) 1.51 (d, 3 H). LC-MS: 452 [M+H]+.
The second eluting compound had a retention time of 3.14 minutes.
Example 69
N--(l-(3,5-Difluoropyridin-2-yl)ethyl)-6-(3-methoxyazetidin-1-yl)-Λ^-(5-methyl-1H-pyrazol-3- vD- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000212_0001
6-Chloro-N2-( 1 -(3 ^-difluoropyridin^-y^ethyrj-Λ^S-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine-
2,4-diamine (Intermediate 40, 200 mg, 0.55 mmol) and 3-methoxyazetidine hydrochloride (74.1 mg, 0.60 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of enantiomers. 1H NMR (300 MHz, MeOD) δ ppm 8.33 (br. s., 1 H) 7.40 - 7.69 (m, 1 H) 6.40 (br. s., 1 H) 5.27 - 5.78 (m, 1 H) 4.01 - 4.43 (m, 3 H) 3.62 - 4.01 (m, 2 H) 2.43 (br.s., 3 H) 1.49 (d, 3 H). LC-MS: 418[M+H]+.
Column and solvent conditions The two enantiomers were purified using conditions (A) and OJ-3-20. Column particle size (μ): 5 Column dimensions (mm): 21x250
Post purification purity check: The sample purity was checked using conditions (B) and OJ-3-20. Column dimensions: 4.6 x 250 mm Flow: 3 mL/min
Detection: 220 nm
Example 69(a), First Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.33 (br. s., 1 H) 7.40 - 7.69 (m, 1 H) 6.40 (br. s., 1 H) 5.27 - 5.78 (m, 1 H) 4.01 - 4.43 (m, 3 H) 3.62 - 4.01 (m, 2 H) 2.43 (br.s., 3 H) 1.49 (d, 3 H). LC-MS: 418[M+H]+.
The first eluting compound had a retention time of 1.78 minutes.
Example 69(b), Second Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.33 (br. s., 1 H) 7.40 - 7.69 (m, 1 H) 6.40 (br. s., 1 H) 5.27 5.78 (m, 1 H) 4.01 - 4.43 (m, 3 H) 3.62 - 4.01 (m, 2 H) 2.43 (br.s., 3 H) 1.49 (d, 3 H). LC-MS: 418[M+H]+. The second eluting compound had a retention time of 3.13 minutes.
Example 70 N2-(l-(3,5-Difluoropyridin-2-yl)-2-methoxyethyl)-6-(3-fluoroazetidin-1-yl)-NA-(5-methyl-1H- pyrazol-3-vD- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000213_0001
6-Chloro-N2-(l-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)-Λ/4-(5-methyl-1H-pyrazol-3-yl)-
1,3,5-triazine-2,4-diamine (Intermediate 41, 166 mg, 0.42 mmol) and 3-fluoroazetidine hydrochloride (Intermediate 29, 51.3 mg, 0.46 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of enantiomers.
1H NMR (300 MHz, MeOD) δ ppm 8.36 (br. s., 1 H) 7.41 - 7.67 (m, 1 H) 6.41 (br. s., 1 H) 5.54 -
5.85 (m, 1 H) 5.49 (m, 1 H) 5.28 (m, 1H) 4.19 - 4.50 (m, 2 H) 3.89 - 4.20 (m, 1 H) 3.61 - 3.89 (m, 2 H) 3.34 (br. s., 3 H) 2.27 (br. s., 3 H).
LC-MS: 436 [M+H]+. Column and solvent conditions
The two enantiomers were purified using conditions (A) and AD-3-20. Column particle size (μ): 5 Column dimensions (mm): 21x250
Post purification purity check:
The sample purity was checked using conditions (B) and AD-3-20.
Column dimensions: 4.6 x 250 mm
Flow: 3 mL/min
Detection: 220 nm
Example 70(a), First Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.36 (br. s., 1 H) 7.41 - 7.67 (m, 1 H) 6.41 (br. s., 1 H) 5.54
5.85 (m, 1 H) 5.49 (m, 1 H) 5.28 (m, 1H) 4.19 - 4.50 (m, 2 H) 3.89 - 4.20 (m, 1 H) 3.61 - 3.89
(m, 2 H) 3.34 (br. s., 3 H) 2.27 (br. s., 3 H). LC-MS: 436 [M+H]+.
The first eluting compound had a retention time of 2.34 minutes.
Example 70(b), Second Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.36 (br. s., 1 H) 7.41 - 7.67 (m, 1 H) 6.41 (br. s., 1 H) 5.54 5.85 (m, 1 H) 5.49 (m, 1 H) 5.28 (m, 1H) 4.19 - 4.50 (m, 2 H) 3.89 - 4.20 (m, 1 H) 3.61 - 3.89 (m, 2 H) 3.34 (br. s., 3 H) 2.27 (br. s., 3 H). LC-MS: 436 [M+H]+. The second eluting ocmpound had a retention time of 3.40 minutes (95.9% e.e.).
Example 71
N--(l-(3,5-Difluoropyridin-2-ylN)-2-methoxyethyl)-6-(4-methoxypiperidin-1-yl)-Λ^-(5-methyl- 1H-pyrazol-3 -vD- 1 ,3 ,5-triazine-2.4-diamine
Figure imgf000215_0001
β-Chloro-Λ^-Cl-CS^-difluoropyridin-1-y^-1-methoxyethy^-V-CS-methyl-1H-pyrazol-S-yl)-
1,3,5-triazine-2,4-diamine (Intermediate 41, 150 mg, 0.38 mmol) and 4-methoxypiperidine hydrochloride (63.1 mg, 0.42 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of enantiomers. 1H NMR (300 MHz, MeOD) δ ppm 8.36 (br. s., 1 H) 7.42 - 7.68 (m, 1 H) 6.36 (br. s., 1 H) 5.65
(t, 1 H) 4.20 (d, 2 H) 3.64 - 3.95 (m, 2 H) 3.41 - 3.53 (m, 1 H) 3.37 (s, 3 H) 3.35 (s, 3 H) 2.23 (m,
3 H) 1.87 (br. s., 2 H) 1.36 (m, 3 H).
LC-MS: 476 [M+H]+.
Column and solvent conditions The title compound was chirally purified using Chiral HPLC.
Column: Chiralpak IB
Dimensions: 250 x 20mm, lOμ
Mobile phase: 93% Hexane, 7% 1:1 ethanobmethanol, 0.1% diethylamine (v/v/v)
Flow rate (ml/min): 20 Detection (nm): 254
Post purification purity check:
The sample purity was checked using the following conditions: Column: Chiralpak IB. 4.6 x 250 mm, 5 μm Mobile phase: 93 :7 :0.1 Hexanes :Ethanol/Methanol (1 :1) :Diethylamine
Flow: 1 mL/min
Detection: 254 nm Example 71 (a). First Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.36 (br. s., 1 H) 7.42 - 7.68 (m, 1 H) 6.36 (br. s., 1 H) 5.65 (t, 1 H) 4.20 (d, 2 H) 3.64 - 3.95 (m, 2 H) 3.41 - 3.53 (m, 1 H) 3.37 (s, 3 H) 3.35 (s, 3 H) 2.23 (m, 3 H) 1.87 (br. s., 2 H) 1.36 (m, 3 H). LC-MS: 476 [M+H]+. The first eluting compound had a retention time of 17.03 minutes.
Example 7 Kb), Second Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.36 (br. s., 1 H) 7.42 - 7.68 (m, 1 H) 6.36 (br. s., 1 H) 5.65 (t, 1 H) 4.20 (d, 2 H) 3.64 - 3.95 (m, 2 H) 3.41 - 3.53 (m, 1 H) 3.37 (s, 3 H) 3.35 (s, 3 H) 2.23 (m, 3 H) 1.87 (br. s., 2 H) 1.36 (m, 3 H). LC-MS: 476 [M+H]+. The second eluting compound had a retention time of 19.49 minutes (96.2% e.e.).
Example 72 N2-(l-(3,5-Difluoropyridin-2-yl)-2-methoxyethyl)-6-(3-methoxyazetidin-1-yl)-NA-(5-methyl-1H- pyrazol-3-vD- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000216_0001
6-Chloro-N2-(l-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)-Λ/4-(5-methyl-1H-pyrazol-3-yl)- 1,3,5-triazine-2,4-diamine (Intermediate 41, 170 mg, 0.43 mmol) and 3-methoxyazetidine hydrochloride (52.9 mg, 0.43 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of enantiomers. 1H NMR (300 MHz, MeOD) δ ppm 8.39 (s, 1 H) 7.56 - 7.74 (m, 1 H) 5.83 (br. s., 1 H) 5.59 - 5.76 (m, 1 H) 3.90 - 4.58 (m, 5 H) 3.62 - 3.91 (m, 2 H) 3.38 (s, 3 H) 3.37 (s, 3 H) 2.31 (s, 3 H). LC-MS: 448 [M+H]+.
Column and solvent conditions
The two enantiomers were purified using conditions (A) and AD-3-20. Column particle size (μ): 5
Column dimensions (mm): 21x250
Post purification purity check:
The sample purity was checked using conditions (B) and AD-3-20. Column dimensions: 4.6 x 250 mm Flow: 3 mL/min
Detection: 220 nm
Example 72(a), First Eluting Compound 1H NMR (300 MHz, MeOD) δ ppm 8.39 (s, 1 H) 7.56 - 7.74 (m, 1 H) 5.83 (br. s., 1 H) 5.59 - 5.76 (m, 1 H) 3.90 - 4.58 (m, 5 H) 3.62 - 3.91 (m, 2 H) 3.38 (s, 3 H) 3.37 (s, 3 H) 2.31 (s, 3 H). LC-MS: 448 [M+H]+. The first eluting compound had a retention time of 1.69 minutes.
Example 72(b), Second Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.39 (s, 1 H) 7.56 - 7.74 (m, 1 H) 5.83 (br. s., 1 H) 5.59 -
5.76 (m, 1 H) 3.90 - 4.58 (m, 5 H) 3.62 - 3.91 (m, 2 H) 3.38 (s, 3 H) 3.37 (s, 3 H) 2.31 (s, 3 H).
LC-MS: 448 [M+H]+.
The second eluting compound had a retention time of 21.8 minutes.
Example 73
((i?)-4-(4-((i?)-1-(3.5-Difluoropyridin-2-yl)-2-methoxyethylamino)-6-(5-methyl-1H-pyrazol-3- ylamino)-1,3,5-triazin-2-yl)morpholin-3-yl)methanoL TFA salt
Figure imgf000218_0001
(Tϊ^β-Chloro-^-Cl-CS^-difluoropyridin-1-y^-1-methoxyethy^-V-CS-methyl-1H-pyrazol-S-yl)- 1,3,5-triazine-2,4-diamine (Intermediate 42, 100 mg, 0.25 mmol) and (7?)-morpholin-3- ylmethanol hydrochloride (42.6 mg, 0.28 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 62, providing the title product. 1H NMR (300 MHz, MeOD) δ ppm 8.40 (s, 1 H) 7.63 (t, 1 H) 5.80 - 6.04 (m, 1 H) 5.58 - 5.80 (m, 1 H) 4.54 - 4.73 (m, 1 H) 4.46 (d, 1 H) 3.40 - 4.15 (m, 10 H) 3.41 (s, 3 H) 2.32 (s, 3 H). LC-MS: 478 [M+H]+.
Example 74 (R)- 1 -(4-( 1 -(3 ,5-Difluoropyridin-2-yl)-2-methoxyethylamino)-6-(5-methyl- 1H-pyrazol-3- ylamino)-1,3.5-triazin-2-yl)-4-methylpiperidin-4-ol, TFA salt
Figure imgf000218_0002
('i?>6-Chloro-N2-(l-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)-N4-(5-methyl-1H-pyrazol-3-yl)- 1,3,5-triazine-2,4-diamine (Intermediate 42, 100 mg, 0.25 mmol) and 4-methylpiperidin-4-ol hydrochloride (Intermediate 31, 42.0 mg, 0.28 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound. 1H NMR (300 MHz, MeOD) δ ppm 8.39 (s, 1 H) 7.63 (t, 1 H) 5.75 - 5.99 (m, 1 H) 5.58 - 5.74 (m, 1 H) 4.13 - 4.55 (m, 2 H) 3.63 - 3.98 (m, 2 H) 3.41 - 3.57 (m, 2 H) 3.39 (s, 3 H) 2.31 (s, 3 H) 1.61 (br. s., 3 H) 1.24 (d, 3 H). LC-MS: 476 [M+H]+.
Example 75
(R)- 1 -(4-( 1 -(3 ,5-Difluoropyridin-2-yl)-2-methoxyethylamino)-6-(5-methyl- 1H-pyrazol-3- ylamino)-1,3,5-triazin-2-yl)piperidine-4-carbonitrile, TFA salt
Figure imgf000219_0001
(R)-6-Chloro-N2 -(1-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)-N4-(5-methyl-1H-pyrazol-3-yl)-
1,3,5-triazine-2,4-diamine (Intermediate 42, 100 mg, 0.25 mmol) and piperidine-4-carbonitrile hydrochloride (Intermediate 32, 40.6 mg, 0.28 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title product.
1H NMR (300 MHz, MeOD) δ ppm 8.40 (s, 1 H) 7.65 (br. s., 1 H) 5.84 (br. s., 1 H) 5.59 - 5.76
(m, 1 H) 4.00 - 4.35 (m, 2 H) 3.46 - 3.98 (m, 4 H) 3.37 (s, 3 H) 3.02 - 3.20 (m, 1 H) 2.32 (s, 3 H)
1.49 - 2.14 (m, 4 H).
LC-MS: 471 [M+H]+
Example 76
(R)-N2-(l-(3,5-Difluoropyridin-2-yl)-2-methoxyethyl)-6-(4-fluoropiperidin-1-yl)-N--(5-methyl- 1H-Pyrazol-3-yl)-1,3,5-triazine-2,4-diamine, TFA salt
Figure imgf000220_0001
(R)-6-Chloro-N2-(1-(3,5-difluoropyridin-1-yl)-2-methoxyethyl)-N4-(5-methyl-1H-pyrazol-3-yl)- 1,3,5-triazine-2,4-diamine (Intermediate 42, 100 mg, 0.25 mmol) and 4-fluoropiperidine hydrochloride (38.7 mg, 0.28 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title product. 1H NMR (300 MHz, MeOD) δ ppm 8.39 (s, 1 H) 7.55 - 7.74 (m, 1 H) 5.83 (br. s., 1 H) 5.66 (t, 1 H) 3.63 - 4.29 (m, 7 H) 3.38 (s, 3 H) 2.32 (s, 3 H) 1.53 - 2.11 (m, 4 H). LC-MS: 464 [M+H]+.
Example 77 (R))-6-(4.4-Difluoropiperidin-1-yl)-N2-(l-(3.5-difluoropyridin-2-yl)-2-methoxyethyl)-N4-(5- methyl- 1H-pyrazol-3-yl)-1,3,5-triazine-2,4-diamine, TFA salt
Figure imgf000220_0002
(R)- 6-Chloro-N2-(l-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)-N4-(5-methyl-1H-pyrazol-3-yl)- 1,3,5-triazine-2,4-diamine (Intermediate 42, 100 mg, 0.25 mmol) and 4,4-difluoropiperidine hydrochloride (43.7 mg, 0.28 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title product.
1H NMR (300 MHz, MeOD) δ ppm 8.40 (s, 1 H) 7.65 (ddd, 1 H) 5.85 (s, 1 H) 5.68 (t, 1 H) 3.65 - 4.21 (m, 4 H) 3.42 (s, 3 H) 2.33 (s, 3 H) 1.81 - 2.15 (m, 4 H). LC-MS: 482 [M+H]+
Example 78 N2-((R)-1-(3,5-Difluoropyridin-2-yl)-2-methoxyethyl)-6-((2S,6R)-2,6 -dimethylmorpholino)-N4- (5-methyl-1H-pyrazol-3-y1)-1,3,5-triazine-2,4-diamine
Figure imgf000221_0001
(R)-6- Chloro-N2-(1-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)-N4-(5-methyl-1H-pyrazol-3-yl)- 1,3,5-triazine-2,4-diamine (Intermediate 42, 100 mg, 0.25 mmol) and cis-2,6- dimethylmorpholine (0.034 mL, 0.28 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound. 1H NMR (300 MHz, MeOD) δ ppm 8.36 (br. s., 1 H) 7.56 (ddd, 1 H) 6.34 (br. s., I H) 5.51 - 5.87 (m, 1 H) 4.53 (d, 2 H) 3.65 - 3.91 (m, 2 H) 3.42 - 3.65 (m, 2 H) 3.35 (s, 3 H) 2.48 (t, 2 H) 2.23 (br. s., 3 H) 1.20 (d, 6 H). LC-MS: 476 [M+H]+.
Example 79
(R) -N2-(1-(3,5-Difluoropyridin-2-yl)-2-methoxyethyl)-N4-(5-methyl-1H-pyrazol-3-yl)-6-(1,4- oxazepan-4-yl)-1,3.5-triazine-2,4-diamine
Figure imgf000222_0001
(Tϊ^β-Chloro-^-Cl-CS^-difluoropyridin-1-y^-1-methoxyethy^-V-CS-methyl-1H-pyrazol-S-yl)- 1,3,5-triazine-2,4-diamine (Intermediate 42, 100 mg, 0.25 mmol) and 1 ,4-oxazepane hydrochloride (38.1 mg, 0.28 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound. 1H NMR (300 MHz, MeOD) δ ppm 8.36 (s, 1 H) 7.47 - 7.64 (m, 1 H) 6.36 (br. s., 1 H) 5.66 (br. s., 1 H) 3.42 - 4.12 (m, 11 H) 3.34 (s, 3 H) 2.23 (br. s., 3 H) 1.82 - 2.00 (m, 2 H) 1.72 (br. s., 1H). LC-MS: 462 [M+H]+.
Example 80 N--(l-(3,5-Difluoropyridin-2-yl)-2-methoxyethyl)-Λ^-(5-methyl-1H-pyrazol-3-yl)-6-morpholino- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000222_0002
6-Chloro-N2-(l-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)-N4-(5-methyl-1H-pyrazol-3-yl)- 1,3,5-triazine-2,4-diamine (Intermediate 41, 653 mg, 1.65 mmol) was dissolved in ethanol (2.194 mL) at 0°C and morpholine (5.02 mL, 57.60 mmol) was added. The reaction was stirred at 25°C for 1 hour. The reaction mixture was concentrated in vacuo leaving a yellow semi-solid (1.633 g). This material was purified by ISCO (0-10% MeOH/DCM). Concentration of the fractions in vacuo provided the title compound, a mixture of enantiomers, as a white solid (610 mg).
For an example of a chiral synthesis of the R-enantiomer of the title compound, refer to Example
113.
Column and solvent conditions
The two enantiomers were purified using conditions (A) and OJ-3-20.
Column particle size (μ): 5
Column dimensions (mm): 21x250
Post purification purity check:
The sample purity was checked using conditions (B) and AD-3-20.
Column dimensions: 4.6 x 100 mm
Flow: 5 mL/min
Example 80(a), First Eluting Compound
LC-MS: 448 [M+H]+.
The first eluting compound had a retention time of 0.56 minutes.
Example 80(b), Second Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.36 (d, 1 H) 7.38 - 7.74 (m, 1 H) 6.36 (br. s., 0.5 H) 5.42 -
5.88 (m, 1.5 H) 3.48 - 3.98 (m, 10 H) 3.34 (s, 3 H) 2.05 - 2.41 (m, 3 H).
LC-MS: 448 [M+H]+.
The second eluting compound had a retention time of 0.87 minutes.
Example 81
N-(((i?)-4-(4-((i?)-1-(3,5-Difluoropyridin-2-yl)-2-methoxyethylamino)-6-(5-methyl-1H-pyrazol-
3-ylamino)-1,3,5-triazin-2-yl)morpholin-3-yl)methyl)methanesulfonamide
Figure imgf000224_0001
(R)-6- Chloro-N2-(1-(3,5,difluoropyridin-2-yl)-2 -methoxyethyl)-N4-(5-methyl-1H-pyrazol-3-yl)- 1,3,5-triazine-2,4-diamine (Intermediate 42, 100 mg, 0.25 mmol) and (R)-N- (morpholin-3- ylmethyl)methanesulfonamide hydrochloride (Intermediate 44, 58.1 mg, 0.25 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 62, providing the title compound.
1H NMR (300 MHz, MeOD) δ ppm 8.36 (s, 1 H) 7.55 (t, 1 H) 6.38 (br. s., 1 H) 5.73 (m., 1 H) 4.69 (m, 1 H) 4.41 (d, 1 H) 4.01 (d, 1 H) 3.90 (d, 1 H) 3.64 - 3.85 (m, 2 H) 3.37 - 3.64 (m, 4 H) 3.34 (s, 3 H) 3.05 - 3.26 (m, 1 H) 2.94 (br. s., 3 H) 2.25 (br. s., 3 H). LC-MS: 555 [M+H]+.
Example 82
Ethyl (R)-4-(4-(R)-1-(3,5-difluoropyridin-2-yl)-2-methoxyethylamino)-6-(5-methyl- IH- pyrazol-3-ylamino)-1,3.5-triazin-2-yl)morpholin-3-yl)methylcarbamate
Figure imgf000224_0002
(R)-6- Chloro-N2-(l-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)-N4-(5-methyl-1H-pyrazol-3-yl)- 1,3,5-triazine-2,4-diamine (Intermediate 42, 100 mg, 0.25 mmol) and ethyl [(3R)- morpholin-3- ylmethyl] carbamate hydrochloride (Intermediate 46, 56.6 mg, 0.25 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 62, providing the title compound.
1H NMR (300 MHz, MeOD) δ ppm 8.36 (s, 1 H) 7.44 - 7.68 (m, 1 H) 6.39 (br. s., 1 H) 5.42 - 5.90 (m, 1 H) 4.76 (br. s., 1 H) 4.39 (br. s., 1 H) 3.39 - 4.19 (m, 10 H) 3.34 (s, 3 H) 3.09 - 3.26 (m, 1 H) 2.28 (br. s., 3 H) 1.26 (br. s., 3 H). LC-MS: 549 [M+H]+.
Example 83
N--((i?)-1-(3.5-Difluoropyridin-2-yl)-2-methoxyethyl)-6-((2i?.6i?)-2.6-dimethylmorDholino)-Ni- (5-methyl-1H-pyrazol-3-yl)-1,3,5-triazine-2,4-diamine
Figure imgf000225_0001
('i?>6-Chloro-N2-(l-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)-N4-(5-methyl-1H-pyrazol-3-yl)-
1,3,5-triazine-2,4-diamine (Intermediate 42, 150 mg, 0.38 mmol) and 2,6-dimethylmorpholine {trans-, cώ-mixture, 43.5 mg, 0.38 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of stereoisomers. The isomers were separated by Gilson chromatography (NH4OAcZMeOH).
1H NMR (300 MHz, MeOD) δ ppm 8.36 (br. s., 1 H) 7.56 (ddd, 2.35 Hz, 1 H) 5.85 - 6.24 (m, 1 H) 5.54 - 5.79 (m, 1 H) 3.63 - 4.15 (m, 7 H) 3.40 - 3.62 (m, 2 H) 3.35 (s, 3 H) 2.23 (s, 3 H) 1.17 (br. s., 6 H). LC-MS: 476 [M+H]+.
N2-((^;-1-(3,5-Difluoropyridin-2-yl)-2-methoxyethyl)-6-((21S',6i?)-2,6-dimethylmorpholino)-N4- (5-methyl-1H-pyrazol-3-yl)-1,3,5-triazine-2,4-diamine (Example 78) was also isolated from the reaction mixture, as a side -product. Column and solvent conditions
The two diastereomers were separated using HPLC.
Column: XBridge C18 column
Mobile phase: 10 mM NH4OAc in H2O (with 5% MeCN), pH 8 with MeOH, gradient from 60 to 75%. Column particle size (μ): 5 Column dimensions (mm): 19x100
Example 84 N--((i?)-1-(3,5-Difluoropyridin-2-yl)-2-methoxyethyl)-6-((R)-3-(methoxymethyl)morpholino)- N--(5-methyl- 1H-pyrazol-3-vP)- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000226_0001
('i?>6-Chloro-N2-(l-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)-N4-(5-methyl-1H-pyrazol-3-yl)- 1,3,5-triazine-2,4-diamine (Intermediate 42, 0.207 g, 0.52 mmol) and (R)S- (methoxymethyl)morpholine (Intermediate 50, 0.076 g, 0.58mmol) were reacted using a procedure similar to the one described for the synthesis of Example 62, providing the title compound.
1H NMR (MeOD) δ 8.24 (s, 1H), 7.41 (t, 1H), 6.27 (br. s, 1H), 5.62 (m, 1H), 4.54 (m, 1H), 4.29 (m, 1H), 3.90 (m, 1H), 3.78 (m, 1H), 3.69 (m, 1H), 3.64 (m, 2H), 3.36 (m, 2H), 3.27 (m, 1H), 3.21(s, 3H), 3.98 (m, 1H), 2.12 (s, 3H). LC-MS: 493 [M]+.
(^>6-Butoxy-N2-(l-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)-N4-(5-methyl-1H-pyrazol-3-yl)- 1,3,5-triazine-2,4-diamine was also isolated from the reaction mixture, as a by-product. 1H NMR (MeOD) δ 8.25 (s, 1H), 7.47 (t, 1H), 5.61 (m, 1H), 4.17(m, 2H), 3.69 (m, 2H), 3.26 (m, 3H), 3.24 (s, 3H), 2.17 (d, 3H), 1.59 (m, 2H), 1.35 (m, 2H), 0.85 (t, 3H). LC-MS: 493 [M+H]+.
Example 85 6-(S)-3-(Difluoromethyl)morpholino)-N2-((R)-1-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)-N4- (5-methyl-1H-pyrazol-3-yl)-1,3,5-triazine-2,4-diamine
Figure imgf000227_0001
(R)-6-Chloro-N2 -(1-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)-N4-(5-methyl-1H-pyrazol-3-yl)- 1,3,5-triazine-2,4-diamine (Intermediate 42, 0.188 g, 0.48 mmol) and (S)-3-
(difluoromethyl)morpholine (Intermediate 53, 0.069 g, 0.5 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 62, providing the title compound.
1H NMR (MeOD) δ 8.32 (s, 1H), 7.51 (t, 1H), 6.20 (m, 1H), 5.60 (m, 1H), 4.78 (m, 1H), 4.47 (m, 1H), 4.10 (d, 1H), 3.90 (m, 1H), 3.75 (m, 1H), 3.68 (m, 1H), 3.55 (m, 1H), 3.47 (m, 1H), 3.25 (s,
3H), 3.19 (m, 1H), 2.20 (br. s, 3H).
LC-MS: 498 [M+H]+.
Example 86 (R)-N2-(5-Cvclopropyl-1H-pyrazol-3-yl)-N4-(l-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)-6- morpholino-1,3,5-triazine-2,4-diamine
Figure imgf000228_0001
^-o-Chloro-Ni-CS-cyclopropyl-1H-pyrazol-S-y^-V-Cl-CS^-difluoropyridin-1-yl)-!- methoxyethyl)-1,3,5-triazine-2,4-diamine (Intermediate 55, 201 mg, 0.48 mmol) was dissolved in ethanol (0.624 mL) and morpholine (1.450 mL, 16.64 mmol) was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was then concentrated in vacuo leaving a clear semi-solid (402 mg). This material was purified by ISCO (2-10% MeOΗ/DCM).
Concentration of the fractions in vacuo provided the title compound as a white solid (194.5 mg). 1H NMR (300 MHz, MeOD) δ ppm 8.35 (br. s., 1 H) 7.45 - 7.63 (m, 1 H) 6.29 (br. s., 1 H) 5.31 - 5.89 (m, 1 H) 3.52 - 3.94 (m, 11 H) 3.34 (s, 3 H) 1.87 (br. s., 1 H) 0.93 (br. s., 2 H) 0.69 (br. s., 2 H). LC-MS: 474 [M+H]+.
Example 87
N2-(l-(3,5-Difluoropyridin-2-vD-2-ethoxyethyl)-Ni-(5-methyl-1H-pyrazol-3-yl)-6-morpholino-
1 ,3 ,5-triazine-2,4-diamine
Figure imgf000228_0002
In a 100 mL round-bottomed flask was added 6-chloro-N2-(l-(3,5-difluoropyridin-2-yl)-2- ethoxyethyl)-Λ/4-(5-methyl-1H-pyrazol-3-yl)-1,3,5-triazine-2,4-diamine (Intermediate 60, 200 mg, 0.49 mmol) and morpholine (42.4 μl, 0.49 mmol) in ethanol (974 μl) to give a yellow solution. The solution was stirred at this temperature for 3 hours whereupon the volatiles were evaporated under reduced pressure. Purification by column chromatography (ISCO, 5%- 10%MeOH/DCM) gave the title compound (61.0 mg, 27.2 %) as a mixture of enantiomers. 1H NMR (300 MHz, MeOD) δ ppm 1.17 (t, J=7.06 Hz, 3 H) 2.34 (s, 3 H) 3.57 (q, J=7.10 Hz, 2 H) 3.65 - 4.04 (m, 10 H) 5.68 (t, J=6.59 Hz, 1 H) 5.86 (br. s., 1 H) 7.64 (ddd, J=9.80, 8.67, 2.26 Hz, 1 H) 8.41 (d, J=2.26 Hz, 1 H). LC-MS: 462 [M+H]+.
Column and solvent conditions The two enantiomersof the title compound were separated using Conditions (A) with OJ-3-20. Column particle size (μ): 5 Column dimensions (mm): 21x250
Post purification purity check Sample purity was checked using conditions (B) with OJ-3-20. Column particle size (μ): 5 Column dimensions (mm): 4.6x250 Elution time: 15 min
Example 87(a), First Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 1.13 (t, J=6.97 Hz, 3 H) 2.28 (br. s., 3 H) 3.45 - 3.92 (m, 12 H) 5.46 - 5.88 (m, 1 H) 6.37 (br. s., 1 H) 7.38 - 7.75 (m, 1 H) 8.38 (s, 1 H). The first eluting compound had a retention time of 2.10 minutes.
Example 87(b), Second Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 1.13 (t, J=6.97 Hz, 3 H) 2.28 (br. s., 3 H) 3.45 - 3.92 (m, 12 H) 5.46 - 5.88 (m, 1 H) 6.37 (br. s., 1 H) 7.38 - 7.75 (m, 1 H) 8.38 (s, 1 H). The second eluting compound had a retention time of 3.43 minutes.
Example 88 2S- 1 -(5-Fluoropyridin-2-yl)- 1 -(4-(5 -methyl- 1H-pyrazol-3-ylamino)-6-morpholino- 1 ,3 ,5-triazin- 2-yloxy)propan-2-ol hydrochloride, Enantiomer (A)
Figure imgf000230_0001
4-Chloro-N-(5-methyl-1H-pyrazol-3-yl)-6-morpholino-1,3,5-triazin-2-amine (Intermediate 15, 66.3 mg, 0.22 mmol) and 21S'-2-(tert-butyldimethylsilyloxy)-1-(5-fluoropyridin-2-yl)propan-1-ol (Intermediate 85(a), 64 mg, 0.22 mmol) were dissolved in tBuOΗ (2 mL) and ^-BuONa (43.1 mg, 0.45 mmol) was added. The reaction was then stirred overnight at 25°C. LC/MS indicated only 18% conversion to product, so another equivalent of sodium tert-butoxide was added and the reaction was stirred at 25°C overnight again. The reaction mixture was then concentrated in vacuo leaving an off-white solid (191 mg). This material was purified by ISCO (80-100% EtOAc/hexanes). Concentration of the fractions in vacuo gave a clear oil (51 mg). This material was dissolved in MeOH (1 mL) and HCl 4M in Dioxane (0.093 mL, 0.37 mmol) was added. The reaction was then stirred at 25°C for 2 hours. The reaction mixture was concentrated in vacuo leaving a clear oil. This material was purified by ISCO (0-10% MeOΗ/DCM). Concentration of the fractions in vacuo provided the title compound as a white solid (17.5 mg). 1H NMR (300 MHz, MeOD) δ ppm 8.28 - 8.60 (m, 1 H) 7.39 - 7.79 (m, 2 H) 6.17 (br. s., 1 H) 5.67 - 5.95 (m, 1 H) 4.09 - 4.37 (m, 1 H) 3.42 - 3.94 (m, 8 H) 2.26 (s, 3 H) 1.03 - 1.50 (m, 3 H). LC-MS: 431 [M+H]+.
Example 89 2S- 1 -(5-Fluoropyridin-2-yl)- 1 -(4-(5 -methyl- 1H-pyrazol-3-ylamino)-6-morpholino- 1 ,3 ,5-triazin- 2-yloxy)propan-2-ol hydrochloride, Enantiomer (B)
Figure imgf000231_0001
4-Chloro-N-(5-methyl-1H-pyrazol-3-yl)-6-morpholino-1,3,5-triazin-2-amine (Intermediate 15,
66.3 mg, 0.22 mmol) and 2S-2-(fert-butyldimethylsilyloxy)-1-(5-fluoropyridin-2-yl)propan-1-ol (Intermediate 85(b), 64 mg, 0.22 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 88, providing the title compound. 1H NMR (300 MHz, MeOD) δ ppm 8.31 - 8.57 (m, 1 H) 7.42 - 7.77 (m, 2 H) 6.24 (br. s., 1 H) 5.79 (d, 1 H) 4.21 (dq, 1 H) 3.45 - 3.96 (m, 8 H) 2.26 (s, 3 H) 1.36 - 1.50 (m, 3 H). LC-MS: 431 [M+H]+.
Example 90 N2-(2-Ethoxy- l-(5-fluoropyridin-2-yl)ethyl)-Ni-(5-methyl- 1H-pyrazol-3-yl)-6-morpholino- 1 ,3 ,5- triazine-2,4-diamine
Figure imgf000231_0002
To a solution of 6-chloro-N2-(2-ethoxy-1-(5-fluoropyridin-2-yl)ethyl)-Λ/4-(5-methyl-1H-pyrazol- 3-yl)-1,3,5-triazine-2,4-diamine (Intermediate 90,_0.452 g, 1.15 mmol) in ethanol (2.300 ml) was added morpholine (3.01 ml, 34.50 mmol). The resulting mixture was stirred at ambient temperature for 3 hours. Evaporation of the volatiles under reduced pressure gave a yellow residue. Purification by column chromatography (ISCO, 5%-10%MeOΗ/DCM) gave the title compound as a mixture of enantiomers.
1H NMR (300 MHz, MeOD) δ ppm 1.15 (t, 3 H) 2.25 (s, 3 H) 3.43 - 3.90 (m, 12 H) 5.12 - 5.42 (m, 1 H) 5.60 (s, 1 H) 7.37 - 7.77 (m, 2 H) 8.48 (s, 1 H). LC-MS: 444 [M+H] +.
Column and solvent conditions
The title compound was chirally purified using conditions (A) and AD-3-40. Column particle size (μ): 5 Column dimensions (mm): 19x100
Post purification purity check
Sample purity was checked using conditions (B) with AD-3-40. Column particle size (μ): 5 Column dimensions (mm): 4.6x100
Example 90(a), First Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 1.16 (t, J=7.06 Hz, 3 H) 2.25 (s, 3 H) 3.46 - 3.98 (m, 12 H) 5.19 - 5.41 (m, 1 H) 5.48 - 6.50 (m, 1 H) 7.35 - 7.76 (m, 2 H) 8.42 (s, 1 H). The first eluting compound had a retention time of 0.97 minutes.
Example 90(b), Second Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 1.05 (t, J=6.97 Hz, 3 H) 2.14 (s, 3 H) 3.36 - 3.81 (m, 12 H) 5.03 - 5.26 (m, 1 H) 5.42 - 6.44 (m, 1 H) 7.30 - 7.66 (m, 2 H) 8.31 (s, 1 H). The second eluting compound had a retention time of 2.13 minutes.
Example 91
(l-(4-((5)-1-(5-Fluoropyridin-2-yl)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-1,3,5-triazin- 2-yl)piperidin-2-yl)methanol
Figure imgf000233_0001
To a solution of fS/)-6-chloro-N2-(l-(5-fluoropyridin-2-yl)ethyl)-Λ/4-(5-methyl-1H-pyrazol-3-yl)- 1,3,5-triazine-2,4-diamine (Intermediate 16, 222 mg, 0.64 mmol) in EtOH (1061 μl) and n- BuOH (1061 μl) was added piperidin-2-ylmethanol (73.3 mg, 0.64 mmol) and DIPEA (111 μl, 0.64 mmol). The resulting mixture was heated to 100 °C for 16 hours. Evaporation of the volatiles under reduced pressure gave a yellow residue. Purification by column chromatography (ISCO, 5%-10%MeOΗ/DCM) gave the title compound (191 mg, 70.2 %) as a white solid. 1H NMR (300 MHz, MeOD) δ ppm 1.41 (d, J=6.97 Hz, 3 H) 1.44 - 1.61 (m, 4 H) 1.63 - 1.86 (m, 1 H) 2.12 (s, 3 H) 2.51 - 2.84 (m, 1 H) 3.46 - 3.74 (m, 2 H) 4.27 - 4.59 (m, 2 H) 4.70 - 4.80 (m, 1 H) 4.96 - 5.23 (m, 1 H) 6.28 (s, 1 H) 7.17 - 7.74 (m, 2 H) 8.27 (s, 1 H). LC-MS: 428 [M+H]+.
Example 92
((S)-4-(4-((S)- 1 -(5-Fluoropyridin-2-yl)ethylamino)-6-(5-methyl- 1H-pyrazol-3-ylamino)- 1.3.5- triazin-2-yl)morpholin-3-yl)methanol
Figure imgf000233_0002
(S>6-Chloro-N2-( 1 -(5-fluoropyridin-2-yl)ethyl)-N4-(5-methyl- 1H-pyrazol-3 -yl> 1 ,3 ,5-triazine-
2,4-diamine (Intermediate 16, 200 mg, 0.57 mmol) and (^-morpholin-3-ylmethanol (73.9 mg, 0.63 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 91, providing the title compound.
1H NMR (300 MHz, MeOD) δ ppm 8.37 (br. s., 1 H) 7.28 - 7.70 (m, 2 H) 6.03 (br. s., 1 H) 5.16 (q, 1 H) 4.17 - 4.69 (m, 2 H) 4.08 (d, 1 H) 3.87 (m, 2 H) 3.36 - 3.71 (m, 2 H) 2.77 - 3.19 (m, 2 H) 2.19 (s, 3 H) 1.54 (d, 3 H). LC-MS: 430 [M+H]+.
Example 93
((R)-4-(4-((S)- 1 -(5-Fluoropyridin-2-yl)ethylamino)-6-(5-methyl- 1H-pyrazol-3-ylamino)- 1.3.5- triazin-2-yl)morpholin-3-yl)methanol
Figure imgf000234_0001
(S>6-Chloro-N2-( 1 -(S-fluoropyridin^-y^ethyrj-Λ^S-methyl- 1H-pyrazol-3 -yl> 1 ,3 ,5-triazine-
2,4-diamine (Intermediate 16, 200 mg, 0.57 mmol) and (^-morpholin-3-ylmethanol hydrochloride (97 mg, 0.63 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 91, providing the title compound. 1H NMR (300 MHz, MeOD) δ ppm 8.37 (br. s., 1 H) 7.32 - 7.70 (m, 2 H) 5.87 - 6.69 (m, 0.5 H) 5.58 (br. s., 0.5 H) 5.15 (q, 1 H) 4.18 - 4.74 (m, 2 H) 4.04 (d, 1 H) 3.72 - 3.97 (m, 2 H) 3.35 - 3.72 (m, 2 H) 2.72 - 3.21 (m, 2 H) 2.23 (br. s., 3 H) 1.51 (d, 3 H). LC-MS: 430 [M+H]+.
Example 9
Methyl 2-(4-(4-((,SV 1 -(5-fluoropyridin-2-yl)ethylamino)-6-(5-methyl- 1H-pyrazol-3-ylamino)- 1,3,5-triazin-2-yl)morpholin-3-yl)acetate
Figure imgf000235_0001
In a 250 mL round-bottomed flask was added fS/)-6-chloro-N2-(l-(5-fluoropyridin-2-yl)ethyl)- Λ^-(5-methyl-1H-pyrazol-3-yl)-1,3,5-triazine-2,4-diamine (Intermediate 16, 300mg, 0.86 mmol) and methyl 2-(morpholin-3-yl)acetate (137 mg, 0.86 mmol) in EtOH (2867 μl) to give a yellow solution. The resulting mixture was heated at 100 °C for 12 hours. Evaporation of the volatiles under reduced pressure gave an oil. Purification by column chromatography (ISCO, 5%MeOΗ/DCM) gave the title compound. LC-MS: 472 [M+H]+.
Example 95
2-(4-(4-((S)- 1 -(5-Fluoropyridin-2-yl)ethylamino)-6-(5-methyl- 1H-pyrazol-3-ylamino)- 1 ,3 ,5- triazin-2-yl)morpholin-3-vP)ethanol
Figure imgf000235_0002
To a solution of methyl 2-(4-(4-(f2^-1-(5-fluoropyridin-2-yl)ethylamino)-6-(5-methyl-1H- pyrazol-3-ylamino)-1,3,5-triazin-2-yl)morpholin-3-yl)acetate (Example 94, 200 mg, 0.42 mmol) in tetrahydrofuran (1.4 ml) at 0 °C was added drop-wise a 2M solution OfLiBH4 (636 μl, 1.27 mmol) in THF. After the evolution of gas ceased, the resulting mixture was stirred at ambient temperature for 1 hour. The mixture was cooled to 0 °C and MeOH (caution: exotherm) was added slowly to quench the excess LiBH4. The volatiles were evaporated under reduced pressure and the residue left was dissolved in EtOAc. The organic phase was washed with H2O, brine and dried. Evaporation gave a yellow residue. Purification by column chromatography (ISCO, 5%- 10%MeOH/DCM) gave the title compound (80 mg, 42.5 %) as a mixture of diastereomers. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.44 (d, 6 H) 1.67 - 1.94 (m, 4 H) 2.15 (s, 6 H) 2.73 - 4.83 (m, 18 H) 5.75 - 6.58 (m, 2 H) 7.20 - 7.96 (m, 4 H) 8.49 (s, 2 H) 9.13 (s, 1 H) 9.46 (s, 1 H). LC-MS: 444 [M+H]+.
Example 96
(S)- 1 -(4-( 1 -(5-Fluoropyridin-2-yl)ethylamino)-6-(5-methyl- 1H-pyrazol-3 -ylaminoV 1 ,3 ,5-triazin- 2-yl)azetidin-3-ol
Figure imgf000236_0001
(S>6-Chloro-N2-( 1 -(5-fluoropyridin-2-yl)ethyl)-N4-(5-methyl- 1H-pyrazol-3 -yl> 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 16, 200 mg, 0.57 mmol) and azetidin-3-ol hydrochloride (69.1 mg, 0.63 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound.
1H NMR (300 MHz, MeOD) δ ppm 8.24 - 8.60 (m, 1 H) 7.34 - 7.73 (m, 2 H) 6.06 (br. s., 1 H) 5.17 (q, 1 H) 4.61 (m, 1 H) 3.97 - 4.40 (m, 2 H) 3.58 - 3.96 (m, 2 H) 2.23 (s, 3 H) 1.51 (d, 3 H). LC-MS: 386 [M+H]+.
Example 97 (y)-N2-(l-(3,5-Difluoropyridin-2-yl)ethyl)-6-(2,2-dimethylmorpholino)-Ni-(5-methyl-1H- pyrazol-3-ylV 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000237_0001
To (S>6-chloro-N2-( 1 -(3 ,5 -difluσropyridm-2-y OethylJ-iV4-^ -methyl- 1H-pyrazol-3 -yl)- 1,3,5- triazine-2,4-diamine (Intermediate 92, 100 mg, 0.27 mmol) in ethanol (1 mL) was added 2,2- dimethylmorpholine hydrochloride (45.5 mg, 0.30 mmol) and DIPEA (0.143 mL, 0.82 mmol). The reaction mixture was stirred overnight at room temperature. The crude reaction mixture was concentrated under reduced pressure and purified directly on an ISCO system (0 -2% MeOH, 0.2% NH4OH in DCM) to obtain desired product 106 mgs as a white solid. 1H NMR (400 MHz, MeOD) δ ppm 8.22 (s, 1 H) 7.44 (t, J=8.46 Hz, 1 H) 5.35 (m, 1 H) 3.60 (d, J=6.57 Hz, 2 H) 3.43 - 3.55 (m, 4 H) 2.13 (s, 3 H) 1.40 (d, J=6.57 Hz, 3 H) 1.12 (m, 3 H) 0.93 (s, 3 H). LC-MS: 446 [M+H]+.
Example 98
Λg.((S)-1-(3,5-Difluoropyridin-2-yl)ethyl)-6-((25',6i?)-2,6-dimethylmorpholino)-Ni-(5-methyl- 1H-pyrazol-3-yl)-1,3.5-triazine-2,4-diamine
Figure imgf000237_0002
(S>6-Chloro-N2-( 1 -(3 ,5 -difluoropyridin-2-yl)ethyl)-N4-(5 -methyl- 1H-pyrazol-3 -yl)- 1,3,5- triazine-2,4-diamine (Intermediate 92) and cώ-2,6-dimethylmorpholine were reacted using a procedure similar to the one described for the synthesis of Example 97, providing the title compound as a white solid.
1H NMR (400 MHz, MeOD) δ ppm 8.33 (s, 1 H) 7.52 - 7.59 (m, 1 H) 4.53 (m, 2 H) 3.58 - 3.68 (m, 1 H) 3.55 (m, 1 H) 2.87 (d, 2 H) 2.42 (m, 2 H) 2.25 (s, 3 H) 1.16 - 1.22 (m, 6 H) 1.13 (d, 3 H). LC-MS: 446 [M+H]+.
Example 99
(y)-N--(l-(3.5-Difluoropyridin-2-yl)ethyl)-Ni-(5-methyl-1H-pyrazol-3-yl)-6-(1.4-oxazepan-4-yl)- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000238_0001
(S>6-Chloro-N2-( 1 -(3 ,5 -difluoropyridin^-y^ethyrj-N4-^ -methyl- 1H-pyrazol-3 -yl> 1,3,5- triazine-2,4-diamine (Intermediate 92) and 1,4-oxazepane hydrochloride were reacted using a procedure similar to the one described for the synthesis of Example 97, providing the title compound as a white solid. 1H NMR (400 MHz, MeOD) δ ppm 8.22 (s, 1 H) 7.39 - 7.48 (m, 1 H) 5.35 (m, 1 H) 3.73 (m, 3 H) 3.65 (m, 2 H) 3.52 - 3.63 (m, 3 H) 2.13 (s, 3 H) 1.81 (m, 2 H) 1.40 (d, J=6.57 Hz, 3 H). LC-MS: 432 [M+H]+.
Example 100 4-ri-(3,5-Difluoropyridin-2-yl)-2-methoxyethoxyl-N-(5-methyl-1H-pyrazol-3-yl)-6-morpholin- 4-yl-1,3,5-triazin-2-amine
Figure imgf000239_0001
Sodium fert-butoxide(508mg, 5.29mmol) was dissolved in t-BuOH(13mL) and the resulting solution was heated at 60°C followed by the addition of l-(3,5-difluoropyridin-2-yl)-2- methoxyethanol (Intermediate 108, 500mg, 2.64mmol). After stirring for 30 mins, the mixture was allowed to cool to ambient temperature and 4-chloro-N-(3-methyl-1H-pyrazol-5-yl)-6- morpholino-1,3,5-triazin-2-amine (Intermediate 15, 782mg, 2.64mmol) was added. The solution was stirred at room temperature over night. Evaporation of the volatiles gave a residue that was purified by ISCO (0-10%MeOΗ/DCM) to give the title compound (750mg) as a mixture of enantiomers. 1H NMR (300 MHz, MeOD) δ ppm 8.37 (s, 1 H) 7.63 (t, 1 H) 6.31 (s, 1 H) 4.00 (t, 1 H) 3.62- 3.82(m, 10H) 3.41 (s, 3 H) 2.29 (s, 3 H). LC-MS: 449 [M+H]+.
Column and solvent conditions
The title compound was chirally purified using conditions (A) and OJ-3-20. Column particle size (μ): 5
Column dimensions (mm): 21x250
Post purification purity check:
The sample purity was checked using conditions (B) and OJ-3-20. Column dimensions: 4.6 x 100 mm Detection: 220 nm
Example 100(a), First Eluting Compound 1H NMR (300 MHz, MeOD) δ ppm 8.37 (s, 1 H) 7.63 (t, 1 H) 6.31 (s, 1 H) 4.00 (t, 1 H) 3.62-
3.82(m, 10H) 3.41 (s, 3 H) 2.29 (s, 3 H).
LC-MS: 449 [M+H]+.
The first eluting compound had a retention time of 1.14 minutes.
Example 100(b), Second Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.37 (s, 1 H) 7.63 (t, 1 H) 6.31 (s, 1 H) 4.00 (t, 1 H) 3.62-
3.82(m, 10H) 3.41 (s, 3 H) 2.29 (s, 3 H).
LC-MS: 449 [M+H]+.
The second eluting compound had a retention time of 1.65 minutes.
Example 101
2,2-Difluoro-3-(5-fluoropyridin-2-yl)-3-({4-[(5-methyl-1H-pyrazol-3-yl)aminol-6-morpholin-4- yl- 1 ,3 ,5-triazin-2-vU amino)propan- 1 -ol
Figure imgf000240_0001
3-(4-Chloro-6-(3-methyl-1H-pyrazol-5-ylamino)-1,3,5-triazin-2-ylamino)-2,2-difluoro-3-(5- fluoropyridin-2-yl)propan-1-ol (Intermediate 117, 466mg, 1.12mmol) and morpholine were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of enantiomers. 1H NMR (300 MHz, MeOD) δ ppm 8.52 (s, 1 H) 7.62-7.71(m., 2 H) 5.98 (t, 1 H) 5.89 (s, 1 H) 3.65-3.91(m, 10H) 2.35 (s, 3 H). LC-MS: 466 [M+H]+. Column and solvent conditions
The title compound was chirally purified using conditions (A) and AD-3-30 Column particle size (μ): 5 Column dimensions (mm): 21x250
Example 10 Ka), First Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.52 (s, 1 H) 7.62-7.71(m., 2 H) 5.98 (t, 1 H) 5.89 (s, 1 H) 3.65-3.91(m, 10H) 2.35 (s, 3 H). LC-MS: 466 [M+H]+.
Example 10 Kb), Second Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.52 (s, 1 H) 7.62-7.71(m., 2 H) 5.98 (t, 1 H) 5.89 (s, 1 H) 3.65-3.91(m, 10H) 2.35 (s, 3 H). LC-MS: 466 [M+H]+.
Example 102
3-(5-Fluoropyridin-2-yl)-3-( {4-[(5-methyl-1H-pyrazol-3-yl)aminol-6-morpholin-4-yl- 1,3,5- triazin-2-vU amino)propanamide
Figure imgf000241_0001
3-(4-Chloro-6-(3-methyl-1H-pyrazol-5-ylamino)-1,3,5-triazin-2-ylamino)-3-(5-fluoropyridin-2- yl)propanamide (Intermediate 118) and morpholine (2mL) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of enantiomers. 1H NMR (300 MHz, MeOD) δ ppm 8.47 (s, 1 H) 7.48-7.64(m., 2 H) 5.86 (br.s, 1 H) 5.66 (t, 1 H) 3.65-3.89(m, 8H) 2.91-2.95(m, 2H) 2.33 (s, 3 H). LC-MS: 443 [M+H]+.
Column and solvent conditions The title compound was chirally separated using chiral HPLC. column: Chirapak AD dimensions: 250 x 20mm, lOμ mobile phase: 50% Hexane, 50% isopropanol, 0.1% diethylamine (v/v/v) flow rate (ml/min): 20 detection (nm): 220
Example 102(a), First Eluting Compound
1H NMR (300 MHz, MeOD) d ppm 8.47 (s, 1 H) 7.48-7.64(m., 2 H) 5.86 (br.s, 1 H) 5.66 (t, 1 H) 3.65-3.89(m, 8H) 2.91-2.95(m, 2H) 2.33 (s, 3 H). LC-MS: 443 [M+H]+.
Example 102(b), Second Eluting Compound
1H NMR (300 MHz, MeOD) d ppm 8.47 (s, 1 H) 7.48-7.64(m., 2 H) 5.86 (br.s, 1 H) 5.66 (t, 1 H) 3.65-3.89(m, 8H) 2.91-2.95(m, 2H) 2.33 (s, 3 H). LC-MS: 443 [M+H]+.
Example 103
N-r(l»S)-1-(5-Fluoropyrimidin-2-yl)ethyl1-6-morpholin-4-yl-N'-r5-(2-phenylethyl)-1H-pyrazol-3- yli- 1 ,3,5-triazine-2,4-diamine
Figure imgf000243_0001
(S>6-Chloro-N2-( 1 -(S-fluoropyrimidin-1-yriethyl)-^4-^ -phenethyl- 1H-pyrazol-5-yl)- 1,3,5- triazine-2,4-diamine (Intermediate 140,75mg, O.lβmmol) and morpholine (2mL, 23.0mmol). were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound. 1H NMR (300 MHz, MeOD) δ ppm 8.71 (s, 2 H) 7.15-7.28 (m, 5 H) 5.50 (q, 1 H) 3.61-3.74(m, 8H) 2.58-3.02(m, 4H) 1.58 (d, 3 H). LC-MS: 491 [M+H]+.
Example 104 6-(3-Ethylmorpholin-4-yl)-N-r(l»y)-1-(5-fluoropyrimidin-2-yl)ethyl1-N'-(5-methyl-1H-pyrazol-3- vD- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000243_0002
(S>6-Chloro-N2-( 1 -(5-fluoropyrimidin-2-yl)ethyl)-N4-(3 -methyl- 1H-pyrazol-5-yl)- 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 17, 200 mg, 0.57 mmol) and 3-ethylmorpholine hydrochloride (87 mg, 0.57 mmol), were reacted using a procedure similar to the one described for the synthesis of
Example 62, providing the title compound as a mixture of diastereomers.
1H NMR (300 MHz, MeOD) δ ppm 8.76 (s, 2 H) 5.89 (br.s, 1 H) 5.32 (q, 1 H) 3.61-4.43(m, 2H)
3.21-3.86 (m, 5H) 2.34(s, 3H) 1.80-2.02 (m, 2H) 1.64 (d, 3 H) 1.39 (t, 3H).
LC-MS: 429 [M+H]+.
Column and solvent conditions
The diastereomers of the title compound were separated using chiral HPLC. column: Chirapak AD dimensions: 250 x 20mm, 10μ mobile phase: 80% Hexane, 20% 1:1 ethanobmethanol, 0.1% diethylamine flow rate (ml/min): 20 detection (nm): 254
Example 104(a), First Eluting Compound 1H NMR (300 MHz, MeOD) δ ppm 8.60 (s, 2 H) 5.89 (br.s, 1 H) 5.13 (q, 1 H) 3.27-4.43(m, 7H) 2.13(s, 3H) 1.50-1.78(m, 2H) 1.57 (d, 3 H) 0.90(t, 3H). LC-MS: 429 [M+H]+.
Example 104(b), Second Eluting Compound 1H NMR (300 MHz, MeOD) δ ppm 8.71 (s, 2 H) 5.24 (q, 1 H) 3.40-4.41(m, 7H) 2.25(br.s, 3H) 1.80-2.02(m, 2H) 1.64 (d, 3 H) 1.39(t, 3H). LC-MS: 429 [M+H]+.
Example 105 N-[l-(5-Fluoropyrimidin-2-ylN)-2-methoxyethyll-Λ/'-(5-methyl-1H-pyrazol-3-yl)-6-morpholin-4- yl- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000245_0001
(6-Chloro-N2-( 1 -(S-fluoropyrimidin^-yl^-methoxyethyrj-N4-^ -methyl- 1H-pyrazol-5-yl)- 1,3,5- triazine-2,4-diamine (Intermediate 119, 363mg, 0.96mmol) and morpholine (2mL, 23.0mmol). were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of enantiomers. 1H NMR (300 MHz, MeOD) δ ppm 8.73 (s, 2 H) 5.45 (t, 1 H) 3.90(d, 2H) 3.63-3.80(m, 8H) 3.33 (s, 3H) 2.28 (s, 3 H). LC-MS: 431 [M+H]+.
Column and solvent conditions The title compound was chirally purified using Chiral HPLC. column: Chiralcel OJ dimensions: 250 x 20mm, lOμ mobile phase: 20% Hexane, 80% 1:1 ethanohmethanol, 0.1% diethylamine (v/v/v) flow rate (ml/min) : 10 detection (nm): 220
Post purification purity check:
The sample purity was checked using the following conditions: Column: Chiralcel OJ 4.6 x 250mm, lOμ Mobile Phase: 20 % Hexane, 80% 1:1 ethanobmethanol, 0.1 % diethylamine
Flow: 0.5 ml/min
Detection: 220 nm Example 105(a), First Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.73 (s, 2 H) 5.45 (t, 1 H) 3.90(d, 2H) 3.63-3.80(m, 8H) 3.33
(s, 3H) 2.28 (s, 3 H).
LC-MS: 431 [M+H]+.
The first eluting compound had a retention time of 10.7 minutes.
Example 105(b), Second Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.73 (s, 2 H) 5.45 (t, 1 H) 3.90(d, 2H) 3.63-3.80(m, 8H) 3.33
(s, 3H) 2.28 (s, 3 H).
LC-MS: 431 [M+H]+. The second eluting compound had a retention time of 18.8 minutes.
Example 106
6-(2,2-Dimethylmorpholin-4-yl)-N-r(l»S)-1-(5-fluoropyrimidin-2-yl)ethyl1-N>-(5-methyl-1H- pyrazol-3-vD- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000246_0001
(S>6-Chloro-N2-( 1 -(5-fluoropyrimidin-2-yl)ethyl)-N4-(3 -methyl- 1H-pyrazol-5-yl)- 1 ,3 ,5-triazine-
2,4-diamine (Intermediate 17, 200 mg, 0.57 mmol) and 2,2-dimethylmorpholine hydrochloride (87 mg, 0.57 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound. 1H NMR (300 MHz, MeOD) δ ppm 8.77(s, 2 H) 5.87 (br.s, 1 H) 5.30 (q, 1 H) 3.44-3.77(m, 6H) 2.34(s, 3H) 1.64(s, 3 H) 1.21(s, 3H) 0.97(s, 3H). LC-MS: 429 [M+H]+. Example 107
4-[l-(5-Fluoropyridin-2-ylN)-2-methoxyethoxyl-N-(5-methyl-1H-pyrazol-3-ylN)-6-morpholin-4-yl- 1 ,3 ,5-triazin-2-amine
Figure imgf000247_0001
l-(5-Fluoropyridin-2-yl)-2-methoxyethanol (Intermediate 80, 750mg, 4.38mmol) and 4-chloro- N-(3 -methyl- 1H-pyrazol-5-yl)-6-morpho lino- 1, 3 ,5-triazin-2-amine (Intermediate 15, 864mg, 2.92mmol) were reacted using a procedure similar to the one described for the synthesis of Example 100, providing the title compound as a mixture of enantiomers. 1H NMR (300 MHz, MeOD) δ ppm 8.46 (s, 1 H) 7.48-7.62(m, 2H) 5.19-6.42 (m, 2 H) 3.87(d, 2H) 3.56-3.83(m, 8H) 3.40(s, 3H) 2.29(s, 3 H). LC-MS: 431 [M+H]+.
Column and solvent conditions
The title compound was chirally purified using conditions (A) and OD-4-40. Column particle size (μ): 5
Column dimensions (mm): 21x250
Example 107(a), First Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.46 (s, 1 H) 7.48-7.62(m, 2H) 5.19-6.42 (m, 2 H) 3.87(d, 2H) 3.56-3.83(m, 8H) 3.40(s, 3H) 2.29(s, 3 H). LC-MS: 431 [M+H]+. Example 107(b), Second Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.46 (s, 1 H) 7.48-7.62(m, 2H) 5.19-6.42 (m, 2 H) 3.87(d, 2H) 3.56-3.83(m, 8H) 3.40(s, 3H) 2.29(s, 3 H). LC-MS: 431 [M+H]+.
Example 108
3-(5-Fluoropyridin-2-yl)-N-methyl-3-(4-(5-methyl- 1H-pyrazol-3-ylamino)-6-morpholino- 1 ,3 ,5- triazin-2-ylamino)propanamide
Figure imgf000248_0001
3-(4-Chloro-6-(3-methyl-1H-pyrazol-5-ylamino)-1,3,5-triazin-2-ylamino)-3-(5-fluoropyridin-2- yl)-N-methylpropanamide (Intermediate 120) and morpholine (3mL) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of enantiomers.
1H NMR (SOO MHz5 MeOD) S pPm S-Sl (s, 1 H) 7.57-7.62 (m, 2H) 5.57 (t, 1H) 3.56-3.80(m,
8H) 3.05 (d, 2H) 2.66(s, 3H) 2.25(s, 3 H). LC-MS: 457 [M+H]+.
Column and solvent conditions
The title compound was chirally purified using conditions (A) and IA-3-40. Column particle size (μ): 5 Column dimensions (mm): 21x250
Example 108(a), First Eluting Compound
1H NMR (SOO MHz5 MeOD) S pPm S-Sl (s, 1 H) 7.57-7.62 (m, 2H) 5.57 (t, 1H) 3.56-3.80(m, 8H) 3.05 (d, 2H) 2.66(s, 3H) 2.25(s, 3 H). LC-MS: 431 [M+H]+.
Example 108(b), Second Eluting Compound
1H NMR (SOO MHz5 MeOD) S pPm S-Sl (s, 1 H) 7.57-7.62 (m, 2H) 5.57 (t, 1H) 3.56-3.80(m,
8H) 3.05 (d, 2H) 2.66(s, 3H) 2.25(s, 3 H).
LC-MS: 431 [M+H]+.
Example 109
3-(5-Fluoropyridin-2-yl)-3-({4-[(5-methyl-1H-pyrazol-3-yl)aminol-6-morpholin-4-yl- 1,3,5- triazin-2-vU amino)propanenitrile
Figure imgf000249_0001
3-(4-Chloro-6-(3-methyl-1H-pyrazol-5-ylamino)-1,3,5-triazin-2-ylamino)-3-(5-fluoropyridin-2- yl)propanenitrile (Intermediate 121, 110 mg, 0.29 mmol) and morpholine (2 mL, 22.96 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of enantiomers.
1H NMR (300 MHz, MeOD) δ ppm 8.42 (s, 1 H) 7.46-7.59(m, 2H) 5.58 (t, 1 H) 3.78(m, 4H)
3.65(m, 4H) 3.22(d, 2H) 2.27(s, 3 H).
LC-MS: 425 [M+H]+.
Column and solvent conditions
The title compound was chirally purified using Chiral HPLC. column: Chirapak AD dimensions: 250 x 20mm, 10μ mobile phase: 50% ethanol, 50% methanol, 0.1% diethylamine (v/v/v) flow rate (ml/min): 20 detection (nm): 220
Example 109(a), First Eluting Compound 1H NMR (300 MHz, MeOD) δ ppm 8.42 (s, 1 H) 7.46-7.59(m, 2H) 5.58 (t, 1 H) 3.78(m, 4H) 3.65(m, 4H) 3.22(d, 2H) 2.27(s, 3 H). LC-MS: 425 [M+H]+.
Example 109(b), Second Eluting Compound 1H NMR (300 MHz, MeOD) δ ppm 8.42 (s, 1 H) 7.46-7.59(m, 2H) 5.58 (t, 1 H) 3.78(m, 4H) 3.65(m, 4H) 3.22(d, 2H) 2.27(s, 3 H). LC-MS: 425 [M+H]+.
Example 110 4-ri-(5-Fluoropyrimidin-2-yl)-2-methoxyethoxyl-N-(5-methyl-1H-pyrazol-3-yl)-6-morpholin-4- yl- 1.3.5-triazin-2-amine
Figure imgf000250_0001
l-(5-Fluoropyrimidin-2-yl)-2-methoxyethanol (Intermediate 91, 366 mg, 2.13 mmol) and 4- chloro-N-(3-methyl-1H-pyrazol-5-yl)-6-morpholino-1,3,5-triazin-2-amine (Intermediate 15) were reacted using a procedure similar to the one described for the synthesis of Example 100, providing the title compound as a mixture of enantiomers.
1H NMR (300 MHz, MeOD) δ ppm 8.78 (s, 2 H) 6.19-6.22(m, 1H) 6.08 (t, 1H) 3.94-4.05(m, 2H) 3.56-3.82(m, 8H) 3.42(s, 3H) 2.38(s, 3 H) . LC-MS: 432 [M+H]4
Column and solvent conditions
The title compound was chirally purified using conditions (A) and OD-3-40. Column particle size (μ): 5 Column dimensions (mm): 21x250
Example 110(a), First Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.78 (s, 2 H) 6.19-6.22(m, 1H) 6.08 (t, 1H) 3.94-4.05(m, 2H) 3.56-3.82(m, 8H) 3.42(s, 3H) 2.38(s, 3 H). LC-MS: 432 [M+H]+.
Example 110(b), Second Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.78 (s, 2 H) 6.19-6.22(m, 1H) 6.08 (t, 1H) 3.94-4.05(m, 2H) 3.56-3.82(m, 8H) 3.42(s, 3H) 2.38(s, 3 H). LC-MS: 432 [M+H]+.
Example 111
3-(5-Fluoropyridin-2-yl)-N,N-dimethyl-3-({4-r(5-methyl-1H-pyrazol-3-yl)aminol-6-morpholin- 4-yl- 1 ,3 ,5-triazin-2-vU amino)propanamide
Figure imgf000251_0001
3-(4-Chloro-6-(3-methyl-1H-pyrazol-5-ylamino)-1,3,5-triazin-2-ylamino)-3-(5-fluoropyridin-2- yl)-N,N-dimethylpropanamide (Intermediate 122, 410 mg, 0.98mmol) and morpholine (4 mL, 46 mmol) were reacted using a procedure similar to the one described for the synthesis of
Example 11, providing the title compound as a mixture of enantiomers.
1H NMR (300 MHz, MeOD) δ ppm 8.42 (s, 1 H) 7.46-7.59(m, 2H) 5.58 (t, 1 H) 3.78(m, 4H)
3.65(m, 4H) 3.22(s, 6H) 2.27(s, 3 H).
LC-MS: 471 [M+H]+.
Column and solvent conditions
The title compound was chirally purified using conditions (A) and AD-3-50.
Column particle size (μ): 5
Column dimensions (mm): 21x250
Example 11 Ka), First Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.42 (s, 1 H) 7.46-7.59(m, 2H) 5.58 (t, 1 H) 3.78(m, 4H)
3.65(m, 4H) 3.22(s, 6H) 2.27(s, 3 H).
LC-MS: 471 [M+H]+.
Example 11 Kb), Second Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.42 (s, 1 H) 7.46-7.59(m, 2H) 5.58 (t, 1 H) 3.78(m, 4H)
3.65(m, 4H) 3.22(s, 6H) 2.27(s, 3 H).
LC-MS: 471 [M+H]+.
Example 112
6-(3,3-Dimethylmorpholin-4-yl)-N-r(l»S)-1-(5-fluoropyrimidin-2-yl)ethyl1-N>-(5-methyl-1H- pyrazol-3-vD- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000253_0001
fS>6-Chloro-N2-( 1 -(5-fluoropyrimidin-2-yl)ethyl)-./V4-(3 -methyl- 1H-pyrazol-5-yl)- 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 17, 200 mg, 0.57 mmol) and 3,3-dimethylmorpholine hydrochloride (87 mg, 0.57 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 62, providing the title compound. 1H NMR (300 MHz, MeOD) δ ppm 8.76 (s, 2 H) 5.87(s, 1H) 5.34(q, 1 H) 3.50-3.86(m, 9H) 2.34(s, 3H) 1.66(d, 3H) 1.54(s, 3 H). LC-MS: 429 [M+H]+.
Example 113 ^)-N--(l-(3.5-Difluoropyridin-2-yl)-2-methoxyethyl)-Ni-(5-methyl-1H-pyrazol-3-yl)-6- morpholino-1,3,5-triazine-2,4-diamine
Figure imgf000253_0002
('i?>6-Chloro-N2-(l-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)-N4-(5-methyl-1H-pyrazol-3-yl)- 1,3,5-triazine-2,4-diamine (Intermediate 42, 574 mg, 1.45 mmol) was dissolved in ethanol (3.5 mL) and morpholine (4.41 mL, 50.63 mmol) was added. The reaction mixture was stirred at
25°C for 1 hour. The reaction mixture was then concentrated in vacuo leaving a clear semi-solid (1.374 g). This material was purified by ISCO (2-10% MeOH/DCM). Concentration of the fractions in vacuo provided the title compound as a white solid (591.7 mg).
1H NMR (300 MHz, MeOD) δ ppm 8.36 (d, 1 H) 7.38 - 7.74 (m, 1 H) 6.36 (br. s., 0.5 H) 5.42
5.88 (m, 1.5 H) 3.48 - 3.98 (m, 10 H) 3.34 (s, 3 H) 2.05 - 2.41 (m, 3 H).
LC-MS: 448 [M+H]+.
Column and solvent conditions
Sample purity was determined with a Chiralcel OJ-H.
Column dimensions: 4.6 x 100 mm
Mobile phase: 20% MeOH/dimethylethylamine
Flow: 5 mL/min
Pressure: 120 bar
Oven Temperature: 35°C
Detection: 220 nm
The compound had a retention time of 0.92 minutes, 97.5% ee.
Example 114
N-r5-(2-Cvclohexylethyl)-1H-pyrazol-3-yl1-N'-r(l»S)-1-(5-fluoropyrimidin-2-yl)ethyl1-6- morpholin-4-yl-1,3,5-triazine-2,4-diamine
Figure imgf000254_0001
(S)-6-Chloro-N2-(3-(2-cyclohexylethyl)-1H-pyrazol-5-yl)-N4-(l-(5-fluoropyrimidin-2-yl)ethyl)- 1,3,5-triazine-2,4-diamine (Intermediate 124, 363 mg, 0.81 mmol) and morpholine (4 mL, 45.91 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound.
1H NMR (300 MHz, MeOD) δ ppm 8.70 (s, 2 H) 5.25 (t, 1 H) 3.57-3.75 (m, 8 H) 2.62 (t, 2H) 0.90-1.83(m, 16H). LC-MS: 497 [M+H]+.
Example 115
N-r(l»y)-1-(5-Fluoropyrimidin-2-yl)ethyl1-N'-r5-(4-methoxyphenyl)-1H-pyrazol-3-yl1-6- morpholin-4-yl-1,3,5-triazine-2,4-diamine
Figure imgf000255_0001
fS>6-Chloro-N2-( 1 -(S-fluoropyrimidin^-yrjethyl)-^4-^ -(4-methoxyphenyl)- 1H-pyrazol-5-yl)-
1,3,5-triazine-2,4-diamine (Intermediate 125, 510 mg, 1.15 mmol) and morpholine (5 mL, 57.39 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound. 1H NMR (300 MHz, MeOD) δ ppm 8.76 (s, 2 H) 7.67(d, 2H) 7.06(d, 2H) 5.36 (q, 1 H) 3.87 (s, 3H) 3.68-3.76 (m, 8 H) 1.66 (d, 3H). LC-MS: 493 [M+H]+.
Example 116 3-(5-Fluoropyridin-2-yl)-3-({4-r(5-methyl-1H-pyrazol-3-yl)aminol-6-morpholin-4-yl-1,3,5- triazin-2-vU amino)propan- 1 -ol
Figure imgf000256_0001
3-(4-Chloro-6-(3-methyl-1H-pyrazol-5-ylamino)-1,3,5-triazin-2-ylamino)-3-(5-fluoropyridin-2- yl)propan-1-ol (Intermediate 126, 110 mg, 0.29 mmol) and morpholine (2 mL, 22.96 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of enantiomers. 1H NMR (300 MHz, MeOD) δ ppm 8.47 (d, 1 H) 7.5 l-7.65(m, 2H) 5.85 (q, 1 H) 5.37(t, 1H) 3.66-3.88 (m, 8 H) 2.33(s, 3H) 2.12-2.18(m, 2H). LC-MS: 430 [M+H]+.
Column and solvent conditions The title compound was chirally purified using Chiral HPLC
Column: Chirapak AD
Dimensions: 250 x 20mm, 10μ
Mobile phase: 70% Hexane, 30% isopropanol 0.1% diethylamine (v/v/v)
Flow rate (ml/min): 20 Detection (nm): 220
Example 116(a), First Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.47 (d, 1 H) 7.51-7.65(m, 2H) 5.85 (q, 1 H) 5.37(t, 1H) 3.66-3.88 (m, 8 H) 2.33(s, 3H) 2.12-2.18(m, 2H). LC-MS: 430 [M+H]+.
Example 116(b), Second Eluting Compound 1H NMR (300 MHz, MeOD) δ ppm 8.47 (d, 1 H) 7.5 l-7.65(m, 2H) 5.85 (q, 1 H) 5.37(t, 1H) 3.66-3.88 (m, 8 H) 2.33(s, 3H) 2.12-2.18(m, 2H). LC-MS: 430[M+H]+.
Example 117 N-ri-(5-Fluoropyridin-2-yl)-2-(methylsulfonyl)ethyl1-N>-(5-methyl-1H-pyrazol-3-yl)-6- morpholin-4-yl-1,3,5-triazine-2,4-diamine
Figure imgf000257_0001
β-Chloro-Λ^-Cl-CS-fluoropyridin-1-y^-1-Cmethylsulfony^ethy^-V-CS-methyl-1H-pyrazol-S-yl)-
1,3,5-triazine-2,4-diamine (Intermediate 127, 407 mg, 0.95 mmol)and morpholine were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of enantiomers.
1H NMR (300 MHz, MeOD) δ ppm 8.54 (s, 1 H) 7.62-7.66(m, 2H) 5.95 (t, 1 H) 5.87 (br.s, 1 H)
3.71-4.04(m, 10H) 3.00(s, 3H) 2.33(s, 3 H).
LC-MS: 478 [M+H]+.
Column and solvent conditions
The title compound was chirally purified using conditions (A) with an IA column.
Modifier: 50% isopropanol, 0.2% TFA, 0.2% dimethylethylamine
Column particle size (μ): 5 Column dimensions (mm): 21x250
Example 117(a), First Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.54 (s, 1 H) 7.62-7.66(m, 2H) 5.95 (t, 1 H) 5.87 (br.s, 1 H) 3.71-4.04(m, 10H) 3.00(s, 3H) 2.33(s, 3 H). LC-MS: 478 [M+H]+.
Example 117(b), Second Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.54 (s, 1 H) 7.62-7.66(m, 2H) 5.95 (t, 1 H) 5.87 (br.s, 1 H) 3.71-4.04(m, 10H) 3.00(s, 3H) 2.33(s, 3 H). LC-MS: 478 [M+H]+.
Example 118
N-[5-(4-Fluorophenyl)-1H-pyrazol-3-yll-N'-[(15f)-1-(5-fluoropyrimidin-2-yl)ethyll-6-morpholin- 4-yl-1,3,5-triazine-2,4-diamine
Figure imgf000258_0001
(S>6-Chloro-N2-(3 -(4-fluorophenyl)- 1H-pyrazol-S-yFj-N4^ 1 -(5-fluoropyrimidin-2-yl)ethyl)- 1,3,5-triazine-2,4-diamine (Intermediate 128, 310 mg, 0.72 mmol) and morpholine were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound.
1H NMR (300 MHz, MeOD) δ ppm 8.77 (s, 2 H) 7.75-7.79(m, 2H) 7.23-7.30(m, 2H) 6.38(br.s, 1H) 5.36 (q, 1 H) 3.61-3.87 (m, 8 H) 1.66 (d, 3H). LC-MS: 481 [M+H]+.
Example 119
4- { \(2S)- 1 -(5-Fluoropyridin-2-yl)-2-methoxypropyHoxy}-N-(5-methyl- 1H-pyrazol-3-yl)-6- morpholin-4-yl-1,3,5-triazin-2-amine
Figure imgf000259_0001
(21Sl)-1-(5-Fluoropyridin-2-yl)-2-methoxypropan-1-ol (Intermediate 83, 505 mg, 2.73 mmol) and
4-chloro-N-(3-methyl-1H-pyrazol-5-yl)-6-morpholino-1,3,5-triazin-2-amine (Intermediate 15,
538 mg, 1.82 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 100, providing a mixture of two different diastereomers.
Example 119(a), First Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.45 (s, 1 H) 7.66-7.71(m, 2H) 5.89 (m, 1 H) 4.81 (d, 1 H)
3.66-3.93(m, HH) 2.33(s, 3 H) 1.05-1. l l(m, 3H).
LC-MS: 445 [M+H]+.
Example 119(b), Second Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 8.48 (s, 1 H) 7.59-7.66(m, 2H) 6.18(br.s, 1 H) 6.07(d, 1H)
4.00 (s, 3 H) 3.66-3.88(m, 8H) 2.38(s, 3 H) 1.15-1.26(m, 3H).
LC-MS: 445 [M+H]+.
Example 120
N-[(1»S)- 1 -(5-Fluoropyrimidin-2-yl)ethyll-6-morpholin-4-yl-N45-(phenoxymethyl)- 1H-pyrazol-
3-vU-1,3,5-triazine-2,,4-diarnine
Figure imgf000260_0001
fS>6-Chloro-N2-( 1 -(S-fluoropyrimidin^-yrjethyl)-^4-^ -(phenoxymethyl)- 1H-pyrazol-5-yl)- 1,3,5-triazine-2,4-diamine (Intermediate 139, 270 mg, 0.61 mmol) and morpholine were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound. 1H NMR (300 MHz, MeOD) δ ppm 8.71 (s, 2 H) 7.29(t, 2H) 6.93-7.03(m, 3H) C-4' proton of pyrazole not obvious 5.25 (q, 1 H) 5.04(s, 2H) 3.53-3.83(m, 8 H) 1.58(d, 3H). LC-MS: 493 [M+H]+
Example 121 N-r(l»y)-1-(5-Fluoropyrimidin-2-yl)ethyl1-6-morpholin-4-yl-N>-(5-thien-2-yl-1H-pyrazol-3-yl)- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000260_0002
fS>6-Chloro-N2-( 1 -(5-fluoropyrimidin-2-yl)ethyl)-N4-(3 -(thiophen-2-yl)- 1H-pyrazol-5-yl)- 1 ,3 ,5- triazine-2,4-diamine (Intermediate 129, 310 mg, 0.74 mmol) and morpholine (2mL, 22.96 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound. 1H NMR (300 MHz, MeOD) δ ppm 8.76 (s, 2 H) 7.55(d, 1H) 7.51(d, 1H) 7.17(dd, 1H) 6.29(br.s, 1 H) 5.35(q, 1H) 3.60-3.86(m, 8 H) 1.66(d, 3H). LC-MS: 469 [M+H]+
Example 122 6-((2S,6R)-2,6-Dimethylmorpholino)-N2-((S)-1-(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl-1H- pyrazol-3-yl)- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000261_0001
(S)-6-Chloro-N2-( 1 -(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 17) and Cis-2,6-dimethylmorpholine were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound.
1H NMR (δ) 8.67 (s, 2H), 6.30 (bs, 1H), 5.20 (m, 1H), 4.44 (m, 2H), 3.53 (m, 2H), 2.44(m, 2H), 2.22 (s, 3H), 1.54 (m, 3H), 1.15 (m, 6H). LC-MS: 429, 430 [M+H]+.
Example 123
6-((2R,6R)-2.6-Dimethylmorpholino)-N2-((S)- 1 -(5-fluoropyrimidin-2-y)ethyl)-N4-(5-methyl- IH- pyrazol-3-vP)- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000262_0001
fS>6-Chloro-N2-( 1 -(S-fluoropyrimidin^-yrjethy^-Λ^S-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 17) and 2,6-dimethylmorpholine (mixture of cis- and trans-) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as mix of both cis and trans. The mixture was further separated by Gilson chromatography (pΗ8, 10 nM NH4OAC, MeCN/H2O, 30%^40%, 15 min), to provide the title compound (minor) along with 6-((21S',6i?)-2,6-dimethylmorpholino)-N2-(fS/)-1-(5-fluoropyrimidin- 2-yl)ethyl)-N4-(5-methyl- 1H-pyrazol-3-yl)- 1 ,3 ,5-triazine-2,4-diamine (Example 122). 1H NMR (δ) 8.69 (s, 2H), 6.00 (bs, 1H), 5.20 (m, 1H), 3.80-3.94 (m, 4H), 3.36 (m, 2H), 2.22 (s, 3H), 1.54 (m, 3H), 1.14 (m, 6H). LC-MS: 429 [M+H]+.
Example 124
6-(2-(Difluoromethyl)morpholino)-N2-((5f)- 1 -(5-fluoropyrimidin-2-yl)ethyl)-NA-(5-methyl- IH- pyrazol-3-vD- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000263_0001
(S)-6-Chloro-N2-( 1 -(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine-
2,4-diamine (Intermediate 17) and 2-(difluoromethyl)morpholine (Intermediate 130) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of diastereomers 1H NMR (δ) 8.73 (m, 2H), 5.84 (m, 2H), 5.31 (m, 1H), 4.36-4.67 (m, 2H), 3.97 (m, 1H), 3.53(m, 2H), 3.08 (m, 2H), 2.32 (s, 3H), 1.61 (m, 3H). LC-MS: 451, 452 [M+H]+.
Example 125 6-(2-(Difluoromethyl)morpholino)-N2-(R)-1-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)-N4-(5- methyl- 1H-pyrazol-3 -yP)- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000263_0002
(R)-6-Chloro-N2-(l-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)-N4-(5-methyl-1H-pyrazol-3-yl)- 1,3,5-triazine-2,4-diamine (Intermediate 42) and 2-(difluoromethyl)morpholine (Intermediate 130) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound.
1H NMR (δ) 8.34 (m, 1H), 7.52 (m, 1H), 6.35 (m, 1H), 5.84 (m, 2H), 4.64 (m, 1H), 4.48 (m, 1H), 3.96 (m, 1H), 3.53-3.71(m, 4H), 3.34 (m, 3H), 3.15 (m, 2H), 2.25 (s, 3H). LC-MS: 498 [M+H]+.
Example 126
(y)-6-(3.3-Difluoropiperidin-1-yl)-N--(l-(5-fluoropyrimidin-2-yl)ethyl)-Ni-(5-methyl-1H- pyrazol-3-yl)- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000264_0001
(S>6-Chloro-N2-( 1 -(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl- 1H-pyrazol-3 -yl> 1 ,3 ,5-triazine-
2,4-diamine (Intermediate 17) and 3,3-difluoropiperidine were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound. 1H NMR (δ) 8.66 (m, 2H), 6.37 (m, 1H), 5.16 (m, 1H), 4.00 (m, 2H), 3.77 (m, 1H), 3.49(m, 1H), 2.25 (s, 3H), 2.03 (m, 2H), 1.57 (m, 5H). LC-MS: 435, 436 [M+H]+.
Example 127
6-(3-((Dimethylamino)methyl)piperidin-1-yl)-N--(^S')-1-(5-fluoropyrimidin-2-yl)ethyl)-Λ^-(5- methyl- 1H-pyrazol-3 -yP)- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000265_0001
(S>6-Chloro-N2-( 1 -(5-fluoropyrimidin-2-yl)ethyl)-Λ^-(5-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 17) and N,N-dimethyl-1-(piperidin-3-yl)methanamine were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of diastereomers. 1H NMR (δ) 8.70 (s, 2H), 6.02 (m, 1H), 5.31 (m, 1H), 3.73 (m, 1H), 2.55 (m, 8H), 2.27 (s, 3H), 1.93 (s, 6H), 1.57 (d, 3H), 1.38 (m, 2H). LC-MS: 456 [M+H]+.
Column and solvent conditions The mixture of diastereomers was separated using Chiral HPLC.
Column: Chirapak AD
Simensions: 250 x 20mm, 10μ
Mobile phase: 50% Hexane, 50% isopropanol, 0.1% diethylamine (v/v/v)
Flow rate (ml/min): 20 Detection (nm): 254
Example 127(a), First Eluting Compound
1H NMR (O) 8.69(s, 2H), 6.25 (bs, 1H), 5.26 (m, 1H), 4.40 (m, 1H), 3.34(m, 2H), 2.25 (m, HH), 1.28-1.89 (m, 9H). LC-MS: 456 [M+H]+. Example 127(b), Second Eluting Compund
1H NMR (δ) 8.74 (s, 2H), 5.88 (m, 1H), 5.28(m, 1H), 4.53 (m, 1H), 3.37-4.12 (m, 1H), 2.97 (m,
9H), 2.32 (s, 3H), 1.99 (s, 3H), 1.22-1.63(s, 6H).
LC-MS: 456 [M+H]+.
Example 128 tert-Butyl ((S)- 1 -(4-((S)- 1 -(5-fluoropyrimidin-2-yl)ethylamino)-6 -(5-methyl- 1H-pyrazol-3- ylamino)- 1 ,3 ,5-triazin-2-yl)piperidin-3 -yl)methylcarbamate
Figure imgf000266_0001
(S)-6--Chloro-N2-( 1 -(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 17) and (R)-tert-butyl piperidin-3-ylmethylcarbamate were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound.
1H NMR (δ) 8.68 (s, 2H), 6.43 (bs, 1H), 5.26 (m, 1H), 3.81 (m, 2H), 3.20 (m, 1H), 2.89 (m,2H),
2.2 l(m, 3H), 1.72 (m, 3H), 1.54 (d, 3H), 1.39 (m, 12 H). LC-MS: 528 [M+H]+.
Example 129
6-((S)-3-(Aminomethyl)piperidin-1-yl)-N--((S)-1-(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine-2,4-diamine hydrochloride
Figure imgf000267_0001
tert-BvLtyl ((S)- 1 -(4-((S)- 1 -(5-fluoropyrimidin-2-yl)ethylamino)-6-(5-methyl- 1H-pyrazol-3- ylamino)-1,3,5-triazin-2-yl)piperidin-3-yl)methylcarbamate (Example 128, 167 mg, 0.32 mmol) was reacted using a procedure similar to the one described for the synthesis of Example 41, providing the title compound. 1H NMR (δ) 8.77 (m, 2H), 6.06 (m, 1H), 5.40 (m, 1H), 3.47 (m, 3H), 2.91 (m, 2H), 2.39 (m, 3H), 2.20(m, 1H), 1.94 (m, 2H), 1.35-1.71(m, 6H). LC-MS: 428 [M+H]+.
Example 130 tert-Butyl ((R)- 1 -(4-((S)-I -(5-fluoropyrimidin-2-yl)ethylamino)-6-(5-methyl- 1H-pyrazol-3- ylamino)- 1 ,3 ,5-triazin-2-yl)piperidin-3 -vDmethylcarbamate
Figure imgf000268_0001
(S)-6-Chloro-N2-( 1 -(5-fluoropyrimidin^-yrjethyl)-N4-(5-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 17) and (S)-tert-butyl piperidin-3-ylmethylcarbamate were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound. 1H NMR (δ) 8.70 (s, 2H), 6.41 (bs, 1H), 5.28 (m, 1H), 3.83 (m, 2H), 3.22 (m, 1H), 2.92 (m,2H), 2.2 l(m, 3H), 1.72 (m, 3H), 1.54 (d, 3H), 1.41 (m, 12 H). LC-MS: 528 [M+H]+.
Example 131 6-((R)-3 -(Aminomethyl)piperidin- 1 -yl)-N2-((S)- 1 -(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl- 1H-pyrazol-3-yl)-1,3,5-triazine-2,4-diamine, TFA salt
Figure imgf000268_0002
tert-Butyl ((R)- 1 -(4-((S)-I -(5-fluoropyrimidin-2-yl)ethylamino)-6-(5-methyl- 1H-pyrazol-3- ylamino)-1,3,5-triazin-2-yl)piperidin-3-yl)methylcarbamate (Example 130) were reacted using a procedure similar to the one described for the synthesis of Example 41, providing the title compound. Purification by Gilson chromatography (MeCN/EkO, O,1%TFA) afforded the title compound as TFA salt.
1H NMR (δ) 8.76 (m, 2H), 5.99 (m, 1H), 5.39 (m, 1H), 3.40 (m, 3H), 2.89 (m, 2H), 2.34 (m, 3H), 2.01 (m, 3H), 1.34-1.72(m, 6H). LC-MS: 428 [M+H]+.
Example 132 fert-Butyl l-(4-(^$')-1-(5-fluoropyrimidin-2-yl)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-
1 ,3 ,5-triazin-2-yl)piperidin-3 -yl(methyl)carbamate
Figure imgf000269_0001
(S>6-Chloro-N2-( 1 -(S-fluoropyrimidin^-yrjethy^-Λ^S-methyl- 1H-pyrazol-3 -yl> 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 17) and tert-butyl methyl(piperidin-3-yl)carbamatewere reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of diastereomers.
1H NMR (δ) 8.67 (m, 2H), 6.32 (m, 1H), 5.22 (m, 1H), 4.64 (m, 2H), 3.79 (m, 1H), 2.8 l(m, 4H),
2.61 (m, 1H), 2.23 (m, 3H), 1.78 (m, 3H), 1.50 (m, 13H). LC-MS: 528, 529 [M+H]+. Column and solvent conditions
The mixture of diastereomers was separated using conditions (A) and AD-4-25.
Column particle size (μ): 5
Column dimensions (mm): 21x250
Example 132(a), First Eluting Compound
1H NMR (δ) 8.67 (s, 2H), 6.32 (bs, 1H), 5.25 (m, 1H), 4.65 (m, 2H), 3.79 (m, 1H), 2.8 l(m, 4H),
2.66 (m, 1H), 2.22 (s, 3H), 1.79 (m, 3H), 1.50 (m, 13H).
LC-MS: 528, 529 [M+H]+.
Example 132(b), Second Eluting Compound
1H NMR (δ) 8.67 (s, 2H), 6.32 (bs, 1H), 5.24 (m, 1H), 4.58 (m, 2H), 3.80 (m, 1H), 2.80(m, 4H),
2.62 (m, 1H), 2.22 (s, 3H), 1.78 (m, 3H), 1.51 (m, 13H).
LC-MS: 529 [M+H]+.
Example 133
4-( l-(3 ,5-Difluoropyridin-2-yl)ethoxy)-N-(5-metriyl- 1H-pyrazol-3-yl)-6-morpholino- 1 ,3 ,5- triazin-2-amine
Figure imgf000270_0001
l-(3,5-Difluoropyridin-2-yl)-2-methoxyethanol (Intermediate 107) and 4-chloro-N-(3-methyl- 1H-pyrazol-5-yl)-6-morpholino-1,3,5-triazin-2-amine (Intermediate 15) were reacted using a procedure similar to the one described for the synthesis of Example 100, providing the title compound as a mixture of enantiomers. 1H NMR (300 MHz, MeOD) δ ppm 1.69 (d, J=6.59 Hz, 3 H) 2.27 (s, 3 H) 3.47 - 4.02 (m, 8 H) 6.11 - 6.44 (m, 2H) , 7.61 (ddd, 1 H) 8.35 (s, 1 H) . LC-MS: 419 [M+H]+.
Column and solvent conditions The title compound was chirally purified using conditions (A) and AD-4-20. Column particle size (μ): 5 Column dimensions (mm): 21x250
Post purification purity check: The sample purity was checked using conditions (B) and AD-4-20. Elution time (min): 5 Flow rate (ml/min): 5
Example 133(a), First Eluting Compound 1H NMR (300 MHz, MeOD) δ ppm 1.69 (d, J=6.59 Hz, 3 H) 2.27 (s, 3 H) 3.47 - 4.02 (m, 8 H) 6.11 - 6.44 (m, 2H) , 7.61 (ddd, 1 H) 8.35 (s, 1 H). LC-MS: 419 [M+H]+. The first eluting compound had a retention time of 1.87 minutes.
Example 133(b), Second Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 1.69 (d, J=6.59 Hz, 3 H) 2.27 (s, 3 H) 3.47 - 4.02 (m, 8 H)
6.11 - 6.44 (m, 2H) , 7.61 (ddd, 1 H) 8.35 (s, 1 H).
LC-MS: 419 [M+H]+.
The second eluting compound had a retention time of 2.53 minutes.
Example 134
N--(l-(5-Fluoropyridin-2-yl)-2-methoxyethyl)-Λ^-(5-methyl-1H-pyrazol-3-yl)-6-morpholino- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000272_0001
N2-(l-(5-Fluoropyridin-2-yl)-2-methoxyethyl)-Λ/4-(5-methyl-1H-pyrazol-3-yl)-6-morpholino-
1,3,5-triazine-2,4-diamine (Intermediate 131) and morpholine were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of enantiomers. 1H NMR (300 MHz, MeOD) δ ppm 2.25 (s, 3 H) 3.36 (s, 3 H) 3.52 - 4.06 (m, 10 H) 5.16 - 5.44 (m, 1 H) 6.05 (s, 1 H) 7.30 - 7.79 (m, 2 H) 8.42 (s, 1 H). LC-MS: 430 [M+H]+.
Column and solvent conditions The title compound was chirally purified using Chiral HPLC.
Column: Chirapak AD
Dimensions: 250 x 20mm, lOμ
Mobile phase: 10% Hexane, 90% 1:1 ethanohmethanol, 0.1% diethylamine (v/v/v)
Flow rate (ml/min): 20 Detection (nm): 220
Example 134(a), First Eluting Compound
1H NMR δ ppm 2.25 (s, 3 H) 3.36 (s, 3 H) 3.52 - 4.06 (m, 10 H) 5.16 - 5.44 (m, 1 H) 6.05 (s, 1 H) 7.30 - 7.79 (m, 2 H) 8.42 (s, 1 H). LC-MS: 430 [M+H]+.
Example 134(b), Second Eluting Compound
1H NMR (300 MHz, MeOD) δ ppm 2.25 (s, 3 H) 3.36 (s, 3 H) 3.52 - 4.06 (m, 10 H) 5.16 - 5.44 (m, 1 H) 6.05 (s, 1 H) 7.30 - 7.79 (m, 2 H) 8.42 (s, 1 H). LC-MS: 430 [M+H]+.
Example 135
6-(3-Fluoropiperidin- l-γϊ)-Nz-((S)- 1 -(5-fluoropyrimidin-2-yl)ethyl)-NA-(5-methyl- 1H-pyrazol-3- vD- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000273_0001
fS>6-Chloro-N2-( 1 -(S-fluoropyrimidin^-y^ethy^-Λ^S-methyl- 1H-pyrazol-3 -yl)- 1 ,3 ,5-triazine- 2,4-diamine (Intermediate 17) and 3-fluoropiperidine hydrochloride were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of enantiomers.
1H NMR (δ) 8.70 (s, 2H), 6.39 (s, 1H), 5.22 (m, 1H), 4.55 (m, 1H), 3.83 (m, 4H), 2.25 (s, 3H), 1.86 (m, 3H), 1.57 (m, 4H). LCMS: 417 [M+H]+.
Column and solvent conditions
The mixture of enantiomers was separated using conditions (A) and OJ-3-20. Column particle size (μ): 5 Column dimensions (mm): 21x250
Example 135(a), First Eluting Compound
1H NMR (δ) 8.68(s, 2H), 5.99 (bs, 1H), 5.19 (m, 1H), 4.64 (m, 1H), 3.71 (m, 4H), 2.23 (s, 3H), 1.84 (m, 3H), 1.55 (m, 4H). LCMS: 417 [M+H]+. Example 135(b), Second Eluting Compound
1H NMR (O) 8.66(s, 2H), 6.10 (bs, 1H), 5.18(m, 1H), 4.53 (m, 1H), 3.71 (m, 4H), 2.23 (s, 3H),
1.83 (m, 3H), 1.55 (m, 4H).
LCMS: 417 [M+H]+.
Example 136
(y)-N2-(l-(5-Fluoropyrimidin-2-yl)ethyl)-6-morpholino-Ni-(5-(2-(pyridin-4-yl)ethyl)-1H- pyrazol-3-yl)- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000274_0001
(S)-4-Ch\oro-N-( 1 -(5-fluoropyrimidin-2-yl)ethyl)-6-morpholino- 1 ,3 ,5-triazin-2-amine (Intermediate 132, 170 mg, 0.50 mmol), 5-(2-(pyridin-4-yl)ethyl)-1H-pyrazol-3-amine (Intermediate 168, 94 mg, 0.50 mmol), BINAP (31.2 mg, 0.05 mmol), Pd2(dba)3 (22.91 mg, 0.03 mmol), and CS2CO3 (408 mg, 1.25 mmol) were loaded in a microwave tube followed by dioxane (1.5 ml). The mixture was degassed and flushed with N2. The reaction was heated at 95°C for 8 hours. Evaporation of the volatiles under reduced pressure and purification by ISCO gave the title compound (13 mg).
1H NMR (400 MHz, MeOD) δ ppm 8.59 (2H, s) 8.30 (2H, s), 7.20 (2H,s), 6.26 (1H, s), 5.48 (1H, m), 5.13 (1H, m), 3.61-3.51 (8H, m), 2.91-2.83 (4H, m). LCMS: 492.2 [M+H]+.
Example 137
N--((i?)-1-(3,5-Difluoropyridin-2-yl)-2-methoxyethyl)-6-(2-(methoxymethyl)morpholino)-Ni-(5- methyl- 1H-pyrazol-3 -vD- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000275_0001
(Tϊ^β-Chloro-^-Cl-CS^-difluoropyridin-1-y^-1-methoxyethy^-V-CS-methyl-1H-pyrazol-S-yl)- 1,3,5-triazine-2,4-diamine (Intermediate 42, 150 mg, 0.38 mmol) and 2-
(methoxymethyl)morpholine (59.5 mg, 0.45 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound as a mixture of diastereoisomers.
1H NMR (300 MHz, MeOD) δ ppm 8.26 (br. s., 1 H), 7.45 (m, 1 H), 5.94 (br. s., 1 H), 5.55 (t, J=6.50 Hz, 1H), 4.46 (d, J=12.62 Hz, 1 H), 4.36 (d, J=13.56 Hz, 1 H), 3.81 (d, J=I 1.11 Hz, I H), 3.67 (m, 2 H), 3.41 (m, 4H), 3.29 (s, 3 H), 3.25 (s, 3 H), 2.92 (m, 1 H), 2.66 (dd, J=12.90, 10.83 Hz, I H), 2.13 (br. s., 3 H). LCMS: 492.2 [M+H]+.
Column and solvent conditions
The mixture of diastereomers was separated using Chiral HPLC. Column dimensions: AD 2 x 25 cm, 10μm, Mobile phase: 70% Hexane, 30% isopropanol, 0.1% diethylamime,
Flow rate (ml/min): 20 mL/min Detection (nm): 254
Post purification purity check Sample purity was checked with a Chiralcel OJ-H (Chiral HPLC). Column dimensions: 4.6 x 100 mm
Mobile phase: 70% Hexane, 30% isopropanol, 0.1% diethylamime
Flow: 5 mL/min
Pressure: 120 bar Oven Temperature: 35°C Detection: 254 nm
Example 137(a), First Eluting Compound
1H NMR (300 MHz, CDCl3) δ ppm 8.51 (br. s., 1 H), 8.26 (d, J=I.88 Hz, 1 H), 7.12 (t, J=9.51Hz, 1 H), 6.10 (br. s., 1 H), 5.76 (br. s., 1 H), 4.41 (m, 2 H), 3.92 (m, 1 H), 3.72 (m, 2 H), 3.45 (m, 8 H), 3.26 (s, 3 H), 2.95 (q, J=7.35 Hz, 2 H), 2.79 (t, J=I 1.77 Hz, 1 H), 2.21 (s, 3 H). LCMS: 492.2 [M+H]+.
Example 137(b) Second Eluting Compound 1H NMR (300 MHz, Chloroform-^) δ ppm 8.54 (br. s., 1 H), 8.26 (d, J=I.70 Hz, 1 H), 7.12 (t,
J=7.63 Hz, 1 H), 6.10 (br. s., 1 H), 5.76 (dd, J=3.77, 1.13 Hz, 1 H), 4.42 (m, 2 H), 3.92 (d, J=9.61
Hz, 1 H), 3.72 (m, 2H), 3.54 (m, 2 H), 3.39 (m, 6 H), 3.27 (s, 3 H), 2.97 (m, 2 H), 2.70 (m, 1 H),
2.17 (m, 3 H).
LC-MS: 492.2 [M+H]+.
Example 138
2-(4-(4-((i?)-1-(3,5-Difluoropyridin-2-yl)-2-methoxyethylamino)-6-(5-methyl-1H-pyrazol-3- ylamino)- 1.3.5-triazin-2-yl)morpholin-2-yl)acetonitrile
Figure imgf000276_0001
(^>6-Chloro-N2-(l-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)-N4-(5-methyl-1H-pyrazol-3-yl)- 1,3,5-triazine-2,4-diamine (Intermediate 42, 150 mg, 0.38 mmol) and 2-(morpholin-2- yl)acetonitrile hydrochloride (Intermediate 135, 47.7 mg, 0.38 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound.
1H NMR (300 MHz, MeOD) δ ppm 8.41 (d, J=2.07 Hz, 1 H), 7.65 (td, J=9.18, 2.35 Hz, 1 H), 5.88 (br. s., 1H), 5.71 (br. s., 1 H), 4.67 (m, 1 H), 4.52 (m, 1 H), 4.01 (dd, J=10.36, 2.45 Hz, 1 H), 3.82 (m, 2 H), 3.64 (m, 2H), 3.40 (s, 3 H), 3.19 (d, J=14.88 Hz, 1 H), 2.99 (m, 1 H), 2.78 (d, J=5.84 Hz, 2 H), 2.35 (s, 3 H). LC-MS: 487.4 [M+H]+.
Example 139
6-(2-(Azetidin-1-ylmethyl)morpholino)-N2-(R)-1-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)-N4-(5-methyl- 1H-pyrazol-3-yl)- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000277_0001
(R)-6-Chloro-N2-(1-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)-N4-(5-methyl-1H-pyrazol-3-yl)- 1,3,5-triazine-2,4-diamine (Intermediate 42, 180 mg, 0.50 mmol) and 2-(azetidin-1- ylmethyl)morpholine hydrochloride (Intermediate 134, 93 mg, 0.60 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 11, providing the title compound.
1H NMR (300 MHz, MeOD) δ ppm 8.29 (m, 1 H), 7.46 (m, 1 H), 6.27 (m, 1 H), 5.61 (m, 2 H), 4.39 (t,j=12.72 Hz, 2 H), 3.80 (d, J=10.93 Hz, 1 H), 3.66 (dd, 3 H), 3.31 (m, 4 H), 2.86 (m, 1 H),2.54 (m, 4 H), 2.07 (m, 6 H).
Example 140 2-(R)-4-(4-(R)-1-(3.5-Difluoropyridin-2-yl)-2-methoxyethylamino)-6-(5-methyl-1H-pyrazol-3- ylamino)- 1 ,3 ,5-triazin-2-yl)morpholin-3-yl)acetonitrile
Figure imgf000278_0001
(R)-6-Chloro-N2-(1-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)-N4-(5-methyl-1H-pyrazol-5-yl)- 1,3,5-triazine-2,4-diamine (Intermediate 42, 180mg, 0.45 mmol) and (R)-2-(morpholin-3- yl)acetonitrile TFA salt (Intermediate 137, 218 mg, 0.91 mmol) were reacted using a procedure similar to the one described for the synthesis of Example 62, providing the title compound
1H NMR (MeOD) δ 8.27 (s, 1H), 7.46 (t, 1H), 6.25 (brs, 1H), 5.57 (m, 1H), 4.83 (m, 1H), 4.29 (m, 1H), 3.85 (d, 2H), 3.71 (m, 1H), 3.66 (m, 1H), 3.54 (m, 1H), 3.40 (m, 1H), 3.26 (s, 3H), 3.04 (m, 1H), 2.89 (m, 1H), 2.73 (m, 1H), 2.16 (s, 3H). LC-MS: 487 [M+H]+.
Examples 141-147 were prepared from the indicated starting material using a procedure similar to the one described for the synthesis of Example 11.
Example 141 N-{3-r2-(4-Fluorophenyl)ethyl1-1H-pyrazol-5-vU-N'-r((1S)-1-(5-fiuoropyrimidin-2-yl)ethyl1-6- morpholin-4-yl-1,3,5-triazine-2,4-diamine
Figure imgf000278_0002
Starting material: (S) -6-Chloro-N2-(5-(4-fluorophenethyl)-1H-pyrazol-3-yl)-N4-(l-(5- fluoropyrimidin-2-yl)ethyl)-1,3,5-triazine-2,4-diamine (Intermediate 141) and morpholine. 1H NMR δ 8.75 (s, 2H) 7.19-7.23 (m, 2H) 7.01 (t, 2 H) 5.83 (bs, 1 H) 5.34(q, 1H) 3.64-3.84 (m, 8H) 2.98(m, 4H) 1.65 (d, 3 H). LC-MS: 509 [M+H]+.
Example 142
N-{3-r2-(3-Fluorophenyl)ethyl1-1H-pyrazol-5-vU-N'-r(1S)-1-(5-fluoropyrimidin-2-yl)ethyl1-6- morpholin-4-yl-1,3.5-triazine-2,4-diamine
Figure imgf000279_0001
Starting material: (S)-6-chloro-N2-(5-(3- fluorophenethyl)-1H-pyrazol-3-yl)-N4-(1-(5- fluoropyrimidin-2-yl)ethyl)-1,3,5-triazine-2,4-diamine (Intermediate 142) and morpholine.
1H NMR δ 8.69 (s, 2H) 7.26 (dd, 1H) 6.86-7.03 (m, 3 H) 5.23(q, 1H) 3.54-3.71 (m, 8H) 2.84-
3.01(m, 4H) 1.56 (d, 3 H).
LC-MS: 509 [M+H]+.
Example 143
N-{3-r2-(3,5-Difluorophenyl)ethyl1-1H-pyrazol-5-vU-N'-r( 1S)-1-(5-fluoropyrimidin-2-yl)ethyl1-
6-morpholin-4-yl- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000279_0002
Starting material: fS>6-Chloro-i^-(5-(3,5-difluorophenethyl)-1H--pyrazol-3-yl)-iV4-(l-(5- fluoropyrimidin-2-yl)ethyl)-1,3,5-triazine-2,4-diamine (Intermediate 143) and morpholine. 1H NMR δ 8.71 (s, 2H) 6.85 (d, 2H) 6.76 (dd, 1 H) 5.25 (q, 1H) 3.58-3.74 (m, 8H) 2.90-3.03 (m, 4H) 1.58 (d, 3 H). LC-MS: 527 [M+H]+.
Example 144
N-{3-r2-(2,4-Difluorophenyl)ethyl1-1H-pyrazol-5-vU-N'-r(l»y)-1-(5-fluoropyrimidin-2-yl)ethyl1- 6-morpholin-4-yl- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000280_0001
Starting material: fS>6-Chloro-N2-(5-(2,4-difluorophenethyl)-1H-pyrazol-3-yl)-N4-(l-(5- fluoropyrimidin-2-yl)ethyl)-1,3,5-triazine-2,4-diamine (Intermediate 144) and morpholine.
1H NMR δ 8.71 (s, 2H) 7.21-7.28 (m, 1H) 6.85-6.94 (m, 2 H) 5.21 (q, 1H) 3.55-3.74 (m, 8H)
2.83-3.04 (m, 4H) 1.58 (d, 3 H).
LC-MS: 527 [M+H]+.
Example 145
N-{3-r2-(3,4-Difluorophenyl)ethyl1-1H-pyrazol-5-vU-N'-r(l»y)-1-(5-fluoropyrimidin-2-yl)ethyl1-
6-morpholin-4-yl- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000281_0001
Starting material: (S)-6-Chloro-N2-(3-(3,4-difluorophenethyl)-1H-pyrazol-5-yl)-N4-(1-(5- fluoropyrimidin-2-yl)ethyl)-1,3,5-triazine-2,4-diamine (Intermediate 145) and morpholine. 1H NMR δ 8.71 (s, 2H) 7.10-7.21 (m, 2H) 7.01 (bs, 1 H) 5.25 (q, 1H) 3.55-3.74 (m, 8H) 2.82-3.0 (m, 4H) 1.58 (d, 3 H). LC-MS: 527 [M+H]+.
Example 146
N-{3-r2-(2,6-Difluorophenyl)ethyl1-1H-pyrazol-5-vU-N'-r(1S)-1-(5-fluoropyrimidin-2-yl)ethyl1- 6-morpholin-4-yl- 1 ,3 ,5-triazine-2,4-diamine
Figure imgf000281_0002
Starting material: 6-Chloro-N-{3-[2-(2,6-difluorophenyl)ethyl]-1H-pyrazol-5-yl}-N'-[(1S)-1-(5- fluoropyrimidin-2-yl)ethyl]-1,3,5-triazine-2,4-diamine (Intermediate 146) and morpholine. 1H NMR (300 MHz, MeOD) δ ppm 8.71 (s, 2 H) 7.19-7.29 (m, 1H) 6.88-6.93 (m, 2 H) 5.79 (br.s, 1 H) 5.30 (q, 1 H) 3.52-3.82 (m, 8H) 2.93-3.05 (m, 4 H) 1.60 (d, 3 H). LC-MS: 527 [M+H]+.
Example 147
(S)-N2-(5-(3.4-Dimethoxyphenethyl)-1H-pyrazol-3-yl)-N4-(l-(5-fluoropyrimidin-2-yl)ethyl)-6- morpholino-1,3,5-triazine-2,4-diamine
Figure imgf000282_0001
Starting material: ((S)-6-Chloro-N2-(5-(3,4-dimethoxyphenethy)-1H-pyrazol-3-yl)-N4-(1-(5- fluoropyrimidin-2-yl)ethyl)-1,3,5-triazine-2,4-diamine (Intermediate 147) and morpholine. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.63 (s, 1H) 9.35 (s, 1H) 8.78 (s, 2 H) 8.28 (s, 1H) 6.80 - 6.93 (m, 2 H) 6.75 (dd, 1 H) 6.28 (s, 1H) 5.24 (m, br, 1H) 3.68 - 3.77 (m, 6 H) 3.58 (d, 8 H) 2.87 (m, 4 H) 1.52 (d, 3 H). LC-MS: 551 [M+H]+.

Claims

ClaimsWhat is claimed is:
1. A compound of Formula (I):
Figure imgf000283_0001
or a pharmaceutically acceptable salt thereof, wherein
Ring A is heterocyclyl, wherein said heterocyclyl is optionally substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R2*;
Ring B is selected from carbocyclyl and heterocyclyl, wherein said carbocyclyl and heterocyclyl are optionally substituted on carbon with one or more R4, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R4*; X is selected from -O-, -NH-, and -S-;
R1 is selected from H, halo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -ORla, -SRla, -N(Rla)2, -N(Rla)C(O)Rlb, -N(Rla)N(Rla)2, -NO2, -N(Rla)ORla, -ON(Rla)2, -C(O)H, -C(O)Rlb, -C(O)2Rla, -C(O)N(Rla)2, -C(O)N(Rla)(ORla), -OC(O)N(Rla)2, -N(Rla)C(O)2Rla, -N(Rla)C(O)N(Rla)2, -OC(O)Rlb, -S(O)Rlb, -S(O)2Rlb, -S(O)2N(Rla)2, -N(Rla)S(O)2Rlb, -C(Rla)=N(Rla), and
-C(Rla)=N(ORla), wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R10*; Rla in each occurrence is independently selected from H, C1-6alkyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R10, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R10*; Rlb in each occurrence is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R10, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R10*; R2 is selected from halo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -OR2a, -SR2a, -N(R2a)2, -N(R2a)C(O)R2b, -N(R2a)N(R2a)2, -NO2,
-N(R2a)OR2a, -ON(R2a)2, -C(O)H, -C(O)R2b, -C(O)2R2a, -C(O)N(R2a)2, -C(O)N(R2a)(OR2a) -OC(O)N(R2a)2, -N(R2a)C(O)2R2a, -N(R2a)C(O)N(R2a)2, -OC(O)R2b, -S(O)R2b, -S(O)2R2b, -S(O)2N(R2a)2, -N(R2a)S(O)2R2b, -C(R2a)=N(R2a), and -C(R2a)=N(OR2a), wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more R , and wherein any
-NH- moiety of said heterocyclyl is optionally substituted with R20*; R2* in each occurrence is independently selected from C1-6alky 1, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R2b, -C(O)2R2c, -C(O)N(R2a)2, -S(O)R2b, -S(O)2R2b, -S(O)2N(R2a)2, -C(R2a)=N(R2a), and -C(R2a)=N(OR2a), wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R20, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R20*;
R2a in each occurrence is independently selected from H, C1-6alkyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R20, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R20*; R2b in each occurrence is selected from C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R20, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R 20*
R2c in each occurrence is independently selected from C1-6alkyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R20*; R3 is selected from H, halo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -OR3a, -SR3a, -N(R3a)2, -N(R3a)C(O)R3b, -N(R3a)N(R3a)2, -NO2, -N(R3a)-OR3a, -O-N(R3a)2, -C(O)H, -C(O)R3b, -C(O)2R3a, -C(O)N(R3a)2, -C(O)N(R3a)(OR3a), -OC(O)N(R3a)2, -N(R3a)C(O)2R3, -N(R3a)C(O)N(R3a)2, -OC(O)R3b, -S(O)R3b, -S(O)2R3b, -S(O)2N(R3a)2, -N(R3a)S(O)2R3b, -C(R3a)=N(R3a), and -C(R3a)=N(OR3a), wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more R30, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R30*; R3a in each occurrence is independently selected from H, C1-6alkyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R30, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R30*; R3b in each occurrence is selected from C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R30, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R30*;
R4 is selected from halo, -CN, C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, heterocyclyl, -OR4a, -SR4a, -N(R4a)2, -N(R4a)C(O)R4b, -N(R4a)N(R4a)2, -NO2, -N(R4a)-OR4a, -O-N(R4a)2, -C(O)H, -C(O)R4b, -C(O)2R4a, -C(O)N(R4a)2, -C(O)N(R4a)(OR4a) -OC(O)N(R4a)2, -N(R4a)C(O)2R4a, -N(R4a)C(O)N(R4a)2, -OC(O)R4b,
-S(O)R4b, -S(O)2R4b, -S(O)2N(R4a)2, -N(R4a)S(O)2R4b, -C(R4a)=N(R4a), and -C(R4a)=N(OR4a), wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more R40, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R40*; R4* in each occurrence is independently selected from C1-6alkyl, carbocyclyl, heterocyclyl, -C(O)H, -C(0)R4b, -C(O)2R4c, -C(O)N(R4a)2, -S(O)R4b, -S(O)2R4b,
-S(O)2N(R4a)2, -C(R4a)=N(R4a), and -C(R4a)=N(OR4a), wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R40, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R40*; R4a in each occurrence is independently selected from H, C1-6alkyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R40*; R4b in each occurrence is selected from C1-6alkyl, C2-6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R40, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R40*; R4c in each occurrence is independently selected from C1-6alky 1, carbocyclyl, and heterocyclyl, wherein said C1-6alky L carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R40*; R10 in each occurrence is independently selected from halo, -CN, C1-6alkyl, C2-6alkenyl, C2_6alkynyl, carbocyclyl, heterocyclyl, -OR10a, -SR10a, -N(R10a)2, -N(R10a)C(O)R10b, -N(R10a)N(R10a)2, -NO2, -N(R10a)-OR10a, -O-N(R10a)2, -C(O)H, -C(O)R10b, -C(O)2R10a,
-C(O)N(R10a)2, -C(O)N(R10a)(OR10a), -OC(O)N(R10a)2, -N(R10a)C(O)2R10a, -N(R10a)C(O)N(R10a)2, -OC(O)R10b, -S(O)R10b, -S(O)2R10b, -S(O)2N(R10a)2, -N(R10a)S(O)2R10b, -C(R10a)=N(R10a), and -C(R10a)=N(OR10a), wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more Ra, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with Ra*; R10* in each occurrence is independently selected from C1-6alky 1, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R10b, -C(O)2R10c, -C(O)N(R10a)2, -S(O)R10b, -S(O)2R10b, -S(O)2N(R10a)2, -C(R10a)=N(R10a), and -C(R10a)=N(OR10a), wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more Ra, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with Ra ;
R10a in each occurrence is independently selected from H, C1-6alkyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more Ra, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with Ra*;
R1Ob in each occurrence is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said
Figure imgf000287_0001
C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more Ra, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with Ra*;
R1Oc in each occurrence is independently selected from C1-6alkyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more Ra, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with Ra*; R20 in each occurrence is independently selected from halo, -CN, C1-6alkyl, C2-6alkenyl,
C2-6alkynyl, carbocyclyl, heterocyclyl, -OR20a, -SR20a, -N(R20a)2, -N(R20a)C(O)R20b, -N(R20a)N(R20a)2, -NO2, -N(R20a)-OR20a, -O-N(R20a)2, -C(O)H, -C(O)R20b, -C(O)2R20a, -C(O)N(R20a)2, -C(O)N(R20a)(OR20a), -OC(O)N(R20a)2, -N(R20a)C(O)2R20a, -N(R20a)C(O)N(R20a)2, -OC(O)R20b, -S(O)R20b, -S(O)2R20b, -S(O)2N(R20a)2, -N(R20a)S(O)2R20b, -C(R20a)=N(R20a), and -C(R20a)=N(OR20a), wherein said C1-6alkyl,
C2_6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more Rb, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R ; R20* in each occurrence is independently selected from C1-6alky 1, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R20b, -C(O)2R20c, -C(O)N(R20a)2, -S(O)R20b, -S(O)2R20b,
-S(O)2N(R20a)2, -C(R20a)=N(R20a), and -C(R20a)=N(OR20a), wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more Rb, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with Rb*; R20a in each occurrence is independently selected from H, C1-6alkyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R b , and wherein any
-NH- moiety of said heterocyclyl is optionally substituted with Rb*;
R20b in each occurrence is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with Rb*;
R20c in each occurrence is independently selected from C1-6alkyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more Rb, and wherein any
-NH- moiety of said heterocyclyl is optionally substituted with Rb*; R30 in each occurrence is independently selected from halo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -OR30a, -SR30a, -N(R30a)2, -N(R30a)C(O)R30b, -N(R30a)N(R30a)2, -NO2, -N(R30a)-OR30a, -O-N(R30a)2, -C(O)H, -C(O)R30b, -C(O)2R30a, -C(O)N(R30a)2, -C(O)N(R30a)(OR30a), -OC(O)N(R30a)2, -N(R30a)C(O)2R30a,
-N(R30a)C(O)N(R30a)2, -OC(O)R30b, -S(O)R30b, -S(O)2R30b, -S(O)2N(R30a)2, -N(R30a)S(O)2R30b, -C(R30a)=N(R30a), and -C(R30a)=N(OR30a), wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more Rc, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R0*;
R30* in each occurrence is independently selected from C1-6alkyl, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R30b, -C(O)2R30c, -C(O)N(R30a)2, -S(O)R30b, -S(O)2R30b, -S(O)2N(R30a)2, -C(R30a)=N(R30a), and -C(R30a)=N(OR30a), wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more Rc, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R0*;
R30a in each occurrence is independently selected from H, C1-6alkyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more Rc, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R0*; R30b in each occurrence is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more Rc, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R0*; R30c in each occurrence is independently selected from C1-6alky 1, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more Rc, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with R0*; R40 in each occurrence is independently selected from halo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -OR40a, -SR40a, -N(R40a)2, -N(R40a)C(O)R40b,
-N(R40a)N(R40a)2, -NO2, -N(R40a)-OR40a, -O-N(R40a)2, -C(O)H, -C(O)R40b, -C(O)2R40a, -C(O)N(R40a)2, -C(O)N(R40a)(OR40a), -OC(O)N(R40a)2, -N(R40a)C(O)2R40a, -N(R40a)C(O)N(R40a)2, -OC(O)R40b, -S(O)R40b, -S(O)2R40b, -S(O)2N(R40a)2, -N(R40a)S(O)2R40b, -C(R40a)=N(R40a), and -C(R40a)=N(OR40a), wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more Rd, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with Rd*; R40* in each occurrence is independently selected from C1-6alkyl, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R40b, -C(O)2R40c, -C(O)N(R40a)2, -S(O)R40b, -S(O)2R40b, -S(O)2N(R40a)2, -C(R40a)=N(R40a), and -C(R40a)=N(OR40a), wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more Rd, and wherein any -NH- moiety of said heterocyclyl is optionally substituted with Rd*; R40a in each occurrence is independently selected from H, C1-6alkyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with Rd*; R40b in each occurrence is independently selected from d-βalkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R d , and wherein any -NH- moiety of said d* heterocyclyl is optionally substituted with R ; R40c in each occurrence is independently selected from C1-6alkyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R , and wherein any -NH- moiety of said heterocyclyl is optionally substituted with Rd*;
Ra, Rb, Rc, and Rd in each occurrence are independently selected from halo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, -ORm, -SRm, -N(Rm)2, -N(Rm)C(O)Rn, -N(Rm)N(Rm)2, -NO2, -N(Rm)-ORm, -O-N(Rm)2, -C(O)H, -C(O)R", -C(O)2R111, -C(O)N(Rm)2, -C(O)N(Rm)(ORm), -OC(O)N(Rm)2, -N(Rm)C(O)2Rm, -N(Rm)C(0)N(Rm)2, -OC(O)R", -S(O)R", -S(O)2R", -S(O)2N(Rm)2, -N(Rm)S(O)2R",
-C(Rm)=N(Rm), and -C(Rm)=N(0Rm);
Ra*, Rb*, Rc*, and Rd*in each occurrence are independently selected from C1-6alkyl, carbocyclyl, heterocyclyl, -C(O)H, -C(O)R", -C(O)2R0, -C(0)N(Rm)2, -S(O)R", -S(O)2R", -S(O)2N(Rm)2, -C(Rm)=N(Rm), and -C(Rm)=N(0Rm); Rm in each occurrence is independently selected from H, C1-6alkyl, carbocyclyl, and heterocyclyl;
R" in each occurrence is independently selected from C1-6alkyl, C2_6alkenyl, C2_6alkynyl, carbocyclyl, and heterocyclyl; and R0 in each occurrence is independently selected from C1-6alkyl, carbocyclyl, and heterocyclyl.
2. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein:
Ring A is 4- to 7-membered non-aromatic heterocyclyl, wherein said 4- to 7-membered non-aromatic heterocyclyl is optionally substituted on carbon with one or more R , and wherein any -NH- moiety of said 4- to 7-membered heterocyclyl is optionally substituted with R2*;
R2 in each occurrence is independently selected from halo, -CN, C1-6alkyl, -0R2a,
-N(R2a)2, -C(O)N(R2a)2, -N(R2a)C(O)R2b, and -N(R2a)C(O)2R2a, wherein said C1-6alkyl is optionally substituted with one or more R20; R2* is C1-6alkyl;
R2a in each occurrence is independently selected from H and C1-6alkyl;
R2b is C1-6alkyl;
R20 in each occurrence is independently selected from halo, -CN, 4- to 6-membered heterocyclyl, -OR20a, -N(R20a)2, -C(O)2R20a, -C(O)N(R20a)2, -N(R20a)C(O)2R20a, and
-N(R20a)S(O)2R20b;
R20a in each occurrence is independently selected from H and C1-6alkyl; and R20b is C1-6alkyl.
3. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in either one of claims 1 or 2, wherein:
Ring B is 6-membered heteroaryl, wherein said 6-membered heteroaryl is substituted on carbon with one or more R4; and R4 is halo.
4. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 3, wherein: X is selected from -O- and -NH-.
5. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 4, wherein:
R1 is selected from C1-6alkyl, 3- to 6-membered carbocyclyl, and 5- or 6-membered heterocyclyl, wherein said C1-6alkyl, 3- to 6-membered carbocyclyl, and 5- or 6- membered heterocyclyl are optionally substituted on carbon with one or more R10;
R in each occurrence is independently selected from halo, 3- to 6-membered carbocyclyl, 5- or 6-membered heterocyclyl, and -OR10a, wherein said 3- to 6-membered carbocyclyl and 5- or 6-membered heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more Ra ;
R10a is selected from C1-6alkyl and 3- to 6-membered carbocyclyl;
Ra in each occurrence is independently selected from halo and -ORm; and Rm is C1-6alkyl.
6. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 5, wherein:
R3 is selected from C1-6alkyl, wherein said C1-6alkyl is optionally substituted with one or more R30;
R30 in each occurrence is independently selected from halo, -CN, -OR30a, -C(O)N(R30a)2,
-S(O)2R30b, and -S(O)2N(R30a)2;
R30a in each occurrence is independently selected from H and C1-6alkyl; and
R30b is C1-6alkyl.
7. A compound of Formula (I):
Figure imgf000292_0001
Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from 3-(acetylamino)azetidin-1-yl, 3-(acetylamino)pyrrolidin-lyl,
3-(amionmethyl)piperidin-1-yl, 3-aminopiperidin-1-yl, 2-(azetidin- 1 -ylmethyl)morpholin-4-yl, 3 -cyanoazetidin- 1 -yl, 2-(cyanomethyl)morpholin-4-yl, 3-(cyanomethyl)morpholin-4-yl, 2-(cyanomethyl)piperidin- 1 -yl, 3 -cyanopiperidin- 1 -yl, 4-cyanopiperidin- 1 -yl, 2-[(diethylamino)methyl]morpholin-4-yl, 3,3-difluoroazetidin-1-y,
2-(difluoromethyl)morpholin-4-yl, 3-(difluoromethyl)morpholin-4-yl, 3,3-difluropiperidin-1-yl , 4,4-difluoropiperidin-1-yl, 3,3-difluoropyrrolidin-1-yl, 3-(dimethylamino)azetidin- 1 -yl, 3-[(dimethylamino)carbonyl]methylmorpholin-4-yl, 3-[(dimethylamino)carbonyl]morpholin-4-yl, 3-[(dimethylamino)methyl]piperidin-1-yl,
3-(dimethylamino)pyrrolidin-1-yl, 2,2-dimethylmorpholin-4-yl, 2,6-dimethylmorpholin-4-yl, 3 ,3-dimethylmorpholin-4-yl, 3- { [(ethoxycarbonyl)amino]methyl}morpholin-4-yl, 2-ethylmorpholin-4-yl, 3 -ethylmorpholin-4-yl, 3 -ethyoxypyrrolidin- 1 -yl, 3 -fluoroazetidin- 1 -yl, 3-fluropiperidin-1-yl, 4-fluoropiperidin-1-yl, 3-hydroxyazetidin-1-yl,
3-(2-hydroxyethyl)morpholin-4-yl, 2-(hydroxymethyl)azetidin-1-yl, 3-hydroxy-3-methylazetidin- 1 -yl, 2-(hydroxymethyl)morpholin-4-yl, 3-(hydroxymethyl)morpholin-4-yl, 3-hydroxy-3-methylpiperidin-1-yl, 4-hydroxy-4-methylpiperidin- 1 -yl, 2-(hydroxymethyl)piperidin- 1 -yl, 3-hydroxypiperidin-1-yl, 4-hydroxypiperidin-1-yl, 3-methoxyazetidin-1-yl,
3-[(methoxycarbonyl)methyl]morpholin-4-yl, 2-(methoxymethyl)morpholin-4-yl, 3 -(methoxymethyl)morpholin-4-yl, 3 -(methoxymethyl)piperidin- 1 -yl, 3-methoxypiperidin-1-yl, 4-methoxypiperidin-1-yl, 3-(methylamino)azetidin-1-yl, 3-[(methylamino)carbonyl]morpholin-4-yl, 3-(methylamino)pyrrolidin-1-yl, 2-methylmorpholin-4-yl, 3 -methylmorpholin-4-yl, 4-methyl-3 -oxopiperazin- 1 -yl,
3- { [(methylsulfonyl)amino]methyl}morpholin-4-yl, morpholin-4-yl, 4-methylpiperazin- 1 -yl, 1 ,4-oxazepan-4-yl, 3- { [(t-butoxycarbonyl)amino]methyl}piperidin- 1 -yl, and 3-[(?-butoxycarbonyl)amino]piperidin-1-yl; Ring B is selected from 3,5-difluoropyridin-2-yl, 5-fluoropyridin-2-yl, and
5 - fluoropyrimidin-2 -yl; X is selected from -O- and -NH-;
R1 is selected from 2-cyclohexylethyl, cyclopropyl, 2-(2,4-difluorophenyl)ethyl, 2-(2,6-difluorophenyl)ethyl, 2-(3,4-difluorophenyl)ethyl , 2-(3,5-difluorophenyl)ethyl, 2-(3,5-dimethoxyphenyl)ethyl, 4-fluorophenyl, 2-(3-fluorophenyl)ethyl,
2-(4-fluorophenyl)ethyl, 2-(1H-imidazol-2-yl)ethyl, 4-methoxyphenyl, methyl, 2-phenylethyl, phenyloxymethyl, 2-pyridin-4-ylethyl, and thiophen-2-yl; and R3 is selected from (aminocarbonyl)methyl, cyanomethyl, l,l-difluoro-2-hydroxyethyl, [(dimethylamino)carbonyl]methyl, (dimethylaminosulfonyl)methyl, ethoxymethyl, 1 -hydroxy ethyl, 2~hydroxyethyl, 1-methoxy ethyl, methoxymethyl, [(methylamino)carbonyl] methyl, and (methylsulfonyl)methyl.
8. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, for use as a medicament.
9. The use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, in the manufacture of a medicament for the treatment of cancer.
10. A method for treating cancer in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7.
11. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, for use in the treatment of cancer in a warm-blooded animal such as man.
12. A pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
13. A process for preparing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, wherein said process is selected from:
Process A - reacting a compound of Formula (A):
Figure imgf000295_0001
with a compound of Formula (B):
Figure imgf000295_0002
Process B - reacting a compound of Formula (C):
Figure imgf000295_0004
with a compound of Formula (D):
Figure imgf000295_0003
and thereafter if necessary: i) converting a compound of Formula (I) into another compound of Formula (I); ii) removing any protecting groups; and/or iii) forming a pharmaceutically acceptable salt.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2440053A1 (en) * 2009-06-09 2012-04-18 Abraxis BioScience, LLC Benzyl substituted triazine derivatives and their therapeutical applications
AU2010259002B2 (en) * 2009-06-08 2014-03-20 Nantbio, Inc. Triazine derivatives and their therapeutical applications
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WO2016113277A1 (en) 2015-01-16 2016-07-21 Bayer Cropscience Aktiengesellschaft Method for preparing 4-cyanopiperidine hydrochloride
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US9662327B2 (en) 2011-06-17 2017-05-30 Agios Pharmaceuticals, Inc Phenyl and pyridinyl substituted piperidines and piperazines as inhibitors of IDH1 mutants and their use in treating cancer
US9856279B2 (en) 2011-06-17 2018-01-02 Agios Pharmaceuticals, Inc. Therapeutically active compositions and their methods of use
US9968595B2 (en) 2014-03-14 2018-05-15 Agios Pharmaceuticals, Inc. Pharmaceutical compositions of therapeutically active compounds
US9982309B2 (en) 2009-10-21 2018-05-29 Agios Pharmaceuticals, Inc. Method for treating cell proliferation related disorders
US9980961B2 (en) 2011-05-03 2018-05-29 Agios Pharmaceuticals, Inc. Pyruvate kinase activators for use in therapy
US10029987B2 (en) 2009-06-29 2018-07-24 Agios Pharmaceuticals, Inc. Therapeutic compounds and compositions
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US10202339B2 (en) 2012-10-15 2019-02-12 Agios Pharmaceuticals, Inc. Therapeutic compounds and compositions
US10376510B2 (en) 2013-07-11 2019-08-13 Agios Pharmaceuticals, Inc. 2,4- or 4,6-diaminopyrimidine compounds as IDH2 mutants inhibitors for the treatment of cancer
WO2019245910A1 (en) * 2018-06-22 2019-12-26 Aduro Biotech, Inc. Triazine compounds and uses thereof
US10610125B2 (en) 2009-03-13 2020-04-07 Agios Pharmaceuticals, Inc. Methods and compositions for cell-proliferation-related disorders
US10653710B2 (en) 2015-10-15 2020-05-19 Agios Pharmaceuticals, Inc. Combination therapy for treating malignancies
US10689414B2 (en) 2013-07-25 2020-06-23 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
CN111454214A (en) * 2020-05-27 2020-07-28 龙曦宁（上海）医药科技有限公司 Synthetic method of 2-methoxy-1-pyrimidineethylamine hydrochloride
US10980788B2 (en) 2018-06-08 2021-04-20 Agios Pharmaceuticals, Inc. Therapy for treating malignancies
US11234976B2 (en) 2015-06-11 2022-02-01 Agios Pharmaceuticals, Inc. Methods of using pyruvate kinase activators
US11419859B2 (en) 2015-10-15 2022-08-23 Servier Pharmaceuticals Llc Combination therapy for treating malignancies
US11844758B2 (en) 2013-07-11 2023-12-19 Servier Pharmaceuticals Llc Therapeutically active compounds and their methods of use

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002022603A1 (en) * 2000-09-15 2002-03-21 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
US20030022885A1 (en) * 2000-12-21 2003-01-30 David Bebbington Pyrazole compounds useful as protein kinase inhibitors
US20040002496A1 (en) * 2002-03-15 2004-01-01 David Bebbington Compositions useful as inhibitors of protein kinases
WO2006123113A2 (en) * 2005-05-16 2006-11-23 Astrazeneca Ab Pyrazolylaminopyrimidine derivatives useful as tyrosine kinase inhibitors
WO2007049041A1 (en) * 2005-10-28 2007-05-03 Astrazeneca Ab 4- (3-aminopyrazole) pyrimidine derivatives for use as tyrosine kinase inhibitors in the treatment of cancer

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002022603A1 (en) * 2000-09-15 2002-03-21 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
US20030022885A1 (en) * 2000-12-21 2003-01-30 David Bebbington Pyrazole compounds useful as protein kinase inhibitors
US20050038023A1 (en) * 2000-12-21 2005-02-17 David Bebbington Pyrazole compounds useful as protein kinase inhibitors
US20040002496A1 (en) * 2002-03-15 2004-01-01 David Bebbington Compositions useful as inhibitors of protein kinases
WO2006123113A2 (en) * 2005-05-16 2006-11-23 Astrazeneca Ab Pyrazolylaminopyrimidine derivatives useful as tyrosine kinase inhibitors
WO2007049041A1 (en) * 2005-10-28 2007-05-03 Astrazeneca Ab 4- (3-aminopyrazole) pyrimidine derivatives for use as tyrosine kinase inhibitors in the treatment of cancer

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AU2010259002B2 (en) * 2009-06-08 2014-03-20 Nantbio, Inc. Triazine derivatives and their therapeutical applications
US9409903B2 (en) 2009-06-09 2016-08-09 Nantbioscience, Inc. Benzyl substituted triazine derivatives and their therapeutical applications
JP2012529517A (en) * 2009-06-09 2012-11-22 アブラクシス バイオサイエンス リミテッド ライアビリティー カンパニー Benzyl-substituted triazine derivatives and their therapeutic applications
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AU2010258964B2 (en) * 2009-06-09 2014-09-11 Nantbio, Inc. Benzyl substituted triazine derivatives and their therapeutical applications
US8877924B2 (en) 2009-06-09 2014-11-04 NantBio Inc. Benzyl substituted triazine derivatives and their therapeutical applications
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US10711314B2 (en) 2009-10-21 2020-07-14 Agios Pharmaceuticals, Inc. Methods for diagnosing IDH-mutant cell proliferation disorders
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JP2016523935A (en) * 2013-07-11 2016-08-12 アジオス ファーマシューティカルズ， インコーポレイテッド Therapeutically active compounds and methods of use thereof
US9579324B2 (en) 2013-07-11 2017-02-28 Agios Pharmaceuticals, Inc Therapeutically active compounds and their methods of use
US10017495B2 (en) 2013-07-11 2018-07-10 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US10689414B2 (en) 2013-07-25 2020-06-23 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US11021515B2 (en) 2013-07-25 2021-06-01 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US11504361B2 (en) 2014-03-14 2022-11-22 Servier Pharmaceuticals Llc Pharmaceutical compositions of therapeutically active compounds
US10449184B2 (en) 2014-03-14 2019-10-22 Agios Pharmaceuticals, Inc. Pharmaceutical compositions of therapeutically active compounds
US9968595B2 (en) 2014-03-14 2018-05-15 Agios Pharmaceuticals, Inc. Pharmaceutical compositions of therapeutically active compounds
US10799490B2 (en) 2014-03-14 2020-10-13 Agios Pharmaceuticals, Inc. Pharmaceutical compositions of therapeutically active compounds
WO2016113277A1 (en) 2015-01-16 2016-07-21 Bayer Cropscience Aktiengesellschaft Method for preparing 4-cyanopiperidine hydrochloride
US11234976B2 (en) 2015-06-11 2022-02-01 Agios Pharmaceuticals, Inc. Methods of using pyruvate kinase activators
US11419859B2 (en) 2015-10-15 2022-08-23 Servier Pharmaceuticals Llc Combination therapy for treating malignancies
US10653710B2 (en) 2015-10-15 2020-05-19 Agios Pharmaceuticals, Inc. Combination therapy for treating malignancies
US10980788B2 (en) 2018-06-08 2021-04-20 Agios Pharmaceuticals, Inc. Therapy for treating malignancies
WO2019245910A1 (en) * 2018-06-22 2019-12-26 Aduro Biotech, Inc. Triazine compounds and uses thereof
CN109020951A (en) * 2018-08-24 2018-12-18 大连理工大学 The naphthalimide analog derivative and its synthetic method that replace Cyanuric Chloride containing three and application
CN111454214B (en) * 2020-05-27 2023-04-07 龙曦宁（上海）医药科技有限公司 Synthetic method of 2-methoxy-1-pyrimidineethylamine hydrochloride
CN111454214A (en) * 2020-05-27 2020-07-28 龙曦宁（上海）医药科技有限公司 Synthetic method of 2-methoxy-1-pyrimidineethylamine hydrochloride

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