WO2016049211A1 - Aminotriazine derivatives useful as tank-binding kinase inhibitor compounds - Google Patents

Aminotriazine derivatives useful as tank-binding kinase inhibitor compounds Download PDF

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Publication number
WO2016049211A1
WO2016049211A1 PCT/US2015/051757 US2015051757W WO2016049211A1 WO 2016049211 A1 WO2016049211 A1 WO 2016049211A1 US 2015051757 W US2015051757 W US 2015051757W WO 2016049211 A1 WO2016049211 A1 WO 2016049211A1
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Prior art keywords
mmol
mixture
compound
triazin
alkyl
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PCT/US2015/051757
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French (fr)
Inventor
Zhimin Du
Juan A. GUERRERO
Joshua A. KAPLAN
John E. KNOX, Jr.
Jennifer R. LO
Scott A. Mitchell
Devan Naduthambi
Barton W. Phillips
Chandrasekar Venkataramani
Peiyuan Wang
William J. Watkins
Zhongdong Zhao
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Gilead Sciences, Inc.
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Priority to EP15775054.8A priority Critical patent/EP3197884B1/en
Priority to EA201790395A priority patent/EA201790395A1/en
Priority to MX2017003930A priority patent/MX2017003930A/en
Priority to ES15775054T priority patent/ES2727376T3/en
Priority to KR1020177010833A priority patent/KR101949624B1/en
Priority to CA2962578A priority patent/CA2962578C/en
Priority to SG11201701724VA priority patent/SG11201701724VA/en
Priority to JP2017516318A priority patent/JP6499282B2/en
Application filed by Gilead Sciences, Inc. filed Critical Gilead Sciences, Inc.
Priority to NZ729618A priority patent/NZ729618A/en
Priority to EP19160625.0A priority patent/EP3517536B1/en
Priority to AU2015320675A priority patent/AU2015320675B2/en
Priority to CN201580052292.6A priority patent/CN106715419A/en
Publication of WO2016049211A1 publication Critical patent/WO2016049211A1/en
Priority to IL250875A priority patent/IL250875A0/en

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    • C07—ORGANIC CHEMISTRY
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • 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
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
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    • 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
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
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    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • This application relates to chemical compounds which may inhibit or otherwise modulate the activity of TANK-binding kinase (TBK1 ) and l-Kappa-B kinase ( ⁇ , IKBKE), and to compositions and formulations containing such compounds, and methods of using and making such compounds.
  • TK1 TANK-binding kinase
  • ⁇ , IKBKE l-Kappa-B kinase
  • TBK1 is a serine/threonine kinase with diverse roles in cancer, inflammation, and the host-pathogen response. Shen, R. R. and W. C. Hahn (201 1 ) Oncogene 30(6): 631- 641. TBK1 activates its substrates IRF3 and IRF7 transcription factors by direct phosphorylation of specific sites that induces their localization to the nucleus to drive transcription of type I IFN genes (Sankar, S., H. Chan, et al., (2006) Cell Signal 18(7): 982-993).
  • NFkB activation can be bolstered by the kinase activity of TBK1 by phosphorylating the inhibitors of NFkB, which enables activation of the canonical or non-canonical NFkB transcription factors.
  • TBK1 has been implicated as being a key gene required for KRAS-dependent cancers, required for HER2+ breast cancers, and contributing to the acquisition of resistance to erlotinib.
  • Depletion of TBK1 by shRNA results in synthetic lethality with KRAS-dependent cancer cell lines and xenograft models (Barbie, D. A., P. Tamayo, et al. (2009) Nature 462(7269): 108-1 12) and TBK1 is required for RAS-mediated transformation of murine embryonic fibroblasts (Ou, Y. H., M. Torres, et al. (201 1 ) Mol Cell 41 (4): 458-470).
  • TBK1 is downstream of RAS and elicits its oncogenic properties via the RALB-NFkB and AKT pathways (Chien, Y., S. Kim, et al. (2006) Cell 127(1 ): 157-170). In addition, TBK1 directly phosphorylates AKT at S473 and results in the downstream activation of the mTORC1/2 pathway (Ou, Y. H., M. Torres, et al. (2011 ) Mol Cell 41 (4): 458-470).
  • TBK1 was also identified as being important for the survival of HER2+ breast cancer cell lines via an shRNA kinome screen and showed combination effects with the EGFR/HER2 kinase inhibitor, lapatinib (Deng, T., J. C. Liu, et al. (2014) Cancer Res 74(7): 21 19-2130). Additionally, integrin alphaVbeta3 was identified as a marker of cells that are resistant to EGFR therapies and have stem-like properties. The signaling cascade required for the survival of these cells was attributed to KRAS-TALB- TBK1-NFkB axis and inhibiting TBK1 was sufficient to block the survival of these cells. Seguin, L, S. Kato, et al. (2014), Nat Cell Biol 16(5): 457-468.
  • ⁇ is a serine/threonine kinase and its gene amplifications have been identified in up to 30% of breast cancers. Depleting ⁇ in cell lines with shRNA that have these amplifications results in their decreased viability (Boehm, J. S., J. J. Zhao, et al. (2007) Cell 129(6): 1065-1079). Overexpression of ⁇ in ovarian cancer has been demonstrated to mediate resistance to cisplatin and is a poor prognostic factor (Guo, J. P., S. K. Shu, et al. (2009) Am J Pathol 175(1 ): 324-333).
  • TBK1 and ⁇ are also both implicated in inflammatory responses and associated disorders.
  • ⁇ has been shown to be involved in manifestations of rheumatoid arthritis (RA) that include extracellular matrix destruction, synovial inflammation, and activation of the innate immune response (Sweeney, S. E., D.
  • inflammatory disorders that manifest as a result of Type I I FN response and upstream activation of TLR3/TLR4 or cytosolic nucleic acid sensors are likely to also rely on a ⁇ 1/ ⁇ signaling axis to initiate and maintain their pathogenic state such as Sjogrens syndrome, inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), systemic lupus erythematosus (SLE), dermatomyositis, polymyositis, systemic sclerosis.
  • IBD inflammatory bowel disease
  • COPD chronic obstructive pulmonary disease
  • SLE systemic lupus erythematosus
  • dermatomyositis polymyositis
  • systemic sclerosis Baccala, R., K. Hoebe, et al. (2007), Nat Med 13(5): 543-551.
  • ⁇ is implicated in obesity, type 2 diabetes, and insulin resistance. Mice deficient for ⁇ are protected from obesity induced by a high-fat diet, hepatic steatosis, insulin resistance, and chronic inflammation of the liver and fat. Chiang, S. H., M. Bazuine, et al. (2009) Cell 138(5): 961-975.
  • One embodiment provides a compound of formula (I):
  • A is C 6 -io aryl or 5-10 membered heteroaryl;
  • X 1 is CR 1 or N;
  • R 1 is selected from the group consisting of H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, -NR a R b , halogen, -CN, and -OR a ;
  • R 2 is selected from the group consisting of H, hydroxyl, Ci_ 6 alkyl, Ci_ 6 heteroalkyl, -NR a R b , halogen, -C(0)R a , -C(0)OR a , -C(0)NR a R b , -OC(0)NR a R b , - NR a C(0)R b , -NR a C(0)OR b , -S(O) 0 - 2 R c , -S(0) 2 NR a R b , -NR a S(0) 2 R b , C 6 _i 0 aryl, C 3 -io cycloalkyl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl
  • R 3 is selected from the group consisting of H, Ci_ 6 alkyl, Ci_ 6 heteroalkyl, -NR a R b , halogen, -C(0)R a , -C(0)OR a , -C(0)NR a R b , -OC(0)NR a R b , -NR a C(0)R b , -
  • R 5 is H; or Ci -6 alkyl, Ci -6 haloalkyl, C 6- io aryl, 5-10 membered heteroaryl, C 3- io cycloalkyi, or 3-12 membered heterocyclyl, each of which is optionally substituted with from one to five R 20 groups; n is 0-2; each R 20 is
  • Another embodiment provides a compound having the following formula (la):
  • Another embodiment provides a compound having the following formula (lb):
  • Another embodiment provides a compound having the following formula (Ic):
  • X 1 is CR 1 . In another embodiment, X 1 is N. In another embodiment, X 2 is CR 4 . In another embodiment, X 2 is N.
  • A is a 5-6 membered heteroaryl. In another embodiment, A is phenyl.
  • R 3 comprises a piperazinyl group.
  • piperazinyl group is substituted with an oxetanyl group.
  • R 3 is:
  • n 0-2;
  • R 20 is H, Ci_6 alkyl, Ci -6 heteroalkyl and Ci -6 hydroxyalkyl.
  • R 3 is:
  • n 0-2;
  • R 20' is H, CN, oxo, CONR ax R x , Ci-e alkyl, d-e heteroalkyi and d-e hydroxyalkyl; wherein R ax and R bx are independently H; or Ci -6 alkyl, C 2 alkenyl, C3-10 cycloalkyl, Ci_ 6 heteroalkyi, 3-12 membered heterocyclyl, C 6- io aryl, 5-10 membered heteroaryl, each of which is optionally substituted with from one to five groups selected from Ci -6 alkyl, C3-10 cycloalkyl, d-e heteroalkyi, 3-12 membered heterocyclyl, C 6 -Ci 0 aryl, 5-10 membered heteroaryl, hydroxyl, d-e alkoxy, amino, -CN, -C(0)H, -C(0)NH 2 , -C(0)NH(d-e alkyl), - C(0)N(d_ 6 al
  • n 0.
  • R 3 is not H.
  • R 4 is H.
  • R 1 is H.
  • R 2 is -NR a R b .
  • R a and R b on R 5 join together with the atoms to which they are attached form a 3-12 membered heterocyclyl which is optionally substituted with one to three of halo, hydroxyl, oxo, Ci_ 6 alkyl, Ci_ 6 alkoxy, Ci_ 6 haloalkyl, Ci_ 6 haloalkoxy, CN, amino, or Ci_ 6 alkylamino.
  • R 2 is -O-R 5 .
  • R 5 is selected from the group consisting of tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, oxetanylmethyl, 1-(oxetan-3-yl)pyrrolidinyl, oxo-propanylnitrile-pyrrolinyl and piperidinyl.
  • R 5 is unsubstituted tetrahydropyranyl.
  • R 2 is N- pyrrolidinyloxy or N-piperidinyloxy substituted with Ci_ 6 alkoxycarbonyl, hydroxyl Ci_ 6 alkylcarbonyl, hydroxyl 3-6 membered heterocyclyl, halo 3-6 membered heterocyclyl, Ci_ 6 alkoxycarbonyl, cyano Ci -6 alkylcabonyl or C 3 -e cycloalkyl-Ci_ 6 alkoxy.
  • R 5 is substituted with one R 20 group selected from Ci_ 6 alkoxycarbonyl, hydroxyl Ci -6 alkylcarbonyl, Ci_ 6 alkoxycarbonyl, cyano Ci_ 6 alkylcabonyl or C 3 -e
  • R 5 group is substituted with one or two fluoro groups. More particularly, the fluoro groups are substituted at the ortho position with respect to the point of attachment of the R 5 group.
  • R is:
  • X a is a bond or C(R x )(R y ), wherein R x and R y are independently selected from the group consisting of H, halo or methyl;
  • X b and X c are independently selected from the group consisting of H, halo or methyl;
  • X d is selected from the group consisting of H; or Ci- 6 alkyl, C 2 . 6 alkenyl, C3-10
  • Ci -6 heteroalkyl Ci -6 heteroalkyl, 3-12 membered heterocyclyl, C 6- io aryl, 5-10 membered heteroaryl, each of which is optionally substituted with from one to five groups selected from Ci -6 alkyl, C3-10 cycloalkyl, d-e heteroalkyl, 3-12 membered heterocyclyl, C 6 -Ci 0 aryl, 5-10 membered heteroaryl, hydroxyl, Ci -6 alkoxy, amino, -CN, -C(0)H, -C(0)NH 2 , -C(0)NH(Ci_ 6 alkyl), -C(0)N(Ci_ 6 alkyl) 2 , -COOH, -C(0)Ci-6 alkyl, -C(0)OCi -6 alkyl, or halogen.
  • X d is Ci_ 6 alkyl substituted with hydroxyl.
  • X a is CH 2 .
  • X b is fluoro.
  • X c is H.
  • R 2 is selected from the roup consisting of:
  • Another embodiment provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Another embodiment provides a method of treating a subject having a disease or condition responsive to the inhibition of TBK1 , comprising administering to the subject a therapeutically effective amount of a compound as described herein, or a
  • the disease is cancer.
  • Another embodiment provides a method of treating a subject having a disease or condition responsive to the inhibition of ⁇ , comprising administering to the subject a therapeutically effective amount of a compound as described herein, or a
  • Another embodiment provides a method of treating a subject suffering from a RAS- dependent/mutant cancer, comprising administering to the subject a therapeutically effective amount of a compound as described herein.
  • the RAS-dependent/mutant cancer is selected from the group consisting of non-small cell lung cancer, colorectal cancer, pancreatic cancer, AML, and melanoma.
  • Another embodiment provides a method of treating a subject suffering from breast or ovarian cancer, comprising administering to the subject a therapeutically effective amount of a compound as described herein.
  • Another embodiment provides a method of treating a subject suffering from cancer resistant to HER2 and EGFR targeted therapies comprising administering to the subject a therapeutically effective amount of a compound as described herein.
  • Another embodiment provides a method of treating a subject suffering from a disease selected from the group consisting of Rheumatoid arthritis (RA), Inflammatory bowel disease (IBD), Chronic obstructive pulmonary disease (COPD), Systemic lupus erythematosus (SLE), Polymositis, Systemic sclerosis, Type 2 diabetes, Obesity and Hepatic steatosis.
  • RA Rheumatoid arthritis
  • IBD Inflammatory bowel disease
  • COPD Chronic obstructive pulmonary disease
  • SLE Systemic lupus erythematosus
  • Polymositis Systemic sclerosis
  • Type 2 diabetes Obesity
  • Obesity Hepatic steatosis
  • Another embodiment provides a method of inhibiting TBK1 in a subject, comprising administering a compound of a compound described herein, or a
  • Another embodiment provides a method of inhibiting ⁇ in a subject, comprising administering a compound as described herein, or a pharmaceutically acceptable salt thereof.
  • the compound is selective against JAK2 or does not substantially inhibit JAK2.
  • Another embodiment provides a compound as described herein, or a
  • Another embodiment provides a compound as described herein, or a
  • the disease is cancer.
  • Another embodiment provides a compound as described herein, or a pharmaceutically acceptable salt thereof for use in a method of treating a subject having a disease or condition responsive to the inhibition of ⁇ .
  • Another embodiment provides a compound as described herein, or a
  • the RAS-dependent/mutant cancer is selected from the group consisting of non-small cell lung cancer, colorectal cancer, pancreatic cancer, AML, and melanoma.
  • Another embodiment provides a compound as described herein, or a
  • Another embodiment provides a compound as described herein, or a pharmaceutically acceptable salt thereof, for use in a method of treating a subject suffering from cancer resistant to HER2 and EGFR targeted therapies.
  • Another embodiment provides a compound as described herein, or a
  • RA Rheumatoid arthritis
  • IBD Inflammatory bowel disease
  • COPD Chronic obstructive pulmonary disease
  • SLE Systemic lupus erythematosus
  • Polymositis Systemic sclerosis
  • Type 2 diabetes Obesity and Hepatic steatosis.
  • Another embodiment provides a compound as described herein, or a
  • Another embodiment provides a compound as described herein, or a
  • Another embodiment provides a compound as described herein, or a pharmaceutically acceptable salt thereof, for use in a method of inhibiting TBK1 in a subject.
  • Another embodiment provides a compound as described herein, or a pharmaceutically acceptable salt thereof, for use in a method of inhibiting ⁇ in a subject.
  • Another embodiment provides the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a subject having a disease or condition responsive to the inhibition of TBK1 .
  • the disease is cancer.
  • Another embodiment the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a subject having a disease or condition responsive to the inhibition of ⁇ .
  • Another embodiment provides the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a subject suffering from a RAS-dependent/mutant cancer.
  • the RAS-dependent/mutant cancer is selected from the group consisting of non-small cell lung cancer, colorectal cancer, pancreatic cancer, AML, and melanoma.
  • Another embodiment provides the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a subject suffering from breast or ovarian cancer.
  • Another embodiment provides the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a subject suffering from cancer resistant to HER2 and EGFR targeted therapies.
  • Another embodiment provides the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a subject suffering from a disease selected from the group consisting of Rheumatoid arthritis (RA), Inflammatory bowel disease (IBD), Chronic obstructive pulmonary disease (COPD), Systemic lupus erythematosus (SLE), Polymositis, Systemic sclerosis, Type 2 diabetes, Obesity and Hepatic steatosis.
  • RA Rheumatoid arthritis
  • IBD Inflammatory bowel disease
  • COPD Chronic obstructive pulmonary disease
  • SLE Systemic lupus erythematosus
  • Polymositis Polymositis
  • Systemic sclerosis Type 2 diabetes
  • Obesity Obesity
  • Hepatic steatosis Hepatic steatosis
  • Another embodiment provides the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting TBK1 in a subject.
  • Another embodiment provides the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting ⁇ in a subject.
  • Another embodiment provides further administering to the subject an additional therapeutic agent, a list of which is provided in the following Detailed Description.
  • PEPPSITM -IPr [l,3-Bis(2,6-Diisopropylphenyl)imidazol-2-ylidene](3- chloropyridyl)palladium(ll) dichloride
  • a wavy line drawn through a line in a structure indicates a point of attachment of a group, e.g. :
  • a dashed line indicates an optional bond.
  • a dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning.
  • C x . y indicates that the following group has from x (e.g. 1 ) to y (e.g. 6) carbon atoms, one or more of which, in certain groups (e.g. heteroalkyl, heteroaryl, heteroarylalkyl, etc.), may be replaced with one or more heteroatoms or heteroatomic groups.
  • x-y membered rings, wherein x and y are numerical ranges, such as “3-12 membered heterocyclyl” refers to a ring containing x-y atoms (e.g. 3-12), of which up to half may be heteroatoms, such as N, O, S, P, and the remaining atoms are carbon.
  • a divalent group such as a divalent "alkyl” group, a divalent “aryl” group, etc., may also be referred to as an "alkylene” group or an “alkylenyl” group, or alkylyl group, an "arylene” group or an “arylenyl” group, or arylyl group, respectively.
  • Alkyl refers to any group derived from a linear or branched saturated
  • Alkyl groups include, but are not limited to, methyl, ethyl, propyl such as propan-1-yl, propan-2-yl (iso-propyl), butyls such as butan-1-yl, butan-2-yl (sec-butyl), 2- methyl-propan-1-yl (iso-butyl), 2-methyl-propan-2-yl (t-butyl), pentyls, hexyls, octyls, dectyls, and the like.
  • an alkyl group has from 1 to 10 carbon atoms, for example from 1 to 6 carbon atoms, for example from 1 to 4 carbon atoms.
  • Alkenyl refers to any group derived from a straight or branched hydrocarbon with at least one carbon-carbon double bond. Alkenyl groups include, but are not limited to, ethenyl (vinyl), propenyl (allyl), 1-butenyl, 1 ,3-butadienyl, and the like. Unless otherwise specified, an alkenyl group has from 2 to 10 carbon atoms, for example from 2 to 6 carbon atoms, for example from 2 to 4 carbon atoms.
  • Alkynyl refers to any group derived from a straight or branched hydrocarbon with at least one carbon-carbon triple bond and includes those groups having one triple bond and one double bond.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), (E)-pent-3-en-1-ynyl, and the like.
  • an alkynyl group has from 2 to 10 carbon atoms, for example from 2 to 6 carbon atoms, for example from 2 to 4 carbon atoms.
  • Amino refers to -NH 2 .
  • Amino groups may also be substituted as described herein, such as with alkyl, carbonyl or other amino groups.
  • alkylamino refers to an amino group substituted with one or two alkyl substituents (e.g. dimethylamino or propylamino).
  • Aryl refers to any group derived from one or more aromatic rings, that is, a single aromatic ring, a bicyclic or a multicyclic ring system.
  • Aryl groups include, but are not limited to, those groups derived from acenaphthylene, anthracene, azulene, benzene, chrysene, a cyclopentadienyl anion, naphthalene, fluoranthene, fluorene, indane, perylene, phenalene, phenanthrene, pyrene and the like.
  • “Arylalkyl” also “aralkyl” refers to any combination aryl group and an alkyl group.
  • Arylalkyl groups include, but are not limited to, those groups derived from benzyl, tolyl, dimethylphenyl, 2-phenylethan-1-yl, 2-naphthylmethyl, and the like.
  • An arylalkyl group comprises from 6 to 30 carbon atoms, for example the alkyl group can comprise from 1 to 10 carbon atoms and the aryl group can comprise from 5 to 20 carbon atoms.
  • Bridged refers to a ring fusion wherein non-adjacent atoms on a ring are joined by a divalent substituent, such as an alkylenyl or heteroalkylenyl group or a single heteroatom.
  • Quinuclidinyl and admantanyl are examples of bridged ring systems.
  • Cycloalkyl refers to a cyclic alkyl and alkenyl groups.
  • a cycloalkyl group can have one or more cyclic rings and includes fused and bridged groups that are fully saturated or partially unsaturated. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, methylcycloproyl (cyclopropylmethyl), ethylcyclopropyl, cyclohexenyl and the like. Another example includes C 5 . 7 cycloakenyl.
  • Halo and halogen refer to fluoro, chloro, bromo and iodo.
  • Haloalkyl refers to an alkyl wherein one or more hydrogen atoms are each replaced by a halogen. Examples include, but are not limited to, -CH 2 CI, -CH 2 F, - CH 2 Br, -CFCIBr, -CH 2 CH 2 CI, -CH 2 CH 2 F, -CF 3 , -CH 2 CF 3 , -CH 2 CCI 3 , and the like, as well as alkyl groups such as perfluoroalkyi in which all hydrogen atoms are replaced by fluorine atoms.
  • Hydroalkyl refers to an alkyl wherein one or more hydrogen atoms are each replaced by a hydroxyl group. Examples include, but are not limited to, -CH 2 OH, - CH 2 CH 2 OH, -C(CH 3 ) 2 OH, and the like.
  • Halo 3-6 membered heterocyclyl refers to a heterocyclyl group substituted at a carbon atom with at least one halogen atom, and may include multiple halogen atoms, such as 3,3-difluoroazetidinyl.
  • Heteroalkyl refers to an alkyl in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatom or heteroatomic group. Heteroatoms include, but are not limited to, N, P, O, S, etc.
  • Heteroatomic groups include, but are not limited to, -NR-, -0-, -S-, -PH-, -P(0) 2 -, -S(O)-, -S(0) 2 -, and the like, where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or cycloheteroalkyl.
  • Heteroalkyl groups include, but are not limited to, -OCH 3 , -CH 2 OCH 3 , -SCH 3 , -CH 2 SCH 3 , -IMRCH 3 , -CH 2 NRCH 3 , -CH 2 OH and the like, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted.
  • a heteroalkyl group comprises from 1 to 10 carbon and up to three hetero atoms, e.g., from 1 to 6 carbon and from 1 to 2 hetero atoms.
  • Heteroaryl refers to mono or multicyclic aryl group in which one or more of the aromatic carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatom or heteroatomic group, as defined above. Multicyclic ring systems are included in heteroaryl and may be attached at the ring with the heteroatom or the aryl ring.
  • Heteroaryl groups include, but are not limited to, groups derived from acridine, benzoimidazole, benzothiophene, benzofuran, benzoxazole, benzothiazole, carbazole, carboline, cinnoline, furan, imidazole, imidazopyridine, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline
  • Heterocycle refers to a saturated or partially unsaturated non-aromatic ring or a partially non-aromatic multiple-ring system with at least one heteroatom or heteroatomic group, as defined above.
  • Heterocycles include, but are not limited to, groups derived from azetidine, aziridine, imidazolidine, morpholine, thiomorpholine, tetrahydro-2H-thiopyran, 1-iminotetrahydro-2H-thiopyran 1- oxide, oxirane (epoxide), oxetane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, N-bromopyrrolidine, N-chloropiperidine, and the like.
  • Heterocyclyl groups also include partially unsaturated ring systems containing one or more double bonds, including fused ring systems with one aromatic ring and one non- aromatic ring, but not fully aromatic ring systems.
  • Examples include dihydroquinolines, e.g. 3,4-dihydroquinoline, dihydroisoquinolines, e.g. 1 ,2-dihydroisoquinoline, dihydroimidazole, tetrahydroimidazole, etc., indoline, isoindoline, isoindolones (e.g.
  • Heterocycle groups may have 3-12 members, or 3-10 members, or 3-7 members, or 5-6 members.
  • “Hydroxyl” and “hydroxy” are used interchangeably and refer to -OH.
  • Spiro refers to a ring substituent which is joined by two bonds at the same carbon atom.
  • Examples of spiro groups include 1 ,1-diethylcyclopentane, dimethyl- dioxolane, and 4-benzyl-4-methylpiperidine, wherein the cyclopentane and piperidine, respectively, are the spiro substituents.
  • pharmaceutically acceptable refers to that substance which is generally regarded as safe and suitable for use without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio.
  • the compounds described herein include isomers, stereoisomers and the like.
  • isomers refers to different compounds that have the same molecular formula but differ in arrangement and configuration of the atoms.
  • an optical isomer or “a stereoisomer” refers to any of the various stereo isomeric configurations which may exist for a given compound of the present invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom. Therefore, the invention includes enantiomers, diastereomers or racemates of the compound.
  • fused refers to a ring which is bound to an adjacent ring.
  • Enantiomers are a pair of stereoisomers that are non-superimposable mirror images of each other.
  • a 1 :1 mixture of a pair of enantiomers is a "racemic" mixture.
  • para refers to attachment of a substituent at the 4-position with respect to the point of attachment of the ring and “meta” refers to attachment of a substituent at the 3-position with respect to the point of attachment of the ring.
  • Diastereoisomers are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
  • the absolute stereochemistry is specified according to the Cahn- Ingold- Prelog R-S system.
  • the stereochemistry at each chiral carbon may be specified by either R or S.
  • Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
  • Certain of the compounds described herein contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound that is pharmaceutically acceptable and that possesses (or can be converted to a form that possesses) the desired pharmacological activity of the parent compound.
  • Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, lactic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, 2- napththalenesulfonic acid, oleic acid, palmitic acid, propionic acid, stearic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, tri
  • ammonium and substituted or quaternized ammonium salts are also included in this definition.
  • Representative non-limiting lists of pharmaceutically acceptable salts can be found in S.M. Berge et al., J. Pharma Sci., 66(1 ), 1-19 (1977), and Remington: The Science and Practice of Pharmacy, R.
  • Subject and “subjects” refers to humans, domestic animals (e.g., dogs and cats), farm animals (e.g., cattle, horses, sheep, goats and pigs), laboratory animals (e.g., mice, rats, hamsters, guinea pigs, pigs, pocket pets, rabbits, dogs, and monkeys), and the like.
  • domestic animals e.g., dogs and cats
  • farm animals e.g., cattle, horses, sheep, goats and pigs
  • laboratory animals e.g., mice, rats, hamsters, guinea pigs, pigs, pocket pets, rabbits, dogs, and monkeys
  • Treating” and “treatment” of a disease include the following:
  • Effective amount refers to an amount that may be effective to elicit the desired biological, clinical, or medical response, including the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment.
  • the effective amount will vary depending on the compound, the disease and its severity and the age, weight, etc., of the subject to be treated.
  • the effective amount can include a range of amounts.
  • Reference to a compound that is "selective" against an enzyme, such as JAK2, indicates relative activity versus a target ezyme, such as TBK1 or ⁇ .
  • the compounds of the invention include solvates, hydrates, tautomers, stereoisomers and salt forms thereof.
  • n hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom, or tritiated with a tritium atom, in which n is the number of hydrogen atoms in the molecule.
  • the deuterium atom is a non-radioactive isotope of the hydrogen atom and tritium is a radioactive isotope.
  • Such compounds, particularly deuterated compounds may increase resistance to metabolism, and thus may be useful for increasing the half-life of the compounds when administered to a mammal. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol.
  • compositions of compounds of Formual (I) may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, for example as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.
  • the compounds described herein may be administered orally. Oral administration may be via, for example, capsule or enteric coated tablets.
  • Oral administration may be via, for example, capsule or enteric coated tablets.
  • the pharmaceutical compositions that include at least one compound of Formula (I), or a pharmaceutically acceptable salt is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it can be in the form of a solid, semisolid, or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy- benzoates; sweetening agents; and flavoring agents.
  • compositions that include at least one compound of Formula (I), or a pharmaceutically acceptable salt can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
  • Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345.
  • Another formulation for use in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos.
  • Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • compositions may, in some embodiments, be formulated in a unit dosage form.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule).
  • the compounds are generally administered in a pharmaceutically effective amount.
  • each dosage unit contains from about 10 mg to about 1000 mg of a compound described herein, for example from about 50 mg to about 500 mg, for example about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, or about 300 mg.
  • each dosage unit contains from 0.1 to 700 mg of a compound a compound described herein. It will be understood, however, that the amount of the compound actually administered usually will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual subject, and the severity of the subject's symptoms.
  • dosage levels may be from 0.1 mg to 100 mg per kilogram of body weight per day, for example from about 1 mg to about 50 mg per kilogram, for example from about 5 mg to about 30 mg per kilogram. Such dosage levels may, in certain instances, be useful in the treatment of the above-indicated conditions.
  • dosage levels may be from about 10 mg to about 2000 mg per subject per day.
  • the amount of active ingredient that may be combined with the vehicle to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms may contain from 1 mg to 500 mg of an active ingredient.
  • Frequency of dosage may also vary depending on the compound used and the particular disease or condition treated. In some embodiments, for example, for the treatment of an autoimmune and/or inflammatory disease, a dosage regimen of 4 times daily or less is used. In some embodiments, a dosage regimen of 1 or 2 or 3 times daily is used. It will be understood, however, that the specific dose level for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy.
  • the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid p reformulation composition containing a homogeneous mixture of a compound of Formula (I), or a pharmaceutically acceptable salt, thereof.
  • a pharmaceutical excipient When referring to these preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • the tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • Kits that include a compound of Formula (I), or a pharmaceutically acceptable salt, thereof, and suitable packaging are provided.
  • a kit further includes instructions for use.
  • a kit includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and instructions for use of the compounds in the treatment of the diseases or conditions described herein.
  • Articles of manufacture that include a compound of Formula (I), or a
  • the container may be a vial, jar, ampoule, preloaded syringe, and intravenous bag.
  • Compounds of Formula (I) may be combined with one or more additional therapeutic agents.
  • the present application provides methods, compositions, kits and articles of manufacture thereof that use or include one or more therapeutic agents inhibiting one or more targets that relate to, directly or indirectly, to cell growth, proliferation, or apoptosis for treating hyperproliferative disorders such as cancers or myeloproliferative neoplasms.
  • the one or more therapeutic agents are compounds or molecules that is an Abl inhibitor, an ACK inhibitor, an A2B inhibitor, an ASK inhibitor, an Auroa kinase inhibitor, a BTK inhibitor, a BRD inhibitor, a c-Kit inhibitor, a c-Met inhibitor, a CAK inhibitor, a CaMK inhibitor, a CDK inhibitor, a CK inhibitor, a DDR inhibitor, an EGFR inhibitor, a FAK inhibitor, a Flt-3 inhibitor, a FYN inhibitor, a GSK inhibitor, a HCK inhibitor, a HDAC inhibitor, an IKK inhibitor, an IDH inhibitor, an IKK inhibitor, a JAK inhibitor, a KDR inhibitor, a LCK hibitor, a LOX inhibitor, a LOXL inhibitor, a LYN inhibitor, a MMP inhibitor, a MEK inhibitor, a MAPK inhibitor, a NEK9 inhibitor, a NPM-ALK inhibitor, a p38 kinase inhibitor,
  • the therapeutic agents are compounds or molecules that target a PI3 kinase (PI3K), a spleen tyrosine kinase (SYK), a Janus kinase (JAK), a Bruton's tyrosine kinase (BTK), or any combination thereof, resulting in the inhibition of one or more targets.
  • PI3K PI3 kinase
  • SYK spleen tyrosine kinase
  • JAK Janus kinase
  • BTK Bruton's tyrosine kinase
  • the therapeutic agent is a PI3K5 inhibitor that selectively inhibits PI3K p1 10 delta isoform (PI3K5).
  • the therapeutic agents are a PI3K5 inhibitor and a JAK1/2 inhibitor.
  • the JAK inhibitor binds and inhibits one or more members of JAK family, including JAK1 , JAK2, and/or JAK3.
  • the JAK inhibitor is Compound A having the structure:
  • Compound A may be referred to by its compound name: N-(cyanomethyl)-4-[2- (4-morpholinoanilino)pyrimidin-4-yl]benzamide using ChemDraw.
  • Compound A also referred to as CYT0387 or momelotinib, is a selective inhibitor to JAK2 and JAK1 , relative to JAK3.
  • Methods for synthesizing compounds of formula I and Compound A are previously described in U.S. Patent No. 8,486,941. This reference is hereby incorporated herein by reference in its entirety.
  • Additional JAK inhibitors include, but are not limited to, ruxolitinib (INCB018424), fedratinib (SAR302503, TG101348), tofacitinib, baricitinib, lestaurtinib, pacritinib (SB1518), XL019, AZD1480, INCB0391 10, LY2784544, BMS91 1543, and NS018.
  • the PI3K inhibitors inhibit one or more isoforms of Class I PI3K, including ⁇ 3 ⁇ , ⁇ 3 ⁇ , ⁇ 3 ⁇ , ⁇ 3 ⁇ , or any combination thereof.
  • the PI3K5 inhibitor is Compound B having the structure:
  • Compound B is predominantly the S-enantiomer, having the structure:
  • the (S)-enantiomer of Compound B may also be referred to by its compound name: (S)-2-(1-((9H-purin-6-yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one using ChemDraw.
  • the PI3K5 inhibitor is Compound C having the structure:
  • Compound C is predominantly the S-enantiomer, having the structure:
  • the (S)-enantiomer of Compound C may also be referred to by its compound name: (S)-2-(1-((9H-purin-6-yl)amino)ethyl)-6-fluoro-3-phenylquinazolin-4(3H)-one using ChemDraw.
  • the PI3K inhibitor is Compound D, having the structure:
  • Compound D is predominantly the S-enantiomer, having the structure:
  • the (S)-enantiomer of Compound D may also be referred to by its compound name: (S)-2-(1-((9H-purin-6-yl)amino)ethyl)-3-(2,6-difluorophenyl)quinazolin-4(3H)-one using ChemDraw.
  • the PI3K inhibitor is Compound E which is named by its compound name: (S)-4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin- 2-yl)ethyl)amino)pyrimidine-5-carbonitrile using ChemDraw.
  • the PI3K inhibitor includes the compounds described in U.S. Provisional Application Nos. 61/543,176; 61/581 ,528; 61/745,429; 61/745,437; and 61/835,333. The references are hereby incorporated herein by reference in their entirety.
  • Compounds B, C, D, and E are ⁇ 3 ⁇ inhibitors, selectively inhibiting PI3K p1 105 compared to other PI3K isoforms.
  • Methods for synthesizing the compounds of formula II, Compounds B, C, D, and E are previously described in U.S. Patent No. 7,932,260 or U.S. Provisional Application No. 61/581 ,528. The references are hereby incorporated herein by reference in their entirety.
  • Additional PI3K inhibitors include but are not limited to XL147, BKM120, GDC- 0941 , BAY80-6946, PX-866, CH5132799, XL756, BEZ235, and GDC-0980, wortmannin, LY294002, PI3K II, TGR-1202, AMG-319, GSK2269557, X-339, X-414, RP5090, KAR4141 , XL499, OXY1 1 1A, IPI-145, IPI-443, GSK2636771 , BAY 10824391 , buparlisib, BYL719, RG7604, MLN1 1 17, WX-037, AEZS-129, PA799, AS252424, TGX221 , TG1001 15, IC871 14, and ZSTK474.
  • the SYK inhibitor includes but is not limited to 6-(1 H-indazol-6-yl)-N-(4- morpholinophenyl)imidazo[1 ,2-a]pyrazin-8-amine, R406 (tamatinib), R788
  • the Syk inhibitor is 6-(1 H- indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1 ,2-a]pyrazin-8-amine as described in U.S. Patent No. 8,450,321.
  • compounds of Formula (I) may be combined with one or more therapeutic agents, which are ID01 inhibitors.
  • the ID01 inhibitor is INCB24360 having the structure:
  • the ID01 inhibitor is NLG-919 having the following
  • the ID01 inhibitor is indoximod having the following structure:
  • Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with a one or more additional therapeutic agents, for example one or more additional therapeutic agents from the above list of additional therapeutic agents, for use in: therapy; a method of treating a subject having a disease or condition responsive to the inhibition of TBK1 , such as cancer; a method of treating a subject having a disease or condition responsive to the inhibition of ⁇ ; a method of treating a subject suffering from a RAS-dependent/mutant cancer, such as non-small cell lung cancer, colorectal cancer, pancreatic cancer, AML, and melanoma; a method of treating a subject suffering from breast or ovarian cancer; a method of treating a subject suffering from cancer resistant to HER2 and EGFR targeted therapies; a method of treating a subject suffering from a disease selected from the group consisting of Rheumatoid arthritis (RA), Inflammatory bowel disease (IBD), Chronic obstructive pulmonary disease (COPD), Systemic
  • Another embodiment provides the use of a compound of formula (I), or a
  • a subject having a disease or condition responsive to the inhibition of TBK1 such as cancer
  • treating a subject having a disease or condition responsive to the inhibition of ⁇ treating a subject suffering from a RAS-dependent/mutant cancer, such as non-small cell lung cancer, colorectal cancer, pancreatic cancer, AML, and melanoma
  • treating a subject suffering from breast or ovarian cancer treating a subject suffering from cancer resistant to HER2 and EGFR targeted therapies
  • the above combinations comprise one additional therapeutic agent, for example one additional therapeutic agent selected from the additional therapeutic agents listed above.
  • Another embodiment of the invention provides a product comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional therpauetic agents, such as one or more of the additional therapeutic agents listed above, as a combined preparation for simultaneous, separate or sequential use in therapy. Synthesis of certain compounds, and intermediates used to prepare compounds, are detailed in the following sections. Example numbers are listed for convenience.
  • NMR Nuclear magnetic resonance
  • Scheme 1 shows a general synthesis of compounds of the invention beginning with the displacement of the one chloro from 2,4-Dichloro-1 ,3,5-triazine with anilines either at rt or at elevated temperature in the presence of an inert solvent such as DMF, DME or acetonitrile or mixture of such solvents in the presence or absence of a base such as DIPEA, or TEA to yield intermediate 1 -1 which undergoes metal catalyzed cross coupling reactions (e.g. Suzuki) of A 1 groups to yield final compounds of the type 1 -2.
  • a 1 is preferably:
  • Scheme 2 shows a general synthesis of compounds of the invention beginning with the Metal catalyzed cross coupling reactions (ex: Suzuki, Negishi) to yield intermediate 2-1 which undergoes displacement of the chloro from 2-1 with anilines as in general scheme 1 (at rt or at elevated temperature in the presence of an inert solvent such as DMF, DME or acetonitrile or mixture of such solvents in the presence or absence of a base such as DIPEA, or TEA) to yield final compounds of the type 2-2.
  • a 1 is preferably: General Scheme 3
  • Scheme 3 shows a general synthesis of compounds of the invention beginning with the benzonitrile (3-1 ), where the Fluorine displacement with nucleophiles (where Z equals Oxygen, Nitrogen or Sulfur) yield 3-2 which on with sodium methoxide gave methyl 3- cyano-4-substituted benzimidate 3-3 which was not isolated and subsequently treated with cyanamide and N-(chloromethylene)-N-methylmethanaminium chloride to give 1 ,3,5-triazine (3-5).
  • Chlorotrizine (3-5) then undergoes displacement of the chloro with anilines as in general scheme 1 (at rt or at elevated temperature in the presence of an inert solvent such as DMF, DME or acetonitrile or mixture of such solvents in the presence or absence of a base such as DIPEA, or TEA) to yield final compounds of the type 3-6.
  • an inert solvent such as DMF, DME or acetonitrile or mixture of such solvents in the presence or absence of a base such as DIPEA, or TEA
  • PE/EA 20/1 to 10/1
  • Stepl To a solution of cyclopropylmethanol (2.7 g, 38 mmol, 1.52 equiv.) in dry DMF (100 mL) , sodium hydride, 60 % suspension in oil (1.5 g, 38 mmol, 1.52 equiv.) at 0 °C under nitrogen. After 30 minutes at 0 °C, 5-bromo-2-fluorobenzonitrile (5 g, 25 mmol, 1 equiv.) in dry DMF (20 mL) was added and the reaction mixture was heated to 50 °C for 16 h. The reaction mixture is mixed with ice water and ethyl acetate.
  • Step2 A solution of 5-bromo-2-(cyclopropylmethoxy)benzonitrile (36 g, 0.144 mol, 1 equiv.) in 1 ,4 -Dioxane (600 mL) was degassed for 10 min, then (Bpin) 2 (40.2 g, 0.156 mol, 1.08 equiv.) , [1 ,1 '-bis ( diphenylphosphino) ferrocene] dichloropalladium (II) (2.64 g, 3.6 mmol, 0.025 equiv.) , 1 ,1 ' bis (diphenylphosphino ) ferrocene ( 1.98 g, 3.6 mmol, 0.025 equiv.) and potassium acetate (28.2 g, 0.288 mol ) are added at room temperature and refluxed for 18h.
  • Stepl To tetrahyropyranol (30.0 g, 294 mmol) in DMF (400 mL) at 0 °C was added NaH (19.6 g, 294 mmol). 5-bromo-2-fluorobenzonitrile (49.0 g, 245 mmol) was added drop wise as a solution in DMF (100 mL). The reaction was stirred at 45 °C for 16 h. The reaction was cooled to rt and quenched by pouring the reaction into H 2 0. The precipitate was filtered and dried under vacuum to 5-bromo-2-((tetrahydro-2H-pyran-4- yl)oxy)benzonitrile which was used further without purification.
  • Step2 To 5-Bromo-2-tetrahydropyran-4-yloxy-benzonitrile (57 g, 202 mmol) in dioxane (550 mL) was added bis(pinacolato)diboron (65 g, 256 mmol), KOAc (50.4 g, 606 mmol), and Pd(dppf)CI 2 (6.3 g, 10 mmol). The reaction was heated to 90 °C for 16 h. The solvent was removed and the residual was quenched with H 2 0 (500 mL), followed by extraction with EtOAc (3 x 1000 mL). The aqueous and organic layers were separated. The organic layer was washed with aq.
  • reaction mixture was subjected to flash chromatography (silica gel) to give a semi-pure material, which was taken up as a suspension in aqueous acetonitrile and extracted three times with dichloromethane.
  • the combined extracts were washed once with dilute citric acid, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
  • the residue was recrystallized from hexanes/ethyl acetate to provide the desired material.
  • the cooled reaction mixture was purified by flash chromatography (silica gel), followed by prep HPLC (10 - 80 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide 5-(4-((3-methoxy-4-(4-methylpiperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-
  • the mixture was filtered through a pad of Celite diatomaceous earth and concentrated to dryness under reduced pressure to provide the putative 2-(oxetan-3-yloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzonitrile.
  • the crude mixture was purified by flash chromatography on silica gel to provide of 4-chloro-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1 ,3,5-triazin-2-amine) (0.15 g, 0.44 mmol), 2-(oxetan-3-yloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzonitrile (0.27 g, 0.88 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.025 g, 5 mol%) in 1 ,2-dimethoxyethane (DME, 6 mL) was treated with 2M aqueous sodium carbonate solution (1 mL).
  • Step 1 Preparation of 5-bromo-2-((3-methyloxetan-3-yl)methoxy)benzonitrile: A solution of 3-methyl-3-oxetanemethanol (Aldrich, 2.0 g, 20 mmol) in N,N- dimethylformamide (40 mL) was stirred in an ice-water bath under an atmosphere of Argon. Sodium hydride (60 % in mineral oil, 0.78 g, 20 mmol) was added in a single portion. Mixture was stirred at 0 °C for 10 minutes and then the cooling bath was removed. The mixture was stirred overnight at room temperature.
  • 3-methyl-3-oxetanemethanol Aldrich, 2.0 g, 20 mmol
  • N,N- dimethylformamide 40 mL
  • Sodium hydride 60 % in mineral oil, 0.78 g, 20 mmol
  • Step 2 Preparation of 2-((3-methyloxetan-3-yl)methoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzonitrile: A mixture of 5-bromo-2-((3-methyloxetan-3- yl)methoxy)benzonitrile (0.25 g, 0.89 mmol), bis(pinacolato)diboron (0.45 g, 1.8 mmol), potassium acetate (0.26 g, 2.7 mmol), and [1 ,1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) complex with dichloromethane (0.066 g, 0.09 mmol) in 1 ,4-dioxane (8 mL) was heated for 60 minutes at 85 °C.
  • Step 3 A mixture of 4-chloro-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1 ,3,5-triazin-2- amine (0.15 g, 0.44 mmol), 2-((3-methyloxetan-3-yl)methoxy)-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)benzonitrile (0.29 g, 0.88 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.025 g, 5 mol%) in 1 ,2-dimethoxyethane (DME, 4 mL) was treated with 2M aqueous sodium carbonate solution (1 mL).
  • Step 1 Preparation of 1-(2,2-difluoroethyl)-4-(2-methoxy-4-nitrophenyl)piperazine: A mixture of 1-fluoro-2-methoxy-4-nitrobenzene (0.83 g, 4.9 mmol), 1-(2,2- difluoroethyl)piperazine hydrochloride (Ryan Scientific, 1.0 g, 5.3 mmol), and potassium carbonate (2.0 g, 15 mmol) in N,N-dimethylformamide (9 mL) was stirred at 100 °C for 20 hours. After cooling to room temperature, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution.
  • Step 2 Preparation of 4-(4-(2,2-difluoroethyl)piperazin-1-yl)-3-methoxyaniline: A degassed mixture of 1-(2,2-difluoroethyl)-4-(2-methoxy-4-nitrophenyl)piperazine (1.5 g, 4.9 mmol) in methanol (30 mL) was treated with 10 % palladium on charcoal (250 mg). Mixture was stirred under a balloon of hydrogen overnight. The catalyst was removed by filtration through a pad of Celite diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure to provide the desired material.
  • Step 3 Preparation of 5-(4-((4-(4-(2,2-difluoroethyl)piperazin-1-yl)-3- methoxyphenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile: A suspension of 5-(4-chloro-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2/-/-pyran-4- yl)oxy)benzonitrile (53 mg, 0.17 mmol) and 4-(4-(2,2-difluoroethyl)piperazin-1-yl)-3- methoxyaniline (54 mg, 0.20 mmol) in acetonitrile (3 mL) was treated with N,N- diisopropylethylamine (0.12 ml_, 0.67 mmol).
  • DMF ⁇ , ⁇ -diisopropylethylamine
  • DIEA ⁇ , ⁇ -diisopropylethylamine
  • 4-amino-1 -methylpyrazole (0.49 g, 5.0 mmol) in DMF (1 ml_).
  • the mixture was stirred at 0 °C for 30 minutes and then allowed to warm to room temperature.
  • the mixture was diluted with ethyl acetate and water and filtered through a pad of Celite diatomaceous earth. The filtered aqueous phase was extracted once with ethyl acetate.
  • the mixture was irradiated for 1 hour in a microwave reactor at 125 °C.
  • the crude mixture was purified by flash chromatography on silica gel to furnish 5-(4-((1- methyl-1 H-pyrazol-4-yl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)benzonitrile.
  • the mixture was irradiated for 1 hour in a microwave reactor at 130 °C.
  • the crude mixture was purified by flash chromatography on silica gel to furnish 5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-
  • the cooled reaction mixture was purified by prep HPLC (10 - 80 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide 5-(4- ((4-(4-acetylpiperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)benzonitrile.
  • LCMS-ESI "1" (m/z): [M+H] + calcd for C27H30N7O 3 : 500.2; found: 500.2
  • N,3-dicyano-4-((tetrahydro-2H-pyran-4-yl)oxy)benzimidamide (0.26 g, 0.96 mmol) was taken up as a suspension in MeCN (3 mL) and treated with (chloromethylene)dimethyliminium chloride (0.15 g, 1 .1 mmol), followed by dichloromethane (2 mL). After warming the mixture to 45 °C, an additional volume of dichloromethane (1 mL) was added. The mixture was stirred for 15 minutes at room temperature, and then the white precipitate was collected by vacuum filtration.
  • the mixture was irradiated for 1 hour in a microwave reactor at 130 °C.
  • the crude mixture was purified by flash chromatography on silica gel, followed by prep HPLC (10 - 70 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer).
  • the concentrated residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution.
  • the aqueous phase was extracted twice with ethyl acetate.
  • the mixture was treated successively with N,/V-diisopropylethylamine (39 ⁇ _, 0.22 mmol) and N-[(dimethylamino)-1 H-1 ,2,3- triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N- oxide (HATU, 63 mg, 0.17 mmol).
  • N,/V-diisopropylethylamine 39 ⁇ _, 0.22 mmol
  • HATU N-[(dimethylamino)-1 H-1 ,2,3- triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N- oxide
  • the mixture was irradiated for 1 hour in a microwave reactor at 130 °C.
  • the crude mixture was purified by flash chromatography on silica gel, followed by recrystallization from methanol, to provide 5-(4-((4-(4-(oxetan-3-yl)piperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-thiopyran-4-yl)oxy)benzonitrile.
  • the mixture was irradiated for 1 hour in a microwave reactor at 130 °C.
  • the crude mixture was purified by flash chromatography on silica gel to provide 4-((4-(3-cyano-4- ((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-1 ,3,5-triazin-2-yl)amino)-2-methoxybenzamide.
  • the mixture was irradiated for 1 hour in a microwave reactor at 130 °C.
  • the layers of the crude mixture were separated.
  • the aqueous phase was extracted three times with dichloromethane.
  • the combined organics were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to provide the desired material, which was carried forward without further purification.
  • the mixture was treated successively with /V,/V-diisopropylethylamine (59 ⁇ _, 0.34 mmol) and N- [(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminiumhexafluorophosphate N-oxide (HATU, 65 mg, 0.17 mmol).
  • HATU N- [(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminiumhexafluorophosphate N-oxide
  • the mixture was treated successively with N,/V-diisopropylethylamine (61 ⁇ _, 0.35 mmol) and N- [(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminiumhexafluorophosphate ⁇ /oxide (HATU, 67 mg, 0.18 mmol).
  • HATU N- [(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminiumhexafluorophosphate ⁇ /oxide
  • the mixture was irradiated for 1 hour in a microwave reactor at 130 °C.
  • the crude mixture was purified by flash chromatography on silica gel to provide two separable diastereomers of unknown relative configuration. Each component was separately flash chromatographed a second time and then triturated with methanol to provide 5-(4-((4-(4- (oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((1-oxidotetrahydro-2H- thiopyran-4-yl)oxy)benzonitrile, non-polar diastereomer 1 and 5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((1-oxidotetrahydro-2H-thiopyran-4- yl
  • 1-(2-fluoro-4-nitrophenyl)-4-(oxetan-3-yl)piperazine (1 .6 g, 5.7 mmol) was taken up in a mixture of 2-methyltetrahydrofuran and methanol. The mixture was degassed, treated with 10 % palladium on carbon (250 mg), and shaken for three days under hydrogen (30 psi). The suspension was filtered through a pad of Celite diatomaceous earth and concentrated under reduced pressure to provide 3-fluoro-4-(4-(oxetan-3-yl)piperazin-1 - yl)aniline.
  • the mixture was irradiated for 1 hour in a microwave reactor at 130 °C.
  • the crude mixture was purified by flash chromatography on silica gel to furnish 5-(4-((3-fluoro-4-(4-(oxetan-3- yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)benzonitrile.
  • reaction mixture was filtered through a pad of Celite diatomaceous earth, and the filtrate was concentrated to dryness under reduced pressure.
  • the residue was purified by flash chromatography (silica gel) to provide (R)-2-((tetrahydrofuran-3-yl)oxy)-5-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile.
  • Step 3 A mixture of 4-chloro-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1 ,3,5-triazin-2- amine (0.12 g, 0.35 mmol), crude 2-((tetrahydro-2/-/-pyran-3-yl)oxy)-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (0.34 g, 1.0 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.030 g, 7.5 mol%) in 1 ,2-dimethoxyethane (DME, 4 mL) was treated with 2M aqueous sodium carbonate solution (0.78 mL).
  • DME 1,2-dimethoxyethane
  • the mixture was irradiated for 1 hour in a microwave reactor at 130 °C.
  • the crude mixture was filtered through a pad of Celite diatomaceous earth.
  • the aqueous phase was extracted twice with ethyl acetate.
  • the combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, concentrated to dryness under reduced pressure.
  • the mixture was irradiated for 1 hour in a microwave reactor at 130 °C.
  • the crude mixture was purified by flash chromatography on silica gel to furnish 5-((4-(3-cyano-4- ((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-1 ,3,5-triazin-2-yl)amino)-2-(4-(oxetan-3- yl)piperazin-1-yl)benzonitrile.
  • N-(4-aminophenyl)acrylamide A nearly homogeneous mixture of p- nitroaniline (2.5 g, 18 mmol) and triethylamine (5.0 mL, 36 mmol) in dichloromethane (40 mL) was stirred in an ice-water bath while acryloyl chloride (1.8 mL, 22 mmol) was added dropwise. At the end of the addition, the mixture was allowed to regain room temperature. The resulting suspension was diluted with water and filtered. The collected solid (assumed 18 mmol) was washed successively with water and dichloromethane and then taken up as a suspension in ethanol/water (5:1 , 100 mL).
  • N-(4-((4-chloro-1 ,3,5-triazin-2-yl)amino)phenyl)acrylamide To a solution of 2, 4-dichloro-1 ,3,5-triazine (0.52 g, 3.4 mmol) in ⁇ , ⁇ -dimethylformamide (DMF, 4 mL) at 0 °C were added sequentially ⁇ , ⁇ -diisopropylethylamine (DIEA, 0.69 mL, 4.0 mmol) and N-(4-aminophenyl)acrylamide (0.51 g, 3.1 mmol) and the mixture was stirred at 0
  • the mixture was irradiated for 1 hour in a microwave reactor at 130 °C.
  • the crude mixture was purified first by flash chromatography on silica gel and then by prep HPLC (10 - 90 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide N-(4-((4-(3-cyano-4- ((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-1 ,3,5-triazin-2-yl)amino)phenyl)acrylamide.
  • Step 1 A solution of 2-(4-nitrophenyl)propan-2-ol (Sigma Aldrich, 0.25 g, 1.4 mmol) in methanol (1 ml_) was added to a stirred suspension of 10 % palladium on carbon in methanol (5 ml_). Ammonium formate (0.44 g, 6.9 mmol) was added in a single portion. The mixture was stirred for two hours at room temperature before filtration of the mixture through a pad of Celite diatomaceous earth and concentration of the filtration under reduced pressure.
  • Step 2 A sample of crude 2-(4-aminophenyl)propan-2-ol (50 mg, 0.33 mmol) in acetonitrile (0.5 ml_) was added to a suspension of 5-(4-chloro-1 ,3,5-triazin-2-yl)-2- ((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile (46 mg, 0.15 mmol) in acetonitrile (1 ml_). The suspension was treated with /V,/V-diisopropylethylamine (100 ⁇ _, 0.58 mmol) and then warmed with a heat gun for approximately one minute until homogeneous.
  • the mixture was irradiated for 1 hour in a microwave reactor at 125 °C.
  • the crude mixture was purified by flash chromatography on silica gel to furnish N-(2-cyano- 4-(4-((4-morpholinophenyl)amino)-1 ,3,5-triazin-2-yl)phenyl)cyclopropanecarboxamide.
  • the cooled reaction mixture was purified by flash chromatography (silica gel) to provide 5-(4-((3-(2-hydroxypropan-2-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro- 2H-pyran-4-yl)oxy)benzonitrile.
  • the mixture was heated in a microwave reactor for 30 minutes at 85 °C.
  • the cooled reaction mixture was purified by flash chromatography (silica gel), followed by prep HPLC (10 - 85 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer), to provide 2-((tetrahydro-2H-pyran- 4-yl)oxy)-5-(4-((3-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile.
  • the mixture was diluted with ethyl acetate and water. A small volume of tetrahydrofuran was added. The layers were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organics were filtered, washed once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to provide 4-chloro-N-(4-(methylsulfonyl)phenyl)-1 ,3,5-triazin-2-amine. An aliquot of desired material in acetonitrile was treated with one drop of pyrrolidine to indirectly confirm the presence of the desired material.
  • the mixture was irradiated for 1 hour in a microwave reactor at 125 °C.
  • the crude mixture was purified first by flash chromatography on silica gel and then by prep HPLC (10 - 95 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to furnish 5-(4-((4-morpholinophenyl)amino)-1 ,3,5- triazin-2-yl)-2-(pyrrolidin-1-yl)benzonitrile.
  • the mixture was allowed to stir at room temperature for about 2 hours before it was added to ice- water (-200 g) and basified with small additions of solid sodium hydrogen carbonate to - pH 5.
  • the mixture was then brought to pH 14 with 50/50 (w/w) sodium hydroxide solution in an exothermic reaction.
  • the mixture was extracted three times with dichloromethane, washed once each with 1 % aqueous sodium hydroxide solution and saturated with sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The gummy residue was triturated with refluxing cyclohexane.
  • the resulting powder was collected by vacuum filtration to provide 4-(4- nitrophenyl)piperidine.
  • aqueous phase was extracted three times with ethyl acetate, The combined organics were washed once each with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and then purified by flash chromatography on silica gel to provide 4-chloro-/V-(4-(1-(oxetan-3-yl)piperidin-4-yl)phenyl)-1 ,3,5-triazin-2- amine.
  • the mixture was treated successively with N,N- diisopropylethylamine (61 ⁇ , 0.35 mmol) and N-[(dimethylamino)-1 H-1 ,2,3-triazolo- [4,5-b]pyridin-1 -ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (HATU, 67 mg, 0.18 mmol).
  • N,N- diisopropylethylamine 61 ⁇ , 0.35 mmol
  • HATU N-[(dimethylamino)-1 H-1 ,2,3-triazolo- [4,5-b]pyridin-1 -ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide
  • the mixture was treated successively with N,N- diisopropylethylamine (160 ⁇ _, 0.91 mmol) and N-[(dimethylamino)-1 H-1 ,2,3-triazolo- [4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (HATU, 260 mg, 0.68 mmol).
  • N,N- diisopropylethylamine 160 ⁇ _, 0.91 mmol
  • HATU N-[(dimethylamino)-1 H-1 ,2,3-triazolo- [4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide
  • the mixture was irradiated for 1 hour in a microwave reactor at 130 °C.
  • the crude mixture was purified by flash chromatography on silica gel to provide 2-(cyclopropylmethoxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-
  • the mixture was irradiated for 1 hour in a microwave reactor at 130 °C.
  • the crude mixture was purified by flash chromatography on silica gel, followed by prep HPLC (10 - 65 % acetonitrile in water, 0.1% trifluoroacetic acid buffer) to provide 5-(4-((1-methyl-1H-pyrazol-3-yl)amino)-1,3,5-triazin-2-yl)-2-
  • the mixture was heated in a microwave reactor for 60 minutes at 100 °C.
  • the cooled reaction mixture was purified by flash chromatography (silica gel), followed by trituration with ethyl acetate, to provide 5-(4-((3-fluoro-5-methoxy-4-(4-(oxetan-3- yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)benzonitrile.
  • the cooled reaction mixture was purified by prep HPLC (10 - 80 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer), followed by flash chromatography (silica gel) to provide 5-(4-((3-(4-methylpiperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro- 2H-pyran-4-yl)oxy)benzonitrile.
  • the mixture was irradiated for 1 hour in a microwave reactor at 130 °C.
  • the crude mixture was purified by flash chromatography on silica gel, followed by prep HPLC (10 - 85 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide 5-(4-((3-morpholinophenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H- pyran-4-yl)oxy)benzonitrile.
  • the mixture was treated successively with /V,/V-diisopropylethylamine (170 ⁇ _, 0.92 mmol) and /V-[(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminiumhexafluorophosphate N-oxide (HATU, 180 mg, 0.48 mmol).
  • the mixture was irradiated for 1 hour in a microwave reactor at 130 °C.
  • the crude mixture was purified by flash chromatography on silica gel to furnish 5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-
  • the mixture was treated successively with /V,/V-diisopropylethylamine (35 ⁇ _, 0.20 mmol) and /V-[(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminiumhexafluorophosphate ⁇ /oxide (HATU, 58 mg, 0.15 mmol).
  • the mixture was irradiated for 1 hour in a microwave reactor at 130 °C.
  • the crude mixture was filtered through a pad of Celite diatomaceous earth.
  • the aqueous phase was extracted twice with ethyl acetate.
  • the combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, concentrated to dryness under reduced pressure.
  • the mixture was stirred at 0 °C for 30 minutes and then allowed to warm to room temperature.
  • the mixture was diluted with ethyl acetate and water.
  • the suspension was filtered through a plastic frit to provide 4- chloro-N-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1 ,3,5-triazin-2-amine.
  • the aqueous phase was extracted twice with ethyl acetate containing a small amount of methanol.
  • the mixture was irradiated for 1 hour in a microwave reactor at 130 °C.
  • the crude mixture was purified by flash chromatography on silica gel to provide 5-(4-((3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-
  • the cooled reaction mixture was purified by prep HPLC (10 - 80 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer), followed by flash chromatography (silica gel) to provide 5-(4-((4-(1-methylpiperidin-4-yl)phenyl)amino)-

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Abstract

Compounds having the following formula (I) and methods of their use and preparation are disclosed:(I).

Description

AMINOTRIAZINE DERIVATIVES USEFUL AS TANK-BINDING KINASE INHIBITOR COMPOUNDS
FIELD OF THE INVENTION
This application relates to chemical compounds which may inhibit or otherwise modulate the activity of TANK-binding kinase (TBK1 ) and l-Kappa-B kinase (ΙΚΚε, IKBKE), and to compositions and formulations containing such compounds, and methods of using and making such compounds.
BACKGROUND OF THE INVENTION
TBK1 is a serine/threonine kinase with diverse roles in cancer, inflammation, and the host-pathogen response. Shen, R. R. and W. C. Hahn (201 1 ) Oncogene 30(6): 631- 641. TBK1 activates its substrates IRF3 and IRF7 transcription factors by direct phosphorylation of specific sites that induces their localization to the nucleus to drive transcription of type I IFN genes (Sankar, S., H. Chan, et al., (2006) Cell Signal 18(7): 982-993). In addition, NFkB activation can be bolstered by the kinase activity of TBK1 by phosphorylating the inhibitors of NFkB, which enables activation of the canonical or non-canonical NFkB transcription factors.
TBK1 has been implicated as being a key gene required for KRAS-dependent cancers, required for HER2+ breast cancers, and contributing to the acquisition of resistance to erlotinib. Depletion of TBK1 by shRNA results in synthetic lethality with KRAS-dependent cancer cell lines and xenograft models (Barbie, D. A., P. Tamayo, et al. (2009) Nature 462(7269): 108-1 12) and TBK1 is required for RAS-mediated transformation of murine embryonic fibroblasts (Ou, Y. H., M. Torres, et al. (201 1 ) Mol Cell 41 (4): 458-470). TBK1 is downstream of RAS and elicits its oncogenic properties via the RALB-NFkB and AKT pathways (Chien, Y., S. Kim, et al. (2006) Cell 127(1 ): 157-170). In addition, TBK1 directly phosphorylates AKT at S473 and results in the downstream activation of the mTORC1/2 pathway (Ou, Y. H., M. Torres, et al. (2011 ) Mol Cell 41 (4): 458-470). TBK1 was also identified as being important for the survival of HER2+ breast cancer cell lines via an shRNA kinome screen and showed combination effects with the EGFR/HER2 kinase inhibitor, lapatinib (Deng, T., J. C. Liu, et al. (2014) Cancer Res 74(7): 21 19-2130). Additionally, integrin alphaVbeta3 was identified as a marker of cells that are resistant to EGFR therapies and have stem-like properties. The signaling cascade required for the survival of these cells was attributed to KRAS-TALB- TBK1-NFkB axis and inhibiting TBK1 was sufficient to block the survival of these cells. Seguin, L, S. Kato, et al. (2014), Nat Cell Biol 16(5): 457-468.
ΙΚΚε is a serine/threonine kinase and its gene amplifications have been identified in up to 30% of breast cancers. Depleting ΙΚΚε in cell lines with shRNA that have these amplifications results in their decreased viability (Boehm, J. S., J. J. Zhao, et al. (2007) Cell 129(6): 1065-1079). Overexpression of ΙΚΚε in ovarian cancer has been demonstrated to mediate resistance to cisplatin and is a poor prognostic factor (Guo, J. P., S. K. Shu, et al. (2009) Am J Pathol 175(1 ): 324-333).
TBK1 and ΙΚΚε are also both implicated in inflammatory responses and associated disorders. ΙΚΚε has been shown to be involved in manifestations of rheumatoid arthritis (RA) that include extracellular matrix destruction, synovial inflammation, and activation of the innate immune response (Sweeney, S. E., D.
Hammaker, et al. (2005) J Immunol 174(10): 6424-6430). ΙΚΚε and IRF3 protein levels are increased in the synovium of RA patients and mice deficient in ΙΚΚε show reduced clinical signs of arthritis in a collagen-induced arthritis model as well as associated reduction of inflammation and erosion. Corr, M., D. L. Boyle, et al. (2009), Ann Rheum Dis 68(2): 257-263. Other inflammatory disorders that manifest as a result of Type I I FN response and upstream activation of TLR3/TLR4 or cytosolic nucleic acid sensors are likely to also rely on a ΤΒΚ1/ΙΚΚε signaling axis to initiate and maintain their pathogenic state such as Sjogrens syndrome, inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), systemic lupus erythematosus (SLE), dermatomyositis, polymyositis, systemic sclerosis. Baccala, R., K. Hoebe, et al. (2007), Nat Med 13(5): 543-551. Furthermore, both TBK1 and ΙΚΚε have been shown to play a role in maintaining macrophages in an activated state in response to IFN. Solis, M., R. Romieu-Mourez, et al. (2007) Eur J Immunol 37(2): 528-539.
In addition to inflammation and cancer, ΙΚΚε is implicated in obesity, type 2 diabetes, and insulin resistance. Mice deficient for ΙΚΚε are protected from obesity induced by a high-fat diet, hepatic steatosis, insulin resistance, and chronic inflammation of the liver and fat. Chiang, S. H., M. Bazuine, et al. (2009) Cell 138(5): 961-975.
Consistent with this, high levels of NFkB activation have been seen in the liver, adipocytes, and adipose tissue resident macrophages as well as increase levels of ΙΚΚε over healthy mice. Treatment with a kinase inhibitor to TBK1/ ΙΚΚε improved obesity- related metabolic dysfunction in mice fed a high fat diet (Reilly, S. M., S. H. Chiang, et al. (2013) Nat Med 19(3): 313-321 ).
Accordingly, there is a need for inhibitors of the kinase activity of TBK1 and/or ΙΚΚε for treating cancers, inflammatory, and metabolic disorders that may have an active TBK1 and/or ΙΚΚε pathway.
SUMMARY OF THE INVENTION
One embodiment provides a compound of formula (I):
Figure imgf000005_0001
(I)
wherein,
A is C6-io aryl or 5-10 membered heteroaryl; X1 is CR1 or N;
R1 is selected from the group consisting of H, Ci_6 alkyl, Ci_6 haloalkyl, -NRaRb, halogen, -CN, and -ORa; R2 is selected from the group consisting of H, hydroxyl, Ci_6 alkyl, Ci_6 heteroalkyl, -NRaRb, halogen, -C(0)Ra, -C(0)ORa, -C(0)NRaRb, -OC(0)NRaRb, - NRaC(0)Rb, -NRaC(0)ORb, -S(O)0-2Rc, -S(0)2NRaRb, -NRaS(0)2Rb, C6_i0 aryl, C3-io cycloalkyl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl and -O-R5, wherein each C-i alkyl, Ci-6 heteroalkyl, C6-io aryl, C3-io cycloalkyl, 5-10 membered heteroaryl and 3-12 membered heterocyclyl is optionally substituted with from one to five R20 groups; or R1 and R2 are taken together to form a fused C6 aryl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl or C5.6 cycloalkyi each optionally substituted with one to five R20 groups;
R3 is selected from the group consisting of H, Ci_6 alkyl, Ci_6 heteroalkyl, -NRaRb, halogen, -C(0)Ra, -C(0)ORa, -C(0)NRaRb, -OC(0)NRaRb, -NRaC(0)Rb, -
NRaC(0)ORb, -S(0)o-2Rc, -S(0)(Rc)=NRb, -S(0)2F, -S(0)2NRaRb, -NRaS(0)2Rb, -N3, - CN, -N02, -ORa, C6-io aryl, C3-io cycloalkyi, 5-10 membered heteroaryl and 3-12 membered heterocyclyl wherein each Ci-6 alkyl, Ci-6 heteroalkyl, C6-io aryl, C3-io cycloalkyi, 5-10 membered heteroaryl and 3-12 membered heterocyclyl is optionally substituted with 1-5 R20 groups; each R4 is independently selected from the group consisting of H, Ci_6 alkyl, Ci_6 heteroalkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, C2.6 alkenyl, C2.6 alkynyl, -NRaRb, halogen, -C(0)Ra, -C(0)ORa, -C(0)NRaRb, -OC(0)NRaRb, -NRaC(0)Rb, -NRaC(0)ORb, -S(O)0-2 Rc, -S(0)2NRaRb, -NRaS(0)2Rb, -N3, -CN, -N02 and -ORa; R5 is H; or Ci-6 alkyl, Ci-6 haloalkyl, C6-io aryl, 5-10 membered heteroaryl, C3-io cycloalkyi, or 3-12 membered heterocyclyl, each of which is optionally substituted with from one to five R20 groups; n is 0-2; each R20 is independently Ci-6 alkyl, C3-io cycloalkyi, Ci-6 heteroalkyl, 3-12 membered heterocyclyl, C6-io aryl, 5-10 membered heteroaryl, halogen, oxo, -ORa, - C(0)Ra, -C(0)ORa, -C(0)NRaRb, -OC(0)NRaRb, -NRaRb, -NRaC(0)Rb, -NRaC(0)ORb, -S(O)0-2Ra, -S(0)(Ra)=NRb, -S(0)2NRaRb, -NRaS(0)2Rb, -N3, -CN, or -N02, or two R20 groups can join together to form a fused, spiro or bridged C3-i0 cylcloalkyl or 3-12 membered heterocyclyl; wherein each Ci-6 alkyl, C3-i0 cycloalkyi, Ci-6 heteroalkyl, 3-12 membered heterocyclyl, C6-io aryl, 5-10 membered heteroaryl is optionally substituted with from one to five halogen, Ci_6 alkyl, d-e heteroalkyl, Ci_6 haloalkyl, oxo, imino, - ORa, -C(0)Ra, -C(0)ORa, -C(0)NRaRb, -OC(0)NRaRb, -NRaRb, -NRaC(0)Rb, - NRaC(0)ORb, -S(O)0-2Ra, -S(0)2NRaRb, -NRaS(0)2Rb, -N3, -CN, or -N02; each R21 is independently Ci-6 alkyl, C3-io cycloalkyi, d-e heteroalkyl, 3-12 membered heterocyclyl, C6-Ci0 aryl, 5-10 membered heteroaryl, hydroxyl, Ci_6 alkoxy, amino, -CN, -C(0)H, -C(0)NH2, -C(0)NH(Ci_6 alkyl), -C(0)N(Ci_6 alkyl)2, -COOH, - C(0)Ci-6 alkyl, -C(0)OCi-6 alkyl, or halogen; and each Ra and each Rb are independently H; or Ci-6 alkyl, C2-e alkenyl, C3-10 cycloalkyl, Ci_6 heteroalkyl, 3-12 membered heterocyclyl, C6-io aryl, 5-10 membered heteroaryl, each of which is optionally substituted with from one to five R21 ; or Ra and Rb together with the atoms to which they are attached form a 3-12 membered heterocyclyl optionally substituted with one to five R21 groups; each Rc is independently Ci-6 alkyl, C2-e alkenyl, C3-io cycloalkyl, Ci-6 heteroalkyl, 3- 12 membered heterocyclyl, C6-io aryl, 5-10 membered heteroaryl, each of which is optionally substituted with from one to five R21 ; or a pharmaceutically acceptable salt thereof.
Another embodiment provides a compound having the following formula (la):
Figure imgf000007_0001
(la) wherein X2 is N or CR4. or a pharmaceutically acceptable salt thereof.
Another embodiment provides a compound having the following formula (lb):
Figure imgf000007_0002
(lb) or a pharmaceutically acceptable salt thereof.
Another embodiment provides a compound having the following formula (Ic):
Figure imgf000008_0001
(Ic) or a pharmaceutically acceptable salt thereof.
In another embodiment, X1 is CR1. In another embodiment, X1 is N. In another embodiment, X2 is CR4. In another embodiment, X2 is N.
In another embodiment, A is a 5-6 membered heteroaryl. In another embodiment, A is phenyl.
In another embodiment, R3 comprises a piperazinyl group. In another embodiment, piperazinyl group is substituted with an oxetanyl group.
In another embodiment, R3 is:
Figure imgf000008_0002
wherein,
m is 0-2; and
R20 is H, Ci_6 alkyl, Ci-6 heteroalkyl and Ci-6 hydroxyalkyl.
In another embodiment, R3 is:
Figure imgf000009_0001
wherein,
m is 0-2; and
R20' is H, CN, oxo, CONRaxR x, Ci-e alkyl, d-e heteroalkyi and d-e hydroxyalkyl; wherein Rax and Rbx are independently H; or Ci-6 alkyl, C2 alkenyl, C3-10 cycloalkyl, Ci_6 heteroalkyi, 3-12 membered heterocyclyl, C6-io aryl, 5-10 membered heteroaryl, each of which is optionally substituted with from one to five groups selected from Ci-6 alkyl, C3-10 cycloalkyl, d-e heteroalkyi, 3-12 membered heterocyclyl, C6-Ci0 aryl, 5-10 membered heteroaryl, hydroxyl, d-e alkoxy, amino, -CN, -C(0)H, -C(0)NH2, -C(0)NH(d-e alkyl), - C(0)N(d_6 alkyl)2, -COOH, -C(0)d_6 alkyl, -C(0)Od_6 alkyl, or halogen.
In another embodiment, m is 0.
(R4)n
* * Γ * *
R3-i- A :
In another embodiment, the following substituent in Formula (I) is selected from the group consisting of:
Figure imgf000009_0002
Figure imgf000010_0001
Figure imgf000011_0001
Figure imgf000012_0001
Figure imgf000013_0001
In another embodiment, R3 is not H. In another embodiment, R4 is H. In another embodiment, R1 is H.
In another embodiment, R2 is -NRaRb. In another embodiment, Ra and Rb on R5 join together with the atoms to which they are attached form a 3-12 membered heterocyclyl which is optionally substituted with one to three of halo, hydroxyl, oxo, Ci_6 alkyl, Ci_6 alkoxy, Ci_6 haloalkyl, Ci_6 haloalkoxy, CN, amino, or Ci_6 alkylamino.
In another embodiment, R2 is -O-R5. In another embodiment, R5 is selected from the group consisting of tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, oxetanylmethyl, 1-(oxetan-3-yl)pyrrolidinyl, oxo-propanylnitrile-pyrrolinyl and piperidinyl. In another embodiment, R5 is unsubstituted tetrahydropyranyl. In another embodiment, R2 is N- pyrrolidinyloxy or N-piperidinyloxy substituted with Ci_6 alkoxycarbonyl, hydroxyl Ci_6 alkylcarbonyl, hydroxyl 3-6 membered heterocyclyl, halo 3-6 membered heterocyclyl, Ci_ 6 alkoxycarbonyl, cyano Ci-6 alkylcabonyl or C3-e cycloalkyl-Ci_6 alkoxy. In another embodiment, R5 is substituted with one R20 group selected from Ci_6 alkoxycarbonyl, hydroxyl Ci-6 alkylcarbonyl, Ci_6 alkoxycarbonyl, cyano Ci_6 alkylcabonyl or C3-e
cycloalkyl-Ci-6 alkoxy.
In another embodiment, the R5 group is substituted with one or two fluoro groups. More particularly, the fluoro groups are substituted at the ortho position with respect to the point of attachment of the R5 group. In another embodiment, R is:
Figure imgf000014_0001
Xa is a bond or C(Rx)(Ry), wherein Rx and Ry are independently selected from the group consisting of H, halo or methyl;
Xb and Xc are independently selected from the group consisting of H, halo or methyl;
Xd is selected from the group consisting of H; or Ci-6 alkyl, C2.6 alkenyl, C3-10
cycloalkyl, Ci-6 heteroalkyl, 3-12 membered heterocyclyl, C6-io aryl, 5-10 membered heteroaryl, each of which is optionally substituted with from one to five groups selected from Ci-6 alkyl, C3-10 cycloalkyl, d-e heteroalkyl, 3-12 membered heterocyclyl, C6-Ci0 aryl, 5-10 membered heteroaryl, hydroxyl, Ci-6 alkoxy, amino, -CN, -C(0)H, -C(0)NH2, -C(0)NH(Ci_6 alkyl), -C(0)N(Ci_6 alkyl)2, -COOH, -C(0)Ci-6 alkyl, -C(0)OCi-6 alkyl, or halogen.
In another embodiment, Xd is Ci_6 alkyl substituted with hydroxyl. In another
embodiment, Xa is CH2. In another embodiment, Xb is fluoro. In another embodiment, Xc is H.
In another embodiment, R2 is selected from the roup consisting of:
Figure imgf000014_0002
Figure imgf000015_0001

Figure imgf000016_0001

Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001

Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
or a pharmaceutically acceptable salt thereof.
Another embodiment provides a pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Another embodiment provides a method of treating a subject having a disease or condition responsive to the inhibition of TBK1 , comprising administering to the subject a therapeutically effective amount of a compound as described herein, or a
pharmaceutically acceptable salt thereof. In another embodiment, the disease is cancer. Another embodiment provides a method of treating a subject having a disease or condition responsive to the inhibition of ΙΚΚε, comprising administering to the subject a therapeutically effective amount of a compound as described herein, or a
pharmaceutically acceptable salt thereof. Another embodiment provides a method of treating a subject suffering from a RAS- dependent/mutant cancer, comprising administering to the subject a therapeutically effective amount of a compound as described herein. In another emobodiment, the RAS-dependent/mutant cancer is selected from the group consisting of non-small cell lung cancer, colorectal cancer, pancreatic cancer, AML, and melanoma. Another embodiment provides a method of treating a subject suffering from breast or ovarian cancer, comprising administering to the subject a therapeutically effective amount of a compound as described herein. Another embodiment provides a method of treating a subject suffering from cancer resistant to HER2 and EGFR targeted therapies comprising administering to the subject a therapeutically effective amount of a compound as described herein.
Another embodiment provides a method of treating a subject suffering from a disease selected from the group consisting of Rheumatoid arthritis (RA), Inflammatory bowel disease (IBD), Chronic obstructive pulmonary disease (COPD), Systemic lupus erythematosus (SLE), Polymositis, Systemic sclerosis, Type 2 diabetes, Obesity and Hepatic steatosis.
Another embodiment provides a method of inhibiting TBK1 in a subject, comprising administering a compound of a compound described herein, or a
pharmaceutically acceptable salt thereof. Another embodiment provides a method of inhibiting ΙΚΚε in a subject, comprising administering a compound as described herein, or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is selective against JAK2 or does not substantially inhibit JAK2.
Another embodiment provides a compound as described herein, or a
pharmaceutically acceptable salt thereof, for use in therapy. Another embodiment provides a compound as described herein, or a
pharmaceutically acceptable salt thereof, for use in a method of treating a subject having a disease or condition responsive to the inhibition of TBK1 . In an embodiment, the disease is cancer. Another embodiment provides a compound as described herein, or a pharmaceutically acceptable salt thereof for use in a method of treating a subject having a disease or condition responsive to the inhibition of ΙΚΚε.
Another embodiment provides a compound as described herein, or a
pharmaceutically acceptable salt thereof, for use in a method of treating a subject suffering from a RAS-dependent/mutant cancer. In an emobodiment, the RAS- dependent/mutant cancer is selected from the group consisting of non-small cell lung cancer, colorectal cancer, pancreatic cancer, AML, and melanoma. Another embodiment provides a compound as described herein, or a
pharmaceutically acceptable salt thereof, for use in a method of treating a subject suffering from breast or ovarian cancer. Another embodiment provides a compound as described herein, or a pharmaceutically acceptable salt thereof, for use in a method of treating a subject suffering from cancer resistant to HER2 and EGFR targeted therapies.
Another embodiment provides a compound as described herein, or a
pharmaceutically acceptable salt thereof, for use in a method of treating a subject suffering from a disease selected from the group consisting of Rheumatoid arthritis (RA), Inflammatory bowel disease (IBD), Chronic obstructive pulmonary disease (COPD), Systemic lupus erythematosus (SLE), Polymositis, Systemic sclerosis, Type 2 diabetes, Obesity and Hepatic steatosis.
Another embodiment provides a compound as described herein, or a
pharmaceutically acceptable salt thereof, for use in a method of treating a subject suffering from cancer. Another embodiment provides a compound as described herein, or a
pharmaceutically acceptable salt thereof, for use in a method of inhibiting TBK1 in a subject. Another embodiment provides a compound as described herein, or a pharmaceutically acceptable salt thereof, for use in a method of inhibiting ΙΚΚε in a subject. Another embodiment provides the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a subject having a disease or condition responsive to the inhibition of TBK1 . In an embodiment, the disease is cancer. Another embodiment the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a subject having a disease or condition responsive to the inhibition of ΙΚΚε.
Another embodiment provides the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a subject suffering from a RAS-dependent/mutant cancer. In an emobodiment, the RAS-dependent/mutant cancer is selected from the group consisting of non-small cell lung cancer, colorectal cancer, pancreatic cancer, AML, and melanoma. Another embodiment provides the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a subject suffering from breast or ovarian cancer. Another embodiment provides the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a subject suffering from cancer resistant to HER2 and EGFR targeted therapies.
Another embodiment provides the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a subject suffering from a disease selected from the group consisting of Rheumatoid arthritis (RA), Inflammatory bowel disease (IBD), Chronic obstructive pulmonary disease (COPD), Systemic lupus erythematosus (SLE), Polymositis, Systemic sclerosis, Type 2 diabetes, Obesity and Hepatic steatosis.
Another embodiment provides the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting TBK1 in a subject. Another embodiment provides the use of a compound as described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting ΙΚΚε in a subject.
Another embodiment provides further administering to the subject an additional therapeutic agent, a list of which is provided in the following Detailed Description. DETAILED DESCRIPTION OF THE INVENTION
The following is a list of abbreviations and acronyms used throughout the application:
Abbreviation Meaning
°C Degree Celsius
ATP Adenosine-5'-triphosphate
AcOH Acetic acid
ACN Acetonitrile
CAN Ceric ammonium nitrate
CDI 1 , 1 '-carbonyldiimidazole
cone. Concentrated
d Doublet DABCO 1 ,4-Diazabicyclo[2.2.2]octane
DAST (Diethylamino)sulfur trifluoride
dd Doublet of doublets
DCE 1 ,2-dichloroethane
DCM Dichloromethane
DEAD Diethyl azodicarboxylate
DIAD Diisopropyl azodicarboxylate
DIPEA DIEA N,N-diisopropylethylamine
DMAP 4-dimethylaminopyridine
DME 1 ,2-dimethoxyethane
DMF Dimethylformamide
DMSO Dimethylsulfoxide
dppf 1 ,1 '-Bis(diphenylphosphino)ferrocene
EA Ethyl alcohol
ECF Extracellular fluid
EDTA Ethylenediaminetetraacetic acid
EGTA Ethylene glycol tetraacetic acid
ETOAC Ethyl acetate
equiv/eq Equivalents
ESI Electrospray ionization
Ac Acetate
Et Ethyl
g Grams
HATU 2-(7-Aza-1 H-Benzotriazole -1-yl)-1 ,1 ,3,3- tetramethyluronium hexafluorophosphate hE G human Ether-a-go-go Related Gene
HMDS hexamethyldisilazane(azide)
HPLC High-performance liquid chromatography h/hr Hours
Hz Hertz
IC50 The half maximal inhibitory concentration
J Coupling constant
Kg Kilogram
LAH Lithium ammonium hydride
LCMS/LC-MS Liquid chromatography-mass spectrometry LDA Lithium diisopropylamide
M Molar
m multiplet
m/z mass-to-charge ratio
M+ Mass peak
M+H Mass peak plus hydrogen
mCPBA 3-chloroperoxybenzoic acid
Me Methyl
MeOH Methyl alcohol/methanol
mg Milligram
MHz Megahertz
min/m Minute
ml/mL Milliliter
mM Millimolar
mmol Millimole
MS Mass spectroscopy
mw Microwave
N Normal
mol Mole
NMP N-methylpyrrolidinone
NMR Nuclear magnetic resonance
Ph Phenyl
Pd(PPh3)4 Tetrakis( nphenysphosphine}pasiadhjm(0)
PEPPSI™ -IPr [l,3-Bis(2,6-Diisopropylphenyl)imidazol-2-ylidene](3- chloropyridyl)palladium(ll) dichloride
ppm Parts per million
prep Preparative
Rf Retention factor
RP Reverse phase
RT/rt Room temperature
s Second
s Singlet
SEM 2-(Trimethylsilyl)ethoxymethyl
t Triplet
TEA Triethylamine
TFA Trifluoroacetic acid THF Tetrahydrofuran
2-MeTHF/Me- 2-Methyl Tetrahydrofuran
THF
TLC Thin layer chromatography
TMS trimethylsilyl
WT Wild type
δ Chemical shift
μ9 Microgram
μΙ_/ μΙ Microliter
μΜ Micromolar
μιη Micrometer
μιηοΙ Micromole
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, e.g. , reference to "the compound" includes a plurality of such compounds and reference to "the assay" includes reference to one or more assays and equivalents thereof known to those skilled in the art, and so forth.
A wavy line drawn through a line in a structure indicates a point of attachment of a group, e.g. :
Figure imgf000035_0001
A dashed line indicates an optional bond. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. When used, a dash indicates the point of attachment, c)=NRb indicates the following structure
with point of attachment at the S:
Figure imgf000035_0002
Where multiple substituent groups are identified the point of attachment is at the terminal substituent (e.g. for "alkylaminocarbonyl" the point of attachment is at the carbonyl substituent).
The prefix "Cx.y" indicates that the following group has from x (e.g. 1 ) to y (e.g. 6) carbon atoms, one or more of which, in certain groups (e.g. heteroalkyl, heteroaryl, heteroarylalkyl, etc.), may be replaced with one or more heteroatoms or heteroatomic groups. For example, "Ci.6 alkyl" indicates that the alkyl group has from 1 to 6 carbon atoms. Likewise, the term "x-y membered" rings, wherein x and y are numerical ranges, such as "3-12 membered heterocyclyl", refers to a ring containing x-y atoms (e.g. 3-12), of which up to half may be heteroatoms, such as N, O, S, P, and the remaining atoms are carbon.
Also, certain commonly used alternative chemical names may or may not be used. For example, a divalent group such as a divalent "alkyl" group, a divalent "aryl" group, etc., may also be referred to as an "alkylene" group or an "alkylenyl" group, or alkylyl group, an "arylene" group or an "arylenyl" group, or arylyl group, respectively.
"Alkyl" refers to any group derived from a linear or branched saturated
hydrocarbon. Alkyl groups include, but are not limited to, methyl, ethyl, propyl such as propan-1-yl, propan-2-yl (iso-propyl), butyls such as butan-1-yl, butan-2-yl (sec-butyl), 2- methyl-propan-1-yl (iso-butyl), 2-methyl-propan-2-yl (t-butyl), pentyls, hexyls, octyls, dectyls, and the like. Unless otherwise specified, an alkyl group has from 1 to 10 carbon atoms, for example from 1 to 6 carbon atoms, for example from 1 to 4 carbon atoms.
"Alkenyl" refers to any group derived from a straight or branched hydrocarbon with at least one carbon-carbon double bond. Alkenyl groups include, but are not limited to, ethenyl (vinyl), propenyl (allyl), 1-butenyl, 1 ,3-butadienyl, and the like. Unless otherwise specified, an alkenyl group has from 2 to 10 carbon atoms, for example from 2 to 6 carbon atoms, for example from 2 to 4 carbon atoms.
"Alkynyl" refers to any group derived from a straight or branched hydrocarbon with at least one carbon-carbon triple bond and includes those groups having one triple bond and one double bond. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), (E)-pent-3-en-1-ynyl, and the like. Unless otherwise specified, an alkynyl group has from 2 to 10 carbon atoms, for example from 2 to 6 carbon atoms, for example from 2 to 4 carbon atoms. "Amino" refers to -NH2. Amino groups may also be substituted as described herein, such as with alkyl, carbonyl or other amino groups. The term "alkylamino" refers to an amino group substituted with one or two alkyl substituents (e.g. dimethylamino or propylamino). "Aryl" refers to any group derived from one or more aromatic rings, that is, a single aromatic ring, a bicyclic or a multicyclic ring system. Aryl groups include, but are not limited to, those groups derived from acenaphthylene, anthracene, azulene, benzene, chrysene, a cyclopentadienyl anion, naphthalene, fluoranthene, fluorene, indane, perylene, phenalene, phenanthrene, pyrene and the like. "Arylalkyl" (also "aralkyl") refers to any combination aryl group and an alkyl group. Arylalkyl groups include, but are not limited to, those groups derived from benzyl, tolyl, dimethylphenyl, 2-phenylethan-1-yl, 2-naphthylmethyl, and the like. An arylalkyl group comprises from 6 to 30 carbon atoms, for example the alkyl group can comprise from 1 to 10 carbon atoms and the aryl group can comprise from 5 to 20 carbon atoms.
"Bridged" refers to a ring fusion wherein non-adjacent atoms on a ring are joined by a divalent substituent, such as an alkylenyl or heteroalkylenyl group or a single heteroatom. Quinuclidinyl and admantanyl are examples of bridged ring systems.
"Cycloalkyl" refers to a cyclic alkyl and alkenyl groups. A cycloalkyl group can have one or more cyclic rings and includes fused and bridged groups that are fully saturated or partially unsaturated. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, methylcycloproyl (cyclopropylmethyl), ethylcyclopropyl, cyclohexenyl and the like. Another example includes C5.7 cycloakenyl.
"Halo" and "halogen" refer to fluoro, chloro, bromo and iodo. "Haloalkyl" refers to an alkyl wherein one or more hydrogen atoms are each replaced by a halogen. Examples include, but are not limited to, -CH2CI, -CH2F, - CH2Br, -CFCIBr, -CH2CH2CI, -CH2CH2F, -CF3, -CH2CF3, -CH2CCI3, and the like, as well as alkyl groups such as perfluoroalkyi in which all hydrogen atoms are replaced by fluorine atoms. "Hydroxyalkyl" refers to an alkyl wherein one or more hydrogen atoms are each replaced by a hydroxyl group. Examples include, but are not limited to, -CH2OH, - CH2CH2OH, -C(CH3)2OH, and the like.
"Halo 3-6 membered heterocyclyl" refers to a heterocyclyl group substituted at a carbon atom with at least one halogen atom, and may include multiple halogen atoms, such as 3,3-difluoroazetidinyl. "Heteroalkyl" refers to an alkyl in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatom or heteroatomic group. Heteroatoms include, but are not limited to, N, P, O, S, etc. Heteroatomic groups include, but are not limited to, -NR-, -0-, -S-, -PH-, -P(0)2-, -S(O)-, -S(0)2-, and the like, where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or cycloheteroalkyl. Heteroalkyl groups include, but are not limited to, -OCH3, -CH2OCH3, -SCH3, -CH2SCH3, -IMRCH3, -CH2NRCH3, -CH2OH and the like, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted. A heteroalkyl group comprises from 1 to 10 carbon and up to three hetero atoms, e.g., from 1 to 6 carbon and from 1 to 2 hetero atoms. "Heteroaryl" refers to mono or multicyclic aryl group in which one or more of the aromatic carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatom or heteroatomic group, as defined above. Multicyclic ring systems are included in heteroaryl and may be attached at the ring with the heteroatom or the aryl ring. Heteroaryl groups include, but are not limited to, groups derived from acridine, benzoimidazole, benzothiophene, benzofuran, benzoxazole, benzothiazole, carbazole, carboline, cinnoline, furan, imidazole, imidazopyridine, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like. Heteroaryl groups may have 5-14 members, 5-10 members, or 5-6 members.
"Heterocycle," "heterocyclic," and "heterocyclyl" refer to a saturated or partially unsaturated non-aromatic ring or a partially non-aromatic multiple-ring system with at least one heteroatom or heteroatomic group, as defined above. Heterocycles include, but are not limited to, groups derived from azetidine, aziridine, imidazolidine, morpholine, thiomorpholine, tetrahydro-2H-thiopyran, 1-iminotetrahydro-2H-thiopyran 1- oxide, oxirane (epoxide), oxetane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, N-bromopyrrolidine, N-chloropiperidine, and the like. Heterocyclyl groups also include partially unsaturated ring systems containing one or more double bonds, including fused ring systems with one aromatic ring and one non- aromatic ring, but not fully aromatic ring systems. Examples include dihydroquinolines, e.g. 3,4-dihydroquinoline, dihydroisoquinolines, e.g. 1 ,2-dihydroisoquinoline, dihydroimidazole, tetrahydroimidazole, etc., indoline, isoindoline, isoindolones (e.g. isoindolin-1-one), isatin, dihydrophthalazine, quinolinone, spiro[cyclopropane-1 ,1 '- isoindolin]-3'-one, and the like. Heterocycle groups may have 3-12 members, or 3-10 members, or 3-7 members, or 5-6 members.
"Hydroxyl" and "hydroxy" are used interchangeably and refer to -OH. "Oxo" refers to =0, or oxide where N-oxide or S-oxide exist. Where tautomeric forms of the compound exist, hydroxyl and oxo groups are interchangeable. It is understood that combinations of chemical groups may be used and will be recognized by persons of ordinary skill in the art. For instance, the group "hydroxyalkyi" would refer to a hydroxyl group attached to an alkyl group. A great number of such combinations may be readily envisaged. Additional examples of substituent combinations used herein include: Ci-6 alkylamiocarbonyl (e.g. CH3CH2NI-IC(0)-) Ci-6 alkoxycarbonyl (e.g. CH30-C(0)-), 5-7 membered heterocyclyl-Ci_6 alkyl (e.g.
piperazinyl-CH2-), Ci-6 alkylsulfonyl-5-7 membered heterocyclyl (e.g. CH3S(0)2- morpholinyl-), 5-7 membered heterocyclyl Ci_6 alkoxy (e.g. pyrrolidinyl-O-), 5-7 membered heterocyclyloxy, (4-7 membered heterocyclyl)-4-7 membered heterocyclyl (e.g. oxetanyl-pyrrolidinyl-), C3_6 Cycloalkylaminocarbonyl (e.g. cyclopropyl-NH-C(O)-), 5- 7 membered heterocyclyl-C2-6 alkynyl (e.g. N-piperazinyl-CH2C≡CCH2_), and C6-io arylaminocarbonyl (e.g. phenyl-NH-C(O)-).
"Spiro" refers to a ring substituent which is joined by two bonds at the same carbon atom. Examples of spiro groups include 1 ,1-diethylcyclopentane, dimethyl- dioxolane, and 4-benzyl-4-methylpiperidine, wherein the cyclopentane and piperidine, respectively, are the spiro substituents.
The term "pharmaceutically acceptable" with respect to a substance refers to that substance which is generally regarded as safe and suitable for use without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio.
The compounds described herein include isomers, stereoisomers and the like. As used herein, the term "isomers" refers to different compounds that have the same molecular formula but differ in arrangement and configuration of the atoms. Also as used herein, the term "an optical isomer" or "a stereoisomer" refers to any of the various stereo isomeric configurations which may exist for a given compound of the present invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom. Therefore, the invention includes enantiomers, diastereomers or racemates of the compound.
The term "fused" refers to a ring which is bound to an adjacent ring.
"Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1 :1 mixture of a pair of enantiomers is a "racemic" mixture.
The phrase ortho, refers to the position on the ring where the substituent is adjoined with respect to the point of attachment of the ring, and is shown below with an arrow, wherein z represents a carbon atom or nitrogen:
Similarly, "para" refers to attachment of a substituent at the 4-position with respect to the point of attachment of the ring and "meta" refers to attachment of a substituent at the 3-position with respect to the point of attachment of the ring.
The term is used to designate a racemic mixture where appropriate. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
The absolute stereochemistry is specified according to the Cahn- Ingold- Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Certain of the compounds described herein contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present invention is meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.
"Pharmaceutically acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and that possesses (or can be converted to a form that possesses) the desired pharmacological activity of the parent compound. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, lactic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, 2- napththalenesulfonic acid, oleic acid, palmitic acid, propionic acid, stearic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and the like, and salts formed when an acidic proton present in the parent compound is replaced by either a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as diethanolamine, triethanolamine, N- methylglucamine and the like. Also included in this definition are ammonium and substituted or quaternized ammonium salts. Representative non-limiting lists of pharmaceutically acceptable salts can be found in S.M. Berge et al., J. Pharma Sci., 66(1 ), 1-19 (1977), and Remington: The Science and Practice of Pharmacy, R.
Hendrickson, ed., 21st edition, Lippincott, Williams & Wilkins, Philadelphia, PA, (2005), at p. 732, Table 38-5, both of which are hereby incorporated by reference herein.
"Subject" and "subjects" refers to humans, domestic animals (e.g., dogs and cats), farm animals (e.g., cattle, horses, sheep, goats and pigs), laboratory animals (e.g., mice, rats, hamsters, guinea pigs, pigs, pocket pets, rabbits, dogs, and monkeys), and the like.
"Treating" and "treatment" of a disease include the following:
(1 ) preventing or reducing the risk of developing the disease, i.e., causing the clinical symptoms of the disease not to develop in a subject that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease,
(2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms, or (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
"Effective amount" refers to an amount that may be effective to elicit the desired biological, clinical, or medical response, including the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment. The effective amount will vary depending on the compound, the disease and its severity and the age, weight, etc., of the subject to be treated. The effective amount can include a range of amounts.
Reference to a compound that is "selective" against an enzyme, such as JAK2, indicates relative activity versus a target ezyme, such as TBK1 or ΙΚΚε. For example a compound that has 2-10 fold greater inhibitory activity— as measured by IC50 values— for a desired enzyme(s), such as TBK1 and/or ΙΚΚε, as compared to the enzyme for which the compound is selective against, such as JAK2, is selective against the referenced enzyme.
The compounds of the invention include solvates, hydrates, tautomers, stereoisomers and salt forms thereof.
Provided are also compounds in which from 1 to n hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom, or tritiated with a tritium atom, in which n is the number of hydrogen atoms in the molecule. As known in the art, the deuterium atom is a non-radioactive isotope of the hydrogen atom and tritium is a radioactive isotope. Such compounds, particularly deuterated compounds, may increase resistance to metabolism, and thus may be useful for increasing the half-life of the compounds when administered to a mammal. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium. The pharmaceutical compositions of compounds of Formual (I) (including compounds of Formulae (la) - (lc)) may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, for example as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.
In one aspect, the compounds described herein may be administered orally. Oral administration may be via, for example, capsule or enteric coated tablets. In making the pharmaceutical compositions that include at least one compound of Formula (I), or a pharmaceutically acceptable salt, is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semisolid, or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy- benzoates; sweetening agents; and flavoring agents.
The compositions that include at least one compound of Formula (I), or a pharmaceutically acceptable salt, can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos.
5,023,252, 4,992,445 and 5,001 ,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
The compositions may, in some embodiments, be formulated in a unit dosage form. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule). The compounds are generally administered in a pharmaceutically effective amount. In some embodiments, for oral administration, each dosage unit contains from about 10 mg to about 1000 mg of a compound described herein, for example from about 50 mg to about 500 mg, for example about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, or about 300 mg. In other embodiments, for parenteral administration, each dosage unit contains from 0.1 to 700 mg of a compound a compound described herein. It will be understood, however, that the amount of the compound actually administered usually will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual subject, and the severity of the subject's symptoms. In certain embodiments, dosage levels may be from 0.1 mg to 100 mg per kilogram of body weight per day, for example from about 1 mg to about 50 mg per kilogram, for example from about 5 mg to about 30 mg per kilogram. Such dosage levels may, in certain instances, be useful in the treatment of the above-indicated conditions. In other embodiments, dosage levels may be from about 10 mg to about 2000 mg per subject per day. The amount of active ingredient that may be combined with the vehicle to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms may contain from 1 mg to 500 mg of an active ingredient.
Frequency of dosage may also vary depending on the compound used and the particular disease or condition treated. In some embodiments, for example, for the treatment of an autoimmune and/or inflammatory disease, a dosage regimen of 4 times daily or less is used. In some embodiments, a dosage regimen of 1 or 2 or 3 times daily is used. It will be understood, however, that the specific dose level for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy.
For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid p reformulation composition containing a homogeneous mixture of a compound of Formula (I), or a pharmaceutically acceptable salt, thereof. When referring to these preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
The tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
Kits that include a compound of Formula (I), or a pharmaceutically acceptable salt, thereof, and suitable packaging are provided. In one embodiment, a kit further includes instructions for use. In one aspect, a kit includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and instructions for use of the compounds in the treatment of the diseases or conditions described herein.
Articles of manufacture that include a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, in a suitable container are provided. The container may be a vial, jar, ampoule, preloaded syringe, and intravenous bag. Compounds of Formula (I) may be combined with one or more additional therapeutic agents. The present application provides methods, compositions, kits and articles of manufacture thereof that use or include one or more therapeutic agents inhibiting one or more targets that relate to, directly or indirectly, to cell growth, proliferation, or apoptosis for treating hyperproliferative disorders such as cancers or myeloproliferative neoplasms. The one or more therapeutic agents are compounds or molecules that is an Abl inhibitor, an ACK inhibitor, an A2B inhibitor, an ASK inhibitor, an Auroa kinase inhibitor, a BTK inhibitor, a BRD inhibitor, a c-Kit inhibitor, a c-Met inhibitor, a CAK inhibitor, a CaMK inhibitor, a CDK inhibitor, a CK inhibitor, a DDR inhibitor, an EGFR inhibitor, a FAK inhibitor, a Flt-3 inhibitor, a FYN inhibitor, a GSK inhibitor, a HCK inhibitor, a HDAC inhibitor, an IKK inhibitor, an IDH inhibitor, an IKK inhibitor, a JAK inhibitor, a KDR inhibitor, a LCK hibitor, a LOX inhibitor, a LOXL inhibitor, a LYN inhibitor, a MMP inhibitor, a MEK inhibitor, a MAPK inhibitor, a NEK9 inhibitor, a NPM-ALK inhibitor, a p38 kinase inhibitor, a PDGF inhibitor, a PI3 kinase (PI3K), a PK inhibitor, a PLK inhibitor, a PK inhibitor, a PYK inhibitor, a SYK inhibitor, a TPL2 inhibitor, a STK inhibitor, a STAT inhibitor, a SRC inhibitor, a TBK inhibitor, a TIE inhibitor, a TK inhibitor , a VEGF inhibitor, a YES inhibitor, a chemotherapeutic agent, an immunotherapeutic agent, a radiotherapeutic agent, an anti-neoplastic agent, an anticancer agent, an anti-proliferation agent, an anti-fibrotic agent, an anti-angiogenic agent, a therapeutic antibody, or any combination thereof. In some embodiment, the therapeutic agents are compounds or molecules that target a PI3 kinase (PI3K), a spleen tyrosine kinase (SYK), a Janus kinase (JAK), a Bruton's tyrosine kinase (BTK), or any combination thereof, resulting in the inhibition of one or more targets. In certain embodiments, the therapeutic agent is a PI3K5 inhibitor that selectively inhibits PI3K p1 10 delta isoform (PI3K5). In some embodiments, the therapeutic agents are a PI3K5 inhibitor and a JAK1/2 inhibitor.
The JAK inhibitor binds and inhibits one or more members of JAK family, including JAK1 , JAK2, and/or JAK3.
In one embodiment, the JAK inhibitor is Compound A having the structure:
Figure imgf000046_0001
Compound A may be referred to by its compound name: N-(cyanomethyl)-4-[2- (4-morpholinoanilino)pyrimidin-4-yl]benzamide using ChemDraw. Compound A, also referred to as CYT0387 or momelotinib, is a selective inhibitor to JAK2 and JAK1 , relative to JAK3. Methods for synthesizing compounds of formula I and Compound A are previously described in U.S. Patent No. 8,486,941. This reference is hereby incorporated herein by reference in its entirety.
Additional JAK inhibitors include, but are not limited to, ruxolitinib (INCB018424), fedratinib (SAR302503, TG101348), tofacitinib, baricitinib, lestaurtinib, pacritinib (SB1518), XL019, AZD1480, INCB0391 10, LY2784544, BMS91 1543, and NS018.
The PI3K inhibitors inhibit one or more isoforms of Class I PI3K, including ΡΙ3Κα, ΡΙ3Κβ, ΡΙ3Κδ, ΡΙ3Κγ, or any combination thereof.
In some embodiments, the PI3K5 inhibitor is Compound B having the structure:
Figure imgf000047_0001
In other embodiments, Compound B is predominantly the S-enantiomer, having the structure:
Figure imgf000047_0002
The (S)-enantiomer of Compound B may also be referred to by its compound name: (S)-2-(1-((9H-purin-6-yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one using ChemDraw. In certain embodiments, the PI3K5 inhibitor is Compound C having the structure:
Figure imgf000048_0001
In additional embodiments, Compound C is predominantly the S-enantiomer, having the structure:
Figure imgf000048_0002
The (S)-enantiomer of Compound C may also be referred to by its compound name: (S)-2-(1-((9H-purin-6-yl)amino)ethyl)-6-fluoro-3-phenylquinazolin-4(3H)-one using ChemDraw.
In another embodiment, the PI3K inhibitor is Compound D, having the structure:
Figure imgf000048_0003
In one embodiment, Compound D is predominantly the S-enantiomer, having the structure:
Figure imgf000049_0001
The (S)-enantiomer of Compound D may also be referred to by its compound name: (S)-2-(1-((9H-purin-6-yl)amino)ethyl)-3-(2,6-difluorophenyl)quinazolin-4(3H)-one using ChemDraw.
In yet other embodiment, the PI3K inhibitor is Compound E which is named by its compound name: (S)-4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin- 2-yl)ethyl)amino)pyrimidine-5-carbonitrile using ChemDraw. In some other embodiment, the PI3K inhibitor includes the compounds described in U.S. Provisional Application Nos. 61/543,176; 61/581 ,528; 61/745,429; 61/745,437; and 61/835,333. The references are hereby incorporated herein by reference in their entirety.
Compounds B, C, D, and E are ΡΙ3Κδ inhibitors, selectively inhibiting PI3K p1 105 compared to other PI3K isoforms. Methods for synthesizing the compounds of formula II, Compounds B, C, D, and E are previously described in U.S. Patent No. 7,932,260 or U.S. Provisional Application No. 61/581 ,528. The references are hereby incorporated herein by reference in their entirety.
Additional PI3K inhibitors include but are not limited to XL147, BKM120, GDC- 0941 , BAY80-6946, PX-866, CH5132799, XL756, BEZ235, and GDC-0980, wortmannin, LY294002, PI3K II, TGR-1202, AMG-319, GSK2269557, X-339, X-414, RP5090, KAR4141 , XL499, OXY1 1 1A, IPI-145, IPI-443, GSK2636771 , BAY 10824391 , buparlisib, BYL719, RG7604, MLN1 1 17, WX-037, AEZS-129, PA799, AS252424, TGX221 , TG1001 15, IC871 14, and ZSTK474.
The SYK inhibitor includes but is not limited to 6-(1 H-indazol-6-yl)-N-(4- morpholinophenyl)imidazo[1 ,2-a]pyrazin-8-amine, R406 (tamatinib), R788
(fostamatinib), PRT062607, BAY-61-3606, NVP-QAB 205 AA, R1 12, or R343, or a pharmaceutically acceptable salt thereof. See Kaur et al., European Journal of
Medicinal Chemistry 67 (2013) 434-446. In one embodiment, the Syk inhibitor is 6-(1 H- indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1 ,2-a]pyrazin-8-amine as described in U.S. Patent No. 8,450,321. In various embodiments, compounds of Formula (I) may be combined with one or more therapeutic agents, which are ID01 inhibitors. In one embodiment, the ID01 inhibitor is INCB24360 having the structure:
Figure imgf000050_0001
In another embodiment, the ID01 inhibitor is NLG-919 having the following
Figure imgf000050_0002
In another embodiment, the ID01 inhibitor is indoximod having the following structure:
Figure imgf000050_0003
Another embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with a one or more additional therapeutic agents, for example one or more additional therapeutic agents from the above list of additional therapeutic agents, for use in: therapy; a method of treating a subject having a disease or condition responsive to the inhibition of TBK1 , such as cancer; a method of treating a subject having a disease or condition responsive to the inhibition of ΙΚΚε; a method of treating a subject suffering from a RAS-dependent/mutant cancer, such as non-small cell lung cancer, colorectal cancer, pancreatic cancer, AML, and melanoma; a method of treating a subject suffering from breast or ovarian cancer; a method of treating a subject suffering from cancer resistant to HER2 and EGFR targeted therapies; a method of treating a subject suffering from a disease selected from the group consisting of Rheumatoid arthritis (RA), Inflammatory bowel disease (IBD), Chronic obstructive pulmonary disease (COPD), Systemic lupus erythematosus (SLE), Polymositis, Systemic sclerosis, Type 2 diabetes, Obesity and Hepatic steatosis; or a method of treating a subject suffering from cancer.
Another embodiment provides the use of a compound of formula (I), or a
pharmaceutically acceptable salt thereof, in combination with a one or more additional therapeutic agents, for example one or more additional therapeutic agents from the above list of additional therapeutic agents, in the manufacture of a medicament for: therapy; treating a subject having a disease or condition responsive to the inhibition of TBK1 , such as cancer; treating a subject having a disease or condition responsive to the inhibition of ΙΚΚε; treating a subject suffering from a RAS-dependent/mutant cancer, such as non-small cell lung cancer, colorectal cancer, pancreatic cancer, AML, and melanoma; treating a subject suffering from breast or ovarian cancer; treating a subject suffering from cancer resistant to HER2 and EGFR targeted therapies; treating a subject suffering from a disease selected from the group consisting of Rheumatoid arthritis (RA), Inflammatory bowel disease (IBD), Chronic obstructive pulmonary disease (COPD), Systemic lupus erythematosus (SLE), Polymositis, Systemic sclerosis, Type 2 diabetes, Obesity and Hepatic steatosis; or treating a subject suffering from cancer.
In an embodiment, the above combinations comprise one additional therapeutic agent, for example one additional therapeutic agent selected from the additional therapeutic agents listed above. Another embodiment of the invention provides a product comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional therpauetic agents, such as one or more of the additional therapeutic agents listed above, as a combined preparation for simultaneous, separate or sequential use in therapy. Synthesis of certain compounds, and intermediates used to prepare compounds, are detailed in the following sections. Example numbers are listed for convenience.
All operations involving moisture and/or oxygen sensitive materials were conducted under an atmosphere of dry nitrogen in pre-dried glassware. Unless noted otherwise, materials were obtained from commercially available sources and used without further purification.
Nuclear magnetic resonance ("NMR") spectra were recorded on a Varian 400 MHz resonance spectrometer. 1 H NMR chemical shifts are given in parts per million (δ) downfield from tetramethylsilane ("TMS") using TMS or the residual solvent signal (CHCI3 = δ 7.24, DMSO = δ 2.50) as internal standard. 1 H NMR information is tabulated in the following format: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), coupling constant(s) (J) in Hertz, number of protons. The prefix app is occasionally applied in cases where the true signal multiplicity was unresolved and br indicates the signal in question was broadened.
The compounds were named using ChemBioDraw Ultra Version 12.0.
When production of starting materials is not particularly described, the compounds are known or may be prepared analogously to methods known in the art or as disclosed in the Examples. One of skill in the art will appreciate that synthetic methodologies described herein are only representative of methods for preparation of the compounds described herein, and that other known methods and variants of methods described herein may be used. Compounds containing -S02F substituents are prepared according to Sulfur(VI) Fluoride Exchange (SuFEx): Another Good Reaction for Click Chemistry, Angew et al., Chem. Int. Ed. 2014, 53, 2 - 21. The methods or features described in various Examples may be combined or adapted in various ways to provide additional ways of making the compounds described herein.
EXAMPLES
Methods for obtaining the novel compounds described herein will be apparent to those of ordinary skill in the art, with suitable procedures being described, for example, in the reaction schemes and examples below, and in the references cited herein.
General Scheme 1
CI
Figure imgf000052_0001
1-2
1-1 Scheme 1 shows a general synthesis of compounds of the invention beginning with the displacement of the one chloro from 2,4-Dichloro-1 ,3,5-triazine with anilines either at rt or at elevated temperature in the presence of an inert solvent such as DMF, DME or acetonitrile or mixture of such solvents in the presence or absence of a base such as DIPEA, or TEA to yield intermediate 1 -1 which undergoes metal catalyzed cross coupling reactions (e.g. Suzuki) of A1 groups to yield final compounds of the type 1 -2. A1 is preferably:
Figure imgf000053_0001
General Scheme 2
Figure imgf000053_0002
2-2
Metal catalyzed cross 2-1
coupling e.g. Suzuki, Negishi
Scheme 2 shows a general synthesis of compounds of the invention beginning with the Metal catalyzed cross coupling reactions (ex: Suzuki, Negishi) to yield intermediate 2-1 which undergoes displacement of the chloro from 2-1 with anilines as in general scheme 1 (at rt or at elevated temperature in the presence of an inert solvent such as DMF, DME or acetonitrile or mixture of such solvents in the presence or absence of a base such as DIPEA, or TEA) to yield final compounds of the type 2-2. A1 is preferably:
Figure imgf000053_0003
General Scheme 3
Figure imgf000054_0001
Scheme 3 shows a general synthesis of compounds of the invention beginning with the benzonitrile (3-1 ), where the Fluorine displacement with nucleophiles (where Z equals Oxygen, Nitrogen or Sulfur) yield 3-2 which on with sodium methoxide gave methyl 3- cyano-4-substituted benzimidate 3-3 which was not isolated and subsequently treated with cyanamide and N-(chloromethylene)-N-methylmethanaminium chloride to give 1 ,3,5-triazine (3-5). Chlorotrizine (3-5) then undergoes displacement of the chloro with anilines as in general scheme 1 (at rt or at elevated temperature in the presence of an inert solvent such as DMF, DME or acetonitrile or mixture of such solvents in the presence or absence of a base such as DIPEA, or TEA) to yield final compounds of the type 3-6.
Intermediates:
tert-butyl 4-(2-cyano-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)piperidine-1-carboxylate
Figure imgf000055_0001
Stepl : 5-bromo-2-hydroxybenzonitrile (45 g, 0.23 mol) in anhydrous THF (1000 ml_) was combined with tert-butyl 4-hydroxypiperidine-1-carboxylate (55 g, 0.27 mol), PPh3 (70.7 g, 0.27 mol), followed by addition of DEAD (47.7 g, 0.27 mol) at r.t. The mixture was stirred at r.t. for 18 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EA = 20/1 to 10/1 ) to give tert-butyl 4-(4-bromo-2-cyanophenoxy)piperidine-1-carboxylate. 1H NMR: (CDCI3, 400 MHz): δ 7.67 (s, 1 H), 7.62-7.59 (m, 1 H), 6.88 (d, J = 9.2 Hz, 1 H), 4.62-4.61 (m, 1 H), 3.63-3.47 (m, 4H), 1.91-1.85 (m, 4H), 1.47 (s, 9H) Step2: To a solution of tert-butyl 4-(4-bromo-2-cyanophenoxy)piperidine-1-carboxylate (46.7 g, 0.12 mol) in dioxane (1000 mL) was added Pd(dppf)CI2 (4.4 g, 6 mmol), (Bpin)2 (37.5 g, 0.14 mol), and KOAc (35.3 g, 0.36 mol). After stirring at 80 °C for 20 h under N2, the mixture was filtered to remove KOAc, and the filtrate was concentrated under reduced pressure. The residue was purified by twice column chromatography (PE/EA = 20/1 to 10/1 ) to give the title compound. 1H NMR: (CDCI3, 400 MHz): δ 8.03 (s, 1 H), 7.92 (d, J = 8.8 Hz, 1 H), 6.95 (d, J = 8.8 Hz, 1 H), 4.70 (m, 1 H), 3.64 (m, 2H), 3.52-3.48 (m, 2H), 1.90-1.84 (m, 4H), 1.59 (s, 9H),1.47-1.34 (m, 12H).
(R)-tert-butyl 3-(2-cyano-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)pyrrolidine-1 -carboxylate
Figure imgf000055_0002
The title compound was prepared following similar procedure to prepare Intermediate B using (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate instead of tert-butyl 4- hydroxypiperidine-1-carboxylate in stepl . 1H NMR: (CDCI3, 400 MHz): δ 8.03 (s, 1 H), 7.92 (d, J = 7.6 Hz, 1 H), 6.89 (d, J = 8.4 Hz, 1 H), 5.02 (s, 1 H), 3.71-3.57 (m, 4H), 2.27- 2.15 (m, 2H), 1.58 (s, 9H),1.34 (s, 12H). (S)-tert-butyl 3-(2-cyano-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)pyrrolidine-1 -carboxylate
Figure imgf000056_0001
The title compound was prepared following similar procedure to prepare Intermediate B using (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate instead of tert-butyl 4- hydroxypiperidine-1-carboxylate in stepL 1H NMR: (CDCI3, 400 MHz): δ 8.04 (s, 1 H), 7.94 (d, J = 7.2 Hz, 1 H), 6.91 (d, J = 8.4 Hz, 1 H), 5.04 (s, 1 H), 3.73-3.59 (m, 4H), 2.29- 2.16 (m, 2H), 1.59 (s, 9H), 1.36 (s, 12H).
2-(cyclopropylmethoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile
Figure imgf000056_0002
Stepl : To a solution of cyclopropylmethanol (2.7 g, 38 mmol, 1.52 equiv.) in dry DMF (100 mL) , sodium hydride, 60 % suspension in oil (1.5 g, 38 mmol, 1.52 equiv.) at 0 °C under nitrogen. After 30 minutes at 0 °C, 5-bromo-2-fluorobenzonitrile (5 g, 25 mmol, 1 equiv.) in dry DMF (20 mL) was added and the reaction mixture was heated to 50 °C for 16 h. The reaction mixture is mixed with ice water and ethyl acetate. The organic phases are washed with water and saturated sodium chloride solution and dried with sodium sulfate. After removal of the solvent the crude product was purified by column by chromatography (PE: EA=30: 1 ) to obtain 5-bromo-2-(cyclopropylmethoxy)benzonitrile. 1H NMR: (CDCI3): δ 7.65 (d, J = 1.6 Hz, 1 H), 7.59 (dd, J = 8.0, 1.6 Hz, 1 H), 6.84 (d, J = 8.0 Hz, 1 H), 3.92 (d, J = 6.8 Hz, 2H), 1.26-1.33 (m, 1 H), 0.65-0.69 (m, 2H), 0.37-0.41 (m, 2H).
Step2: A solution of 5-bromo-2-(cyclopropylmethoxy)benzonitrile (36 g, 0.144 mol, 1 equiv.) in 1 ,4 -Dioxane (600 mL) was degassed for 10 min, then (Bpin)2 (40.2 g, 0.156 mol, 1.08 equiv.) , [1 ,1 '-bis ( diphenylphosphino) ferrocene] dichloropalladium (II) (2.64 g, 3.6 mmol, 0.025 equiv.) , 1 ,1 ' bis (diphenylphosphino ) ferrocene ( 1.98 g, 3.6 mmol, 0.025 equiv.) and potassium acetate (28.2 g, 0.288 mol ) are added at room temperature and refluxed for 18h. The reaction mixture is mixed with ice water (200 mL) and ethyl acetate extracted. The organic phases are washed with water and saturated sodium chloride solution and dried with sodium sulfate. After removal of the solvent the crude product was purified by column by chromatography to obtain the title compound. 1H NMR: (CDCI3): δ 8.01 (d, J = 1.6 Hz, 1 H), 7.91 (dd, J = 8.4, 1.6 Hz, 1 H), 6.91 (d, J = 8.4 Hz, 1 H), 3.96 (d, J = 6.8 Hz, 2H), 1.33 (s, 12H), 1.28-1.34 (m, 1 H), 0.65-0.69 (m, 2H), 0.38-0.42 (m, 2H). 2-((tetrahydro-2H-pyran-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzonitrile
Figure imgf000057_0001
Stepl : To tetrahyropyranol (30.0 g, 294 mmol) in DMF (400 mL) at 0 °C was added NaH (19.6 g, 294 mmol). 5-bromo-2-fluorobenzonitrile (49.0 g, 245 mmol) was added drop wise as a solution in DMF (100 mL). The reaction was stirred at 45 °C for 16 h. The reaction was cooled to rt and quenched by pouring the reaction into H20. The precipitate was filtered and dried under vacuum to 5-bromo-2-((tetrahydro-2H-pyran-4- yl)oxy)benzonitrile which was used further without purification.
Step2: To 5-Bromo-2-tetrahydropyran-4-yloxy-benzonitrile (57 g, 202 mmol) in dioxane (550 mL) was added bis(pinacolato)diboron (65 g, 256 mmol), KOAc (50.4 g, 606 mmol), and Pd(dppf)CI2 (6.3 g, 10 mmol). The reaction was heated to 90 °C for 16 h. The solvent was removed and the residual was quenched with H20 (500 mL), followed by extraction with EtOAc (3 x 1000 mL). The aqueous and organic layers were separated. The organic layer was washed with aq. saturated NaCI and dried (Na2S04). Purification by silica gel chromatography (0-100%, EtOAc in Hexanes) provided the title compound. 1H NMR: (CDCI3): δ 8.02 (d, 1 H), 7.92-7.89 (m, 1 H), 6.95-6.93 (d, 1 H), 4.71- 4.69 (m, 1 H), 4.00-3.98 (m, 2H), 3.63-3.60(m, 2H), 2.04-2.01 (m, 2H), 1.90-1.85 (m, 2H), 1.33 (s, 12H).
Example 1
5-(4-((4-(1 ,1 -dioxidothiomorpholino)phenyl)amino)-1 ,3,5-triazin-2-yl)-2- ((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile
Figure imgf000058_0001
A suspension of 5-(4-chloro-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2/-/-pyran-4- yl)oxy)benzonitrile (100 mg, 0.32 mmol) and 4-(4-aminophenyl)thiomorpholine-1 ,1- dioxide (TCI, 86 mg, 0.38 mmol) in acetonitrile (3 ml_) was treated with N,N- diisopropylethylamine (0.28 ml_, 1.6 mmol). The mixture was heated in a microwave reactor for 20 minutes at 80 °C. The reaction mixture was subjected to flash chromatography (silica gel) to give a semi-pure material, which was taken up as a suspension in aqueous acetonitrile and extracted three times with dichloromethane. The combined extracts were washed once with dilute citric acid, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexanes/ethyl acetate to provide the desired material.
LCMS-ESI+ (m/z): [M+H]+ calcd for C25H27N604S: 507.2; found: 507.2
1H NMR (400 MHz, DMSO-c/6) δ 10.21 (m, 1 H), 8.79 (s, 1 H), 8.60 (m, 2H), 7.67 (m, 2H), 7.59 (d, J = 9.2 Hz, 1 H), 7.10 (m, 2H), 4.98 (m, 1 H), 3.91 (m, 2H), 3.79 (m, 4H), 3.59 (m, 2H), 3.18 (m, 4H), 2.09 (m, 2H), 1.73 (m, 2H).
Example 2
(R)-methyl 3-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5- triazin-2-yl)phenoxy)pyrrolidine-1 -carboxylate
Figure imgf000059_0001
(R)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-(pyrrolidin- 3-yloxy)benzonitrile (50 mg, 0.10 mmol) was taken up as suspension in dichloromethane (1 mL) and treated successively with /V,/V-diisopropylethylamine (37 μΙ_, 0.20 mmol) and methyl chloroformate (12 μΙ_, 0.15 mmol). The mixture was stirred for five minutes at room temperature and then purified by flash chromatography (silica gel) to provide (R)-methyl 3-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenoxy)pyrrolidine-1-carboxylate.
LCMS-ESI+ (m/z): [M+H]+ calcd for C29H33N804: 557.3; found: 557.3
1H NMR (400 MHz, DMSO-c/6) δ 10.17 (m, 1 H), 8.78 (d, J = 2.7 Hz, 1 H), 8.60 (m, 2H), 7.58 (m, 3H), 7.01 (br, 2H), 5.37 (br, 1 H), 4.61 (m, 2H), 4.51 (m, 3H), 3.71 (m, 1 H), 3.64 (d, J = 7.8 Hz, 3H), 3.49 (m, 2H), 3.19 (m, 4H), 2.45 (m, 4H), 2.26 (m, 2H). Example 3
( ?)-2-((1-acetylpyrrolidin-3-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- ,5-triazin-2-yl)benzonitrile
Figure imgf000059_0002
(R)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-(pyrrolidin- 3-yloxy)benzonitrile (50 mg, 0.10 mmol) was taken up as suspension in dichloromethane (1 mL) and treated successively with /V,/V-diisopropylethylamine (37 μΙ_, 0.20 mmol) and acetyl chloride (11 μΙ_, 0.15 mmol). The mixture was stirred for five minutes at room temperature and then purified by flash chromatography (silica gel) to provide (R)-2-((1 -acetylpyrrolidin-3-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile.
LCMS-ESI+ (m/z): [M+H]+ calcd for C29H33N803: 541 .3; found: 541 .4
1H NMR (400 MHz, DMSO-c/6) δ 10.17 (m, 1 H), 8.78 (s, 1 H), 8.61 (m, 2H), 7.58 (m, 3H), 7.01 (br, 2H), 5.39 (m, 1 H), 4.61 (m, 2H), 4.51 (m, 2H), 3.66 (m, 3H), 3.49 (m, 1 H), 3.19 (m, 4H), 2.45 (m, 4H), 2.28 (m, 2H), 2.03 (s, 2H), 1 .99 (s, 1 H).
Example 4
5-(4-((3-methoxy-4-(4-methylpiperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin
((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile
Figure imgf000060_0001
A suspension of 5-(4-chloro-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2/-/-pyran-4- yl)oxy)benzonitrile (53 mg, 0.17 mmol) and 3-methoxy-4-(4-methylpiperazin-1 -yl)aniline (44 mg, 0.20 mmol) in acetonitrile (2.5 ml_) was treated with /V,/V-diisopropylethylamine (0.12 ml_, 0.67 mmol). The mixture was heated on a 90 °C block for 60 minutes. The cooled reaction mixture was purified by flash chromatography (silica gel), followed by prep HPLC (10 - 80 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide 5-(4-((3-methoxy-4-(4-methylpiperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-
((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for C27H32N7O3: 502.3; found: 502.3 1H NMR (400 MHz, DMSO-c/6) δ 10.53 (bs, 1 H), 10.34 (m, 1 H), 8.83 (s, 1 H), 8.64 (d, J = 2.1 Hz, 1 H), 8.62 (dd, J = 8.9, 2.2 Hz, 1 H), 7.61 (d, J = 9.0 Hz, 1 H), 7.29 (m, 1 H), 7.00 (d, J = 8.5 Hz, 1 H), 4.99 (m, 1 H), 4.03 - 3.78 (m, 4H), 3.59 (m, 2H), 3.47 (m, 5H), 3.13 (m, 4H), 2.85 (s, 3H), 2.09 (m, 2H), 1 .73 (m, 2H). Example 5
5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,54riazin-2-yl)-2-(oxetan-3- yloxy)benzonitrile
Figure imgf000061_0001
A solution of 3-hydroxyoxetane (1.33 g, 18 mmol) in N,N-dimethylformamide (36 mL) was stirred in an ice-water bath under an atmosphere of Argon. Sodium hydride (60 % dispersion in mineral oil, 0.72 g, 18 mmol) was added in a single portion and the mixture was stirred at 0 °C for 10 minutes, and then the bath was removed. After 30 minutes of stirring at room temperature, to the mixture was added 5-bromo-2-fluorobenzonitrile (3.0 g, 18 mmol) via syringe as a solution in N,N-dimethylformamide (15 mL). The mixture was stirred overnight at 50 °C. After the mixture cooled to room temperature, water was added, giving a granular precipitate. It was collected by filtration, washed with water and dried in a vacuum oven over P2O5 to provide 5-bromo-2-(oxetan-3- yloxy)benzonitrile. 1 H NMR (400 MHz, DMSO-c/6) δ 8.1 1 (d, J = 2.5 Hz, 1 H), 7.84 (dd, J
= 9.0, 2.5 Hz, 1 H), 6.90 (d, J = 9.0 Hz, 1 H), 5.48 (tt, J = 5.9, 4.7 Hz, 1 H), 4.99 (ddd, J = 7.2, 6.0, 1.0 Hz, 2H), 4.61 (ddd, J = 7.6, 4.7, 1.0 Hz, 2H).
A mixture of 5-bromo-2-(oxetan-3-yloxy)benzonitrile (0.22 g, 0.88 mmol), bis(pinacolato)diboron (0.45 g, 1.8 mmol), potassium acetate (0.26 g, 2.6 mmol), and [1 ,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (0.065 g, 10 mol%) in 1 ,4- dioxane (5 mL) was heated at 90 °C overnight. LC/MS analysis indicated the consumption of the bromide starting material. The mixture was filtered through a pad of Celite diatomaceous earth and concentrated to dryness under reduced pressure to provide the putative 2-(oxetan-3-yloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzonitrile.
A mixture of 4-chloro-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1 ,3,5-triazin-2-amine (Prepared by treating 2,4-dichloro-1 ,3,5-triazine and 4-(4-(oxetan-3-yl)piperazin-1- yl)aniline (WO2013188856) in DMF at 0 °C in the presence of added DIEA at 0 °C for 30 minutes and then allowed to warm to r.t. where it remained till the reaction goes to completion. The mixture was diluted with ethyl acetate and washed with water and brine and dried. The crude mixture was purified by flash chromatography on silica gel to provide of 4-chloro-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1 ,3,5-triazin-2-amine) (0.15 g, 0.44 mmol), 2-(oxetan-3-yloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzonitrile (0.27 g, 0.88 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.025 g, 5 mol%) in 1 ,2-dimethoxyethane (DME, 6 mL) was treated with 2M aqueous sodium carbonate solution (1 mL). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel to provide 5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2- (oxetan-3-yloxy)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for C26H28N7°3: 486.2; found: 486.3
1 H NMR (400 MHz, DMSO-c/6) δ 10.15 (m, 1 H), 8.78 (s, 1 H), 8.60 (m, 2H), 7.63 (d, J =
9.1 Hz, 1 H), 7.13 (d, J = 8.9 Hz, 1 H), 7.01 (t, J = 7.4 Hz, 2H), 5.58 (p, J = 5.4 Hz, 1 H), 5.04 (t, J = 6.8 Hz, 2H), 4.67 (m, 2H), 4.61 (t, J = 6.5 Hz, 2H), 4.52 (t, J = 6.0 Hz, 2H), 3.49 (p, J = 6.3 Hz, 1 H), 3.19 (m, 4H), 2.45 (m, 4H).
Example 6
2-((3-methyloxetan-3-yl)methoxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000062_0001
Step 1 : Preparation of 5-bromo-2-((3-methyloxetan-3-yl)methoxy)benzonitrile: A solution of 3-methyl-3-oxetanemethanol (Aldrich, 2.0 g, 20 mmol) in N,N- dimethylformamide (40 mL) was stirred in an ice-water bath under an atmosphere of Argon. Sodium hydride (60 % in mineral oil, 0.78 g, 20 mmol) was added in a single portion. Mixture was stirred at 0 °C for 10 minutes and then the cooling bath was removed. The mixture was stirred overnight at room temperature. To the mixture was added via syringe 5-bromo-2-fluorobenzonitrile (Matrix Scientific, 4.7 g, 24 mmol) as a solution in N,N-dimethylformamide (20 mL) at room temperature. Mixture was stirred for 8 hours at 50 °C block and then allowed to cool to room temperature. Water was added and the resulting suspension was extracted three times with ethyl acetate. The combined extracts were washed once each with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude material was purified via flash chromatography on silica gel to give the desired material. LCMS-ESI+ (m/z): [M+H]+ calcd for C12H12BrN02: 282.0; found: 281.9
Step 2: Preparation of 2-((3-methyloxetan-3-yl)methoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzonitrile: A mixture of 5-bromo-2-((3-methyloxetan-3- yl)methoxy)benzonitrile (0.25 g, 0.89 mmol), bis(pinacolato)diboron (0.45 g, 1.8 mmol), potassium acetate (0.26 g, 2.7 mmol), and [1 ,1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) complex with dichloromethane (0.066 g, 0.09 mmol) in 1 ,4-dioxane (8 mL) was heated for 60 minutes at 85 °C. The reaction mixture was filtered through a pad of Celite diatomaceous earth, and the filtrate was concentrated to dryness under reduced pressure to provide 2-((3-methyloxetan-3- yl)methoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile. LCMS-ESI+
(m/z): [M+H]+ calcd for C18H24BNO4: 330.2; found: 330.0
Step 3: A mixture of 4-chloro-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1 ,3,5-triazin-2- amine (0.15 g, 0.44 mmol), 2-((3-methyloxetan-3-yl)methoxy)-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)benzonitrile (0.29 g, 0.88 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.025 g, 5 mol%) in 1 ,2-dimethoxyethane (DME, 4 mL) was treated with 2M aqueous sodium carbonate solution (1 mL). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel to provide 2-((3-methyloxetan-3- yl)methoxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile LCMS-ESI+ (m/z): [M+H]+ calcd for C28H31 N7O3: 514.3; found: 514.3
1H NMR (400 MHz, DMSO-c/6) δ 10.13 (m, 1 H), 8.76 (s, 1 H), 8.70 - 8.44 (m, 2H), 7.75 - 7.56 (m, 2H), 7.52 (d, J = 9.0 Hz, 1 H), 6.99 (m, 2H), 4.64 - 4.53 (m, 4H), 4.50 (t, J = 6.0 Hz, 2H), 4.37 (m, 4H), 3.47 (p, J = 6.3 Hz, 1 H),3.17 (m, 4H), 2.44 (m, 4H), 1.44 (s, 3H).
Example 7
5-(4-((4-(4-(2,2-difluoroethyl)piperazin-1 -yl)-3-methoxyphenyl)amino)-1 ,3,5-triazin- 2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile
Figure imgf000064_0001
Step 1 : Preparation of 1-(2,2-difluoroethyl)-4-(2-methoxy-4-nitrophenyl)piperazine: A mixture of 1-fluoro-2-methoxy-4-nitrobenzene (0.83 g, 4.9 mmol), 1-(2,2- difluoroethyl)piperazine hydrochloride (Ryan Scientific, 1.0 g, 5.3 mmol), and potassium carbonate (2.0 g, 15 mmol) in N,N-dimethylformamide (9 mL) was stirred at 100 °C for 20 hours. After cooling to room temperature, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The mixture was filtered through a pad of Celite diatomaceous earth. The collected solid was discarded, while the aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to provide the desired material. LCMS-ESI+ (m/z): [M+H]+ calcd for Ci 3H 8F2N303: 302.1 ; found: 302.1
Step 2: Preparation of 4-(4-(2,2-difluoroethyl)piperazin-1-yl)-3-methoxyaniline: A degassed mixture of 1-(2,2-difluoroethyl)-4-(2-methoxy-4-nitrophenyl)piperazine (1.5 g, 4.9 mmol) in methanol (30 mL) was treated with 10 % palladium on charcoal (250 mg). Mixture was stirred under a balloon of hydrogen overnight. The catalyst was removed by filtration through a pad of Celite diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure to provide the desired material. LCMS- ESI+ (m/z): [M+H]+ calcd for C13H20 2N3O: 272.2; found: 272.1
Step 3: Preparation of 5-(4-((4-(4-(2,2-difluoroethyl)piperazin-1-yl)-3- methoxyphenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile: A suspension of 5-(4-chloro-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2/-/-pyran-4- yl)oxy)benzonitrile (53 mg, 0.17 mmol) and 4-(4-(2,2-difluoroethyl)piperazin-1-yl)-3- methoxyaniline (54 mg, 0.20 mmol) in acetonitrile (3 mL) was treated with N,N- diisopropylethylamine (0.12 ml_, 0.67 mmol). The mixture was heated in a microwave reactor for 20 minutes at 80 °C. The cooled reaction mixture was purified by flash chromatography (silica gel) and then recrystallized from acetonitrile to provide 5-(4-((4- (4-(2,2-difluoroethyl)piperazin-1 -yl)-3-methoxyphenyl)amino)-1 ,3,5-triazin-2-yl)-2- ((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C28H32F2N7°3: 552-3; found : 552 3
1 H NMR (400 MHz, DMSO-c/6) δ 10.22 (m, 1 H), 8.81 (s, 1 H), 8.67 - 8.58 (m, 2H), 7.66 (bs, 1 H), 7.60 (d, J = 9.0 Hz, 1 H), 7.44 - 7.20 (br, 1 H), 6.93 (d, J = 8.5 Hz, 1 H), 6.21 (tt, J = 55.8, 4.3 Hz, 1 H), 4.98 (m, 1 H), 3.92 (m, 5H), 3.59 (m, 2H), 3.00 (m, 4H), 2.82 (td, J = 15.7, 4.3 Hz, 2H), 2.72 (m, 4H), 2.09 (m, 2H), 1 .73 (m, 2H).
Example 8
5-(4-((1 -methyl-1 H-pyrazol-4-yl)amino)-1 ,3,5-triazin-2-yl)-2-(pyrrolidin-1 - yl)benzonitrile
Figure imgf000065_0001
To a solution of 2,4-dichloro-1 ,3,5-triazine (0.83 g, 5.6 mmol) in N,N-dimethylformamide
(DMF, 3 ml_) at 0 °C were added sequentially Ν,Ν-diisopropylethylamine (DIEA, 1 .0 ml_, 5.8 mmol) and a solution of 4-amino-1 -methylpyrazole (0.49 g, 5.0 mmol) in DMF (1 ml_). The mixture was stirred at 0 °C for 30 minutes and then allowed to warm to room temperature. The mixture was diluted with ethyl acetate and water and filtered through a pad of Celite diatomaceous earth. The filtered aqueous phase was extracted once with ethyl acetate. The combined extracts were washed once each with water and a saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 4-chloro-N-(1 -methyl- 1 H-pyrazol-4-yl)-1 ,3,5-triazin-2-amine, which carried forward without further purification.
LCMS-ESI+ (m/z): [M+H]+ calcd for C7H8CIN6: 21 1 .0; found: 21 1 .1
A mixture of 4-chloro-N-( 1 -methyl-1 H-pyrazol-4-yl)-1 ,3,5-triazin-2-amine (0.15 g, 0.71 mmol) and 2-(pyrrolidin-1 -yl)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (0.23 g, 0.78 mmol) in 1 ,2-dimethoxyethane (DME, 2 mL) was treated successively with palladium (II) acetate (0.016 g, 10 mol%), triphenylphosphine (0.056 g, 0.21 mmol), and 2M aqueous sodium carbonate solution (1.6 mL). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel to furnish 5-(4-((1-methyl-1 H-pyrazol-4-yl)amino)-1 ,3,5- triazin-2-yl)-2-(pyrrolidin-1-yl)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for C 8H19N8: 347.2; found: 347.3
1H NMR (400 MHz, DMSO-c/6) δ 10.16 (d, J = 5.4 Hz, 1 H), 8.74 (s, 0.5H), 8.65 (s, 0.5H), 8.46 (dd, J = 5.3, 2.2 Hz, 1 H), 8.35 (ddd, J = 25.3, 9.2, 2.2 Hz, 1 H), 8.01 - 7.93 (m, 1 H), 7.69 (s, 0.5H), 7.57 (s, 0.5H), 6.94 (t, J = 9.0 Hz, 1 H), 3.91 (s, 1.5H), 3.86 (s, 1.5H), 3.79 - 3.55 (m, 4H), 2.02 (m, 4H).
Example 9
5-(4-((1 -methyl-1 H^yrazol-4-yl)amino)-1 ,3,54riazin-2-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)benzonitrile
Figure imgf000066_0001
A suspension of 4-chloro-N-(1-methyl-1 H-pyrazol-4-yl)-1 ,3,5-triazin-2-amine (0.13 g, 0.59 mmol) and 2-((tetrahydro-2H-pyran-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzonitrile (0.21 g, 0.65 mmol) in 1 ,2-dimethoxyethane (DME, 2 mL) was treated successively with palladium (II) acetate (0.013 g, 10 mol%), triphenylphosphine (0.047 g, 0.18 mmol), and 2M aqueous sodium carbonate solution (1.3 mL). The mixture was irradiated for 1 hour in a microwave reactor at 125 °C. The crude mixture was purified by flash chromatography on silica gel to furnish 5-(4-((1- methyl-1 H-pyrazol-4-yl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)benzonitrile.
LCMS-ESI+ (m/z): [M+H]+ calcd for C-19H20N7O2: 378.2; found: 378.2
1H NMR (400 MHz, DMSO-c/6) δ 10.33 (d, J = 5.1 Hz, 1 H), 8.83 (s, 0.5H), 8.74 (s, 0.5H), 8.70 - 8.55 (m, 2H), 8.00 (d, J = 6.2 Hz, 1 H), 7.70 (s, 0.5H), 7.64 - 7.56 (m, 1.5H), 4.99 (m, 1 H), 4.00 - 3.82 (m, 5H), 3.70 - 3.52 (m, 2H), 2.09 (m, 2H), 1.74 (m, 2H). Example 10
5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin
(pyrrolidin-1 -yl)benzonitrile
Figure imgf000067_0001
To a solution of 2,4-dichloro-1 ,3,5-triazine (0.1 1 g, 0.71 mmol) in DMF (1 mL) at 0 C were added DIEA (0.13 mL, 0.73 mmol), followed by 4-(4-(oxetan-3-yl)piperazin-1 - yl)aniline (0.15 g, 0.64 mmol) and the mixture was stirred at 0 °C for 30 minutes and then allowed to stir overnight at room temperature. The mixture was concentrated to dryness under reduced pressure to provide 4-chloro-N-(4-(4-(oxetan-3-yl)piperazin-1 - yl)phenyl)-1 ,3,5-triazin-2-amine, which was carried forward without further purification as a solution in 1 ,2-dimethoxyethane/N,N-dimethylformamide (1 : 1 ). LCMS-ESI+ (m/z):
[M+H]+ calcd for C 6H2oCIN60: 347.1 ; found: 347.3
A mixture of 4-chloro-N-(4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)-1 ,3,5-triazin-2-amine (0.1 1 g, 0.32 mmol) and 2-(pyrrolidin-1 -yl)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzonitrile (0.10 g, 0.35 mmol) in 1 ,2-dimethoxyethane (DME, 2 mL)/N,N- dimethylformamide (DMF, 1 mL) was treated successively with palladium (II) acetate (0.007 g, 10 mol%), triphenylphosphine (0.025 g, 0.21 mmol), and 2M aqueous sodium carbonate solution (0.7 mL). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel to furnish 5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-
(pyrrolidin-l -yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C28H3-| N80: 483.3; found: 483.4
1H NMR (400 MHz, DMSO-c/6) δ 10.09 (s, 1 H), 8.71 (s, 1 H), 8.44 (s, 1 H), 8.34 (dd, J = 9.2, 2.1 Hz, 1 H), 7.65 (d, J = 24.3 Hz, 2H), 7.09 (s, 2H), 6.94 (d, J = 9.3 Hz, 1 H), 4.81 (m, 4H), 4.50 (m, 1 H), 3.70 (m, 4H), 3.40 - 2.80 (m, 8H), 2.02 (m, 4H).
Example 11
5-(4-((4-(4-acetylpiperazin-1 -yl)phenyl)amino)-1 ,3,54riazin-2-yl)-2-((tetrahydro-2H- yran-4-yl)oxy)benzonitrile
Figure imgf000068_0001
A suspension of 5-(4-chloro-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2/-/-pyran-4- yl)oxy)benzonitrile (53 mg, 0.16 mmol) and 1-(4-(4-aminophenyl)piperazin-1- yl)ethanone (44 mg, 0.20 mmol) in acetonitrile (2.5 mL) was treated with N,N- diisopropylethylamine (0.12 mL, 0.67 mmol). The mixture was heated in a microwave reactor for 60 minutes at 100 °C. The cooled reaction mixture was purified by prep HPLC (10 - 80 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide 5-(4- ((4-(4-acetylpiperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for C27H30N7O3: 500.2; found: 500.2
1H NMR (400 MHz, DMSO-c/6) δ 10.22 (m, 1 H), 8.79 (s, 1 H), 8.60 (m, 2H), 7.66 (bs, 2H), 7.60 (d, J = 9.3 Hz, 1 H), 7.06 (bs, 2H), 4.98 (m, 1 H), 3.99 - 3.83 (m, 2H), 3.63 (m, 4H), 3.60 (m, 2H), 3.16 (m, 4H), 2.09 (m, 5H), 1.73 (m, 2H).
Example 12
5-(4-((4-(4-methylpiperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-^ pyran-4-yl)oxy)benzonitrile.
Figure imgf000068_0002
4-hydroxytetrahydropyran (14 g, 140 mmol) was taken up in tetrahydrofuran (300 mL) and cooled in an ice-water bath. Potassium tert-butoxide (17 g, 150 mmol) was added, and the reaction mixture was stirred for 20 minutes in the bath before the addition of 4- fluoroisophthalonitnle (10 g, 68 mmol). The mixture continued to stir in the bath for 5 minutes before the removal of the bath. The mixture was stirred at room temperature overnight and then concentrated almost to dryness under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. The combined organics were washed once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, concentrated to dryness under reduced pressure. The residue was recrystallized from methanol to provide 4-((tetrahydro-2H-pyran-4- yl)oxy)isophthalonitrile. 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 2.1 Hz, 1 H), 8.16 (dd, J = 8.9, 2.1 Hz, 1 H), 7.60 (d, J = 9.0 Hz, 1 H), 5.01 (m, 1 H), 3.88 (m, 2H), 3.57 (m, 2H), 2.05 (m, 2H), 1 .70 (m, 2H).
A suspension of 4-((tetrahydro-2H-pyran-4-yl)oxy)isophthalonitrile (1.0 g, 4.4 mmol) in methanol (15 mL) was treated with sodium methoxide (24 mg, 0.44 mmol). The suspension was stirred at room temperature for two days. Cyanamide (0.28 g, 6.6 mmol) was added and the mixture was allowed to stir for 20 days before the addition of saturated aqueous sodium chloride solution (approximately 5 mL). The solid was collected by vacuum filtration, washed with water, and dried in a vacuum oven over P2O5 to provide N,3-dicyano-4-((tetrahydro-2H-pyran-4-yl)oxy)benzimidamide. LCMS-
ESI+ (m/z): [M+H]+ calcd for C-14H -15N4O2: 271 .1 ; found: 270.9
N,3-dicyano-4-((tetrahydro-2H-pyran-4-yl)oxy)benzimidamide (0.26 g, 0.96 mmol) was taken up as a suspension in MeCN (3 mL) and treated with (chloromethylene)dimethyliminium chloride (0.15 g, 1 .1 mmol), followed by dichloromethane (2 mL). After warming the mixture to 45 °C, an additional volume of dichloromethane (1 mL) was added. The mixture was stirred for 15 minutes at room temperature, and then the white precipitate was collected by vacuum filtration.
The solid and filtrate were combined in dichloromethane and washed with saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted three times with dichloromethane. The combined organics were washed with water, precipitating a solid. The aqueous washings were back-extracted 3 times with dichloromethane. The organics were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to provide 5-(4-chloro-1 ,3,5-triazin-2-yl)-2- ((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile.
1H NMR (400 MHz, Chloroform-c ) δ 9.01 (s, 1 H), 8.78 (d, J = 2.2 Hz, 1 H), 8.67 (dd, J = 9.0, 2.2 Hz, 1 H), 7.09 (d, J = 9.0 Hz, 1 H), 4.80 (tt, J = 7.2, 3.7 Hz, 1 H), 4.04 (ddd, J = 1 1 .2, 7.1 , 3.6 Hz, 2H), 3.67 (ddd, J = 1 1 .4, 7.2, 3.6 Hz, 2H), 2.27 - 2.02 (m, 2H), 2.02 -
I .84 (m, 2H).
A suspension of 5-(4-chloro-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)benzonitrile (0.22 g, 0.70 mmol) in acetonitrile (4 ml_) was treated with 4-(4- methylpiperazin-1 -yl)aniline (0.13 g, 0.70 mmol) and /V,/V-diisopropylethylamine (0.24 ml_, 1 .4 mmol). The suspension was warmed with a heat gun until homogeneous. The mixture was purified by flash chromatography (silica gel) to provide the impure desired material, which was recrystallized from methanol to provide 5-(4-((4-(4-methylpiperazin- 1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C26H30N7O2: 472.2; found: 472.3. 1 H NMR (400
MHz, DMSO-c/6) 5 10.15 (m, 1 H), 8.77 (s, 1 H), 8.60 (m, 2H), 7.59 (m, 3H), 7.00 (dd, J =
I I .0, 6.9 Hz, 2H), 4.98 (m, 1 H), 3.91 (m, 2H), 3.59 (m, 2H), 3.15 (m, 4H), 2.50 (m, 4H), 2.26 (s, 3H), 2.09 (m, 2H), 1 .74 (m, 2H). Example 13
5-(4-((3-methoxy-4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1,3,5-triazin-2-yl)- H-pyran-4-yl)oxy)benzonitrile
Figure imgf000070_0001
A mixture of 1 -fluoro-2-methoxy-4-nitrobenzene (1 .0 g, 5.8 mmol), 1 -(oxetan-3- yl)piperazine (0.91 g, 6.4 mmol), and potassium carbonate (1 .6 g, 12 mmol) in N,N- dimethylformamide (9 ml_) was stirred at 100 °C for 16 hours. The mixture was allowed to cool to room temperature. The supernatant was removed by pipette and concentrated under reduced pressure. This residue was combined with the solids and partitioned between ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed twice with water, once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to give 1 -(2-methoxy-4-nitrophenyl)-4-(oxetan-3- yl)piperazine. LCMS-ESI+ (m/z): [M+H]+ calcd for C14H20N3O4: 294.1 ; found: 294.2
1-(2-methoxy-4-nitrophenyl)-4-(oxetan-3-yl)piperazine (1 .6 g, 5.5 mmol) was taken up in a mixture of 2-methyltetrahydrofuran/methanol (1 : 1 , 60 ml_) . The suspension was warmed until nearly homogeneous. After cooling to room temperature, the mixture was degassed before the addition of 10 % palladium on charcoal (250 mg). The mixture was stirred under a balloon of hydrogen for three days, then filtered through a pad of Celite diatomaceous earth. The filtrate was concentrated under reduced pressure to provide 3-methoxy-4-(4-(oxetan-3-yl)piperazin-1 -yl)aniline. LCMS-ESI+ (m/z): [M+H]+ calcd for C-|4H22N302: 264.2; found: 264.2
To a solution of 2,4-dichloro-1 ,3,5-triazine (0.41 g, 2.7 mmol) in N,N-dimethylformamide
(DMF, 6 ml_) at 0 °C were added sequentially Ν,Ν-diisopropylethylamine (DIEA, 0.49 ml_, 2.8 mmol) and 3-methoxy-4-(4-(oxetan-3-yl)piperazin-1 -yl)aniline (0.65 g, 2.5 mmol). The mixture was stirred at 0 °C for 30 minutes and then allowed to warm to room temperature. The mixture was diluted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined extracts were washed once each with water and a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via flash chromatography on silica gel to provide 4-chloro-N-(3- methoxy-4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)-1 ,3,5-triazin-2-amine. LCMS-ESI+
(m/z): [M+H]+ calcd for
Figure imgf000071_0001
377.1 ; found: 377.4 A mixture of 4-chloro-N-(3- methoxy-4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)-1 ,3,5-triazin-2-amine (0.15 g, 0.40 mmol), 2-((tetrahydro-2H-pyran-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzonitrile (0.14 g, 0.44 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.023 g, 5 mol%) in 1 ,2-dimethoxyethane (DME, 6 ml_) was treated with 2M aqueous sodium carbonate solution (0.90 ml_). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel, followed by prep HPLC (10 - 70 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer). The concentrated residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The aqueous phase was extracted twice with ethyl acetate. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to provide 5-(4-((3-methoxy-4-(4-(oxetan-3- yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C29H34N7O4: 544.3; found:
544.2 . 1H NMR (400 MHz, DMSO-c/6) δ 10.23 (br, 1 H), 8.81 (s, 1 H), 8.64 (d, J = 2.1 Hz, 1 H), 8.61 (dd, J = 8.9, 2.2 Hz, 1 H), 7.67 (bs, 1 H), 7.61 (d, J = 9.0 Hz, 1 H), 7.45 - 7.18 (br, 1 H), 6.94 (d, J = 8.5 Hz, 1 H), 4.98 (m, 1 H), 4.60 (t, J = 6.5 Hz, 2H), 4.50 (t, J = 6.1 Hz, 2H), 3.99 - 3.76 (m, 5H), 3.59 (m, 2H), 3.51 (m, 1 H), 3.36 (s, 3H), 3.02 (br, 4H), 2.45 (br, 4H), 2.18 - 2.03 (m, 2H), 1.73 (m, 2H).
Example 14
4-((4-(3-cyano-4-((tetrahydro-2H^yran-4-yl)oxy)phenyl)-1 ,3,54riazin-2-yl)amino) methyl benzamide
Figure imgf000072_0001
A suspension of 5-(4-chloro-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)benzonitrile (53 mg, 0.17 mmol) and 4-amino-/V-methylbenzamide (30 mg, 0.20 mmol) in acetonitrile (2.5 ml_) was treated with /V,/V-diisopropylethylamine (0.12 ml_, 0.67 mmol). The mixture was heated in a microwave reactor for 120 minutes at 120 °C. After cooling to room temperature, the solid was collected by filtration, washed with acetonitrile, and dried under house vacuum and then in a vacuum oven (60 °C) over P2O5 to provide 4-((4-(3-cyano-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-1 ,3,5-triazin-2- yl)amino)-N-methylbenzamide. LCMS-ESI+ (m/z): [M+H]+ calcd for C23H23N6O3: 431 .2; found: 431 .0 1 H NMR (400 MHz, DMSO-c/6) δ 10.61 (s, 1 H), 8.91 (s, 1 H), 8.64 (m, 2H), 8.40 (m, 1 H), 7.90 (m, 4H), 7.61 (d, J = 9.5 Hz, 1 H), 4.99 (m, 1 H), 3.91 (m, 2H), 3.59 (m, 2H), 2.83 (d, J = 4.4 Hz, 3H), 2.10 (m, 2H), 1 .74 (m, 2H).
Example 15
(S)-2-((1 -(2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3- l)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000072_0002
5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-(piperidin-4- yloxy)benzonitrile (78 mg, 0.15 mmol) and L-(-)-lactic acid (Sigma Aldrich, 21 mg, 0.23 mmol) were taken up as suspension in acetonitrile (3 ml_). The mixture was treated successively with N,/V-diisopropylethylamine (80 μΙ_, 0.46 mmol) and N- [(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminiumhexafluorophosphate Λ/oxide (HATU, 87 mg, 0.23 mmol). The mixture was stirred for two hours at room temperature and then purified by flash chromatography (silica gel) to provide (S)-2-((1-(2-hydroxypropanoyl)piperidin-4-yl)oxy)- 5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile.
LCMS-ESI+ (m/z): [M+H]+ calcd for C3 H37N804: 585.3; found: 585.4
1H NMR (400 MHz, DMSO-c/6) δ 10.16 (m, 1 H), 8.77 (s, 1 H), 8.70 - 8.45 (m, 2H), 7.60 (d, J = 9.3 Hz, 2H), 6.99 (m, 2H), 5.07 (m, 1 H), 4.97 (m, 1 H), 4.61 (m, 2H), 4.56 - 4.46 (m, 3H), 3.94 - 3.68 (m, 2H), 3.68 - 3.43 (m, 3H), 3.17 (m, 4H), 2.51 - 2.39 (m, 4H), 2.12 - 1.94 (m, 2H), 1.84 - 1.63 (m, 2H), 1.24 (d, J = 6.5 Hz, 3H).
Example 16
2-((1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- riazin-2-yl)benzonitrile
Figure imgf000073_0001
5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-(piperidin-4- yloxy)benzonitrile (57 mg, 0.1 1 mmol), and glycolic acid (13 mg, 0.17 mmol) were taken up as suspension in dichloromethane (3 mL). The mixture was treated successively with N,/V-diisopropylethylamine (39 μΙ_, 0.22 mmol) and N-[(dimethylamino)-1 H-1 ,2,3- triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N- oxide (HATU, 63 mg, 0.17 mmol). The suspension was stirred for three hours at room temperature and then purified by flash chromatography (silica gel) to provide 2-((1-(2- hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)- 1 ,3,5-triazin-2-yl)benzonitrile.
LCMS-ESI+ (m/z): [M+H]+ calcd for C3oH35N804: 571.3; found: 571.4
1H NMR (400 MHz, DMSO-c/6) δ 10.18 (m, 1 H), 8.77 (s, 1 H), 8.60 (m, 2H), 7.61 (m, 2H), 7.01 (s, 2H), 5.04 (m, 1 H), 4.60 (m, 3H), 4.52 (m, 2H), 4.17 (d, J = 5.4 Hz, 2H), 3.75 (m, 1 H), 3.61 (m, 1 H), 3.49 (m, 2H), 3.38 (m, 1 H), 3.18 (m, 4H), 2.45 (m, 4H), 2.06 (m, 2H), 1.76 (m, 2H).
Example 17
2-((1 ,1 -dioxidotetrahydro-2H4hiopyran-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin
1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000074_0001
Preparation of 5-bromo-2-((1 ,1-dioxidotetrahydro-2/-/-thiopyran-4-yl)oxy)benzonitrile: A solution of 5-bromo-2-((tetrahydro-2/-/-thiopyran-4-yl)oxy)benzonitrile (1.2 g, 4.0 mmol) in dichloromethane (50 ml_) was treated with calcium carbonate (1.6 g, 16 mmol). The resulting suspension was cooled in an ice-water bath. Meta-chloroperbenzoic acid (mCPBA, Sigma Aldrich, < 77 %, 2.3 g, 10 mmol) was added in a single portion. The mixture was stirred overnight while ice-water bath gradually regained room temperature. The mixture was filtered through a fritted funnel, eluting with dichloromethane. The filtrate was washed twice each with aqueous solutions of 5 % sodium bisulfite and saturated sodium hydrogen carbonate. The organics were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to provide the desired material. LCMS-ESI"1" (m/z): [M+H]+ calcd for C-|2H-| 3BrNC>3S: 330.0; found:
329.9
Preparation of 2-((1 ,1 -dioxidotetrahydro-2/-/-thiopyran-4-yl)oxy)-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)benzonitrile: A mixture of 5-bromo-2-((1 ,1-dioxidotetrahydro-2/-/- thiopyran-4-yl)oxy)benzonitrile (0.55 g, 1.7 mmol), bis(pinacolato)diboron (0.84 g, 3.3 mmol), potassium acetate (0.49 g, 5.0 mmol), and [1 ,1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (0.12 g, 10 mol%) in 1 ,4-dioxane (6 ml_) was heated at 90 °C overnight. LC/MS analysis indicated the consumption of the bromide starting material. The mixture was filtered through a pad of Celite diatomaceous earth and concentrated to dryness under reduced pressure to provide the desired material, which was carried forward without further purification. LCMS-ESI+
(m/z): [M+H]+ calcd for C18H25BNO5S: 378.2; found: 378.1
Preparation of 2-((1 ,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile: A mixture of 4-chloro-N-(4- (4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1 ,3,5-triazin-2-amine (0.17 g, 0.49 mmol), crude 2-((1 ,1-dioxidotetrahydro-2/-/-thiopyran-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzonitrile (1.6 mmol assumed), and tetrakis(triphenylphosphine)palladium(0) (0.042 g, 7.5 mol%) in 1 ,2-dimethoxyethane (DME, 6 ml_) was treated with 2M aqueous sodium carbonate solution (1.1 ml_). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel, followed by trituration with methanol, to provide 2-((1 ,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C28H31 N7O4S: 562.2; found: 562.3. 1H NMR (400 MHz, DMSO-c/6) δ 10.16
(m, 1 H), 8.78 (s, 1 H), 8.61 (m, 2H), 7.60 (m, 2H), 7.01 (m, 2H), 5.1 1 (m, 1 H), 4.61 (m, 2H), 4.52 (m, 2H), 3.49 (m, 1 H), 3.27 (m, 4H), 3.19 (s, 4H), 2.46 (m, 4H), 2.36 (m, 4H). Example 18
5-(4-((4-(piperazin-1 -yl)phenyl)amino)-1,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4- , trifluoroacetic acid salt
Figure imgf000075_0001
tert-butyl 4-(4-((4-(3-cyano-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-1 ,3,5-triazin-2- yl)amino)phenyl)piperazine-1-carboxylate (0.15 g, 0.27 mmol assumed) was taken up in dichloromethane (5 ml_) and treated with trifluoroacetic acid (0.9 ml_). After standing overnight at room temperature, the mixture was purified by prep HPLC (10 - 60 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide 5-(4-((4-(piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile, trifluoroacetic acid salt. LCMS-ESI"1" (m/z): [M+H]+ calcd for C25H28 7O2: 458.2; found: 458.3 1H NMR (400 MHz, DMSO-c/6) δ 10.23 (m, 1 H), 8.81 (m, 3H), 8.60 (m, 2H), 7.68 (m, 2H), 7.60 (d, J = 9.1 Hz, 1 H), 7.07 (s, 2H), 4.99 (m, 1 H), 3.91 (m, 2H), 3.59 (m, 2H), 3.33 (m, 8H), 2.09 (m, 2H), 1.73 (m, 2H). Example 19 5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1,3,5-triazin-2-yl)-2- ((tetrahydro-2H-thiopyran-4-yl)oxy)benzonitrile
Figure imgf000076_0001
Preparation of 5-bromo-2-((tetrahydro-2H-thiopyran-4-yl)oxy)benzonitrile: A solution of tetrahydrothiopyran-4-ol (Sigma Aldrich, 2.0 g, 17 mmol) in N,N-dimethylformamide (DMF, 30ml_) was treated with sodium hydride (60 % in mineral oil, 0.68 g, 17 mmol) in a single portion at room temperature. The mixture was stirred for one hour at room temperature before 5-bromo-2-fluorobenzonitrile (2.8 g, 14 mmol) was added in a single portion. An additional volume of DMF (20 ml_) was added. The mixture was stirred on a 50 °C heating block for two hours before it was poured onto ice (approximately 100 g), precipitating a solid that was then collected by vacuum filtration and dried in a vacuum oven over phosphorus pentoxide to provide the desired product. 1H NMR (400 MHz, DMSO-c/6) δ 8.03 (d, J = 2.5 Hz, 1 H), 7.82 (dd, J = 9.1 , 2.6 Hz, 1 H), 7.31 (d, J = 9.1 Hz, 1 H), 4.74 (m, 1 H), 2.83 (m, 2H), 2.63 (m, 2H), 2.16 (m, 2H), 1 .90 (m, 2H).
Preparation of 2-((tetrahydro-2H-thiopyran-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzonitrile: A mixture of 5-bromo-2-((tetrahydro-2H-thiopyran-4- yl)oxy)benzonitrile (0.38 g, 1 .3 mmol), bis(pinacolato)diboron (0.65 g, 2.5 mmol), potassium acetate (0.38 g, 3.8 mmol), and [1 , 1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (0.095 g, 10 mol%) in 1 ,4- dioxane (6 ml_) was heated at 90 °C overnight. LC/MS analysis indicated the consumption of the bromide starting material. The mixture was filtered through a pad of Celite diatomaceous earth and concentrated to dryness under reduced pressure to provide the putative desired material.
Preparation of 5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2- ((tetrahydro-2H-thiopyran-4-yl)oxy)benzonitrile: A mixture of 4-chloro-N-(4-(4-(oxetan-3- yl)piperazin-1 -yl)phenyl)-1 ,3,5-triazin-2-amine (0.13 g, 0.38 mmol), crude 2-((tetrahydro- 2H-thiopyran-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (1 .3 mmol assumed), and tetrakis(triphenylphosphine)palladium(0) (0.033 g, 7.5 mol%) in 1 ,2-dimethoxyethane (DME, 6 ml_) was treated with 2M aqueous sodium carbonate solution (0.86 mL). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel, followed by recrystallization from methanol, to provide 5-(4-((4-(4-(oxetan-3-yl)piperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-thiopyran-4-yl)oxy)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C28H32N7O2S: 530.2; found: 530.3 1 H NMR (400 MHz, DMSO-c/6) δ 10.15 (m, 1 H), 8.77 (s, 1 H), 8.58 (m, 2H), 7.62 (m, 2H), 7.55 (d, J = 9.2 Hz, 1 H), 6.99 (d, J = 10.7 Hz, 2H), 4.89 (m, 1 H), 4.61 (m, 2H), 4.52 (m, 2H), 3.49 (m, 1 H), 3.19 (m, 4H), 2.88 (m, 2H), 2.70 (m, 2H), 2.45 (m, 4H), 2.25 (m, 2H), 1 .98 (m, 2H).
Example 20
5-(4-((3-methoxy-4-(1 -(oxetan-3-yl)piperidin-4-yl)phenyl)amino)-1 ,3,54riazin-2-yl)-2- -pyran-4-yl)oxy)benzonitrile
Figure imgf000077_0001
Preparation of tert-butyl 4-(2-methoxy-4-nitrophenyl)-5,6-dihydropyridine-1 (2/-/)- carboxylate: 2-bromo-5-nitroanisole (5.0 g, 22 mmol), 4-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1 -carboxylic acid tert-butyl ester (Boron Molecular, 7.0 g, 23 mmol), tetrakis(triphenylphosphine)palladium(0) (1 .5 g, 1 .3 mmol), sodium carbonate aqueous solution (2M, 32 mL, 65 mmol), and 1 ,4-dioxane (75 mL) were combined in a sealed tube, and the mixture was heated at 80 °C for 3 days. After cooling to room temperature, the mixture was diluted with ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed once with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to provide the desired material. LCMS-ESI+ (m/z): [M - tBu +H]+ calcd for C-13H-15N2O5: 279.1 ; found: 279.0.
Preparation of 4-(2-methoxy-4-nitrophenyl)-1 ,2,3,6-tetrahydropyridin-1 -ium 2,2,2- trifluoroacetate: tert-butyl 4-(2-methoxy-4-nitrophenyl)-5,6-dihydropyridine-1 {2H)- carboxylate (1 .3 g, 3.8 mmol) was taken up in dichloromethane (6 mL) and treated with trifluoroacetic acid (5.8 ml_, 75 mmol). The mixture was allowed to stand at room temperature for 3 hours and then concentrated under reduced pressure. The residue was reconstituted in dichloromethane and concentrated. This cycle was repeated three times with dichloromethane, then once with diethyl ether, to provide the desired material, which was carried forward without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C-12H-15N2O3: 235.1 ; found: 234.9.
Preparation of 4-(2-methoxy-4-nitrophenyl)-1 -(oxetan-3-yl)-1 ,2,3,6-tetrahydropyridine: 3- iodooxetane (0.66 ml_, 7.5 mmol) was added via syringe to a suspension of 4-(2- methoxy-4-nitrophenyl)-1 ,2,3,6-tetrahydropyridin-1 -ium 2,2,2-trifluoroacetate (3.8 mmol assumed) and potassium carbonate (2.6 g, 19 mmol) in acetonitrile. Mixture stirred overnight with heating on a 130 °C block. After cooling to room temperature, the mixture was filtered though a pad of Celite diatomaceous earth, eluting with dichloromethane and acetonitrile. The filtrate was concentrated to dryness under reduced pressure and then purified by flash chromatography (silica gel) to provide the desired material. LCMS-ESI"1" (m/z): [M+H]+ calcd for C-15H-19N2O4: 291 .1 ; found:
291 .1 .
Preparation of 3-methoxy-4-(1 -(oxetan-3-yl)piperidin-4-yl)aniline: 4-(2-methoxy-4- nitrophenyl)-1 -(oxetan-3-yl)-1 ,2,3,6-tetrahydropyridine (0.64 g, 2.2 mmol) was taken up in methanol (~ 50 ml_) in a Parr bottle. After being degassed, the mixture was treated with 10 % palladium on charcoal (150 mg) and shaken overnight under hydrogen (55 psi). The mixture was filtered through a pad of Celite diatomaceous earth, and the filtrate was concentrated under reduced pressure to provide the desired material.
LCMS-ESI+ (m/z): [M+H]+ calcd for C-15H23N2O2: 263.2; found: 263.1
Preparation of 5-(4-((3-methoxy-4-(1 -(oxetan-3-yl)piperidin-4-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile: A suspension of 5-(4-chloro- 1 ,3,5-triazin-2-yl)-2-((tetrahydro-2/-/-pyran-4-yl)oxy)benzonitrile (100 mg, 0.32 mmol) and 3-methoxy-4-(1 -(oxetan-3-yl)piperidin-4-yl)aniline (1 10 mg, 0.41 mmol) in acetonitrile (3 ml_) was treated with /V,/V-diisopropylethylamine (0.22 ml_, 1 .3 mmol). The mixture was heated in a microwave reactor for 20 minutes at 80 °C. The cooled reaction mixture was purified by flash chromatography (silica gel) and then triturated with methanol to provide 5-(4-((3-methoxy-4-(1 -(oxetan-3-yl)piperidin-4- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile. LCMS-
ESI+ (m/z): [M+H]+ calcd for C3oH35N604: 543.3; found: 543.4
1H NMR (400 MHz, DMSO-c/6) δ 10.34 (bs, 1 H), 8.84 (s, 1 H), 8.63 (m, 2H), 7.74 (br, 1 H), 7.62 (m, 1 H), 7.42 (m, 1 H), 7.25 (m, 1 H), 5.00 (m, 1 H), 4.58 (m, 2H), 4.49 (m, 2H), 4.00 - 3.78 (m, 5H), 3.59 (m, 2H), 3.44 (m, 1 H), 3.02 - 2.74 (m, 3H), 2.09 (m, 2H), 1 .89 (m, 2H), 1 .73 (m, 6H).
Example 21 :
4-((4-(3-cyano-4-((tetrahydro-2H^yran-4-yl)oxy)phenyl)-1,3,5-triazin-2-yl)amino) e
Figure imgf000079_0001
Preparation of 4-amino-2-methoxybenzamide: 2-methoxy-4-nitrobenzonitrile (1 .0 g, 5.6 mmol) was taken up as a suspension in ethanol/water (3: 1 , 15 mL). Hydrido(dimethylphosphinous acid-kP)[hydrogen bis(dimethylphosphinito- kP)]platinum(ll) (Strem Chemicals, Inc., 24 mg, 56 pmol) was added. The mixture was stirred overnight in a sealed vessel at 120 °C. After cooling to room temperature, the suspension was concentrated to dryness under reduced pressure to provide the desired carboxamide, which was carried forward without further purification.
The concentrated residue was diluted with methanol and 2-methyltetrahydrofuran. The suspension was warmed with a heat gun and was then allowed to cool to room temperature. The mixture was degassed and then treated with 10 % palladium on carbon (catalytic). The mixture was shaken under 50 psi hydrogen for 3 days. The catalyst was removed by filtration through a pad of Celite diatomaceous earth. The filtrate was concentrated under reduced pressure to provide 4-amino-2- methoxybenzamide. LCMS-ESI"1" (m/z): [M+H]+ calcd for C8H-1 1 N2O2: 167.1 ; found:
167.0.
Preparation of 4-((4-chloro-1 ,3,5-triazin-2-yl)amino)-2-methoxybenzamide: To a solution of 2, 4-dichloro-1 ,3,5-triazine (0.40 g, 2.6 mmol) in N,/V-dimethylformamide (DMF, 6 mL) at 0 °C were added sequentially Ν,Ν-diisopropylethylamine (DIEA, 0.48 mL, 2.7 mmol)
4-amino-2-methoxybenzamide (0.40 g, 2.4 mmol), and the mixture was stirred at 0 °C and then allowed to warm to room temperature. The mixture was diluted with ethyl acetate and water. A small volume of tetrahydrofuran was added. The biphasic mixture was filtered, providing 4-((4-chloro-1 ,3,5-triazin-2-yl)amino)-2-methoxybenzamide. Additional desired material was obtained by separation of the filtered mixture and extraction of the aqueous phase twice with ethyl acetate. The combined organics were filtered, washed once with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to provide 4-((4-chloro-1 ,3,5-triazin-2-yl)amino)-2-methoxybenzamide. LCMS-ESI+ (m/z):
[M+H]+ calcd for C-| H -| -| CIN602: 280.1 ; found: 280.0.
Preparation of 4-((4-(3-cyano-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-1 ,3,5-triazin-2- yl)amino)-2-methoxybenzamide: A mixture of 4-((4-chloro-1 ,3,5-triazin-2-yl)amino)-2- methoxybenzamide (0.33 g, 1.2 mmol), 2-((tetrahydro-2H-pyran-4-yl)oxy)-5-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (0.31 g, 0.94 mmol), tetrakis(triphenylphosphine)palladium(0) (0.10 g, 7.5 mol%) in 1 ,2-dimethoxyethane (DME, 3 ml_) was treated with 2M aqueous sodium carbonate solution (2.6 ml_). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel to provide 4-((4-(3-cyano-4- ((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-1 ,3,5-triazin-2-yl)amino)-2-methoxybenzamide.
LCMS-ESI+ (m/z): [M+H]+ calcd for C23H23N604: 447.2; found: 447.1 1H NMR (400
MHz, DMSO-c/6) δ 10.62 (s, 1 H), 8.93 (s, 1 H), 8.65 (m, 2H), 7.92 (d, J = 8.5 Hz, 1 H), 7.62 (m, 2H), 7.46 (m, 2H), 4.99 (m, 1 H), 4.02 (s, 3H), 3.92 (m, 2H), 3.60 (m, 2H), 2.09 (m, 2H), 1.74 (m, 2H).
Example 22
( ?)-2-((1-(2-hydroxyacetyl)pyrrolidin-3-yl)oxy)-5-(4-((3-methoxy-4-(4-(oxetan-3- yl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000080_0001
Preparation of (R)-tert-butyl 3-(2-cyano-4-(4-((3-methoxy-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenoxy)pyrrolidine-1-carboxylate: A mixture of 4- chloro-N-(3-methoxy-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1 ,3,5-triazin-2-amine (0.20 g, 0.53 mmol), (R)-tert-butyl 3-(2-cyano-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)pyrrolidine-1 -carboxylate (0.24 g, 0.58 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.046 g, 7.5 mol%) in 1 ,2-dimethoxyethane (DME, 3 ml_) was treated with 2M aqueous sodium carbonate solution (1.2 ml_). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The layers of the crude mixture were separated. The aqueous phase was extracted three times with dichloromethane. The combined organics were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to provide the desired material, which was carried forward without further purification.
LCMS-ESI+ (m/z): [M+H]+ calcd for C33H41 N805: 629.3; found: 629.2.
Preparation of (R)-5-(4-((3-methoxy-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)- 1 ,3,5-triazin-2-yl)-2-(pyrrolidin-3-yloxy)benzonitrile: Crude (R)-tert-butyl 3-(2-cyano-4-(4- ((3-methoxy-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)phenoxy)pyrrolidine-1-carboxylate (0.53 mmol assumed) was taken up in dichloromethane (8 ml_) and treated with trifluoroacetic acid (2 ml_). After 30 minutes, the mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography (silica gel) to provide the desired material. LCMS-ESI+ (m/z):
[M+H]+ calcd for C28H33N803: 529.3; found: 529.3.
Preparation of (R)-2-((1-(2-hydroxyacetyl)pyrrolidin-3-yl)oxy)-5-(4-((3-methoxy-4-(4- (oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile: (R)-5-(4-((3- methoxy-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-(pyrrolidin- 3-yloxy)benzonitrile (60 mg, 0.1 1 mmol) and glycolic acid (13 mg, 0.17 mmol) were taken up as suspension in dichloromethane (3 ml_). The mixture was treated successively with /V,/V-diisopropylethylamine (59 μΙ_, 0.34 mmol) and N- [(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminiumhexafluorophosphate N-oxide (HATU, 65 mg, 0.17 mmol). The mixture stood overnight at room temperature before being purified by flash chromatography (silica gel) to provide (R)-2-((1-(2-hydroxyacetyl)pyrrolidin-3-yl)oxy)-5- (4-((3-methoxy-4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C3oH35N805: 587.3; found: 587.4 H NMR (400 MHz, DMSO-c/6) δ 10.25 (m, 1 H), 8.81 (d, J = 3.9 Hz, 1 H), 8.64 (m, 2H),
7.78 - 7.51 (m, 2H), 7.33 (br, 1 H), 6.99 (m, 1 H), 5.41 (m, 1 H), 4.68 (m, 2H), 4.60 (m, 2H), 4.51 (m, 2H), 4.07 (m, 1 H), 3.86 (m, 4H), 3.70 (m, 2H), 3.49 (m, 1 H), 3.35 (m, 1 H), 3.02 (m, 4H), 2.45 (m, 4H), 2.41 - 2.10 (m, 2H).
Example 23
(S)-2-((1-(2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4-(1-(oxetan-3-yl)piperidin- 4-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000082_0001
5-(4-((4-(1-(oxetan-3-yl)piperidin-4-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-(piperidin-4- yloxy)benzonitrile (60 mg, 0.12 mmol) and L-(-)-lactic acid (Sigma Aldrich, 16 mg, 0.18 mmol) were taken up as suspension in acetonitrile (3 ml_). The mixture was treated successively with N,/V-diisopropylethylamine (61 μΙ_, 0.35 mmol) and N- [(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminiumhexafluorophosphate Λ/oxide (HATU, 67 mg, 0.18 mmol). The suspension was sonicated for a few minutes and diluted with dichloromethane (2 ml_). The mixture stood overnight at room temperature before being purified by flash chromatography (silica gel) to provide (S)-2-((1-(2-hydroxypropanoyl)piperidin-4-yl)oxy)- 5-(4-((4-(1-(oxetan-3-yl)piperidin-4-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile.
LCMS-ESI+ (m/z): [M+H]+ calcd for C32H38N704: 584.3; found: 584.4.
1H NMR (400 MHz, DMSO-c/6) δ 10.33 (s, 1 H), 8.81 (m, 1 H), 8.60 (m, 2H), 7.72 (m, 2H), 7.60 (m, 1 H), 7.31 (m, 2H), 5.18 - 4.91 (m, 3H), 4.85 (t, J = 7.2 Hz, 1 H), 4.60 (t, J = 6.5 Hz, 2H), 4.51 (m, 3H), 3.80 (m, 2H), 3.59 (m, 3H), 2.91 (m, 2H), 2.33 (m, 1 H), 2.04 (m, 4H), 1.89 - 1.61 (m, 4H), 1.24 (dd, J = 6.6, 1.9 Hz, 3H).
Example 24
2-((tetrahydro-2H-pyran-4-yl)oxy)-5-(4-((3,4,5-trimethoxyphenyl)amino)-1,3,5- triazin-2-yl)benzonitrile
Figure imgf000083_0001
A suspension of 5-(4-chloro-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2/-/-pyran-4- yl)oxy)benzonitrile (100 mg, 0.32 mmol) and 3,4,5-trimethoxyaniline (69 mg, 0.38 mmol) in acetonitrile (3 mL) was treated with /V,/V-diisopropylethylamine (0.22 mL, 1.3 mmol). The mixture was heated in a microwave reactor for 20 minutes at 80 °C. The precipitated solid was collected by filtration, washed with methanol, and dried under vacuum to provide the desired material. LCMS-ESI+ (m/z): [M+H]+ calcd for C24H26N5°5: 464.2; found: 464.1 1H NMR (400 MHz, DMSO-c/6) δ 10.29 (bs, 1 H), 8.84 (s, 1 H), 8.66 (d, J = 2.2 Hz, 1 H), 8.62 (dd, J = 9.0, 2.2 Hz, 1 H), 7.61 (d, J = 9.1 Hz, 1 H), 7.28 (br, 2H), 4.99 (m, 1 H), 4.03 - 3.77 (m, 8H), 3.70 (s, 3H), 3.59 (m, 2H), 2.09 (m, 2H), 1.74 (m, 2H).
Example 25 and Example 26
5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((1 - oxidotetrahydro-2H-thiopyran-4-yl)oxy)benzonitrile, (non-polar diastereomer 1) and 5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)-2-((1- oxidotetrahydro-2H-thiopyran-4-yl)oxy)benzonitrile, (polar diastereomer 2).
5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((1 - hiopyran-4-yl)oxy)benzonitrile, diastereomer 1
Figure imgf000083_0002
Preparation of 2-((1-oxidotetrahydro-2H-thiopyran-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzonitrile (1 :1 mixture of disastereomers): 5-bromo-2-((tetrahydro-
2H-thiopyran-4-yl)oxy)benzonitrile (0.59 g, 2.0 mmol) was taken up in acetonitrile (5 mL) by warming with a heat gun. After cooling, the mixture was treated with iron (III) chloride (10 mg, 3 mol%). The mixture was stirred for about 5 minutes at room temperature before the addition of periodic acid (0.50 g, 2.2 mmol) in a single portion. After 15 minutes of stirring, the mixture was quenched by the addition of 25 % wt/wt aqueous sodium thiosulfate solution (Na2S2C>3, ~ 10 ml_). The suspension was allowed to stir for 10 minutes, then was extracted three times with dichloromethane. After first extraction, the mixture was filtered through a pad of Celite diatomaceous earth. The combined extracts were dried over anhydrous magnesium sulfate, filtered, concentrated to dryness under reduced pressure to give the desired product as a 1 :1 mixture of diasteromers. LCMS-ESI"1" (m/z): [M+H]+ calcd for C-|2H-| 3BrNC>2S: 314.0; found:
314.0.
Preparation of 2-((1-oxidotetrahydro-2H-thiopyran-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzonitrile (1 :1 mixture of diastereomers): A mixture of 2-((1- oxidotetrahydro-2H-thiopyran-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzonitrile (1 :1 mixture of disastereomers, 0.60 g, 1.9 mmol), bis(pinacolato)diboron (0.97 g, 3.8 mmol), potassium acetate (0.56 g, 5.7 mmol), and [1 ,1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (0.14 g, 10 mol%) in 1 ,4-dioxane (6 ml_) was heated at 90 °C overnight. LC/MS analysis indicated an incomplete conversion. To the mixture was added additional and [1 , 1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (1.3 g, 90 mol%) The mixture continued to heat for another 4 hours, at which time LC/MS analysis indicated a complete conversion. The mixture was filtered through a pad of Celite diatomaceous earth, and the filtrate was concentrated under reduced pressure to provide the desired product as a 1 :1 mixture of diasteromers, which was carried forward without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C18H25BNO4S: 362.2; found: 362.2
Preparation of 5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2- ((1-oxidotetrahydro-2H-thiopyran-4-yl)oxy)benzonitrile, diastereomer 1 : A mixture of 4- chloro-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1 ,3,5-triazin-2-amine (0.40 g, 1.2 mmol), crude 2-((1-oxidotetrahydro-2H-thiopyran-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzonitrile (1 :1 mixture of diastereomers, 1.9 mmol assumed), and tetrakis(triphenylphosphine)palladium(0) (0.10 g, 7.5 mol%) in 1 ,2-dimethoxyethane (DME, 8 ml_) was treated with 2M aqueous sodium carbonate solution (2.6 ml_). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel to provide two separable diastereomers of unknown relative configuration. Each component was separately flash chromatographed a second time and then triturated with methanol to provide 5-(4-((4-(4- (oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((1-oxidotetrahydro-2H- thiopyran-4-yl)oxy)benzonitrile, non-polar diastereomer 1 and 5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((1-oxidotetrahydro-2H-thiopyran-4- yl)oxy)benzonitrile, polar diastereomer 2.
5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((1- oxidotetrahydro-2H-thiopyran-4-yl)oxy)benzonitrile, non-polar diastereomer 1 :
5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((1- oxidotetrahydro-2H-thiopyran-4-yl)oxy)benzonitrile, non-polar diastereomer 1 : LCMS- ESI+ (m/z): [M+H]+ calcd for C28H32N7O3S: 546.3; found: 546.3 1H NMR (400 MHz,
DMSO-c/6) δ 10.16 (m, 1 H), 8.78 (s, 1 H), 8.61 (m, 2H), 7.61 (m, 3H), 7.02 (d, J = 10.4 Hz, 2H), 5.09 (m, 1 H), 4.61 (m, 2H), 4.52 (m, 2H), 3.49 (m, 1 H), 3.18 (m, 4H), 2.90 (m, 4H), 2.46 (m, 6H), 2.04 (m, 2H).
5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((1- oxidotetrahydro-2H-thiopyran-4-yl)oxy)benzonitrile, polar diastereomer 2: LCMS-ESI+
(m/z): [M+H]+ calcd for C28H32N7O3S: 546.3; found: 546.3 1H NMR (400 MHz, DMSO- d6) δ 10.16 (m, 1 H), 8.78 (s, 1 H), 8.60 (m, 2H), 7.62 (m, 3H), 6.99 (d, J = 1 1.6 Hz, 2H), 4.88 (m, 1 H), 4.61 (m, 2H), 4.52 (m, 2H), 3.49 (m, 1 H), 3.19 (m, 4H), 3.10 - 2.87 (m, 4H), 2.45 (m, 4H), 2.31 (m, 2H), 2.14 (m, 2H). Example 27
5-(4-((3-fluoro-4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,54riazin-2-yl)-2 ran-4-yl)oxy)benzonitrile
A mixture of 3,4-difluoronitrobenzene (1.0 g, 6.3 mmol) and 1-(oxetan-3-yl)piperazine (1.1 g, 7.5 mmol) in acetonitrile (100 mL) was refluxed (95 °C heating block) with stirring for 16 hours. Reaction mixture was concentrated to dryness under reduced pressure. The resulting solid was collected by filtration, washed with acetonitrile, and dried under vacuum to provide 1 -(2-fluoro-4-nitrophenyl)-4-(oxetan-3-yl)piperazine. LCMS-ESI+ (m/z): [M+H]+ calcd for C13H-17FN3O3: 282.1 ; found: 282.1
1-(2-fluoro-4-nitrophenyl)-4-(oxetan-3-yl)piperazine (1 .6 g, 5.7 mmol) was taken up in a mixture of 2-methyltetrahydrofuran and methanol. The mixture was degassed, treated with 10 % palladium on carbon (250 mg), and shaken for three days under hydrogen (30 psi). The suspension was filtered through a pad of Celite diatomaceous earth and concentrated under reduced pressure to provide 3-fluoro-4-(4-(oxetan-3-yl)piperazin-1 - yl)aniline. LCMS-ESI+ (m/z): [M+H]+ calcd for C-13H-19FN3O: 252.1 ; found: 252.1 . To a solution of 2,4-dichloro-1 ,3,5-triazine (0.44 g, 2.9 mmol) in N,N-dimethylformamide (DMF, 5 mL) at 0 °C were added Ν,Ν-diisopropylethylamine (DIEA, 0.53 ml_, 3.0 mmol), followed by a solution of 3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)aniline in DMF (10 mL). The mixture was stirred at 0 °C for 30 minutes and then allowed to warm to room temperature. The mixture was partitioned between ethyl acetate and water. The layers were separated and aqueous phase was extracted twice with ethyl acetate. The combined extracts were washed once each with water and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to provide 4-chloro-N-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-
1-yl)phenyl)-1 ,3,5-triazin-2-amine. LCMS-ESI"1" (m/z): [M+H]+ calcd for C 6H1 9CIFN60: 365.1 ; found: 365.3.
A mixture of 4-chloro-N-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)-1 ,3,5-triazin-2- amine (0.16 g, 0.44 mmol), 2-((tetrahydro-2H-pyran-4-yl)oxy)-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)benzonitrile (0.16 g, 0.49 mmol), palladium (II) acetate (0.01 g, 10 mol%), and triphenylphosphine (0.035 g, 0.13 mmol) in 1 ,2-dimethoxyethane (DME, 6 mL) was treated with 2M aqueous sodium carbonate solution (1 .0 mL). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel to furnish 5-(4-((3-fluoro-4-(4-(oxetan-3- yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C28H31 FN7O3: 532.2; found: 532.5 1H NMR (400 MHz, DMSO-c/6) δ 10.47 (s, 1 H), 8.87 (s, 1 H), 8.78 - 8.47 (m, 2H), 7.79 (m, 1 H), 7.62 (d, J = 9.4 Hz, 1 H), 7.53 (s, 1 H), 7.31 - 7.07 (m, 1 H), 5.00 (tt, J = 8.0, 4.0 Hz, 1 H), 4.92 - 4.69 (m, 4H), 4.53 (m, 1 H), 3.91 (m, 2H), 3.60 (m, 2H), 3.55 - 3.00 (m, 8H), 2.09 (m, 2H), 1 .74 (m, 2H). Example 28
5-[4-[4-[4-(oxetan-3-yl)piperazin-1-yl]anilino]-1,3,5-triazin-2-yl]-2-(2-oxopyrrolidi 1- l)benzonitrile
Figure imgf000087_0001
Preparation of /V-(4-bromo-2-cyanophenyl)-4-chlorobutanamide: To a solution of 2- amino-5-bromobenzonitrile (1 .5 g, 7.6 mmol) in pyridine (15 ml_) was added dropwise 4- chlorobutanoyl chloride (Sigma Aldrich 1 .0 ml_, 9.1 mmol) at 0 °C. The ice-water bath was allowed to slowly regain room temperature and the mixture was allowed to stir overnight at room temperature. The reaction mixture was poured into water, and the mixture was extracted thrice with ethyl acetate. The organic layers were combined, and the mixture was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to provide the desired material, which carried forward without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C-| H -| -| BrCIN20: 303.0; found: 303.0 Preparation of 5-bromo-2-(2-oxopyrrolidin-1 -yl)benzonitrile: To a solution of crude N-(4- bromo-2-cyanophenyl)-4-chlorobutanamide (7.6 mmol assumed) in 2- methyltetrahydrofuran (30 ml_) was added sodium hydride (60 % dispersion in mineral oil) at 0°C, and the mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched with glacial acetic acid (approximately 5 ml_) and poured into water. The mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel) to provide the desired material. LCMS-ESI"1" (m/z): [M+H]+ calcd for C-| -| H-| oBrN20: 265.0; found: 265.1 .
Preparation of (3-cyano-4-(2-oxopyrrolidin-1 -yl)phenyl)boronic acid: A mixture of 5- bromo-2-(2-oxopyrrolidin-1 -yl)benzonitrile (0.23 g, 0.87 mmol), bis(pinacolato)diboron (0.44 g, 1 .7 mmol), potassium acetate (0.26 g, 2.6 mmol), and [1 , 1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (0.064 g, 10 mol%) in 1 ,4- dioxane (4 ml_) was heated at 90 °C overnight. The mixture was allowed to cool to room temperature, filtered through a pad of Celite diatomaceous earth, and concentrated to dryness under reduced pressure to provide the desired product, which was carried forward without further purification.
LCMS-ESI+ (m/z): [M+H]+ calcd for C-| -1 H-12BN2O3: 231 .1 ; found: 231 .2.
Preparation of 5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2- (2-oxopyrrolidin-1 -yl)benzonitrile: A mixture of 4-chloro-N-(4-(4-(oxetan-3-yl)piperazin-1 - yl)phenyl)-1 ,3,5-triazin-2-amine (0.15 g, 0.43 mmol), crude (3-cyano-4-(2-oxopyrrolidin- 1-yl)phenyl)boronic acid (0.20 g, 0.87 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.025 g, 5 mol%) in 1 ,2-dimethoxyethane (DME, 6 ml_) was treated with 2M aqueous sodium carbonate solution (0.98 ml_). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel to provide the desired material.
LCMS-ESI+ (m/z): [M+H]+ calcd for C27H29N802: 497.2; found: 497.2
Example 29
( ?)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin
((tetrahydrofuran-3-yl)oxy)benzonitrile
Figure imgf000088_0001
Preparation of (R)-5-bromo-2-((tetrahydrofuran-3-yl)oxy)benzonitrile: A solution of {R)-{- )-3-hydroxytetrahydrofuran (Sigma Aldrich, 2.0 g, 22 mmol) in N,N-dimethylformamide (40 ml_) was stirred in an ice-water bath under an atmosphere of Argon. Sodium hydride (60 % in mineral oil, 0.91 g, 23 mmol) was added in a single portion. The mixture was stirred at 0 °C for 10 minutes and then the cooling bath was removed. The mixture was stirred overnight at room temperature. To the mixture was added via syringe 5-bromo-2-fluorobenzonitrile (Matrix Scientific, 3.8 g, 19 mmol) as a solution in Ν,Ν-dimethylformamide (20 ml_) at room temperature. Mixture was stirred for 2 hours on a 50 °C block and then allowed to cool to room temperature. Water was added and the resulting precipitate was collected by filtration, washed with water, dried under house vacuum and then in vacuum oven over P2O5 to provide the desired material. "Ή NMR (400 MHz, DMSO-c/6) δ 8.06 (d, J = 2.5 Hz, 1 H), 7.87 (dd, J = 9.1 , 2.5 Hz, 1 H), 7.26 (d, J = 9.1 Hz, 1 H), 5.24 (m, 1 H), 3.87 (m, 4H), 2.31 (m, 1 H), 2.02 (m, 1 H).
Preparation of (R)-2-((tetrahydrofuran-3-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzonitrile: A mixture of (R)-5-bromo-2-((tetrahydrofuran-3- yl)oxy)benzonitrile (1.4 g, 5.2 mmol), bis(pinacolato)diboron (2.6 g, 10 mmol), potassium acetate (1.5 g, 16 mmol), and [1 ,1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) complex with dichloromethane (0.22 g, 5 mol%) in 1 ,4-dioxane (20 ml.) was heated for 5 hours at 90 °C. The reaction mixture was filtered through a pad of Celite diatomaceous earth, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel) to provide (R)-2-((tetrahydrofuran-3-yl)oxy)-5-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile.1H NMR (400 MHz, DMSO-c 6) δ 7.99 - 7.88 (m, 2H), 7.31 (d, J = 8.5 Hz, 1 H), 5.29 (m, 1 H), 4.02 - 3.74 (m, 4H), 2.33 (m, 1 H), 2.13 - 1.91 (m, 1 H), 1.33 (s, 12H).
A mixture of 4-chloro-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1 ,3,5-triazin-2-amine (0.12 g, 0.35 mmol), (R)-2-((tetrahydrofuran-3-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzonitrile (0.14 g, 0.43 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.030 g, 7.5 mol%) in 1 ,2-dimethoxyethane (DME, 2.5 ml_) was treated with 2M aqueous sodium carbonate solution (0.78 ml_). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel to provide (R)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydrofuran-3- yl)oxy)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for C27H30N7O3: 500.2; found:
500.3 1H NMR (400 MHz, DMSO-c/6) δ 10.16 (m, 1 H), 8.78 (s, 1 H), 8.71 - 8.50 (m, 2H), 7.61 (m, 2H), 7.49 (d, J = 9.0 Hz, 1 H), 7.01 (m, 2H), 5.36 (m, 1 H), 4.61 (m, 2H), 4.52 (m, 2H), 4.07 - 3.89 (m, 3H), 3.85 (m, 1 H), 3.49 (m, 1 H), 3.19 (m, 4H), 2.45 (m, 4H), 2.36 (m, 1 H), 2.09 (m, 1 H).
Example 30
( ?)-2-((1-(2-hydroxyacetyl)pyrrolidin-3-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000090_0001
Preparation of (R)-tert-butyl 3-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenoxy)pyrrolidine-1-carboxylate
A mixture of 4-chloro-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1 ,3,5-triazin-2-amine (0.25 g, 0.72 mmol), (R)-tert-butyl 3-(2-cyano-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-
2- yl)phenoxy)pyrrolidine-1-carboxylate (0.37 g, 0.90 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.054 g, 7.5 mol%) in 1 ,2-dimethoxyethane (DME, 4 ml_) was treated with 2M aqueous sodium carbonate solution (1.6 ml_). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel to provide the desired product.
LCMS-ESI+ (m/z): [M+H]+ calcd for C32H39N804: 599.3; found: 599.1
Preparation of (R)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2- yl)-2-(pyrrolidin-3-yloxy)benzonitrile(R)-tert-butyl 3-(2-cyano-4-(4-((4-(4-(oxetan-3- yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenoxy)pyrrolidine-1 -carboxylate
(0.72 mmol assumed) was taken up in dichloromethane (8 ml_) and treated with trifluoroacetic acid (2 ml_). After one hour, the mixture was pipetted into saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted three times with approximately 10 % MeOH/dichloromethane. The combined organics were washed once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to provide the desired material.
LCMS-ESI+ (m/z): [M+H]+ calcd for C27H31 N802: 499.3; found: 499.3
Preparation of (R)-2-((1-(2-hydroxyacetyl)pyrrolidin-3-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
(R)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-(pyrrolidin-
3- yloxy)benzonitrile (50 mg, 0.10 mmol) and glycolic acid (1 1 mg, 0.15 mmol) were taken up as suspension in dichloromethane (1 ml_). The mixture was treated successively with /V,/V-diisopropylethylamine (35 μΙ_, 0.20 mmol) and N- [(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminiumhexafluorophosphate Λ/oxide (HATU, 57 mg, 0.15 mmol). The suspension was stirred for three hours at room temperature and then purified by flash chromatography (silica gel) to provide (R)-2-((1 -(2-hydroxyacetyl)pyrrolidin-3-yl)oxy)-5- (4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile.
LCMS-ESI+ (m/z): [M+H]+ calcd for C29H33N804: 557.3; found: 557.3 1 H NMR (400 MHz, DMSO-c/6) δ 10.17 (m, 1 H), 8.78 (s, 1 H), 8.61 (m, 2H), 7.59 (m, 3H), 7.01 (br, 2H), 5.41 (m, 1 H), 4.70 (m, 1 H), 4.61 (m, 2H), 4.52 (m, 2H), 4.09 (m, 2H), 3.74 (m, 3H), 3.51 (m, 1 H), 3.18 (m, 4H), 2.45 (m, 4H), 2.28 (m, 2H).
Example 31
5-(4-((4-(difluoromethoxy)-3-methoxyphenyl)amino)-1 ,3,5-triazin-2-yl)-2- ((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile
Figure imgf000092_0001
A suspension of 5-(4-chloro-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2/-/-pyran-4- yl)oxy)benzonitrile (100 mg, 0.32 mmol) and 4-difluoromethoxy-3-methoxyaniline hydrochloride (Princeton Biomolecular Research, 85 mg, 0.38 mmol) in acetonitrile (3 mL) was treated with /V,/V-diisopropylethylamine (0.28 mL, 1.6 mmol). The mixture was heated in a microwave reactor for 20 minutes at 80 °C. The reaction mixture was purified by flash chromatography (silica gel) to provide the desired material. LCMS-ESI+
(m/z): [M+H]+ calcd for C23H22 2N5O4: 470.2; found: 470.1 1H NMR (400 MHz,
DMSO-d6) δ 10.46 (bs, 1 H), 8.88 (s, 1 H), 8.65 (d, J = 2.2 Hz, 1 H), 8.62 (dd, J = 8.9, 2.2 Hz, 1 H), 7.90 (bs, 1 H), 7.61 (d, J = 9.0 Hz, 1 H), 7.31 (bs, 1 H), 7.24 (m, 1 H), 7.05 (m, 1 H), 4.99 (m, 1 H), 3.91 (m, 5H), 3.60 (m, 2H), 2.08 (m, 2H), 1.74 (m, 2H).
Example 32
5-(4-((4-(4-acetylpiperazin-1 -yl)-3-methoxyphenyl)amino)-1 ,3,5-triazin-2-yl)-2- pyran-4-yl)oxy)benzonitrile
Figure imgf000092_0002
Preparation of 1-(4-(2-methoxy-4-nitrophenyl)piperazin-1-yl)ethanone: A mixture of 1- fluoro-2-methoxy-4-nitrobenzene (0.83 g, 4.9 mmol), 1-acetylpiperazine (0.68 g, 5.3 mmol), and potassium carbonate (1.3 g, 9.7 mmol) in N,N-dimethylformamide (9 mL) was stirred at 100 °C for 20 hours. The mixture was allowed to cool to room temperature and was partitioned between ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed twice with water, once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to provide the desired material. LCMS-
ESI+ (m/z): [M+H]+ calcd for C1 3H1 8N304: 280.1 ; found: 280.1
Preparation of 1 -(4-(4-amino-2-methoxyphenyl)piperazin-1 -yl)ethanone: A degassed mixture of 1-(4-(2-methoxy-4-nitrophenyl)piperazin-1 -yl)ethanone (approximately 4.9 mmol) in methanol/2-methyltetrahydrofuran (1 : 1 , 60 ml_) was treated with 10 % palladium on charcoal (250 mg). The mixture was stirred under a balloon of hydrogen overnight. The catalyst was removed by filtration through a pad of Celite diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure to provide the desired material.
LCMS-ESI+ (m/z): [M+H]+ calcd for C-13H20N3O2: 250.2; found: 250.1
Preparation of 5-(4-((4-(4-acetylpiperazin-1 -yl)-3-methoxyphenyl)amino)-1 ,3,5-triazin-2- yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile: A suspension of 5-(4-chloro-1 ,3,5- triazin-2-yl)-2-((tetrahydro-2/-/-pyran-4-yl)oxy)benzonitrile (57 mg, 0.18 mmol) and 1 -(4- (4-amino-2-methoxyphenyl)piperazin-1 -yl)ethanone (54 mg, 0.22 mmol) in acetonitrile (3 ml_) was treated with /V,/V-diisopropylethylamine (0.13 ml_, 0.72 mmol). The mixture was heated in a microwave reactor for 20 minutes at 80 °C. The cooled reaction mixture was purified by flash chromatography (silica gel) and then recrystallized from methanol to provide 5-(4-((4-(4-acetylpiperazin-1-yl)-3-methoxyphenyl)amino)-1 ,3,5- triazin-2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for C28H32N7O4: 530.2; found: 530.3
1H NMR (400 MHz, DMSO-c/6) δ 10.28 (s, 1 H), 8.82 (s, 1 H), 8.64 (d, J = 2.1 Hz, 1 H), 8.61 (dd, J = 8.9, 2.2 Hz, 1 H), 7.69 (bs, 1 H), 7.60 (d, J = 9.0 Hz, 1 H), 7.54 - 7.17 (br, 1 H), 6.93 (d, J = 8.5 Hz, 1 H), 4.98 (m, 1 H), 3.92 (m, 5H), 3.60 (m, 6H), 2.94 (m, 4H), 2.07 (m, 5H), 1 .73 (m, 2H).
Example 33
2-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-5-(4-((3-methoxy-4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000094_0001
A mixture of 4-chloro-N-(3-methoxy-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1 ,3,5- triazin-2-amine (0.10 g, 0.27 mmol), crude 2-((1 ,1-dioxidotetrahydro-2/-/-thiopyran-4- yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (1.0 mmol assumed), and tetrakis(triphenylphosphine)palladium(0) (0.023 g, 7.5 mol%) in 1 ,2- dimethoxyethane (DME, 6 mL) was treated with 2M aqueous sodium carbonate solution (0.60 mL). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel, followed by precipitation from isopropanol/dichloromethane, to provide the desired material. LCMS- ESI+ (m/z): [M+H]+ calcd for C29H34N7O5S: 592.2; found: 592.3 1H NMR (400 MHz,
DMSO-c/6) δ 10.29 (m, 1 H), 8.82 (s, 1 H), 8.65 (m, 2H), 7.67 (s, 1 H), 7.61 (d, J = 8.9 Hz, 1 H), 7.33 (m, 1 H), 6.94 (d, J = 8.5 Hz, 1 H), 5.12 (m, 1 H), 4.60 (m, 2H), 4.51 (m, 2H), 3.51 (m, 1 H), 3.35 (s, 3H), 3.27 (m, 4H), 3.01 (m, 4H), 2.49 - 2.32 (m, 8H). Example 34
5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1,3,5-triazin-2-yl)-2- n-3-yl)oxy)benzonitrile
Figure imgf000094_0002
Preparation of 5-bromo-2-((tetrahydro-2/-/-pyran-3-yl)oxy)benzonitrile: A solution of 3- hydroxytetrahydropyran (Astatech, 2.0 g, 20 mmol) in /V,/V-dimethylform amide (40 mL) was stirred in an ice-water bath under an atmosphere of Argon. Sodium hydride (60 % in mineral oil, 0.79 g, 20 mmol) was added in a single portion. Mixture was stirred at 0 °C for one hour and then the cooling bath was removed. To the mixture was added via syringe 5-bromo-2-fluorobenzonitrile (Matrix Scientific, 3.3 g, 17 mmol) as a solution in N,N-dimethylformamide (20 mL) at room temperature. Mixture was stirred for 3 hours at 50 °C block and then allowed to cool to room temperature. Water was added and the resulting precipitate was collected by filtration, washed with water, dried under house vacuum and then in vacuum oven over P2O5 to provide the desired material. 1H NMR (400 MHz, DMSO-c/6) δ 8.04 (d, J = 2.5 Hz, 1 H), 7.84 (dd, J = 9.1 , 2.6 Hz, 1 H), 7.35 (d, J = 9.1 Hz, 1 H), 4.64 (m, 1 H), 3.82 (m, 1 H), 3.63 (m, 3H), 2.05 (m, 1 H), 1.83 (m, 2H), 1.57 (m, 1 H).
Preparation of 2-((tetrahydro-2/-/-pyran-3-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzonitrile: A mixture of 5-bromo-2-((tetrahydro-2/-/-pyran-3- yl)oxy)benzonitrile (0.29 g, 1.0 mmol), bis(pinacolato)diboron (0.53 g, 2.1 mmol), potassium acetate (0.31 g, 3.1 mmol), and [1 ,1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) complex with dichloromethane (77 mg, 10 mol%) in 1 ,4-dioxane (5 mL) was heated for 2.5 hours at 90 °C. The reaction mixture was filtered through a pad of Celite diatomaceous earth, and the filtrate was concentrated to dryness under reduced pressure. The crude 2-((tetrahydro-2/-/- pyran-3-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile was carried forward without further purification. LCMS-ESI+ (m/z): [M+OH+H]+ calcd for C 8H26BN05: 347.2; found: 347.1
Step 3: A mixture of 4-chloro-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1 ,3,5-triazin-2- amine (0.12 g, 0.35 mmol), crude 2-((tetrahydro-2/-/-pyran-3-yl)oxy)-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (0.34 g, 1.0 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.030 g, 7.5 mol%) in 1 ,2-dimethoxyethane (DME, 4 mL) was treated with 2M aqueous sodium carbonate solution (0.78 mL). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel to provide 5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-3- yl)oxy)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for C28H32 7O3: 514.3; found:
514.2.
1H NMR (400 MHz, DMSO-c/6) δ 10.15 (m, 1 H), 8.92 - 8.72 (m, 1 H), 8.58 (m, 2H), 7.58 (m, 3H), 7.00 (m, 2H), 4.77 (m, 1 H), 4.61 (m, 2H), 4.51 (m, 2H), 3.88 (m, 1 H), 3.68 (m, 3H), 3.49 (p, J = 6.3 Hz, 1 H), 3.18 (m, 4H), 2.45 (m, 4H), 2.12 (m, 1 H), 1.89 (m, 2H), 1.61 (m, 1 H).
Example 35
2-(3-hydroxyazetidin-1-yl)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)- 1,3,5-triazin-2-yl)benzonitrile
Figure imgf000096_0001
Preparation of 2-(3-hydroxyazetidin-1-yl)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzonitrile: 2-Fluoro-5-(4,4,5,5-tetramethyl[1 ,3,2]dioxaborolan-2-yl)benzonitrile (2.0 g, 8.1 mmol), potassium carbonate (2.2 g, 16 mmol), and 3-hydroxyazetidine hydrochloride (0.89 g, 8.1 mmol) were taken up as a suspension in N,N- dimethylacetamide (20 mL) and heated on a 120 °C block overnight. The mixture was allowed to cool to room temperature and then was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel) to provide 2-(3-hydroxyazetidin-1-yl)-5-(4,4,5,5-tetramethyl-
1 ,3,2-dioxaborolan-2-yl)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for C16H22BN203: 301.2; found: 301.1
A mixture of 4-chloro-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1 ,3,5-triazin-2-amine (0.12 g, 0.35 mmol), 2-(3-hydroxyazetidin-1-yl)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzonitrile (0.16 g, 0.53 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.030 g, 7.5 mol%) in 1 ,2-dimethoxyethane (DME, 2.5 mL) was treated with 2M aqueous sodium carbonate solution (0.78 mL). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel to provide 2-(3-hydroxyazetidin-1-yl)- 5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C26H29N8O2: 485.2; found: 485.3
1H NMR (400 MHz, DMSO-c/6) δ 10.01 (m, 1 H), 8.69 (s, 1 H), 8.53 - 8.25 (m, 2H), 7.60 (br, 2H), 6.99 (br, 2H), 6.71 (d, J = 9.0 Hz, 1 H), 5.86 (d, J = 6.1 Hz, 1 H), 4.62 (m, 3H), 4.52 (m, 4H), 4.02 (m, 2H), 3.48 (p, J = 6.3 Hz, 1 H), 3.17 (m, 4H), 2.45 (m, 4H). Example 36
5-((4-(3-cyano-4-((tetrahydro-2H^yran-4-yl)oxy)pheny^
((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile
Figure imgf000097_0001
Potassium tert-butoxide (0.62 g, 5.5 mmol) was added in one portion to a solution of 4- hydroxytetrahydropyran (0.51 g, 5.0 mmol) in 2-methyltetrahydrofuran (15 ml_), cooled in an ice-water bath. The reaction mixture was stirred for 20 minutes before the addition of 2-fluoro-5-nitrobenzonitrile (0.42 g, 2.5 mmol). The mixture continued to stir in the bath for about 15 minutes before the removal of the bath. The mixture was allowed to remain at room temperature. The aqueous phase was extracted twice with dichloromethane. The combined organics were washed twice with water, dried over anhydrous magnesium sulfate, filtered, concentrated to dryness under reduced pressure to provide 5-amino-2-(tetrahydro-2H-pyran-4-yloxy)benzonitrile. The crude product was carried forward without further purification.
To a solution of 2, 4-dichloro-1 ,3,5-triazine (0.27 g, 1.8 mmol) in N,N-dimethylformamide
(DMF, 2 mL) at 0 °C were added Ν,Ν-diisopropylethylamine (DIEA, 0.32 ml_, 1.9 mmol), followed by a solution of 5-amino-2-(tetrahydro-2H-pyran-4-yloxy)benzonitrile (0.36 g,
1.6 mmol) in DMF (6 mL). The mixture was stirred at 0 °C for 30 minutes and then allowed to warm to room temperature where it remained overnight.
The mixture was partitioned between ethyl acetate and water. The layers were separated and aqueous phase was extracted twice with ethyl acetate. The combined extracts were washed once each with water and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to provide 5-((4-chloro-1 ,3,5-triazin-2-yl)amino)-2-((tetrahydro-2H-pyran-4- yl)oxy)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C-15H-15CIN5O2: 332.1 ; found:
332.1 A mixture of 5-((4-chloro-1 ,3,5-triazin-2-yl)amino)-2-((tetrahydro-2H-pyran-4- yl)oxy)benzonitrile (0.16 g, 0.48 mmol), 2-((tetrahydro-2H-pyran-4-yl)oxy)-5-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (0.17 g, 0.53 mmol), palladium (II) acetate (0.01 g, 10 mol%), and triphenylphosphine (0.038 g, 0.14 mmol) in 1 ,2- dimethoxyethane (DME, 6 mL) was treated with 2M aqueous sodium carbonate solution (1.1 mL). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was filtered through a pad of Celite diatomaceous earth. The aqueous phase was extracted twice with ethyl acetate. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, concentrated to dryness under reduced pressure. The residue was purified via prep HPLC (10 - 95 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to furnish 5-((4-(3-cyano-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-1 ,3,5- triazin-2-yl)amino)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C27H27N604: 499.2; found: 499.1 1H NMR (400 MHz, DMSO-c/6) δ 10.46 (s, 1 H), 8.87 (s, 1 H), 8.59 (d, J = 9.2 Hz, 2H), 8.13 (s, 1 H), 7.94 (br, 1 H), 7.60 (m, 1 H), 7.45 (m, 1 H), 5.00 (m, 1 H), 4.81 (m, 1 H), 3.91 (m, 4H), 3.58 (m, 4H), 2.21 - 1.97 (m, 4H), 1.72 (m, 4H).
Example 37
(S)-N-(2-cyano-4-(4-((4-morpholinophenyl)amino)-1 ,3,5-triazin-2- yl)phenyl)pyrrolidine-2-carboxamide
Figure imgf000098_0001
Preparation of 2-amino-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile: A mixture of 2-amino-5-bromobenzonitrile (1.5 g, 7.6 mmol), bis(pinacolato)diboron (2.9 g, 11 mmol), potassium acetate (2.2 g, 23 mmol), and [1 ,1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (0.28 g, 5 mol%) in 1 ,4-dioxane (23 mL) was heated at 80 °C for two days. The mixture was partitioned between water and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed once each with water and saturated aqueous sodium chloride solutions. A portion of the combined extracts was filtered through a pad of Celite diatomaceous earth. The extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a solid mass, which was purified by flash chromatography (silica gel) to provide the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C 3H1 8BN202: 245.1 ; found: 245.4
Preparation of (S)-tert-butyl 2-((2-cyano-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)carbamoyl)pyrrolidine-1-carboxylate: A mixture of 2-amino-5-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (0.37 g, 1.5 mmol) and Boc-L-proline (0.33 g, 1.5 mmol) in chloroform (15 mL) was treated successively with triethylamine (0.32 mL, 2.3 mmol) and 2-ethoxy-1-ethoxycarbonyl-1 ,2-dihydroquinoline (EEDQ, 0.45 g, 1.8 mmol). The mixture was heated with magnetic stirring overnight at 70 °C, then concentrated under reduced pressure and purified by flash chromatography (silica gel) to provide the desired material.
LCMS-ESI+ (m/z): [M+H]+ calcd for C23H33BN3O5: 442.2; found: 442.0.
Preparation of (S)-tert-butyl 2-((2-cyano-4-(4-((4-morpholinophenyl)amino)-1 ,3,5-triazin- 2-yl)phenyl)carbamoyl)pyrrolidine-1-carboxylate: A suspension of 4-chloro-/V-(4- morpholinophenyl)-1 ,3,5-triazin-2-amine (0.10 g, 0.34 mmol) and (S)-tert-butyl 2-((2- cyano-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)carbamoyl)pyrrolidine-1- carboxylate (0.17 g, 0.38 mmol) in 1 ,2-dimethoxyethane (DME, 2 mL) was treated successively with palladium (II) acetate (0.008 g, 10 mol%), triphenylphosphine (0.027 g, 0.1 mmol), and 2M aqueous sodium carbonate solution (0.78 mL). The mixture was irradiated for 1 hour in a microwave reactor at 125 °C. The crude mixture was purified first by flash chromatography on silica gel to furnish the desired material. LCMS-ESI+ (m/z): [M+H]+ calcd for 03(^35^04: 571.3; found: 571.5.
Preparation of (S)-N-(2-cyano-4-(4-((4-morpholinophenyl)amino)-1 ,3,5-triazin-2- yl)phenyl)pyrrolidine-2-carboxamide, trifluoroacetic acid salt: A solution of (S)-tert-butyl 2-((2-cyano-4-(4-((4-morpholinophenyl)amino)-1 ,3,5-triazin-2- yl)phenyl)carbamoyl)pyrrolidine-1-carboxylate (0.16 g, 0.28 mmol) in dichloromethane (2 mL) was treated with trifluoroacetic acid (0.86 mL, 1 1 mmol) and allowed to stand overnight at room temperature. The mixture was then concentrated to dryness under reduced pressure, and the residue was purified by prep HPLC (10 - 36 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to furnish the desired material as its TFA salt. LCMS-ESI+ (m/z): [M+H]+ calcd for C25H27N802: 471 .2; found: 471 .3.
Example 38
5-((4-(3-cyano-4-((tetrahydro-2H^yran-4-yl)oxy)pheny^
(4-(oxetan-3-yl)piperazin-1 -yl)benzonitrile
Figure imgf000100_0001
A mixture of 1 -(oxetan-3-yl)piperazine (0.86 g, 6.0 mmol) and 2-fluoro-5-nitrobenzonitrile (1 .0 g, 6.0 mmol) in acetonitrile (10 ml_) was treated with potassium carbonate (0.83 g, 6.0 mmol). The mixture was allowed to stand overnight at room temperature. The supernatant was decanted and the remaining insoluble material was taken up in water, collected by vacuum filtration, washed with diethyl ether, and dried under vacuum to provide 5-nitro-2-(4-(oxetan-3-yl)piperazin-1 -yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C-|4H 7N403: 289.1 ; found: 289.1
5-nitro-2-(4-(oxetan-3-yl)piperazin-1 -yl)benzonitrile (1 .4 g, 4.9 mmol) was taken up as a suspension in methanol/2-methyltetrahydrofuran (1 : 1 , 40 ml_). The suspension was heated to homogeneity, and then allowed to cool to room temperature. After being degassed, to the mixture was introduced 10 % palladium on charcoal (approximately 200 mg). The suspension was stirred under balloon of hydrogen for one hour. The mixture was filtered through a pad of Celite diatomaceous earth, and the filtrate was concentrated to dryness under reduced pressure to give 5-amino-2-(4-(oxetan-3- yl)piperazin-1 -yl)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for C-14H-19N4O: 259.2; found: 259.2.
To a solution of 2,4-dichloro-1 ,3,5-triazine (0.42 g, 2.8 mmol) in N,N-dimethylformamide
(DMF, 6 ml_) at 0 °C were added sequentially Ν,Ν-diisopropylethylamine (DIEA, 0.50 ml_, 2.9 mmol) and 5-amino-2-(4-(oxetan-3-yl)piperazin-1 -yl)benzonitrile (0.65 g, 2.5 mmol). The mixture was stirred at 0 °C for 30 minutes and then allowed to warm to room temperature. The mixture was diluted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined extracts were washed once each with water and a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via flash chromatography on silica gel to provide 5-((4-chloro-1 ,3,5- triazin-2-yl)amino)-2-(4-(oxetan-3-yl)piperazin-1-yl)benzonitrile. LCMS-ESI+ (m/z):
[M+H]+ calcd for C-17H-19CIN7O: 372.1 ; found: 372.4.
A mixture of 5-((4-chloro-1 ,3,5-triazin-2-yl)amino)-2-(4-(oxetan-3-yl)piperazin-1- yl)benzonitrile (0.15 g, 0.40 mmol), 2-((tetrahydro-2H-pyran-4-yl)oxy)-5-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (0.15 g, 0.44 mmol), tetrakis(triphenylphosphine)palladium(0) (0.023 g, 5 mol%) in 1 ,2-dimethoxyethane (DME, 6 mL) was treated with 2M aqueous sodium carbonate solution (0.91 mL). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel to furnish 5-((4-(3-cyano-4- ((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-1 ,3,5-triazin-2-yl)amino)-2-(4-(oxetan-3- yl)piperazin-1-yl)benzonitrile.
LCMS-ESI+ (m/z): [M+H]+ calcd for C29H31 N803: 539.2; found: 539.3 1H NMR (400
MHz, DMSO-c/6) 5 10.58 (s, 1 H), 8.90 (s, 1 H), 8.62 (m, 2H), 8.21 (m, 1 H), 8.00 (m, 1 H), 7.61 (d, J = 9.4 Hz, 1 H), 7.38 (m, 1 H), 5.01 (tt, J = 8.0, 4.0 Hz, 1 H), 4.82 (m, 4H), 4.60 (m, 1 H), 3.91 (m, 2H), 3.60 (ddd, J = 1 1.6, 8.5, 3.1 Hz, 2H), 3.55 - 2.91 (m, 8H), 2.09 (m, 2H), 1.73 (dtd, J = 12.5, 8.3, 3.9 Hz, 2H).
Example 39
A -(4-((4-(3-cyano-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-1,3,5-triazin-2- crylamide
Figure imgf000102_0001
Preparation of N-(4-aminophenyl)acrylamide: A nearly homogeneous mixture of p- nitroaniline (2.5 g, 18 mmol) and triethylamine (5.0 mL, 36 mmol) in dichloromethane (40 mL) was stirred in an ice-water bath while acryloyl chloride (1.8 mL, 22 mmol) was added dropwise. At the end of the addition, the mixture was allowed to regain room temperature. The resulting suspension was diluted with water and filtered. The collected solid (assumed 18 mmol) was washed successively with water and dichloromethane and then taken up as a suspension in ethanol/water (5:1 , 100 mL). Iron powder (2.0 g, 36 mmol) was added, followed by saturated aqueous ammonium chloride solution (10 mL). The mixture was heated on a 90 °C block for three hours and then filtered through a pad of Celite diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure. The residue was partitioned between dichloromethane and water. The aqueous phase was extracted twice with dichloromethane. The combined extracts were washed once each with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure to give N-(4-aminophenyl)acrylamide.
LCMS-ESI+ (m/z): [M+H]+ calcd for CgH-| -| N20: 163.1 ; found: 163.1.
Preparation of N-(4-((4-chloro-1 ,3,5-triazin-2-yl)amino)phenyl)acrylamide: To a solution of 2, 4-dichloro-1 ,3,5-triazine (0.52 g, 3.4 mmol) in Ν,Ν-dimethylformamide (DMF, 4 mL) at 0 °C were added sequentially Ν,Ν-diisopropylethylamine (DIEA, 0.69 mL, 4.0 mmol) and N-(4-aminophenyl)acrylamide (0.51 g, 3.1 mmol) and the mixture was stirred at 0
°C for 30 minutes and then allowed to warm to room temperature. The mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined organics were washed once each with water and a solution of saturated aqueous sodium chloride. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to provide N-(4-((4-chloro-1 ,3,5-triazin-2-yl)amino)phenyl)acrylamide.
LCMS-ESI+ (m/z): [M+H]+ calcd for C 2H-| -| CIN50: 276.1 ; found: 276.2.
Preparation of N-(4-((4-(3-cyano-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-1 ,3,5-triazin- 2-yl)amino)phenyl)acrylamide: A suspension of N-(4-((4-chloro-1 ,3,5-triazin-2- yl)amino)phenyl)acrylamide (0.14 g, 0.49 mmol), 2-((tetrahydro-2H-pyran-4-yl)oxy)-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (0.19 g, 0.59 mmol), palladium (II) acetate (0.005 g, 10 mol%), and triphenylphosphine (0.039 g, 0.15 mmol) in 1 ,4- dioxane (3 ml_) was treated with 2M aqueous sodium carbonate solution (1.1 ml_). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified first by flash chromatography on silica gel and then by prep HPLC (10 - 90 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide N-(4-((4-(3-cyano-4- ((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-1 ,3,5-triazin-2-yl)amino)phenyl)acrylamide.
LCMS-ESI+ (m/z): [M+H]+ calcd for C24H23N603: 443.2; found: 443.1 1H NMR (400
MHz, DMSO-c/6) δ 10.35 (s, 1 H), 10.19 (s, 1 H), 8.83 (s, 1 H), 8.62 (m, 2H), 7.74 (m, 3H), 7.63 (m, 2H), 6.48 (dd, J = 17.0, 10.1 Hz, 1 H), 6.30 (dd, J = 17.0, 2.0 Hz, 1 H), 5.79 (dd, J = 10.1 , 2.1 Hz, 1 H), 4.98 (tt, J = 8.0, 4.0 Hz, 1 H), 3.91 (m, 2H), 3.59 (m 2H), 2.09 (m, 2H), 1.73 (m, 2H).
Example 40
5-(4-((4-(2-hydroxypropan-2-yl)phenyl)amino)-1 ,3,54riazin-2-yl)-2-((tetrahydro-2H- enzonitrile
Figure imgf000103_0001
Step 1 : A solution of 2-(4-nitrophenyl)propan-2-ol (Sigma Aldrich, 0.25 g, 1.4 mmol) in methanol (1 ml_) was added to a stirred suspension of 10 % palladium on carbon in methanol (5 ml_). Ammonium formate (0.44 g, 6.9 mmol) was added in a single portion. The mixture was stirred for two hours at room temperature before filtration of the mixture through a pad of Celite diatomaceous earth and concentration of the filtration under reduced pressure. The residue was taken up in ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to provide 2- (4-aminophenyl)propan-2-ol, which was carried forward without further purification.
LCMS-ESI+ (m/z): [M+H]+ calcd for C9H1 4NO: 152.1 ; found: 152.0
Step 2: A sample of crude 2-(4-aminophenyl)propan-2-ol (50 mg, 0.33 mmol) in acetonitrile (0.5 ml_) was added to a suspension of 5-(4-chloro-1 ,3,5-triazin-2-yl)-2- ((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile (46 mg, 0.15 mmol) in acetonitrile (1 ml_). The suspension was treated with /V,/V-diisopropylethylamine (100 μΙ_, 0.58 mmol) and then warmed with a heat gun for approximately one minute until homogeneous. Another portion crude 2-(4-aminophenyl)propan-2-ol (approximately 50 mg) was taken up in acetonitrile (approximately 0.5 ml_) and added to the mixture, which was warmed with a heat gun for approximately one minute and then heated on a 70 °C block for 20 minutes. The reaction mixture was concentrated to dryness under reduced pressure and purified by prep HPLC (10 - 85 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to furnish 5-(4-((4-(2-hydroxypropan-2-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-
((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C24H26N5O3: 432.2; found: 432.1 1H NMR (400 MHz, DMSO-c/6) δ 10.39 (m, 1 H), 8.85
(m, 1 H), 8.69 - 8.56 (m, 2H), 7.81 (m, 2H), 7.71 (s, 1 H), 7.59 (m, 2H), 4.99 (m, 1 H), 3.91 (m, 2H), 3.59 (m, 2H), 2.10 (m, 2H), 1.74 (m, 2H), 1 .47 (s, 6H).
Example 41
4-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2- lpiperidine-1-carboxamide
Figure imgf000104_0001
Preparation of tert-butyl 4-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenoxy)piperidine-1 -carboxylate: A mixture of 4- chloro-N-(4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)-1 ,3,5-triazin-2-amine (0.31 g, 0.88 mmol), tert-butyl 4-(2-cyano-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)piperidine-1 -carboxylate (0.47 g, 1 .1 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.076 g, 7.5 mol%) in 1 ,2-dimethoxyethane (DME, 4 ml_) was treated with 2M aqueous sodium carbonate solution (2.0 ml_). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel to provide the desired product.
LCMS-ESI+ (m/z): [M+H]+ calcd for C33H41 N804: 613.3; found: 613.1
Preparation of 5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2- (piperidin-4-yloxy)benzonitrile: tert-butyl 4-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenoxy)piperidine-1 -carboxylate (0.88 mmol assumed) was taken up in dichloromethane (8 mL) and treated with trifluoroacetic acid (2 mL). After one hour, the mixture was pipetted into saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted three times with dichloromethane. The combined organics were washed once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to provide the desired material.
LCMS-ESI+ (m/z): [M+H]+ calcd for C28H33N802: 513.3; found: 513.3.
Preparation of 4-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5- triazin-2-yl)phenoxy)-N-methylpiperidine-1 -carboxamide: 5-(4-((4-(4-(oxetan-3- yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-(piperidin-4-yloxy)benzonitrile (35 mg, 0.07 mmol), as a suspension in dichloromethane (1 mL), was treated with first with /V,/V-diisopropylethylamine (DIEA, 130 μί, 0.68 mmol), then (methylimino)(oxo)methane (Matrix Scientific, 21 μί, 0.34 mmol). After 5 minutes of stirring, the mixture was concentrated to dryness under reduced pressure. The residual solid was triturated with hot acetonitrile, filtered, and dried to provide 4-(2-cyano-4-(4-((4-(4-(oxetan-3- yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenoxy)-N-methylpiperidine-1 - carboxamide. LCMS-ESI"1" (m/z): [M+H]+ calcd for C30H36N9O3: 570.3; found: 570.4
1H NMR (400 MHz, DMSO-c/6) δ 10.16 (m, 1 H), 8.77 (s, 1 H), 8.59 (m, 2H), 7.60 (m, 3H), 6.99 (m, 2H), 6.53 (m, 1 H), 4.95 (m, 1 H), 4.61 (m, 2H), 4.52 (m, 2H), 3.64 (m, 2H), 3.49 (m, 1 H), 3.28 (m, 2H), 3.18 (m, 4H), 2.62 (d, J = 4.2 Hz, 3H), 2.46 (m, 4H), 1 .98 (m, 2H), 1.66 (m, 2H).
Example 42
N-(2-cyano-4-(4-((4-morpholinophenyl)amino)-1 ,3,5-triazin-2- yl)phenyl)cyclopropanecarboxamide
Figure imgf000106_0001
A solution of 2-amino-5-bromo-benzonitrile )2.5 g, 13 mmol) in pyridine (25 mL) was treated with cyclopropanecarbonyl chloride (1.3 mL, 14 mmol) dropwise over a 30 minute period. The reaction was left for 3 days at room temperature, then concentrated under vacuum. The residue was partitioned between ethyl acetate and water, giving a suspension, which was then concentrated to dryness under reduced pressure. The residue was taken up in 1 :1 pyridine/MeOH (60 mL) and treated with 2 M aqueous sodium hydroxide solution (12 mL) The mixture was stirred at room temperature for 90 minutes before concentration almost to dryness under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous phase was extracted once with water. The combined organics were washed successively with water, 1 % aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to leave N-(4-bromo-2-cyanophenyl)cyclopropanecarboxamide as a solid. LCMS-ESI+
(m/z): [M+H]+ calcd for C-| -| H1 0BrN2O: 265.0; found: 265.1.
To a solution of N-(4-bromo-2-cyanophenyl)cyclopropanecarboxamide (3.4 g, 13 mmol) in 1 ,4-dioxane (60 mL), bis(pinacolato)diborane (4.0 g, 16 mmol), potassium acetate (3.7 g, 38 mmol), and [1 ,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (0.47 g, 5 mol%) were added. The resulting mixture was stirred for 3 days at 80 °C. The cooled reaction mixture was diluted with ethyl acetate and water. Layers were separated. Aqueous phase was extracted once with ethyl acetate. The organics were combined, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to provide N-(2- cyano-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)
cyclopropanecarboxamide. LCMS-ESI"1" (m/z): [M+H]+ calcd for C-17H22BN2O3: 313.2; found: 313.3.
A suspension of 4-chloro-N-(4-morpholinophenyl)-1 ,3,5-triazin-2-amine (0.1 1 g, 0.37 mmol) and N-(2-cyano-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl) cyclopropanecarboxamide (0.14 g, 0.44 mmol) in 1 ,2-dimethoxyethane (DME, 3 mL) was treated successively with palladium (II) acetate (0.008 g, 10 mol%), triphenylphosphine (0.029 g, 0.1 1 mmol), and 2M aqueous sodium carbonate solution (0.8 mL). The mixture was irradiated for 1 hour in a microwave reactor at 125 °C. The crude mixture was purified by flash chromatography on silica gel to furnish N-(2-cyano- 4-(4-((4-morpholinophenyl)amino)-1 ,3,5-triazin-2-yl)phenyl)cyclopropanecarboxamide.
LCMS-ESI+ (m/z): [M+H]+ calcd for C24H24N7O2: 442.2; found: 442.5 1H NMR (400 MHz, DMSO-c/6) δ 10.69 (s, 1 H), 10.22 (d, J = 13.2 Hz, 1 H), 8.81 (s, 1 H), 8.74 - 8.52 (m, 2H), 7.93 (d, J = 8.8 Hz, 1 H), 7.63 (m, 2H), 7.00 (m, 2H), 3.79 (m, 4H), 3.13 (s, 4H), 2.02 (m, 1 H), 0.93 (m, 4H).
Example 43
5-(4-((6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)amino)-1,3,5-triazin-2-yl)-^ ((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile
Figure imgf000107_0001
To a solution of 2-chloro-5-nitropyridine (1.0 g, 6.3 mmol) in 2-methyltetrahydrofuran (60 mL) was added 1-(oxetan-3-yl)piperazine (0.99g, 6.9 mmol), followed by triethylamine (1.3 mL, 9.5 mmol), and the reaction mixture was stirred at room temperature overnight. After the mixture was concentrated under reduced pressure, the residue was partitioned between dichloromethane and water. The aqueous phase was extracted three times with dichloromethane. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to give 1 -(5-nitropyridin-2-yl)-4-(oxetan-3-yl)piperazine. LCMS-ESI+ (m/z): [M+H]+ calcd for C12H 17N4O3: 265.1 ; found: 265.1 .
A suspension of 1 -(5-nitropyridin-2-yl)-4-(oxetan-3-yl)piperazine (1 .7 g, 6.3 mmol) was taken up as a suspension in tetrahydrofuran/methanol/ethyl acetate (approximately 1 : 1 : 1 , 100 ml_) was degassed and then charged with 10 % wt. palladium on charcoal (300 mg). The suspension was stirred overnight under a balloon of hydrogen. The reaction mixture was filtered over Celite diatomaceous earth, and the filtrate was concentrated under reduced pressure to provide 6-(4-(oxetan-3-yl)piperazin-1 -yl)pyridin-
3-amine. LCMS-ESI+ (m/z): [M+H]+ calcd for C12H19N4O: 235.2; found: 235.2.
To a solution of 2,4-dichloro-1 ,3,5-triazine (0.35 g, 2.3 mmol) in N,N-dimethylformamide
(6 ml_) at 0 °C were added /V,/V-diisopropylethylamine, followed by 6-(4-(oxetan-3- yl)piperazin-1 -yl)pyridin-3-amine (0.50 g, 2.1 mmol) and the mixture was stirred at 0 °C for 30 minutes and then allowed to warm to room temperature. The mixture was concentrated under reduced pressure and purified by flash chromatography (silica gel) to provide 4-chloro-N-(6-(4-(oxetan-3-yl)piperazin-1 -yl)pyridin-3-yl)-1 ,3,5-triazin-2-amine.
LCMS-ESI+ (m/z): [M+H]+ calcd for C-15H-19CIN7O: 348.1 ; found: 348.3.
A mixture of 4-chloro-N-(6-(4-(oxetan-3-yl)piperazin-1 -yl)pyridin-3-yl)-1 ,3,5-triazin-2- amine (0.12 g, 0.35 mmol), 2-((tetrahydro-2H-pyran-4-yl)oxy)-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)benzonitrile (0.12 g, 0.38 mmol), tetrakis(triphenylphosphine)palladium(0) (0.020 g, 5 mol%) in 1 ,2-dimethoxyethane (DME, 3 ml_) was treated with 2M aqueous sodium carbonate solution (0.78 ml_). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel to furnish 5-(4-((6-(4-(oxetan-3- yl)piperazin-1 -yl)pyridin-3-yl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C27H3 N803: 515.2; found:
515.3 1H NMR (400 MHz, DMSO-c/6) δ 10.24 (br, 1 H), 8.80 (s, 1 H), 8.58 (m, 2H), 8.46 (s, 1 H), 8.02 (br, 1 H), 7.60 (d, J = 9.2 Hz, 1 H), 7.08 (br, 1 H), 4.99 (tt, J = 7.8, 4.0 Hz, 1 H), 4.77 (m, 4H), 4.40 (m, 1 H), 3.91 (m, 2H), 3.59 (m, 2H), 3.50 - 2.80 (m, 8H), 2.09 (m, 2H), 1 .73 (m, 2H). Example 44
2-((1 -(2-cyanoacetyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 - 5-triazin-2-yl)benzonitrile
Figure imgf000109_0001
5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-(piperidin-4- yloxy)benzonitrile (78 mg, 0.15 mmol), and cyanoacetic acid (19 mg, 0.23 mmol) were taken up as suspension in acetonitrile (3 mL). The mixture was treated successively with N,/V-diisopropylethylamine (80 μί, 0.46 mmol) and N-[(dimethylamino)-1 H-1 ,2,3- triazolo-[4,5-b]pyridin-1 -ylmethylene]-N-methylmethanaminiumhexafluorophosphate N- oxide (HATU, 87 mg, 0.23 mmol). The mixture was stirred for one hour at room temperature and then purified by flash chromatography (silica gel) to provide 2-((1 -(2- cyanoacetyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-
1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C3-1 H34N9O3: 580.3; found: 580.3 1H NMR (400 MHz, DMSO-c/6) δ 10.16 (m, 1 H), 8.78 (s, 1 H), 8.61 (m, 2H), 8.10 (br, 1 H), 7.61 (m, 2H), 7.01 (m, 2H), 5.05 (m, 1 H), 4.61 (m, 2H), 4.52 (m, 2H), 4.13 (s, 2H), 3.82 - 3.39 (m, 5H), 3.18 (m, 4H), 2.46 (m, 4H), 2.03 (m, 2H), 1 .76 (m, 2H).
Example 45
2-((1 -(2-hydroxy-2-methylpropanoyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000109_0002
5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-(piperidin-4- yloxy)benzonitrile (52 mg, 0.10 mmol), and 2-hydroxyisobutyric acid (16 mg, 0.15 mmol) were taken up as suspension in dichloromethane (3 mL). The mixture was treated successively with A/,A/-diisopropylethylamine (35 μΙ_, 0.20 mmol) and N- [(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminiumhexafluorophosphate Λ/oxide (HATU, 58 mg, 0.15 mmol). The mixture was stirred for 20 minutes at room temperature and then purified by flash chromatography (silica gel) to provide 2-((1-(2-hydroxy-2-methylpropanoyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile.
LCMS-ESI+ (m/z): [M+H]+ calcd for C32H38N804: 599.3; found: 599.3 1H NMR (400 MHz, DMSO-c 6) δ 10.16 (m, 1 H), 8.77 (s, 1 H), 8.60 (m, 2H), 7.60 (m, 2H), 7.01 (m, 2H), 5.48 (s, 1 H), 5.06 (m, 1 H), 4.61 (m, 2H), 4.52 (m, 2H), 3.64 (m, 2H), 3.52 (m, 3H), 3.19 (m, 4H), 2.46 (m, 4H), 2.06 (m, 2H), 1.74 (m, 2H), 1.37 (s, 6H).
Example 46
4-((4-(3-cyano-4-((tetrahydro-2H^yran-4-yl)oxy)phenyl)-1 ,3,54riazin-2-yl)amino)-N- isopropylbenzamide
Figure imgf000110_0001
A suspension of 5-(4-chloro-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)benzonitrile (46 mg, 0.15 mmol) and 4-amino-A/-isopropylbenzamide (31 mg, 0.17 mmol) in acetonitrile (4 ml_) was treated with A/,A/-diisopropylethylamine (0.10 ml_, 0.58 mmol). The mixture was heated in a microwave reactor in the following successive intervals: 15 minutes at 85 °C, 30 minutes at 120 °C, and 120 minutes at 120 °C. After cooling to room temperature, the solid was collected by filtration, washed with acetonitrile, and dried under house vacuum and then in a vacuum oven (60 °C) over P2O5 to provide 4-((4-(3-cyano-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-1 ,3,5-triazin-2- yl)amino)-N-isopropylbenzamide. LCMS-ESI+ (m/z): [M+H]+ calcd for C25H27N6O3: 459.2; found: 459.2
1H NMR (400 MHz, DMSO-c/6) δ 10.59 (s, 1 H), 8.91 (s, 1 H), 8.64 (m, 2H), 8.16 (m, 1 H), 7.91 (m, 4H), 7.61 (d, J = 9.4 Hz, 1 H), 4.99 (m, 1 H), 4.15 (m, 1 H), 3.91 (m, 2H), 3.59 (m, 2H), 2.09 (m, 2H), 1.74 (m, 2H), 1.21 (d, J = 6.6 Hz, 6H).
Example 47
5-(4-((3-(2-hydroxypropan-2-yl)phenyl)amino)-1 ,3,54riazin-2-yl)-2-((tetrahydro-2H- nzonitrile
Figure imgf000111_0001
A suspension of 5-(4-chloro-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2/-/-pyran-4- yl)oxy)benzonitrile (53 mg, 0.16 mmol) and 2-(3-aminophenyl)propan-2-ol (Enamine, 30 mg, 0.20 mmol) in acetonitrile (2.5 mL) was treated with /V,/V-diisopropylethylamine (0.12 mL, 0.67 mmol). The mixture was heated in a microwave reactor for 60 minutes at 85 °C. The cooled reaction mixture was purified by flash chromatography (silica gel) to provide 5-(4-((3-(2-hydroxypropan-2-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro- 2H-pyran-4-yl)oxy)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for C24H26N5O3: 432.2; found: 432.1 1H NMR (400 MHz, DMSO-c/6) δ 10.33 (s, 1 H), 8.84 (s, 1 H), 8.65 (m, 2H), 8.13 (s, 1 H), 7.59 (m, 1 H), 7.50 (br, 1 H), 7.34 (m, 1 H), 7.26 (m, 1 H), 5.07 (s, 1 H), 5.00 (m, 1 H), 3.91 (m, 2H), 3.60 (m, 2H), 2.09 (m, 2H), 1.73 (m, 2H), 1.51 (s, 6H).
Example 48
2-((tetrahydro-2H-pyran-4-yl)oxy)-5-(4-((3-(2,2,2-trifluoro-1 - )amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000111_0002
Preparation of 1-(3-aminophenyl)-2,2,2-trifluoroethanol: A solution of 1-(3-aminophenyl)- 2,2,2-trifluoroethanone (Enamine, 0.20 g, 0.91 mmol) in methanol (5 mL) was degassed before the introduction of 10 % palladium on carbon (40 mg). The mixture was stirred overnight under a balloon of hydrogen gas. The catalyst was removed by filtration through pad of Celite diatomaceous earth. The filtrate was concentrated under reduced pressure to provide 1-(3-aminophenyl)-2,2,2-trifluoroethanol. LCMS-ESI+ (m/z): [M+H]+calcd for C8H9F3NO: 192.1 ; found: 192.0.
Preparation of 2-((tetrahydro-2H-pyran-4-yl)oxy)-5-(4-((3-(2,2,2-trifluoro-1 - hydroxyethyl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile: A suspension of 5-(4-chloro- 1 ,3,5-triazin-2-yl)-2-((tetrahydro-2/-/-pyran-4-yl)oxy)benzonitrile (100 mg, 0.32 mmol) and 1-(3-aminophenyl)-2,2,2-trifluoroethanol (170 mg, 0.9 mmol) in isopropanol (2.5 mL) was treated with /V,/V-diisopropylethylamine (0.22 mL, 1.3 mmol). The mixture was heated in a microwave reactor for 30 minutes at 85 °C. The cooled reaction mixture was purified by flash chromatography (silica gel), followed by prep HPLC (10 - 85 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer), to provide 2-((tetrahydro-2H-pyran- 4-yl)oxy)-5-(4-((3-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C23H21 F3N503: 472.2; found: 472.1 1H NMR (400 MHz, DMSO-c/6) δ 10.47 (s, 1 H), 8.87 (s, 1 H), 8.65 (m, 2H), 8.17 (br, 1 H), 7.68 (m, 1 H), 7.58 (d, J = 8.8 Hz, 1 H), 7.45 (t, J = 7.9 Hz, 1 H), 7.27 (d, J = 7.6 Hz, 1 H), 6.90 (m, 1 H), 5.21 (m, 1 H), 5.00 (m, 1 H), 3.91 (m, 2H), 3.60 (m, 2H), 2.09 (m, 2H), 1.74 (m, 2H).
Example 49
5-(4-((4-morpholinophenyl)amino)-1,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4- le
Figure imgf000112_0001
A suspension of 4-chloro-N-(4-morpholinophenyl)-1 ,3,5-triazin-2-amine (0.15 g, 0.51 mmol) and 2-((tetrahydro-2H-pyran-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)benzonitrile (0.19 g, 0.57 mmol) in 1 ,2-dimethoxyethane (DME, 2 mL) was treated successively with palladium (II) acetate (0.012 g, 10 mol%), triphenylphosphine (0.049 g, 0.15 mmol), and 2M aqueous sodium carbonate solution (1.2 mL). The mixture was irradiated for 1 hour in a microwave reactor at 125 °C. The crude mixture was purified first by flash chromatography on silica gel and then by prep HPLC (10 - 95 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to furnish 5-(4-((4- morpholinophenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for C25H27N6O3: 459.2; found:
459.4 1H NMR (400 MHz, DMSO-c/6) δ 10.19 (br, 1 H), 8.79 (s, 1 H), 8.60 (d, J = 9.5 Hz, 2H), 7.65 (br, 2H), 7.60 (d, J = 9.3 Hz, 1 H), 7.05 (br, 2H), 4.98 (m, 1 H), 3.91 (m, 2H), 3.85 - 3.77 (m, 4H), 3.59 (m, 2H), 3.16 (m, 4H), 2.18 - 2.02 (m, 2H), 1.74 (m, 2H). Example 50
5-(4-((4-(methylsulfonyl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran- rile
Figure imgf000113_0001
Preparation of 4-chloro-N-(4-(methylsulfonyl)phenyl)-1 ,3,5-triazin-2-amine: To a solution of 2,4-dichloro-1 ,3,5-triazine (0.50 g, 3.3 mmol) in N,/V-dimethylformamide (DMF, 6 mL) at 0 °C were added sequentially Ν,Ν-diisopropylethylamine (DIEA, 0.60 mL, 3.5 mmol) and 4-(methylsulfonyl)aniline (0.52 g, 3.0 mmol), and the mixture was stirred at 0 °C for 30 minutes and then allowed to warm to room temperature. The mixture was diluted with ethyl acetate and water. A small volume of tetrahydrofuran was added. The layers were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organics were filtered, washed once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to provide 4-chloro-N-(4-(methylsulfonyl)phenyl)-1 ,3,5-triazin-2-amine. An aliquot of desired material in acetonitrile was treated with one drop of pyrrolidine to indirectly confirm the presence of the desired material.
LCMS-ESI+ (m/z): [M+pyrrolidine - HCI + H]+ calcd for C 4H1 8N502S: 320.1 ; found: 320.2.
Preparation of 5-(4-((4-(methylsulfonyl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro- 2H-pyran-4-yl)oxy)benzonitrile: A mixture of 4-chloro-N-(4-(methylsulfonyl)phenyl)-1 ,3,5- triazin-2-amine (0.15 g, 0.53 mmol), 2-((tetrahydro-2H-pyran-4-yl)oxy)-5-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (0.19 g, 0.58 mmol), tetrakis(triphenylphosphine)palladium(0) (0.046 g, 7.5 mol%) in 1 ,2-dimethoxyethane (DME, 3 mL) was treated with 2M aqueous sodium carbonate solution (1.2 mL). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel to provide 5-(4-((4- (methylsulfonyl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C22H22N504S: 452.1 ; found:
452.1.
1H NMR (400 MHz, DMSO-c/6) δ 10.85 (s, 1 H), 8.97 (s, 1 H), 8.66 (m, 2H), 8.10 (m, 2H), 7.97 (d, J = 8.7 Hz, 2H), 7.62 (d, J = 9.6 Hz, 1 H), 5.00 (m, 1 H), 3.92 (m, 2H), 3.60 (m, 2H), 3.24 (s, 3H), 2.10 (m, 2H), 1.74 (m, 2H).
Example 51
W-(2-(4-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-tri 2-yl)phenoxy)piperidin-1 -yl)-2-oxoethyl)formamide
Figure imgf000114_0001
5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-(piperidin-4- yloxy)benzonitrile (60 mg, 0.12 mmol), and /V-formylglycine (Sigma Aldrich, 18 mg, 0.18 mmol) were taken up as suspension in dichloromethane (3 mL). The mixture was treated successively with N,/V-diisopropylethylamine (41 μί, 0.23 mmol) and N- [(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminiumhexafluorophosphate Λ/oxide (HATU, 67 mg, 0.18 mmol). The mixture was stirred for three days at room temperature and then purified by flash chromatography (silica gel) to provide N-(2-(4-(2-cyano-4-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenoxy)piperidin-1-yl)-2- oxoethyl)formamide. LCMS-ESI"1" (m/z): [M+H]+ calcd for C31 H36N9O4: 598.3; found:
598.3
1H NMR (400 MHz, DMSO-c/6) δ 10.16 (m, 1 H), 8.78 (s, 1 H), 8.60 (m, 2H), 8.20 (m, 1 H), 8.14 (s, 1 H), 7.61 (m, 2H), 7.02 (m, 2H), 5.12 - 5.00 (m, 2H), 4.61 (m, 3H), 4.52 (m, 2H), 4.10 (t, J = 4.8 Hz, 2H), 379 (m, 1 H), 3.74 - 3.42 (m, 3H), 3.18 (m, 4H), 2.46 (m, 4H), 2.05 (m, 2H), 1.76 (m, 2H).
Example 52
W-(2-(4-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin- 2-yl)phenoxy)piperidin-1-yl)-2-oxoethyl)acetamide
Figure imgf000115_0001
5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-(piperidin-4- yloxy)benzonitrile (55 mg, 0.1 1 mmol), and N-acetylglycine (Sigma Aldrich, 19 mg, 0.16 mmol) were taken up as suspension in dichloromethane (3 mL). The mixture was treated successively with /V,/V-diisopropylethylamine (38 μΙ_, 0.22 mmol) and N- [(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminiumhexafluorophosphate Λ/oxide (HATU, 61 mg, 0.16 mmol). The mixture was stirred for three days at room temperature and then purified by flash chromatography (silica gel) to provide N-(2-(4-(2-cyano-4-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenoxy)piperidin-1-yl)-2- oxoethyl)acetamide. LCMS-ESI"1" (m/z): [M+H]+ calcd for C32H38N9O4: 612.3; found: 612.4.
1H NMR (400 MHz, DMSO-c 6) δ 10.17 (m, 1 H), 8.78 (s, 1 H), 8.61 (m, 2H), 8.19 (bs, 1 H), 8.01 (t, J = 5.5 Hz, 1 H), 7.61 (m, 2H), 7.02 (m, 2H), 5.04 (m, 1 H), 4.61 (m, 2H), 4.52 (m, 2H), 4.02 (t, J = 5.0 Hz, 2H), 3.80 (m, 1 H), 3.65 (m, 2H), 3.48 (m, 2H), 3.18 (m, 4H), 2.46 (m, 4H), 2.05 (m, 2H), 1.91 (s, 3H), 1.76 (m, 2H).
Example 53 5-(4-((4-morpholinophenyl)amino)-1 ,3,5-triazin-2-yl)-2-(pyrrolidin-1 -yl)benzonitrile
Figure imgf000116_0001
To a solution of 2,4-dichloro-1 ,3,5-triazine (0.65 g, 4.3 mmol) in N,N-dimethylformamide
(DMF, 3 mL) at 0 °C were added sequentially Ν,Ν-diisopropylethylamine (DIEA, 0.78 mL, 4.5 mmol) and 4-morpholinoaniline (0.70 g, 3.9 mmol) and the mixture was stirred at 0 °C for 30 minutes and then allowed to warm to room temperature. The mixture was diluted with ethyl acetate and washed once each with water and a solution of saturated aqueous sodium chloride. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure and then purified by flash chromatography on silica gel to provide 4-chloro-N-(4-morpholinophenyl)-1 ,3,5- triazin-2-amine. LCMS-ESI+ (m/z): [M+H]+ calcd for C-13H-15CIN5O: 292.1 ; found:
292.2.
A suspension of 4-chloro-N-(4-morpholinophenyl)-1 ,3,5-triazin-2-amine (0.15 g, 0.51 mmol) and 2-(pyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (0.17 g, 0.57 mmol) in 1 ,2-dimethoxyethane (DME, 2 mL) was treated successively with palladium (II) acetate (0.012 g, 10 mol%), triphenylphosphine (0.049 g, 0.15 mmol), and 2M aqueous sodium carbonate solution (1.2 mL). The mixture was irradiated for 1 hour in a microwave reactor at 125 °C. The crude mixture was purified first by flash chromatography on silica gel and then by prep HPLC (10 - 95 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to furnish 5-(4-((4-morpholinophenyl)amino)-1 ,3,5- triazin-2-yl)-2-(pyrrolidin-1-yl)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for C24H25N7O: 428.2; found: 428.3 1H NMR (400 MHz, DMSO-c/6) δ 10.01 (bs, 1 H), 8.69
(s, 1 H), 8.46 (br, 1 H), 8.33 (d, J = 9.0 Hz, 1 H), 7.63 (br, 2H), 7.00 (br, 2H), 6.94 (d, J = 9.2 Hz, 1 H), 3.84 - 3.75 (m, 4H), 3.75 - 3.64 (m, 4H), 3.12 (m, 4H), 2.10 - 1.96 (m, 4H).
Example 54
5-(4-((4-(1 -(oxetan-3-yl)piperidin-4-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2- ((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile
Figure imgf000117_0001
Preparation of 4-(4-nitrophenyl)piperidine: 4-Phenylpiperidine (5.5 g, 34 mmol) was dissolved in glacial acetic acid (28 mL) and stirred in an ice-water bath (internal temp < 20 °C) while a solution of 1 .8 mL concentrated sulfuric acid (1 .8 mL) in glacial acetic acid (28 mL) was added, followed by a solution of 90% nitric acid (1 .6 mL) in acetic acid (14 mL). The cooling bath was removed and sulfuric acid (28 mL) was added without cooling, causing the internal temperature to reach a maximum of 50 °C. The mixture was allowed to stir at room temperature for about 2 hours before it was added to ice- water (-200 g) and basified with small additions of solid sodium hydrogen carbonate to - pH 5. The mixture was then brought to pH 14 with 50/50 (w/w) sodium hydroxide solution in an exothermic reaction. The mixture was extracted three times with dichloromethane, washed once each with 1 % aqueous sodium hydroxide solution and saturated with sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The gummy residue was triturated with refluxing cyclohexane. The resulting powder was collected by vacuum filtration to provide 4-(4- nitrophenyl)piperidine.
Preparation of 4-(4-nitrophenyl)-1 -(oxetan-3-yl)piperidine: 3-iodooxetane (Astatech, 1 .9 g, 10 mmol) was added via syringe to a suspension of 4-(4-nitrophenyl)piperidine (1 .1 g, 5.2 mmol) and potassium carbonate (0.72 g, 5.2 mmol) in acetonitrile. Vial was sealed. The mixture was stirred with heating in a sealed vessel on a 125 °C. After five hours, an additional quantity of potassium carbonate (0.72 g, 5.2 mmol) was added. The mixture was heated overnight. After cooling to room temperature, the mixture was filtered through a pad of Celite diatomaceous earth, eluting with dichloromethane and acetonitrile. The filtrate was concentrated to dryness under reduced pressure to provide 4-(4-nitrophenyl)-1 -(oxetan-3-yl)piperidine, which was carried forward without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C14H-19N2O3: 263.1 ; found: 263.2
Preparation of 4-(1 -(oxetan-3-yl)piperidin-4-yl)aniline: Crude 4-(4-nitrophenyl)-1 -(oxetan- 3-yl)piperidine (5.2 mmol assumed) was taken up in methanol (10 mL) with a heat gun. After cooling, the mixture was degassed, then treated with 10 % palladium on carbon (150 mg). The mixture was stirred for 5 hours under a balloon of hydrogen. The mixture was filtered through a pad of Celite diatomaceous earth. The filtrate was concentrated under reduced pressure. The residue was re-dissolved in methanol (approximately 50 mL). After the mixture was degassed, it was treated with 10 % palladium on carbon (150 mg). The mixture was shaken overnight under 45 psi hydrogen. The mixture was filtered through a pad of Celite diatomaceous earth. The filtrate was concentrated under reduced pressure to provide the desired product.
LCMS-ESI+ (m/z): [M+H]+ calcd for C 4H2i N20: 233.2; found: 233.1.
Preparation of 4-chloro-N-(4-(1-(oxetan-3-yl)piperidin-4-yl)phenyl)-1 ,3,5-triazin-2-amine: To a solution of 2, 4-dichloro-1 ,3,5-triazine (0.36 g, 2.4 mmol) in N,N-dimethylformamide
(DMF, 6 mL) at 0 °C were added sequentially N,/V-diisopropylethylamine (DIEA, 0.39 mL, 2.3 mmol) and 4-(1-(oxetan-3-yl)piperidin-4-yl)aniline (0.46 g, 2.0 mmol) and the mixture was stirred at 0 °C for 30 minutes and then allowed to warm to room temperature. After one hour, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. A solid was collected by filtration and discarded. The aqueous phase was extracted three times with ethyl acetate, The combined organics were washed once each with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and then purified by flash chromatography on silica gel to provide 4-chloro-/V-(4-(1-(oxetan-3-yl)piperidin-4-yl)phenyl)-1 ,3,5-triazin-2- amine.
LCMS-ESI+ (m/z): [M+H]+ calcd for C-17H21 CIN5O: 346.1 ; found: 346.2
Preparation of 5-(4-((4-(1-(oxetan-3-yl)piperidin-4-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2- ((tetrahydro-2/-/-pyran-4-yl)oxy)benzonitrile: A mixture of 4-chloro-/V-(4-(1-(oxetan-3- yl)piperidin-4-yl)phenyl)-1 ,3,5-triazin-2-amine (0.10 g, 0.29 mmol), 2-((tetrahydro-2H- pyran-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (0.10 g, 0.32 mmol), tetrakis(triphenylphosphine)palladium(0) (0.025 g, 7.5 mol%) in 1 ,2- dimethoxyethane (DME, 3 mL) was treated with 2M aqueous sodium carbonate solution (0.66 mL). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel to provide 5-(4-((4-(1- (oxetan-3-yl)piperidin-4-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2/-/-pyran-4- yl)oxy)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for C29H33N6O3: 513.3; found:
513.4 1H NMR (400 MHz, DMSO-c/6) δ 10.32 (m, 1 H), 8.83 (s, 1 H), 8.62 (dd, J = 9.0, 1.9 Hz, 2H), 7.70 (m, 2H), 7.61 (d, J = 9.4 Hz, 1 H), 7.30 (d, J = 8.0 Hz, 2H), 4.99 (m, 1 H), 4.59 (m, 2H), 4.49 (m, 2H), 3.98 - 3.88 (m, 3H), 3.59 (m, 2H), 3.44 (m, 1 H), 2.84 (d, J = 11.1 Hz, 2H), 2.09 (m, 2H), 1.90 (m, 2H), 1.85 - 1.60 (m, 6H). Example 55
5-((4-chloro-1,3,5-triazin-2-yl)amino)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile
Figure imgf000119_0001
To a solution of 2,4-dichloro-1 ,3,5-triazine (0.41 g, 2.7 mmol) in N,N-dimethylformamide
(DMF, 6 ml.) at 0 °C were added sequentially N,/V-diisopropylethylamine (DIEA, 0.49 ml_, 2.8 mmol) and 4-aminobenzamide (0.34 g, 2.5 mmol). The mixture was stirred at 0
°C for 30 minutes and then allowed to warm to room temperature. The mixture was diluted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined extracts were washed once each with water and a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to provide 4-((4-chloro-1 ,3, 5-triazin-2- yl)amino)benzamide. LCMS-ESI"1" (m/z): [M+H]+ calcd for C10H9CIN5O: 250.0; found: 250.1.
A mixture of 4-((4-chloro-1 ,3,5-triazin-2-yl)amino)benzamide (0.19 g, 0.57 mmol), 2- ((tetrahydro-2H-pyran-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzonitrile (0.19 g, 0.57 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.026 g, 5 mol%) in 1 ,2-dimethoxyethane (DME, 3 ml_) was treated with 2M aqueous sodium carbonate solution (1.2 ml_). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel to provide 5-((4-chloro-1 ,3,5-triazin-2-yl)amino)-2-((tetrahydro-2H-pyran-4- yl)oxy)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for C22H21 N6O3: 417.2; found:
417.1 1H NMR (400 MHz, DMSO-c/6) δ 10.61 (s, 1 H), 8.92 (s, 1 H), 8.64 (m, 2H), 8.03 - 7.81 (m, 5H), 7.62 (d, J = 9.6 Hz, 1 H), 7.30 (s, 1 H), 4.99 (tt, J = 8.0, 3.9 Hz, 1 H), 3.92 (m, 2H), 3.60 (m, 2H), 2.10 (m, 2H), 1.74 (m, 2H).
Example 56
2-((1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4-(1-(oxetan-3-yl)piperidin-4- riazin-2-yl)benzonitrile
Figure imgf000120_0001
Preparation of tert-butyl 4-(2-cyano-4-(4-((4-(1 -(oxetan-3-yl)piperidin-4-yl)phenyl)amino)- 1 ,3,5-triazin-2-yl)phenoxy)piperidine-1 -carboxylate: A mixture of 4-chloro-N-(4-(1 - (oxetan-3-yl)piperidin-4-yl)phenyl)-1 ,3,5-triazin-2-amine (0.20 g, 0.58 mmol), tert-butyl 4- (2-cyano-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)piperidine-1 - carboxylate (0.27 g, 1 .1 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.050 g, 7.5 mol%) in 1 ,2-dimethoxyethane (DME, 3 mL) was treated with 2M aqueous sodium carbonate solution (1 .3 mL). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel to provide the desired product.
LCMS-ESI+ (m/z): [M+H]+ calcd for C34H42N7O4: 612.3; found: 612.1
Preparation of 5-(4-((4-(1 -(oxetan-3-yl)piperidin-4-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2- (piperidin-4-yloxy)benzonitrile: tert-butyl 4-(2-cyano-4-(4-((4-(1 -(oxetan-3-yl)piperidin-4- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenoxy)piperidine-1 -carboxylate (0.58 mmol assumed) was taken up in dichloromethane (8 mL) and treated with trifluoroacetic acid (2 mL). After 30 minutes, the mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography (silica gel) to provide the desired material. LCMS-ESI+ (m/z): [M+H]+ calcd for C28H33N802: 512.3; found: 512.3.
Preparation of 2-((1 -(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4-(1 -(oxetan-3- yl)piperidin-4-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile: 5-(4-((4-(1 -(oxetan-3- yl)piperidin-4-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-(piperidin-4-yloxy)benzonitrile (60 mg, 0.12 mmol) and glycolic acid (13 mg, 0.18 mmol) were taken up as suspension in dichloromethane (3 mL). The mixture was treated successively with N,N- diisopropylethylamine (61 μί, 0.35 mmol) and N-[(dimethylamino)-1 H-1 ,2,3-triazolo- [4,5-b]pyridin-1 -ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (HATU, 67 mg, 0.18 mmol). The suspension was stirred for three hours at room temperature and then purified by flash chromatography (silica gel) to provide 2-((1 -(2- hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4-(1 -(oxetan-3-yl)piperidin-4-yl)phenyl)amino)- 1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for C3i H36N704: 570.3; found: 570.4 1H NMR (400 MHz, DMSO-c/6) δ 10.33 (s, 1 H), 8.84 (s, 1 H), 8.62 (m, 2H), 7.72 (m, 2H), 7.60 (m, 1 H), 7.30 (d, J = 8.3 Hz, 2H), 5.05 (m, 1 H), 4.59 (m, 3H), 4.50 (m, 2H), 4.17 (m, 2H), 3.82 (m, 1 H), 3.74 - 3.45 (m, 5H), 2.87 (m, 2H), 2.02 (m, 2H), 1.94 (m, 2H), 1.87 - 1.61 (m, 6H).
Example 57
2-((1 -(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4-(methylsulfonyl)phenyl)amino)- nitrile
Figure imgf000121_0001
Preparation of tert-butyl 4-(2-cyano-4-(4-((4-(methylsulfonyl)phenyl)amino)-1 ,3,5-triazin- 2-yl)phenoxy)piperidine-1-carboxylate: A mixture of 4-chloro-N-(4- (methylsulfonyl)phenyl)-1 ,3,5-triazin-2-amine (0.27 g, 0.95 mmol), tert-butyl 4-(2-cyano- 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)piperidine-1-carboxylate (0.45 g, 1.0 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.082 g, 7.5 mol%) in 1 ,2- dimethoxyethane (DME, 43 mL) was treated with 2M aqueous sodium carbonate solution (2.1 mL). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel to provide the desired product. LCMS-ESI"1" (m/z): [M - tBu +H]+ calcd for C23H23N605S: 495.1 ; found: 495.2.
Preparation of 5-(4-((4-(methylsulfonyl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-(piperidin-4- yloxy)benzonitrile: tert-butyl 4-(2-cyano-4-(4-((4-(methylsulfonyl)phenyl)amino)-1 ,3,5- triazin-2-yl)phenoxy)piperidine-1-carboxylate (0.25 g, 0.45 mmol) was taken up in dichloromethane (3 mL) and treated with trifluoroacetic acid (1 mL). After stirring for four hours at room temperature, the mixture was added to a separatory funnel containing 10 % aqueous hydrochloric acid and dichloromethane. The thick slurry that resulted was basified with concentrated ammonium hydroxide solution and then extracted three times with dichloromethane. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to provide the desired material. LCMS-ESI+ (m/z): [M+H]+ calcd for C22H23N6O3S: 451.2; found: 451.2 Preparation of 2-((1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4-
(methylsulfonyl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile: 5-(4-((4- (methylsulfonyl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-(piperidin-4-yloxy)benzonitrile (0.20 g, 0.45 mmol), and glycolic acid (52 mg, 0.68 mmol) were taken up as suspension in dichloromethane (3 mL). The mixture was treated successively with N,N- diisopropylethylamine (160 μΙ_, 0.91 mmol) and N-[(dimethylamino)-1 H-1 ,2,3-triazolo- [4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (HATU, 260 mg, 0.68 mmol). The suspension was stirred for three days at room temperature and then was purified by flash chromatography (silica gel) to provide 2-((1- (2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4-(methylsulfonyl)phenyl)amino)-1 ,3,5-triazin-
2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C24H25N605S: 509.2; found: 509.2 1H NMR (400 MHz, DMSO-c/6) δ 10.84 (s, 1 H), 8.98 (s, 1 H), 8.71 - 8.65 (m, 2H), 8.16 - 8.07 (m, 2H), 8.02 - 7.92 (m, 2H), 7.63 (d, J = 9.6 Hz, 1 H), 5.06 (m, 1 H), 4.60 (t, J = 5.5 Hz, 1 H), 4.17 (d, J = 5.3 Hz, 2H), 3.79 (m, 1 H), 3.61 (m, 1 H), 3.51 (m, 1 H), 3.42 (m, 1 H), 3.24 (s, 3H), 2.07 (m, 2H), 1.77 (m, 2H).
Example 58
2-(cyclopropylmethoxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1,3,5- triazin-2-yl)benzonitrile
Figure imgf000122_0001
A mixture of 4-chloro-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1 ,3,5-triazin-2-amine (0.15 g, 0.43 mmol), 2-(cyclopropylmethoxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)benzonitrile (0.14 g, 0.48 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.025 g, 5 mol%) in 1 ,2-dimethoxyethane (DME, 3 mL) was treated with 2M aqueous sodium carbonate solution (1 mL). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel to provide 2-(cyclopropylmethoxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-
1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for C27H30N7O2: 484.2; found: 484.3 1H NMR (400 MHz, DMSO-c/6) δ 10.28 (m, 1 H), 8.80 (s, 1 H), 871 - 8.47 (m, 2H), 7.67 (bs, 2H), 7.47 (d, J = 9.1 Hz, 1 H), 7.10 (br, 2H), 5.01 (t, J = 6.8 Hz, 2H), 4.73 (t, J = 7.4 Hz, 2H), 4.64 - 4.46 (m, 1 H), 4.16 (d, J = 7.0 Hz, 2H), 3.84 (m, 2H), 3.49 (m, 2H), 3.33 - 3.01 (m, 4H), 1.35 (m, 1 H), 0.85 - 0.55 (m, 2H), 0.57 - 0.26 (m, 2H).
Example 59
5-(4-((1 -methyl-1 H^yrazol-3-yl)amino)-1 ,3,54riazin-2-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)benzonitrile
Figure imgf000123_0001
To a solution of 2,4-dichloro-1 ,3,5-triazine (0.90 g, 6.0 mmol) in N,N-dimethylformamide
(DMF, 6 mL) at 0 °C were added sequentially /V,/V-diisopropylethylamine (DIEA, 1.1 mL, 6.2 mmol) and 1-methyl-1 H-pyrazol-3-amine (0.53 g, 5.5 mmol). The mixture was stirred at 0 °C for 30 minutes and then allowed to warm to room temperature. The mixture was diluted with ethyl acetate and water and filtered through a pad of Celite diatomaceous earth. The aqueous phase was extracted twice with ethyl acetate. The combined extracts were washed once each with water and a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel) to provide 4-chloro-N-(1-methyl-1 H-pyrazol-3-yl)-1 ,3,5- triazin-2-amine. LCMS-ESI+ (m/z): [M+H]+ calcd for C7H8CIN6: 21 1.0; found: 21 1.1.
A mixture of 4-chloro-N-(1-methyl-1 H-pyrazol-3-yl)-1 ,3,5-triazin-2-amine (0.12 g, 0.56 mmol), 2-((tetrahydro-2H-pyran-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzonitrile (0.20 g, 0.62 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.032 g, 5 mol%) in 1 ,2-dimethoxyethane (DME, 3 mL) was treated with 2M aqueous sodium carbonate solution (1.3 mL). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel, followed by prep HPLC (10 - 65 % acetonitrile in water, 0.1% trifluoroacetic acid buffer) to provide 5-(4-((1-methyl-1H-pyrazol-3-yl)amino)-1,3,5-triazin-2-yl)-2-
((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C-19H20N7O2: 378.2; found: 378.1 1H NMR (400 MHz, DMSO-c/6) δ 10.65 (m, 1H), 8.81
(s, 1H), 8.72 - 8.54 (m, 2H), 7.74 (m, 1H), 7.61 (d, J = 9.1 Hz, 1H), 6.68 (m, 1H), 4.98 (m, 1H), 3.91 (m, 2H), 3.83 (s, 3H), 3.59 (m, 2H), 2.08 (m, 2H), 1.73 (m, 2H).
Example 60
2-((4,4-difluorocyclohexyl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- ,5-triazin-2-yl)benzonitrile
Figure imgf000125_0001
Preparation of 5-bromo-2-((4,4-difluorocyclohexyl)oxy)benzonitrile: A solution of 4,4- difluorocyclohexanol (Sigma Aldrich, 1.0 g, 7.3 mmol) in Ν,Ν-dimethylformamide (DMF, 17 ml_) was treated with sodium hydride (60 % dispersion in mineral oil, 0.29, 7.3 mmol) in a single portion at room temperature. The mixture was stirred for two hours at room temperature before 5-bromo-2-fluorobenzonitrile (1.3 g, 6.7 mmol) was added in a single portion at room temperature. The mixture was stirred on a 50 °C block for 1 hour. Ice- water was added to the mixture, which was then partitioned with ethyl acetate. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed twice with water and once with saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reducd pressure. The residue was purified by flash chromatography (silica gel) to provide the desired material. 1H NMR (400 MHz, DMSO-c/6) δ 8.06 (d, J = 2.5 Hz, 1 H), 7.87 (dd, J = 9.1 , 2.6 Hz, 1 H), 7.38 (d, J = 9.1 Hz, 1 H), 4.89 (m, 1 H), 2.23 - 1.98 (m, 4H), 1.98 - 1.90 (m, 4H).
Preparation of 2-((4,4-difluorocyclohexyl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)benzonitrile : A mixture of 5-bromo-2-((4,4-difluorocyclohexyl)oxy)benzonitrile
(0.42 g, 1.3 mmol), bis(pinacolato)diboron (0.67 g, 2.6 mmol), potassium acetate (0.39 g, 4.0 mmol), and [1 ,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (0.10 g, 10 mol%) in 1 ,4-dioxane (8 ml.) was heated at 90 °C overnight. LC/MS analysis indicated the complete consumption of the bromide starting material. The mixture was filtered through a pad of Celite diatomaceous earth, and the filtrate was concentrated under reduced pressure to provide the desired product, which was carried forward without further purification.
Preparation of 2-((4,4-difluorocyclohexyl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile: A mixture of 4-chloro-/V-(4-(4-(oxetan-3- yl)piperazin-1 -yl)phenyl)-1 ,3,5-triazin-2-amine (0.15 g, 0.43 mmol), crude 2-((4,4- difluorocyclohexyl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (1 .3 mmol assumed), and tetrakis(triphenylphosphine)palladium(0) (0.037 g, 7.5 mol%) in 1 ,2-dimethoxyethane (DME, 6 mL) was treated with 2M aqueous sodium carbonate solution (0.97 mL). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel to provide 2- ((4,4-difluorocyclohexyl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5- triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C29H32F2N7O2: 548.3; found: 548.4
1H NMR (400 MHz, DMSO-c/6) δ 10.16 (m, 1 H), 8.78 (s, 1 H), 8.60 (m, 2H), 7.61 (m, 3H), 7.01 (m, 2H), 5.02 (m, 1 H), 4.61 (m, 2H), 4.52 (m, 2H), 3.49 (m, 1 H), 3.18 (m, 4H), 2.46 (m, 4H), 2.27 - 1 .87 (m, 8H).
Example 61
5-(4-((3-fluoro-5-methoxy-4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5- trahydro-2H-pyran-4-yl)oxy)benzonitrile
Figure imgf000126_0001
Preparation of 1 -(2-fluoro-6-methoxy-4-nitrophenyl)-4-(oxetan-3-yl)piperazine: 1 -(2,6- difluoro-4-nitrophenyl)-4-(oxetan-3-yl)piperazine (1 .8 g, 5.9 mmol) was taken up as a suspension in dimethylsulfoxide (10 mL) and treated with suspension of sodium methoxide in methanol (2 mL). The mixture was heated with magnetic stirring on an 80 °C block. After 20 minutes, an additional portion of solid sodium methoxide (300 mg) was added. The mixture was stirred with heating overnight on the 80 °C block. After cooling to room temperature, the mixture was quenched by the addition of ice and water, precipitating a powder, which was collected by filtration. The solid was washed with water, dried under house vacuum and then in a vacuum oven (60 °C) to provide 1 - (2-fluoro-6-methoxy-4-nitrophenyl)-4-(oxetan-3-yl)piperazine.
1-(2-fluoro-6-methoxy-4-nitrophenyl)-4-(oxetan-3-yl)piperazine (0.20 g, 0.64 mmol) was taken up in a mixture of 2-methyltetrahydrofuran and methanol (1 : 1 , 6 mL). The mixture was degassed, treated with 10 % palladium on carbon (45 mg), and stirred overnight under a balloon of hydrogen. The suspension was filtered through a pad of Celite diatomaceous earth and concentrated under reduced pressure to provide 3-fluoro-5- methoxy-4-(4-(oxetan-3-yl)piperazin-1 -yl)aniline. LCMS-ESI+ (m/z): [M+H]+ calcd for C 4H21 FN302: 282.2; found: 282.1 .
Preparation of 5-(4-((3-fluoro-5-methoxy-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)- 1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile: A suspension of 5-(4- chloro-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2/-/-pyran-4-yl)oxy)benzonitrile (50 mg, 0.16 mmol) and 3-fluoro-5-methoxy-4-(4-(oxetan-3-yl)piperazin-1 -yl)aniline (140 mg, 0.50 mmol) in acetonitrile (2.5 mL) was treated with /V,/V-diisopropylethylamine (0.1 1 mL, 0.63 mmol). The mixture was heated in a microwave reactor for 60 minutes at 100 °C. The cooled reaction mixture was purified by flash chromatography (silica gel), followed by trituration with ethyl acetate, to provide 5-(4-((3-fluoro-5-methoxy-4-(4-(oxetan-3- yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for C29H33FN7O4: 562.3; found: 562.3 1H NMR (400 MHz, DMSO-c/6) δ 10.43 (bs, 1 H), 8.88 (bs, 1 H), δ 8.64 (d, J = 2.2 Hz, 1 H), 8.61 (dd, J = 9.0, 2.2 Hz, 1 H), 7.63 (d, J = 9.0 Hz, 1 H), 7.55 - 7.15 (br, 2H), 4.99 (m, 1 H), 4.59 (m, 2H), 4.49 (m, 2H), 3.91 (m, 2H), 3.61 (m, 5H), 3.48 (m, 1 H), 3.1 1 (m, 4H), 2.37 (m, 4H), 2.09 (m, 2H), 1.73 (m, 2H). Example 62
5-(4-((3-(4-methylpiperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)-2-((tetrahydro-2H pyran-4-yl)oxy)benzonitrile
Figure imgf000127_0001
A suspension of 5-(4-chloro-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2/-/-pyran-4- yl)oxy)benzonitrile (53 mg, 0.16 mmol) and 3-(4-methylpiperazin-1 -yl)aniline (38 mg, 0.20 mmol) in isopropanol (2.5 mL) was treated with /V,/V-diisopropylethylamine (0.12 mL, 0.67 mmol). The mixture was heated in a microwave reactor for 30 minutes at 80 °C. The cooled reaction mixture was purified by prep HPLC (10 - 80 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer), followed by flash chromatography (silica gel) to provide 5-(4-((3-(4-methylpiperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro- 2H-pyran-4-yl)oxy)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for C26H30 7O2:
472.2; found: 472.3 1H NMR (400 MHz, DMSO-c/6) δ 10.22 (s, 1 H), 8.84 (s, 1 H), 8.62 (m, 2H), 7.60 (d, J = 9.4 Hz, 1 H), 7.45 (br, 1 H), 7.24 (m, 1 H), 7.16 (br, 1 H), 6.74 (d, J = 7.3 Hz, 1 H), 5.00 (m, 1 H), 3.91 (m, 2H), 3.60 (m, 2H), 3.21 (m, 4H), 2.53 (m, 4H), 2.27 (s, 3H), 2.08 (m, 2H), 1.74 (m, 2H).
Example 63
5-(4-((3-morpholinophenyl)amino)-1,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)benzonitrile
Figure imgf000128_0001
To a solution of 2,4-dichloro-1 ,3,5-triazine (0.50 g, 3.3 mmol) in N,N-dimethylformamide
(DMF, 6 ml.) at 0 °C were added sequentially N,/V-diisopropylethylamine (DIEA, 0.60 ml_, 3.4 mmol) and 3-morpholin-4-ylaniline (0.54 g, 3.0 mmol). The mixture was stirred at 0 °C for 30 minutes and then allowed to warm to room temperature. The mixture was diluted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined extracts were washed once each with water and a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to provide 4-chloro-N-(3- morpholinophenyl)-1 ,3,5-triazin-2-amine. LCMS-ESI+ (m/z): [M+H]+ calcd for Ci3H15CIN5: 292.1 ; found: 292.3. A mixture of 4-chloro-N-(3-morpholinophenyl)-1 ,3,5-triazin-2-amine (0.15 g, 0.52 mmol), 2-((tetrahydro-2H-pyran-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzonitrile (0.19 g, 0.58 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.026 g, 5 mol%) in 1 ,2-dimethoxyethane (DME, 3 ml_) was treated with 2M aqueous sodium carbonate solution (1.2 ml_). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel, followed by prep HPLC (10 - 85 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide 5-(4-((3-morpholinophenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H- pyran-4-yl)oxy)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for C25H27N6O3: 459.2; found: 459.3 1H NMR (400 MHz, DMSO-c/6) δ 10.27 (bs, 1 H), 8.84 (s, 1 H), 8.62 (m, 2H), 7.66 (m, 1 H), 7.59 (m, 1 H), 7.19 (bs, 1 H), 6.77 (m, 1 H), 4.99 (tt, J = 8.0, 3.8 Hz, 1 H), 4.02 - 3.87 (m, 2H), 3.82 (m, 4H), 3.59 (ddd, J = 1 1.5, 8.5, 3.1 Hz, 2H), 3.19 (m, 4H), 2.09 (m, 2H), 1.73 (m, 2H).
Example 64
5-(4-((4-(4-(2-hydroxyacetyl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2- ((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile
Figure imgf000129_0001
Preparation of tert-butyl 4-(4-((4-(3-cyano-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)- 1 ,3,5-triazin-2-yl)amino)phenyl)piperazine-1-carboxylate: A suspension of 5-(4-chloro- 1 ,3,5-triazin-2-yl)-2-((tetrahydro-2/-/-pyran-4-yl)oxy)benzonitrile (50 mg, 0.16 mmol) and tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate (52 mg, 0.19 mmol) in acetonitrile (2.5 mL) was treated with /V,/V-diisopropylethylamine (0.1 1 mL, 0.63 mmol). The mixture was heated in a microwave reactor for 30 minutes at 85 °C and then concentrated to dryness under reduced pressure to provide tert-butyl 4-(4-((4-(3-cyano-4-((tetrahydro- 2H-pyran-4-yl)oxy)phenyl)-1 ,3,5-triazin-2-yl)amino)phenyl)piperazine-1-carboxylate, which was carried forward without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C3oH36N704: 558.3; found: 558.0.
Preparation of 5-(4-((4-(piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro- 2H-pyran-4-yl)oxy)benzonitrile: Crude tert-butyl 4-(4-((4-(3-cyano-4-((tetrahydro-2H- pyran-4-yl)oxy)phenyl)-1 ,3,5-triazin-2-yl)amino)phenyl)piperazine-1-carboxylate (0.16 mmol assumed) was taken up in dichloromethane (3 mL) and treated with trifluoroacetic acid (0.5 mL). After one hour of standing at room temperature, the mixture was purified by flash chromatography (silica gel) to provide 5-(4-((4-(piperazin-1-yl)phenyl)amino)-
1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile. LCMS-ESI"1" (m/z):
[M+H]+ calcd for C25H28N7O2: 458.2; found: 458.2. Preparation of 5-(4-((4-(4-(2-hydroxyacetyl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile: 5-(4-((4-(piperazin-1-yl)phenyl)amino)- 1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile (1 10 mg, 0.24 mmol) and glycolic acid (27 mg, 0.36 mmol) were taken up as suspension in dichloromethane (2 ml_). The mixture was treated successively with /V,/V-diisopropylethylamine (170 μΙ_, 0.92 mmol) and /V-[(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminiumhexafluorophosphate N-oxide (HATU, 180 mg, 0.48 mmol). The mixture was stirred overnight at room temperature and then purified by flash chromatography (silica gel) to provide 5-(4-((4-(4-(2-hydroxyacetyl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile. LCMS-
ESI+ (m/z): [M+H]+ calcd for C27H30N7O4: 516.2; found: 516.2 1H NMR (400 MHz, DMSO-c/6) δ 10.21 (s, 1 H), 8.73 (m, 1 H), 8.55 (m, 2H), 7.56 (m, 3H), 7.02 (m, 2H), 4.98 (m, 1 H), 4.66 (t, J = 5.5 Hz, 1 H), 4.18 (d, J = 5.5 Hz, 2H), 3.91 (m, 2H), 3.61 (m, 2H), 3.53 (m, 4H), 3.16 (m, 4H), 2.08 (m, 2H), 1.74 (m, 2H).
Example 65
5-(4-((4-(1 -(2,2-difluoroethyl)piperidi^
((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile
Figure imgf000130_0001
Preparation of 1-(2,2-difluoroethyl)-4-(4-nitrophenyl)piperidine: A solution of 4-(4- nitrophenyl)piperidine (0.77 g, 3.7 mmol) in 2-methyltetrahydrofuran/acetonitrile (1 : 10, 16.5 ml_) was treated with potassium carbonate (3.1 g, 22 mmol), followed by 2,2- difluoroethyl triflate (0.65 ml_, 4.9 mmol). The mixture was heated for 4 hrs on a 65 °C block, then allowed to cool to room temperature. Insoluble material was removed by filtration. The filtrate was concentrated to provide the desired material, which was carried forward without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C13H17F2N2°2: 271.1 ; found: 271.1.
Preparation of 4-(1-(2,2-difluoroethyl)piperidin-4-yl)aniline: Crude 1-(2,2-difluoroethyl)-4- (4-nitrophenyl)piperidine (3.3 mmol assumed) was taken up in methanol (approximately 25 mL) in a Parr bottle. After the mixture was degassed, it was treated with 10 % palladium on charcoal (150 mg) and shaken overnight under hydrogen (55 psi). The mixture was filtered through a pad of Celite diatomaceous earth, and the filtrate was concentrated under reduced pressure to provide the desired material, which was carried forward without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C13H-19F2N2:
241 .1 ; found: 241 .1 .
Preparation of 5-(4-((4-(1-(2,2-difluoroethyl)piperidin-4-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile: A suspension of 5-(4-chloro-1 ,3,5- triazin-2-yl)-2-((tetrahydro-2/-/-pyran-4-yl)oxy)benzonitrile (100 mg, 0.32 mmol) and 4- (1 -(2,2-difluoroethyl)piperidin-4-yl)aniline (91 mg, 0.38 mmol) in acetonitrile (3 mL) was treated with /V,/V-diisopropylethylamine (0.22 mL, 1 .3 mmol). The mixture was heated in a microwave reactor for 20 minutes at 80 °C. The cooled reaction mixture was purified by flash chromatography (silica gel) to provide 5-(4-((4-(1 -(2,2-difluoroethyl)piperidin-4- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile. LCMS- ESI+ (m/z): [M+H]+ calcd for C28H31 F2N602: 521 .2; found: 521 .4 1H NMR (400 MHz,
DMSO-c/6) δ 10.31 (s, 1 H), 8.83 (s, 1 H), 8.61 (m, 2H), 7.70 (d, J = 7.9 Hz, 2H), 7.60 (d, J = 9.4 Hz, 1 H), 7.29 (d, J = 8.2 Hz, 2H), 6.19 (tt, J = 55.8, 4.3 Hz, 1 H), 4.99 (m, 1 H), 3.91 (m, 2H), 3.59 (m, 3H), 3.04 (m, 2H), 2.79 (td, J = 15.7, 4.4 Hz, 2H), 2.30 (m, 2H), 2.09 (m, 2H), 1 .91 - 1 .59 (m, 6H).
Example 66
5-(4-((4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin
pyran-4-yl)oxy)benzonitrile
Figure imgf000131_0001
5-(4-((4-(piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)benzonitrile, trifluoroacetic acid salt (approximately 0.14 mmol) was taken up in dichloromethane (5 mL) and treated with /V,/V-diisopropylethylamine (0.47 mL, 2.7 mmol). Mixture was stirred while cooling in an ice-water bath while methanesulfonyl chloride (31 μί, 0.41 mmol) was added via syringe. The cooling bath was removed, and the mixture was allowed to regain room temperature. After 15 minutes, the mixture was quenched with methanol and concentrated under reduced pressure. The residue was purified by prep HPLC (10 - 70 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide 5-(4-((4-(4-(methylsulfonyl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2- ((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C26H30N7° S: 536.2; found: 536.2.
1H NMR (400 MHz, DMSO-c/6) δ 10.20 (m, 1 H), 8.79 (s, 1 H), 8.61 (m, 2H), 7.62 (m, 3H), 7.06 (s, 2H), 4.98 (m, 1 H), 3.91 (m, 2H), 3.59 (m, 2H), 3.29 (m, 8H), 2.97 (s, 3H), 2.09 (m, 2H), 1 .74 (m, 2H). Example 67
Figure imgf000132_0001
5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2- ((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile
A mixture of 4-chloro-N-(4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)-1 ,3,5-triazin-2-amine (0.1 1 g, 0.32 mmol) and 2-((tetrahydro-2H-pyran-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzonitrile (0.12 g, 0.35 mmol) in 1 ,2-dimethoxyethane (DME, 2 mL)/N,N-dimethylformamide (DMF, 1 ml_) was treated successively with palladium (II) acetate (0.007 g, 10 mol%), triphenylphosphine (0.025 g, 0.21 mmol), and 2M aqueous sodium carbonate solution (0.7 ml_). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel to furnish 5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-
2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for C28H32N7°3: 51 4-3; found : 51 4 5 1 H NMR ( °0 MHz, DMSO-c/6) δ 10.23 (d, J = 19.4 Hz, 1 H), 8.80 (s, 1 H), 8.74 - 8.50 (m, 2H), 7.68 (br, 2H), 7.60 (d, J = 9.0 Hz, 1 H), 7.1 1 (br, 2H), 4.99 (m, 1 H), 4.91 - 4.74 (m, 4H), 4.52 (m, 1 H), 3.91 (m, 2H), 3.59 (ddd, J = 1 1 .6, 8.5, 3.0 Hz, 2H), 3.80 - 3.30 (m, 4H), 3.30 - 2.90 (m, 4H), 2.09 (m, 2H), 1 .87 - 1.64 (m, 2H).
Example 68
2-((tetrahydro-2H-pyran-4-yl)oxy)-5-(4-((4-(2,2,2-trifluoroacetyl)phenyl)amino)- l)benzonitrile
Figure imgf000133_0001
Preparation of 1-(4-((4-chloro-1 ,3,5-triazin-2-yl)amino)phenyl)-2,2,2-trifluoroethanone: To a solution of 2,4-dichloro-1 ,3,5-triazine (0.26 g, 1.7 mmol) in N,N-dimethylformamide
(DMF, 2 ml.) at 0 °C were added sequentially N,/V-diisopropylethylamine (DIEA, 0.78 mL, 4.5 mmol) and 1-(4-aminophenyl)-2,2,2-trifluoroethanone (Key Organics, 0.30 g, 1.6 mmol) and the mixture was stirred at 0 °C for 30 minutes before the addition of more 2, 4-dichloro-1 ,3,5-triazine (50 mg). After another 10 minutes of stirring at room temperature, additional quantities of 2, 4-dichloro-1 ,3,5-triazine (50 mg) and DIEA (0.20 mL) were added. After stirring overnight at room temperature, the mixture was purified by flash chromatography on silica gel to provide 1 -(4-((4-chloro-1 ,3,5-triazin-2- yl)amino)phenyl)-2,2,2-trifluoroethanone. LCMS-ESI"1" (m/z): [M+H20+H]+ calcd for C-1 -1 H9CIF3N4O2: 321.0; found: 321.1.
Preparation of 2-((tetrahydro-2H-pyran-4-yl)oxy)-5-(4-((4-(2,2,2- trifluoroacetyl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile: A mixture of 1-(4-((4-chloro- 1 ,3,5-triazin-2-yl)amino)phenyl)-2,2,2-trifluoroethanone (0.13 g, 0.43 mmol), 2- ((tetrahydro-2H-pyran-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzonitrile (0.18 g, 0.56 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.037 g, 7.5 mol%) in 1 ,2-dimethoxyethane (DME, 3 mL) was treated with 2M aqueous sodium carbonate solution (0.97 mL). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel to provide 2-((tetrahydro-2H-pyran-4-yl)oxy)-5-(4-((4-(2,2,2- trifluoroacetyl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z):
[M+H20+H]+calcd for C23H21 F3N5O4: 488.2; found: 488.1 1H NMR (400 MHz, DMSO-c/6) δ 1 1.04 (s, 1 H), 9.02 (s, 1 H), 8.67 (m, 2H), 8.16 (m, 3H), 7.63 (m, 1 H), 5.00 (m, 1 H), 3.92 (m, 2H), 3.60 (m, 2H), 2.10 (m, 2H), 1.75 (m, 2H). Example 69
5-(4-((3-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1,3,5-triazin-2-yl)-2- ((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile
Figure imgf000134_0001
Preparation of 1-(3-nitrophenyl)-4-(oxetan-3-yl)piperazine: To a suspension of 1-fluoro- 3-nitrobenzene (1.0 g, 7.1 mmol) and potassium carbonate (2.0 g, 14 mmol) in dimethylsulfoxide (DMSO, 5 mL) was added 1-(oxetan-3-yl)piperazine (1.5 g, 1 1 mmol) and a DMSO rinsate ( 2ml_). The mixture was stirred overnight on a 125 °C block. After cooling to room temperature, the mixture was poured into water (approximately 50 mL). The solid was collected by filtration and dried under vacuum to provide the desired material. LCMS-ESI+ (m/z): [M+H]+ calcd for C 3H1 8N303: 264.1 ; found: 264.1
Preparation of 3-(4-(oxetan-3-yl)piperazin-1-yl)aniline: 1-(3-nitrophenyl)-4-(oxetan-3- yl)piperazine (0.20 g, 0.76 mmol) was taken up in a methanol/tetrahydrofuran mixture (4:1 , 10 mL). After degassing the mixture, 10 % palladium on charcoal (40 mg) was added. The suspension was left stirring overnight under a balloon of hydrogen gas. The catalyst was removed by filtration through pad of Celite diatomaceous earth. The filtrate concentrated under reduced pressure to provide the desired material. LCMS- ESI+ (m/z): [M+H]+ calcd for C-13H20N3O: 234.2; found: 234.1.
Preparation of 5-(4-((3-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2- ((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile: A suspension of 5-(4-chloro-1 ,3,5-triazin-2- yl)-2-((tetrahydro-2/-/-pyran-4-yl)oxy)benzonitrile (57 mg, 0.18 mmol) and 3-(4-(oxetan- 3-yl)piperazin-1-yl)aniline (74 mg, 0.32 mmol) in acetonitrile (3 mL) was treated with N,/V-diisopropylethylamine (0.13 mL, 0.72 mmol). The mixture was heated in a microwave reactor for 20 minutes at 85 °C. The cooled reaction mixture was purified by flash chromatography (silica gel) to provide 5-(4-((3-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile. LCMS-
ESI+ (m/z): [M+H]+ calcd for C28H32N7O3: 514.3; found: 514.3 1H NMR (400 MHz, DMSO-c e) δ 10.26 (s, 1 H), 8.84 (s, 1 H), 8.62 (m, 2H), 7.66 (bs, 1 H), 7.60 (m, 1 H), 7.24 (m, 1 H), 7.13 (bs, 1 H), 6.75 (m, 1 H), 4.99 (m, 1 H), 4.60 (m, 2H), 4.51 (m, 2H), 3.92 (m, 2H), 3.60 (m, 2H), 3.49 (m, 1 H), 3.25 (m, 4H), 2.48 (m, 4H), 2.08 (m, 2H), 1.73 (m, 2H).
Example 70
2-((1 -(1 -hydroxycyclopropanecarbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3- l)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000135_0001
5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-(piperidin-4- yloxy)benzonitrile (52 mg, 0.10 mmol), and 1-hydroxy-1-cyclopropanecarboxylic acid (Acros Organics, 16 mg, 0.15 mmol) were taken up as suspension in dichloromethane (3 ml_). The mixture was treated successively with /V,/V-diisopropylethylamine (35 μΙ_, 0.20 mmol) and /V-[(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminiumhexafluorophosphate Λ/oxide (HATU, 58 mg, 0.15 mmol). The mixture was stirred overnight at room temperature and then purified by flash chromatography (silica gel) to provide 2-((1-(1-hydroxycyclopropanecarbonyl)piperidin- 4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H37N804: 597.3; found: 597.3
1H NMR (400 MHz, DMSO-c/6) δ 10.16 (m, 1 H), 8.78 (s, 1 H), 8.63 (m, 2H), 7.62 (m, 2H), 7.01 (m, 2H), 6.38 (s, 1 H), 5.05 (m, 1 H), 4.61 (m, 2H), 4.52 (m, 2H), 4.35 - 3.45 (m, 4H), 3.49 (m, 1 H), 3.19 (m, 4H), 2.46 (m, 4H), 2.08 (m, 2H), 1.76 (m, 2H), 0.98 (dd, J = 4.7, 4.3 Hz, 2H), 0.81 (dd, J = 4.6 Hz, 2H).
Example 71
5-(4-((3-methoxy-4-(4-(oxetan-3-yl)piperazine-1 -carbonyl)phenyl)amino)-1 ,3,5- trahydro-2H-pyran-4-yl)oxy)benzonitrile
Figure imgf000136_0001
Preparation of (2-methoxy-4-nitrophenyl)(4-(oxetan-3-yl)piperazin-1 -yl)methanone: A mixture of 2-methoxy-4-nitrobenzoic acid (1 .0 g, 5.0 mmol) and 1 -(oxetan-3- yl)piperazine (0.79 g, 5.6 mmol) in Ν,Ν-dimethylformamide (DMF, 15 mL) was treated with /V,/V-diisopropylethylamine, followed by 50 % propylphosphonic anhydride solution in DMF (Sigma Aldrich, 5 mL). The mixture was left to stir for one hour at room temperature before it was concentrated under reduced pressure. The residue was diluted with ethyl acetate (~ 100 mL) and washed successively with saturated aqueous sodium hydrogen carbonate solution (twice) and once with saturated aqueous sodium chloride solution. The organics were dried over anhydrous magnesium sulfate, filtered, concentrated to provide the desired material. LCMS-ESI+ (m/z): [M+H]+ calcd for C15H20 3O5: 322.1 ; found: 322.1 .
Preparation of (4-amino-2-methoxyphenyl)(4-(oxetan-3-yl)piperazin-1 -yl)methanone: (2- methoxy-4-nitrophenyl)(4-(oxetan-3-yl)piperazin-1 -yl)methanone (5.1 mmol assumed) was taken up as a suspension in methanol/tetrahydrofuran/ethyl acetate (5:2: 1 , 80 mL) in a Parr bottle. After mixture was de-gassed, 10 % palladium on charcoal (200 mg) was introduced. The mixture was shaken under 50 psi hydrogen overnight and then filtered through pad of Celite diatomaceous earth. The filtrate was concentrated under reduced pressure to provide the desired material. LCMS-ESI+ (m/z): [M+H]+ calcd for C-15H22N3O3: 292.2; found: 291 .9.
Preparation of 5-(4-((3-methoxy-4-(4-(oxetan-3-yl)piperazine-1-carbonyl)phenyl)amino)- 1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile: A suspension of 5-(4- chloro-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2/-/-pyran-4-yl)oxy)benzonitrile (100 mg, 0.32 mmol) (4-amino-2-methoxyphenyl)(4-(oxetan-3-yl)piperazin-1 -yl)methanone (92 mg, 0.32 mmol) in acetonitrile (3 ml_) was treated with /V,/V-diisopropylethylamine (0.22 ml_, 1.3 mmol). The mixture was heated in a microwave reactor for 20 minutes at 80 °C. The reaction mixture was purified by flash chromatography (silica gel), followed by recrystallization from acetonitrile, to provide the desired material. LCMS-ESI+ (m/z): [M+H]+ calcd for C30H34N7O5: 572.3; found: 572.1.
1 H NMR (400 MHz, DMSO-c/6) δ 10.53 (s, 1 H), 8.90 (s, 1 H), 8.66 (d, J = 2.2 Hz, 1 H),
8.63 (dd, J = 9.0, 2.2 Hz, 1 H), 7.86 (br, 1 H), 7.61 (d, J = 9.0 Hz, 1 H), 7.36 (br, 1 H), 7.22 (d, J = 8.1 Hz, 1 H), 4.99 (m, 1 H), 4.57 (m, 2H), 4.47 (m, 2H), 3.92 (m, 5H), 3.70 (m, 2H), 3.60 (m, 2H), 3.47 (m, 1 H), 3.25 (m, 2H), 2.34 (m, 2H), 2.24 (m, 2H), 2.09 (m, 2H), 1.74 (m, 2H).
Example 72
5-(4-((4-methoxyphenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)benzonitrile
Figure imgf000137_0001
A suspension of 5-(4-chloro-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2/-/-pyran-4- yl)oxy)benzonitrile (80 mg, 0.25 mmol) and para-anisidine (37 mg, 0.30 mmol) in acetonitrile (3 ml_) was treated with /V,/V-diisopropylethylamine (0.13 ml_, 0.76 mmol). The mixture was heated in a microwave reactor for 20 minutes at 80 °C. The solid was collected from the mixture by filtration, washed with acetonitrile and dried in a vacuum oven to provide the desired material. LCMS-ESI+ (m/z): [M+H]+ calcd for
C22H22N5°3: 404-2; found: 404-1 1 | NMR (400 MHz> DMSO-c/6) δ 10.21 (m, 1 H), 8.79 (s, 1 H), 8.60 (m, 2H), 7.72 (m, 2H), 7.60 (d, J = 9.2 Hz, 1 H), 7.00 (m, 2H), 4.98 (m, 1 H), 3.91 (m, 2H), 3.80 (s, 3H), 3.59 (m, 2H), 2.09 (m, 2H), 1.73 (m, 2H).
Example 73
5-(4-((1 -methyl-1 H-pyrazol-5-yl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)benzonitrile
Figure imgf000138_0001
To a solution of 2,4-dichloro-1 ,3,5-triazine (0.74 g, 4.9 mmol) in N,N-dimethylformamide
(DMF, 6 mL) at 0 °C were added sequentially Ν,Ν-diisopropylethylamine (DIEA, 0.89 mL, 5.1 mmol) and 1-methyl-5-aminopyrazole (0.44 g, 4.5 mmol). The mixture was stirred at 0 °C for 30 minutes and then allowed to warm to room temperature. The mixture was diluted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined extracts were washed once each with water and a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via flash chromatography on silica gel to provide 4-chloro-N-(1-methyl-1 H-pyrazol-5-yl)-
1 ,3,5-triazin-2-amine. LCMS-ESI+ (m/z): [M+H]+ calcd for C7H8CIN6: 21 1.0; found:
21 1.1.
A mixture of 4-chloro-N-(1-methyl-1 H-pyrazol-5-yl)-1 ,3,5-triazin-2-amine (0.12 g, 0.55 mmol), 2-((tetrahydro-2H-pyran-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzonitrile (0.20 g, 0.60 mmol), palladium (II) acetate (0.012 g, 10 mol%), and triphenylphosphine (0.043 g, 0.16 mmol) in 1 ,2-dimethoxyethane (DME, 6 mL) was treated with 2M aqueous sodium carbonate solution (1.2 mL). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was filtered through a pad of Celite diatomaceous earth. The aqueous phase was extracted twice with ethyl acetate. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, concentrated to dryness under reduced pressure. The residue was purified via prep HPLC (10 - 85 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to furnish 5-(4- ((1-methyl-1 H-pyrazol-5-yl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for C-19H -19N7O2: 378.2; found:
378.3 1H NMR (400 MHz, DMSO-c/6) δ 10.30 (br, 1 H), 8.86 (s, 1 H), 8.57 (br, 2H), 7.60 (d, J = 9.6 Hz, 1 H), 7.48 (s, 1 H), 6.40 (m, 1 H), 4.97 (m, 1 H), 3.91 (m, 2H), 3.75 (s, 3H), 3.59 (ddd, J = 1 1.7, 8.4, 3.1 Hz, 2H), 2.08 (m, 2H), 1.73 (m, 2H). Example 74
5-(4-((3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1,3,5-triazin-2-yl)- 2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile
Figure imgf000139_0001
Preparation of 1 -(2,6-difluoro-4-nitrophenyl)-4-(oxetan-3-yl)piperazine: A stirred mixture of 1 -(oxetan-3-yl)piperazine (0.88 g, 6.2 mmol) and potassium carbonate (1 .6 g, 1 1 mol) in N,N-dimethylformamide (9 ml_) was treated via syringe with 3,4,5- trifluoronitrobenzene (1 .0 g, 5.6 mmol). The reaction mixture was stirred at 85 °C overnight. The cooled reaction mixture was partitioned between ethyl acetate and water. A small volume of methanol was added to the ethyl acetate. The pH of the aqueous phase was brought basic via the addition of solid sodium carbonate. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed once each with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to give 1 -(2,6- difluoro-4-nitrophenyl)-4-(oxetan-3-yl)piperazine. LCMS-ESI+ (m/z): [M+H]+ calcd for C13H16F2N3°3: 300.1 ; found: 300.1
Preparation of 3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1 -yl)aniline: 1 -(2,6-difluoro-4- nitrophenyl)-4-(oxetan-3-yl)piperazine (1 .7 g, 5.6 mmol) was taken up in a mixture of tetrahydrofuran/methanol/ethyl acetate (1 :3:2, 60 ml_) . The mixture was degassed before the addition of 10 % palladium on charcoal (250 mg). The mixture was stirred under a balloon of hydrogen overnight, then filtered through a pad of Celite diatomaceous earth. The filtrate was concentrated under reduced pressure to provide
3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1 -yl)aniline. LCMS-ESI+ (m/z): [M+H]+ calcd for C13H-I 8F2N3O: 270.1 ; found: 270.2.
Preparation of 4-chloro-N-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)-1 ,3,5- triazin-2-amine: To a solution of 2,4-dichloro-1 ,3,5-triazine (0.33 g, 2.3 mmol) in N,N- dimethylformamide (DMF, 6 ml_) at 0 °C were added sequentially N,N- diisopropylethylamine (DIEA, 0.41 ml_, 2.4 mmol) and 3,5-difluoro-4-(4-(oxetan-3- yl)piperazin-1-yl)aniline (0.56 g, 2.1 mmol). The mixture was stirred at 0 °C for 30 minutes and then allowed to warm to room temperature. The mixture was diluted with ethyl acetate and water. The suspension was filtered through a plastic frit to provide 4- chloro-N-(3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1 ,3,5-triazin-2-amine. The aqueous phase was extracted twice with ethyl acetate containing a small amount of methanol. The combined extracts were washed once each with water and a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to provide additional 4-chloro-N-(3,5- difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1 ,3,5-triazin-2-amine. LCMS-ESI+
(m/z): [M+H]+ calcd for Ci6H18CIF2N60: 383.1 ; found: 383.4.
Preparation of 5-(4-((3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile A mixture of 4-chloro-N-(3,5- difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1 ,3,5-triazin-2-amine (0.13 g, 0.33 mmol), 2-((tetrahydro-2H-pyran-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzonitrile (0.12 g, 0.36 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.019 g, 5 mol%) in 1 ,2-dimethoxyethane (DME, 3 ml_) was treated with 2M aqueous sodium carbonate solution (0.74 ml_). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel to provide 5-(4-((3,5-difluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-
2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for ¾8Η30ρ 2 7θ3: 550.2; found: 550.3 1H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1 H),
8.91 (s, 1 H), 8.60 (m, 2H), 7.62 (m, 1 H), 7.59 - 7.50 (m, 2H), 5.00 (tt, J = 8.0, 4.2 Hz, 1 H), 4.59 (t, J = 6.5 Hz, 2H), 4.50 (t, J = 6.1 Hz, 2H), 3.91 (m, 2H), 3.59 (ddd, J = 1 1.6, 8.5, 3.0 Hz, 2H), 3.52 (m, 1 H), 3.14 (m, 4H), 2.41 (m, 4H), 2.09 (m, 2H), 1.73 (m, 2H).
Example 75
4-((4-(3-cyano-4-((tetrahydro-2H^yran-4-yl)oxy)phenyl)-1,3,54riazin-2-yl)amino)-N- nza m i d e
Figure imgf000141_0001
Preparation of 4-nitro-/V-(oxetan-3-yl)benzamide: To a mixture of 3-aminooxetane (Sigma Aldrich, 0.47 g, 6.5 mmol) and /V,/V-diisopropylethylamine (2.3 mL, 13 mmol) in
2- methyltetrahydrofuran (20 mL) at 0 °C was added dropwise via syringe a solution of 4- nitrobenzoyl chloride (1.0 g, 5.4 mmol) in 2-methyltetrahydrofuran (15 mL), immediately giving a precipitate. At the end of the addition, the cooling bath was removed. The suspension stirred at room temperature for about 2 hours and was then allowed to stand for two weeks. The suspension was concentrated under reduced pressure and then diluted with ethyl acetate and water. Collection of the solid by vacuum filtration and drying under vacuum provided the desired material. Additional desired material was obtained by the evaporation of the organic phase and the collection of the residual solid, as above. LCMS-ESI+ (m/z): [M+H]+calcd for C10H11N2O4: 223.1 ; found: 223.2.
Preparation of 4-amino-/V-(oxetan-3-yl)benzamide: 4-nitro-/V-(oxetan-3-yl)benzamide (0.14 g, 0.63 mmol) and 10 % Pd/C taken up in 1 :1 methanol/2-methyltetrahydrofuran (1 :1 , 4 mL). After degassing of the mixture, 10 % palladium on charcoal (30 mg) was introduced. The mixture was stirred for 3 hours under a balloon of hydrogen gas. The mixture was filtered through a pad of Celite diatomaceous earth, and the filtrate was concentrated under reduced pressure to provide the desired material. LCMS-ESI+ (m/z): [M+H]+calcd for C10H13N2O2: 193.1 ; found: 193.0.
Preparation of 4-((4-(3-cyano-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-1 ,3,5-triazin-2- yl)amino)-N-(oxetan-3-yl)benzamide: A suspension of 5-(4-chloro-1 ,3,5-triazin-2-yl)-2- ((tetrahydro-2/-/-pyran-4-yl)oxy)benzonitrile (53 mg, 0.17 mmol) and 4-amino-/V-(oxetan-
3- yl)benzamide (39 mg, 0.20 mmol) in acetonitrile (2.5 mL) was treated with N,N- diisopropylethylamine (0.12 mL, 0.67 mmol). The mixture was heated in a microwave reactor for 30 minutes at 85 °C and then for 2 hours at 120 °C. The precipitated solid was collected by vacuum filtration, washed with acetonitrile, and dried in a vacuum oven to provide 4-((4-(3-cyano-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-1 ,3,5-triazin-2- yl)amino)-N-(oxetan-3-yl)benzamide. LCMS-ESI+ (m/z): [M+H]+ calcd for C25H25N6°4: 473-2; found: 473.2.
1H NMR (400 MHz, DMSO-c/6) δ 10.64 (s, 1 H), 9.05 (d, J = 6.5 Hz, 1 H), 8.93 (s, 1 H), 8.65 (m, 2H), 7.94 (m, 4H), 7.63 (m, 1 H), 5.17 - 4.94 (m, 2H), 4.82 (t, J = 6.5 Hz, 2H), 4.65 (t, J = 6.4 Hz, 2H), 3.92 (m, 2H), 3.60 (m, 2H), 2.10 (m, 2H), 1.74 (m, 2H).
Example 76
5-(4-((4-(1-methylpiperidin-4-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H- nzonitrile
Figure imgf000142_0001
A suspension of 5-(4-chloro-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2/-/-pyran-4- yl)oxy)benzonitrile (53 mg, 0.16 mmol) and 4-(1-methylpiperidin-4-yl)aniline (ChemShuttle, 38 mg, 0.20 mmol) in acetonitrile (2.5 mL) was treated with N,N- diisopropylethylamine (0.12 mL, 0.67 mmol). The mixture was heated in a microwave reactor for 30 minutes at 85 °C. The cooled reaction mixture was purified by prep HPLC (10 - 80 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer), followed by flash chromatography (silica gel) to provide 5-(4-((4-(1-methylpiperidin-4-yl)phenyl)amino)-
I , 3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile. LCMS-ESI"1" (m/z):
[M+H]+ calcd for C27H3 N602: 471.2; found: 471.3 1H NMR (400 MHz, DMSO-c/6) δ 10.32 (bs, 1 H), 8.83 (s, 1 H), 8.62 (m, 2H), 7.71 (m, 2H), 7.61 (d, J = 9.4 Hz, 1 H), 7.29 (d, J = 8.4 Hz, 2H), 4.99 (m, 1 H), 3.91 (m, 2H), 3.59 (m, 2H), 3.35 (bs, 3H), 2.99 (d, J =
I I .2 Hz, 2H), 2.32 (s, 3H), 2.1 1 (m, 4H), 1.74 (m, 4H).
Example 77
5-(4-((6-methoxypyridin-3-yl)amino)-1 ,3,54riazin-2-yl)-2-((tetrahydro-2H-pyran-4-
Figure imgf000143_0001
A suspension of 5-(4-chloro-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2/-/-pyran-4- yl)oxy)benzonitrile (80 mg, 0.25 mmol) and 5-methoxy-2-aminopyridine (38 mg, 0.30 mmol) in acetonitrile (3 mL) was treated with /V,/V-diisopropylethylamine (0.13 mL, 0.76 mmol). The mixture was heated in a microwave reactor for 20 minutes at 80 °C. The reaction mixture was purified by flash chromatography (silica gel), followed by recrystallization from acetonitrile, to provide the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C2i H2i N603: 405.2; found: 405.2 1 H NMR (400 MHz, DMSO-c/6) δ 10.32 (s, 1 H), 8.82 (s, 1 H), 8.51 (m, 2H), 8.05 (dd, J = 8.9, 2.7 Hz, 1 H), 7.61 (d, J = 9.4 Hz, 1 H), 6.91 (m, 1 H), 4.98 (m, 1 H), 3.90 (m, 5H), 3.59 (m, 2H), 2.08 (m, 2H), 1.73 (m, 2H).
Example 78
5-(4-((3-methoxyphenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)benzonitrile
Figure imgf000143_0002
A suspension of 5-(4-chloro-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2/-/-pyran-4- yl)oxy)benzonitrile (93 mg, 0.29 mmol) and meta-anisidine (43 mg, 0.35 mmol) in acetonitrile (3 mL) was treated with /V,/V-diisopropylethylamine (0.15 mL, 0.88 mmol). The mixture was heated in a microwave reactor for 20 minutes at 80 °C. The reaction mixture was concentrated to dryness under reduced pressure. The residue was taken up in acetonitrile, and water was added to precipitate a solid. The solid was collected by filtration, washed with aqueous methanol, and dried in a vacuum oven to provide the desired material. LCMS-ESI"1" (m/z): [M+H]+ calcd for C22H22N5°3: 404.2; found: 404.1 1 H NMR (400 MHz, DMSO-ce) δ 10.38 (s, 1 H), 8.87 (s, 1 H), 8.62 (m, 2H), 7.62
(m, 2H), 7.32 (m, 2H), 6.73 (m, 1 H), 5.00 (m, 1 H), 3.91 (m, 2H), 3.84 (s, 3H), 3.59 (m, 2H), 2.09 (m, 2H), 1.73 (m, 2H).
Example 79
5-(4-(phenylamino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)benzonitrile
Figure imgf000144_0001
Step 1 : To a solution of 2,4-dichloro-1 ,3,5-triazine (530 mg, 3.54 mmol) in DMF (6 mL) at 0 °C were added DIEA (475 mg, 3.67 mmol), followed by a solution of aniline (300 mg, 3.22 mmol) in DMF (9 mL). The clear, golden mixture was stirred at 0 °C for 30 minutes and then allowed to warm to r.t. where it remained. The mixture was partitioned between ethyl acetate and water. Layers were separated and aqueous phase was extracted twice with EtOAc. The combined extracts were washed once each with water and brine, then dried over anhydrous MgSC>4, filtered, and concentrated under reduced pressure. Crude material was purified by silica gel column chromatography eluted 10-20 of % EtOAc in hexanes to give the product.
Step 2: A sealed tube containing a suspension of 4-chloro-N-phenyl-1 ,3,5-triazin-2- amine (150 mg, 0.73 mmol) and Pd(PPh3)4 (38 mg, 0.033 mmol) in a degassed mixture of dioxane/H20 (3 mL, 4/1 ), was preheated at 85 °C for 5 min. Next, K2CO3 (227 mg, 2 mmol) and 2-((tetrahydro-2H-pyran-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzonitrile (263 mg, 0.8 mmol) , were added to the mixture and the reaction was additionally heated at 100 °C in the sealed tube for 15 h. The clear was partitioned between ethyl acetate and water. Layers were separated and aqueous phase was extracted twice with EtOAc. The combined extracts were washed once each with water and brine, then dried over anhydrous MgSC>4, filtered, and concentrated under reduced pressure. The residue was then purified via HPLC (20 imL/min, 20- 90percent MeCN/h^O (0.1 % TFA v/v) gradient over 30 min) to give the title compound as a solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1 H), 8.80 (s, 1 H), 8.67 - 8.45 (m, 2H), 7.75 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 9.5 Hz, 1 H), 7.37 (t, J = 7.8 Hz, 2H), 7.10 (t, J = 7.4 Hz, 1 H), 4.93 (dt, J = 8.2, 4.2 Hz, 1 H), 3.97 - 3.76 (m, 2H), 3.54 (m, 2H), 2.04 (m, 2H), 1 .68 (m, 2H).
LCMS-ESI+ (m/z): [M+H]+ calcd for C21 H-19N5O2: 374.2; found: 374.1 . Example 80
(R)-5-(4-((4-morpholinophenyl)amino)-1 ,3,5-triazin-2-yl)-2-(pyrrolidin-3- yloxy)benzonitrile.
Figure imgf000145_0001
Step 1 : To solution of 2,4-dichloro-1 ,3,5-triazine (500 mg, 3.33 mmol ) in DMF (10 mL) at 0 °C under argon atmosphere were added DIEA (0.602 mL, 3.45 mmol), followed by 4-amino phenyl morpholine (535 mg, 3.0 mmol) at once. The reaction mixture was stirred at 0 °C for 1 h. The solvent was concentrated to dryness under reduced pressure. The crude product was purified by flash column chromatography on silica gel to afford 4- chloro-N-(4-morpholinophenyl)-1 ,3,5-triazin-2-amine. LCMS-ESI+ (m/z): [M+H]+ calcd for C13H14CIN50: 292.12 found:292.3
Step 2: To a mixture of 4-chloro-N-(4-morpholinophenyl)-1 ,3,5-triazin-2-amine (0.25g, 0.86 mmol), 4-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)morpholine (0.39 g, 0.94 mmol), and Pd(PPh3)4 (74 mg, 0.06 mmol) in a 20 mL micro wave vial was added DME (6 mL). To well stirred mixture was added a solution of sodium carbonate (409 mg, 3.85 mmol) in water (3 mL)). The mixture was microwaved for one hour at 130 °C. The reaction mixture was diluted with DCM and filtered through short pad of silica gel and washed with 10%MeOH/DCM. The solvent was concentrated to dryness under reduced pressure. The crude product was purified by flash column chromatography on silica gel to afford (R)-tert-butyl 3-(2-cyano-4-(4-((4-morpholinophenyl)amino)-1 ,3,5- triazin-2-yl)phenoxy)pyrrolidine-1-carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for C29H33N7O4: 544.2.12 found:544.2. Step 3: (R)-tert-butyl 3-(2-cyano-4-(4-((4-morpholinophenyl)amino)-1 ,3,5-triazin-2- yl)phenoxy)pyrrolidine-1-carboxylate (431 mg, 0.79 mmol) was dissolved in 20% TFA/DCM (10 ml_) and stirred at room temperature for 1 h. The solvent was concentrated under reduced pressure and the residue was purified via prep HPLC (5- 95% acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to isolate (R)-5-(4-((4- morpholinophenyl)amino)-1 ,3,5-triazin-2-yl)-2-(pyrrolidin-3-yloxy)benzonitrile. LCMS-
ESI+ (m/z): [M+H]+ calcd for C24H25N702: 444.2.2; found:444.3_1H NMR (400 MHz, DMSO-c/6) δ 10.13 (d, J = 30.2 Hz, 1 H), 9.1 1 (br s, 1 H), 8.74 (s, 1 H), 8.67 - 8.44 (m, 2H), 7.607.48 (m, 3H), 6.95 (t, J = 9.5 Hz, 2H), 5.41 (t, J = 4.8 Hz, 1 H), 3.84 - 3.68 (m, 4H), 3.59 (dd, J = 13.5, 4.8 Hz, 1 H), 3.50 - 3.35 (m, 3H), 3.07 (d, J = 6.4 Hz, 4H), 2.39 - 2.17 (m, 2H).
Example 81
(R)-2-((1-(2-hydroxyacetyl)pyrrolidin-3-yl)oxy)-5-(4-((3-morpholinophenyl)amino)- 1,3,5-triazin-2-yl)benzonitrile
Figure imgf000146_0001
The title compound was prepared by glycolic acid coupling to (R)-5-(4-((3- morpholinophenyl)amino)-1 ,3,5-triazin-2-yl)-2-(pyrrolidin-3-yloxy)benzonitrile using the same procedure reported in Example 103. LCMS-ESI+ (m/z): [M+H]+ calcd for C26H27N704: 502.2; found:502.3_1H NMR (400 MHz, DMSO-c/6) δ 10.22 (s, 1 H), 8.79 (s, 1 H), 8.69 - 8.43 (m, 2H), 7.51 (d, J = 9.0 Hz, 2H), 7.20 (d, J = 7.9 Hz, 2H), 6.82 - 6.56 (m, 1 H), 5.36 (d, J = 32.9 Hz, 1 H), 4.75 (s, 1 H), 4.18 - 3.91 (m, 2H), 3.86
8H), 3.13 (s, 4H), 2.35 - 2.06 (m, 3H).
Example 82
(R)-5-(4-((3-morpholinophenyl)amino)-1,3,5-triazin-2-yl)-2-(pyrrolidin-3- yloxy)benzonitrile
Figure imgf000147_0001
The title compound was prepared following a similar procedure reported in Example-80 using 3-morpholinoaniline instead of 4-morpholineaniline. LCMS-ESI+ (m/z): [M+H]+ calcd for C24H25N7O2: 444.2; found:444.3_1H NMR (400 MHz, DMSO-c/6) δ 10.24 (s, 1 H), 9.13 (br s, 2H), 8.80 (s, 1 H), 8.69 - 8.48 (m, 2H), 7.66 - 7.42 (m, 2H), 7.29 - 6.97 (m, 2H), 6.79 - 6.60 (m, 1 H), 5.43 (t, J = 4.9 Hz, 1 H), 3.76 (s, 4H), 3.59 (dd, J = 13.5, 4.9 Hz, 1 H), 3.54 - 3.18 (m, 5H), 3.13 (s, 4H), 2.38-2.19 (m, 2H).
Example 83 (R)-4-((4-(3-cyano-4-((1-(2-hydroxyacetyl)pyrrolidin-3-yl)oxy)phenyl)-1,3,5-triazin- 2-yl)amino)-N-isopropylbenzamide
Figure imgf000147_0002
The title compound was prepared by glycolic acid coupling to (R)-4-((4-(3-cyano-4- (pyrrolidin-3-yloxy)phenyl)-1 ,3,5-triazin-2-yl)amino)-N-isopropylbenzamide (Example 84) using the same procedure reported in Example 103. LCMS-ESI+ (m/z): [M+H]+ calcd for C26H27N704: 502.2; found:502.3
1H NMR (400 MHz, DMSO-c/6) δ 10.55 (s, 1 H), 8.87 (s, 1 H), 8.72 - 8.50 (m, 2H), 8.1 1 (d, J = 7.7 Hz, 1 H), 7.85 (m, 4H), 7.53 (dd, J = 9.1 , 2.4 Hz, 1 H), 5.36 (dd, J = 33.4, 4.4 Hz, 1 H), 4.64 (d, J = 6.2 Hz, 1 H), 4.17 - 3.90 (m, 2H), 3.85 - 3.35 (m, 4H), 3.12 (m, 1 H), 2.38 - 2.04 (m, 2H), 1.16 (d, J = 6.5 Hz, 6H).
Example 84
(R)-4-((4-(3-cyano-4-(pyrrolidin-3-yloxy)phenyl)-1,3,5-triazin-2-yl)am
isopropylbenzamide
Figure imgf000148_0001
The title compound was prepared following the similar procedure reported in Example- 80 using 4-amino-N-isopropylbenzamide instead of 4-Phenylmorpholine. LCMS-ESI+ (m/z): [M+H]+ calcd for C24H25N702: 444.2.2; found:444.3
Example 85
(R)-4-((4-(3-cyano-4-((1-(2-hydroxyacetyl)pyrrolidin-3-yl)oxy)phenyl)-1,3,5-triazin- 2-yl)amino)benzamide
Figure imgf000148_0002
The title compound was prepared following the similar procedure reported in Example- 80 using 4-aminobenzamide instead of 4-Phenylmorpholine followed by glycolic acid coupling to (R)-4-((4-(3-cyano-4-(pyrrolidin-3-yloxy)phenyl)-1 ,3,5-triazin-2- yl)amino)benzamide as shown in Example-103. LCMS-ESI+ (m/z): [M+H]+ calcd for C23H2i N704: 460.2; found:460.2_1H NMR (400 MHz, DMSO-c/6) δ 10.58 (s, 1 H), 8.88 (s, 1 H), 8.74 (dd, J = 4.4, 1 .4 Hz, 1 H), 8.67 - 8.56 (m, 2H), 8.51 (dd, J = 8.4, 1.4 Hz, 1 H), 7.91 -7.84 (m, 3H), 7.55-7.48 (m, 2H), 5.37 (d, J = 32.3 Hz, 3H), 4.05 - 3.97 (m, 2H), 3.82 - 3.64 (m, 3H), 3.48-3.41 (m, 2H), 2.31 -2.15 (m, 2H).
Example 86 (R)-2-((1 -(2-hydroxyacetyl)pyrrolidin-3-yl)oxy)-5-(4-((4-(4-methylpiperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000149_0001
The title compound was prepared following the similar procedure reported in Example- 80 using 4-(4-methylpiperazin-1-yl)aniline instead of 4-Phenylmorpholine followed by glycolic acid coupling to (R)-5-(4-((4-(4-methylpiperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-
2-yl)-2-(pyrrolidin-3-yloxy)benzonitrile as shown in Example103. LCMS-ESI+ (m/z):
[M+H]+ calcd for C23H2iN704: 515.2; found: 515.4 1H NMR (400 MHz, Acetonitrile-c 3) δ 9.96 (s, 1 H), 8.73 (s, 1 H), 8.54-8.45 (m, 2H), 7.82 - 7.51 (m, 3H), 7.20 (s, 2H), 5.38 (d, J = 33.1 Hz, 1 H), 4.88 - 4.52 (m, 2H), 4.32 - 4.02 (m, 3H), 3.97-3.85 (m, 4H), 3.48 - 3.07 (m, 6H), 2.93 (s, 3H), 2.47-2.23 (m, 2H).
Example 87
2-Fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile
Figure imgf000150_0001
To solution of 2,4-dichloro-1 ,3,5-triazine (2.5 g, 16.67 mmol ) in DMF (100 mL) at 0 C under nitrogen atmosphere was added solution of 4-(4-(oxetan-3-yl)piperazin-1- yl)aniline (3.5 g, 15.1 mmol) in DMF (120 mL) over 5 minutes. The reaction mixture was stirred at 0 °C for 1 h and the solvent concentrated to dryness under reduced pressure. The crude product was added 40%MeOH\DCM and sonicated for 2 minutes to bring solid particles in to the solution and left at RT for 5 minutes. The solid particles was filtered, washed with DCM twice and dried to afford creamy solid product. LCMS-ESI+
(m/z): [M+H]+ calcd for C16H19CIN60: 347.1 found:347.3. A mixture of 4-chloro-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1 ,3,5-triazin-2-amine (1g, 2.88 mmol), 2-fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (0.783g, 3.17 mmol) and Pd(PPh3)4 (0.25g, 0.21 mmol) was taken up in 1 ,2-DME (24 mL) in a 100 mL round bottom flask. To well stirred mixture was added solution of sodium carbonate (1.375 g 12.98 mmol) in water (12 mL). The mixture heated at 95 °C for 4h. The reaction mixture was diluted with 30% MeOH/DCM (50 mL) and filtered through short pad of silica gel and washed twice with 30% MeOH/DCM. The filtrate was adsorbed on silica gel and solvent was concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel to afford 2- fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C23H22FN70: 432.2; found:432.3 1H NMR (400 MHz, DMSO-c/6) δ 10.20 (d, J = 21.0 Hz, 1 H), 8.77 (s, 1 H), 8.65 (d, J = 10.8 Hz, 2H), 7.72 (s, 1 H), 7.64 - 7.43 (m, 2H), 6.96 (t, J = 10.8 Hz, 2H), 4.55 (t, J = 6.5 Hz, 2H), 4.46 (t, J = 6.0 Hz, 2H), 3.47-3.40 (m, 1 H), 3.13 (d, J = 6.6 Hz, 4H), 2.46 - 2.32 (m, 4H).
Example 88
2-(((R)-1-((S)-2-hydroxypropanoyl)pyrrolidin-3-yl)oxy)-5-(4-((4-(4-(oxetan-3- )amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000151_0001
Step 1 : (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (430 mg, 2.29 mmol) was added Me-THF (20 mL) under argon atmosphere and cooled at 0 °C. To well stirred solution was added potassium tert-butoxide at one portion and stirred for 30 minutes. To well stirred solution was added 2-fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (900 mg, 2.09 mmol) and warmed to room temperature over 10 min. The reaction was heated at 60 °C overnight. The solvent was concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel to afford (R)-tert-butyl 3-(2-cyano-4-(4-((4-(4- (oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenoxy)pyrrolidine-1- carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H38FN804: 599.3; found: 599.2 Step 2: (R)-tert-butyl 3-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)- 1 ,3,5-triazin-2-yl)phenoxy)pyrrolidine-1-carboxylate (90 mg, 0.15 mmol) was dissolved in 20% TFA DCM (5 mL) and stirred at room temperature for 1 h. The solvent was concentrated under reduced pressure to afford (R)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-(pyrrolidin-3-yloxy)benzonitrile. The dried residue was used for next step without purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C27H30N8O2: 499.2; found: 499.3.
1H NMR (400 MHz, DMSO-c/6) δ 10.30 - 10.01 (m, 1 H), 9.13 (d, J = 37.7 Hz, 1 H), 8.75 (s, 1 H), 8.64 - 8.55 (m, 2H), 7.75 - 7.39 (m, 3H), 7.03 (d, J = 8.5 Hz, 2H), 5.52 - 5.28 (m, 1 H), 4.73 (d, J = 5.9 Hz, 4H), 4.39 - 4.36 (m, 1 H) 4.00 - 3.53 (m, 7H), 3.27 - 2.91 (m, 5H), 2.44 - 1.81 (m, 2H).
Step 3: To solution of (R)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)-2-(pyrrolidin-3-yloxy)benzonitrile (60 mg, 0.09 mmol), (S)-2- hydroxypropanoic acid (13 mg, 0.15 mmol), HATU (74 mg, 0.19 mmol) in DMF (3 mL) was added DIPEA (0.205 mL, 1.17 mmol) in a 10 mL microwave vial and sealed. This reaction mixture was stirred at room temperature overnight. The solvent was concentrated and the crude product purified via prep HPLC (5-95% acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to isolate 2-(((R)-1-((S)-2-hydroxypropanoyl)pyrrolidin-3- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C3oH34N804: 571.2; found: 571.4 1H NMR (400 MHz, DMSO-c/6) δ 10.17 (dd, J = 23.9, 10.4 Hz, 1 H), 8.75 (s, 1 H), 8.66 - 8.42 (m, 2H), 7.62 (s, 2H), 7.51 (d, J = 8.8 Hz, 1 H), 7.04 (s, 2H), 5.36 (d, J = 19.8 Hz, 1 H), 4.77-4.75 (m, 5H), 4.42 - 4.20 (m, 4H), 3.98 - 3.76 (m, 4H), 3.73 - 3.36 (m, 6H), 2.31- 2.12 (m, 2H), 1.17 (dd, J = 12.3, 6.5 Hz, 3H).
Example 89
(R)-2-((1-(3-hydroxypropanoyl)pyrrolidin-3-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000152_0001
The title compound was prepared following the same procedure reported in Example 88 by coupling 3-hydroxypropanoic acid to (R)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-(pyrrolidin-3-yloxy)benzonitrile instead of (S)-2- hydroxypropanoic acid.
LCMS-ESI+ (m/z): [M+H]+ calcd for C30H34N8O4: 571.2 found: 571.4.
1H NMR (400 MHz, DMSO-c/6) δ 10.13 (d, J = 19.5 Hz, 1 H), 8.73 (s, 1 H), 8.63 - 8.46 (m, 2H), 7.68 - 7.41 (m, 3H), 6.97 (s, 2H), 5.34 (d, J = 27.8 Hz, 1 H), 4.59-4.50 (m, 4H), 3.70-3.60 (m, 2H), 3.59-3.56 (m, 8H), 3.15-3.09 (m, 7H), 2.37 - 2.12 (m, 4H).
Example 90
(R)-2-((1-(2-cyanoacetyl)pyrrolidin-3-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000153_0001
The title compound was prepared following the same procedure reported in Example 88 by coupling 2-cyanoacetic acid to (R)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-(pyrrolidin-3-yloxy)benzonitrile instead of (S)-2- hydroxypropanoic acid.
LCMS-ESI+ (m/z): [M+H]+ calcd for C3oH3iN903: 566.2 found: 566.3.
1H NMR (400 MHz, DMSO-c 6) δ 10.12 (d, J = 21 .2 Hz, 1 H), 8.73 (s, 1 H), 8.65 - 8.46 (m, 2H), 7.70 - 7.38 (m, 3H), 6.96 (s, 2H), 5.42 - 5.36 (m, 1 H), 4.57-4.49 (m, 4H), 4.00 (d, J = 10.1 Hz, 1 H), 3.96 - 3.76 (m, 1 H), 3.68 - 3.57 (m, 6H), 3.45 - 3.40 (m, 1 H), 3.15 - 3.09 (m, 6H), 2.31 - 2.08 (m, 2H).
Example 91
2-(((R)-1-((R)-2-hydroxypropanoyl)pyrrolidin-3-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000153_0002
The title compound was prepared following the same procedure reported in Example 88 by coupling (R)-2-hydroxypropanoic acid to (R)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-(pyrrolidin-3-yloxy)benzonitrile instead of (S)-2- hydroxypropanoic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C30H34N8O4: 571 .2; found: 571 .4. 1H NMR (400 MHz, DMSO-c/6) δ 10.12 (d, J = 20.3 Hz, 1 H), 8.73 (s, 1 H), 8.57 (d, J = 7.8 Hz, 1 H), 8.36 (s, 1 H), 7.68 - 7.41 (m, 3H), 6.97 (d, J = 10.5 Hz, 2H), 5.34 (d, J = 30.1 Hz, 1 H), 4.93 (d, J = 28.9 Hz, 1 H), 4.67 - 4.38 (m, 3H), 4.36 - 4.10 (m, 2H), 4.02 - 3.65 (m, 1 H), 3.67-3.60 (m, 4H), 3.52 - 3.34 (m, 2H), 3.15-3.09 (m, 6H), 2.35 - 2.05 (m, 2H), 1.21 - 1.10 (m, 3H).
Example 92
(R)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((1 - (oxetane-3-carbonyl)pyrrolidin-3-yl)oxy)benzonitrile
Figure imgf000154_0001
The title compound was prepared following the same procedure reported in Example 88 by coupling oxetane-3-carboxylic acid to (R)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-(pyrrolidin-3-yloxy)benzonitrile instead of (S)-2- hydroxypropanoic acid. LCMS-ESI"1" (m/z): [M+H]+ calcd for C31 H34N8O4: 583.3 found: 583.3.
1H NMR (400 MHz, DMSO-c/6) δ 10.19 (s, 1 H), 8.75 (s, 1 H), 8.59 - 8.57 (m, 2H), 7.75 - 7.43 (m, 3H), 7.04 (s, 2H), 5.33 - 5.30 (m, 1 H), 4.91 - 4.56 (m, 8H), 4.10 - 3.81 (m, 4H), 3.65 - 3.47 (m,5H), 3.21 - 2.91 (m, 4H), 2.35 - 2.31 (m, 4H). Example 93
(R)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)-2- (pyrrolidin-3-yloxy)benzonitrile
Figure imgf000155_0001
Step 1 : (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (430 mg, 2.29 mmol) was added Me-THF (20 ml_) under argon atmosphere and cooled at 0 °C. To well stirred solution was added potassium tert-butoxide at one portion and stirred for 30 minutes. To well stirred solution was added 2-fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (900 mg, 2.09 mmol) and warmed to room temperature over 10 min. The reaction was heated at 60 °C overnight. The solvent was concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel to afford (R)-tert-butyl 3-(2-cyano-4-(4-((4-(4- (oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenoxy)pyrrolidine-1- carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H38FN804: 599.3; found: 599.2 Step 2: (R)-tert-butyl 3-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)- 1 ,3,5-triazin-2-yl)phenoxy)pyrrolidine-1-carboxylate (90 mg, 0.15 mmol) was dissolved in 20% TFA DCM (5 ml_) and stirred at room temperature for 1 h. The solvent was concentrated under reduced pressure to afford (R)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-(pyrrolidin-3-yloxy)benzonitrile. The dried residue was used for next step without purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C27H30N8O2: 499.2; found: 499.3.
1H NMR (400 MHz, DMSO-c/6) δ 10.30 - 10.01 (m, 1 H), 9.13 (d, J = 37.7 Hz, 1 H), 8.75 (s, 1 H), 8.64 - 8.55 (m, 2H), 7.75 - 7.39 (m, 3H), 7.03 (d, J = 8.5 Hz, 2H), 5.52 - 5.28 (m, 1 H), 4.73 (d, J = 5.9 Hz, 4H), 4.39 - 4.36 (m, 1 H) 4.00 - 3.53 (m, 7H), 3.27 - 2.91 (m, 5H), 2.44 - 1.81 (m, 2H).
Example 94 (R)-2-((1-(1-hydroxycyclopropanecarbonyl)pyrrolidin-3-yl)oxy)-5-(4-((4-(4-(oxetan- 3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile.
Figure imgf000156_0001
The title compound was prepared following the same procedure reported in Example 88 by coupling 1 -hydroxycyclopropanecarboxylic acid to (R)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-(pyrrolidin-3-yloxy)benzonitrile instead of (S)-2-hydroxypropanoic acid.
LCMS-ESI+ (m/z): [M+H]+ calcd for C31 H34N8O4: 583.2 found: 583.5.
1H NMR (400 MHz, DMSO-c 6) δ 10.17 (d, J = 18.3 Hz, 1 H), 8.75 (s, 1 H), 8.68 - 8.44 (m, 2H), 7.62 (s, 2H), 7.52 (d, J = 8.5 Hz, 1 H), 7.05 (s, 2H), 6.16 (s, 1 H), 5.34 (d, J = 32.5 Hz, 2H), 4.75 (d, J = 6.2 Hz, 4H), 4.41 (br s, 2H), 4.27 - 3.81 (m, 5H), 3.21 -2.98 (m, 5H), 2.43 - 1 .97 (m, 2H), 1 .17 - 0.64 (m, 4H).
Example 95
(R)-2-((1-formylpyrrolidin-3-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000156_0002
The title compound was prepared following the same procedure reported in Example 88 by coupling formic acid to (R)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)- 1 ,3,5-triazin-2-yl)-2-(pyrrolidin-3-yloxy)benzonitrile instead of (S)-2-hydroxypropanoic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C28H30N8O3: 527.2 found: 527.4 1H NMR (400 MHz, DMSO-c/6) 5 10.17 (d, J = 20.0 Hz, 1 H), 8.75 (s, 1 H), 8.65 - 8.43 (m, 2H), 8.21 (d, J = 19.5 Hz, 1 H), 7.72 - 7.42 (m, 3H), 7.04 (s, 2H), 5.37-5.33 (m, 1 H), 4.75-4.72 (m, 4H), 4.50-4.29 (m, 1 H), 3.81 - 3.48 (m, 7H), 3.16 - 2.85 (m, 5H), 2.31 - 2.13 (m, 2H).
Example 96 (R)-2-((1-(2,2-difluoroacetyl)pyrrolidin-3-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazi yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000157_0001
The title compound was prepared following the same procedure reported in Example 88 by coupling 2,2-difluoroacetic acid to (R)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-(pyrrolidin-3-yloxy)benzonitrile instead of (S)-2- hydroxypropanoic acid.
LCMS-ESI+ (m/z): [M+H]+ calcd for C29H30N8O3: 577.2 found: 577.4 1 H NMR (400 MHz, DMSO-c/6) δ 10.18 (d, J = 19.9 Hz, 1 H), 8.75 (s, 1 H), 8.70 - 8.45 (m, 2H), 7.76 - 7.46 (m, 3H), 7.03 (d, J = 9.5 Hz, 2H), 6.57 (td, J = 52.9, 27.6 Hz, 1 H), 5.41 (d, J = 30.9 Hz, 1 H), 4.75 (d, J = 6.0 Hz, 4H), 4.39 (br s, 1 H), 4.01 - 3.59 (m, 7H), 3.27 - 2.79 (m, 5H), 2.35 - 2.15 (m, 2H).
Example 97
2-((1-(2-hydroxyacetyl)azepan-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000157_0002
The title compound was prepared by substituting intermediate 2-fluoro-5-(4-((4-(4- (oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (Example 87) with tert-butyl 4-hydroxyazepane-1-carboxylate, followed by Boc-deprotection and coupling with glycolic acid as shown in Example-88 LCMS-ESI+ (m/z): [M+H]+ calcd for Csi HseNgCU: 585.3; found: 585.2.
1H NMR (400 MHz, DMSO-c/6) δ 10.13 (d, J = 18.1 Hz, 1 H), 8.72 (s, 1 H), 8.63 - 8.45 (m, 2H), 7.70 - 7.36 (m, 3H), 6.99 (s, 2H), 4.90 (s, 1 H), 4.65-4.61 (m, 2H), 4.17 - 3.95 (m, 2H), 3.64-3.41 (m, 8H), 3.22-3.09 (m, 8H), 2.19 - 1.42 (m, 6H). Example 98
2-((4,4-difluoro-1-(2-hydroxyacetyl)pyrrolidin-3-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000158_0001
The title compound was prepared by substituting intermediate 2-fluoro-5-(4-((4-(4- (oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (Example 87) with tert-butyl 3,3-difluoro-4-hydroxypyrrolidine-1-carboxylate, followed by Boc- deprotection and coupling with glycolic acid as shown in Example-88 LCMS-ESI+ (m/z):
[M+H]+ calcd for C29H30F2N8O4: 593.2; found:593.3 1H NMR (400 MHz, DMSO-c/6) δ 10.15 (d, J = 23.3 Hz, 1 H), 8.74 (s, 1 H), 8.68 - 8.47 (m, 2H), 7.71 - 7.44 (m, 3H), 6.97 (d, J = 1 1.3 Hz, 2H), 5.60 (d, J = 34.2 Hz, 1 H), 4.96 (d, J = 23.5 Hz, 1 H), 4.57-4.48 (m, 4H), 4.18 - 4.07 (m, 5H), 3.90 - 3.53 (m, 4H), 3.16-3.09 (m, 5H), 2.42 (br s, 1 H).
Example 99
2-(((3R,5R)-1-(2-hydroxyacetyl)-5-methylpyrrolidin-3-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000159_0001
The title compound was prepared by substituting intermediate 2-fluoro-5-(4-((4-(4- (oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (Example 87) with (2R,4R)-tert-butyl 4-hydroxy-2-methylpyrrolidine-1-carboxylate, followed by Boc- deprotection and coupling with glycolic acid as shown in Example-88. LCMS-ESI+ (m/z):
[M+H]+ calcd for C3oH34N804: 571.2; found: 571.3 1H NMR (400 MHz, DMSO-c/6) δ 10.13 (d, J = 19.9 Hz, 1 H), 8.73 (s, 1 H), 8.65 - 8.46 (m, 2H), 7.72 - 7.39 (m, 2H), 6.99 (d, J = 10.2 Hz, 2H), 5.34 (s, 1 H), 4.77 - 4.36 (m, 4H), 4.19-4.14 (m, 2H), 4.07 - 3.74 (m, 4H), 3.69-3.56 (m, 5H), 3.30 - 3.02 (m, 4H), 2.47-2.31 (m, 3H), 2.19 - 1.94 (m, 2H). Example 100
2-(((3R,5S)-1-(2-hydroxyacetyl)-5-methylpyrrolidin-3-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000159_0002
The title compound was prepared by substituting intermediate 2-fluoro-5-(4-((4-(4- (oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (Example 87) with (2S,4R)-tert-butyl 4-hydroxy-2-methylpyrrolidine-1-carboxylate, followed by Boc- deprotection and coupling with glycolic acid as shown in Example-88. LCMS-ESI+ (m/z):
[M+H]+ calcd for C3oH34N804: 571.2; found: 571.3 1H NMR (400 MHz, DMSO-c/6) δ 10.12 (d, J = 20.8 Hz, 1 H), 8.73 (s, 1 H), 8.65 - 8.43 (m, 2H), 7.69 - 7.40 (m, 3H), 6.97 (brs, 2H), 5.34 (s, 1 H), 4.70-4.52 (m, 4H), 4.19-4,17 (m, 1 H), 3.94-3.81 (m, 3H), 3.64- 3.57 (m, 5H), 3.16-3.09 (m, 6H), 2.47-2.31 (m, 3H), 2.21-1.92 (m, 2H). Example 101
2-(((3R,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidin-3-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000160_0001
The title compound was prepared by substituting intermediate 2-fluoro-5-(4-((4-(4- (oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (Example 87) with (3S,4S)-tert-butyl 3-fluoro-4-hydroxypyrrolidine-1-carboxylate, followed by Boc- deprotection and coupling with glycolic acid as shown in Example-88. LCMS-ESI+ (m/z):
[M+H]+ calcd for C29H3i FN804: 575.2; found: 575.4 1H NMR (400 MHz, DMSO-c/6) δ 10.20 (d, J = 20.8 Hz, 1 H), 8.76 (s, 1 H), 8.68 - 8.34 (m, 2H), 7.63-7.61 (m, 3H), 7.07- 7.02 (m, 2H), 5.77 - 5.26 (m, 3H), 4.81- 4.46 (m, 4H), 4.44 (s, 2H), 4.22 - 3.67 (m, 8H), 3.66-3.60 (m, 2H), 3.40 - 3.25 (m, 2H).
Example 102
2-(((1 R,4S,6S)-2-(2-hydroxyacetyl)-2-azabicyclo[2.2.1]heptan-6-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000160_0002
The title compound was prepared by substituting intermediate 2-fluoro-5-(4-((4-(4- (oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (Example 87) with (1 R,4S,6S)-tert-butyl 6-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate, followed by Boc-deprotection and coupling with glycolic acid as shown in Example 88. LCMS- ESI+ (m/z): [M+H]+ calcd for C31 H34N8O4: 583.2; found: 583.3 1H NMR (400 MHz, DMSO-c/6) 5 10.17 (d, J = 22.7 Hz, 1 H), 8.74 (s, 1 H), 8.56 (m, 2H), 7.61 (m, 3H), 7.05 (s, 2H), 4.97 - 4.64 (m, 4H), 4.64 - 4.35 (m, 3H), 4.12 (d, J = 4.0 Hz, 1 H), 4.04 - 3.91 (m, 3H), 3.38 - 3.16 (m, 4H), 3.07 - 2.85 (m, 2H), 2.69 (d, J = 26.3 Hz, 2H), 2.21 - 1 .98 (m, 1 H), 1 .86 - 1 .48 (m, 4H).
Example 103
(R)-2-((1-(2-hydroxyacetyl)pyrrolidin-3-yl)oxy)-5-(4-((4-morpholinophenyl)amino)- 1,3,5-triazin-2- l)benzonitrile
Figure imgf000161_0001
To solution of (R)-5-(4-((4-morpholinophenyl)amino)-1 ,3,5-triazin-2-yl)-2-(pyrrolidin-3- yloxy)benzonitrile (100 mg, 0.23 mmol), glycolic acid (34 mg, 0.45 mmol), HATU (171 mg, 0.45 mmol) in dichloromethane (6 mL) was added DIPEA (0.471 mL, 2.7 mmol) in a 10 mL microwave vial and sealed. This reaction mixture was stirred at room temperature overnight. The solvent was concentrated and the crude product purified by flash column chromatography on silica gel to afford (R)-2-((1 -(2-hydroxyacetyl)pyrrolidin-3-yl)oxy)-5-
(4-((4-morpholinophenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z):
[M+H]+ calcd for C26H27N704: 502.2; found:502.3_1H NMR (400 MHz, DMSO-c/6) δ 10.17 (s, 1 H), 8.74 (s, 1 H), 8.58-8.52 (m, 2H), 7.75 - 7.41 (m, 3H), 6.99 (br s, 2H), 5.47 - 5.25 (m, 1 H), 4.87 - 4.75 (m, 1 H), 4.14 - 3.91 (m, 2H), 3.88 - 3.55 (m, 7H), 3.55 - 3.33 (m, 1 H), 3.10 (d, J = 5.5 Hz, 4H), 2.37 - 2.06 (m, 2H).
Example 104
2-methoxy-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile.
Figure imgf000162_0001
To an appropriate sized microwave vial, 4-chloro-N-(4-(4-(oxetan-3-yl)piperazin- 1-yl)phenyl)-1 ,3,5-triazin-2-amine (50 mgs, 0.144mmol), 2-methoxy-5-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (41 mgs, 0.159mmol), and sodium carbonate (69 mgs, 0.66mmol), 1 ,4-dioxane and water were added. The mixture was degassed with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium (0) (8 mgs) was added and the solution was heated at 95°C for 2h. After cooling to room temperature, the mixture was poured into water, and extracted with dichloromethane. The combined organic layers were washed with brine, dried with magnesium sulfate, filtered and concentrated under reduced pressure. Solids were purified via preparative HPLC (10-95% acetonitrile in water, 0.1 % trifluoroacteic acid buffer) to yield the compound 2-methoxy-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. 1H NMR (400 MHz, DMSO-d6) δ 10.18 (d, J= 20Hz, 1 H), 8.74 (s, 1 H), 8.66 - 8.45 (m, 2H), 7.68-7.55 (m, 2H), 7.48-7.4 (m, 1 H), 7.12 - 7.00 (m, 2H), 4.76 (d, J = 6.4 Hz, 4H), 4.48-4.38 (m, 1 H), 4.01 (s, 3H), 3.82-2.85 (m, 8H). LCMS-ESI+ (m/z): [M+H]+ calcd for C24H25N702: 444.2; found: 444.2
Example 105
3-methoxy-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin yl)benzonitrile.
Figure imgf000163_0001
To an appropriate sized microwave vial, 4-chloro-N-(4-(4-(oxetan-3-yl)piperazin- 1-yl)phenyl)-1 ,3,5-triazin-2-amine (50 mgs, 0.144mmol), 3-methoxy-5-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (41 mgs, 0.159mmol), and sodium carbonate (69 mgs, 0.66mmol), 1 ,4-dioxane and water were added. The mixture was degassed with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium (0) (8 mgs) was added and the solution was heated at 95°C for 2h. After cooling to room temperature, the mixture was poured into water, and extracted with dichloromethane. The combined organic layers were washed with brine, dried with magnesium sulfate, filtered and concentrated under reduced pressure. Solids were purified via preparative HPLC (10-95% acetonitrile in water, 0.1 % trifluoroacteic acid buffer) to yield the compound 3-methoxy-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. 1H NMR (400 MHz, DMSO-d6) δ 10.22 (d, J = 21.8 Hz, 1 H), 8.75 (s, 1 H), 8.26 - 8.01 (m, 2H), 7.66 (dd, J = 2.7, 1.4 Hz, 1 H), 7.62-7.53 (m, 2H), 7.05-6.95 (m, 2H), 4.70 (d, J = 6.9 Hz, 4H), 4.49-4.28 (m, 1 H), 3.85
(s, 3H), 3.80-2.85 (m, 8H). LCMS-ESI+ (m/z): [M+H]+ calcd for C24H25N702: 444.2; found: 444.1
Example 106
5-(4-((4-((1 H-imidazol-1 -yl)methyl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro- 2H-pyran-4-yl)oxy)benzonitrile.
Figure imgf000164_0001
To an appropriate sized microwave vial, 5-(4-chloro-1 ,3,5-triazin-2-yl)-2- ((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile (50 mg, 0.158 mmol) and 4-((1 H-imidazol-1- yl)methyl)aniline (33 mg, 0.189 mmol) were dissolved in acetonitrile (1.5ml) and N,N- dimethylformamide (1.5ml) and stirred at room temperature for 24 hr. The mixture was purified via preparative HPLC (10-95% acetonitrile in water, 0.1 % trifluoroacteic acid buffer). Clean fractions poured into a saturated solution of sodium bicarbonate in water and extracted with dichloromethane. Organic layer was dried over Mg2S04 and evaporate under reduces pressure to yield 5-(4-((4-((1 H-imidazol-1- yl)methyl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile. 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1 H), 8.80 (s, 1 H), 8.62 - 8.50 (m, 2H), 7.82- 7.68 (m, 3H), 7.56 (d, J = 9.6 Hz, 1 H), 7.27 (d, J = 8.2 Hz, 2H), 7.17 (s, 1 H), 6.88 (s, 1 H), 5.15 (s, 2H), 4.97-4.9 (m, 1 H), 3.91-3.83 (m, 2H), 3.61 - 3.50 (m, 2H), 2.08 - 1.96
(m, 2H), 1.74-1.62 (m, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd for C25H23N7O2: 454.19; found: 454.1.
Example 107
(R)-5-(4-((4-(2-(hydroxymethyl)morpholino)phenyl)amino)-1 ,3,5-triazin-2-yl)-2- ((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile.
Figure imgf000164_0002
To an appropriate sized microwave vial, 5-(4-chloro-1 ,3,5-triazin-2-yl)-2- ((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile (50 mg, 0.158 mmol), (R)-(4-(4- aminophenyl)morpholin-2-yl)methanol (39 mg, 0.189 mmol) and N-ethyl-N- isopropylpropan-2-amine (0.137 ml, 0.789 mmol) were dissolved in acetonitrile (3 ml_) and heated at 80°C for 20min. After cooling to room temperature, solids were collected by filtration. Solids were suspended and stirred with acetonitrile for 1 hr and then filtered off to yield the residue (R)-5-(4-((4-(2-(hydroxymethyl)morpholino)phenyl)amino)-1 ,3,5- triazin-2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile. 1H NMR (400 MHz, DMSO- d6) δ 10.22 - 9.97 (m, 1 H), 8.72 (s, 1 H), 8.54 (q, J = 8.2 Hz, 2H), 7.63-7.51 (m, 3H), 7.0-6.89 (m, 2H), 4.94-4.88 (m, 1 H), 4.75 (d, J = 5.9 Hz, 1 H), 3.99 - 3.89 (m, 1 H), 3.88- 3.81 (m, 2H), 3.69 - 3.35 (m, 10H), 2.05 - 1.97 (m, 2H), 1.71-1.62 (m, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd for C26H28N604: 489.22; found: 489.1.
Example 108
5-(4-((4-(3-hydroxy-3-methylpyrrolidin-1 -yl)phenyl)amino)-1,3,5-triazin-2-yl)-2- ((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile.
Figure imgf000165_0001
To an appropriate sized microwave vial, 5-(4-chloro-1 ,3,5-triazin-2-yl)-2- ((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile (50 mg, 0.158 mmol), 1-(4-aminophenyl)-3- methylpyrrolidin-3-ol (36 mg, 0.189 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.137 ml, 0.789 mmol) were dissolved in acetonitrile (3 ml_) and heated at 80°C for 20min. After cooling to room temperature, solids were collected by filtration. The residue was purified via preparative HPLC (10-95% acetonitrile in water, 0.1 % trifluoroacteic acid buffer). Clean fractions poured into a saturated solution of sodium bicarbonate in water and extracted with dichloromethane. Organic layer was dried over Mg2S04 and evaporate under reduces pressure to yield 5-(4-((4-(3-hydroxy-3-methylpyrrolidin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile. 1H NMR (400 MHz, DMSO-d6) δ 10.1 - 9.92 (m, 1 H), 8.66 (s, 1 H), 8.58 - 8.47 (m, 2H), 7.53 (d, J = 9.0 Hz, 1 H), 7.5-7.4 (m, 2H), 6.4-6.52 (m, 2H), 4.92-4.88 (m, 1 H), 4.76 (s, 1 H), 3.89-3.83 (m, 2H), 3.57 - 3.47 (m, 2H), 3.39-3.22 (m, 2H), 3.22-3.14 (m, 2H), 2.1 1 - 1.98 (m, 2H), 1.9-1.85 (m, 2H), 1.72-1.62 (m, 2H), 1.34 (s, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C26H28N603: 473.2; found: 473.2.
Example 109
5-(4-((2-methyl-4-morpholinophenyl)amino)-1,3,54riazin-2-yl)-2-((tetrahydro-2H- pyran-4-yl)oxy)benzonitrile
Figure imgf000166_0001
To an 5ml_ microwave vial, 5-(4-chloro-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)benzonitrile (53 mgs, 0.167 mmol), 2-methyl-4-morpholinoaniline (32 mgs, 0.167 mmol) and DIPEA (0.12 ml_, 0.789 mmol) were dissolved in acetonitrile (2 ml_) and heated in microwave at 80°C for 20min. The residue was purified via preparative HPLC (10-95% acetonitrile in water, 0.1 % trifluoroacteic acid buffer). Clean fractions were then lyophilized to yield the title compound. LCMS-ESI+ (m/z): [M+H]+ calcd for C26H28 603: 473.2; found: 473.2 1H NMR (400 MHz, DMSO-c/6) δ 9.59 (br, 1 H), 8.67
(s, 1 H), 8.57 (s, 1 H), 8.34 (brs, 1 H), 7.52 (m, 1 H), 7.23 (m, 1 H), 6.54 (m, 2H), 4.91 (m, 1 H), 3.84 (m, 2H), 3.73 - 3.70 (m, 4H), 3.53 (m, 2H), 3.10 (m, 4H), 2.15 (s, 3H), 2.01 (m, 2H), 1.66 (m, 2H). Example 110: 2-(((3R,4S)-3-fluoro-1-(tetrahydrofuran-3-yl)piperidin-4-yl)oxy)-5-(4- ((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000167_0001
A solution of 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (100 mg, 0.188 mmol) and dihydrofuran- 3(2H)-one (16 mg, 0.188 mmol) in 1 mL DCM was treated with and AcOH (14 mg, 0.226 mmol). After 5 min of stirring sodium triacetoxyborohydride (60 mg, 0.283 mmol) was added and the mixture stirred at rt overnight. The reaction was diluted with EtOAc and neutralized with sat. NaHC03 solution. The organic layer was concentrated and the residue purified HPLC eluting with 5%-95% water/acetonitrile (0.1 %v/v trifluoroacetic acid). The appropriate fractions were pooled and lyophilized to provide 2-(((3R,4S)-3- fluoro-1 -(tetrahydrofuran-3-yl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile as mixture of diastereomers. 1H NMR (400 MHz, DMSO) δ 10.1 1 (d, J = 1 1 Hz, 1 H), 8.72 (s, 1 H), 8.54 (m, 2H), 7.56 (m, 3H), 6.95 (m, 2H), 4.95 - 5.03 (m, 2H), 4.55 (t, J = 6 Hz, 2H), 4.45 (t, J = 6 Hz, 2H), 3.70 - 3.82 (m, 2H), 3.35 - 3.65 (m, 7H), 3.14 (s, 4H), 3.05 - 3.1 1 (m, 1 H), 2.40 (s, 4H), 1.94 - 2.03 (m, 2H), 1.80 - 1.89 (m, 1 H), 1.70 - 1.80 (m, 1 H). ES/MS 601.4 (M+H+).
Example 111 : 2-(((3R,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000167_0002
A solution of 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (290 mg, 0.547 mmol) and oxetan-3-one (39 mg, 0.547 mmol) in 2 mL DCM was treated with and AcOH (38 uL, 0.656 mmol). After 5 min of stirring sodium triacetoxyborohydride (173 mg, 0.82 mmol) was added and the mixture stirred at rt overnight. The reaction was diluted with EtOAc and neutralized with sat. NaHC03 solution. The organic layer was concentrated and the residue purified HPLC eluting with 5%-95% water/acetonitrile (0.1 %v/v trifluoroacetic acid). The appropriate fractions were pooled and lyophilized to provide 2-(((3R,4S)-3- fluoro-1-(oxetan-3-yl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. ES/MS 587.3 (M+H+).
Example 112: 2-(((3R)-3-fluoro-1-((S)-5-oxopyrrolidine-2-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2- yl)benzonitrile
Figure imgf000168_0001
l-Pyroglutamic acid (26 mg, 0.20 mmol) was taken up in 1 ml_ DMF and treated with HATU (84 mg, 0.221 mmol). After stirring for 30 sec, 2-(((3R,4S)-3-fluoropiperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile (1 10 mg, 0.20 mmol) and DIEA (51 uL, 0.30 mmol) were added and the reaction stirred at rt for 45 min. The reaction was diluted with DCM and 2M Na2C03 solution. The organic layer was concentrated and the residue purified by silica gel chromatography gave 2-(((3R)-3-fluoro-1-((S)-5-oxopyrrolidine-2-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile. 1H NMR (400 MHz, DMSO-d6) δ 10.1 1 (d, J = 26.0 Hz, 1 H), 8.73 (s, 1 H), 8.65 - 8.48 (m, 2H), 7.72 (d, J = 21.2 Hz, 1 H), 7.63 (d, J = 9.0 Hz, 1 H), 7.55 (d, J = 13.8 Hz, 2H), 6.95 (s, 2H), 5.13 (s, 1 H), 5.04 (d, J = 24.9 Hz, 1 H), 4.65 - 4.58 (m, 1 H), 4.55 (t, J = 6.5 Hz, 3H), 4.46 (t, J = 6.0 Hz, 2H), 4.39 (m, 1 H), 4.25 - 4.06 (m, 1 H), 3.44 (t, J = 6.3 Hz, 1 H), 3.13 (s, 4H), 2.40 (s, 4H), 2.31 (d, J = 9.9 Hz, 1 H), 2.10 (q, J = 9.2 Hz, 2H), 1.99 (s, 1 H). ES/MS 642.4 (M+H+). Example 113: 2-(((3R)-3-f luoro-1 -((R)-5-oxopyrrolidine-2-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2- yl)benzonitrile
Figure imgf000169_0001
(R)-5-oxopyrrolidine-2-carboxylic acid (17 mg, 0.13 mmol) was taken up in 1 ml_ DMF and treated with HATU (53 mg, 0.14 mmol). After stirring for 30 sec, 2-(((3R,4S)-3- fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)benzonitrile (71 mg, 0.13 mmol) and DIEA (47 uL, 0.27 mmol) were added and the reaction stirred at rt for 45 min. The reaction was diluted with DCM and 2M Na2C03 solution. The organic layer was concentrated and the residue purified by HPLC eluting with 5%-95% water/acetonitrile (0.1 %v/v trifluoroacetic acid). The appropriate fractions were pooled and lyophilized to provide 2-(((3R)-3-fluoro-1-((R)-5- oxopyrrolidine-2-carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. ES/MS 642.4 (M+H+). Example 114: (S)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)-2-((6-oxopiperidin-3-yl)oxy)benzonitrile
Figure imgf000169_0002
Potassium ferf-butoxide (58 mg, 0.52 mmol) was added to a solution of (S)-5 hydroxypiperidin-2-one (68 mg, 0.52 mmol) in THF (3 ml_) and stirred at rt for 30 min. 2
Fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile (0.15 g, 0.35 mmol) was added and the reaction heated to 60 °C for 16 h Mixture diluted with MeCN and neutralized to pH 7 with AcOH. The filtrate was loaded onto silica gel and purified by silica gel chromatography to give (S)-5-(4-((4-(4-(oxetan- 3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((6-oxopiperidin-3- yl)oxy)benzonitrile. 1H NMR (400 MHz, DMSO-d6) δ 10.17 (d, J = 17.1 Hz, 1 H), 8.74 (s, 1 H), 8.63 - 8.48 (m, 2H), 7.70 - 7.51 (m, 3H), 7.46 (s, 1 H), 7.03 (s, 2H), 5.17 - 5.06 (m, 1 H), 4.85 (m, 2H), 4.69 (t, J = 7.2 Hz, 2H), 3.80 (s, 2H), 3.69 - 3.29 (m, 5H), 3.26 - 2.93 (m, 3H), 2.41 - 2.14 (m, 2H), 2.1 1 (m, 1 H), 1.19 (m, 2H). ES/MS 527.29 (M+H+).
Example 115: 2-(((2S,4S,5R)-5-fluoro-1 -(2-hydroxyacetyl)-2-methylpiperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile
Figure imgf000170_0001
Glycolic acid (10 mg, 0.138 mmol) was taken up in 1 mL DMF and treated with HATU (58 mg, 0.151 mmol). After stirring for 30 sec, 2-(((2S,4S,5R)-5-fluoro-2- methylpiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)benzonitrile (75 mg, 0.138 mmol) and DIEA (35 uL, 0.207 mmol) were added and the reaction stirred at rt for 45 min. The reaction was diluted with DCM and 2M Na2C03 solution. The organic layer was concentrated and the residue purified by silica gel chromatography gave 2-(((2S,4S,5R)-5-fluoro-1-(2-hydroxyacetyl)-2- methylpiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)benzonitrile. 1H NMR (400 MHz, DMSO-d6) δ 10.18 (d, J = 28.7 Hz, 1 H), 8.79 (s, 1 H), 8.69 - 8.55 (m, 2H), 7.71 (d, J = 9.2 Hz, 1 H), 7.66 - 7.55 (m, 3H), 7.06 - 6.96 (m, 2H), 5.35 - 4.93 (m, 2H), 4.66 (s, 1 H), 4.61 (t, J = 6.5 Hz, 2H), 4.52 (t, J = 6.1 Hz, 2H), 4.35 - 4.26 (m, 1 H), 4.16 - 4.08 (m, 1 H), 3.72 - 3.58 (m, 1 H), 3.49 (t, J = 6.3 Hz, 1 H), 3.22 - 3.13 (m, 5H), 2.46 (s, 4H), 2.24 - 2.15 (m, 1 H), 2.07 - 1.89 (m, 1 H), 1.41 - 1.34 (m, 2H), 1.34 - 1.25 (m, J = 1 1 Hz, 6H). ES/MS 603.3 (M+H+). Example 116: 2-(((S)-3,3-difluoro-1-((S)-5-oxopyrrolidine-2-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2- yl)benzonitrile
Figure imgf000171_0001
l-Pyroglutamic acid (26 mg, 0.20 mmol) was taken up in 1 mL DMF and treated with HATU (84 mg, 0.221 mmol). After stirring for 30 sec, 2-(((3R,4S)-3,3-difluoropiperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile (1 10 mg, 0.20 mmol) and DIEA (51 uL, 0.30 mmol) were added and the reaction stirred at rt for 45 min. The reaction was diluted with DCM and 2M Na2C03 solution. The organic layer was concentrated and the residue purified by silica gel chromatography gave 2-(((3R)-3-fluoro-1-((S)-5-oxopyrrolidine-2-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile. 1H NMR (400 MHz, DMSO-d6) δ 10.13 (d, J = 23.3 Hz, 1 H), 8.73 (s, 1 H), 8.57 (m, 1 H), 7.76 (d, J = 23.7 Hz, 1 H), 7.65 (dd, J = 9.2, 6.3 Hz, 1 H), 7.62 - 7.44 (m, 2H), 6.96 (s, 2H), 5.37 (s, 1 H), 4.63 (dd, J = 7.1 , 2.8 Hz, 1 H), 4.55 (t, J = 6.5 Hz, 2H), 4.46 (t, J = 6.0 Hz, 2H), 4.25 - 4.05 (m, 1 H), 3.95 - 3.84 (m, 1 H), 3.83 - 3.71 (m, 1 H), 3.44 (q, J = 5.8, 5.0 Hz, 1 H), 3.12 (s, 5H), 2.46 - 2.27 (m, 5H), 2.1 1 (m, 3H), 2.07 - 1.76 (m, 2H). ES/MS 660.42 (M+H+).
Example 117: 2-(((3R,4S)-3-fluoro-1-((S)-6-oxopiperidine-2-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2- yl)benzonitrile
Figure imgf000172_0001
(S)-6-Oxopiperidine-2-carboxylic acid (30 mg, 0.21 mmol) was taken up in 2 mL DMF and treated with HATU (86 mg, 0.23 mmol). After stirring for 30 sec, 2-(((3R,4S)-3,3- difluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)benzonitrile (100 mg, 0.19 mmol) and DIEA (48 mg, 0.38 mmol) were added and the reaction stirred at rt for 45 min. The reaction was diluted with DCM and 2M Na2C03 solution. The organic layer was concentrated and the residue purified by silica gel chromatography gave 2-(((3R,4S)-3-fluoro-1-((S)-6-oxopiperidine-2- carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)benzonitrile. 1H NMR (400 MHz, DMSO-d6) δ 10.12 (d, J = 26.4 Hz, 1 H), 8.73 (s, 1 H), 8.67 - 8.46 (m, 2H), 7.63 (d, J = 9.1 Hz, 1 H), 7.61 - 7.50 (m, 2H), 6.95 (s, 2H), 5.13 (s, 1 H), 4.56 (t, J = 6.5 Hz, 2H), 4.46 (t, J = 6.0 Hz, 2H), 4.55 - 4.23 (m, 1 H), 3.51 - 3.32 (m, 2H), 3.13 (s, 4H), 2.98 - 3.10 (m, 1 H), 2.41 (s, 3H), 2.14 - 2.08 (m, 2H), 1.95 - 2.04 (m, 1 H), 1.91 - 1.56 (m, 4H). ES/MS 656.3 (M+H+).
Example 118: 2-(((3R,4S)-1-(1,1-dioxidoisothiazolidine-3-carbonyl)-3- fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)- 1,3,5-triazin-2-yl)benzonitrile
Figure imgf000173_0001
(+/-)-lsothiazolidine-3-carboxylic acid 1 ,1-dioxide (34 mg, 0.21 mmol) was taken up in 2 mL DMF and treated with HATU (84 mg, 0.23 mmol). After stirring for 30 sec, 2- (((3R,4S)-3,3-difluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (100 mg, 0.19 mmol) and DIEA (48 uL, 0.28 mmol) were added and the reaction stirred at rt for 45 min. The reaction was diluted with DCM and 2M Na2C03 solution. The organic layer was concentrated and the residue purified by silica gel chromatography gave 2-(((3R,4S)-1-(1 ,1- dioxidoisothiazolidine-3-carbonyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile as a mixture of epimers. δ 1H NMR (400 MHz, DMSO-d6) δ 10.12 (d, J = 26.4 Hz, 1 H), 8.67 - 8.46 (m, 2H), 7.63 (d, J = 9.1 Hz, 1 H), 7.61 - 7.50 (m, 2H), 7.24 (d, J = 40.0 Hz, 1 H), 6.95 (s, 2H), 5.17 - 4.96 (m, 1 H), 4.56 (t, J = 6.5 Hz, 2H), 4.46 (t, J = 6.0 Hz, 2H), 4.26 - 4.1 1 (m, 1 H), 3.64 - 3.56 (m, OH), 3.51 - 3.32 (m, 2H), 3.13 (s, 5H), 2.41 (m, 3H), 2.13 - 2.07 (m, 2H), 1.98 (s, 1 H), 1.91 - 1.56 (m, 4H). ES/MS 678.37 (M+H+).
Example 119: 2-(((3R,4S)-3-fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4- (4-methylpiperazine-1-carbonyl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000173_0002
A solution of glycolic acid (12 mg, 0.16 mmol) in 2 mL DMF was treated w/ HATU (61 mg, 0.16 mmol) and stirred for 30 sec. DIEA (37 mL, 0.218 mmol) was added, followed by 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-methylpiperazine-1- carbonyl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (75 mg, 1.45 mmol) and the mixture was stirred for 1 h. The reaction was concentrated and the residue taken up in THF and loaded on silica gel. Purification by silica gel chromatography provided the desired glycolamide. 1H NMR (400 MHz, DMSO) δ 10.55 (s, 1 H), 8.86 (m, 1 H), 8.60 (dd, J = 6.5, 2.8 Hz, 2H), 7.84 (d, J = 8.7, 2H), 7.64 (d, J = 9.5 Hz, 1 H), 7.43 (d, J = 8.6 Hz, 2H), 5.20 - 4.93 (m, 2H), 4.75 - 4.60 (m, 1 H), 4.18 - 4.04 (m, 3H), 3.89 (s, 1 H), 3.74 - 3.07 (m, 4 H), 2.52 (s, 5H), 2.52 (s, 3H), 2.33 (m, 3H), 2.01 - 1.94 (m, 1 H). ES/MS 575.1 (M+H+).
Example 120: 2-(((3R,4S)-3-fluoro-1 -((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5- (4-((4-(4-methylpiperazine-1 -carbonyl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000174_0001
Title compound was prepared via the same procedure as Example 1 19. 1H NMR (400 MHz, DMSO) δ 10.54 (s, 1 H), 8.86 (s, 1 H), 8.68 - 8.52 (m, 2H), 7.84 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 9.5 Hz, 1 H), 7.47 - 7.33 (m, 2H), 5.13 (d, J = 21.8 Hz, 2H), 5.05 - 4.97 (m, 1 H), 4.52 - 4.29 (m, 1 H), 4.23 - 3.83 (m, 2H), 3.49 (s, 4H), 2.33 (s, 5H), 1.97 (s, 1 H), 1.41 - 1.24 (m, 1 H), 1.24 - 1.12 (m, 4H). ES/MS 589.1 (M+H+).
Example 121 : 5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2- H-pyran-4-yl)amino)benzonitrile
Figure imgf000174_0002
To a solution of 2-fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5- triazin-2-yl)benzonitrile (60 mgs, 0.14 mmol) in 2-propanol (2.0 mL) was added tetrahydro-2H-pyran-4-amine (38 mgs, 0.28 mmol) in 5 mL microwave vial and sealed. This reaction mixture was stirred at 150 °C. After 2h, tetrahydro-2H-pyran-4-amine (3.0 equiv) in NMP (1 mL) was added and heated at 150 °C for 3h. The reaction mixture was cooled to rt, evaporated under reduced pressure and purified via preparative HPLC (5- 65% acetonitrile in water, 0.1 % trifluoroacteic acid buffer) to yield the title compound.
LCMS-ESI+ (m/z): [M+H]+ calcd for C28H32N8O2: 513.6; found: 513.2.
1H NMR (400 MHz, DMSO-c/6) δ 10.01 (brs, 1 H), 8.65 (s, 1 H), 8.32 (dd, J = 9.1 , 2.0 Hz, 2H), 7.81 (s, 2H), 7.61 (m, 1 H), 7.13 - 6.96 (m, 2H), 6.54 (d, J = 8.0 Hz, NH), 4.74 (m, 4H), 4.03 - 3.88 (m, 2H), 3.60 - 3.40 (m, 4H), 3.20 - 3.00(m, 4H), 1 .90 - 1 .82 (m, 4H), 1.70 - 1 .64 (m, 4H).
Example 122: 2-((4-methoxycyclohexyl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- ,5-triazin-2-yl)benzonitrile
Figure imgf000175_0001
To a solution of 4-methoxycyclohexanol (45 mgs, 0.35 mmol) in Me-THF (5.0 mL) at 0 °C was added potassium tert-butoxide solution (1 .0 M, 0.35 mL, 0.35 mmol). After 45 minutes at 0 °C, 2-fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5- triazin-2-yl)benzonitrile (100 mgs, 0.232 mmol) was added and heated at 60 °C. After 16 h, the mixture cooled to room temperature, water (1 .0 mL) was added, and the mixture was then evaporated under reduced pressure and purified via preparative HPLC (5-65% acetonitrile in water, 0.1 % trifluoroacteic acid buffer) to yield the title compound as mixture of isomers. LCMS-ESI"1" (m/z): [M+H]+ calcd for C30H35N7O3: 542.6; found: 542.2.
Example 123: 2-(((3R,4S)-3-fluoro-1-((S)-3-hydroxy-2-methylpropanoyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2- yl)benzonitrile
Figure imgf000176_0001
To a solution of 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin- 1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (50 mgs, 0.09 mmol) in DMF (3.0 mL) was added (S)-3-hydroxy-2-methylpropanoic acid sodium salt (24 mgs, 0.18 mmol), HATU (72 mgs, 0.19 mmol) and TEA (0.02 mL, 0.18 mmol). The above reaction mixture was stirred at room temperature for 16 h. The mixture was then evaporated under reduced pressure and purified via preparative HPLC (5-65% acetonitrile in water, 0.1 % trifluoroacteic acid buffer) to yield the title compound. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H37FN8O4: 617.7; found: 617.3
Example 124: 2-(((3R,4S)-3-fluoro-1-((R)-3-hydroxy-2-methylpropanoyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-
Figure imgf000176_0002
To a solution of 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin- 1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (50 mgs, 0.09 mmol) in DMF (3 mL) was added (R)-3-hydroxy-2-methylpropanoic acid sodium salt (24 mgs, 0.18 mmol), HATU (72 mgs, 0.19 mmol) and TEA (0.02 mL, 0.18 mmol). The above reaction mixture was stirred at room temperature for 16 h. The mixture was then evaporated under reduced pressure and purified via preparative HPLC (5-65% acetonitrile in water, 0.1 % trifluoroacteic acid buffer) to yield the title compound. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H37FN8O4: 617.7; found: 617.3 Example 125: (R)-2-((1-(2-hydroxyacetyl)piperidin-3-yl)oxy)-5-(4-((4-(4-(oxetan-3- ino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000177_0001
Step 1 : To a solution of (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate (51 mgs, 0.26 mmol) in Me-THF (2.0 ml_) at 0 °C was added potassium tert-butoxide solution (1.0 M, 0.4 ml_, 0.4 mmol). After 45 minutes at 0 °C, 2-fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin- 1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (100 mgs, 0.23 mmol) was added and heated at 60 °C. After 16 h, the mixture cooled to room temperature, water (0.6 ml_) was added, and mixture evaporated under reduced pressure to yield (R)-5-(4-((4-(4-(oxetan- 3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((1-pivaloylpiperidin-3- yl)oxy)benzonitrile which was used further without purification.
Step 2: The crude solids from previous step was diluted with DCM/TFA (6.0 ml_, 1 :1 ) and stirred at rt for 1 h. The reaction mixture was evaporated under reduced pressure and residue was suspended in a saturated aqueous solution of NaHC03 and extracted with DCM. The combined organic layers were then dried over magnesium sulfate and evaporated under reduced pressure to give (R)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-(piperidin-3-yloxy)benzonitrile which was further used without purification.
Step 3: To the above crude amine (from step 2, 45 mgs, 0.09 mmol) in DMF (1.0 ml_) was added glycolic acid (13 mgs, 0.18 mmol), HATU (67 mgs, 0.18 mmol) and DIPEA (0.07 ml_, 0.4 mmol). The above reaction mixture was stirred at room temperature for 16 h, evaporated under reduced pressure and purified via preparative HPLC (5-65% acetonitrile in water, 0.1 % trifluoroacteic acid buffer) to yield the title compound. LCMS-
ESI+ (m/z): [M+H]+ calcd for C3oH34N804: 571.6; found: 571.4
Example 126: 2-(((R)-1-((S)-2-hydroxypropanoyl)piperidin-3-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000178_0001
The title compound was prepared following a similar procedure reported in Example- 125 (step 3) using (S)-2-hydroxypropanoic acid instead of glycolc acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C3iH36N804: 585.7; found: 585.3
Example 127: (S)-2-((1 -(2-hydroxyacetyl)piperidin-3-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000178_0002
The title compound was prepared following a similar procedure reported in Example- 125 (step 1 ) using (S)-tert-butyl 3-hydroxypiperidine-1 -carboxylate instead of (R)-tert- butyl 3-hydroxypiperidine-1 -carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for C30H34N8O4: 571 .6; found: 571 .3
Example 128: 2-(((S)-1 -((S)-2-hydroxypropanoyl)piperidin-3-yl)oxy)-5-(4-((4-(4- l)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000178_0003
The title compound was prepared following a similar procedure reported in Example- 125 (step 1) using (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate instead of (R)-tert- butyl 3-hydroxypiperidine-1-carboxylate and using (S)-2-hydroxypropanoic acid instead of glycolc acid. LCMS-ESI"1" (m/z): [M+H]+ calcd for C31 H36N8O4: 585.7; found: 585.3
Example 129: 2-(((3R,4S)-3-fluoro-1-((R)-piperidine-2-carbonyl)piperidin-4-yl)oxy)- perazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000179_0001
To a solution of 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin- 1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (35 mgs, 0.07 mmol) in DMF (1.0 mL) was added (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (30 mgs, 0.13 mmol), HATU (50 mgs, 0.13 mmol) and TEA (0.02 mL, 0.13 mmol). The above reaction mixture was stirred at room temperature for 16 h, evaporated under reduced pressure. The residue was dissolved in DCM/TFA (3 mL, 2:1 ) and stirred at rt for 1 h. The mixture was then evaporated under reduced pressure and purified via preparative HPLC (5-65% acetonitrile in water, 0.1 % trifluoroacteic acid buffer) to yield the title compound. LCMS-
ESI+ (m/z): [M+H]+ calcd for C34H4oFN903: 642.7; found: 642.2
Example 130: 2-(((3R,4S)-3-fluoro-1-((R)-pyrrolidine-2-carbonyl)piperidin-4-yl)oxy)- azin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000179_0002
To a solution of 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin- 1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (35 mgs, 0.07 mmol) in DMF (1 ml.) was added N-Boc-D-proline (28 mgs, 0.13 mmol), HATU (50 mgs, 0.13 mmol) and TEA (0.02 ml_, 0.13 mmol). The above reaction mixture was stirred at room temperature for 2 h, evaporated under reduced pressure. The residue was dissolved in DCM/TFA (3 ml_, 2:1 ) and stirred at rt for 1 h. The mixture was then evaporated under reduced pressure and purified via preparative HPLC (5-65% acetonitrile in water, 0.1 % trifluoroacteic acid buffer) to yield the title compound. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H38FN9O3: 628.7; found: 628.2
Example 131 : 2-(((3R,4S)-3-fluoro-1-((S)-piperidine-2-carbonyl)piperidin-4-yl)oxy)- piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000180_0001
To a solution of 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin- 1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (35 mgs, 0.07 mmol) in DMF (1.0 ml.) was added (S)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (30 mgs, 0.13 mmol), HATU (50 mgs, 0.13 mmol) and TEA (0.02 ml_, 0.13 mmol). The above reaction mixture was stirred at room temperature for 16 h, evaporated under reduced pressure. The residue was dissolved in DCM/TFA (3 imL 2:1 ) and stirred at rt for 1 h. The mixture was then evaporated under reduced pressure and purified via preparative HPLC (5-65% acetonitrile in water, 0.1 % trifluoroacteic acid buffer) to yield the title compound. LCMS-
ESI+ (m/z): [M+H]+ calcd for C34H4oFN903: 642.7; found: 642.2
Example 132: 2-(((3R,4S)-1 -((R)-4,4-difluoropyrrolidine-2-carbonyl)-3- fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)- 1 ,3,5-triazin-2-yl)benzonitrile:
Figure imgf000181_0001
To a solution of 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin- 1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (35 mgs, 0.07 mmol) in DMF (1 mL) was added N-Boc-4,4-difluoro-L-proline (33 mgs, 0.13 mmol), HATU (50 mgs, 0.13 mmol) and TEA (0.02 mL, 0.13 mmol). The above reaction mixture was stirred at room temperature for 16 h, evaporated under reduced pressure. The residue was dissolved in DCM/TFA (3 mL. 2: 1 ) and stirred at rt for 1 h. The mixture was then evaporated under reduced pressure and purified via preparative HPLC (5-65% acetonitrile in water, 0.1 % trifluoroacteic acid buffer) to yield the title compound. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H36F3N9O3: 664.7; found: 664.2
Example 133: 2-(((3R,4S)-3-fluoro-1 -((S)-pyrrolidine-2-carbonyl)piperidin-4-yl)oxy)- erazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000181_0002
To a solution of 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin- 1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (35 mgs, 0.07 mmol) in DMF (1 mL) was added N-Boc-D-proline (28 mg, 0.13 mmol), HATU (50 mgs, 0.1 3 mmol) and TEA (0.02 mL, 0.13 mmol). The above reaction mixture was stirred at room temperature for 2 h, evaporated under reduced pressure. The residue was dissolved in DCM/TFA (3 mL. 2: 1 ) and stirred at rt for 1 h. The mixture was then evaporated under reduced pressure and purified via preparative HPLC (5-65% acetonitrile in water, 0.1 % trifluoroacteic acid buffer) to yield the title compound. LCMS-ESI"1" (m/z): [M+H]+ calcd for C33H38FN9O3: 628.7; found: 628.3
Example 134: (S)-3-((1-(2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan- mino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000182_0001
Step 1 : To a suspension of triphenylphosphine resin (1.7 g) in THF (6 mL), 3-hydroxy-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (400 mgs, 1.632 mmol) in THF (10 mL) and Diisopropyl azodicarboxylate (0.41 mL, 2.2 mmol) was added and the mixture was stirred at rt. After 30min, tert-butyl 4-hydroxypiperidine-1-carboxylate (41 1 mgs, 2.04 mmol) in THF (10 mL) was added and the mixture was stirred at rt. After 16h, the reaction mixture was filtered and washed with THF and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5-50% EtOAc/Hexanes) to provide tert-butyl-4-(3-cyano-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenoxy)piperidine-1 -carboxylate.
Step 2: A mixture of 4-chloro-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1 ,3,5-triazin-2- amine (135 mgs, 0.39 mmol), tert-butyl 4-(3-cyano-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenoxy)piperidine-1 -carboxylate (167 mgs, 0.39 mmol), potassium carbonate (48 mgs, 0.78 mmol) and Pd(dppf)CI2 (36 mgs) in dioxane/water (9 mL, 2:1 ) was heated for 1 hour at 105 °C. The crude mixture was then diluted with ethyl acetate and the organic layer was washed with 1 N HCI. The aqueous layer was then basified to pH -7-8 with saturated aqueous solution of NaHC03 and extracted with ethyl acetate and dried (MgS04). Filtration, followed by concentration of the organic layer gave tert- butyl 4-(3-(4-chloro-6-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)- 5-cyanophenoxy)piperidine-1 -carboxylate which was further used without purification. '
Step 3: To tert-butyl 4-(3-(4-chloro-6-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)- 1 ,3, 5-triazin-2-yl)-5-cyanophenoxy)piperidine-1 -carboxylate in DCM (3.0 mL), TFA (1.0 mL) was added and the mixture was stirred at rt for 1 h. The reaction mixture was evaporated under reduced pressure and residue was suspended in a saturated aqueous solution of NaHC03 and extracted with DCM. The combined organic layers were then dried over magnesium sulfate and evaporated under reduced pressure to give 3-(4-chloro-6-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-5- (piperidin-4-yloxy)benzonitrile which was further used without purification.
Step 4: To a solution of 3-(4-chloro-6-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)- 1 ,3,5-triazin-2-yl)-5-(piperidin-4-yloxy)benzonitrile (35 mgs, 0.07 mmol) in DMF (1 mL) was added L-lactic acid (12 mgs, 0.14 mmol), HATU (52 mgs, 0.14 mmol) and DIPEA (0.06 mL, 0.30 mmol). The above reaction mixture was stirred at room temperature for 16 h, evaporated under reduced pressure and purified via preparative HPLC (5-65% acetonitrile in water, 0.1 % trifluoroacteic acid buffer) to yield the title compound. LCMS-
ESI+ (m/z): [M+H]+ calcd for C3iH36N804: 585.7; found: 585.3 Example 135: 2-(((3R,4S)-1-(3,5-dimethyl-1 H-pyrazole-4-carbonyl)-3- fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-
Figure imgf000183_0001
To a solution of 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin- 1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (35 mgs, 0.07 mmol) in DMF (1.0 mL) was added 3,5-Dimethyl-1 H-pyrazole-4-carboxylic acid (19 mgs, 0.13 mmol), HATU (50 mgs, 0.13 mmol) and TEA (0.02 mL, 0.13 mmol). The above reaction mixture was stirred at room temperature for 2 h, evaporated under reduced pressure and purified via preparative HPLC (5-65% acetonitrile in water, 0.1 % trifluoroacteic acid buffer) to yield the title compound. LCMS-ESI"1" (m/z): [M+H]+ calcd for C34H37FN10O3: 652.7; found: 653.3 1H NMR (400 MHz, DMSO-c/6) δ 10.74 (brs, 1 H), 10.24 - 10.09 (m, 1 H), 8.75 (s, 1 H), 8.57 (m, 2H), 7.67 - 7.43 (m, 3H), 7.06 (d, J = 9.6 Hz, 2H), 5.26 - 5.01 (m, 3H), 4.76 (m, 4H), 4.44 (m, 1 H), 4.27 - 3.61 (m, 5H), 3.59 - 3.40 (m, 2H), 3.10 - 2.88 (m, 4H), 2.50 (s, 6H), 2.02-1.97 (m, 2H).
Example 136: 2-(((3R,4S)-1 -(5-chloro-1 H-pyrazole-4-carbonyl)-3-fluoropiperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2- yl)benzonitrile
Figure imgf000184_0001
To a solution of 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin- 1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (35 mgs, 0.07 mmol) in DMF (1 mL) was added 5-chloro-1 H-pyrazole-4-carboxylic acid (19 mgs, 0.13 mmol), HATU (50 mgs, 0.13 mmol) and TEA (0.02 mL, 0.13 mmol). The above reaction mixture was stirred at room temperature for 2 h, evaporated under reduced pressure and purified via preparative HPLC (5-65% acetonitrile in water, 0.1 % trifluoroacteic acid buffer) to yield the title compound. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H32CIFN10O3: 659.1 ; found: 659.3
Example 137: 2-(((3R,4S)-3-fluoro-1-(2-oxo-1,2-dihydropyridine-4- carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)- 1,3,5-triazin-2-yl)benzonitrile
Figure imgf000184_0002
To a solution of 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-
1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (35 mgs, 0.07 mmol) in DMF (1 mL) was added 2-hydroxyisonicotinic acid (18 mgs, 0.13 mmol), HATU (50 mgs, 0.13 mmol) and TEA (0.02 ml_, 0.13 mmol). The above reaction mixture was stirred at room temperature for 2 h, evaporated under reduced pressure and purified via preparative HPLC (5-65% acetonitrile in water, 0.1 % trifluoroacteic acid buffer) to yield the title compound. LCMS-ESI+ (m/z): [M+H]+ calcd for C34H34FN9O4: 652.7; found: 652.3_1H NMR (400 MHz, DMSO-c/6) δ 10.71 (brs, 1 H), 10.19 (d, J = 24.4 Hz, 1 H), 8.75 (s, 1 H), 8.59 - 8.57 (m, 2H), 7.63 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 6.6 Hz, 1 H), 7.10 -7.05 (m, 3H), 6.23 (s, 1 H), 6.12 (t, J = 7.5 Hz, 1 H), 5.26 - 5.03 (m, 3H), 4.82 - 4.72 (m, 4H), 4.42-4.35 (m, 2H), 3.63 - 3.41 (m, 4H), 3.3-3.30 (m, 2H), 3.10-2.9 (m, 4H), 2.15 - 1 .85 (m, 2H).
Example 138: 2-(((3R,4S)-1-(2-cyanoacetyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000185_0001
To solution of 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (65 mg, 0.12 mmol), 2-cyanoacetic acid (20 mg, 0.24 mmol), HATU (58 mg, 0.24 mmol) in DMF (3 mL) was added DIPEA (0.26 ml_) in a 10 mL microwave vial and sealed. This reaction mixture was stirred at room temperature overnight. The solvent was concentrated and the crude product purified via prep HPLC (5-95% acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to isolate 2- (((3R,4S)-1 -(2-cyanoacetyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-
1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for C3iH32FN903: 598.3: found:598.4 1 H NMR (400 MHz, DMSO-c/6) δ 10.19 (d, J = 20.3 Hz, 1 H), 8.75 (s, 1 H), 8.63 - 8.46 (m, 2H), 7.63 (t, J = 8.8 Hz, 3H), 7.14 - 6.90 (m, 2H), 5.24 - 4.92 (m, 3H), 4.75 (d, J = 6.6 Hz, 5H), 4.55 - 4.26 (m, 2H), 4.25 - 3.81 (m, 4H), 3.74 - 3.49 (m, 1 H), 3.31 (ddt, J = 24.2, 18.0, 12.8 Hz, 2H), 3.19 - 2.83 (m, 4H), 2.10 - 1 .79 (m, 2H). Example 139: 2-(((3R,4S)-3-fluoro-1-(3-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4- ((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000186_0001
The title compound was prepared following the same procedure reported in Example 138 by coupling 3-hydroxypropanoic acid to 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4- ((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile instead of
2-cyanoacetic acid. LCMS-ESI"1" (m/z): [M+H]+ calcd for C31 H35FN8O4: 603.3: found:603.5 1H NMR (400 MHz, DMSO-c 6) δ 10.18 (d, J = 19.3 Hz, 1 H), 8.75 (s, 1 H), 8.69 - 8.39 (m, 2H), 7.63 (t, J = 8.2 Hz, 3H), 7.03 (d, J = 10.5 Hz, 2H), 5.22 - 4.87 (m, 3H), 4.75 (d, J = 6.3 Hz, 5H), 4.49 - 4.23 (m, 1 H), 4.09 (td, J = 13.9, 6.7 Hz, 1 H), 3.91 - 3.70 (m, 1 H), 3.62 (q, J = 10.1 , 8.4 Hz, 3H), 3.49 - 3.27 (m, 1 H), 3.24 - 2.81 (m, 5H), 2.67 - 2.36 (m, 4H), 2.05 - 1.68 (m, 2H).
Example 140: 2-(((3R,4S)-3-fluoro-1-(1-hydroxycyclopropanecarbonyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile
Figure imgf000186_0002
The title compound was prepared following the same procedure reported in Example 138 by coupling 1-hydroxycyclopropanecarboxylic acid to 2-(((3R,4S)-3-fluoropiperidin- 4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile instead of 2-cyanoacetic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H35FN804: 615.3: found:615.4 1H NMR (400 MHz, DMSO-c/6) δ 10.18 (d, J = 21.8 Hz, 1 H), 8.75 (s, 1 H), 8.66 - 8.40 (m, 2H), 7.62 (d, J = 9.2 Hz, 3H), 7.05 (d, J = 1 1.2 Hz, 2H), 6.39 (s, 1 H), 5.25 - 4.88 (m, 2H), 4.75 (d, J = 6.3 Hz, 5H), 4.41 (s, 2H), 3.79 (s, 1 H), 3.46 (s, 4H), 3.04 (s, 5H), 1.96 (s, 2H), 1.14 - 0.61 (m, 4H).
Example 141 : 2-(((3R,4S)-3-fluoro-1-(1 H-pyrrole-2-carbonyl)piperidin-4-yl)oxy)-5- (4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000187_0001
The title compound was prepared following the same procedure reported in Example 138 by coupling 1-(tert-butoxycarbonyl)-1 H-pyrrole-2-carboxylic acid to 2-(((3R,4S)-3- fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)benzonitrile instead of 2-cyanoacetic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H34FN903: 624.3: found:624.4 1H NMR (400 MHz, DMSO-c/6) δ 11.49 (d, J = 3.4 Hz, 1 H), 10.31 - 10.06 (m, 1 H), 8.75 (s, 1 H), 8.69 - 8.45 (m, 2H), 7.64 (d, J = 9.2 Hz, 3H), 7.06 (d, J = 10.8 Hz, 2H), 6.89 (td, J = 2.8, 1.4 Hz, 1 H), 6.53 (t, J = 2.6 Hz, 1 H), 6.12 (q, J = 2.7 Hz, 1 H), 5.26 - 5.07 (m, 2H), 4.77 (d, J = 6.5 Hz, 5H), 4.48 (t, J = 15.0 Hz, 3H), 4.37 - 4.08 (m, 2H), 3.63 (dd, J = 31.2, 14.1 Hz, 1 H), 3.35 (s, 1 H), 3.13 - 2.91 (m, 5H), 2.14 - 1.87 (m, 2H).
Example 142: 2-(((3R,4S)-3-fluoro-1-(1 H-imidazole-2-carbonyl)piperidin-4-yl)oxy)-5- (4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000187_0002
The title compound was prepared following the same procedure reported in Example 138 by coupling 1H-imidazole-2-carboxylic acid to 2-(((3R,4S)-3-fluoropiperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile instead of 2-cyanoacetic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H33FN10O3: 625.3: found:625.41H NMR (400 MHz, DMSO-c/6) δ 10.19 (d, J = 20.4 Hz, 1H), 8.75 (s, 1H), 8.66-8.46 (m, 2H), 7.63 (t, J= 11.3 Hz, 3H), 7.31 -7.15 (m, 2H), 7.05 (s, 2H), 5.71 (d, J= 17.7 Hz, 1H), 5.17 (td, J = 46.5, 45.7, 12.7 Hz, 3H), 4.91 -4.70 (m, 5H), 4.49 (d, J= 37.3 Hz, 3H), 4.30 (d, J= 13.0 Hz, 1H), 4.06 (dd, J = 31.3, 14.4 Hz, 1H), 3.90 (d, J = 37.2 Hz, 1H), 3.67 - 3.42 (m, 1H), 3.28 (t, J = 11.5 Hz, 1H), 3.15 (s, 2H), 2.19-1.83 (m, 3H), 1.23 (q, J= 7.1, 6.6 Hz, 1H).
Example 143: 2-(((3R,4S)-3-fluoro-1-(1H-1,2,3-triazole-5-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2- yl)benzonitrile
Figure imgf000188_0001
The title compound was prepared following the same procedure reported in Example 138 by coupling 1H-1,2,3-triazole-5-carboxylic acid to 2-(((3R,4S)-3-fluoropiperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile instead of 2-cyanoacetic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C31H32FNHO3: 626.3: found:626.5 1H NMR (400 MHz, DMSO-c/6) δ 10.18 (d, J = 21.7 Hz, 1H), 8.75 (s, 1H), 8.68-8.41 (m, 3H), 7.62 (t, J= 12.4 Hz, 4H), 7.19-6.91 (m, 2H), 5.30 - 4.94 (m, 3H), 4.87 - 4.65 (m, 5H), 4.65 - 4.21 (m, 3H), 3.81 (s, 1 H), 3.53 (dd, J = 31.0, 14.3 Hz, 1H), 3.30 (t, J= 12.4 Hz, 1H), 3.08 (s, 5H), 2.17-1.83 (m, 2H).
Example 144: 2-(((3R,4S)-3-fluoro-1-(4H-1,2,4-triazole-3-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2- yl)benzonitrile
Figure imgf000189_0001
The title compound was prepared following the same procedure reported in Example 138 by coupling 4H-1 ,2,4-triazole-3-carboxylic acid to 2-(((3R,4S)-3-fluoropiperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile instead of 2-cyanoacetic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C31 H32FN11 O3: 626.3: found:626.4 1H NMR (400 MHz, DMSO-c 6) δ 10.18 (d, J = 21.1 Hz, 1 H), 8.75 (s, 1 H), 8.67 - 8.44 (m, 2H), 8.37 (s, 1 H), 7.63 (t, J = 10.0 Hz, 4H), 7.04 (s, 2H), 5.1 1 (dd, J = 50.3, 23.7 Hz, 3H), 4.75 (d, J = 6.7 Hz, 5H), 4.62 - 4.24 (m, 3H), 3.96 - 3.73 (m, 2H), 3.54 (dd, J = 34.4, 17.7 Hz, 2H), 3.35 - 3.18 (m, 2H), 3.02 (d, J = 36.8 Hz, 2H), 2.17 - 1.82 (m, 2H).
Example 145: 2-(((3R,4S)-3-fluoro-1-(1 H-pyrazole-5-carbonyl)piperidin-4-yl)oxy)-5- (4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000189_0002
The title compound was prepared following the same procedure reported in Example 138 by coupling 1 H-pyrazole-5-carboxylic acid to 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)- 5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile instead of 2-cyanoacetic acid. LCMS-ESI"1" (m/z): [M+H]+ calcd for C32H33FN10O3: 625.3: found:625.5 1H NMR (400 MHz, DMSO-c/6) δ 10.18 (d, J = 21.0 Hz, 1 H), 8.75 (s, 1 H), 8.69 - 8.42 (m, 2H), 7.79 (s, 1 H), 7.62 (t, J = 1 1.2 Hz, 4H), 7.04 (s, 2H), 6.60 (d, J = 2.3 Hz, 1 H), 5.28 - 4.92 (m, 3H), 4.75 (d, J = 6.3 Hz, 5H), 4.61 - 4.17 (m, 2H), 3.94 - 3.37 (m, 4H), 3.15 (s, 5H), 1.98 (d, J = 36.7 Hz, 2H). Example 146: 2-(((3R,4S)-3-fluoro-1-(1 H-imidazole-5-carbonyl)piperidin-4-yl)oxy)-5- (4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000190_0001
The title compound was prepared following the same procedure reported in Example 138 by coupling 1 H-imidazole-5-carboxylic acid to 2-(((3R,4S)-3-fluoropiperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile instead of 2-cyanoacetic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H33 FN10O3: 625.3: found:625.4 1H NMR (400 MHz, DMSO-c 6) δ 10.18 (d, J = 19.9 Hz, 1 H), 8.75 (s, 1 H), 8.65 - 8.30 (m, 3H), 7.88 (s, 1 H), 7.63 (t, J = 9.2 Hz, 4H), 7.04 (s, 3H), 5.31 - 4.94 (m, 3H), 4.76 (d, J = 6.6 Hz, 5H), 4.41 (t, J = 6.8 Hz, 3H), 3.24 (s, 8H), 2.05 (t, J = 7.4 Hz, 2H).
Example 147: 2-(((3R,4S)-3-f luoro-1 -(1 -methyl-1 H-1 ,2,3-triazole-4- carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)- 1,3,5-triazin-2-yl)benzonitrile
Figure imgf000190_0002
The title compound was prepared following the same procedure reported in Example 138 by coupling 1 -methyl-1 H-1 ,2, 3-triazole-4-carboxylic acid to 2-(((3R,4S)-3- fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)benzonitrile instead of 2-cyanoacetic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H34FNH O3: 640.3: found:640.4 1H NMR (400 MHz, DMSO-c/6) δ 10.28 - 10.09 (m, 1 H), 8.75 (s, 1 H), 8.66 - 8.55 (m, 2H), 8.52 (s, 2H), 7.74 - 7.49 (m, 2H), 7.04 (s, 2H), 5.10 (dd, J = 49.4, 20.3 Hz, 3H), 4.76 (d, J = 6.6 Hz, 4H), 4.68 - 4.25 (m, 2H), 4.08 (s, 3H), 3.98 - 3.61 (m, 5H), 3.18 (dt, J = 47.1 , 25.8 Hz, 5H), 2.18 - 1 .81 (m, 2H).
Example 148: 2-((3,3-difluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin- 1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000191_0001
Step-1 : tert-butyl 3,3-difluoro-4-hydroxypiperidine-1 -carboxylate (154 mg, 0.46 mmol) was added Me-THF (9 mL) under argon atmosphere and cooled at 0 °C. To well stirred solution was added potassium tert-butoxide (73 mg) at one portion and stirred for 30 minutes. To well stirred solution was added 2-fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (200 mg, 0.46 mmol) and warmed to room temperature over 10 min. The reaction was heated at 80 °C overnight. The reaction was cooled to RT and diluted with DCM, quenched with water (5-8 mL) and the mixture was adsorbed on silica gel, the solvent concentrated to dryness. The crude product was purified by flash column chromatography on silica gel to afford tert-butyl 4- (2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2- yl)phenoxy)-3,3-difluoropiperidine-1 -carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H38F2N8O4: 649.3; found: 649.2
Step-2: tert-butyl 4-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5- triazin-2-yl)phenoxy)-3,3-difluoropiperidine-1 -carboxylate (90 mg) was dissolved in 20% TFA/DCM (5 mL) and stirred at room temperature for 1 h. The solvent was concentrated under reduced pressure to afford 2-((3,3-difluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-
3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z):
[M+H]+ calcd for C28H3oF2N802: 549.2: found:549.4 1 H NMR (400 MHz, DMSO-c/6) δ 10.24 (s, 1 H), 9.62 (s, 1 H), 8.76 (s, 1 H), 8.68 - 8.46 (m, 2H), 7.64 (d, J = 9.2 Hz, 3H), 7.04 (s, 2H), 5.42 (ddt, J = 12.8, 7.9, 3.8 Hz, 1 H), 4.74 (d, J = 6.3 Hz, 4H), 3.75 (qq, J = 13.4, 6.5, 5.6 Hz, 6H), 3.39 - 2.99 (m, 7H), 2.27 (ddd, J = 78.6, 13.0, 7.2 Hz, 2H). Example 149 and Example 150 : (S)-2-((3,3-difluoropiperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile and (R)-2- ((3,3-difluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000192_0001
Racemic mixtures Example 148 was separated by chiral separation using chiral column to afford title compounds and the stereochemistry were assigned tentatively. Peak A: .
LCMS-ESI+ (m/z): [M+H]+ calcd for C28H3oF2N802 549.2.2: found:549.4 1H NMR (400 MHz, DMSO-c/6) δ 10.24 (s, 1 H), 9.62 (s, 1 H), 8.76 (s, 1 H), 8.68 - 8.46 (m, 2H), 7.64 (d, J = 9.2 Hz, 3H), 7.04 (s, 2H), 5.42 (ddt, J = 12.8, 7.9, 3.8 Hz, 1 H), 4.74 (d, J = 6.3 Hz, 4H), 3.75 (qq, J = 13.4, 6.5, 5.6 Hz, 6H), 3.39 - 2.99 (m, 7H), 2.27 (ddd, J = 78.6, 13.0,
7.2 Hz, 2H). Peak B: LCMS-ESI+ (m/z): [M+H]+ calcd for C28H3oF2N802 549.2.2: found:549.4
Example 151 : 2-((3,3-difluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile.
Figure imgf000192_0002
To solution of 2-((3,3-difluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (75 mg, 0.14 mmol) , 2-hydroxyacetic acid (21 mg, 0.27 mmol), HATU (103 mg, 0.27 mmol) in DMF (4 mL) was added DIPEA (0.28 mL) in a 25 mL round bottom flask. This reaction mixture was stirred at room temperature overnight. The solvent was concentrated and the crude product purified via prep HPLC (5-95% acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to isolate 2- ((3,3-difluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C3oH32F2N804: 607.2: found:607.4_1H NMR (400 MHz, DMSO-c/6) δ 10.20 (d, J = 20.9 Hz, 1 H), 8.76 (s, 1 H), 8.67 - 8.41 (m, 2H), 7.66 (d, J = 9.3 Hz, 2H), 7.05 (d, J = 10.4 Hz, 3H), 5.36 (ddd, J = 12.7, 8.3, 4.1 Hz, 1 H), 4.76 (d, J = 6.6 Hz, 5H), 4.42 (s, 1 H), 4.16 (d, J = 14.5 Hz, 3H), 3.96 - 3.31 (m, 6H), 3.15 (s, 5H), 2.06 (d, J = 64.9 Hz, 2H). Example 152 and 153 : (S)-2-((3,3-difluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)- 5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile and (R)-2-((3,3-difluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000193_0001
Racemic mixtures Example 151 was separated by chiral separation using chiral column to afford title compounds and the stereochemistry were assigned tentatively Peak A:
.LCMS-ESI+ (m/z): [M+H]+ calcd for C3oH32F2N804: 607.2: found:607.4. Peak B LCMS-
ESI+ (m/z): [M+H]+ calcd for C3oH32F2N804: 607.2: found:607.4
Example 154 : 2-((3,3-difluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4- ((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000194_0001
The title compound was prepared following the same procedure reported in Example 151 by coupling (S)-2-hydroxypropanoic acid to 2-((3,3-difluoropiperidin-4-yl)oxy)-5-(4- ((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-
ESI+ (m/z): [M+H]+ calcd for
Figure imgf000194_0002
621 .2: found:621 .4 1H NMR (400 MHz, DMSO-c/6) δ 10.20 (d, J = 20.7 Hz, 1 H), 8.76 (s, 1 H), 8.66 - 8.45 (m, 2H), 7.75 - 7.49 (m, 3H), 7.05 (d, J = 10.3 Hz, 2H), 5.45 - 5.29 (m, 1 H), 4.76 (d, J = 6.8 Hz, 4H), 4.57 - 4.32 (m, 3H), 4.17-3.61 (m, 8H) 3.15 - 2.92 (m, 3H), 2.23 - 1 .80 (m, 3H), 1.21 (d, J = 6.5 Hz, 3H).
Example 155 and Example 156: 2-(((S)-3,3-difluoro-1 -((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile and 2-(((R)-3,3-difluoro-1 -((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000194_0003
Racemic mixtures Example 154 was separated by chiral separation using chiral column to afford title compounds and the stereochemistry were assigned tentatively Peak A:
LCMS-ESI+ (m/z): [M+H]+ calcd for C3i H34F2N903 620.3: found:620.4 1 H NMR (400 MHz, DMSO-c/6) δ 10.20 (d, J = 20.7 Hz, 1 H), 8.76 (s, 1 H), 8.66 - 8.45 (m, 2H), 7.75 - 7.49 (m, 3H), 7.05 (d, J = 10.3 Hz, 2H), 5.45 - 5.29 (m, 1 H), 4.76 (d, J = 6.8 Hz, 4H), 4.57 - 4.32 (m, 3H), 4.24 - 3.49 (m, 8H), 3.15 - 2.92 (m, 3H), 2.23 - 1.80 (m, 2H), 1.21
(d, J = 6.5 Hz, 3H). Peak B: LCMS-ESI+ (m/z): [M+H]+ calcd for
Figure imgf000195_0001
621.3: found:621.4
Example 157: 2-((3,3-difluoro-1-((R)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4- ((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000195_0002
The title compound was prepared as mixture of isomers following the same procedure reported in Example 151 by coupling (R)-2-hydroxypropanoic acid to 2-((3,3- difluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for C31 H34F2N8O4: 621.2: found:621.4 1H NMR (400 MHz, DMSO-c/6) δ 10.20 (d, J = 21.3 Hz, 1 H), 8.76 (s, 1 H), 8.66 - 8.46 (m, 2H), 7.76 - 7.51 (m, 3H), 7.06 (d, J = 8.9 Hz, 2H), 5.49 - 5.26 (m, 2H), 4.77 (dd, J = 6.4, 2.1 Hz, 5H), 4.49 (q, J = 9.1 , 7.7 Hz, 3H), 4.18 (d, J = 15.8 Hz, 2H),4.16-3.45 (m, 5H) 3.07 (s, 2H), 2.25 - 1.78 (m, 3H), 1.21 (d, J = 6.5 Hz, 3H). Example 158 and Example 159: 2-(((S)-3,3-difluoro-1-((R)-2- hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile and 2-(((R)-3,3-difluoro-1-((R)-2- hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000195_0003
Racemic mixtures Example 154 was separated by chiral separation using chiral column to afford title compounds and the stereochemistry were assigned tentatively Peak A:
LCMS-ESI+ (m/z): [M+H]+ calcd for Csi
Figure imgf000196_0001
621 .3: found:621 .4 1 H NMR (400 MHz, DMSO-c/6) δ 10.20 (d, J = 21 .3 Hz, 1 H), 8.76 (s, 1 H), 8.66 - 8.46 (m, 2H), 7.76 - 7.51 (m, 3H), 7.06 (d, J = 8.9 Hz, 2H), 5.49 - 5.26 (m, 2H), 4.77 (dd, J = 6.4, 2.1 Hz, 5H), 4.49 (q, J = 9.1 , 7.7 Hz, 3H), 4.18 (d, J = 15.8 Hz, 2H), 3.89 (d, J = 45.9 Hz, 3H), 3.54 (d, J = 70.9 Hz, 3H), 3.07 (s, 2H), 2.25 - 1 .78 (m, 2H), 1 .21 (d, J = 6.5 Hz, 3H).
Peak B: LCMS-ESI+ (m/z): [M+H]+ calcd for C3iH34F2N903 621 .3: found:621 .4
Example 160: (S)-2-((1 -(2-cyanoacetyl)-3,3-difluoropiperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000196_0002
The title compound was prepared following the same procedure reported in Example 151 by coupling 2-cyanoacetic acid to (S)-2-((3,3-difluoropiperidin-4-yl)oxy)-5-(4-((4-(4-
(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C31 H31 F2N9O3: 616.3: found:616.4 1H NMR (400 MHz, DMSO- d6) δ 10.21 (d, J = 23.4 Hz, 1 H), 8.76 (s, 1 H), 8.70 - 8.46 (m, 2H), 7.63 (dd, J = 20.9, 10.5 Hz, 3H), 7.03 (d, J = 10.8 Hz, 2H), 5.37 (ddd, J = 12.6, 8.4, 4.2 Hz, 1 H), 4.75 (d, J = 6.3 Hz, 5H), 4.40 (s, 1 H), 4.16 (d, J = 38.0 Hz, 3H), 3.96 - 3.40 (m, 5H), 3.09 (d, J = AAA Hz, 5H), 2.28 - 1 .79 (m, 2H). Example 161 : (S)-2-((3,3-difluoro-1 -(3-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4- ((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000197_0001
The title compound was prepared following the same procedure reported in Example 151 by coupling 2-hydroxypropionic acid to (S)-2-((3,3-difluoropiperidin-4-yl)oxy)-5-(4- ((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS- ESI+ (m/z): [M+H]+ calcd for
Figure imgf000197_0002
621.3: found:621.4 1H NMR (400 MHz, DMSO-c/6) δ 10.21 (dd, J = 19.7, 6.4 Hz, 1 H), 8.76 (s, 1 H), 8.69 - 8.45 (m, 2H), 7.79 - 7.51 (m, 3H), 7.04 (t, J = 9.6 Hz, 2H), 5.46 - 5.26 (m, 1 H), 4.74 (d, J = 6.3 Hz, 5H), 4.39 (s, 1 H), 4.10 (td, J = 15.7, 7.7 Hz, 1 H), 3.96 - 3.67 (m, 3H), 3.64 (t, J = 6.5 Hz, 2H), 3.60 - 3.40 (m, 3H), 3.12 - 2.90 (m, 3H), 2.56 (dt, J = 1 1.3, 6.4 Hz, 3H), 2.25 - 1.75 (m, 3H). Example 162: 2-((3,3-difluoro-1-(1 H-pyrrole-2-carbonyl)piperidin-4-yl)oxy)-5-(4-((4- (4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000197_0003
The title compound was prepared following the same procedure reported in Example 151 by coupling 1-(tert-butoxycarbonyl)-1 H-pyrrole-2-carboxylic acid to 2-((3,3- difluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5- triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H33F2N903: 642.3: found:642.4 1H NMR (400 MHz, DMSO-c/6) δ 10.19 (d, J = 19.4 Hz, 1 H), 8.76 (s, 1 H), 8.68 - 8.34 (m, 2H), 8.23 - 8.01 (m, 1 H), 7.75 - 7.41 (m, 2H), 7.05 (ddd, J = 13.6, 6.6, 3.0 Hz, 3H), 6.93 (td, J = 2.7, 1.3 Hz, 1 H), 6.59 (ddd, J = 3.9, 2.6, 1.4 Hz, 1 H), 6.14 (dt, J = 3.7, 2.4 Hz, 1 H), 5.42 (ddt, J = 12.7, 8.3, 4.3 Hz, 1 H), 4.74 (d, J = 6.3 Hz, 5H), 4.30 (td, J = 15.2, 6.6 Hz, 1 H), 4.13 - 3.37 (m, 7H), 3.03 (s, 4H), 2.21 (d, J = 13.5 Hz, 1 H), 1.98 (d, J = 15.2 Hz, 1 H).
Example 163: 2-((3,3-dif luoro-1 -(1 H-imidazole-2-carbonyl)piperidin-4-yl)oxy)-5-(4- ((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000198_0001
The title compound was prepared following the same procedure reported in Example 16 by coupling 1 H-imidazole-2-carboxylic acid to 2-((3,3-difluoropiperidin-4-yl)oxy)-5-(4-((4-
(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. ESI+ (m/z):
[M+H]+ calcd for C32H32F2N10O3: 643.3: found:643.4 1H NMR (400 MHz, DMSO-c/6) δ 10.32 - 10.06 (m, 1 H), 8.76 (s, 1 H), 8.70 - 8.44 (m, 2H), 7.65 (dd, J = 28.2, 10.3 Hz, 3H), 7.21 (s, 2H), 7.1 1 - 6.91 (m, 3H), 5.45 (d, J = 19.6 Hz, 2H), 4.89 (d, J = 18.3 Hz, 1 H), 4.76 (d, J = 6.4 Hz, 5H), 4.36 (d, J = 47.4 Hz, 2H), 4.02 (dd, J = 19.6, 12.1 Hz, 1 H), 3.92 - 3.57 (m, 2H), 3.17 (d, J = 101.5 Hz, 4H), 2.78 (s, 1 H), 2.27 (d, J = 32.5 Hz, 1 H), 2.13 - 1.85 (m, 1 H). Example 164: (S)-2-((3,3-dif luoro-1 -(1 H-pyrazole-5-carbonyl)piperidin-4-yl)oxy)-5- (4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000198_0002
The title compound was prepared following the same procedure reported in Example 151 by coupling 1 H-pyrazole-5-carboxylic acid to (S)-2-((3,3-difluoropiperidin-4-yl)oxy)- 5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile.
LCMS-ESI+ (m/z): [M+H]+ calcd for C32H32F2N10O3: 643.3: found:643.4 1H NMR (400 MHz, DMSO-c/6) δ 13.30 (s, 1 H), 10.20 (d, J = 20.9 Hz, 1 H), 8.76 (s, 1 H), 8.67 - 8.41 (m, 2H), 7.83 (d, J = 2.4 Hz, 1 H), 7.76 - 7.50 (m, 3H), 7.04 (s, 2H), 6.68 (d, J = 13.5 Hz, 1 H), 5.41 (s, 1 H), 4.75 (d, J = 6.3 Hz, 5H), 4.35 (d, J = 52.6 Hz, 3H), 4.10 - 3.55 (m, 4H), 3.09 (d, J = 48.5 Hz, 5H), 2.25 (d, J = 45.3 Hz, 1 H), 2.02 (d, J = 37.2 Hz, 1 H).
Example 165: (S)-2-((3,3-difluoro-1-(1 H-1,2,3-triazole-5-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2- yl)benzonitrile
Figure imgf000199_0001
The title compound was prepared following the same procedure reported in Example 151 by coupling 1 H-1 ,2,3-triazole-5-carboxylic acid to (S)-2-((3,3-difluoropiperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C31 H31 F2NHO3: 644.3: found:644.4 1H NMR (400 MHz, DMSO-c/6) δ 10.32 - 10.05 (m, 1 H), 8.76 (s, 1 H), 8.69 - 8.46 (m, 2H), 7.76 - 7.49 (m, 4H), 7.16 - 6.93 (m, 3H), 5.44 (t, J = 1 1.5 Hz, 1 H), 4.75 (d, J = 6.5 Hz, 5H), 4.57 - 4.19 (m, 3H), 3.98 (d, J = 25.7 Hz, 2H), 3.91 - 3.58 (m, 1 H), 3.43 (s, 1 H), 3.05 (s, 5H), 2.23 (s, 1 H), 2.13 - 1.88 (m, 1 H).
Example 166: (S)-2-((3,3-difluoro-1 -(4H-1 ,2,4-triazole-3-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile
Figure imgf000200_0001
The title compound was prepared following the same procedure reported in Example 151 by coupling 4H-1,2,4-triazole-3-carboxylic acid to (S)-2-((3,3-difluoropiperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C31H31F2N11O3: 644.3: found:644.4 1H NMR(400 MHz, DMSO-c6) δ 10.16 (d, J = 21.6 Hz, 1H), 8.71 (s, 1H), 8.64-8.40 (m, 2H), 7.59 (dd, J = 26.9, 10.9 Hz, 4H), 7.01 (d, J = 10.9 Hz, 3H), 5.38 (d, J = 12.8 Hz, 1H), 4.71 (d, J= 6.3 Hz, 5H), 4.46-4.16 (m, 2H), 3.97 (d, J= 15.4 Hz, 1H), 3.83-3.28 (m, 3H), 3.04 (d, J = 45.8 Hz, 6H), 2.17 (dd, J= 12.9, 6.7 Hz, 1H), 1.94 (d, J= 10.3 Hz, 1H).
Example 167: (S)-2-((3,3-difluoro-1-(1H-imidazole-5-carbonyl)piperidin-4-yl)oxy)-5- (4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile:
Figure imgf000200_0002
The title compound was prepared following the same procedure reported in Example 151 by coupling 1H-imidazole-5-carboxylic acid to (S)-2-((3,3-difluoropiperidin-4-yl)oxy)- 5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile.
LCMS-ESI+ (m/z): [M+H]+ calcd for C31H31F2NHO3: 643.3: found:643.4 1H NMR (400 MHz, DMSO-c/6)510.21 (d, J = 22.2 Hz, 1H), 8.76 (s, 1H), 8.68-8.48 (m, 2H), 8.31 (s, 1H), 7.91 (s, 1H), 7.65 (dd, J = 24.6, 11.0 Hz, 4H), 7.06 (d, J= 11.1 Hz, 2H), 5.41 (d, J = 13.9 Hz, 1 H), 4.77 (dd, J = 6.5, 2.1 Hz, 5H), 4.46 (q, J = 6.3 Hz, 1 H), 4.31-3.62 (m, 5H), 3.43-2.98 (s, 6H), 2.21 (s, 1 H), 2.01 (d, J = 14.6 Hz, 1 H).
Example 168: 2-(((2R,4S)-1 -(2-hydroxyacetyl)-2-methylpiperidin-4-yl)oxy)-5-(4-((4- (4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile.
Figure imgf000201_0001
(2R,4S)-tert-butyl 4-hydroxy-2-methylpiperidine-1-carboxylate (55 mg, 0.25 mmol) was
added Me-THF (4.6 mL) under argon atmosphere and cooled at 0 C. . To well stirred solution was added potassium tert-butoxide (31 mg, 0.28 mmol) at one portion and stirred for 30 minutes. To well stirred solution was added 2-fluoro-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (100 mg, 0.23 mmol) and warmed to room temperature over 10 min. The reaction was heated at 60 °C overnight. The reaction was cooled to RT and diluted with DCM and quenched with water (5 mL). The mixture was adsorbed on silica gel, the solvent concentrated to dryness. The crude product was purified by flash column chromatography on silica gel to afford (2R,4S)-tert- butyl 4-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)phenoxy)-2-methylpiperidine-1-carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for C34H42N804: 627.3; found: 627.4
(2R,4S)-tert-butyl 4-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)- 1 ,3,5-triazin-2-yl)phenoxy)-2-methylpiperidine-1-carboxylate (98mg, 0.15 mmol) was dissolved in 20% TFA/DCM (5 mL) and stirred at room temperature for 1 h. The solvent was concentrated under reduced pressure to afford 2-(((2R,4S)-2-methylpiperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile. The dried residue was used for next step LCMS-ESI+ (m/z): [M+H]+ calcd for C29H34N8O2: 527.2; found: 527.4
To solution of_2-(((2R,4S)-2-methylpiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin- 1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (75 mg, 0.14 mmol), (2-hydroxyacetic acid (22 mg, 0.28 mmol), HATU (108 mg, 0.28 mmol) in DMF (4 mL) was added DIPEA (0.29 mL) in a 10 mL microwave vial and sealed. This reaction mixture was stirred at room temperature overnight. The solvent was concentrated and the crude product purified via prep HPLC (5-95% acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to isolate 2-(((2R,4S)-1 -(2-hydroxyacetyl)-2-methylpiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for Csi HseNeC : 585.3: found:585.5_1H NMR (400 MHz, DMSO-d6) δ 10.17 (d, J = 23.9 Hz, 1 H), 8.74 (s, 1 H), 8.62 - 8.41 (m, 2H), 7.60 (d, J = 9.3 Hz, 3H), 7.04 (s, 2H), 5.08 (tt, J = 10.7, 4.5 Hz, 1 H), 4.87 - 4.64 (m, 6H), 4.44 (s, 1 H), 4.25 - 3.96 (m, 2H), 3.94 - 3.33 (m, 4H), 3.16-3.04 (m, 6H), 2.27 - 1.96 (m, 2H), 1.49 (d, J = 196.6 Hz, 5H).
Example 169: 2-(((2S,4S)-1 -(2-hydroxyacetyl)-2-methylpiperidin-4-yl)oxy)-5-(4-((4- (4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile.
Figure imgf000203_0001
The title compound was prepared following the similar procedure reported in Example 168 by substituting (2S,4S)-tert-butyl 4-hydroxy-2-methylpiperidine-1-carboxylate to 2- fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitril followed by Boc deprotection and glycolic acid coupling. LCMS-ESI+ (m/z): [M+H]+ calcd for C3i H36N804: 585.3: found:585.4.4_1H NMR (400 MHz, DMSO-c/6) δ 10.17 (d, J = 18.9 Hz, 1 H), 8.75 (s, 1 H), 8.66 - 8.42 (m, 2H), 7.62 (s, 2H), 7.48 (d, J = 8.7 Hz, 1 H), 7.06 (d, J = 9.8 Hz, 2H), 5.19 - 5.05 (m, 1 H), 4.76 (d, J = 6.3 Hz, 5H), 4.43 (s, 2H), 4.08 (s, 6H), 3.05 (s, 6H), 1.94 (s, 4H), 1.30 (s, 3H). Example 170: 2-((1-(2-hydroxyacetyl)-3-methylpiperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000203_0002
The title compound was prepared following the similar procedure reported in Example 168 by substituting tert-butyl 4-hydroxy-3-methylpiperidine-1-carboxylate to 2-fluoro-5- (4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile followed by Boc deprotection and glycolic acid coupling. LCMS-ESI+ (m/z): [M+H]+ calcd for C3iH36N804: 585.3: found:585.4 1H NMR (400 MHz, DMSO-d6) δ 10.17 (d, J = 20.7 Hz, 1 H), 8.74 (s, 1 H), 8.66 - 8.45 (m, 2H), 7.74 - 7.47 (m, 3H), 7.04 (s, 2H), 4.91 (d, J = 24.7 Hz, 1 H), 4.74 (d, J = 6.0 Hz, 4H), 4.57 (s, 1 H), 4.24 - 4.01 (m, 3H), 3.95 - 3.57 (m, 4H), 3.35 - 2.78 (m, 8H), 2.21 - 2.03 (m, 1 H), 2.01 - 1.77 (m, 1 H), 1.65 - 1.36 (m, 1 H), 0.97 (dd, J = 12.1 , 5.8 Hz, 3H).
Example 171 : 2-((1-(2-hydroxyacetyl)-2,6-dimethylpiperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000204_0001
The title compound was prepared following the similar procedure reported in Example 168 by substituting tert-butyl 4-hydroxy-2,6-dimethylpiperidine-1-carboxylate to 2-fluoro- 5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile followed by Boc deprotection and glycolic acid coupling. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H38N804: 599.3: found:599.4 1H NMR (400 MHz, DMSO-d6) δ 10.18 (d, J = 30.3 Hz, 1 H), 8.75 (s, 1 H), 8.69 (s, 3H), 8.61 - 8.46 (m, 2H), 7.58 (t, J = 9.6 Hz, 3H), 7.03 (d, J = 8.8 Hz, 2H), 5.1 1 (t, J = 7.7 Hz, 1 H), 4.95 - 4.81 (m, 1 H), 4.75 (d, J = 6.5 Hz, 5H), 4.39 (s, 1 H), 3.78 (s, 1 H), 3.71 - 3.55 (m, 1 H), 3.35 (s, 1 H), 3.05 (s, 4H), 2.41 - 2.16 (m, 2H), 2.12 - 1.88 (m, 2H), 1.78 - 1.43 (m, 2H), 1.35 (d, J = 6.7 Hz, 3H), 1.25 (dd, J = 15.2, 7.1 Hz, 3H).
Example 172: 2-((3-(2-hydroxyacetyl)-3-azabicyclo[3.1.1]heptan-6-yl)oxy)-5-(4-((4- (4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000204_0002
The title compound was prepared following the similar procedure reported in Example 168 by substituting tert-butyl 6-hydroxy-3-azabicyclo[3.1.1]heptane-3-carboxylate to 2- fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile, followed by Boc deprotection and glycolic acid coupling. LCMS-ESI+ (m/z): [M+H]+ calcd for C3i H34N804: 583.3: found:583.5_1H NMR (400 MHz, DMSO-c/6) δ 10.13 (d, J = 17.6 Hz, 1 H), 8.80 - 8.64 (m, 1 H), 8.61 - 8.46 (m, 2H), 7.70 - 7.39 (m, 3H), 6.99 (d, J = 19.0 Hz, 2H), 4.92 (t, J = 5.7 Hz, 1 H), 4.66 - 4.44 (m, 4H), 4.22 - 3.85 (m, 2H), 3.61 (dtq, J = 10.4, 6.6, 3.4 Hz, 6H), 3.16 - 3.06 (m, 7H), 2.99 - 2.88 (m, 2H), 1.81 (dt, J = 1 1.1 , 6.2 Hz, 1 H), 1.54 - 1.30 (m, 1 H), 1.18 - 0.96 (m, 1 H). Example 173: 2-((8-(2-hydroxyacetyl)-8-azabicyclo[3.2.1]octan-3-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000205_0001
The title compound was prepared following the similar procedure reported in Example 168 by substituting tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate to 2- fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile, followed by Boc deprotection and glycolic acid coupling. LCMS-ESI+
(m/z): [M+H]+ calcd for C32H36N804 597.3: found:597.4 1H NMR (400 MHz, DMSO-c/6) δ 10.19 (s, 1 H), 8.74 (s, 1 H), 8.65 - 8.46 (m, 2H), 7.62 (s, 2H), 7.35 (d, J = 8.9 Hz, 1 H), 7.04 (s, 2H), 5.01 (t, J = 4.6 Hz, 1 H), 4.73 (s, 5H), 4.51 (d, J = 7.5 Hz, 1 H), 4.26 (s, 1 H), 4.05 (q, J = 14.9 Hz, 2H), 3.51 (s, 6H), 3.18 - 2.80 (m, 3H), 2.24 - 2.03 (m, 4H), 2.03 - 1.89 (m, 3H), 1.82 (d, J = 1 1.6 Hz, 1 H).
Example 174: 2-((1-(2-hydroxyacetyl)-3,3-dimethylpiperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000206_0001
The title compound was prepared following the similar procedure reported in Example 168 by substituting tert-butyl 4-hydroxy-3,3-dimethylpiperidine-1-carboxylate to 2-fluoro- 5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile followed by Boc deprotection and glycolic acid coupling. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H38N804: 599.3: found:599.4 1H NMR (400 MHz, DMSO-d6) δ 10.17 (d, J = 19.7 Hz, 1 H), 8.74 (s, 1 H), 8.64 - 8.52 (m, 2H), 7.75 - 7.47 (m, 3H), 7.04 (d, J = 8.8 Hz, 2H), 4.75 (d, J = 6.6 Hz, 5H), 4.59 (d, J = 8.2 Hz, 1 H), 4.39 (s, 1 H), 4.22 - 4.03 (m, 3H), 3.85 (d, J = 13.6 Hz, 1 H), 3.69 (d, J = 13.0 Hz, 1 H), 3.53 (dt, J = 1 1.9, 5.0 Hz, 1 H), 3.44 - 3.22 (m, 3H), 3.19 - 2.95 (m, 5H), 2.07 - 1.86 (m, 1 H), 1.82 - 1.53 (m, 1 H), 1.09 - 0.89 (m, 6H).
Example 175 and Example 176: (S)-2-((1-(2-hydroxyacetyl)-3,3-dimethylpiperidin- 4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2- yl)benzonitrile and (R)-2-((1-(2-hydroxyacetyl)-3,3-dimethylpiperidin-4-yl)oxy)-5-(4- ((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000206_0002
Racemic mixtures Example 174 was separated by chiral separation using chiral column to afford title compounds and the stereochemistry were assigned tentatively Peak A:
LCMS-ESI+ (m/z): [M+H]+ calcd for C32H38N804: 599.3: found:599.4 1H NMR (400 MHz, DMSO-c/6) δ 10.17 (d, J = 19.7 Hz, 1 H), 8.74 (s, 1 H), 8.64 - 8.52 (m, 1 H), 8.50 (s, 1 H), 7.75 - 7.47 (m, 3H), 7.04 (d, J = 8.8 Hz, 2H), 4.75 (d, J = 6.6 Hz, 5H), 4.59 (d, J = 8.2 Hz, 1 H), 4.39 (s, 1 H), 4.22 - 4.03 (m, 3H), 3.85 (d, J = 13.6 Hz, 1 H), 3.69 (d, J = 13.0 Hz, 1 H), 3.53 (dt, J = 1 1.9, 5.0 Hz, 1 H), 3.44 - 3.22 (m, 4H), 3.19 - 2.95 (m, 2H), 2.07 -
1.86 (m, 1 H), 1.82 - 1.53 (m, 1 H), 1.09 - 0.89 (m, 7H). Peak B: LCMS-ESI+ (m/z): [M+H]+ calcd for C32H38N804: 599.3: found:599.4
Example 177: 2-((5-fluoro-1-(2-hydroxyacetyl)-3,3-dimethylpiperidin-4-yl)oxy)-5- (4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000207_0001
The title compound was prepared following the similar procedure reported in Example 168 by substituting tert-butyl 5-fluoro-4-hydroxy-3,3-dimethylpiperidine-1-carboxylate to 2-fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile, followed by Boc deprotection and glycolic acid coupling. LCMS-ESI+
(m/z): [M+H]+ calcd for C32H37FN804: 617.3: found:617.4 1H NMR (400 MHz, DMSO-c/6) δ 10.19 (d, J = 21.2 Hz, 1 H), 8.75 (s, 1 H), 8.66 - 8.43 (m, 2H), 7.64 (dd, J = 9.6, 3.3 Hz, 3H), 7.04 (s, 2H), 5.09 (d, J = 51.6 Hz, 1 H), 4.88 (dd, J = 20.4, 9.5 Hz, 1 H), 4.76 (d, J = 6.5 Hz, 5H), 4.44 (s, 1 H), 4.28 - 4.07 (m, 2H), 3.72 (s, 7H), 3.66 - 3.52 (m, 2H), 3.32 (dd, J = 50.9, 13.3 Hz, 1 H), 3.18 - 2.76 (m, 2H), 1.12 - 0.93 (m, 6H).
Example 178 and Example 179: 2-(((4R,5S)-5-fluoro-1-(2-hydroxyacetyl)-3,3- dimethylpiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)benzonitrile and 2-(((4S,5R)-5-fluoro-1-(2-hydroxyacetyl)-3,3- dimethylpiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)benzonitrile
Figure imgf000208_0001
Racemic mixtures Example 174 was separated by chiral separation using chiral column to afford title compounds and the stereochemistry were assigned tentatively Peak A:.
LCMS-ESI+ (m/z): [M+H]+ calcd for C32H37FN804: 617.3: found:617.4 Peak B: LCMS- ESI+ (m/z): [M+H]+ calcd for C32H37FN804: 617.3: found:617.4
Example 180: 2-((5-fluoro-1-((S)-2-hydroxypropanoyl)-3,3-dimethylpiperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2- yl)benzonitrile
Figure imgf000208_0002
The title compound was prepared following the similar procedure reported in Example 168 by substituting tert-butyl 5-fluoro-4-hydroxy-3,3-dimethylpiperidine-1-carboxylate to 2-fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile, followed by Boc deprotection and (S)-2-hydroxypropanoic acid coupling.
LCMS-ESI+ (m/z): [M+H]+ calcd for C33H39FN804: 631.3: found:631.4 1H NMR (400 MHz, DMSO-c/6) δ 10.19 (d, J = 21.9 Hz, 1 H), 8.75 (s, 1 H), 8.67 - 8.46 (m, 2H), 7.63 (t, J = 10.3 Hz, 3H), 7.05 (s, 2H), 5.23 - 4.97 (m, 2H), 4.96 - 4.83 (m, 1 H), 4.83 - 4.71 (m, 5H), 4.49 (dd, J = 14.8, 8.9 Hz, 4H), 3.98 - 3.71 (m, 1 H), 3.65 - 3.38 (m, 1 H), 3.27 (s, 1 H), 3.06 (s, 6H), 1.49 -1.16 (m, 3H), 1.13 - 0.93 (m, 6H). Example 181 : 2-(((2S,4S)-1-((S)-2-hydroxypropanoyl)-2-methylpiperidin-4-yl)oxy)- 5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000209_0001
The title compound was prepared following the similar procedure reported in Example 168 by substituting (2S,4S)-tert-butyl 4-hydroxy-2-methylpiperidine-1-carboxylate to 2- fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile, followed by Boc deprotection and (S)-2-hydroxypropanoic acid coupling.
LCMS-ESI+ (m/z): [M+H]+ calcd for CssHseNsCU: 599.3: found:599.4 1H NMR (400 MHz, DMSO-c 6) δ 10.16 (d, J = 17.0 Hz, 1 H), 8.74 (s, 1 H), 8.67 - 8.43 (m, 2H), 7.62 (s, 2H), 7.53 - 7.38 (m, 1 H), 7.03 (d, J = 10.2 Hz, 2H), 5.1 1 (s, 1 H), 4.87 - 4.65 (m, 5H), 4.42 (q, J = 6.5 Hz, 3H), 3.62 (d, J = 163.6 Hz, 6H), 3.1 1 (d, J = 55.0 Hz, 4H), 1.96 (d, J = 12.0 Hz, 3H), 1.88 - 1.23 (m, 4H), 1.19 (d, J = 6.4 Hz, 3H).
Example 182: 2-(((2S,4S)-1-((R)-2-hydroxypropanoyl)-2-methylpiperidin-4-yl)oxy)- 5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000209_0002
The title compound was prepared following the similar procedure reported in Example
168 by substituting (2S,4S)-tert-butyl 4-hydroxy-2-methylpiperidine-1-carboxylate to 2- fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile, followed by Boc deprotection and (R)-2-hydroxypropanoic acid coupling. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H38N8O4: 599.3: found:599.41H NMR (400 MHz, DMSO-c/6) δ 10.16 (d, J = 17.2 Hz, 1H), 8.74 (s, 1H), 8.62 - 8.44 (m, 2H), 7.62 (s, 2H), 7.48 (d, J = 8.9 Hz, 1H), 7.03 (d, J= 10.8 Hz, 3H), 5.20-5.01 (m, 1H), 4.75 (d, J = 6.4 Hz, 5H), 4.58-4.19 (m, 3H), 3.81 (s, 3H), 3.39 (s, 1H), 3.24-2.77 (m, 4H), 1.95 (d, J = 12.8 Hz, 3H), 1.52-1.32 (m, 2H), 1.30-1.10 (m, 6H).
Example 183: 2-(((2R,4S)-1-((S)-2-hydroxypropanoyl)-2-methylpiperidin-4-yl)oxy)- 5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000210_0001
The title compound was prepared following the similar procedure reported in Example 168 by substituting (2R,4S)-tert-butyl 4-hydroxy-2-methylpiperidine-1-carboxylate to 2- fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile, followed by Boc deprotection and (S)-2-hydroxypropanoic acid coupling.
LCMS-ESI+ (m/z): [M+H]+ calcd for C32H38N8O4: 599.3: found:599.4
Example 184: 2-(((2R,4S)-1-((R)-2-hydroxypropanoyl)-2-methylpiperidin-4-yl)oxy)- 5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000210_0002
The title compound was prepared following the similar procedure reported in Example 168 by substituting (2R,4S)-tert-butyl 4-hydroxy-2-methylpiperidine-1-carboxylate to 2- fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile, followed by Boc deprotection and (R)-2-hydroxypropanoic acid coupling.
LCMS-ESI+ (m/z): [M+H]+ calcd for C32H38N8O4: 599.3: found:599.4
Example 185: 2-(((2R,4R)-1 -((S)-2-hydroxypropanoyl)-2-methylpiperidin-4-yl)oxy)- 5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000211_0001
The title compound was prepared following the similar procedure reported in Example 168 by substituting (2R,4R)-tert-butyl 4-hydroxy-2-methylpiperidine-1 -carboxylate to 2- fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile, followed by Boc deprotection and (S)-2-hydroxypropanoic acid coupling.
LCMS-ESI+ (m/z): [M+H]+ calcd for C32H38N8O4: 599.3: found:599.4
Example 186: 2-(((2R,4R)-1 -((R)-2-hydroxypropanoyl)-2-methylpiperidin-4-yl)oxy)- 5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000211_0002
The title compound was prepared following the similar procedure reported in Example 168 by substituting (2R,4R)-tert-butyl 4-hydroxy-2-methylpiperidine-1 -carboxylate to 2- fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile, followed by Boc deprotection and (R)-2-hydroxypropanoic acid coupling. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H38N8O4: 599.3: found:599.4
Example 187: 2-(((2S,4S)-1-(2-cyanoacetyl)-2-methylpiperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000212_0001
The title compound was prepared following the similar procedure reported in Example 168 by substituting (2S,4S)-tert-butyl 4-hydroxy-2-methylpiperidine-1-carboxylate to 2- fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile, followed by Boc deprotection and 2-cyanoacetic acid coupling. LCMS- ESI+ (m/z): [M+H]+ calcd for C32H35N903: 594.3: found:594.4 1H NMR (400 MHz, DMSO-c/6) δ 10.17 (d, J = 19.3 Hz, 1 H), 8.74 (s, 1 H), 8.68 - 8.44 (m, 2H), 7.64 (d, J = 11.9 Hz, 2H), 7.49 (d, J = 8.9 Hz, 1 H), 7.05 (d, J = 9.7 Hz, 2H), 5.10 (s, 1 H), 4.75 (d, J = 6.2 Hz, 5H), 4.54 - 3.92 (m, 4H), 3.81 (d, J = 4.9 Hz, 1 H), 3.46 (s, 3H), 3.09 (d, J = 44.2 Hz, 5H), 1.83 (d, J = 78.8 Hz, 4H), 1 .30 (dd, J = 54.1 , 8.1 Hz, 3H). Example 188: 2-(((2S,4S)-2-methyl-1-(1 H-1,2,3-triazole-5-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2- yl)benzonitrile
Figure imgf000212_0002
The title compound was prepared following the similar procedure reported in Example 168 by substituting (2S,4S)-tert-butyl 4-hydroxy-2-methylpiperidine-1-carboxylate to 2- fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile, followed by Boc deprotection and 1 H-1 ,2,3-triazole-5-carboxylic acid coupling. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H35N11 O3: 622.3: found:622.4 1H NMR (400 MHz, DMSO-c/6) δ 10.17 (d, J = 17.1 Hz, 1 H), 8.74 (s, 1 H), 8.67 - 8.44 (m, 2H), 8.15 - 7.78 (m, 1 H), 7.63 (d, J = 12.8 Hz, 2H), 7.50 (dd, J = 7.8, 3.9 Hz, 1 H), 7.04 (s, 2H), 5.14 (dd, J = 5.6, 2.8 Hz, 1 H), 4.75 (d, J = 6.2 Hz, 6H), 4.41 (s, 2H), 3.80 (s, 3H), 3.15 (s, 5H), 2.14 - 1.79 (m, 4H), 1.39 (t, J = 8.7 Hz, 3H). Example 189: 2-((1-(1 H-imidazole-2-carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000213_0001
The title compound was prepared following the similar procedure reported in Example 168 by substituting tert-butyl 4-hydroxypiperidine-1-carboxylate to 2-fluoro-5-(4-((4-(4- (oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile, followed by Boc deprotection and 1 H-imidazole-2-carboxylic acidcoupling. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H34N10O3 607.3: found:607.4 1H NMR (400 MHz, DMSO-c/6) δ 10.18 (d, J = 19.7 Hz, 1 H), 8.75 (s, 1 H), 8.58 (dd, J = 8.9, 2.0 Hz, 1 H), 8.52 (s, 1 H), 7.73 - 7.47 (m, 4H), 7.22 (s, 2H), 7.06 (d, J = 1 1.0 Hz, 2H), 5.05 (dp, J = 7.3, 3.3 Hz, 1 H), 4.87 - 4.71 (m, 5H), 4.62 (d, J = 13.4 Hz, 1 H), 4.45 (t, J = 6.7 Hz, 1 H), 4.29 (d, J = 13.8 Hz, 1 H), 3.90 (d, J = 13.4 Hz, 2H), 3.64 (s, 1 H), 3.10 (s, 6H), 2.07 (s, 2H), 1.77 (d, J = 12.9 Hz, 2H).
Example 190: 2-((1-(1 H-pyrrole-2-carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan- 3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000214_0001
The title compound was prepared following the similar procedure reported in Example 168 by substituting tert-butyl 4-hydroxypiperidine-1-carboxylate to 2-fluoro-5-(4-((4-(4- (oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile, followed by Boc deprotection and 1 H-pyrrole-2-carboxylic acid coupling. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H35N9O3 606.3: found:606.4 1H NMR (400 MHz, Chloroform-d) δ 9.63 (s, 1 H), 9.19 (s, 1 H), 8.69 (s, 1 H), 8.62 (dd, J = 8.9, 2.2 Hz, 1 H), 7.51 (d, J = 17.2 Hz, 2H), 7.09 (d, J = 9.0 Hz, 1 H), 7.06 - 6.86 (m, 3H), 6.56 (t, J = 3.2 Hz, 1 H), 6.35 - 6.21 (m, 2H), 4.89 (t, J = 4.6 Hz, 1 H), 4.78 - 4.60 (m, 4H), 4.09 (d, J = 13.6 Hz, 2H), 3.96 (s, 2H), 3.67 - 3.51 (m, 1 H), 3.27 (s, 4H), 2.05 (dd, J = 8.9, 3.9 Hz, 4H), 1.28 (s, 2H), 0.95 - 0.73 (m, 2H).
Example 191 : 2-((1-(1 H-pyrrole-3-carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan- 3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000214_0002
The title compound was prepared following the similar procedure reported in Example 168 by substituting tert-butyl 4-hydroxypiperidine-1-carboxylate to 2-fluoro-5-(4-((4-(4- (oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile, followed by Boc deprotection and 1 H-pyrrole-3-carboxylic acid coupling. LCMS-ESI+ (m/z): [M+H]+ calcd for CssHssNgOs 606.3: found:606.4 1H NMR (400 MHz, DMSO-d6) δ 10.18 (d, J = 24.5 Hz, 2H), 8.75 (s, 1 H), 8.66 - 8.46 (m, 2H), 7.99 (s, 1 H), 7.57 (d, J = 9.2 Hz, 4H), 7.04 (s, 3H), 5.06 (td, J = 6.8, 6.4, 3.1 Hz, 1 H), 4.74 (q, J = 7.9, 6.1 Hz, 5H), 4.38 (s, 1 H), 3.96 - 3.53 (m, 6H), 3.24 (s, 3H), 2.17 (ddt, J = 12.3, 7.7, 3.8 Hz, 2H), 1.93 (ddq, J = 14.1 , 7.2, 3.6 Hz, 2H), 1.84 - 1.70 (m, 1 H), 1.47 - 1.30 (m, 1 H).
Example 192: 2-(((3R,4S)-1-(2-hydroxyacetyl)-4-methylpyrrolidin-3-yl)oxy)-5-(4-((4- (4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000215_0001
The title compound was prepared following the similar procedure reported in Example 168 by substituting (3R,4S)-tert-butyl 3-hydroxy-4-methylpyrrolidine-1-carboxylate to 2- fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile, followed by Boc deprotection and glycolic acid coupling. LCMS-ESI+
(m/z): [M+H]+ calcd for C3oH34N804: 571.2: found:571.4 1H NMR (400 MHz, DMSO-c/6) δ 10.18 (d, J = 21.2 Hz, 1 H), 8.75 (s, 1 H), 8.64 - 8.44 (m, 2H), 7.62 (s, 2H), 7.48 (d, J = 8.9 Hz, 1 H), 7.04 (d, J = 1 1.1 Hz, 2H), 5.07 - 4.89 (m, 1 H), 4.87 - 4.68 (m, 5H), 4.45 (s, 2H), 4.09 - 3.80 (m, 4H), 3.71 - 3.41 (m, 4H), 3.38 - 2.80 (m, 5H), 2.70 - 2.52 (m, 1 H), 1.06 (dd, J = 7.1 , 5.4 Hz, 3H).
Example 193: 2-(((3R,4R)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidin-3-yl)oxy)-5-(4-((4- (4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile.
Figure imgf000216_0001
The title compound was prepared following the similar procedure reported in Example 168 by substituting (3R,4R)-tert-butyl 3-fluoro-4-hydroxypyrrolidine-1-carboxylate to 2- fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile, followed by Boc deprotection and glycolic acid coupling. LCMS-ESI+
(m/z): [M+H]+ calcd for C29H31 FN.8O4: 575.2: found:575.4_ 1H NMR (400 MHz, DMSO- cfe) δ 10.20 (d, J = 21.9 Hz, 1 H), 8.76 (s, 1 H), 8.66 - 8.45 (m, 2H), 7.63 (d, J = 14.5 Hz, 3H), 7.05 (s, 2H), 5.62 - 5.27 (m, 2H), 4.76 (d, J = 6.6 Hz, 5H), 4.43 (s, 1 H), 4.16 - 3.98 (m, 3H), 3.96 - 3.65 (m, 6H), 3.15 (s, 5H). Example 194: 2-((4,4-difluoropyrrolidin-3-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin- 1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000216_0002
The title compound was prepared following the similar procedure reported in Example 168 by substituting tert-butyl 3,3-difluoro-4-hydroxypyrrolidine-1-carboxylate to 2-fluoro- 5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile, followed by Boc deprotection. LCMS-ESI"1" (m/z): [M+H]+ calcd for C27H28F2N.8O2: 535.2: found:535.4 1H NMR (400 MHz, DMSO-c/6) δ 10.21 (d, J = 27.2 Hz, 1 H), 8.77 (s, 1 H), 8.70 - 8.46 (m, 2H), 7.74 - 7.43 (m, 3H), 7.02 (d, J = 10.6 Hz, 2H), 5.64 (d, J = 3.6 Hz, 1 H), 4.86 - 4.62 (m, 4H), 4.32 (s, 2H), 4.02 - 3.86 (m, 3H), 3.86 - 3.63 (m, 4H), 3.15 (s, 4H).
Example 195 and Example 196: (S)-2-((4,4-difluoro-1-(2-hydroxyacetyl)pyrrolidin- 3-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2- yl)benzonitrile and (R)-2-((4,4-difluoro-1-(2-hydroxyacetyl)pyrrolidin-3-yl)oxy)-5-(4- ((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000217_0001
The title compound was prepared by substituting intermediate 2-fluoro-5-(4-((4-(4- (oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile with tert-butyl 3,3-difluoro-4-hydroxypyrrolidine-1-carboxylate, followed by Boc-deprotection and coupling with glycolic acid as shown in Example 168. Racemic mixtures were then separated by chiral separation using chiral column to afford title compounds and the stereochemistry were assigned tentatively Peak A: LCMS-ESI+ (m/z): [M+H]+ calcd for C29H3oF2N804: 593.2; found:593.31H NMR (400 MHz, DMSO-c/6) δ 10.15 (d, J = 23.3 Hz, 1 H), 8.74 (s, 1 H), 8.68 - 8.47 (m, 2H), 7.71 - 7.44 (m, 3H), 6.97 (d, J = 1 1.3 Hz, 2H), 5.60 (d, J = 34.2 Hz, 1 H), 4.96 (d, J = 23.5 Hz, 1 H), 4.57-4.48 (m, 4H), 4.18 - 4.07 (m, 5H), 3.90 - 3.53 (m, 4H), 3.16-3.09 (m, 5H), 2.42 (br s, 1 H). Peak B: LCMS-ESI+ (m/z): [M+H]+ calcd for C29H3oF2N804: 593.2; found:593.3
Example 197: (R)-2-((1-(methylsulfonyl)pyrrolidin-3-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000218_0001
The title compound was prepared following the similar procedure reported in Example 168 by substituting (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate to 2-fluoro-5-(4-((4- (4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile, followed by Boc deprotection and methanesulfonyl chloride coupling. LCMS-ESI+ (m/z): [M+H]+ calcd for C28H32N804S: 577.2: found:577.4 1H NMR (400 MHz, DMSO-c/6) δ 10.20 (s, 1 H), 8.75 (s, 1 H), 8.65 - 8.43 (m, 2H), 7.61 (s, 2H), 7.50 (d, J = 8.9 Hz, 1 H), 7.02 (d, J = 1 1.6 Hz, 2H), 5.34 (s, 1 H), 4.73 (s, 4H), 3.86 - 3.64 (m, 4H), 3.55 - 3.36 (m, 6H), 3.04 (s, 3H), 2.95 (s, 3H), 2.35 - 2.14 (m, 2H). Example 198: 2-((4,4-difluoro-1-((S)-2-hydroxypropanoyl)pyrrolidin-3-yl)oxy)-5-(4- ((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000218_0002
The title compound was prepared following the similar procedure reported in Example 168 by substituting tert-butyl 3,3-difluoro-4-hydroxypyrrolidine-1-carboxylate to 2-fluoro- 5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile, followed by Boc deprotection and (S)-2-hydroxypropanoic acid coupling. LCMS-ESI+
(m/z): [M+H]+ calcd for C3oH32F2N804 607.2: found:607.4 1H NMR (400 MHz, DMSO-c/6) δ 10.21 (d, J = 21.4 Hz, 1 H), 8.76 (s, 1 H), 8.70 - 8.50 (m, 2H), 7.63 (d, J = 8.3 Hz, 3H), 7.04 (t, J = 9.2 Hz, 2H), 5.62 (d, J = 29.2 Hz, 1 H), 4.75 (d, J = 6.6 Hz, 5H), 4.51 - 4.24 (m, 3H), 4.24 - 3.59 (m, 6H), 3.09 (s, 5H), 1.19 (dd, J = 8.2, 6.5 Hz, 3H).
Example 199: (R)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin- 2-yl)-2-((6-oxopiperidin-3-yl)oxy)benzonitrile
Figure imgf000219_0001
The title compound was prepared following the similar procedure reported in Example 168 by substituting (R)-5-hydroxypiperidin-2-one to 2-fluoro-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C28H3oN803: 527.3: found:527.4.4 1H NMR (400 MHz, DMSO-c/6) δ 10.29 - 10.07 (m, 1 H), 8.75 (s, 1 H), 8.67 - 8.44 (m, 2H), 7.74 - 7.50 (m, 3H), 7.46 (d, J = 2.9 Hz, 1 H), 7.05 (s, 2H), 5.19 - 5.05 (m, 1 H), 4.77 (d, J = 6.6 Hz, 5H), 4.45 (s, 1 H), 3.82 (s, 2H), 3.60 - 3.30 (m, 2H), 3.06 (s, 5H), 2.43 - 2.18 (m, 2H), 2.17 - 2.02 (m, 2H).
Example 200: (R)-2-(3-fluoropyrrolidin-1-yl)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile.
Figure imgf000219_0002
To the mixture of (R)-3-fluoropyrrolidine (35 mg, 0.27 mmol) and 2-fluoro-5-(4-((4-(4- (oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (60 mg, 0.14 mmol) were added IPA (2 mL) followed by DIPEA (0.15 mL) in a 10 mL microwave vial and sealed. The mixture was irradiated at 150 °C for 3h. The reaction mixture was transferred in to 25 mL round bottom-flask and the solvent concentrated. The crude product purified via prep HPLC (5-95% acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to isolate (R)-2-(3-fluoropyrrolidin-1 -yl)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C27H29FN80: 501.2; found:501 .3 1H NMR (400 MHz, DMSO-c/6) δ 10.05 (s, 1 H), 8.67 (s, 1 H), 8.43 (d, J = 27.3 Hz, 1 H), 8.32 (dd, J = 9.2, 2.2 Hz, 1 H), 7.62 (s, 2H), 7.04 (s, 2H), 6.94 (d, J = 9.2 Hz, 1 H), 5.49 (dt, J = 53.0, 3.4 Hz, 1 H), 4.87 - 4.65 (m, 5H), 4.44 (s, 1 H), 4.08 - 3.66 (m, 6H), 3.07 (s, 5H), 2.40 - 2.05 (m, 2H).
Example 201 : (S)-2-(3-fluoropyrrolidin-1 -yl)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000220_0001
The title compound was prepared following the similar procedure reported in Example 200 by substituting (S)-3-fluoropyrrolidine to 2-fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin- 1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile instead of (R)-3-fluoropyrrolidine.
LCMS-ESI+ (m/z): [M+H]+ calcd for C27H29FN80: 501 .2; found:501 .3 1 H NMR (400 MHz, DMSO-c/6) δ 9.98 (s, 1 H), 8.64 (s, 1 H), 8.43 (d, J = 29.4 Hz, 1 H), 8.31 (d, J = 8.7 Hz, 1 H), 7.70 - 7.43 (m, 3H), 6.94 (d, J = 9.3 Hz, 2H), 5.61 - 5.35 (m, 1 H), 4.50 (dt, J = 37.5, 6.3 Hz, 4H), 4.07 - 3.68 (m, 4H), 3.43 (p, J = 6.3 Hz, 1 H), 3.13 (d, J = 6.3 Hz, 4H), 2.39 (dd, J = 6.5, 3.4 Hz, 4H), 2.34 - 2.06 (m, 2H).
Example 202: (R)-2-(3-hydroxypyrrolidin-1 -yl)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000221_0001
The title compound was prepared following the similar procedure reported in Example 200 by substituting (R)-3-hydroxypyrrolidine to 2-fluoro-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile instead of (R)-3- fluoropyrrolidine. LCMS-ESI+ (m/z): [M+H]+ calcd for C27H3oN802: 499.2: found:499.4 1H NMR (400 MHz, DMSO-c/6) δ 11.90 (s, 1 H), 10.08 (s, 1 H), 8.66 (s, 1 H), 8.39 (s, 1 H), 8.28 (dd, J = 9.3, 2.2 Hz, 1 H), 7.63 (d, J = 10.4 Hz, 2H), 7.03 (s, 2H), 6.89 (d, J = 9.3 Hz, 1 H), 4.91 (dd, J = 7.7, 6.0 Hz, 2H), 4.70 (t, J = 7.5 Hz, 2H), 4.62 - 4.33 (m, 4H), 3.93 - 3.59 (m, 5H), 3.57 - 3.37 (m, 3H), 3.12 (dd, J = 33.2, 20.0 Hz, 3H), 2.14 - 1.83 (m, 2H).
Example 203: (S)-2-(3-hydroxypyrrolidin-1-yl)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000221_0002
The title compound was prepared following the similar procedure reported in Example 200 by substituting (S)-3-hydroxypyrrolidine to 2-fluoro-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile instead of (R)-3- fluoropyrrolidine. LCMS-ESI+ (m/z): [M+H]+ calcd for C27H3oN802: 499.2: found:499.4 1H NMR (400 MHz, DMSO-c/6) δ 10.03 (s, 1 H), 8.65 (s, 1 H), 8.38 (s, 1 H), 8.29 (dd, J = 9.2, 2.2 Hz, 1 H), 7.62 (s, 2H), 7.03 (s, 2H), 6.88 (d, J = 9.2 Hz, 1 H), 4.92 - 4.66 (m, 4H), 4.55 - 4.33 (m, 2H), 3.89 - 3.40 (m, 8H), 3.03 (d, J = 40.8 Hz, 6H), 2.17 - 1.85 (m, 2H). Example 204: 2-((2R,4R)-4-hydroxy-2-methylpyrrolidin-1-yl)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000222_0001
The title compound was prepared following the similar procedure reported in Example 200 by substituting (3R,5R)-5-methylpyrrolidin-3-ol to 2-fluoro-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile instead of (R)-3- fluoropyrrolidine. LCMS-ESI"1" (m/z): [M+H]+ calcd for C28H32N8O2: 513.3: found:513.4 1H NMR (400 MHz, DMSO-c/6) δ 10.06 - 9.89 (m, 1 H), 8.64 (s, 1 H), 8.44-8.37 (m, 1 H) 8.35 - 8.24 (m, 1 H), 7.58 (d, J = 9.2 Hz, 2H), 7.01 (d, J = 9.3 Hz, 1 H), 6.94 (s, 2H), 4.99 (d, J = 3.1 Hz, 1 H), 4.55 (t, J = 6.5 Hz, 2H), 4.46 (t, J = 6.1 Hz, 2H), 4.35 (dd, J = 13.4, 6.4 Hz, 2H), 4.01 (dd, J = 10.9, 4.1 Hz, 1 H), 3.51 - 3.37 (m, 2H), 3.12 (d, J = 5.8 Hz, 4H), 2.39 (t, J = 4.9 Hz, 4H), 2.12 (dd, J = 13.0, 6.8 Hz, 1 H), 1.78 (ddd, J = 12.6, 8.0, 4.4 Hz, 1 H), 1.21 (d, J = 5.9 Hz, 3H).
Example 205: 2-((2S,4R)-4-hydroxy-2-methylpyrrolidin-1-yl)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000223_0001
The title compound was prepared following the similar procedure reported in Example 200 by substituting (3R,5S)-5-methylpyrrolidin-3-ol to 2-fluoro-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile instead of (R)-3- fluoropyrrolidine LCMS-ESI"1" (m/z): [M+H]+ calcd for C28H32N8O2: 513.3: found:513.4 1H NMR (400 MHz, DMSO-c/6) δ 9.95 (d, J = 15.6 Hz, 1 H), 8.64 (s, 1 H), 8.46-8.39 (m, 1 H) 8.35 - 8.23 (m, 1 H), 7.58 (d, J = 12.0 Hz, 2H), 7.01 (d, J = 9.3 Hz, 1 H), 6.94 (s, 2H), 4.99 (d, J = 3.3 Hz, 1 H), 4.55 (t, J = 6.5 Hz, 2H), 4.46 (t, J = 6.0 Hz, 2H), 4.35 (dt, J = 13.2, 3.6 Hz, 2H), 4.01 (dd, J = 10.9, 4.1 Hz, 1 H), 3.53 - 3.37 (m, 2H), 3.12 (d, J = 6.1 Hz, 4H), 2.44 - 2.32 (m, 4H), 2.12 (dd, J = 12.9, 7.0 Hz, 1 H), 1.78 (ddd, J = 12.6, 8.1 , 4.5 Hz, 1 H), 1.21 (d, J = 5.9 Hz, 3H).
Example 206: 5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2- yl)-2-(2-oxa-6-azaspiro[3.4]octan-6-yl)benzonitrile
Figure imgf000223_0002
The title compound was prepared following the similar procedure reported in Example 200 by substituting 2-oxa-6-azaspiro[3.4]octane to 2-fluoro-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile instead of (R)-3- fluoropyrrolidine. LCMS-ESI"1" (m/z): [M+H]+ calcd for C29H32N8O2: 525.2: found:525.4 1H NMR (400 MHz, DMSO-c/6) δ 9.97 (s, 1 H), 8.63 (s, 1 H), 8.40 (d, J = 29.1 Hz, 1 H), 8.33 - 8.18 (m, 1 H), 7.56 (s, 2H), 7.09 - 6.77 (m, 3H), 4.58 (dd, J = 15.2, 6.3 Hz, 3H), 4.52 (dd, J = 7.4, 3.9 Hz, 2H), 4.50 - 4.42 (m, 3H), 3.89 (s, 2H), 3.72 - 3.60 (m, 2H), 3.50 - 3.37 (m, 2H), 3.12 (s, 3H), 2.39 (t, J = 4.8 Hz, 3H), 2.27 (t, J = 6.9 Hz, 2H), 2.10 (td, J = 7.0, 2.1 Hz, 1 H).
Example 207: 5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2- yl)-2-(1-oxa-6-azaspiro[3.4]octan-6-yl)benzonitrile
Figure imgf000224_0001
The title compound was prepared following the similar procedure reported in Example 200 by substituting 1-oxa-6-azaspiro[3.4]octane to 2-fluoro-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile instead of (R)-3- fluoropyrrolidine. LCMS-ESI"1" (m/z): [M+H]+ calcd for C29H32N8O2: 525.2: found:525.4 1H NMR (400 MHz, DMSO-c/6) δ 10.04 (s, 1 H), 8.66 (s, 1 H), 8.41 (d, J = 25.7 Hz, 1 H), 8.30 (dd, J = 9.2, 2.2 Hz, 1 H), 7.62 (s, 2H), 7.03 (s, 2H), 6.87 (dd, J = 15.4, 9.1 Hz, 1 H), 4.76 (d, J = 6.8 Hz, 4H), 4.54 - 4.34 (m, 4H), 3.96 - 3.77 (m, 4H), 3.77 - 3.54 (m, 4H), 3.05 (s, 3H), 2.85 - 2.59 (m, 2H), 2.36 (ddd, J = 10.8, 6.7, 3.3 Hz, 1 H), 2.15 (dt, J = 12.6, 9.0 Hz, 1 H).
Example 208: 5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2- yl)-2-(1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)benzonitrile
Figure imgf000225_0001
The title compound was prepared following the similar procedure reported in Example 200 by substituting 1 ,4-dioxa-7-azaspiro[4.4]nonane to 2-fluoro-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile instead of (R)-3- fluoropyrrolidine LCMS-ESI+ (m/z): [M+H]+ calcd for C29H32N803: 541.2: found:541.4 1H NMR (400 MHz, DMSO-c/6) δ 10.05 (s, 1 H), 8.66 (s, 1 H), 8.38 (s, 1 H), 8.31 (dd, J = 9.2, 2.2 Hz, 1 H), 7.62 (s, 2H), 7.03 (s, 2H), 6.90 (d, J = 9.2 Hz, 1 H), 4.76 (dd, J = 6.4, 2.7 Hz, 4H), 4.43 (s, 2H), 3.96 (s, 4H), 3.81 - 3.64 (m, 4H), 3.5-3.40 (m, 3H) 3.06 (s, 4H), 2.15 (t, J = 7.2 Hz, 2H). Example 209: 2-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000225_0002
The title compound was prepared following the similar procedure reported in Example 200 by substituting 2-methyl-2,7-diazaspiro[3.5]nonane to 2-fluoro-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile instead of (R)-3- fluoropyrrolidine LCMS-ESI+ (m/z): [M+H]+ calcd for C3iH37N90: 552.2.3: found:552.4 1H NMR (400 MHz, DMSO-c/6) δ 9.95 (d, J = 15.6 Hz, 1 H), 8.63 (s, 1 H), 8.36 (s, 1 H), 8.32 - 8.20 (m, 1 H), 7.55 (s, 2H), 6.93 (s, 2H), 6.87 (d, J = 9.3 Hz, 1 H), 4.55 (t, J = 6.5 Hz, 2H), 4.46 (t, J = 6.0 Hz, 2H), 3.67 (q, J = 6.8 Hz, 2H), 3.63 - 3.48 (m, 2H), 3.43 (p, J = 6.3 Hz, 1 H), 3.1 1 (d, J = 5.7 Hz, 4H), 2.67 - 2.52 (m, 2H), 2.45 - 2.29 (m, 6H), 2.22 (s, 3H), 1.95 (ddq, J = 19.0, 12.1 , 6.8 Hz, 2H), 1.77 (td, J = 6.7, 2.5 Hz, 2H). Example 210: 5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- y I ) -2-( 1 -oxa -6-azas p i ro [3.3] h e pta n -6-y I ) be n zo n i tri le
Figure imgf000226_0001
The title compound was prepared following the similar procedure reported in Example 200 by substituting 1 -oxa-6-azaspiro[3.3]heptane to 2-fluoro-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile instead of (R)-3- fluoropyrrolidine. LCMS-ESI+ (m/z): [M+H]+ calcd for CseHsoNsOs: 51 1.2: found:511.4 1H NMR (400 MHz, DMSO-c/6) δ 10.06 (s, 1 H), 8.66 (s, 1 H), 8.47 - 8.22 (m, 2H), 7.61 (s, 2H), 7.04 (s, 2H), 6.67 (d, J = 9.0 Hz, 1 H), 4.87 - 4.69 (m, 4H), 4.60 - 4.39 (m, 6H), 4.33 (dd, J = 10.1 , 1.6 Hz, 4H), 3.80-3.46 (m, 2H) 3.23 - 2.95 (m, 3H), 2.90 (t, J = 7.5 Hz, 2H).
Example 211 : 5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2- yl)-2-(7-oxa-2-azaspiro[3.5]nonan-2-yl)benzonitrile
Figure imgf000226_0002
The title compound was prepared following the similar procedure reported in Example 200 by substituting 7-oxa-2-azaspiro[3.5]nonane to 2-fluoro-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile instead of (R)-3- fluoropyrrolidine. LCMS-ESI+ (m/z): [M+H]+ calcd for C3oH34N802: 539.2: found:549.4 1H NMR (400 MHz, DMSO-c/6) δ 10.02 (d, J = 14.9 Hz, 1 H), 8.65 (s, 1 H), 8.48 - 8.19 (m, 2H), 7.61 (s, 2H), 7.02 (s, 2H), 6.65 (d, J = 9.0 Hz, 1 H), 4.88 (s, 2H), 4.70 (t, J = 7.4 Hz, 2H), 4.47 (s, 1 H), 4.03 (s, 4H), 3.54 (t, J = 5.2 Hz, 8H), 3.1 1 (s, 4H), 1.77 (t, J = 5.2 Hz, 4H).
Example 212: 5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)-2-(8-oxa-2-azaspiro[4.5]decan-2-yl)benzonitrile
Figure imgf000227_0001
The title compound was prepared following the similar procedure reported in Example 200 by substituting 8-oxa-2-azaspiro[4.5]decane to 2-fluoro-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile instead of (R)-3- fluoropyrrolidine. LCMS-ESI"1" (m/z): [M+H]+ calcd for Csi
Figure imgf000227_0002
553.3: found:553.4 1H NMR (400 MHz, DMSO-c/6) δ 10.02 (s, 1 H), 8.65 (s, 1 H), 8.38 (d, J = 16.6 Hz, 1 H), 8.28 (dd, J = 9.2, 2.1 Hz, 1 H), 7.61 (s, 2H), 7.02 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 9.3 Hz, 1 H), 4.75 (d, J = 6.4 Hz, 4H), 4.41 (s, 1 H), 3.75 (t, J = 7.0 Hz, 6H), 3.68 - 3.47 (m, 6H), 3.03 (s, 4H), 1.93 (t, J = 7.0 Hz, 2H), 1.55 (td, J = 6.8, 5.8, 3.9 Hz, 4H). Example 213 : 5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2- yl)-2-(2-oxa-8-azaspiro[4.5]decan-8-yl)benzonitrile
Figure imgf000228_0001
The title compound was prepared following the similar procedure reported in Example 200 by substituting 2-oxa-8-azaspiro[4.5]decane to 2-fluoro-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile instead of (R)-3- fluoropyrrolidine. LCMS-ESI+ (m/z): [M+H]+ calcd for C3i H36N802 553.3: found:553.4 1H NMR (400 MHz, DMSO-c/6) δ 10.10 (d, J = 16.8 Hz, 1 H), 8.71 (s, 1 H), 8.59 - 8.34 (m, 2H), 7.62 (d, J = 9.5 Hz, 2H), 7.27 (d, J = 8.9 Hz, 1 H), 7.03 (s, 2H), 4.72 (d, J = 6.0 Hz, 5H), 3.76 (t, J = 7.1 Hz, 2H), 3.55 - 3.29 (m, 8H), 3.09 (d, J = 46.4 Hz, 6H), 1.77 (t, J = 7.1 Hz, 2H), 1.69 (t, J = 5.6 Hz, 4H). Example 214: 5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)-2-(1-oxa-7-azaspiro[3.5]nonan-7-yl)benzonitrile
Figure imgf000228_0002
The title compound was prepared following the similar procedure reported in Example 200 by substituting 1 -oxa-7-azaspiro[3.5]nonane to 2-fluoro-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile instead of (R)-3- fluoropyrrolidine. LCMS-ESI+ (m/z): [M+H]+ calcd for C3oH34N802 539.3: found:539.4 1H NMR (400 MHz, DMSO-c/6) δ 10.37 - 10.00 (m, 1 H), 8.84 - 8.61 (m, 1 H), 8.57 - 8.35 (m, 1 H), 7.67 (d, J = 40.5 Hz, 2H), 7.35 - 7.17 (m, 1 H), 7.05 (s, 2H), 4.90 - 4.67 (m, 4H), 4.61 - 4.39 (m, 2H), 4.06 - 3.77 (m, 12H), 3.68 - 3.43 (m, 2H), 3.38 - 3.23 (m, 1 H), 3.08 - 2.65 (m, 1 H), 2.36 - 2.12 (m, 1 H), 1 .79 - 1 .57 (m, 3H).
Example 215: 3-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile
Figure imgf000229_0001
To 4-chloro-N-(4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)-1 ,3,5-triazin-2-amine (50mgs, 0.14mmol), 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (36 mgs, 0.15mmol), Tetrakis(triphenylphosphine)Palladium(0) (9mg) and a de-gassed saturated aqueous solution of sodium carbonate (0.3ml) mixture in argon atmosphere was added a mixture of de-gassed solvents ( 1 ,4-dioxane and water 2: 1 ). The mixture was heated under argon atmosphere at 95 °C for 2hr in a heating block. After cooling at room temperature, water was poured into the reaction mixture and desired product was extracted with DCM. Organic layer was dried over Mg2S04 and evaporated to dryness. Solids re-dissolved in acetonitrile and purified via preparative HPLC (5-65% acetonitrile in water, 0.1 % trifluoroacteic acid buffer). Fractions containing desired product were collected and combined with a saturated aqueous solution of NaHC03 to be extracted with DCM. Organic layer was collected, dried over magnesium sulfate and evaporated under reduced pressure to yield 3-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)- 1 ,3,5-triazin-2-yl)benzonitrile. 1 H NMR (400 MHz, DMSO-c 6) δ 10.21 (d, J = 13.6 Hz, 1 H), 8.78 (s, 1 H), 8.68-8.55 (m, 2H), 8.08 (dt, J = 7.8, 1.4 Hz, 1 H), 7.78 (t, J = 7.9 Hz, 1 H), 7.67 - 7.45 (m, 2H), 7.02-6.94 (m, 2H), 4.56 (t, J = 6.5 Hz, 2H), 4.46 (t, J = 6.0 Hz, 2H), 3.43 (p, J = 6.3 Hz, 1 H), 3.22-3.09 (m, 4H), 2.40 (t, J = 4.9 Hz, 4H). LCMS-ESI+ (m/z): [M+H]+ calcd for C23H23N70: 414.2; found 414.0.
Example 216: (S)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin- 2-yl)-2-((tetrahydrofuran-3-yl)oxy)benzonitrile
Figure imgf000230_0001
A solution of (S)-tetrahydrofuran-3-ol (22 mgs, 0.23 mmol) in THF (3 mL) was stirred in an ice-water bath under an atmosphere of Argon. Potassium tert-butoxide (1.0 M, 0.28 ml, 0.29 mmol) was added in a single portion and the mixture was stirred at 0 °C for 30 minutes, and then 2-fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile was added (l OOmgs, 0.23mmol). The mixture was stirred for 1 hr at 60 °C. After the mixture cooled to room temperature, water was added, and mixture evaporated under reduced pressure. Solids were purified via preparative HPLC (5-65% acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to yield the compound (S)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)-2-((tetrahydrofuran-3-yl)oxy)benzonitrile. 1H NMR (400 MHz, DMSO-c/6) δ 10.1 (s. 1 H), 8.69 (s, 1 H), 8.56 - 8.41 (m, 2H), 7.61-7.52 (m, 2H), 7.43 - 7.33 (m, 1 H),
7.00 (t, J = 10.0 Hz, 2H), 5.26 (ddt, J = 6.1 , 4.2, 1.8 Hz, 1 H), 4.78 - 4.64 (m, 4H), 4.41 (q, J = 7.3, 6.5 Hz, 1 H), 3.93 - 3.65 (m, 5H), 3.02-2.89 (m, 7H), 2.28 (dtd, J = 14.1 , 8.1 ,
6.1 Hz, 1 H), 2.03 - 1.90 (m, 1 H). LCMS-ESI+ (m/z): [M+H]+ calcd for C27H29N703: 500.2; found: 500.3
Example 217: 2-(cyclohexyloxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000231_0001
The title compound was prepared following a similar procedure reported in Example- 216 using cyclohexanol. 1H NMR (400 MHz, DMSO-c 6) δ 10.23 - 10.03 (m, 1 H), 8.69 (s, 1 H), 8.59 - 8.37 (m, 2H), 7.70 - 7.48 (m, 2H), 7.43 (d, J = 9.1 Hz, 1 H), 7.00 (dd, J = 9.4, 4.9 Hz, 2H), 4.81 - 4.58 (m, 5H), 4.43-4.32 (m, 2H), 4.12-2.8 (m, 7H), 1.88 (ddd, J = 1 1.7, 7.5, 4.0 Hz, 2H), 1.68 (dp, J = 12.7, 5.5, 4.4 Hz, 2H), 1.57 - 1.20 (m, 6H).
LCMS-ESI+ (m/z): [M+H]+ calcd for C29H33N7O2: 512.3; found:512.3
Example 218: 2-((cis-3-fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4-(4- enyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000231_0002
To a solution of 2,4-dichloro-1 ,3,5-triazine (9.5 g, 63.3 mmol) in DMF at 0 °C (flushed with Argon) was added a solution of 4-(4-(oxetan-3-yl)piperazin-1-yl)aniline (14 g, 60.2 mmol) in DMF over 15 min and stirred in an ice-bath for 1 h. A solution of 40%MeOH/DCM was added to the reaction mixture and stirred for 1 hr. The insoluble particles were filtered off and washed with di-ethyl-ether twice. Solids were separated by filtration. 1H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1 H), 8.54 (d, J = 7.2 Hz, 1 H), 7.49 (t, J = 9.6 Hz, 2H), 7.01 (t, J = 8.0 Hz, 2H), 4.93 (t, J = 6.9 Hz, 2H), 4.67 (t, J = 7.4 Hz,
2H), 4.46 (q, J = 7.0, 6.0 Hz, 1 H), 3.86-3.70 (m, 4H), 3.24 - 3.01 (m, 4H). LCMS-ESI+
(m/z): [M+H]+ calcd for C16H19CIN60: 347.1 ; found: 347.0. To 4-chloro-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1 ,3,5-triazin-2-amine (4.1 g, 1 1.7 mmol), 2-fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (3.2 gr, 12.8 mmol), Pd(dppf)CI2CH2CI2 (854 mg) and potassium carbonate (3.2g, 23.4 mmol) mixture in argon atmosphere was added a mixture of de-gassed solvents (DME:water = 2:1 ). The mixture was heated under argon atmosphere at 104 °C for 40 min in a heating block. After cooling at room temperature, water was poured into the reaction mixture and it was stirred for 20 min. Solids were filtered off and washed out with diethyl-ether. The formed solids were re-suspended in ACN and heated to boiling point and then stirred at room temperature for 2hr. To this suspension di-ethyl ether was added and stirred at room temperature overnight. Solids were taken by filtration to yield desired product.
A solution of a racemic mixture of Cis-tert-butyl 3-fluoro-4-hydroxypiperidine-1- carboxylate (56 mgs, 0.26 mmol) in THF (5 mL) was stirred in an ice-water bath under an atmosphere of Argon. Potassium tert-butoxide (1.0 M, 0.28 ml, 0.28 mmol) was added in a single portion and the mixture was stirred at 0 °C for 40 minutes, and then 2- fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile was added (100 mgs, 0.23mmol). The mixture was stirred for 1 hr at 60 °C. After the mixture cooled to room temperature, water was added, and mixture evaporated under reduced pressure to yield the crude Cis-tert-butyl 4-(2-cyano-4-(4-((4-(4-(oxetan-3- yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-1 - carboxylate.
Solids were dissolved with DCM and TFA. Reaction mixture was stirred at room temperature for 1 hr. Reaction mixture was evaporated under reduced pressure and solids were suspended in a saturated aqueous solution of NaHC03 and extracted with DCM. Organic phase was collected dried over magnesium sulfate and evaporated under reduced pressure to yield 2-((Cis-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile.
To a solution of 2-((Cis-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (70 mg, 0.013 mmol), glycolic acid (20 mg, 0.026 mmol), HATU (100 mgs, 0.026 mmol) in DMF (3 mL) was added TEA (0.02 mL, 0.026 mmol) in a 10 mL microwave vial and sealed. This reaction mixture was stirred at room temperature for 2 hrs. Water was added and it was extracted with DCM. Organic layer was dried over Mg2S04 and evaporated to dryness. Solids re-dissolved in acetonitrile and purified via preparative HPLC (5-65% acetonitrile in water, 0.1 % trifluoroacteic acid buffer). Fractions containing desired product were collected and combined with a saturated aqueous solution of NaHC03 to be extracted with DCM. Organic layer was collected, dried over magnesium sulfate and evaporated under reduced pressure to yield 2-((Cis-3-fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)- 5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. 1H NMR (400 MHz, DMSO-c 6) δ 10.14 (s, 1 H), 8.73 (s, 1 H), 8.56 (q, J = 9.0 Hz, 2H), 7.65- 7.49 (m, 3H), 7.04 - 6.84 (m, 2H), 5.19-4.95 (m, 2H), 4.84-4.6 (m, 1 H), 4.55 (t, J = 6.5 Hz, 2H), 4.46 (t, J = 6.0 Hz, 2H), 4.39 - 3.86 (m, 4H), 3.71-3.35 (m, 3H), 3.13 (d, J = 6.4
Hz, 4H), 2.40 (t, J = 4.9 Hz, 4H), 2.03 - 1.68 (m, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd for C30H33FN8O4: 589.3; found:589.2. Example 219: (R)-2-((1-(2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan- 3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000233_0001
To solution of 5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2- (piperidin-4-yloxy)benzonitrile (50 mg, 0.09 mmol), (R)-2-hydroxypropanoic acid (17 mg, 0.19 mmol), HATU (74 mgs, 0.19 mmol) in DMF (3 mL) was added 4-methylmorpholine (0.021 mL, 0.19 mmol) in a 10 mL microwave vial and sealed. This reaction mixture was stirred at room temperature for 2hrs. Water was added and it was extracted with DCM. Organic layer was dried over Mg2S04 and evaporated to dryness. Solids re-dissolved in acetonitrile and purified via preparative HPLC (5-65% acetonitrile in water, 0.1 % trifluoroacteic acid buffer) to yield (R)-2-((1-(2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4- ((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. 1H NMR (400 MHz, DMSO-c 6) δ 10.18 (d, J = 21.0 Hz, 1 H), 8.74 (s, 1 H), 8.66 - 8.44 (m, 2H), 7.71 - 7.42 (m, 3H), 7.05-6.95 (m, 2H), 5.05-4.95 (m, 1 H), 4.82-4.75 (m, 4H), 4.45 (q, J = 6.5 Hz, 2H), 3.98 - 2.77 (m, 13H), 2.12-1.9 (m, 2H), 1.8-1.59 (m, 2H), 1.18 (d, J = 6.5 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C3iH36N804: 585.3; found:585.4.
Example 220: 2-((trans-3-f luoro-1 -(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000234_0001
The title compound was prepared following a similar procedure reported in Example-218 using a racemic mixture of trans-tert-butyl 3-fluoro-4-hydroxypiperidine-1- carboxylate. 1H NMR (400 MHz, DMSO-c/6) δ 10.12 (d, J = 23.5 Hz, 1 H), 8.72 (s, 1 H), 8.62 - 8.46 (m, 2H), 7.65-7.45 (m, 3H), 6.96 (d, J = 9.5 Hz, 2H), 5.18-5.05 (m, 1 H), 4.94 - 4.61 (m, 2H), 4.55 (t, J = 6.5 Hz, 2H), 4.46 (t, J = 6.0 Hz, 2H), 4.29 - 3.74 (m, 4H), 3.60-3.25 (m, 4H), 2.45 - 2.33 (m, 4H), 2.21-2.05 (m, 4H), 1.87 - 1.53 (m, 1 H). LCMS-
ESI+ (m/z): [M+H]+ calcd for C3oH33FN804: 589.3; found:589.2. Example 221 : 2-(((2S,4R)-1-(2-hydroxyacetyl)-2-methylpiperidin-4-yl)oxy)-5-(4-((4- (4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000234_0002
The title compound was prepared following a similar procedure reported in Example 218 using (2S,4R)-tert-butyl 4-hydroxy-2-methylpiperidine-1 -carboxylate. 1H NMR (400 MHz, DMSO-c/6) δ 10.10 (d, J = 26.9 Hz, 1 H), 8.72 (s, 1 H), 8.61 - 8.43 (m, 2H), 7.62- 7.51 (m, 3H), 7.00-6.91 (m, 2H), 5.19 - 4.97 (m, 1 H), 4.55 (t, J = 6.5 Hz, 2H), 4.49-4.41 (m, 3H), 4.31-3.95 (m, 3H), 3.64 (s, 1 H), 3.43 (p, J = 6.4 Hz, 1 H), 3.28-3.12 (m, 5H), 2.44-2.38 (m, 4H), 2.25-2.1 (m, 1 H), 2.08-1.99 (m, 1 H), 1.92-1.19 (m, 5H). LCMS-ESI+ (m/z): [M+H]+ calcd for C3iH36N804: 585.3; found:585.3.
Example 222: 2-(((2R,4R)-1-(2-hydroxyacetyl)-2-methylpiperidin-4-yl)oxy)-5-(4-((4- (4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000235_0001
The title compound was prepared following a similar procedure reported in Example 218 using (2R,4R)-tert-butyl 4-hydroxy-2-methylpiperidine-1-carboxylate. 1H NMR (400 MHz, DMSO-c/e) δ 10.08 (s, 1 H), 8.72 (s, 1 H), 8.62 - 8.47 (m, 2H), 7.67 - 7.35 (m, 3H), 7.03-6.84 (m, 2H), 5.18 - 5.04 (m, 1 H), 4.55 (t, J = 6.5 Hz, 2H), 4.50-4.41 (m, 3H), 4.2- 4.01 (m, 3H), 3.43 (p, J = 6.3 Hz, 1 H), 3.20 - 2.99 (m, 4H), 2.44-2.32 (m, 5H), 2.00-1.65
(m, 4H), 1.41-1.2 (m, 4H). LCMS-ESI+ (m/z): [M+H]+ calcd for C3iH36N804: 585.3; found:585.2. Example 223: 2-(((3S,4S)-3-fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000235_0002
The title compound was prepared following a similar procedure reported in Example 218 using (3S,4S)-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate. 1H NMR (400 MHz, DMSO-c/6) δ 10.12 (d, J = 23.7 Hz, 1 H), 8.73 (s, 1 H), 8.64 - 8.47 (m, 2H), 7.65-7.5 (m, 3H), 7.0-6.85 (m, 2H), 5.15-5.05 (m, 1 H), 4.83 - 4.61 (m, 2H), 4.55 (t, J = 6.5 Hz, 2H), 4.46 (t, J = 6.0 Hz, 2H), 4.25-3.98 (m, 3H), 3.92-3.75 (m, 1 H), 3.6-3.4 (m, 2H), 3.38-3.3 (m, 1 H), 3.2-3.09 (m, 4H), 2.43 - 2.30 (m, 4H), 2.2-2.05 (m, 1 H), 1.85-1.55 (m,
1 H).LCMS-ESI+ (m/z): [M+H]+ calcd for C30H33FN8O4: 589.3; found:589.2.
Example 224: 2-(((3S,4R)-3-fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4- (4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000236_0001
The title compound was prepared following a similar procedure reported in Example 218 using (3S,4R)-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate. 1H NMR (400 MHz, DMSO-c/6) δ 10.12 (d, J = 25.2 Hz, 1 H), 8.73 (s, 1 H), 8.65 - 8.45 (m, 2H), 7.78 - 7.36 (m, 3H), 7.0-6.85 (m, 2H), 5.18-4.95 (m, 2H), 4.66 (dt, J = 10.6, 5.7 Hz, 1 H), 4.55 (t, J = 6.5 Hz, 2H), 4.46 (t, J = 6.0 Hz, 2H), 4.40 - 3.86 (m, 4H), 3.67 (d, J = 13.9 Hz, 1 H), 3.60 - 3.35 (m, 2H), 3.13 (d, J = 6.4 Hz, 4H), 2.44 - 2.32 (m, 4H), 2.02 -
1.70 (m, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd for C3oH33FN804: 589.3; found:589.2.
Example 225: 5-(4-((4-((R)-2-(hydroxymethyl)morpholino)phenyl)amino)-1 ,3,5- triazin-2-yl)-2-((1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)benzonitrile
Figure imgf000237_0001
Step 1 : (R)-(4-(4-aminophenyl)morpholin-2-yl)methanol: To a stirred solution of 1-fluoro- 4-nitrobenzene (1084 mgs,7.7 mmol) in DMSO under a nitrogen atmosphere was added (R)-morpholin-2-ylmethanol (l OOOmgs, 8.5 mmol) followed by DIPEA (1.9ml, 17 mmol). The mixture was stirred at 120°C for 4 h, and then cooled to room temperature. The mixture was then poured into water and extracted with DCM. The combined organic layers were washed with brine, dried over magnesium sulfate, concentrated in vacuo to obtain (R)-(4-(4-nitrophenyl)morpholin-2-yl)methanol.
Step 2: To a stirred solution (R)-(4-(4-nitrophenyl)morpholin-2-yl)methanol (1410mgs, 5.9mmol) in ethanol was added Fe (1657mgs, 29.64 mmol) followed by a saturated aqueous solution of ammonium chloride (5ml). The mixture was stirred at 60°C for 3hrs then cooled to room temperature. The mixture was then poured into water and extracted with DCM. The combined organic layers were evaporated and concentrated in vacuo to obtain (R)-(4-(4-aminophenyl)morpholin-2-yl)methanol. Step 3: The title compound was prepared following a similar procedure reported in Example 218 using (R)-(4-(4-aminophenyl)morpholin-2-yl)methanol, tert-butyl 4- hydroxypiperidine-1-carboxylate and (S)-2-hydroxypropanoic acid. 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1 H), 8.73 (s, 1 H), 8.63 - 8.45 (m, 2H), 7.65-5.49 (m, 3H), 6.97 (d, J = 9.8 Hz, 2H), 4.99 (s, 2H), 4.44 (q, J = 6.5 Hz, 2H), 4.17 - 3.25 (m, 9H), 2.79 (d, J = 4.0 Hz, 1 H), 2.69 - 2.57 (m, 2H), 2.41 (d, J = 14.8 Hz, 1 H), 2.15-1.92 (m, 2H), 1.68 (d, J
= 36.0 Hz, 2H), 1.18 (d, J = 6.5 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C29H33FN705: 560.3; found:560.2.
Example 226: 2-((3,3-difluoropiperidin-4-yl)oxy)-5-(4-((4-((R)-2-
(hydroxymethyl)morpholino)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000238_0001
The title compound was prepared following a similar procedure reported in Example 225 using a racemic mixture of tert-butyl 3,3-difluoro-4-hydroxypiperidine-1-carboxylate. 1H NMR (400 MHz, DMSO-c/6) δ 10.22 (d, J = 25.2 Hz, 1 H), 8.76 (s, 1 H), 8.61 (d, J = 9.4 Hz, 2H), 7.63 (d, J = 9.3 Hz, 3H), 7.02 (d, J = 8.4 Hz, 2H), 5.42 (d, J = 1 1.4 Hz, 1 H), 4.00 - 3.90 (m, 2H), 3.85 - 3.71 (m, 2H), 3.70 - 3.53 (m, 2H), 3.52 - 3.38 (m, 2H), 3.34 - 3.15 (m, 2H), 2.87 (s, 1 H), 2.82 - 2.61 (m, 2H), 2.6-2.45 (m, 2H), 2.41 - 2.26 (m, 1 H),
2.17 (s, 1 H). LCMS-ESI+ (m/z): [M+H]+ calcd for C26H27F2N703: 524.3; found:524.2.
Example 227: (R)-2-((1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4-(2- (hydroxymethyl)morpholino)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000238_0002
The title compound was prepared following a similar procedure reported in Example 225 using tert-butyl 4-hydroxypiperidine-1-carboxylate and glycolic acid. 1H NMR (400 MHz, DMSO-c/6) δ 10.20 - 9.97 (m, 1 H), 8.72 (d, J = 2.9 Hz, 1 H), 8.65-8.49 (m, 2H), 7.68-7.48 (m, 3H), 7.05 - 6.80 (m, 2H), 5.74 (s, 1 H), 4.99 (d, J = 6.8 Hz, 1 H), 4.78-4.5 (m, 2H), 4.18-4.09 (m, 2H), 3.93 (d, J = 12.1 Hz, 1 H), 3.80 - 3.69 (m, 1 H), 3.66 - 3.37 (m, 8H), 2.65 (d, J = 13.2 Hz, 1 H), 2.39 (s, 1 H), 2.00 (q, J = 16.6, 1 1.9 Hz, 2H), 1.70 (d,
J = 31.9 Hz, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd for C28H3iN705: 546.24; found:546.4.
Example 228: 2-((3,3-difluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4- ((4-((R)-2-(hydroxymethyl)morpholino)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000239_0001
The title compound was prepared following a similar procedure reported in Example 225 using a racemic mixture of tert-butyl 3,3-difluoro-4-hydroxypiperidine-1-carboxylate. 1H NMR (400 MHz, DMSO-c/6) δ 10.25-10.10 (m, 1 H), 8.75 (s, 1 H), 8.68 - 8.45 (m, 2H), 7.77-7.5 (m, 3H), 6.98-6.89 (m, 2H), 5.38 (d, J = 1 1.9 Hz, 1 H), 5.22 (d, J = 6.9 Hz, 1 H), 4.76 (t, J = 5.7 Hz, 1 H), 4.48 (d, J = 6.9 Hz, 1 H), 4.17 (s, 1 H), 3.88 (dd, J = 36.2, 10.4 Hz, 3H), 3.68 - 3.35 (m, 5H), 2.66 (d, J = 1 1.9 Hz, 1 H), 2.39 (qd, J = 9.8, 8.4, 4.4 Hz,
1 H), 2.26 - 1.67 (m, 2H), 1.20 (d, J = 6.5 Hz, 3H), 0.98 - 0.84 (m, 2H). LCMS-ESI+
(m/z): [M+H]+ calcd for C29H3i F2N705: 596.2; found:596.4 Example 229: 2-(((3R,4S)-3-fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4- ((R)-2-(hydroxymethyl)morpholino)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000239_0002
The title compound was prepared following a similar procedure reported in Example 225 using (3R,4S)-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate and 2- hydroxyacetic acid.1H NMR (400 MHz, DMSO-c/6) δ 10.14 (s, 1 H), 8.73 (s, 1 H), 8.56 (q, J = 8.4, 7.8 Hz, 2H), 7.60 (dd, J = 19.8, 1 1.2 Hz, 3H), 6.95 (t, J = 10.5 Hz, 2H), 5.25 - 4.91 (m, 2H), 4.74 (s, 2H), 4.40 - 4.29 (m, 1 H), 4.21 - 3.83 (m, 5H), 3.76 - 3.03 (m,
7H), 2.64 (t, J = 1 1.4 Hz, 1 H), 2.39 (t, J = 10.9 Hz, 1 H), 2.07 - 1.68 (m, 2H). LCMS-ESI+
(m/z): [M+H]+ calcd for C28H3oFN705: 564.2; found:563.5 Example 230: 2-(((S)-1-acetyl-3,3-difluoropiperidin-4-yl)oxy)-5-(4-((4-((R)-2- (hydroxymethyl)morpholino)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000240_0001
The title compound was prepared following a similar procedure reported in Example 225 using (S)-tert-butyl 3,3-difluoro-4-hydroxypiperidine-1-carboxylate and acetic acid. 1H NMR (400 MHz, DMSO-c/6) δ 10.14 (s, 1 H), 8.73 (s, 1 H), 8.56 (q, J = 8.4, 7.8 Hz, 2H), 7.60 (dd, J = 19.8, 1 1.2 Hz, 3H), 6.95 (t, J = 10.5 Hz, 2H), 5.25 - 4.91 (m, 2H), 4.82-4.69 (m, 2H), 4.40 - 4.29 (m, 1 H), 4.21 - 3.83 (m, 5H), 3.76 - 3.03 (m, 6H), 2.64 (t,
J = 1 1.4 Hz, 1 H), 2.39 (t, J = 10.9 Hz, 1 H), 2.07 - 1.68 (m, 2H). LCMS-ESI+ (m/z):
[M+H]+ calcd for C28H29F2N704: 566.2; found:565.5
Example 231 : 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-
(4-((4-((R)-2-(hydroxymethyl)morpholino)phenyl)amino)-1,3,5-triazin-2- yl)benzonitrile
Figure imgf000240_0002
The title compound was prepared following a similar procedure reported in Example 225 using (3R,4S)-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate. 1H NMR (400 MHz, DMSO-c/6) δ 10.13 (d, J = 24.8 Hz, 1 H), 8.74 (d, J = 4.7 Hz, 1 H), 8.64 - 8.46 (m, 2H), 7.60 (dd, J = 17.3, 10.6 Hz, 3H), 6.95 (t, J = 10.6 Hz, 2H), 5.25 - 4.89 (m, 2H), 4.55 - 4.30 (m, 2H), 4.24 - 4.02 (m, 1 H), 3.98 - 3.84 (m, 2H), 3.76 - 3.25 (m, 6H), 3.14 (s, 1 H), 2.71 - 2.58 (m, 1 H), 2.39 (t, J = 11.4 Hz, 1 H), 2.05 - 1.68 (m, 2H), 1.48 - 1.38 (m,
1 H), 1.26 (d, J = 6.9 Hz, 1 H), 1.19 (dd, J = 6.5, 4.1 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C29H32FN7O5: 578.2; found:577.5. Example 232: 2-(((3R,4S)-3-fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4- ((S)-2-(hydroxymethyl)morpholino)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000241_0001
The title compound was prepared following a similar procedure reported in Example 225 using (S)-morpholin-2-ylmethanol, (3R,4S)-tert-butyl 3-fluoro-4-hydroxypiperidine-1- carboxylate and 2-hydroxyacetic acid. 1H NMR (400 MHz, DMSO-c 6) δ 10.14 (s, 1 H), 8.73 (s, 1 H), 8.56 (q, J = 8.3, 7.0 Hz, 2H), 7.71 - 7.44 (m, 3H), 6.95 (t, J = 10.4 Hz, 2H), 5.25 - 4.93 (m, 2H), 4.78 (d, J = 16.7 Hz, 2H), 4.33 (d, J = 14.0 Hz, 1 H), 4.22 - 4.00 (m, 3H), 3.99 - 3.84 (m, 2H), 3.75 - 3.03 (m, 7H), 2.64 (t, J = 12.1 Hz, 1 H), 2.44 - 2.30 (m, 1 H), 2.04 - 1.71 (m, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd for C28H3oFN705: 564.2; found:563.5
Example 233: 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-
(4-((4-((S)-2-(hydroxymethyl)morpholino)phenyl)amino)-1,3,5-triazin-2- yl)benzonitrile
Figure imgf000241_0002
The title compound was prepared following a similar procedure reported in Example 225 using (S)-morpholin-2-ylmethanol and (3R,4S)-tert-butyl 3-fluoro-4- hydroxypiperidine-1-carboxylate. 1H NMR (400 MHz, DMSO-c/6) δ 10.13 (d, J = 24.5 Hz, 1 H), 8.73 (s, 1 H), 8.57 (d, J = 10.4 Hz, 2H), 7.60 (dd, J = 20.2, 1 1.7 Hz, 3H), 7.20-6.89 (m, 2H), 5.23 - 4.87 (m, 3H), 4.76 (t, J = 5.7 Hz, 1 H), 4.46 (dt, J = 13.8, 6.8 Hz, 2H), 4.23 - 3.82 (m, 3H), 3.70 - 3.05 (m, 7H), 2.64 (s, 1 H), 2.40 (d, J = 1 1.9 Hz, 1 H), 1.90 (d,
J = 59.1 Hz, 2H), 1.24 - 1.15 (m, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C29H32FN705: 578.2; found:577.5
Example 234: 2-(((3R,4R)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5- (4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000242_0001
The title compound was prepared following a similar procedure reported in Example 218 using (3R,4R)-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate and (S)-2- hydroxypropanoic acid. 1H NMR (400 MHz, DMSO-c 6) δ 10.17 (s, 1 H), 8.74 (s, 1 H), 8.63 - 8.41 (m, 2H), 7.65-7.48 (m, 3H), 7.08-6.9 (m, 2H), 5.20-5.10 (m, 2H), 4.92 - 4.34 (m, 7H), 4.21 - 3.95 (m, 1 H), 3.87 (s, 1 H), 3.66 - 3.38 (m, 2H), 3.22-3.09 (m, 4H), 2.52- 2.35 (m, 4H), 2.13 (d, J = 14.0 Hz, 1 H), 1.8-1.55 (m, 1 H), 1.19 (d, J = 6.5 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C3iH35FN804: 603.3; found:603.4. Example 235: 2-(((3R,4R)-3-fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4- (4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000242_0002
The title compound was prepared following a similar procedure reported in Example 218 using (3R,4R)-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate. 1H NMR (400 MHz, DMSO-c/6) δ 10.21 (d, J = 12.3 Hz, 1 H), 8.81 (s, 1 H), 8.68-8.58 (m, 2H), 7.81 - 7.51 (m, 3H), 7.08-6.98 (m, 2H), 5.25-5.12 (m, 1 H), 5.08-4.7 (m, 2H), 4.64 (t, J = 6.5 Hz, 2H), 4.54 (t, J = 6.0 Hz, 2H), 4.36 - 4.06 (m, 3H), 4.05-3.85 (m, 1 H), 3.71 - 3.46 (m, 3H), 3.22 (d, J = 6.5 Hz, 4H), 2.48 (t, J = 4.9 Hz, 4H), 2.25-2.15 (m, 1 H), 1.95-1.65 (m, 1 H). LCMS-ESI+ (m/z): [M+H]+ calcd for C3oH33FN804: 589.3; found:589.4.
Example 236: 2-(((3R,4R)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3- l)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000243_0001
A solution of a racemic mixture of (3R,4R)-tert-butyl 3-fluoro-4-hydroxypiperidine-1- carboxylate (76 mgs, 0.35 mmol) in THF (5 mL) was stirred in an ice-water bath under an atmosphere of Argon. Potassium tert-butoxide (1.0 M, 0.35 ml, 0.35mmol) was added in a single portion and the mixture was stirred at 0 °C for 40 minutes, and then 2- fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile was added (l OOmgs, 0.23mmol). The mixture was stirred for 1 hr at 60 °C. After the mixture cooled to room temperature, water was added, and mixture evaporated under reduced pressure to yield the crude (3R,4R)-tert-butyl 4-(2-cyano-4-(4-((4-(4-(oxetan-3- yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-1 - carboxylate.
Solids were dissolved with DCM and TFA. Reaction mixture was stirred at room temperature for 1 hr. Reaction mixture was evaporated under reduced pressure and solids were re-dissolved in DCM and a saturated aqueous solution of NaHC03 was added. Organics were collected and evaporated under reduced pressure. Solids were purified via preparative HPLC (5-65% acetonitrile in water, 0.1 % trifluoroacteic acid buffer). Fractions containing desired product were collected and DCM and a saturated aqueous solution of NaHC03 were added. Organics were collected dried over magnesium sulfate and evaporated under reduced pressure to yield 2-(((3R,4R)-3- fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)benzonitrile. 1H NMR (400 MHz, DMSO-c/6) δ 10.2 (s, 1 H), 8.72 (s, 1 H), 8.54 (q, J = 9.3 Hz, 2H), 7.65-8.45 (m, 3H), 6.97 (d, J = 10.7 Hz, 2H), 4.92-4.82 (m, 1 H), 4.65-4.42 (m, 5H), 3.43 (p, J = 6.3 Hz, 1 H), 3.26 - 3.18 (m, 1 H), 3.18-3.06 (m, 4H), 2.65-2.54 (m, 3H), 2.48-2.35 (m, 4H), 2.34 - 2.24 (m, 1 H), 2.13 (d, J = 12.2 Hz, 1 H), 1.55-1.43 (m, 1 H). LCMS-ESI+ (m/z): [M+H]+ calcd for C28H31 FN8O2: 531.3; found:531.4.
Example 237: 2-(((3R,4S)-3-fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4- )phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000244_0001
The title compound was prepared following a similar procedure reported in Example 218 using (3R,4S)-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate. 1H NMR (400 MHz, DMSO-c/6) δ 10.13 (s, 1 H), 8.72 (s, 1 H), 8.6-8.5 (m, 2H), 7.7-7.50 (m, 3H), 6.98- 6.8 (m, 2H), 5.22 - 4.93 (m, 2H), 4.68 (s, 1 H), 4.55 (t, J = 6.5 Hz, 2H), 4.46 (t, J = 6.0 Hz, 2H), 4.39 - 3.84 (m, 4H), 3.74 - 3.21 (m, 3H), 3.12 (d, J = 7.0 Hz, 4H), 2.44 - 2.34
(m, 4H), 2.06 - 1.73 (m, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd for C3oH33FN804: 589.3; found:589.4.
Example 238: 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5- n-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000244_0002
A solution of (3R,4S)-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (PharmaBlock) (400 mgs, 0.93 mmol) in 2-methyl-tetrahydrofuran (5 mL) was stirred in an ice-water bath under an atmosphere of Argon. Potassium tert-butoxide (1.0 M, 1.9 ml, 1.9mmol) was added in a single portion and the mixture was stirred at 0 °C for 40 minutes, and then 2-fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)benzonitrile was added (406mgs, 1.9 mmol). The mixture was stirred at 60 °C for one hour. After the mixture cooled to room temperature, water was added, and mixture evaporated under reduced pressure to yield the crude (3R,4S)-tert-butyl 4-(2- cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenoxy)- 3-fluoropiperidine-1-carboxylate.
(3R,4S)-tert-butyl 4-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-1-carboxylate was dissolved with a 1 :1 mixture of DCM and TFA (6 mL). Reaction mixture was stirred at room temperature for 30 min and then evaporated under reduced pressure. Solids were suspended in a saturated aqueous solution of NaHC03 and extracted with DCM. Organic phase was dried over magnesium sulfate and evaporated under reduced pressure to yield 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile.
To solution of 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (100 mgs, 0.19 mmol), (S)-2-hydroxypropanoic acid (34 mgs, 0.38 mmol), HATU (144 mgs, 0.38 mmol) in DMF (3 mL) was added triethylamine (0.043 mL, 0.38 mmol) in a 10 mL microwave vial and sealed. This reaction mixture was stirred at room temperature for 2 hrs. Water was added and it was extracted with dichloromethane. Organic layer was dried over Mg2S04 and evaporated to dryness. Solids re-dissolved in acetonitrile and purified via preparative HPLC (5-65% acetonitrile in water, 0.1 % trifluoroacteic acid buffer) to yield 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. 1H NMR (400 MHz, DMSO-c 6) δ 10.13 (d, J = 7.5 Hz, 1 H), 8.73 (s, 1 H), 8.63 - 8.44 (m, 2H), 7.65-7.44 (m, 3H), 7.0-6.88 (m, 2H), 5.22 - 4.94 (m, 3H), 4.55 (t, J = 6.5 Hz, 2H), 4.48-4.30 (m, 3H), 4.23 - 3.88 (m, 2H), 3.72 - 3.51 (m, 1 H), 3.49 - 3.33 (m, 2H), 3.13 (dd, J = 10.3, 5.4 Hz, 4H), 2.39 (t, J = 5.0 Hz, 4H), 2.06 - 1.70 (m, 2H), 1.19 (dd, J = 6.5, 4.3 Hz, 3H). LCMS- ESI+ (m/z): [M+H]+ calcd for C3iH35FN804: 603.3; found:603.2
Example 239: 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000246_0001
The title compound was prepared following a similar procedure reported in Example 236 using (3R,4S)-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate. 1H NMR (400 MHz, DMSO-c/6) δ 10.19 (d, J = 19.4 Hz, 1 H), 8.80 (s, 1 H), 8.69-8.55 (m, 2H), 7.74 - 7.56 (m, 3H), 7.08-6.95 (m, 2H), 5.18 - 5.02 (m, 1 H), 4.98-4.82 (m, 1 H), 4.64 (t, J = 6.5 Hz, 2H), 4.54 (t, J = 6.1 Hz, 2H), 3.52 (p, J = 6.3 Hz, 1 H), 3.24-3.18 (m, 4H), 2.98-2.82 (m, 3H), 2.73-2.61 (m, 1 H), 2.48 (t, J = 4.9 Hz, 4H), 2.22 - 2.07 (m, 1 H), 2.00-1.87 (d, J
= 6.6 Hz, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd for C28H3i FN802: 531.3; found:531.4
Example 240: 2-(((3R,4S)-3-fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((3- zin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000246_0002
The title compound was prepared following a similar procedure reported in Example 218 using 2-fluoro-5-(4-((3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)benzonitrile, (3R,4S)-tert-butyl 3-fluoro-4-hydroxypiperidine-1 -carboxylate and glycolic acid. 1H NMR (400 MHz, DMSO-c/6) δ 10.36 (s, 1 H), 8.79 (s, 1 H), 8.66 - 8.43 (m, 2H), 7.73 - 7.57 (m, 2H), 7.41 (s, 1 H), 7.04 (t, J = 9.3 Hz, 1 H), 5.19-4.92 (m, 2H), 4.89-4.6 (m, 1 H), 4.55 (t, J = 6.5 Hz, 2H), 4.45 (t, J = 6.1 Hz, 2H), 4.40 - 3.81 (m, 3H), 3.77 - 3.60 (m, 1 H), 3.54-3.34 (m, 2H), 3.00 (d, J = 4.9 Hz, 4H), 2.41 (t, J = 4.8 Hz,
4H), 2.03 - 1.70 (m, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C30H32F2N8O4: 607.3; found:607.2 Example 241 : 2-(((3R,4S)-3-fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4-
((S)-3-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile
Figure imgf000247_0001
To a stirred solution of 1-fluoro-4-nitrobenzene (634mg, 4.5 mmol) in DMSO was added (S)-tert-butyl 2-methylpiperazine-1-carboxylate (1000 mg, 5 mmol) followed by DIPEA (1.2ml_, 10 mmol). The mixture was heated at 160 °C for 4 hrs, and then cooled to room temperature. The mixture was then poured into water and extracted with DCM. The combined organic layers were concentrated in vacuo to obtain (S)-tert-butyl 2-methyl-4- (4-nitrophenyl)piperazine-1-carboxylate.
(S)-tert-butyl 2-methyl-4-(4-nitrophenyl)piperazine-1-carboxylate was dissolved with a mixture of DCM and TFA and stirred at room temperature for 1 hr. Reaction mixture was evaporated under reduced pressure and solids were re-dissolved in DCM and then poured slowly into a stirred saturated aqueous solution of NaHC03 and extracted three times with DCM. The organic layer was evaporated and concentrated in vacuo to obtain (S)-3-methyl-1-(4-nitrophenyl)piperazine.
To a mixture of (S)-3-methyl-1-(4-nitrophenyl)piperazine (620mg, 3 mmol), zinc chloride (495mg, 4 mmol), oxetan-3-one (2.0 g, 28mmol) in methanol was added NaBH3CN (434mg, 7mmol). The mixture was stirred at 75 °C for 2 hours. Reaction mixture was diluted with 1 N HCI in water. It was extracted with dichloromethane three times and the combined organic layer was discharged. To aqueous layer a saturated aqueous solution of NaHC03 was added in portions. It was extracted with DCM three times and the combined organic layer was evaporated under reduced pressure to obtain (S)-2-methyl- 4-(4-nitrophenyl)-1-(oxetan-3-yl)piperazine.
To a stirred solution of (S)-2-methyl-4-(4-nitrophenyl)-1-(oxetan-3-yl)piperazine (610mg, 2.2 mmol) in ethanol was added Fe (615mg, 1 1 mmol) followed by an saturated aqueous solution of ammonium chloride (3.1 ml). The mixture was stirred at 60°C for 3hrs then cooled to room temperature and filtered thought celite. The filtrate was poured into a saturated aqueous solution of NaHC03 and extracted with DCM three times. The combined organic layers were evaporated and concentrated in vacuo to obtain (S)-4-(3- methyl-4-(oxetan-3-yl)piperazin-1-yl)aniline. To a solution of 2,4-dichloro-1 ,3,5-triazine (109mg, 0.7mmol) in DMF at 0 °C (flushed with Argon) was added a solution of (S)-4-(3-methyl-4-(oxetan-3-yl)piperazin-1-yl)aniline (200mg, 0.8mmol) in DMF over 15 min and stirred in an ice-bath for 1 h.
Reaction mixture was poured into a saturated aqueous solution of NaHC03 and extracted with DCM three times. The combined organic layers were evaporated and concentrated in vacuo to obtain (S)-4-chloro-N-(4-(3-methyl-4-(oxetan-3-yl)piperazin-1- yl)phenyl)-1 ,3,5-triazin-2-amine.
To (S)-4-chloro-N-(4-(3-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1 ,3,5-triazin-2- amine (120mg, 0.33mmol), 2-fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzonitrile (90mg, 0.36mmol), Pd(dppf)CI2CH2CI2 (30mg) and potassium carbonate (92mgs, 0.67mmol) mixture in argon atmosphere was added a mixture of de-gassed solvents (DME and water 2:1 ). The mixture was stirred under argon atmosphere at 104 °C for 40min.After cooling at room temperature; reaction mixture was poured into water and extracted with DCM. The combined organic layers were evaporated and concentrated in vacuo to obtain (S)-2-fluoro-5-(4-((4-(3-methyl-4-(oxetan-3-yl)piperazin- 1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile.
A solution of a (3R,4S)-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (81 mg, 0.3 mmol) in THF (5 ml_) was stirred in an ice-water bath under an atmosphere of Argon. Potassium tert-butoxide (1.0 M, 0.37 ml, 0.38mmol) was added in a single portion and the mixture was stirred at 0 °C for 40 minutes, and then (S)-2-fluoro-5-(4- ((4-(3-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile was added (83mgs, 0.19mmol). The mixture was stirred for 1 hr at 60 °C. After the mixture cooled to room temperature, water was added, and mixture evaporated under reduced pressure to yield the crude (3R,4S)-tert-butyl 4-(2-cyano-4-(4-((4-((S)-3-methyl- 4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenoxy)-3- fluoropiperidine-1 -carboxylate.
(3R,4S)-tert-butyl-4-(2-cyano-4-(4-((4-((S)-3-methyl-4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 , 3, 5-triazin-2-yl)phenoxy)-3-fluoropiperidine-1 -carboxylate was dissolved with DCM and TFA. Reaction mixture was stirred at room temperature for 1 hr. Reaction mixture was evaporated under reduced pressure and solids were re-dissolved in DCM and a saturated aqueous solution of NaHC03 was added. Organics were collected dried over magnesium sulfate and evaporated under reduced pressure to yield 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-((S)-3-methyl-4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile.
To a solution of 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-((S)-3-methyl-4-(oxetan- 3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (75 mg, 0.013 mmol), glycolic acid (10 mg, 0.026 mmol), HATU (105 mgs, 0.027 mmol) in DMF (3 mL) was added TEA (56mg, 0.05 mmol) in a 10 mL microwave vial and sealed. This reaction mixture was stirred at room temperature for 2hrs. DCM and water were added to this crude reaction mixture. Organic layer was extracted and evaporated to dryness. Solids were purified via preparative HPLC (5-65% acetonitrile in water, 0.1 % trifluoroacteic acid buffer). Fractions containing desired product were collected and DCM and a saturated aqueous solution of NaHC03 were added. Organics were collected dried over magnesium sulfate and evaporated under reduced pressure to yield 2-(((3R,4S)-3- fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4-((S)-3-methyl-4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. 1H NMR (400 MHz, DMSO-c/6) 5 10.1 1 (d, J = 25.9 Hz, 1 H), 8.72 (s, 1 H), 8.64 - 8.45 (m, 2H), 7.62-7.45 (m, 3H), 7.00-6.85 (m, 2H), 5.17 - 4.93 (m, 2H), 4.66 (dt, J = 10.5, 5.6 Hz, 1 H), 4.55 (td, J = 6.4, 3.3 Hz, 2H), 4.49 (q, J = 6.3 Hz, 2H), 4.4-4.3.9 (m, 3H), 3.71-3.65 (m, 2H), 3.42 - 3.2 (m, 2H), 3.2-3.12 (m, 1 H), 2.82 (t, J = 10.7 Hz, 1 H), 2.69 (dd, J = 1 1.5, 3.9 Hz, 1 H), 2.60 - 2.49 (m, 2H), 2.42-2.35 (m, 1 H), 2.19 - 2.07 (m, 1 H), 2.04 - 1.72 (m, 2H), 0.89 (d, J = 6.3 Hz, 3H).
LCMS-ESI+ (m/z): [M+H]+ calcd for C3iH35FN804: 603.3; found:603.4.
Example 242: 2-(((3R,4S)-3-fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4- ((R)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-
Figure imgf000249_0001
The title compound was prepared following a similar procedure reported in Example 241 using (R)-tert-butyl 3-methylpiperazine-1-carboxylate. 1H NMR (400 MHz, DMSO- d6) δ 10.1 1 (d, J = 24.3 Hz, 1 H), 8.72 (s, 1 H), 8.66 - 8.39 (m, 2H), 7.68-7.42 (m, 3H), 6.99-6.83 (m, 2H), 5.19-4.82 (m, 2H), 4.66 (dt, J = 10.6, 5.7 Hz, 1 H), 4.55 (tt, J = 6.7, 3.3 Hz, 2H), 4.47 (t, J = 6.0 Hz, 2H), 4.41 (t, J = 6.0 Hz, 2H), 4.42-4.02 (m, 3H), 4.02 - 3.85 (m, 1 H), 3.73 - 3.59 (m, 1 H), 3.43 - 3.1 (m, 3H), 3.12-2.92 (m, 1 H), 2.72-2.65 (m, 1 H), 2.24 (dd, J = 10.8, 3.4 Hz, 1 H), 2.07 (td, J = 10.7, 3.4 Hz, 1 H), 2.01 - 1.73 (m, 2H),
1.02 (s, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C3iH35FN804: 603.2; found:603.4
Example 243: 2-(((3R,4S)-3-fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4-
((R)-3-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile
Figure imgf000250_0001
The title compound was prepared following a similar procedure reported in Example 241 using (R)-tert-butyl 2-methylpiperazine-1-carboxylate. 1H NMR (400 MHz, DMSO- d6) 6 10.1 1 (d, J = 23.9 Hz, 1 H), 8.73 (s, 1 H), 8.63 - 8.46 (m, 2H), 7.58 (dd, J = 30.4, 11.9 Hz, 3H), 6.95 (d, J = 10.0 Hz, 2H), 5.3-4.95 (m, 2H), 4.75-4.6 (m, 1 H), 4.55 (td, J = 6.5, 3.2 Hz, 2H), 4.52 - 4.43 (m, 2H), 4.40 - 3.9 (m, 3H), 3.66-3.21 (m, 6H), 2.81 (t, J = 10.5 Hz, 1 H), 2.69 (dd, J = 11.5, 3.9 Hz, 1 H), 2.59 - 2.50 (m, 1 H), 2.42-2.33 (m, 1 H), 2.13 (td, J = 1 1.0, 9.9, 3.0 Hz, 1 H), 2.02 - 1.73 (m, 2H), 0.89 (d, J = 6.3 Hz, 3H). LCMS- ESI+ (m/z): [M+H]+ calcd for C3iH35FN804: 603.2; found:603.2
Example 244: 2-(((3R,4S)-3-fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4-
((S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile
Figure imgf000251_0001
The title compound was prepared following a similar procedure reported in Example 241 using (S)-tert-butyl 3-methylpiperazine-1-carboxylate. 1H NMR (400 MHz, DMSO- c 6) 5 10.1 1 (d, J = 23.5 Hz, 1 H), 8.73 (s, 1 H), 8.67 - 8.60-8.45 (m, 2H), 7.64-4.48 (m, 3H), 6.92 (m, 2H), 5.19 - 4.95 (m, 2H), 4.7-4.6 (m, 1 H), 4.58-4.51 (m, 2H), 4.47 (t, J = 6.1 Hz, 2H), 4.41 (t, J = 6.0 Hz, 2H), 4.21-3.35 (m, 8H), 3.05-2.9 (m, 1 H), 2.75-2.62 (m, 1 H), 2.24 (dd, J = 10.9, 3.4 Hz, 1 H), 2.07 (td, J = 10.6, 3.3 Hz, 1 H), 1.90-1.78 (m, 2H),
1.22 (s, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C3i H35FN804: 603.2; found:603.2
Example 245: 2-(((R)-3,3-difluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5- (4-((4-((R)-3-methyl-4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-
Figure imgf000251_0002
The title compound was prepared following a similar procedure reported in Example 241 using (R)-tert-butyl 2-methylpiperazine-1-carboxylate, (R)-tert-butyl 3,3-difluoro-4- hydroxypiperidine-1-carboxylate and (S)-2-hydroxypropanoic acid. 1H NMR (400 MHz, DMSO-c/e) δ 10.19 (d, J = 23.4 Hz, 1 H), 8.76 (s, 1 H), 8.67 - 8.45 (m, 2H), 7.71 - 7.47 (m, 3H), 7.14 - 6.76 (m, 2H), 5.42-5.35 (m, 1 H), 4.98 - 4.37 (m, 6H), 4.31 - 2.55 (m,
12H), 2.22-1.8 (m, 2H), 1.3-1.02 (m, 6H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H36F2N8O4: 635.3; found:635.3
Example 246: 2-(((S)-3,3-difluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5- (4-((4-((R)-3-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2- yl)benzonitrile
Figure imgf000252_0001
The title compound was prepared following a similar procedure reported in Example 241 using (R)-tert-butyl 2-methylpiperazine-1-carboxylate, (S)-tert-butyl 3,3-difluoro-4- hydroxypiperidine-1-carboxylate and (S)-2-hydroxypropanoic acid. 1H NMR (400 MHz, DMSO-c 6) δ 10.17 (d, J = 22.9 Hz, 1 H), 8.75 (s, 1 H), 8.66 - 8.44 (m, 2H), 7.75 - 7.48 (m, 3H), 7.14 - 6.77 (m, 2H), 5.49 - 5.02 (m, 2H), 4.98 - 4.34 (m, 7H), 4.25-4.15 (m, 1 H), 4.06 - 3.39 (m, 6H), 3.05-2.58 (m, 3H), 2.20 - 1.69 (m, 2H), 1.32-0.8 (m, 6H).
LCMS-ESI+ (m/z): [M+H]+ calcd for C32H36F2N804: 635.3; found:635.3
Example 247: 2-(((R)-3,3-difluoro-1-((R)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-
(4-((4-((R)-3-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2- yl)benzonitrile
Figure imgf000252_0002
The title compound was prepared following a similar procedure reported in Example 241 using (R)-tert-butyl 2-methylpiperazine-1-carboxylate, (R)-tert-butyl 3,3-difluoro-4- hydroxypiperidine-1-carboxylate and (R)-2-hydroxypropanoic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H36F2N8O4: 635.3; found:635.3 Example 248: 2-(((S)-3,3-difluoro-1-((R)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-
(4-((4-((R)-3-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2- yl)benzonitrile
Figure imgf000253_0001
The title compound was prepared following a similar procedure reported in Example 241 using (R)-tert-butyl 2-methylpiperazine-1-carboxylate, (S)-tert-butyl 3,3-difluoro-4- hydroxypiperidine-1-carboxylate and (R)-2-hydroxypropanoic acid. 1H NMR (400 MHz, DMSO-c 6) δ 10.17 (d, J = 22.9 Hz, 1 H), 8.75 (s, 1 H), 8.66 - 8.44 (m, 2H), 7.75 - 7.48 (m, 3H), 7.14 - 6.77 (m, 2H), 5.49 - 5.02 (m, 2H), 4.98 - 4.34 (m, 7H), 4.25-4.15 (m, 1 H), 4.06 - 3.39 (m, 6H), 3.05-2.58 (m, 3H), 2.20 - 1.69 (m, 2H), 1.32-0.8 (m, 6H).
LCMS-ESI+ (m/z): [M+H]+ calcd for C32H36F2N804: 635.3; found:635.3LCMS-ESI+
(m/z): [M+H]+ calcd for C32H36F2N804: 635.3; found:635.3
Example 249: 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-
(4-((4-((S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-
Figure imgf000253_0002
The title compound was prepared following a similar procedure reported in Example 241 using (3R,4S)-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate and (S)-2- hydroxypropanoic acid. 1H NMR (400 MHz, DMSO-c/6) δ 10.11 (d, J = 22.9 Hz, 1 H), 8.73 (s, 1 H), 8.65 - 8.46 (m, 2H), 7.75-7.49 (m, 3H), 6.75-6.85 (m, 2H), 5.21 - 4.91 (m, 3H), 4.56 (td, J = 6.5, 3.0 Hz, 2H), 4.48-4.38 (m, 4H), 4.21 - 4.00 (m, 1 H), 3.99-3.84 (m, 1 H), 3.45 - 3.33 (m, 1 H), 3.30-3.1 1 (m, 4H), 2.98 (d, J = 12.2 Hz, 1 H), 2.68 (d, J = 10.4 Hz, 1 H), 2.24 (dd, J = 10.8, 3.4 Hz, 1 H), 2.07 (td, J = 10.5, 3.3 Hz, 1 H), 1.95-1.78 (m, 2H),
1.2 (s, 3H), 1.00 (s, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H37FN804: 617.3; found:617.4
Example 250: 2-(((3R,4S)-1-(2-cyanoacetyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-((S)- zin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000254_0001
The title compound was prepared following a similar procedure reported in Example 241 using (3R,4S)-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate and 2- cyanoacetic acid. 1H NMR (400 MHz, DMSO-c/6) δ 10.1 1 (d, J = 23.8 Hz, 1 H), 8.73 (s, 1 H), 8.64 - 8.47 (m, 2H), 7.70 - 7.44 (m, 3H), 6.95-6.87 (m, 2H), 5.2-4.92 (m, 2H), 4.56 (td, J = 6.5, 3.0 Hz, 2H), 4.47 (t, J = 6.0 Hz, 1 H), 4.41 (t, J = 6.0 Hz, 1 H), 4.27 - 4.03 (m, 1 H), 3.94-3.82 (m, 2H), 3.72-3.5 (m, 3H), 3.4-3.32 (m, 1 H), 3.35-3.15 (m,3H), 3.1-2.92 (m, 1 H), 2.72-2.65 (m, 1 H), 2.24 dd, J = 10.7, 3.3 Hz, 1 H), 2.10 - 1.92 (m, 3H), 1.00 (s,
3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H34FN903: 612.3; found:612.3
Example 251 : 2-(((3R,4S)-3-f luoro-1 -(3-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-
((4-((S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2- yl)benzonitrile
Figure imgf000254_0002
The title compound was prepared following a similar procedure reported in Example 241 using (3R,4S)-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate and 3- hydroxypropanoic acid. 1H NMR (400 MHz, DMSO-c/6) δ 10.08 (s, 1 H), 8.73 (s, 1 H),
8.56 (d, J = 1 1.2 Hz, 2H), 7.74 - 7.38 (m, 3H), 6.97-6.85 (m, 2H), 5.18-4.9 (m, 2H), 4.60 - 4.44 (m, 4H), 4.41 (t, J = 6.0 Hz, 1 H), 4.35-4.02 (m, 2H), 3.98 - 3.74 (m, 2H), 3.69 -
3.57 (m, 2H), 3.38 (h, J = 5.6, 5.2 Hz, 2H), 3.32-3.15 (m, 2H), 3.1-2.92 (m, 2H), 2.75- 2.65 (m, 1 H), 2.61 - 2.52 (m, 1 H), 2.24 (dd, J = 10.8, 3.5 Hz, 1 H), 2.12 - 2.02 (m, 1 H),
1.99-1.9 (m, 2H), 1.00 (s, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H37FN804: 617.3; found:617.3 Example 252: 2-(((S)-3,3-difluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5- (4-((4-((S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-
Figure imgf000255_0001
The title compound was prepared following a similar procedure reported in Example 241 using (S)-tert-butyl 3,3-difluoro-4-hydroxypiperidine-1-carboxylate and (S)-2- hydroxypropanoic acid. 1H NMR (400 MHz, DMSO-c/6) δ 10.13 (d, J = 22.4 Hz, 1 H), 8.74 (s, 1 H), 8.65 - 8.51 (m, 2H), 7.66 (d, J = 9.2 Hz, 1 H), 7.65-7.51 (m, 2H), 7.01-6.85 (m, 2H), 5.45-5.32 (m, 1 H), 5.21 (d, J = 6.9 Hz, 1 H), 4.56 (td, J = 6.5, 3.0 Hz, 2H), 4.48 (q, J = 5.7 Hz, 2H), 4.41 (t, J = 6.0 Hz, 1 H), 4.25-4.06 (m, 1 H), 4.05 - 3.69 (m, 3H), 3.64-3.16 (m, 3H), 3.09-2.91 (m, 1 H), 2.67 (s, 1 H), 2.26 - 1.73 (m, 5H), 1.20 (d, J = 9.0 Hz, 3H),
1.00 (s, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H36F2N804: 635.3; found:635.2
Example 253: 2-(((S)-1-(2-cyanoacetyl)-3,3-difluoropiperidin-4-yl)oxy)-5-(4-((4-((S)- 2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000256_0001
The title compound was prepared following a similar procedure reported in Example 241 using (S)-tert-butyl 3,3-difluoro-4-hydroxypiperidine-1-carboxylate and 2- cyanoacetic acid. 1H NMR (400 MHz, DMSO-c/6) δ 10.13 (d, J = 23.8 Hz, 1 H), 8.74 (s, 1 H), 8.65 - 8.45 (m, 2H), 7.65 (d, J = 9.2 Hz, 1 H), 7.69-7.49 (m, 2H), 6.92 (s, 2H), 5.44- 5.32 (m, 1 H), 4.56 (td, J = 6.5, 3.0 Hz, 2H), 4.47 (t, J = 6.0 Hz, 1 H), 4.41 (t, J = 6.0 Hz, 1 H), 4.21 (s, 1 H), 4.16 - 3.72 (m, 2H), 3.65 - 3.36 (m, 2H), 3.25 - 3.07 (m, 2H), 2.97 (s,
1 H), 2.67 (s, 1 H), 2.29 - 1.96 (m, 4H), 1.22 (s, 3H), 1.09 - 0.93 (m, 3H). LCMS-ESI+
(m/z): [M+H]+ calcd for C32H33F2N903: 630.3; found:630.3 Example 254: 2-(((S)-3,3-difluoro-1 -(3-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4- ((4-((S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2- yl)benzonitrile
Figure imgf000256_0002
The title compound was prepared following a similar procedure reported in Example 241 using (S)-tert-butyl 3,3-difluoro-4-hydroxypiperidine-1-carboxylate and 3- hydroxypropanoic acid. 1H NMR (400 MHz, DMSO-c/6) δ 10.10 (s, 1 H), 8.74 (s, 1 H), 8.65 - 8.47 (m, 2H), 7.71 - 7.62 (m, 1 H), 7.56 (d, J = 15.1 Hz, 2H), 6.91 (d, J = 10.2 Hz, 2H), 5.35 (s, 1 H), 4.56 (td, J = 6.5, 2.9 Hz, 3H), 4.47 (t, J = 6.0 Hz, 1 H), 4.41 (t, J = 6.0 Hz, 1 H), 4.18 - 3.99 (m, 1 H), 3.95-3.68 (m, 2H), 3.64 (q, J = 6.2 Hz, 3H), 3.39 (p, J = 6.3 Hz, 1 H), 3.25 - 2.64 (m, 4H), 2.56 (dt, J = 10.7, 6.3 Hz, 2H), 2.25 - 1.64 (m, 5H), 1.00 (s, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H36F2N804: 635.3; found:635.2
Example 255 :2-(((3R,4S)-3-fluoro-1-(1 H-1,2,3-triazole-5-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-((S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5- triazin-2-yl)benzonitrile
Figure imgf000257_0001
The title compound was prepared following a similar procedure reported in Example 241 using (3R,4S)-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate and 1 H-1 ,2,3-triazole-5-carboxylic acid. 1H NMR (400 MHz, DMSO-c/6) δ 10.12 (s, 1 H), 8.73 (s, 1 H), 8.60-8.5 (m, 2H), 7.92 (s, 1 H), 7.65-7.5 (m, 4H), 6.95-6.85 (m, 2H), 5.26 - 4.85 (m, 2H), 4.56 (td, J = 6.4, 2.9 Hz, 2H), 4.48 (t, J = 6.0 Hz, 1 H), 4.41 (t, J = 6.0 Hz, 1 H), 4.21 - 3.97 (m, 1 H), 3.98-3.85 (m, 1 H), 3.40 (q, J = 6.3 Hz, 1 H), 3.25 - 3.08 (m, 3H), 3.05-2.92 (m, 1 H), 2.71-2.65 (m, 2H), 2.27 - 2.17 (m, 1 H), 2.14 - 2.02 (m, 2H), 2.01 -
1.88 (m, 2H), 1.01 (d, J = 6.3 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H34FNH O3: 640.3; found:640.2.
Example 256: 2-(((3R,4S)-3-fluoro-1-(1 H-imidazole-5-carbonyl)piperidin-4-yl)oxy)-5- (4-((4-((S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2- yl)benzonitrile
Figure imgf000258_0001
The title compound was prepared following a similar procedure reported in Example-G using (3R,4S)-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate and 1 H-imidazole-5- carboxylic acid. 1H NMR (400 MHz, DMSO-c/6) δ 10.32-10.12 (m, 1 H), 8.83 - 8.65 (m, 1 H), 8.65 - 8.22 (m, 3H), 7.84 (s, 1 H), 7.61 (dd, J = 1 1.3, 7.1 Hz, 3H), 7.22-6.95 (m, 2H), 5.13 (d, J = 22.7 Hz, 3H), 4.82 - 4.58 (m, 5H), 4.46 - 3.00 (m, 1 1 H), 2.16 - 1.70
(m, 2H), 0.95 (d, J = 15.0 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for CssHssFN^Os: 639.3; found:639.3 Example 257: 2-(((3R,4S)-3-f luoro-1 -(1 H-pyrazole-5-carbonyl)piperidin-4-yl)oxy)-5- (4-((4-((S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2- yl)benzonitrile
Figure imgf000258_0002
The title compound was prepared following a similar procedure reported in Example 241 using (3R,4S)-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate and 1 H- pyrazole-5-carboxylic acid. 1H NMR (400 MHz, DMSO-c/6) δ 10.21 (d, J = 56.9 Hz, 1 H), 8.72 (d, J = 7.6 Hz, 1 H), 8.60-8.45 (m, 2H), 7.8-7.5 (m, 4H), 7.2-6.85 (m, 2H), 6.55 (d, J = 2.3 Hz, 1 H), 5.2-5.0 (m, 1 H), 4.85-4.6 (m, 3H), 4.51 - 4.08 (m, 3H), 3.32 - 2.66 (m, 11 H), 2.05-1.8 (m, 2H), 0.96 (d, J = 65.4 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for CssHssFN^Os: 639.3; found:639.3
Example 258: 2-(((S)-3,3-difluoro-1 -(1 H-1 ,2,3-triazole-5-carbonyl)piperid yl)oxy)-5-(4-((4-((S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5- triazin-2-yl)benzonitrile
Figure imgf000259_0001
The title compound was prepared following a similar procedure reported in Example 242 using (S)-tert-butyl 3,3-difluoro-4-hydroxypiperidine-1-carboxylate and 1 H-1 ,2,3- triazole-5-carboxylic acid.1H NMR (400 MHz, DMSO-c/6) δ 10.59 - 9.84 (m, 2H), 8.74 (s, 1 H), 8.65 - 8.42 (m, 2H), 8.12-8.01 (m, 1 H), 7.63 (t, J = 8.5 Hz, 2H), 7.3-6.92 (m, 2H), 5.39 (s, 1 H), 4.96 - 4.50 (m, 3H), 4.33-3.0 (m, 15H), 2.29 - 1.58 (m, 2H), 1.44 - 0.59
(m, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H33F2NHO3: 658.3; found:658.3
Example 259: 2-(((S)-3,3-difluoro-1-(1 H-imidazole-5-carbonyl)piperidin-4-yl)oxy)-5-
(4-((4-((S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2- yl)benzonitrile
Figure imgf000259_0002
The title compound was prepared following a similar procedure reported in Example 241 using (S)-tert-butyl 3,3-difluoro-4-hydroxypiperidine-1-carboxylate and 1 H- imidazole-5-carboxylic acid. 1H NMR (400 MHz, DMSO-c 6) δ 10.21 (s, 1 H), 8.74 (s, 1 H), 8.55 (dt, J = 15.0, 7.5 Hz, 2H), 8.1 1 (s, 1 H), 7.81 (s, 1 H), 7.62 (t, J = 1 1.2 Hz, 3H), 7.14- 6.99 (m, 2H), 5.50 - 5.26 (m, 1 H), 4.81 - 4.52 (m, 5H), 4.4-2.6 (m, 10H), 2.05 (d, J =
84.1 Hz, 4H), 1.25 - 0.59 (m, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C33H34F2N10O3: 657.3; found:657.2
Example 260: 2-(((S)-3,3-difluoro-1-(4H-1,2,4-triazole-3-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-((S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-
Figure imgf000260_0001
The title compound was prepared following a similar procedure reported in Example 241 using (S)-tert-butyl 3,3-difluoro-4-hydroxypiperidine-1-carboxylate and 4H- 1 ,2,4-triazole-3-carboxylic acid. 1H NMR (400 MHz, DMSO-c/6) δ 10.4-10.1 (m, 2H), 8.83 - 8.65 (m, 1 H), 8.56 (d, J = 8.9 Hz, 2H), 7.63 (d, J = 9.2 Hz, 3H), 7.05 (d, J = 81.4 Hz, 3H), 5.39 (s, 1 H), 4.88 - 3.85 (m, 8H), 3.6-2.65 (m, 7H), 2.28 - 1.75 (m, 3H), 1.25 -
0.57 (m, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H33F2NH O3: 658.3; found:658.2
Example 261 : 2-(((S)-3,3-difluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4-
((S)-3-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile
Figure imgf000261_0001
The title compound was prepared following a similar procedure reported in Example 241 using (S)-tert-butyl 2-methylpiperazine-1 -carboxylate , (S)-tert-butyl 3,3-difluoro-4- hydroxypiperidine-1 -carboxylate and 2-hydroxyacetic acid. 1 H NMR (400 MHz, DMSO- cfe) δ 10.21 - 10.00 (m, 1 H), 8.73 (s, 1 H), 8.64 - 8.50 (m, 2H), 7.71 - 7.62 (m, 1 H), 7.62 - 7.44 (m, 2H), 6.95 (d, J = 9.4 Hz, 2H), 5.41 -5.32 (m, 1 H), 4.93-4.84 (m, 1 H), 4.62 - 4.42 (m, 4H), 4.23 - 3.93 (m, 3H), 3.95-3.82 (m, 1 H), 3.72 - 3.55 (m, 3H), 3.50-3.32 (m, 2H), 2.88 - 2.60 (m, 2H), 2.60 - 2.34 (m, 2H), 2.22 - 2.03 (m, 2H), 1 .98 (d, J = 1 1 .3 Hz,
1 H), 0.89 (d, J = 6.3 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C3i H34F2N804: 621 .3; found:621 .2
Example 262: 2-(((S)-3,3-difluoro-1 -((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-
(4-((4-((S)-3-methyl-4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile
Figure imgf000261_0002
The title compound was prepared following a similar procedure reported in Example 241 using (S)-tert-butyl 2-methylpiperazine-1 -carboxylate, (S)-tert-butyl 3,3-difluoro-4- hydroxypiperidine-1 -carboxylate and (S)-2-hydroxypropanoic acid. 1 H NMR (400 MHz, DMSO-c/6) 5 10.13 (d, J = 22.7 Hz, 1 H), 8.73 (d, J = 2.3 Hz, 1 H), 8.62-8.49 (m, 2H), 7.66 (d, J = 9.2 Hz, 1 H), 7.62-7.48 (m, 2H), 6.93 (d, J = 8.3 Hz, 2H), 5.32-5.26 (m, 2H), 4.59 - 4.35 (m, 5H), 4.13 (s, 1 H), 3.88 - 3.54 (m, 4H), 3.42-3.25 (m, 3H), 2.89 - 2.59 (m, 2H), 2.59 - 2.32 (m, 2H), 2.14 (td, J = 10.0, 9.1 , 5.3 Hz, 2H), 1.21 (t, J = 5.1 Hz, 3H),
0.89 (d, J = 6.3 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H36F2N804: 635.3; found:635.2
Example 263: 2-(((3R,4S)-3-fluoro-1-(1 H-1,2,3-triazole-5-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-((S)-3-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5- triazin-2-yl)benzonitrile
Figure imgf000262_0001
The title compound was prepared following a similar procedure reported in Example 241 using (S)-tert-butyl 2-methylpiperazine-1-carboxylate , (3R,4S)-tert-butyl 3-fluoro-4- hydroxypiperidine-1-carboxylate and 1 H-1 ,2,3-triazole-5-carboxylic acid. 1H NMR (400 MHz, DMSO-c/e) δ 10.14 (s, 1 H), 8.73 (s, 1 H), 8.64 - 8.48 (m, 2H), 8.05 (d, J = 43.5 Hz, 1 H), 7.71-7.52 (m, 4H), 6.93 (d, J = 7.2 Hz, 2H), 5.07 (d, J = 52.8 Hz, 2H), 4.59 - 4.38 (m, 4H), 4.23 (s, 1 H), 3.72-3.59 (m, 2H), 3.39-3.25 (m, 5H), 3.09 - 2.59 (m, 4H), 2.20 - 1.72 (m, 2H), 0.89 (d, J = 6.3 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H34FNH O3: 640.3; found: 640.2
Example 264: 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5- (4-((4-((S)-3-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2- yl)benzonitrile
Figure imgf000263_0001
The title compound was prepared following a similar procedure reported in Example 241 using (S)-tert-butyl 2-methylpiperazine-1-carboxylate, (3R,4S)-tert-butyl 3-fluoro-4- hydroxypiperidine-1-carboxylate and (S)-2-hydroxypropanoic acid. 1H NMR (400 MHz, DMSO-c/6) δ 10.1 1 (d, J = 25.3 Hz, 1 H), 8.73 (s, 1 H), 8.63 - 8.47 (m, 2H), 7.70 - 7.41 (m, 3H), 7.02-6.89 (m, 2H), 5.21 - 4.82 (m, 3H), 4.66 - 4.29 (m, 2H), 4.24 - 3.84 (m, 2H), 3.75 - 3.53 (m, 3H), 3.36 (d, J = 12.6 Hz, 3H), 3.13 (s, 2H), 2.82 (t, J = 10.6 Hz, 1 H), 2.69 (d, J = 1 1.2 Hz, 1 H), 2.53-2.40 (m, 2H), 2.13 (t, J = 10.3 Hz, 1 H), 2.04 - 1.69
(m, 2H), 1.25-1.19 (m, 3H), 0.89 (d, J = 6.3 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H37FN8O4 Exact Mass: 617.3 found:617.2
Example 265: 5-(4-((4-((2S,5R)-2,5-dimethyl-4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1,3,5-triazin-2-yl)-2-(((3R,4S)-3-fluoro-1-((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)benzonitrile
Figure imgf000263_0002
The title compound was prepared following a similar procedure reported in Example 241 using (2R,5S)-tert-butyl 2,5-dimethylpiperazine-1-carboxylate, (3R,4S)-tert-butyl 3- fluoro-4-hydroxypiperidine-1-carboxylateand (S)-2-hydroxypropanoic acid. 1H NMR (400 MHz, DMSO-c/6) δ 10.2 (s, 1 H), 8.75 (s, 1 H), 8.65 - 8.51 (m, 2H), 7.70 - 7.45 (m, 3H), 6.95-6.82 (m, 2H), 5.21 - 4.82 (m, 3H), 4.66 - 4.29 (m, 2H), 4.26 - 3.91 (m, 2H), 3.79 - 3.42 (m, 2H), 3.39-2.92 (m, 3H), 2.88-2.65 (m, 4H), 2.25-1.92 (m, 5H), 1.52-1.39 (m,
3H), 0.88-0.79 (m, 6H). LCMS-ESI+ (m/z): [M+H]+ calcd for C33H39FN8O4 Exact Mass: 631.3 found:631.2
Example 266: 2-(((3R,4S)-1 -(1 ,2-dimethyl-1 H-imidazole-5-carbonyl)-3- fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)- 1,3,5-triazin-2-yl)benzonitrile
Figure imgf000264_0001
The title compound was prepared following a similar procedure reported in Example 241 using (3R,4S)-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate and 1 ,2- dimethyl-1 H-imidazole-5-carboxylic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C34H37FN10O3Exact Mass: 653.3 found:653.2
Example 267: 2-(((3R,4S)-3-fluoro-1 -(1 -methyl-1 H-imidazole-5-carbonyl)piperidin-
4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2- yl)benzonitrile
Figure imgf000264_0002
The title compound was prepared following a similar procedure reported in Example 241 using (3R,4S)-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate and 1-methyl- 1 H-imidazole-5-carboxylic acid LCMS-ESI"1" (m/z): [M+H]+ calcd for C33H35FN10O3 Exact Mass: 639.3 found:639.2
Example 268: 2-((1 ,1 -dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-5-(4-((3-fluoro-4-(4- in-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000265_0001
A mixture of 4-chloro-N-(3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1 ,3,5-triazin-2- amine (0.10 g, 0.27 mmol), crude 2-((1 ,1-dioxidotetrahydro-2/-/-thiopyran-4-yl)oxy)-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (0.53 mmol assumed), and tetrakis(triphenylphosphine)palladium(0) (0.024 g, 7.5 mol%) in 1 ,2-dimethoxyethane (DME, 6 mL) was treated with 2M aqueous sodium carbonate solution (0.62 mL). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel to provide 2-((1 ,1-dioxidotetrahydro- 2H-thiopyran-4-yl)oxy)-5-(4-((3-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)- 1 ,3,5-triazin-2-yl)benzonitrile.
LCMS-ESI+ (m/z): [M+H]+ calcd for C28H31 FN7O4S: 580.2; found: 580.3 1 H NMR (400 MHz, DMSO-c/6) δ 10.40 (bs, 1 H), 8.85 (s, 1 H), 8.63 (m, 2H), 7.72 (dd, J = 15.0, 2.4 Hz, 1 H), 7.62 (m, 1 H), 7.48 (bs, 1 H), 7.09 (t, J = 9.4 Hz, 1 H), 5.12 (p, J = 4.7 Hz, 1 H), 4.60 (t, J = 6.5 Hz, 2H), 4.51 (t, J = 6.0 Hz, 2H), 3.51 (p, J = 6.2 Hz, 1 H), 3.27 (m, 4H), 3.06 (m, 4H), 2.47 (m, 4H), 2.36 (m, 4H).
Example 269: 2-(3-methoxyazetidin-1 -yl)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 - -1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000266_0001
Step 1 : Preparation of 2-(3-methoxyazetidin-1 -yl)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzonitrile: 2-Fluoro-5-(4,4,5,5-tetramethyl[1 ,3,2]dioxaborolan-2- yl)benzonitrile (Combi-Blocks, 2.0 g, 8.1 mmol), potassium carbonate (2.2 g 16 mmol), and 3-methoxyazetidine hydrochloride (Chem-lmpex, 1.0 g, 8.1 mmol) were taken up as a suspension in /V,/V-dimethylacetamide (20 mL) and heated on at 120 °C overnight. After the mixture had cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to provide 2-(3-methoxyazetidin-1 -yl)-5-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile.
LCMS-ESI+ (m/z): [M+H]+ calcd for C17H24BN2O3: 315.2; found: 315.1
Step 2: Preparation of 2-(3-methoxyazetidin-1 -yl)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile: A mixture of 4-chloro- N-(4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)-1 ,3,5-triazin-2-amine (0.12 g, 0.35 mmol), 2- (3-methoxyazetidin-1 -yl)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (0.14 g, 0.43 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.030 g, 7.5 mol%) in 1 ,2-dimethoxyethane (DME, 2.5 mL) was treated with 2M aqueous sodium carbonate solution (0.80 mL). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel, followed by precipitation with isopropanol, to provide 2-(3-methoxyazetidin-1 -yl)-5-(4-((4-(4-(oxetan- 3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C27H31 N802: 499.3; found: 499.3 1 H NMR (400 MHz, DMSO-c/6) δ 10.02 (d, J = 17.7 Hz, 1 H), 8.79 - 8.63 (m, 1 H), 8.53 - 8.30 (m, 2H), 7.61 (m, 2H), 6.99 (m, 2H), 6.73 (d, J = 9.0 Hz, 1 H), 4.61 (t, J = 6.5 Hz, 2H), 4.52 (m, 4H), 4.39 (m, 1 H), 4.10 (m, 2H), 3.50 (m, 1 H), 3.32 (s, 3H), 3.17 (m, 4H), 2.45 (m, 4H).
Example 270: 2-((1 ,1 -dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-5-(4-((4-(1 -(oxetan- enyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000267_0001
A mixture of 4-chloro-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1 ,3,5-triazin-2-amine (0.10 g, 0.29 mmol), crude 2-((1 ,1 -dioxidotetrahydro-2/-/-thiopyran-4-yl)oxy)-5-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (assumed 0.61 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.025 g, 7.5 mol%) in 1 ,2-dimethoxyethane (DME, 4 mL) was treated with 2M aqueous sodium carbonate solution (0.66 mL). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel, followed by precipitation with isopropanol, to provide (0.12 g, 0.35 mmol), 2-(3-methoxyazetidin-1 -yl)-5-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile. (0.14 g, 0.43 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.030 g, 7.5 mol%) in 1 ,2-dimethoxyethane (DME, 2.5 mL) was treated with 2M aqueous sodium carbonate solution (0.80 mL). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel, followed by precipitation with isopropanol, to provide 2-((1 ,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-5-(4-((4-(1-
(oxetan-3-yl)piperidin-4-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+
(m/z): [M+H]+ calcd for C29H33N6C>4S: 561.2; found: 561.4 1 H NMR (400 MHz,
DMSO-c/6) δ 10.33 (bs, 1 H), 8.84 (s, 1 H), 8.64 (dd, J = 8.8, 1.8 Hz, 2H), 7.70 (m, 2H), 7.62 (d, J = 9.4 Hz, 1 H), 7.30 (d, J = 8.0 Hz, 2H), 5.12 (p, J = 4.9 Hz, 1 H), 4.59 (t, J = 6.5 Hz, 2H), 4.49 (t, J = 6.1 Hz, 2H), 3.44 (p, J = 6.4 Hz, 1 H), 3.34 - 3.18 (m, 4H), 2.84 (d, J = 1 1.3 Hz, 2H), 2.37 (m, 4H), 1.96 - 1.85 (m, 2H), 1.80 (m, 2H), 1.72 (m, 2H).
Example 271 : 2-((1 ,1 -dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-3-fluoro-5-(4-((4-(4- in-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000268_0001
Step 1 : Preparation of 5-bromo-3-fluoro-2-hydroxybenzonitrile: N-
Bromosuccinimide (3.9 g, 22 mmol) was added in a single portion to a stirred solution of 3-fluoro-2-hydroxybenzonitrile (Matrix Scientific, 3.0 g, 22 mmol) in acetonitrile (100 ml_). The mixture was stirred for one hour at room temperature, then concentrated to dryness under reduced pressure. The residue was taken up in saturated aqueous sodium carbonate solution (approximately 100 ml_) and extracted twice with diethyl ether. The aqueous phase was acidified to pH 2 with concentrated hydrochloric acid, then extracted three times with diethyl ether. These combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, concentrated to dryness under reduced pressure to provide 5-bromo-3-fluoro-2-hydroxybenzonitrile. LCMS-ESI+ (m/z): [M+H20+H]+ calcd for C7H6BrFN02: 234.0; found: 233.9
Step 2: Preparation of 5-bromo-3-fluoro-2-((tetrahydro-2H-thiopyran-4- yl)oxy)benzonitrile: 5-bromo-3-fluoro-2-hydroxybenzonitrile (1 .2 g, 5.6 mmol), tetrahydrothiopyran-4-ol (0.79 g, 6.7 mmol), and 1 , 1 '-(azodicarbonyl)dipiperidine (ADDP, 2.8 g, 1 1 mmol)) were taken up in anhydrous toluene. The stirred mixture was cooled in an ice-water bath while tributylphosphine (4.1 g, 5.0 ml_, 20 mmol) was added via syringe. The mixture was stirred in the ice-water bath for 10 minutes after the addition. The bath was then removed. After stirring at room temperature for 2 hours, mixture was heated for 4 hours at 120 °C and was left to stir overnight at room temperature. The mixture was concentrated to under reduced pressure and purified by flash chromatography on silica gel to provide 5-bromo-3-fluoro-2-((tetrahydro-2H-thiopyran-4- yl)oxy)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C 2H12BrFNOS: 316.0; found:
316.0 Step 3: Preparation of 5-bromo-2-((1 ,1 -dioxidotetrahydro-2H-thiopyran-4-yl)oxy)- 3-fluorobenzonitrile: A solution of 5-bromo-3-fluoro-2-((tetrahydro-2H-thiopyran-4- yl)oxy)benzonitrile (1 .4 g, 4.3 mmol) in dichloromethane was treated with calcium carbonate (1 .7 g, 17 mmol). The resulting suspension was cooled in an ice-water bath. 3-chloroperbenzoic acid (< 77 %, 2.4 g, 1 1 mmol) was added in a single portion, and the mixture was allowed to stir overnight, gradually regaining room temperature. The suspension was filtered, and the filtrate was washed twice each with aqueous solutions of 5 % sodium bisulfite and saturated sodium hydrogen carbonate. The organics were dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure to provide 5-bromo-2-((1 , 1 -dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-
3-fluorobenzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C 2H 2BrFN03S: 348.0; found: 347.9
Step 4: Preparation of (3-cyano-4-((1 ,1 -dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-5- fluorophenyl)boronic acid
A mixture of 5-bromo-2-((1 , 1 -dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-3- fluorobenzonitrile (0.18 g, 0.52 mmol), bis(pinacolato)diboron (0.26 g, 1 .0 mmol), potassium acetate (0.15 g, 1 .6 mmol), and [1 , 1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) complex with dichloromethane (39 mg, 10 mol%) in 1 ,4-dioxane (6 ml_) was heated overnight at 90 °C. The reaction mixture was filtered through a pad of Celite diatomaceous earth, and the filtrate was concentrated to dryness under reduced pressure. The crude (3-cyano-4-((1 , 1 - dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-5-fluorophenyl)boronic acid was carried forward without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C-12H-14BFNO5S: 314.1 ; found: 314.0 Step 5: Preparation of 2-((1 ,1 -dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-3-fluoro- 5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
A mixture of 4-chloro-N-(4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)-1 ,3,5-triazin-2-amine (0.12 g, 0.35 mmol), crude (3-cyano-4-((1 , 1 -dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-5- fluorophenyl)boronic acid (assumed 0.52 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.030 g, 7.5 mol%) in 1 ,2-dimethoxyethane (DME, 8 ml_) was treated with 2M aqueous sodium carbonate solution (2.0 ml_). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel to provide 2-((1 , 1 -dioxidotetrahydro- 2H-thiopyran-4-yl)oxy)-3-fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)- 1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for C28H31 FN7O4S: 580.2; found: 580.3
1 H NMR (400 MHz, DMSO-c/6) δ 10.27 (d, J = 28.9 Hz, 1 H), 8.82 (s, 1 H), 8.60 - 8.33
(m, 2H), 7.60 (m, 2H), 7.01 (dd, J = 16.0, 8.4 Hz, 2H), 4.94 (m, 1 H), 4.61 (t, J = 6.5 Hz, 2H), 4.52 (t, J = 6.0 Hz, 2H), 3.49 (p, J = 6.5 Hz, 1 H), 3.31 (m, 4H), 3.19 (m, 4H), 2.45 (m, 4H), 2.38 (m, 4H).
Example 272: 2-(3-(methylsulfonyl)azetidin-1 -yl)-5-(4-((4-(4-(oxetan-3-yl)piperazin- )-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000270_0001
Step 1 : Preparation of 2-(3-(methylsulfonyl)azetidin-1 -yl)-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)benzonitrile
2-Fluoro-5-(4,4,5,5-tetramethyl[1 ,3,2]dioxaborolan-2-yl)benzonitrile (1.4 g, 5.8 mmol), potassium carbonate (1.6 g 12 mmol), and 3-methylsulfonylazetidine hydrochloride (Synnovator, 1.0 g, 5.8 mmol) were taken up as a suspension in /V,/V-dimethylacetamide (14 mL) and heated on at 120 °C overnight. After the mixture had cooled to room temperature it was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to provide 2-(3- (methylsulfonyl)azetidin-1-yl)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile.
LCMS-ESI+ (m/z): [M+H]+ calcd for C-17H24BN2O4S: 363.2; found: 363.1
Step 2: Preparation of 2-(3-(methylsulfonyl)azetidin-1 -yl)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
A mixture of 4-chloro-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1 ,3,5-triazin-2-amine (0.12 g, 0.35 mmol), 2-(3-(methylsulfonyl)azetidin-1-yl)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzonitrile (0.16 g, 0.43 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.030 g, 7.5 mol%) in 1 ,2-dimethoxyethane (DME, 3 mL) was treated with 2M aqueous sodium carbonate solution (0.78 mL). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude mixture was purified by flash chromatography on silica gel, followed by precipitation with isopropanol, to provide 2-(3-(methylsulfonyl)azetidin-1-yl)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C27H3 N803S: 547.2; found: 547.3
Example 273: 2-((1-(methylsulfonyl)azetidin-3-yl)oxy)-5-(4-((4-(4-(oxetan-3- henyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000271_0001
Step 1 : Preparation of tert-butyl 3-(4-bromo-2-cyanophenoxy)azetidine-1- carboxylate
Sodium hydride (60 % dispersion in mineral oil, 0.69 g, 17 mmol) was added in a single portion to a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (Sigma Aldrich, 3.0 g, 17 mmol) in A/,A/-dimethylformamide (30 mL) at room temperature. Stirring was continued for about 30 minutes at room temperature before the addition of 5-bromo-2- fluorobenzonitrile 3.3 g, 17 mmol) in a single portion. The mixture was stirred overnight at 50 °C. The reaction was quenched by the addition of water and ice. The resulting off-white solid was collected by Buchner filtration, washed with isopropanol, and dried over phosphorus pentoxide to provide tert-butyl 3-(4-bromo-2-cyanophenoxy)azetidine- 1-carboxylate. LCMS-ESI"1" (m/z): [M-isobutylene+H]+ calcd for Ci i H-| oBrN203: 297.0; found: 296.9
Step 2: Preparation of tert-butyl 3-(2-cyano-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenoxy)azetidine-1-carboxylate
A mixture of tert-butyl 3-(4-bromo-2-cyanophenoxy)azetidine-1-carboxylate (0.50 g, 1.4 mmol), bis(pinacolato)diboron (0.72 g, 2.8 mmol), potassium acetate (0.42 g, 4.2 mmol), and [1 ,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) complex with dichloromethane (1 10 mg, 10 mol%) in 1 ,4-dioxane (10 mL) was heated overnight at 90 °C. The reaction mixture was filtered through a pad of Celite diatomaceous earth, and the filtrate was concentrated to dryness under reduced pressure. The crude tert-butyl 3- (2-cyano-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)azetidine-1 - carboxylate was carried forward without further purification. LCMS-ESI+ (m/z): [M- isobutylene+H]+ calcd for C-17H22BN2O5: 345.2; found: 345.0
Step 3: Preparation of tert-butyl 3-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenoxy)azetidine-1 -carboxylate
A mixture of 4-chloro-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1 ,3,5-triazin-2-amine (0.33 g, 0.94 mmol), crude tert-butyl 3-(2-cyano-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenoxy)azetidine-1-carboxylate (assumed 1.4 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.081 g, 7.5 mol%) in 1 ,2-dimethoxyethane (DME, 8 mL) was treated with 2M aqueous sodium carbonate solution (2.1 mL). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The crude biphasic mixture
was filtered through a short pad of Celite diatomaceous earth, eluting with ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, concentrated to dryness under reduced pressure to provide the crude tert-butyl 3-(2-cyano-4-(4-((4-(4-(oxetan-3- yl)piperazin-1 -yl)phenyl)amino)-1 , 3, 5-triazin-2-yl)phenoxy)azetidine-1 -carboxylate, which was carried on without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C31 H37N8O4: 585.3; found: 585.2
Step 4: Preparation of 2-(azetidin-3-yloxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Crude tert-butyl 3-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)phenoxy)azetidine-1 -carboxylate was taken up in dichloromethane (10 mL) and treated with trifluoroacetic acid (2 mL). The mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel to provide 2- (azetidin-3-yloxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C26H29N802: 485.2; found: 485.3
Step 5: Preparation of 2-((1-(methylsulfonyl)azetidin-3-yl)oxy)-5-(4-((4-(4-(oxetan- 3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
A solution of 2-(azetidin-3-yloxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)- 1 ,3,5-triazin-2-yl)benzonitrile (56 mg, 0.12 mmol) in N,N-dimethylformamide (2 mL) was treated successively with /V,/V-diisopropylethylamine (50 μί, 0.29 mmol) and methanesulfonyl chloride 18 μί, 0.23 mmol). The mixture was refrigerated overnight, then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to provide 2-((1-(methylsulfonyl)azetidin-3-yl)oxy)-5-(4-((4- (4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C27H31 N804S: 563.2; found: 563.3 Example 274: 2-((1-(2-hydroxyacetyl)azetidin-3-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000273_0001
A mixture of 2-(azetidin-3-yloxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)- 1 ,3,5-triazin-2-yl)benzonitrile (56 mg, 0.12 mmol) and glycolic acid (13 mg, 0.17 mmol) in N,N-dimethylformamide (2 ml_) was treated successively with N,N- diisopropylethylamine (50 μΙ_, 0.29 mmol) and W-[(dimethylamino)-1 H-1,2,3-triazolo- [4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate Ay- oxide (HATU, 66 mg, 0.17 mmol). After standing overnight at room temperature, the mixture was purified by flash chromatography on silica gel to provide 2-((1-(2- hydroxyacetyl)azetidin-3-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-
1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C28H3i N804: 543.2; found: 543.4
Example 275: 5-(4-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-1,3,5-triazin-2-yl)- H-pyran-4-yl)oxy)benzonitrile
Figure imgf000273_0002
A suspension of 5-(4-chloro-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2/-/-pyran-4- yl)oxy)benzonitrile (93 mg, 0.29 mmol) and 5-amino-2,2-difluorobenzodioxole (Combi- Blocks, 61 mg, 0.35 mmol) in acetonitrile (3 ml_) was treated with N,N- diisopropylethylamine (0.15 mL, 0.88 mmol). The mixture was heated in a microwave reactor for 30 minutes at 90 °C. The precipitated solid was collected by filtration, washed with acetonitrile, and dried under vacuum to provide 5-(4-((2,2- difluorobenzo[d][1 ,3]dioxol-5-yl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for C22H18 2N5O4: 454.1 ; found:
454.1
Example 276: 1 -(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)- nyl)azetidin-3-yl methanesulfonate
Figure imgf000274_0001
Step 1 : Preparation of 2-(3-hydroxyazetidin-1 -yl)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzonitrile
2-Fluoro-5-(4,4,5,5-tetramethyl[1 ,3,2]dioxaborolan-2-yl)benzonitrile (2.0 g, 8.1 mmol), potassium carbonate (2.2 g 16 mmol), and 3-hydroxyazetidine hydrochloride (0.89 g, 8.1 mmol) were taken up as a suspension in /V,/V-dimethylacetamide (20 mL) and heated on at 120 °C overnight. After the mixture had cooled to room temperature it was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to provide 2-(3-hydroxyazetidin-1-yl)-5-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for C16H22BN203: 301.2; found: 301.1
Step 2: Preparation of 2-(3-hydroxyazetidin-1 -yl)-5-(4-((4-(4-(oxetan-3-yl)piperazin- 1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
A mixture of 4-chloro-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1 ,3,5-triazin-2-amine (0.24 g, 0.69 mmol), 2-(3-hydroxyazetidin-1-yl)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzonitrile (0.23 g, 0.76 mmol), and [1 ,1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (0.051 g, 10 mol%) in 1 ,2- dimethoxyethane (DME, 8 mL) was treated with 2 M aqueous sodium carbonate solution (1.6 mL). The mixture was purified by flash chromatography on silica gel to provide 2- (3-hydroxyazetidin-1-yl)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for C26H29N802: 485.2; found: 485.3
Step 3: Preparation of 1 -(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenyl)azetidin-3-yl methanesulfonate
2-(3-hydroxyazetidin-1-yl)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)benzonitrile (60 mg, 0.12 mmol) was taken up as a suspension in dichloromethane. The suspension was treated with /V,/V-diisopropylethylamine (25 μΙ_, 0.15 mmol) and cooled in an ice-water bath. Methanesulfonyl chloride (1 1 μΙ_, 0.14 mmol) was added and the mixture was allowed to regain room temperature. After 5 minutes of stirring at room temperature, the mixture cooled in an ice-water bath and treated with the original stoichiometries of /V,/V-diisopropylethylamine and methanesulfonyl chloride. After one hour of stirring at room temperature, the mixture was purified by flash chromatography on silica gel to provide 1-(2-cyano-4-(4-((4-(4- (oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenyl)azetidin-3-yl methanesulfonate. LCMS-ESI"1" (m/z): [M+H]+ calcd for C27H31 N8O4S: 563.2; found:
563.3 1 H NMR (400 MHz, DMSO-c/6) δ 10.04 (d, J = 18.6 Hz, 1 H), 8.71 (s, 1 H), 8.54 -
8.32 (m, 2H), 7.61 (m, 2H), 7.00 (m, 2H), 6.81 (d, J = 9.0 Hz, 1 H), 5.50 (m, 1 H), 4.79 - 4.67 (m, 2H), 4.61 (t, J = 6.5 Hz, 2H), 4.52 (t, J = 6.0 Hz, 2H), 4.43 - 4.37 (m, 2H), 3.57 - 3.44 (m, 1 H), 3.36 (s, 3H), 3.18 (m, 4H), 2.45 (m, 4H).
Example 277: 5-(4-((2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)amino)-1 ,3,5-triazin-2- yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile
Figure imgf000275_0001
A suspension of 5-(4-chloro-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2/-/-pyran-4- yl)oxy)benzonitrile (93 mg, 0.29 mmol) and 5-amino-1 ,3-benzoxazol-2(3/-/)-one (Enamine, 53 mg, 0.35 mmol) in acetonitrile (3 ml_) was treated with N,N- diisopropylethylamine (0.15 mL, 0.88 mmol). The mixture was heated in a microwave reactor for 20 minutes at 80 °C. The mixture was purified by flash chromatography on silica gel to provide 5-(4-((2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)amino)-1,3,5-triazin-2- yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile.
LCMS-ESI+ (m/z): [M+H]+ calcd for C22Hi9N604: 431.1; found: 431.1
1H NMR (400 MHz, DMSO-c/6) δ 11.70 (s, 1H), 10.41 (s, 1H), 8.86 (s, 1H), 8.62 (m, 2H), 7.69 (bs, 1H), 7.59 (m, 1H), 7.41 (bs, 1H), 7.31 (m, 1H), 4.99 (m, 1H), 3.92 (m, 2H), 3.60 (ddd, J= 11.6, 8.5, 3.1 Hz, 2H), 2.09 (m, 2H), 1.74 (m, 2H). Example 278: 5-(4-((3,3-dimethyl-2-oxoindolin-5-yl)amino)-1,3,5-triazin-2-yl)-2- ((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile
Figure imgf000276_0001
A suspension of 5-(4-chloro-1,3,5-triazin-2-yl)-2-((tetrahydro-2/-/-pyran-4- yl)oxy)benzonitrile (93 mg, 0.29 mmol) and 5-amino-3,3dimethylindolin-2-one (Princeton BioMolecular Research, 62 mg, 0.35 mmol) in acetonitrile (3 mL) was treated with N,N- diisopropylethylamine (0.15 mL, 0.88 mmol). The mixture was heated in a microwave reactor for 20 minutes at 80 °C. The mixture was purified by flash chromatography on silica gel to provide 5-(4-((3,3-dimethyl-2-oxoindolin-5-yl)amino)-1 ,3,5-triazin-2-yl)-2- ((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for
C25H25N6°3: 457-2; found: 4572 1| NMR (400 MHz> DMSO-c/6) δ 10.37 (s, 1H), 10.26 (m, 1H), 8.79 (s, 1H), 8.57 (m, 2H), 7.85 (s, 1H), 7.71 - 7.52 (m, 1H), 7.33 (m, 1H), 6.90 (d, J = 8.3 Hz, 1H), 4.99 (m, 1H), 3.90 (m, 2H), 3.59 (ddd, J = 11.7, 8.5, 3.2 Hz, 2H), 2.09 (m, 2H), 1.73 (m, 2H), 1.33 (m, 6H). Example 279: 2-(1 ,4-dioxaspiro[4.5]decan-8-yloxy)-5-(4-((4-(4-(oxetan-3- yl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000277_0001
Potassium tert-butoxide (0.12 g, 1.0 mmol) was added to a solution of 4- hydroxycyclohexanone ethylene ketal (0.16 g, 1.0 mmol) in 2-methyltetrahydrofuran (5 mL). The resulting suspension was stirred at room temperature for 30 minutes before the addition of 2-fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)benzonitrile (0.15 g, 0.35 mmol). The mixture was heated at 60 °C overnight, then purified by flash chromatography on silica gel to provide 2-(1 ,4- dioxaspiro[4.5]decan-8-yloxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)- 1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C3-| H36N704:
570.3; found: 570.4 1 H NMR (400 MHz, DMSO-c/e) δ 10.15 (d, J = 20.9 Hz, 1 H), 8.77
(d, J = 2.6 Hz, 1 H), 8.68 - 8.52 (m, 2H), 7.74 - 7.53 (m, 3H), 7.00 (m, 2H), 4.91 (m, 1 H), 4.61 (t, J = 6.5 Hz, 2H), 4.52 (t, J = 6.0 Hz, 2H), 3.94 (m, 4H), 3.49 (p, J = 6.2 Hz, 1 H), 3.18 (m, 4H), 2.46 (m, 4H), 2.05 - 1.76 (m, 6H), 1.75 - 1.59 (m, 2H).
Example 280: 2-((3-fluorooxetan-3-yl)methoxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 - azin-2-yl)benzonitrile
Figure imgf000277_0002
Potassium tert-butoxide (0.08 g, 0.70 mmol) was added to a solution of 3-fluoro-3- oxetanemethanol (Synnovator, 0.07 g, 0.70 mmol) in 2-methyltetrahydrofuran (5 ml_). The resulting suspension was stirred at room temperature for 30 minutes before the addition of 2-fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)benzonitrile (0.10 g, 0.23 mmol). The mixture was heated at 60 °C overnight and then purified by flash chromatography on silica gel to provide 2-((3-fluorooxetan-3- yl)methoxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C27H29FN7O3: 518.2; found:
518.3 1 H NMR (400 MHz, DMSO-c/6) δ 10.17 (s, 1 H), 8.78 (s, 1 H), 8.70 - 8.50 (m, 2H),
7.63 - 7.54 (m, 3H), 7.01 (m, 2H), 4.88 - 4.70 (m, 6H), 4.61 (t, J = 6.5 Hz, 2H), 4.52 (t, J = 6.0 Hz, 2H), 3.49 (m, 1 H), 3.18 (m, 4H), 2.45 (m, 4H).
Example 281 : (S)-2-((1-(2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((3-methoxy-4- -1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000278_0001
Step 1 : Preparation of tert-butyl 4-(2-cyano-4-(4-((3-methoxy-4-(4-(oxetan-3- yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenoxy)piperidine-1 -carboxylate
A mixture of 4-chloro-N-(3-methoxy-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1 ,3,5- triazin-2-amine (0.1 1 g, 0.28 mmol), tert-butyl 4-(2-cyano-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenoxy)piperidine-1 -carboxylate (0.13 g, 0.31 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.025 g, 7.5 mol%) in 1 ,2-dimethoxyethane (DME, 3 ml_) was treated with 2M aqueous sodium carbonate solution (0.64 ml_). The mixture was irradiated for 1 hour in a microwave reactor at 130 °C. The layers of the biphasic mixture were separated. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to provide crude tert-butyl 4-(2-cyano-4-(4-((3-methoxy-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)phenoxy)piperidine-1 -carboxylate, which was carried on without further purification. LCMS-ESI"1" (m/z): [M+H]+ calcd for C34H43N8O5: 643.3; found: 643.2 Step 2: Preparation of 5-(4-((3-methoxy-4-(4-(oxetan-3-yl)piperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-(piperidin-4-yloxy)benzonitrile
tert-butyl 4-(2-cyano-4-(4-((3-methoxy-4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)- 1 ,3,5-triazin-2-yl)phenoxy)piperidine-1 -carboxylate (assumed 0.28 mmol) was taken up in dichloromethane (5 mL) and treated with trifluoroacetic acid (1 mL). The mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel to provide 5-(4-((3-methoxy-4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-
2-yl)-2-(piperidin-4-yloxy)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C29H35N803: 543.3; found: 543.3
Step 3: Preparation of (S)-2-((1-(2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((3- methoxy-4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile
5-(4-((3-methoxy-4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2- (piperidin-4-yloxy)benzonitrile (0.15 g, 0.28 mmol) and L-(-)-lactic acid (Sigma Aldrich, 38 mg, 0.43 mmol) were taken up in N,N-dimethylformamide (3 mL). The mixture was treated successively with /V,/V-diisopropylethylamine (150 μί, 0.85 mmol) and N- [(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1 -ylmethylene]-N- methylmethanaminiumhexafluorophosphate W-oxide (HATU, 160 mg, 0.43 mmol). The mixture remained at room temperature overnight and was then purified by prep HPLC (5 - 85 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide (S)-2-((1 -(2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((3-methoxy-4-(4-(oxetan-3- yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for 032^9^05: 615.3; found: 615.4 1 H NMR (400 MHz, DMSO-c/6) δ 10.35
(m, 1 H), 8.84 (s, 1 H), 8.65 - 8.62 (m, 2H), 7.76 (bs, 1 H), 7.66 - 7.58 (m, 1 H), 7.55 - 7.18 (br, 1 H), 7.02 (d, J = 8.6 Hz, 1 H), 5.06 (m, 1 H), 4.88 - 4.75 (m, 3H), 4.50 (m, 2H), 3.93 - 3.77 (m, 4H), 3.65 - 3.40 (m, 4H), 3.30 - 2.90 (m, 3H), 2.13 - 1 .96 (m, 2H), 1 .84 - 1 .64 (m, 2H), 1 .24 (d, J = 6.5 Hz, 3H).
Example 282: (S)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5- triazin-2-yl)-2-(1 -(tetrahydro-2H-pyran-4-yl)ethoxy)benzonitrile
Figure imgf000280_0001
Potassium tert-butoxide (0.10 g, 0.90 mmol) was added to a solution of (1 S)-1-(oxan-4- yl)ethan-1-ol (Enamine, 0.12 g, 0.90 mmol) in 2-methyltetrahydrofuran (5 mL). The resulting suspension was stirred at room temperature for 30 minutes before the addition of 2-fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile (0.13 g, 0.30 mmol). The mixture was heated at 60 °C overnight and then purified by flash chromatography on silica gel to provide (S)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-(1-(tetrahydro-2H-pyran-4- yl)ethoxy)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for C30H36N7O3: 542.3; found: 542.4 H NMR (400 MHz, DMSO-c/6) δ 10.15 (d, J = 20.5 Hz, 1 H), 8.77 (s, 1 H), 8.67 - 8.48 (m, 2H), 7.61 (m, 2H), 7.53 (d, J = 9.2 Hz, 1 H), 7.00 (m, 2H), 4.66 (m, 1 H), 4.61 (t, J = 6.5 Hz, 2H), 4.51 (t, J = 6.0 Hz, 2H), 3.95 (m, 2H), 3.49 (p, J = 6.5 Hz, 1 H), 3.36 (m, 2H), 3.18 (m 4H), 2.44 (m, 4H), 2.02 - 1.86 (m, 1 H), 1.78 (d, J = 12.9 Hz, 1 H), 1.62 (d, J = 12.8 Hz, 1 H), 1.53 - 1.38 (m, 2H), 1.35 (d, J = 6.1 Hz, 3H). Example 283: (R)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5- rahydro-2H-pyran-4-yl)ethoxy)benzonitrile
Figure imgf000280_0002
Potassium tert-butoxide (0.10 g, 0.90 mmol) was added to a solution of (1 R)-1-(oxan-4- yl)ethan-1 -ol (Enamine, 0.12 g, 0.90 mmol) in 2-methyltetrahydrofuran (5 mL). The resulting suspension was stirred at room temperature for 30 minutes before the addition of 2-fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile (0.13 g, 0.30 mmol). The mixture was heated at 60 °C overnight and then purified by flash chromatography on silica gel to provide (R)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-(1 -(tetrahydro-2H-pyran-4- yl)ethoxy)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for C30H36N7O3: 542.3; found:
542.4 1 H NMR (400 MHz, DMSO-c/6) δ 10.15 (m, 1 H), 8.77 (s, 1 H), 8.66 - 8.50 (m,
2H), 7.61 (m, 2H), 7.53 (d, J = 9.2 Hz, 1 H), 7.01 (s, 2H), 4.66 (m, 1 H), 4.61 (t, J = 6.5 Hz, 2H), 4.52 (t, J = 6.1 Hz, 2H), 3.95 (m, 2H), 3.49 (p, J = 6.3 Hz, 1 H), 3.35 (m, 2H), 3.21 (m, 4H), 2.45 (m, 4H), 1 .94 (m, 1 H), 1 .78 (m, 1 H), 1.62 (m, 1 H), 1 .44 (m, 2H), 1 .35 (d, J = 6.1 Hz, 3H).
Example 284: 2-((4-methyl-1,2,3-thiadiazol-5-yl)methoxy)-5-(4-((4-(4-(oxetan-3- enyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000281_0001
Potassium tert-butoxide (0.10 g, 0.90 mmol) was added to a solution of 4-methyl-1 ,2,3- thiadiazole-5-methanol (Astatech, 0.12 g, 0.90 mmol) in 2-methyltetrahydrofuran (5 mL). The resulting suspension was stirred at room temperature for 30 minutes before the addition of 2-fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5- triazin-2-yl)benzonitrile ( 0.13 g, 0.30 mmol). The mixture was heated at 60 °C overnight and then purified by flash chromatography on silica gel to provide 2-((4- methyl-1 ,2,3-thiadiazol-5-yl)methoxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for
C27H28N9°2S : 542-2; found : 542 2
Example 285: 5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2- H-pyran-4-yl)methoxy)benzonitrile
Figure imgf000282_0001
Potassium tert-butoxide (0.10 g, 0.90 mmol) was added to a solution of tetrahydropyran- 4-methanol (0.10 g, 0.90 mmol) in 2-methyltetrahydrofuran (4 mL). The resulting suspension was stirred at room temperature for 30 minutes before the addition of 2- fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (0.13 g, 0.30 mmol). The mixture was heated at 70 °C overnight and then purified by flash chromatography on silica gel to provide 5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4-yl)methoxy)benzonitrile.
LCMS-ESI+ (m/z): [M+H]+ calcd for C29H34N7O3: 528.3; found: 528.4 1 H NMR (400
MHz, DMSO-c/6) δ 10.15 (m, 1 H), 8.77 (s, 1 H), 8.68 - 8.51 (m, 2H), 7.61 (m, 2H), 7.49
(d, J = 9.0 Hz, 1 H), 7.00 (m, 2H), 4.61 (t, J = 6.5 Hz, 2H), 4.52 (t, J = 6.0 Hz, 2H), 4.16 (d, J = 6.4 Hz, 2H), 4.00 - 3.87 (m, 2H), 3.47 (p J = 6.4 Hz, 1 H), 3.38 (m, 2H), 3.18 (m, 4H), 2.43 (m, 4H), 2.12 (m, 1 H), 1.73 (m, 2H), 1.44 (m, 2H).
Example 286: (S)-2-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)- noxy)-3-methylbutanamide
Figure imgf000282_0002
Step 1 : Preparation of (S)-methyl 2-(4-bromo-2-cyanophenoxy)-3- methylbutanoate
A solution of 5-bromo-2-hydroxybenzonitrile (1.2 g, 6.1 mmol) was in 2- methyltetrahdrofuran (10 mL) was cooled in an ice-water bath while stirring under an atmosphere of Argon. Triphenylphosphine (1.7 g, 6.4 mmol) was added in a single portion. To the stirred mixture was added dropwise via syringe (R)-methyl 2-hydroxy-3- methylbutanoate (BOC Sciences, 0.85 g, 6.4 mmol) followed by diisopropyl azodicarboxylate (1.9 g, 9.2 mmol). The mixture was stirred overnight under an Argon atmosphere, gradually regaining room temperature. The mixture was concentrated under reduced pressure and then purified by flash chromatography on silica gel to provide (S)-methyl 2-(4-bromo-2-cyanophenoxy)-3-methylbutanoate. LCMS-ESI+ (m/z):
[M+H]+ calcd for C 3H1 5BrN03: 312.0; found: 31 1.8
Step 2: Preparation of (S)-2-(4-bromo-2-cyanophenoxy)-3-methylbutanamide
(S)-methyl 2-(4-bromo-2-cyanophenoxy)-3-methylbutanoate (1.7 g, 5.3 mmol) was taken up in 2-methyltetrahydrofuran/methanol/water (2:2:1 , 25 ml_). The mixture was cooled in an ice-water bath while lithium hydroxide monohydrate (0.33 g, 7.9 mmol) was added in a single portion. After two hours of stirring, the mixture was removed from bath and acidified to ~ pH 2 with 10 % aqueous citric acid solution. The mixture was extracted three times with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution that was made acidic by the addition of < 5 % of 10 % aqueous hydrochloric acid solution. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated to provide the putative intermediate (S)-2-(4-bromo-2-cyanophenoxy)-3-methylbutanoic acid, of which a portion thereof (0.71 g, 2.4 mmol) was taken up in N,N-dimethylformamide (10 ml_), cooled in an ice-water bath, and treated successively with /V,/V-diisopropylethylamine (1.0 ml_, 6.0 mmol) and A -[(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1 -ylmethylene]-N- methylmethanaminiumhexafluorophosphate W-oxide (HATU, 1.4 g, 3.6 mmol). After 20 minutes of stirring in the bath, the mixture was treated with concentrated ammonium hydroxide solution (28 %, 1.3 ml_, 9.5 mmol). The mixture was allowed to continue stirring overnight, gradually regaining room temperature. The mixture was quenched by the addition of saturated aqueous sodium bicarbonate solution and was made homogeneous by the addition of water and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed once with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to provide (S)-2-(4-bromo-2-cyanophenoxy)-3- methylbutanamide.
LCMS-ESI+ (m/z): [M+H]+ calcd for Ci2Hi4BrN202: 297.0; found: 297.0 Step 3: Preparation of (S)-2-(2-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy)-3-methylbutanamide
A mixture of (S)-2-(4-bromo-2-cyanophenoxy)-3-methylbutanamide (0.16 g, 0.55 mmol), bis(pinacolato)diboron (0.28 g, 1 .1 mmol), potassium acetate (0.16 g, 1 .6 mmol), and [1 , 1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) complex with dichloromethane (45 mg, 10 mol%) in 1 ,4-dioxane (3 mL) was heated for 4hours at 95 °C. The reaction mixture was filtered through a pad of Celite diatomaceous earth, and the filtrate was concentrated to dryness under reduced pressure. The crude (S)-2-(2- cyano-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)-3-methylbutanamide was carried forward without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C 8H26BN204: 345.2; found: 345.1
Step 4: Preparation of (S)-2-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1,3,5-triazin-2-yl)phenoxy)-3-methylbutanamide
A mixture of 4-chloro-N-(4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)-1 ,3,5-triazin-2-amine (0.16 g, 0.36 mmol), crude (S)-2-(2-cyano-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)-3-methylbutanamide (0.54 mmol assumed), and tetrakis(triphenylphosphine)palladium(0) (0.031 g, 7.5 mol%) in 1 ,2-dimethoxyethane (DME, 3 mL) was treated saturated aqueous sodium hydrogen carbonate solution (1 .6 mL). The mixture was irradiated for 1 hour in a microwave reactor at 120 °C. The crude mixture was purified by flash chromatography on silica gel to provide (S)-2-(2-cyano-4- (4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenoxy)-3- methylbutanamide. LCMS-ESI"1" (m/z): [M+H]+ calcd for C28H33N8O3: 529.3; found: 529.3
Example 287: 5-(4-((6-(3-hydroxyazetidin-1-yl)pyridin-3-yl)amino)-1,3,5-triazin-2- yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile
Figure imgf000284_0001
Step 1 : Preparation of 1-(5-nitropyridin-2-yl)azetidin-3-ol
A mixture of 2-chloro-5-nitropyridine (2.0 g, 13 mmol) and 3-hydroxyazetidine hydrochloride (1 .5 g, 13 mmol) in N,N-dimethylformamide (8 mL) was cooled in an ice- water bath while triethylamine (3.8 mL, 28 mmol) was added dropwise. At the end of the addition, the mixture was removed from the bath was allowed to stir over the weekend at room temperature. The Slurry was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed once with saturated aqueous sodium chloride solution. The brine wash was back-extracted three times with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated to provide a crude solid, which was triturated with toluene, collected by filtration, and dried under house vacuum to provide 1-(5- nitropyridin-2-yl)azetidin-3-ol. LCMS-ESI"1" (m/z): [M+H]+ calcd for C8H-10 3O3: 196.1 ; found: 196.0
Step 2: Preparation of 1-(5-aminopyridin-2-yl)azetidin-3-ol
A solution of 1-(5-nitropyridin-2-yl)azetidin-3-ol (0.20 g, 1.0 mmol) in ethanol (20 mL) was degassed before the addition of 10 % palladium on carbon (25 mg). The suspension was shaken overnight under 55 psi of hydrogen gas. The suspension was filtered through a pad of Celite diatomaceous earth, and the filtrate was concentrated under reduced pressure to provide 1-(5-aminopyridin-2-yl)azetidin-3-ol. LCMS-ESI+ (m/z): [M+H]+ calcd for C8H12N30: 166.1 ; found: 166.0
Step 3: Preparation of 5-(4-((6-(3-hydroxyazetidin-1-yl)pyridin-3-yl)amino)-1,3,5- triazin-2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile
A suspension of 5-(4-chloro-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2/-/-pyran-4- yl)oxy)benzonitrile (0.13 g, 0.40 mmol) 1-(5-aminopyridin-2-yl)azetidin-3-ol (0.17 g, 1.0 mmol) in acetonitrile (5 mL) was treated with /V,/V-diisopropylethylamine (0.20 mL, 1.2 mmol). The mixture was heated for 20 minutes at 100 °C and was purified by flash chromatography on silica gel to provide 5-(4-((6-(3-hydroxyazetidin-1-yl)pyridin-3- yl)amino)-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile. LCMS-ESI+
(m/z): [M+H]+ calcd for C23H24N7O3: 446.2; found: 446.2
1 H NMR (400 MHz, DMSO-ce) δ 10.10 (m, 1 H), 8.76 (s, 1 H), 8.65 - 8.49 (m, 2H), 8.47
- 8.28 (m, 1 H), 7.84 (t, J = 9.3 Hz, 1 H), 7.60 (d, J = 9.3 Hz, 1 H), 6.49 (dd, J = 17.1 , 8.8 Hz, 1 H), 5.67 (d, J = 6.5 Hz, 1 H), 4.96 (m, 1 H), 4.61 (m, 1 H), 4.19 (m, 2H), 3.90 (m, 2H), 3.71 (m, 2H), 3.59 (t, J = 10.0 Hz, 2H), 2.09 (m, 2H), 1.72 (m, 2H).
Example 288: 2-(((3 ?,4S)-1 -(2,2-difluoroacetyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4- (4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000286_0001
Step 1 : Preparation of (3 ?,4S)-tert-butyl 4-(2-cyano-4-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-1^ carboxylate
Potassium tert-butoxide (0.066 g, 0.58 mmol) was added to a solution of (3R,4S)-tert- butyl 3-fluoro-4-hydroxypiperidine-1 -carboxylate (PharmaBlock, 0.13 g, 0.58 mmol) in 2- methyltetrahydrofuran (5 mL), cooled in an ice-water bath. The resulting suspension was stirred at 0 °C for 30 minutes before the addition of 2-fluoro-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (0.18 g, 0.42 mmol). The mixture was heated at 72 °C overnight and then concentrated under reduced pressure to provide crude (3R,4S)-tert-butyl 4-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 , 3, 5-triazin-2-yl)phenoxy)-3-fluoropiperidine-1 -carboxylate, which was carried forward without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H40FN8O4: 631.3; found: 631.2
Step 2: Preparation of 2-(((3 ?,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Crude (3R,4S)-tert-butyl 4-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 , 3, 5-triazin-2-yl)phenoxy)-3-fluoropiperidine-1 -carboxylate (assumed 0.42 mmol) was taken up in dichloromethane (5 mL) and treated with trifluoroacetic acid (1.3 mL, 17 mmol). After the passage of one hour, the mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (silica gel) to provide 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile.
LCMS-ESI+ (m/z): [M+H]+ calcd for C28H32 N802: 531.3; found: 531.2
Step 3: Preparation of 2-(((3 ?,4S)-1-(2,2-difluoroacetyl)-3-fluoropiperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2- yl)benzonitrile, trifluoroacetic acid salt
2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (74 mg, 0.14 mmol) and difluoroacetic acid (13 μί, 0.21 mmol) were taken up as suspension in dichloromethane (3 mL). The mixture was treated with successively with /V,/V-diisopropylethylamine (49 μί, 0.28 mmol) and HATU (80 mg, 0.21 mmol). The suspension was stirred for approximately 30 minutes and was purified first by flash chromatography (silica gel) and then by prep HPLC (5 - 70 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide 2- (((3R,4S)-1 -(2,2-difluoroacetyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile, trifluoroacetic acid salt.
LCMS-ESI+ (m/z): [M+H]+ calcd for 030^^3^03: 609.3; found: 609.4 1H NMR
(400 MHz, DMSO-c/e) δ 10.82 (bs, 1 H), 10.25 (d, J = 22.9 Hz, 1 H), 8.81 (s, 1 H), 8.63 (dd, J = 9.0, 2.2 Hz, 1 H), 8.58 (bs, 1 H), 7.69 (d, J = 9.2 Hz, 2H), 7.65 (m, 1 H), 7.1 1 (m, 2H), 6.84 (td, J = 52.5, 23.1 Hz, 1 H), 5.23 (m, 1 .5H), 5.19 (m, 1 H), 5.10 (m, 0.5H), 4.82 (m, 4H), 4.59 - 4.39 (m, 1 H), 4.26 - 4.09 (m, 1 H), 3.93 (m, 1 H), 3.82 - 3.24 (m, 2H) 3.13 (s, 4H), 2.24 - 1 .82 (m, 2H).
Example 289: 2-(((3 ?,4S)-1 -acetyl-3-f luoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000287_0001
2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (74 mg, 0.14 mmol) was taken up as suspension in dichloromethane (3 mL) and treated successively with N,N- diisopropylethylamine (51 μΙ_, 0.28 mmol) and acetyl chloride (15 μΙ_, 0.21 mmol). The mixture turned homogeneous, and after approximately 90 minutes, it was concentrated to dryness under reduced pressure. The residue was taken up in pyridine (5 mL) and treated with concentrated ammonium hydroxide solution (28 %, 2 mL). The mixture was stirred for 10 minutes at 60 °C and then concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel) to provide 2- (((3R,4S)-1 -acetyl-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C30H34FN8°3: 573-3; found : 573 4 1 | NMR (400 MHz> DMSO-c/6) δ 10.18 (d, J = 24.9 Hz, 1 H), 8.79 (s, 1 H), 8.60 (m, 2H), 7.68 (d, J = 9.2 Hz, 1 H), 7.60 (m, 1 H), 7.01 (m, 3H), 5.23 - 4.94 (m, 2H), 4.62 (t, J = 6.6 Hz, 2H), 4.52 (m, 2H), 4.37 (m, 0.5H), 4.19 (m, 0.5H), 4.09 (m, 0.5H), 3.81 (m, 0.5H), 3.61 (dd, J = 30.6, 14.5 Hz, 0.5H), 3.53 - 3.45 (m, 1 H), 3.18 (s, 4H), 3.09 (m, 0.5H), 2.46 (m, 4H), 2.1 1 (s, 1.5H), 2.08 (s, 1.5H), 2.06 - 1.94 (m, 2H), 1.91 - 1.77 (m, 1 H). Example 290: (3 ?,4S)-methyl 4-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-1-carboxylate
Figure imgf000288_0001
2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (74 mg, 0.14 mmol) was taken up as suspension in dichloromethane (2 ml_) and treated successively with N,N- diisopropylethylamine (49 μΙ_, 0.28 mmol) and methyl chloroformate (16 μΙ_, 0.21 mmol). The mixture turned homogeneous, and after approximately 5 minutes, it was concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel) to provide (3R,4S)-methyl 4-(2-cyano-4-(4-((4-(4-(oxetan-3- yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-1 - carboxylateA LCMS-ESI+ (m/z): [M+H]+ calcd for C3oH34FN804: 589.3; found: 589.4
1 H NMR (400 MHz, DMSO-ce) δ 10.17 (d, J = 24.9 Hz, 1 H), 8.78 (s, 1 H), 8.71 - 8.52
(m, 2H), 7.66 (d, J = 9.2 Hz, 1 H), 7.61 (m, 2H), 7.02 (m, 2H), 5.14 (m, 1 H), 5.10 - 4.98 (m, 1 H), 4.61 (t, J = 6.5 Hz, 2H), 4.52 (t, J = 6.5 Hz, 2H), 4.16 (m, 1 H), 3.94 (m, 1 H). 3.67 (s, 3H), 3.55 - 3.43 (m, 2H), 3.18 (m, 4H), 2.46 (m, 4H), 2.10 - 1.83 (m, 2H).
Example 291 : 2-(((1 S,2 ?)-2-aminocyclohexyl)oxy)-5-(4-((4-(4-(oxetan-3- enyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000289_0001
Step 1 : Preparation of tert-butyl ((1 ?,2S)-2-(4-bromo-2- cyanophenoxy)cyclohexyl)carbamate
A mixture of 5-bromo-2-hydroxybenzonitrile (1 .0 g, 5.1 mmol) and triphenylphosphine (1 .3 g, 5.1 mmol) in 2-methyltetrahydrofuran (20 ml_) was cooled in an ice-water bath while stirring under an atmosphere of Argon. To the stirred mixture was added dropwise via syringe tert-butyl N-[(1 R,2R)-2-hydroxycyclohexyl]carbamate (PharmaBlock, 1 .0 g, 4.6 mmol, as a solution in 5 ml_ 2-MeTHF), followed by diethyl azodicarboxylate (40 % in toluene, 2.7 ml_, 5.1 mmol). The mixture was stirred overnight under an Ar atmosphere while gradually regaining room temperature. The mixture was concentrated under reduced pressure and purified by flash chromatography (silica gel) to provide tert- butyl ((1 R,2S)-2-(4-bromo-2-cyanophenoxy)cyclohexyl)carbamate. LCMS-ESI+ (m/z): [M-isobutylene+H]+ calcd for C-|4H 6BrN2C>3: 339.0; found: 338.9
Step 2: Preparation of tert-butyl ((1 ?,2S)-2-(2-cyano-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenoxy)cyclohexyl)carbamate
A mixture of tert-butyl ((1 R,2S)-2-(4-bromo-2-cyanophenoxy)cyclohexyl)carbamate (0.13 g, 0.32 mmol), bis(pinacolato)diboron (0.16 g, 0.64 mmol), potassium acetate (0.10 g, 0.96 mmol), and [1 , 1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(l l) complex with dichloromethane (25 mg, 10 mol%) in 1 ,4-dioxane (2 ml_) was heated for 90 minutes at 95 °C. The reaction mixture was filtered through a pad of Celite diatomaceous earth, and the filtrate was concentrated to dryness under reduced pressure. The crude tert-butyl ((1 R,2S)-2-(2-cyano-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenoxy)cyclohexyl)carbamate was carried forward without further purification. LCMS-ESI"1" (m/z): [M-isobutylene+H]+ calcd for C2oH28BN2°5: 387.2; found: 387.0
Step 3: Preparation of tert-butyl ((1 ?,2S)-2-(2-cyano-4-(4-((4-(4-(oxetan-3- yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenoxy)cyclohexyl)carbamate
A mixture of 4-chloro-N-(4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)-1 ,3,5-triazin-2-amine (0.14 g, 0.42 mmol), crude tert-butyl ((1 R,2S)-2-(2-cyano-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenoxy)cyclohexyl)carbamate (0.32 mmol assumed), and tetrakis(triphenylphosphine)palladium(0) (0.028 g, 7.5 mol%) in 1 ,2-dimethoxyethane (DME, 3 ml_) was treated with 2 M aqueous sodium carbonate solution (0.72 ml_). The mixture was irradiated for 75 minutes in a microwave reactor at 120 °C. Additional quantities of 4-chloro-N-(4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)-1 ,3,5-triazin-2-amine (75 mg) and palladium catalyst (25 mg) were added. The mixture was again irradiated for 75 minutes at 130 °C. An additional portion of 4-chloro-N-(4-(4-(oxetan-3- yl)piperazin-1 -yl)phenyl)-1 ,3,5-triazin-2-amine (75 mg) was added, and the mixture was again heated for 75 minutes at 130 °C. After cooling, the biphasic mixture was separated. The aqueous phase was extracted five times with ethyl acetate. The combined extracts were concentrated to dryness under reduced pressure and purified by flash chromatography on silica gel to provide tert-butyl ((1 R,2S)-2-(2-cyano-4-(4-((4- (4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2- yl)phenoxy)cyclohexyl)carbamate. LCMS-ESI+ (m/z): [M+H]+ calcd for C34H43N8O4: 627.3; found: 627.2
Step 4: Preparation of 2-(((1 S,2 ?)-2-aminocyclohexyl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
tert-butyl ((1 R,2S)-2-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)- 1 ,3,5-triazin-2-yl)phenoxy)cyclohexyl)carbamate (86 mg, 0.14 mmol) was taken up in dichloromethane (6 ml_) and treated with trifluoroacetic acid (0.42 ml_, 5.5 mmol). After standing for 2 hours at room temperature, the acidic mixture was basified with 1 : 1 1 M aqueous sodium hydroxide solution/saturated aqueous sodium chloride solution. The aqueous phase was extracted three times with dichloromethane. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated to provide 2-(((1 S,2R)-2-aminocyclohexyl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile.
LCMS-ESI+ (m/z): [M+H]+ calcd for C29H35N802: 527.3; found: 527.3 Example 292: rac-2-(((1 S,2 ?)-2-fluorocyclohexyl)oxy)-5-(4-((4-(piperidin-4- )-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000291_0001
Step 1 : Preparation of rac-5-bromo-2-(((1 S,2R)-2- fluorocyclohexyl)oxy)benzonitrile
A mixture of 5-bromo-2-hydroxybenzonitrile (0.60 g, 3.0 mmol) and triphenylphosphine (0.95 g, 3.6 mmol) in 2-methyltetrahydrofuran (15 ml_) was cooled in an ice-water bath while stirring under an atmosphere of Argon. To the stirred mixture was added dropwise via syringe trans-2-fluoro-1-cyclohexanol (0.43 g, 3.6 mmol), followed by diethyl azodicarboxylate (40 % solution in toluene, 2.1 ml_, 4.5 mmol). The mixture was stirred overnight under an Argon atmosphere, gradually regaining room temperature. The mixture was purified by flash chromatography on silica gel to provide rac-5-bromo-2- (((1 S,2R)-2-fluorocyclohexyl)oxy)benzonitrile. 1H NMR (400 MHz, DMSO-c/6) δ 8.04 (d, J = 2.5 Hz, 1 H), 7.85 (dd, J = 9.1 , 2.6 Hz, 1 H), 7.38 (d, J = 9.1 Hz, 1 H), 4.96 (m, 1 H), 4.87 (m, 1 H), 2.01 (m, 1 H), 1.87 (m, 2H), 1.75 (m, 1 H), 1.63 (m, 2H), 1.45 (m, 2H). Step 2: Preparation of rac-2-(((1 S,2 ?)-2-fluorocyclohexyl)oxy)-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile
A mixture of rac-5-bromo-2-(((1 S,2R)-2-fluorocyclohexyl)oxy)benzonitrile.(0.31 g, 1.0 mmol), bis(pinacolato)diboron (0.53 g, 2.1 mmol), potassium acetate (0.30 g, 3.1 mmol), and [1 ,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) complex with dichloromethane (76 mg, 10 mol%) in 1 ,4-dioxane (6 ml_) was heated for 4 hours at 95 °C. The reaction mixture was filtered through a pad of Celite diatomaceous earth, and the filtrate was concentrated to dryness under reduced pressure. The crude rac-2- (((1 S,2R)-2-fluorocyclohexyl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzonitrile was carried forward without further purification. LCMS-ESI+ (m/z):
[M+OH+H]+ calcd for C-19H27BFNO4: 363.2; found: 363.1
Step 3: Preparation of tert-butyl 4-(4-((4-chloro-1,3,5-triazin-2- yl)amino)phenyl)piperidine-1-carboxylate
To a solution of 2,4-dichloro-1 ,3,5-triazine (0.60 g, 4.0 mmol) in N,N-dimethylformamide
(DMF, 8 ml.) at 0 °C were added sequentially N,/V-diisopropylethylamine (DIEA, 0.73 ml_, 4.2 mmol) and tert-butyl 4-(4-aminophenyl)piperidine-1 -carboxylate (1 .0 g, 3.6 mmol). The mixture was stirred at 0 °C for 30 minutes and then allowed to warm to room temperature. The mixture was diluted with ethyl acetate and water and filtered through a pad of Celite diatomaceous earth. The aqueous phase was extracted twice with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel) to provide tert-butyl 4-(4-((4-chloro-1 ,3,5-triazin-2- yl)amino)phenyl)piperidine-1 -carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for C-19H25CIN5O2: 390.2; found: 389.8
Step 4: Preparation of rac-tert-butyl 4-(4-((4-(3-cyano-4-(((1 S,2 ?)-2- fluorocyclohexyl)oxy)phenyl)-1 ,3,5-triazin-2-yl)amino)phenyl)piperidine-1 - carboxylate
A mixture of tert-butyl 4-(4-((4-chloro-1 ,3,5-triazin-2-yl)amino)phenyl)piperidine-1 - carboxylate (0.16 g, 0.40 mmol), crude rac-2-(((1 S,2R)-2-fluorocyclohexyl)oxy)-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (0.52 mmol assumed), and tetrakis(triphenylphosphine)palladium(0) (0.035 g, 7.5 mol%) in 1 ,2-dimethoxyethane (DME, 3 ml_) was treated with 2 M aqueous sodium carbonate solution (0.90 ml_). The mixture was irradiated for 75 minutes in a microwave reactor at 130 °C. After cooling, the biphasic mixture was separated. The aqueous phase was extracted five times with ethyl acetate. The combined extracts were concentrated to dryness under reduced pressure and purified by flash chromatography on silica gel to provide rac-tert-butyl 4-(4- ((4-(3-cyano-4-(((1 S,2R)-2-fluorocyclohexyl)oxy)phenyl)-1 ,3,5-triazin-2- yl)amino)phenyl)piperidine-1 -carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for
C32H38FN6°3: 573-3; found : 573 3
Step 5: Preparation of rac-2-(((1 S,2 ?)-2-fluorocyclohexyl)oxy)-5-(4-((4-(piperidin- 4-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
rac-tert-butyl 4-(4-((4-(3-cyano-4-(((1 S,2R)-2-fluorocyclohexyl)oxy)phenyl)-1 ,3,5-triazin- 2-yl)amino)phenyl)piperidine-1 -carboxylate (0.15 g, 0.25 mmol) was taken up in dichloromethane (6 ml_) and treated with trifluoroacetic acid (0.78 ml_, 10 mmol). After completion of the deprotection, the mixture was concentrated under reduced pressure. The residue was partitioned between dichloromethane and 0.5 M aqueous sodium hydroxide solution. The aqueous phase was extracted three times with dichloromethane. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated to provide rac-2-(((1 S,2R)-2-fluorocyclohexyl)oxy)-5- (4-((4-(piperidin-4-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C27H30N6O3: 473.2; found: 473.4 1 H NMR (400
MHz, DMSO-c/6) δ 10.31 (bs, 1 H), 8.83 (s, 1 H), 8.68 - 8.55 (m, 2H), 7.71 (m, 2H), 7.61
(d, J = 9.4 Hz, 1 H), 7.27 (d, J = 8.0 Hz, 2H), 5.13 - 4.84 (m, 2H), 3.38 (br, 4H), 3.07 (d, J = 1 1.7 Hz, 2H), 2.63 (m, 2H), 2.06 (m, 1 H), 1.93 (m, 1 H), 1.88 - 1.62 (m, 4H), 1.62 - 1.41 (m, 4H).
Example 293: 2-(((3 ?,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5- (4-((4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000293_0001
Step 1 : Preparation of 4-chloro-W-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-1 ,3,5- triazin-2-amine
To a solution of 2,4-dichloro-1 ,3,5-triazine (0.93 g, 6.2 mmol) in N,N-dimethylformamide
(DMF, 10 ml.) at 0 °C were added sequentially N,/V-diisopropylethylamine (DIEA, 1.1 ml_, 6.5 mmol) and a solution of 4-(oxan-4-yl)aniline (Combi-Blocks, 1.0 g, 5.6 mmol) in
DMF (5 ml_). The mixture was stirred at 0 °C for 30 minutes and then allowed to warm to room temperature overnight. The mixture was diluted with first with toluene and half- saturated aqueous sodium hydrogen carbonate solution and then with ethyl acetate and water. The mixture was filtered through a pad of Celite diatomaceous earth. The aqueous phase was extracted thrice with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel) to provide 4- chloro-/V-(4-(tetrahydro-2/-/-pyran-4-yl)phenyl)-1 ,3,5-triazin-2-amine.
LCMS-ESI+ (m/z): [M+H]+ calcd for C-|4H 6CIN40: 291.1 ; found: 291.2
Step 2: Preparation of (3 ?,4S)-tert-butyl 4-(4-bromo-2-cyanophenoxy)-3- fluoropiperidine-1 -carboxylate
A solution (3R,4S)-tert-butyl 3-fluoro-4-hydroxypiperidine-1 -carboxylate (PharmaBlock, 0.60 g, 2.8 mmol) in N,N-dimethylformamide (10 ml_) was treated with sodium hydride (60 % dispersion in mineral oil, 0.1 1 g, 2.8 mmol) in a single portion at room temperature. After the mixture was stirred for 30 minutes at room temperature, 5- bromo-2-fluorobenzonitrile (0.50 g, 2.5 mmol) was added in a single portion at room temperature. The mixture was stirred overnight with heating at 50 °C. The mixture was quenched with glacial acetic acid and purified by flash chromatography on silica gel to provide (3R,4S)-tert-butyl 4-(4-bromo-2-cyanophenoxy)-3-fluoropiperidine-1- carboxylate. LCMS-ESI"1" (m/z): [M-isobutylene+H]+ calcd for C-| 3H-| 3BrFN2C>3: 343.0; found: 342.9
Step 3: Preparation of (3 ?,4S)-tert-butyl 4-(2-cyano-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenoxy)-3-fluoropiperidine-1 -carboxylate
A mixture of (3R,4S)-tert-butyl 4-(4-bromo-2-cyanophenoxy)-3-fluoropiperidine-1- carboxylate (0.27 g, 0.67 mmol), bis(pinacolato)diboron (0.34 g, 1.3 mmol), potassium acetate (0.20 g, 2.0 mmol), and [1 ,1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) complex with dichloromethane (67 mg, 10 mol%) in 1 ,4-dioxane (3 ml_) was heated overnight at 90 °C. The reaction mixture was filtered through a pad of Celite diatomaceous earth, and the filtrate was concentrated to dryness under reduced pressure. The crude (3R,4S)-tert-butyl 4-(2- cyano-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)-3-fluoropiperidine-1- carboxylate was carried forward without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C23H33BFN2C>5: 447.2; found: 446.8
Step 4: Preparation of (3 ?,4S)-tert-butyl 4-(2-cyano-4-(4-((4-(tetrahydro-2H-pyran- 4-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-1 -carboxylate
A mixture of 4-chloro-/V-(4-(tetrahydro-2/-/-pyran-4-yl)phenyl)-1 ,3,5-triazin-2-amine (0.15 g, 0.51 mmol), (3R,4S)-tert-butyl 4-(2-cyano-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)phenoxy)-3-fluoropiperidine-1 -carboxylate (0.66 mmol assumed), and tetrakis(triphenylphosphine)palladium(0) (0.044 g, 7.5 mol%) in 1 ,2-dimethoxyethane (DME, 3 ml_) was treated with 2 M aqueous sodium carbonate solution (1.1 ml_). The mixture was irradiated for 75 minutes in a microwave reactor at 130 °C. After cooling, the biphasic mixture was separated. The aqueous phase was extracted five times with ethyl acetate. The combined extracts were concentrated to dryness under reduced pressure to provide crude (3R,4S)-tert-butyl 4-(2-cyano-4-(4-((4-(tetrahydro-2/-/-pyran-4- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-1-carboxylate, which was carried forward without further purification.
LCMS-ESI+ (m/z): [M+H]+ calcd for C31 H36FN604: 575.3; found: 575.1
Step 5: Preparation of 2-(((3 ?,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(tetrahydro- 2H-pyran-4-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Crude (3R,4S)-tert-butyl 4-(2-cyano-4-(4-((4-(tetrahydro-2/-/-pyran-4-yl)phenyl)amino)- 1 ,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-1 -carboxylate (0.51 mmol assumed) was taken up in dichloromethane (6 mL) and treated with trifluoroacetic acid (1 .6 mL, 20 mmol). After the completion of the deprotection, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel) to provide 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(tetrahydro-2/-/-pyran-4- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for
C26H28FN6°2: 475-2; found : 475 2
Step 6: Preparation of 2-(((3 ?,4S)-3-fluoro-1 -((S)-2-hydroxypropanoyl)piperidin-4- yl)oxy)-5-(4-((4-(tetrahydro-2H^yran-4-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile
2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(tetrahydro-2/-/-pyran-4-yl)phenyl)amino)- 1 ,3,5-triazin-2-yl)benzonitrile (73 mg, 0.15 mmol) and L-(-)-lactic acid (Sigma Aldrich, 21 mg, 0.23 mmol) were taken up in N,N-dimethylformamide (1 mL). The mixture was treated successively with /V,/V-diisopropylethylamine (80 μί, 0.46 mmol) and N- [(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1 -ylmethylene]-N- methylmethanaminiumhexafluorophosphate W-oxide (HATU, 88 mg, 0.23 mmol). The mixture remained at room temperature for one hour and was then purified by prep HPLC (5 - 85 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide 2-(((3R,4S)-3-fluoro-1 -((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4-(tetrahydro- 2/-/-pyran-4-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for C29H32FN604: 547.2; found: 547.3 1 H NMR (400 MHz, DMSO-c/6) δ 10.32 (bs, 1 H), 8.84 (s, 1 H), 8.64 (dd, J = 9.2, 1 .9 Hz, 2H), 7.84 - 7.64 (m, 3H), 7.31 (m, 2H), 5.27 - 4.98 (m, 2H), 4.51 (m, 2H), 4.31 - 4.06 (m, 1 H), 3.99 (m, 2H), 3.69 (dd, J = 28.6, 14.2 Hz, 0.5H), 3.56 - 3.31 (m, 3H), 3.20 (m, 0.5H), 2.79 (m, 1 H), 2.02 (m, 1 H), 1 .89 (m, 1 H), 1 .72 (m, 4H), 1 .25 (m, 3H).
Example 294: 5-(4-((1 -(ferf-butyl)-l H-pyrazol-4-yl)amino)-1 ,3,5-triazin-2-yl)-2- -2-hydroxypropanoyl)piperidin-4-yl)oxy)benzonitrile
Figure imgf000296_0001
Step 1 : Preparation of W-(1 -(ferf-butyl)-1 H-pyrazol-4-yl)-4-chloro-1,3,5-triazin-2- amine
To a solution of 2,4-dichloro-1 ,3,5-triazine (1.2 g, 7.9 mmol) in N,N-dimethylformamide
(DMF, 10 ml.) at 0 °C were added sequentially N,/V-diisopropylethylamine (DIEA, 1.4 ml_, 8.3 mmol) and a solution of 1-(ferf-butyl)-1 /-/-pyrazol-4-amine (Matrix Scientific, 1 .0 g, 7.2 mmol) in DMF (15 ml_). The mixture was allowed to warm to room temperature. The mixture was diluted with ethyl acetate and water. The aqueous phase basified with saturated aqueous sodium hydrogen carbonate solution and then was extracted thrice with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel) to provide W-(1-(fert-butyl)-1 - -pyrazol-4-yl)-4-chloro-
1 ,3,5-triazin-2-amine. LCMS-ESI+ (m/z): [M+H]+ calcd for C 0H 4CIN6: 253.1 ; found: 252.9
Step 2: Preparation of (3 ?,4S)-ferf-butyl 4-(4-(4-((1 -(ferf-butyl)-1 H-pyrazol-4- yl)amino)-1 ,3,5-triazin-2-yl)-2-cyanophenoxy)-3-fluoropiperidine-1 -carboxylate A mixture of N-(1-(ferf-butyl)-1 /-/-pyrazol-4-yl)-4-chloro-1 ,3,5-triazin-2-amine (0.1 1 g, 0.42 mmol), crude (3R,4S)-tert-butyl 4-(2-cyano-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenoxy)-3-fluoropiperidine-1-carboxylate (0.52 mmol assumed), and tetrakis(triphenylphosphine)palladium(0) (0.036 g, 7.5 mol%) in 1 ,2-dimethoxyethane (DME, 3 ml_) was treated with 2 M aqueous sodium carbonate solution (0.94 ml_). The mixture was irradiated for 75 minutes in a microwave reactor at 130 °C. After cooling, the biphasic mixture was separated. The aqueous phase was extracted five times with ethyl acetate. The combined extracts were concentrated to dryness under reduced pressure to provide crude (3R,4S)-ferf-butyl 4-(4-(4-((1-(ferf-butyl)-1 /-/-pyrazol-4- yl)amino)-1 ,3,5-triazin-2-yl)-2-cyanophenoxy)-3-fluoropiperidine-1 -carboxylate, which was carried forward without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C27H34FN803: 537.3; found: 537.1
Step 3: Preparation of 5-(4-((1-(ferf-butyl)-1H-pyrazol-4-yl)amino)-1,3,5-triazin-2- yl)-2-(((3 ?,4S)-3-fluoropiperidin-4-yl)oxy)benzonitrile
(3R,4S)-ferf-butyl 4-(4-(4-((1-(iert-butyl)-1 H^yrazol-4-yl)amino)-1 ,3,5-triazin-2-yl)-2- cyanophenoxy)-3-fluoropiperidine-1-carboxylate (0.42 mmol assumed) was taken up in dichloromethane (6 mL) and treated with trifluoroacetic acid (1.3 mL, 17 mmol). After the passage of two hours, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel) to provide 5-(4-((1-(fert-butyl)- 1 /-/-pyrazol-4-yl)amino)-1 ,3,5-triazin-2-yl)-2-(((3R,4S)-3-fluoropiperidin-4- yl)oxy)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for C22H26FN80: 437.2; found: 437.1
Step 4: Preparation of 5-(4-((1-(ferf-butyl)-1H-pyrazol-4-yl)amino)-1,3,5-triazin-2- yl)-2-(((3 ?,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)benzonitrile
5-(4-((1-(ferf-butyl)-1 H-pyrazol-4-yl)amino)-1 ,3,5-triazin-2-yl)-2-(((3R,4S)-3- fluoropiperidin-4-yl)oxy)benzonitrile (87 mg, 0.20 mmol) and L-(-)-lactic acid (Sigma Aldrich, 27 mg, 0.30 mmol) were taken up in N,N-dimethylformamide (1 mL). The mixture was treated successively with /V,/V-diisopropylethylamine (100 μί, 0.60 mmol) and A -[(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1 -ylmethylene]-N- methylmethanaminiumhexafluorophosphate W-oxide (HATU, 110 mg, 0.30 mmol). The mixture remained at room temperature for one hour and then was refrigerated for 2 days. The mixture was purified by prep HPLC (5 - 85 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide 5-(4-((1-(ferf-butyl)-1 /-/-pyrazol-4- yl)amino)-1 ,3,5-triazin-2-yl)-2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4- yl)oxy)benzonitrile.
LCMS-ESI+ (m/z): [M+H]+ calcd for C25H3oFN803: 509.2; found: 509.2 H NMR (400
MHz, DMSO-d6) δ 10.35 (s, 0.6H), 10.30 (s, 0.4H), 8.86 (s, 0.4H), 8.76 (s, 0.6H), 8.70 -
8.55 (m, 2H), 8.15 (s, 0.6H), 8.05 (s, 0.4H), 7.72 (s, 0.6H), 7.68 (m, 1 H), 7.65 (s, 0.4H), 5.28 - 4.99 (m, 3H), 4.52 (m, 1 H), 4.45 (m, 0.5H), 4.22 (m, 0.5H), 4.12 (m, 0.5H), 4.00 (m, 0.5H), 3.69 (dd, J = 28.7, 14.4 Hz, 0.5H), 3.39 (m, 1 H), 3.22 (m, 0.5H), 2.01 (m, 1.5H), 1.89 (m, 0.5H), 1.61 (s, 5H), 1.56 (s, 4H), 1.25 (dd, J = 6.4, 3.5 Hz, 3H). Example 295: rac-2-(((1 S,2 ?)-2-f luorocyclohexyl)oxy)-5-(4-((1 -(piperidin-4-yl)-1 H- pyrazol-4-yl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000298_0001
Step 1 : Preparation of ferf-butyl 4-(4-((4-chloro-1 ,3,5-triazin-2-yl)amino)-1 H- pyrazol-1 -yl)piperidine-1 -carboxylate: To a solution of 2,4-dichloro-1 ,3,5-triazine (0.62 g, 4.1 mmol) in Ν,Ν-dimethylformamide (DMF, 10 mL) at 0 °C were added sequentially N,/V-diisopropylethylamine (DIEA, 0.75 mL, 4.3 mmol) and ferf-butyl 4-(4-amino-1 /-/- pyrazol-1 -yl)piperidine-1 -carboxylate (Combi-Blocks, 1 .0 g, 3.8 mmol). The mixture was allowed to warm to room temperature. The mixture was diluted with ethyl acetate and water. The aqueous phase basified with saturated aqueous sodium hydrogen carbonate solution and then was extracted thrice with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel) to provide ferf-butyl 4-(4-((4-chloro-1 ,3,5-triazin-2-yl)amino)-1 H-pyrazol-1 -yl)piperidine-1 - carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for C 6H23CIN702: 380.2; found: 379.8
Step 2: Preparation of rac-ferf-butyl 4-(4-((4-(3-cyano-4-(((1 S,2 ?)-2- fluorocyclohexyl)oxy)phenyl)-1 ,3,5-triazin-2-yl)amino)-1 H-pyrazol-1 -yl)piperidine- 1 -carboxylate: A mixture ferf-butyl 4-(4-((4-chloro-1 ,3,5-triazin-2-yl)amino)-1 /-/-pyrazol- 1-yl)piperidine-1 -carboxylate (0.15 g, 0.40 mmol), crude rac-2-(((1 S,2R)-2- fluorocyclohexyl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (0.52 mmol assumed), and tetrakis(triphenylphosphine)palladium(0) (0.035 g, 7.5 mol%) in 1 ,2-dimethoxyethane (DME, 3 mL) was treated with 2 M aqueous sodium carbonate solution (0.90 mL). The mixture was irradiated for 75 minutes in a microwave reactor at 130 °C. After cooling, the biphasic mixture was separated. The aqueous phase was extracted five times with ethyl acetate. The combined extracts were concentrated to dryness under reduced pressure and purified by flash chromatography on silica gel to provide rac-ferf-butyl 4-(4-((4-(3-cyano-4-(((1 S,2R)-2-fluorocyclohexyl)oxy)phenyl)-1 ,3,5- triazin-2-yl)amino)-1 /-/-pyrazol-1 -yl)piperidine-1 -carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for C29H36FN803: 563.3; found: 563.2 Step 3: Preparation of rac-2-(((1 S,2 ?)-2-fluorocyclohexyl)oxy)-5-(4-((1 -(piperidin- 4-yl)-1 H-pyrazol-4-yl)amino)-1 ,3,5-triazin-2-yl)benzonitrile: rac-ferf-butyl 4-(4-((4-(3- cyano-4-(((1 S,2R)-2-fluorocyclohexyl)oxy)phenyl)-1 ,3,5-triazin-2-yl)amino)-1 /-/-pyrazol- 1 -yl)piperidine-1 -carboxylate (0.13 g, 0.24 mmol) was taken up in dichloromethane (6 mL) and treated with trifluoroacetic acid (0.72 mL, 9.4 mmol). After standing overnight at room temperature, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel) to provide rac-2-(((1 S,2R)-2- fluorocyclohexyl)oxy)-5-(4-((1 -(piperidin-4-yl)-1 /-/-pyrazol-4-yl)amino)-1 ,3,5-triazin-2- yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C24H28 N80: 463.2; found: 463.3 H NMR (400 MHz, DMSO-c/6) δ 10.35 (s, 1 H), 8.85 (s, 0.5H), 8.76 (s, 0.5H), 8.68 - 8.57 (m, 2H), 8.06 (d, J = 5.4 Hz, 1 H), 7.79 (s, 0.5H), 7.67 (s, 0.5H), 7.64 - 7.56 (m, 1 H), 5.15 - 4.86 (m, 2H), 4.48 (m, 1 H), 3.36 (m, 3H), 2.98 (m, 2H), 2.28 - 2.00 (m, 5H), 2.00 - 1 .77 (m, 2H), 1 .77 - 1 .60 (m, 2H), 1 .48 (m, 3H). Example 296: 2-(((3 ?,4S)-3-fluoro-1-formylpiperidin-4-yl)oxy)-5-(4-((3-fluoro-4- (piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000299_0001
Step 1 : Preparation of ferf-butyl 4-(4-((4-chloro-1 ,3,5-triazin-2-yl)amino)-2- fluorophenyl)piperazine-1-carboxylate: To a solution of 2,4-dichloro-1 ,3,5-triazine
(0.95 g, 6.3 mmol) in N,/V-dimethylformamide (DMF, 10 mL) at 0 °C were added sequentially /V,/V-diisopropylethylamine (DIEA, 1 .2 mL, 6.6 mmol) and a solution of ferf- butyl 4-(4-amino-2-fluorophenyl)piperazine-1 -carboxylate (1 .7 g, 5.8 mmol) in DMF (10 mL). The mixture was allowed to warm to room temperature. The mixture was diluted with ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The aqueous phase was extracted thrice each with ethyl acetate and dichloromethane. The combined extracts were concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel) to provide ferf-butyl 4-(4-((4-chloro-1 ,3,5- triazin-2-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for C-|8H23CIFN6C>2: 409.2; found: 408.8
Step 2: Preparation of 5-bromo-2-(((3 ?,4S)-3-fluoropiperidin-4-yl)oxy)benzonitrile hydrochloride: A mixture of (3R,4S)-tert-butyl 4-(4-bromo-2-cyanophenoxy)-3- fluoropiperidine-1-carboxylate (1.4 g, 3.4 mmol) in 4 N hydrogen chloride/dioxanes (20 ml_) was stirred for 30 minutes at 35 - 40 °C. At the completion of the reaction, as determined by LC analysis, the mixture was concentrated under reduced pressure to provide 5-bromo-2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)benzonitrile hydrochloride.
LCMS-ESI+ (m/z): [M+H]+ calcd for C 2H 3BrFN20: 299.0; found: 299.1
Step 3: Preparation of 5-bromo-2-(((3 ?,4S)-3-fluoro-1-formylpiperidin-4- yl)oxy)benzonitrile: 5-bromo-2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)benzonitrile hydrochloride (1.1 g, 3.2 mmol) was taken up as a suspension in N,N- dimethylformamide and was treated sequentially with the following reagents: N,N- diisopropylethylamine (2.2 ml_, 13 mmol), formic acid (0.14 ml_, 3.8 mmol), and N- [(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1 -ylmethylene]-N- methylmethanaminiumhexafluorophosphate W-oxide (HATU, 1.5 g, 3.9 mmol). in an effervescent and exothermic reaction. The resulting suspension was swirled manually for about one minute until homogeneous. The mixture was refrigerated for 2 days.
Mixture was diluted with saturated aqueous sodium hydrogen carbonate solution and extracted three times with ethyl acetate. The combined organic extracts were washed once with water and once with saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, filtered, concentrated to dryness under reduced pressure to provide 5-bromo-2-(((3R,4S)-3-fluoro-1-formylpiperidin-4- yl)oxy)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C 3H1 3BrFN202: 327.0; found: 327.1
Step 4: Preparation of 2-(((3 ?,4S)-3-fluoro-1-formylpiperidin-4-yl)oxy)-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile: A mixture of 5-bromo-2-(((3R,4S)-3- fluoro-1-formylpiperidin-4-yl)oxy)benzonitrile (0.38 g, 1.2 mmol), bis(pinacolato)diboron (0.59 g, 2.3 mmol), potassium acetate (0.34 g, 3.5 mmol), and [1 ,1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) complex with dichloromethane (84 mg, 10 mol%) in 1 ,4-dioxane (6 ml_) was heated overnight at 90 °C. The reaction mixture was filtered through a pad of Celite diatomaceous earth, and the filtrate was concentrated to dryness under reduced pressure. The crude 2-(((3R,4S)-3-fluoro-1- formylpiperidin-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile was carried forward without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C-19H25BFN2O4: 375.2; found: 375.3
Step 5: Preparation of ferf-butyl 4-(4-((4-(3-cyano-4-(((3 ?,4S)-3-fluoro-1- formylpiperidin-4-yl)oxy)phenyl)-1 ,3,5-triazin-2-yl)amino)-2- fluorophenyl)piperazine-1-carboxylate: A mixture of ferf-butyl 4-(4-((4-chloro-1 ,3,5- triazin-2-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (0.31 g, 0.75 mmol), crude
2- (((3R,4S)-3-fluoro-1-formylpiperidin-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzonitrile (1.1 mmol assumed), and tetrakis(triphenylphosphine)palladium(0) (0.065 g, 7.5 mol%) in 1 ,2-dimethoxyethane (DME, 7 ml_) was treated with 2 M aqueous sodium carbonate solution (2.5 ml_). The mixture was irradiated for 75 minutes in a microwave reactor at 130 °C. After cooling, the biphasic mixture was separated. The aqueous phase was extracted five times with ethyl acetate. The combined extracts were concentrated to dryness under reduced pressure to provide crude ferf-butyl 4-(4-((4-(3-cyano-4-(((3R,4S)-3-fluoro-1- formylpiperidin-4-yl)oxy)phenyl)-1 ,3,5-triazin-2-yl)amino)-2-fluorophenyl)piperazine-1- carboxylate, which was carried forward without further purification.
LCMS-ESI+ (m/z): [M+H]+ calcd for C31 H34F2N804: 621.3; found: 620.8
Step 6: Preparation of 2-(((3 ?,4S)-3-fluoro-1-formylpiperidin-4-yl)oxy)-5-(4-((3- fluoro-4-(piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile: Crude ferf- butyl 4-(4-((4-(3-cyano-4-(((3R,4S)-3-fluoro-1-formylpiperidin-4-yl)oxy)phenyl)-1 ,3,5- triazin-2-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (0.75 mmol assumed) was taken up in dichloromethane (6 ml_) and treated with trifluoroacetic acid (2.3 ml_, 30 mmol). After standing for two hours at room temperature, the mixture was concentrated under reduced pressure. The residue was purified first by flash chromatography (silica gel) and then by prep HPLC (5 - 75 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer). The combined HPLC fractions were basified with 0.5 M sodium hydroxide solution and extracted three times with dichloromethane. The combined organics were dried over anhydrous magnesium sulfate, filtered, concentrated to provide 2-(((3R,4S)-
3- fluoro-1-formylpiperidin-4-yl)oxy)-5-(4-((3-fluoro-4-(piperazin-1-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C26H27 2N8O2: 521.2; found: 521.4 1H NMR (400 MHz, DMSO-c/6) δ 10.40 (bs, 1 H), 8.86 (bs, 1 H), 8.71 - 8.55 (m, 2H), 8.17 (s, 0.5H), 8.06 (s, 0.5H), 7.78 - 7.65 (m, 2H), 7.47 (bs, 1 H), 7.07 (dd, J = 9.3 Hz, 1 H), 5.26 - 5.1 1 (m, 1.5H), 5.07 (m, 0.5H), 4.36 - 4.24 (m, 0.5H), 4.17 - 4.05 (m, 0.5H), 3.97 (m, 0.5H), 3.79 (m, 1 H), 3.69 - 3.52 (m, 0.5H), 3.36 (m, 2H), 3.09 (m, 0.5H), 3.02 - 2.83 (m, 8H), 2.18 - 1.90 (m, 1.5H), 1.90 - 1.75 (m, 0.5H). Example 297: 2-(((3 ?,4S)-3-fluorotetrahydro-2H-pyran-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000302_0001
Step 1 : Preparation of (3 ?,4S)-3-fluorotetrahydro-2H-pyran-4-ol: (R)-3- fluorodihydro-2/-/-pyran-4(3/-/)-one was prepared according to Kwiatkowski, P. et al J. Am. Chem. Soc, 201 1 , 133 (6), 1738-1741.
A stirred solution of (R)-3-fluorodihydro-2/-/-pyran-4(3/-/)-one (1.0 g, 8.5 mmol) in tetrahydrofuran (10 mL) was cooled to -78 °C under an Argon atmosphere. L-Selectride solution in tetrahydrofuran (1.0 M, 8.9 mL) was added dropwise and the reaction was stirred for 30 minutes. Methanol (32 μί) and 1 M aqueous sodium hydroxide solution (25 mL) were then added, and the reaction was allowed to warm to 0 °C. To the solution was added slowly dropwise 30 wt % hydrogen peroxide solution (4.3 mL), and the reaction was stirred for an additional 30 minutes. The reaction mixture was extracted four times with ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate, decanted, concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel) to provide (3R,4S)-3-fluorotetrahydro-2/-/-pyran-4-ol. 1 H NMR (400 MHz, Chloroform-c ) δ 4.74 - 4.49 (m, 1 H), 4.04 (dddd, J = 12.7, 9.4, 5.0,
I .1 Hz, 1 H), 3.97 - 3.84 (m, 2H), 3.58 (ddd, J = 27.0, 12.6, 2.3 Hz, 1 H), 3.46 (dddd, J =
I I .9, 8.6, 3.4, 1.9 Hz, 1 H), 2.00 - 1.79 (m, 2H).
Step 2: Preparation of 2-(((3 ?,4S)-3-fluorotetrahydro-2H-pyran-4-yl)oxy)-5-(4-((4- (4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Potassium tert-butoxide (0.066 g, 0.58 mmol) was added to a solution of (3R,4S)-3- fluorotetrahydro-2/-/-pyran-4-ol (0.07 g, 0.59 mmol) in 2-methyltetrahydrofuran (3 mL), cooled in an ice-water bath. The resulting suspension was stirred at room temperature for 5 hours before the addition of 2-fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (0.085 g, 0.20 mmol). The mixture was heated at 75 °C overnight and was then purified by flash chromatography (silica gel) to provide 2-(((3R,4S)-3-fluorotetrahydro-2/-/-pyran-4-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C28H31 FN7O3: 532.2; found: 532.3
1H NMR (400 MHz, DMSO-c/6) δ 10.17 (d, J = 23.9 Hz, 1 H), 8.78 (s, 1 H), 8.62 (m, 2H), 7.68 (d, J = 9.2 Hz, 1 H), 7.64 (m, 2H), 7.01 (m, 2H), 5.24 - 5.01 (m, 1 .5H), 4.95 (m, 0.5H), 4.61 (t, J = 6.5 Hz, 2H), 4.52 (t, J = 6.0 Hz, 2H), 4.05 (m, 1 H), 3.98 - 3.89 (m, 1 H), 3.80 - 3.64 (m, 1 H), 3.64 - 3.55 (m, 1 H), 3.50 (m, 1 H), 3.18 (m, 4H), 2.45 (m, 4H), 2.14 - 1 .95 (m, 2H).
Example 298: 5-(4-((3-fluoro-4-(piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2- 3 ?,4S)-3-fluorotetrahydro-2H-pyran-4-yl)oxy)benzonitrile
Figure imgf000303_0001
Step 1 : Preparation of ferf-butyl 4-(4-((4-(3-cyano-4-fluorophenyl)-1 ,3,5-triazin-2- yl)amino)-2-fluorophenyl)piperazine-1 -carboxylate: A mixture of ferf-butyl 4-(4-((4- chloro-1 ,3,5-triazin-2-yl)amino)-2-fluorophenyl)piperazine-1 -carboxylate (0.50 g, 1 .2 mmol), 2-fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (0.33 g, 1 .3 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.1 1 g, 7.5 mol%) in 1 ,2- dimethoxyethane (DME, 7 mL) was treated with 2 M aqueous sodium carbonate solution (2.7 mL). The mixture was irradiated for 75 minutes in a microwave reactor at 130 °C. After cooling, the biphasic mixture was separated. The aqueous phase was extracted five times with ethyl acetate. The combined extracts were concentrated to dryness under reduced pressure and the residue was purified by flash chromatography (silica gel) to provide ferf-butyl 4-(4-((4-(3-cyano-4-fluorophenyl)-1 ,3,5-triazin-2-yl)amino)-2- fluorophenyl)piperazine-1 -carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for C25H26F2N7°2: 494-2; found: 493.8
Step 2: Preparation of ferf-butyl 4-(4-((4-(3-cyano-4-(((3 ?,4S)-3-fluorotetrahydro-
2H-pyran-4-yl)oxy)phenyl)-1 ,3,5-triazin-2-yl)amino)-2-fluorophenyl)piperazine-1 - carboxylate
Potassium tert-butoxide (0.1 1 g, 0.97 mmol) was added to a solution of (3R,4S)-3- fluorotetrahydro-2/-/-pyran-4-ol (0.12 g, 0.97 mmol) in 2-methyltetrahydrofuran (5 mL), cooled in an ice-water bath. The resulting suspension was stirred at room temperature for 5 hours before the addition of ferf-butyl 4-(4-((4-(3-cyano-4-fluorophenyl)-1 ,3,5- triazin-2-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (0.24 g, 0.49 mmol). The mixture was concentrated under reduced pressure to provide crude ferf-butyl 4-(4-((4-(3- cyano-4-(((3R,4S)-3-fluorotetrahydro-2/-/-pyran-4-yl)oxy)phenyl)-1 ,3,5-triazin-2- yl)amino)-2-fluorophenyl)piperazine-1-carboxylate, which was carried forward without further purification.
LCMS-ESI+ (m/z): [M+H]+ calcd for C30H34F2N7O4: 594.3; found: 593.9
Step 3: Preparation of 5-(4-((3-fluoro-4-(piperazin-1-yl)phenyl)amino)-1,3,5-triazin- 2-yl)-2-(((3 ?,4S)-3-fluorotetrahydro-2H-pyran-4-yl)oxy)benzonitrile
Crude ferf-butyl 4-(4-((4-(3-cyano-4-(((3R,4S)-3-fluorotetrahydro-2/-/-pyran-4- yl)oxy)phenyl)-1 ,3,5-triazin-2-yl)amino)-2-fluorophenyl)piperazine-1-carboxylate (0.49 mmol assumed) was taken up in dichloromethane (5 mL) and treated with trifluoroacetic acid (1.5 mL, 19 mmol). After standing for one hour at room temperature, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel) to provide 5-(4-((3-fluoro-4-(piperazin-1-yl)phenyl)amino)- 1 ,3,5-triazin-2-yl)-2-(((3R,4S)-3-fluorotetrahydro-2/-/-pyran-4-yl)oxy)benzonitrile. LCMS-
ESI+ (m/z): [M+H]+ calcd for C25H26 2N7O2: 494.2; found: 494.3 1H NMR (400 MHz, DMSO-c/6) 5 10.45 (bs, 1 H), 8.88 (s, 1 H), 8.62 (m, 2H), 8.44 (bs, 2H), 7.79 (dd, J = 14.9, 2.4 Hz, 1 H), 7.69 (d, J = 9.2 Hz, 1 H), 7.51 (d, J = 8.9 Hz, 1 H), 7.17 (dd, J = 9.4 Hz, 1 H), 5.24 - 5.09 (m, 1 H), 5.01 (d, J = 49.5 Hz, 1 H), 4.12 - 3.99 (m, 1 H), 3.94 (m, 1 H), 3.81 - 3.65 (m, 1 H), 3.61 (m, 1 H), 3.48 - 3.13 (m, 8H), 2.05 (m, 2H).
Example 299: 5-(4-((3-f luoro-4-(4-formylpiperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin- 2-yl)-2-(((3 ?,4S)-3-fluorotetrahydro-2H-pyran-4-yl)oxy)benzonitrile
Figure imgf000305_0001
Formic acid (14 mg, 0.30 mmol) was added to a solution of 5-(4-((3-fluoro-4-(piperazin- 1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-(((3R,4S)-3-fluorotetrahydro-2/-/-pyran-4- yl)oxy)benzonitrile (71 mg, 0.14 mmol) in N,N-dimethylformamide (1 mL). The mixture was treated successively with /V,/V-diisopropylethylamine (100 μΙ_, 0.58 mmol) and N- [(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1 -ylmethylene]-N- methylmethanaminiumhexafluorophosphate W-oxide (HATU, 110 mg, 0.29 mmol). The mixture was purified by prep HPLC (5 - 70 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide 5-(4-((3-fluoro-4-(4-formylpiperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-(((3R,4S)-3-fluorotetrahydro-2/-/-pyran-4- yl)oxy)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C26H26F2 7O3: 522.2; found:
522.3 1H NMR (400 MHz, DMSO-c/6) δ 10.44 (bs, 1 H), 8.87 (bs, 1 H), 8.61 (m, 2H), 8.12 (s, 1 H), 7.77 (dd, J = 14.8, 2.4 Hz, 1 H), 7.70 (d, J = 9.0 Hz, 1 H), 7.51 (br, 1 H), 7.12 (dd, J = 9.3 Hz, 1 H), 5.15 (m, 1 H), 5.00 (m, 1 H), 4.06 (m, 1 H), 3.94 (m, 1 H), 3.69 (m, 1 H), 3.58 (m, 5H), 3.01 (dt, J = 24.4, 5.0 Hz, 4H), 2.14 - 1 .96 (m, 2H).
Example 300: 2-(((3 ?,4S)-3-fluorotetrahydro-2H-pyran-4-yl)oxy)-5-(4-((4-(1 - methylpiperidin-4-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000305_0002
Step 1 : Preparation of ferf-butyl 4-(4-((4-(3-cyano-4-fluorophenyl)-1 ,3,5-triazin yl)amino)phenyl)piperidine-1 -carboxylate: A mixture of ferf-butyl 4-(4-((4-chloro- 1 ,3,5-triazin-2-yl)amino)phenyl)piperidine-1 -carboxylate (0.41 g, 1 .2 mmol), 2-fluoro-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (0.29 g, 1 .2 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.09 g, 7.5 mol%) in 1 ,2-dimethoxyethane (DME, 7 ml_) was treated with 2 M aqueous sodium carbonate solution (2.4 ml_). The mixture was irradiated for 75 minutes in a microwave reactor at 130 °C. After cooling, the biphasic mixture was separated. The aqueous phase was extracted five times with ethyl acetate. The combined extracts were concentrated to dryness under reduced pressure and the residue was purified by flash chromatography (silica gel) to provide ferf-butyl 4-(4-((4-(3-cyano-4-fluorophenyl)-1 ,3,5-triazin-2-yl)amino)phenyl)piperidine-1 - carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for C26H28FN6°2: 475-2; found : 475 0 Step 2: Preparation of ferf-butyl 4-(4-((4-(3-cyano-4-(((3 ?,4S)-3-fluorotetrahydro- 2H-pyran-4-yl)oxy)phenyl)-1 ,3,5-triazin-2-yl)amino)phenyl)piperidine-1 -carboxylate
Potassium tert-butoxide (0.14 g, 1 .3 mmol) was added to a solution of (3R,4S)-3- fluorotetrahydro-2/-/-pyran-4-ol (0.15 g, 1 .3 mmol) in 2-methyltetrahydrofuran (6 ml_), cooled in an ice-water bath. The resulting suspension was stirred in the bath for 10 minutes and then at room temperature for 30 minutes before the addition of ferf-butyl 4- (4-((4-(3-cyano-4-fluorophenyl)-1 ,3,5-triazin-2-yl)amino)phenyl)piperidine-1 -carboxylate (0.38 g, 0.80 mmol). The mixture was heated at 75 °C overnight and then concentrated under reduced pressure to provide crude ferf-butyl 4-(4-((4-(3-cyano-4-(((3R,4S)-3- fluorotetrahydro-2/-/-pyran-4-yl)oxy)phenyl)-1 ,3,5-triazin-2-yl)amino)phenyl)piperidine-1 - carboxylate, which was carried forward without further purification. LCMS-ESI+ (m/z):
[M+H]+ calcd for C3 H36FN604: 575.3; found: 575.2
Step 3: Preparation of 2-(((3 ?,4S)-3-fluorotetrahydro-2H-pyran-4-yl)oxy)-5-(4-((4- (piperidin-4-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile: A mixture of crude ferf- butyl 4-(4-((4-(3-cyano-4-(((3R,4S)-3-fluorotetrahydro-2/-/-pyran-4-yl)oxy)phenyl)-1 ,3,5- triazin-2-yl)amino)phenyl)piperidine-1 -carboxylate (0.80 mmol assumed) in dichloromethane (8 ml_) was treated with trifluoroacetic acid (2.5 ml_, 32 mmol). After three hours of standing at room temperature, the mixture was concentrated under reduced pressure and purified by flash chromatography (silica gel) to provide 2- (((3R,4S)-3-fluorotetrahydro-2/-/-pyran-4-yl)oxy)-5-(4-((4-(piperidin-4-yl)phenyl)amino)-
1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C26H28FN6°2: 475.2; found: 475.3
Step 4: Preparation of 2-(((3 ?,4S)-3-fluorotetrahydro-2H-pyran-4-yl)oxy)-5-(4-((4- (1 -methylpiperidin-4-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile: A solution of 2- (((3R,4S)-3-fluorotetrahydro-2H-pyran-4-yl)oxy)-5-(4-((4-(piperidin-4-yl)phenyl)am 1 ,3,5-triazin-2-yl)benzonitrile (67 mg, 0.14 mmol) in methanol was treated with 37% formalin solution (42 μΙ_, 0.57 mmol). After five minutes of stirring at room temperature, the mixture was treated with sodium tri(acetoxy)borobydride (0.15 g, 0.71 mmol), and the reaction mixture was stirred overnight at room temperature. The mixture was concentrated to dryness under reduced pressure. The residue was suspended in 1 M aqueous sodium hydroxide solution (~2 ml_). After five minutes, the mixture was extracted three times with dichloromethane. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue was purified first by flash chromatography (silica gel) and then by prep HPLC (5 - 65 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer). The combined HPLC fractions were basified with 0.5 M sodium hydroxide solution and extracted three times with dichloromethane. The combined organics were dried over anhydrous magnesium sulfate, filtered, concentrated to provide 2-(((3R,4S)-3-fluorotetrahydro-2/-/-pyran-4-yl)oxy)-5-(4-((4-(1- methylpiperidin-4-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z):
[M+H]+ calcd for C27H30FN6O2: 489.2; found: 489.4 1H NMR (400 MHz, DMSO-c/6) δ
10.37 (bs, 1 H), 8.85 (s, 1 H), 8.62 (m, 2H), 7.74 (bs, 2H), 7.70 (d, J = 9.4 Hz, 1 H), 7.29 (m, 2H), 5.15 (m, 1 H), 5.00 (m, 1 H), 4.05 (m, 1 H), 3.94 (m, 1 H), 3.72 (ddd, J = 31.5, 12.8, 1.6 Hz, 1 H), 3.61 (m, 1 H), 3.36 (bs, 2H), 3.25 (m, 2H), 2.66 (m, 1 H), 2.57 (bs, 3H), 2.04 (m, 2H), 1.97 - 1.75 (m, 4H).
Example 301 : (S)-2-((1-acetyl-3,3-difluoropiperidin-4-yl)oxy)-5-(4-((4-(piperidin-4- l)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000307_0001
Step 1 : Preparation of (S)-tert-butyl 4-(4-bromo-2-cyanophenoxy)-3,3- difluoropiperidine-1-carboxylate: Sodium hydride (60 % dispersion in mineral oil, 88 mg, 2.2 mmol) was added slowly in a single portion to a stirred solution of (S)-tert-butyl 3,3-difluoro-4-hydroxypiperidine-1-carboxylate (0.52 g, 2.2 mmol) in N,N- dimethylformamide at room temperature. After the passage of 30 minutes, 5-bromo-2- fluorobenzonitrile (0.42 g, 2.1 mmol) was added in a single portion. The mixture was stirred overnight while heating at 60 °C. Water was added to the reaction mixture. The resulting aqueous suspension was extracted three times with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to provide crude (S)-tert-butyl 4-(4-bromo-2-cyanophenoxy)-3,3- difluoropiperidine-1 -carboxylate, which was carried forward without further purification.
LCMS-ESI+ (m/z): [M-Boc+H]+ calcd for C-^H-^B^I^O: 317.0; found: 317.1
Step 2: Preparation of provide (S)-5-bromo-2-((3,3-difluoropiperidin-4- yl)oxy)benzonitrile
Crude (S)-tert-butyl 4-(4-bromo-2-cyanophenoxy)-3,3-difluoropiperidine-1 -carboxylate (2.1 mmol assumed) was taken up in dichloromethane (8 mL) and treated with trifluoroacetic acid (2 mL). The mixture was allowed to stand at room temperature overnight and was then purified by flash chromatography (silica gel) to provide (S)-5- bromo-2-((3,3-difluoropiperidin-4-yl)oxy)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for Ci 2Hi 2 rF2N20: 317.0; found: 317.2
Step 3: Preparation of (S)-2-((1-acetyl-3,3-difluoropiperidin-4-yl)oxy)-5- bromobenzonitrile
To a solution of (S)-5-bromo-2-((3,3-difluoropiperidin-4-yl)oxy)benzonitrile (0.32 g, 1 .0 mmol) in dichloromethane (5 mL) was added sequentially /V,/V-diisopropylethylamine (0.53 mL, 3.0 mmol) and acetyl chloride (0.1 1 mL, 1 .5 mmol, dropwise via syringe). After the passage of 20 minutes, the mixture was washed with 10 % aqueous hydrochloric acid solution, followed by saturated aqueous sodium hydrogen carbonate solution. The organics were dried over anhydrous magnesium sulfate, filtered, concentrated to dryness under reduced pressure to give crude (S)-2-((1 -acetyl-3,3- difluoropiperidin-4-yl)oxy)-5-bromobenzonitrile, which was carried forward without further purification. LCMS-ESI"1" (m/z): [M+H]+ calcd for C-^H-^B^I^C^: 359.0; found: 359.1
Step 3: Preparation (S)-2-((1-acetyl-3,3-difluoropiperidin-4-yl)oxy)-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile
A mixture of crude (S)-2-((1 -acetyl-3,3-difluoropiperidin-4-yl)oxy)-5-bromobenzonitrile (0.29 g, 0.82 mmol), bis(pinacolato)diboron (0.41 g, 1 .6 mmol), potassium acetate (0.24 g, 2.4 mmol), and [1 , 1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) complex with dichloromethane (60 mg, 10 mol%) in 1 ,4-dioxane (6 mL) was heated overnight at 88 °C. The reaction mixture was filtered through a pad of Celite diatomaceous earth, and the filtrate was concentrated to dryness under reduced pressure. The crude (S)-2- ((1-acetyl-3,3-difluoropiperidin-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan yl)benzonitrile was carried forward without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C2oH26BF2N2°4: 407-2; found: 407 2
Step 4: Preparation of (S)-tert-butyl 4-(4-((4-(4-((1-acetyl-3,3-difluoropiperidin-4- yl)oxy)-3-cyanophenyl)-1,3,5-triazin-2-yl)amino)phenyl)piperidine-1-carboxylate
A mixture of ferf-butyl 4-(4-((4-chloro-1 ,3,5-triazin-2-yl)amino)phenyl)piperidine-1- carboxylate (0.26 g, 0.67 mmol), (S)-2-((1-acetyl-3,3-difluoropiperidin-4-yl)oxy)-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (0.81 mmol assumed), and tetrakis(triphenylphosphine)palladium(0) (0.06 g, 7.5 mol%) in 1 ,2-dimethoxyethane (DME, 4 mL) was treated with 2 M aqueous sodium carbonate solution (1.5 mL). The mixture was irradiated for 75 minutes in a microwave reactor at 130 °C. After cooling, the biphasic mixture was separated. The aqueous phase was extracted five times with ethyl acetate. The combined extracts were concentrated to dryness under reduced pressure and the residue was purified by flash chromatography (silica gel) to provide (S)-tert-butyl 4-(4-((4-(4-((1-acetyl-3,3-difluoropiperidin-4-yl)oxy)-3-cyanophenyl)-1 ,3,5- triazin-2-yl)amino)phenyl)piperidine-1-carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H38F2N7°4: 634-3; found: 633.8
Step 5: Preparation of (S)-2-((1-acetyl-3,3-difluoropiperidin-4-yl)oxy)-5-(4-((4- (piperidin-4-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile: (S)-tert-butyl 4-(4-((4-(4- ((1-acetyl-3,3-difluoropiperidin-4-yl)oxy)-3-cyanophenyl)-1 ,3,5-triazin-2- yl)amino)phenyl)piperidine-1-carboxylate (0.12 g, 0.18 mmol) was taken up in dichloromethane (3 mL) and treated with trifluoroacetic acid (0.78 mL, 10 mmol). The mixture was allowed to stand at room temperature for one hour and was then partitioned between dichloromethane and 0.5 M aqueous sodium hydroxide solution. The aqueous phase was extracted three times with dichloromethane. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated to provide (S)-2-((1- acetyl-3,3-difluoropiperidin-4-yl)oxy)-5-(4-((4-(piperidin-4-yl)phenyl)amino)-1 ,3,5-triazin-
2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C28H30F2N7O2: 534.2; found:
534.4 1 H NMR (400 MHz, DMSO-c/6) δ 10.35 (bs, 1 H), 8.85 (s, 1 H), 8.65 (m, 2H), 7.74 (dd, J = 9.6, 3.9 Hz, 1 H), 7.71 (d, J = 4.6 Hz, 2H), 7.28 (m, 2H), 5.41 (ddd, J = 12.6, 8.5, 4.1 Hz, 1 H), 4.13 (m, 1 H), 3.86 (m, 2H), 3.56 (m, 1 H), 3.34 (m, 4H), 3.06 (m, 2H), 2.63 (m, 2H), 2.15 (s, 1.5H), 2.12 (s, 1.5H), 1.73 (m, 2H), 1.55 (m, 2H).
Example 302: (S)-2-((1-acetyl-3,3-difluoropiperidin-4-yl)oxy)-5-(4-((4-(1- methylpiperidin-4-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000310_0001
A solution of (S)-2-((1-acetyl-3,3-difluoropiperidin-4-yl)oxy)-5-(4-((4-(piperidin-4- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (50 mg, 0.09 mmol) in methanol (4 mL) was treated with 37% formalin solution (28 μΙ_, 0.38 mmol). After five minutes of stirring at room temperature, the mixture was treated with sodium tri(acetoxy)borohydride (0.10 g, 0.47 mmol), and the reaction mixture was stirred for two hous at room temperature. The mixture was concentrated to dryness under reduced pressure. The residue was suspended in 1 M aqueous sodium hydroxide solution (~2 mL). After five minutes, the mixture was extracted three times with dichloromethane. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and evaporated to provide (S)-2- ((1-acetyl-3,3-difluoropiperidin-4-yl)oxy)-5-(4-((4-(1-methylpiperidin-4-yl)phenyl)amino)-
1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C29H32F2N7O2:
548.3; found: 548.4 1H NMR (400 MHz, DMSO-c/6) δ 10.34 (m, 1 H), 8.85 (s, 1 H), 8.65 (m, 2H), 7.73 (m, 3H), 7.29 (d, J = 8.1 Hz, 2H), 5.41 (m, 1 H), 4.13 (ddt, J = 23.9, 1 1.4, 6.5 Hz, 1 H), 4.04 - 3.68 (m, 2H), 3.66 - 3.47 (m, 1 H), 3.36 (s, 2H), 2.90 (m, 2H), 2.48 (m, 1 H), 2.23 (s, 3H), 2.15 (s, 1.5H), 2.12 (s, 1.5H), 2.00 (m, 2H), 1.84 - 1.61 (m, 4H).
Example 303: (S)-2-((3,3-difluoro-1 -formylpiperidin-4-yl)oxy)-5-(4-((3-methyl-4- (piperidin-4-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000311_0001
Step 1 : Preparation of ferf-butyl 4-(2-methyl-4-nitrophenyl)-5,6-dihydropyridine- 1(2H)-carboxylate 2-bromo-5-nitrotoluene (5.0 g, 23 mmol), 4-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2/-/-pyridine-1 -carboxylic acid ferf-butyl ester (Boron Molecular, 7.5 g, 24 mmol), tetrakis(triphenylphosphine)palladium(0) (1 .5 g, 1 .3 mmol), sodium carbonate aqueous solution (2M, 32 ml_, 65 mmol), and 1 ,4-dioxane (75 ml_) were combined in a sealed tube, and the mixture was heated at 80 °C for 3 days. After cooling to room temperature, the mixture was diluted with ethyl acetate and water and filtered through a pad of Celite diatomaceous earth. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed once with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to provide ferf-butyl 4-(2-methyl-4-nitrophenyl)-5,6- dihydropyridine-1 (2/- )-carboxylate. LCMS-ESI"1" (m/z): [M - tBu +H]+ calcd for C-13H-15N2O4: 263.1 ; found: 263.0
Step 2: Preparation of ferf-butyl 4-(4-amino-2-methylphenyl)piperidine-1 - carboxylate
ferf-butyl 4-(2-methyl-4-nitrophenyl)-5,6-dihydropyridine-1 (2/-/)-carboxylate (2.6 g, 8.2 mmol) was taken up methanol (50 ml_) in a Parr bottle. After the degassing of the mixture, it was treated with 10 % palladium on charcoal (260 mg). The suspension was shaken under 55 psi hydrogen overnight and then filtered through a bed of Celite diatomaceous earth. The filtrate was concentrated under reduced pressure to provide ferf-butyl 4-(4-amino-2-methylphenyl)piperidine-1 -carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for C-17H27N2O2: 291 .2; found: 290.6
Step 3: Preparation of ferf-butyl 4-(4-((4-chloro-1 ,3,5-triazin-2-yl)amino)-2- methylphenyl)piperidine-1 -carboxylate
To a solution of 2,4-dichloro-1 ,3,5-triazine (1 .2 g, 8.0 mmol) in N,N-dimethylformamide
(DMF, 15 ml.) at 0 °C were added sequentially N,/V-diisopropylethylamine (DIEA, 1 .5 ml_, 8.4 mmol) ferf-butyl 4-(4-amino-2-methylphenyl)piperidine-1 -carboxylate (1 .9 g, 6.5 mmol), followed by a DMF rinsate (15 ml_). The mixture was allowed to warm to room temperature. After the passage of two days, the mixture was diluted with ethyl acetate and half-saturated aqueous sodium hydrogen carbonate solution. The mixture was filtered through a pad of Celite diatomaceous earth and then was diluted with more water. The aqueous phase was extracted thrice each with diethyl ether. The combined extracts were washed with water, was filtered again through a pad of Celite diatomaceous earth, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel) to provide ferf-butyl 4-(4-((4-chloro-1 ,3,5- triazin-2-yl)amino)-2-methylphenyl)piperidine-1 -carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for C20H27CIN5O2: 404.2; found: 404.0
Step 4: Preparation of (S)-5-bromo-2-((3,3-difluoro-1 -formylpiperidin-4- yl)oxy)benzonitrile
Formic acid (96 μΙ_, 2.5 mmol) was added to a solution (S)-5-bromo-2-((3,3- difluoropiperidin-4-yl)oxy)benzonitrile (0.54 g, 1 .7 mmol) in N,N-dimethylformamide (5 ml_). Mixture was treated with successively with /V,/V-diisopropylethylamine (0.89 ml_, 5.1 mmol) and A -[(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1 -ylmethylene]- W-methylmethanaminiumhexafluorophosphate W-oxide (HATU, 1 .3 g, 3.4 mmol). The suspension was shaken vigorously for 1 minute until homogeneous and then left to stir for 4 hours at room temperature. The mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The aqueous phase was extracted three times with ethyl acetate. The combined organics were washed with 1 : 1 saturated aqueous sodium chloride solution/saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, filtered, concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel) to provide (S)- 5-bromo-2-((3,3-difluoro-1 -formylpiperidin-4-yl)oxy)benzonitrile. LCMS-ESI+ (m/z):
[M+H]+ calcd for Ci 3H 2BrF2N202: 345.0; found: 345.0
Step 5: Preparation of (S)-2-((3,3-difluoro-1 -formylpiperidin-4-yl)oxy)-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile
A mixture of (S)-5-bromo-2-((3,3-difluoro-1 -formylpiperidin-4-yl)oxy)benzonitrile (0.17 g, 0.50 mmol), bis(pinacolato)diboron (0.26 g, 1 .0 mmol), potassium acetate (0.15 g, 1 .5 mmol), and [1 ,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) complex with dichloromethane (37 mg, 10 mol%) in 1 ,4-dioxane (3 mL) was heated overnight at 85 °C. The reaction mixture was filtered through a pad of Celite diatomaceous earth, and the filtrate was concentrated to dryness under reduced pressure. The crude (S)-2-((3,3- difluoro-1-formylpiperidin-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzonitrile was carried forward without further purification. LCMS-ESI+ (m/z):
[M+H]+ calcd for C-19H24BF2N2O4: 393.2; found: 393.2
Step 6: Preparation of (S)-tert-butyl 4-(4-((4-(3-cyano-4-((3,3-difluoro-1- formylpiperidin-4-yl)oxy)phenyl)-1 ,3,5-triazin-2-yl)amino)-2- methylphenyl)piperidine-1 -carboxylate
A mixture of ferf-butyl 4-(4-((4-chloro-1 ,3,5-triazin-2-yl)amino)-2- methylphenyl)piperidine-1 -carboxylate (0.20 g, 0.51 mmol), crude (S)-2-((3,3-difluoro-1- formylpiperidin-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (0.51 mmol assumed), and tetrakis(triphenylphosphine)palladium(0) (0.04 g, 7.5 mol%) in 1 ,2-dimethoxyethane (DME, 3 mL) was treated with 2 M aqueous sodium carbonate solution (0.72 mL). The mixture was irradiated for 75 minutes in a microwave reactor at 130 °C. After cooling, the biphasic mixture was separated. The aqueous phase was extracted five times with ethyl acetate. The combined extracts were concentrated to dryness under reduced pressure and the residue was purified by flash chromatography (silica gel) to provide (S)-tert-butyl 4-(4-((4-(3-cyano-4-((3,3-difluoro-1-formylpiperidin-4- yl)oxy)phenyl)-1 , 3, 5-triazin-2-yl)amino)-2-methylphenyl)piperidine-1 -carboxylate. LCMS-
ESI+ (m/z): [M+H]+ calcd for C33H37F2N7O4: 634.3; found: 633.8
Step 7: Preparation of (S)-2-((3,3-difluoro-1-formylpiperidin-4-yl)oxy)-5-(4-((3- methyl-4-(piperidin-4-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
(S)-tert-butyl 4-(4-((4-(3-cyano-4-((3,3-difluoro-1-formylpiperidin-4-yl)oxy)phenyl)-1 ,3,5- triazin-2-yl)amino)-2-methylphenyl)piperidine-1 -carboxylate (0.20 g, 0.31 mmol) was taken up in dichloromethane (4 mL) and treated with trifluoroacetic acid (2.0 mL, 26 mmol). The mixture was allowed to stand overnight at room temperature and was then concentrated to dryness under reduced pressure. The residue was purified by prep HPLC (5 - 65 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer). The combined HPLC fractions were basified to pH 10 with 1 M sodium hydroxide solution and extracted five times with dichloromethane. The combined organics were dried over anhydrous magnesium sulfate, filtered, and concentrated to provide (S)-2-((3,3-difluoro- 1-formylpiperidin-4-yl)oxy)-5-(4-((3-methyl-4-(piperidin-4-yl)phenyl)amino)-1 ,3,5-triazin- 2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C28H30F2N7O2: 534.2; found: 534.31H NMR (400 MHz, DMSO-c/6) δ 10.29 (br, 1H), 8.84 (s, 1H), 8.65 (d, J = 7.4 Hz, 2H), 8.21 (s, 0.5H), 8.14 (s, 0.5H), 7.74 (d, J= 9.6 Hz, 1H), 7.70-7.43 (m, 2H), 7.23 (d, J= 8.3 Hz, 1H), 5.47 (m, 1H), 4.16-4.00 (m, 1H), 4.00-3.82 (m, 1H), 3.82-3.65 (m, 1H), 3.65-3.43 (m, 1H), 3.35 (bs, 1H), 3.07 (d, J= 11.8 Hz, 2H), 2.79 (m, 1H), 2.65 (m, 2H), 2.37 (s, 3H), 2.19 (m, 1H), 2.08- 1.82 (m, 1H), 1.65 (m, 2H), 1.54 (m, 2H).
Example 304: (S)-2-((3,3-difluoro-1-formylpiperidin-4-yl)oxy)-5-(4-((3-methyl-4-(1- )phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000314_0001
A solution of (S)-2-((3,3-difluoro-1-formylpiperidin-4-yl)oxy)-5-(4-((3-methyl-4-(piperidin- 4-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile (43 mg, 0.08 mmol) in methanol (4 mL) was treated with 37% formalin solution (24 μΙ_, 0.32 mmol). After five minutes of stirring at room temperature, the mixture was treated with sodium tri(acetoxy)borohydride (0.10 g, 0.47 mmol), and the reaction mixture was stirred for 45 minutes at room temperature. The mixture was concentrated to dryness under reduced pressure. The residue was suspended in 1 M aqueous sodium hydroxide solution (~2 mL). After five minutes, the mixture was extracted three times with dichloromethane. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and evaporated to provide (S)-2- ((3,3-difluoro-1-formylpiperidin-4-yl)oxy)-5-(4-((3-methyl-4-(1-methylpiperidin-4- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile.
LCMS-ESI+ (m/z): [M+H]+ calcd for C29H32F2N7O2: 548.3; found: 548.4 1H NMR (400 MHz, DMSO-c/6) δ 10.31 (m, 1H), 8.84 (s, 1H), 8.66 (m, 2H), 8.21 (s, 0.5H), 8.14
(s, 0.5H), 7.74 (d, J = 9.5 Hz, 1 H), 7.71 - 7.60 (m, 1 H), 7.57 (m, 1 H), 7.25 (d, J = 8.2 Hz, 1H), 5.47 (ddt, J= 12.8, 8.1, 4.0 Hz, 1H), 4.15-3.99 (m, 1H), 3.99-3.82 (m, 1H), 3.82 - 3.65 (m, 1 H), 3.53 (m, 1 H), 3.36 (s, 1 H), 2.95 (d, J = 11.2 Hz, 2H), 2.68 (p, J = 7.8 Hz, 1H), 2.37 (s, 3H), 2.28 (s, 3H), 2.19-1.98 (m, 3H), 1.71 (m, 4H).
Example 305: 2-(((3R,4S)-3-fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4- (1-(oxetan-3-yl)piperidin-4-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000315_0001
2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(1 -(oxetan-3-yl)piperidin^-yl)phenyl)amino)-1 ,3,5-tri yl)benzonitrile (100 mg, 0.19 mmol) was dissolved in dichloromethane (2.7 mL), N,N-Diisopropylethylamine (0.07 ml, 0.38 mmol), W-[(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminiumhexafluorophosphate W-oxide (107.98 mg, 0.28 mmol), glycolic acid (28.72 mg, 0.38 mmol) followed and the reaction was allowed to stir for 1 hour at room temperature. The mixture was diluted with dichloromethane and water. The aqueous phase was extracted three times with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via prep HPLC (0 - 40 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide 2-(((3R,4S)-3-fluoro-1 -(2-hydroxyacetyl)piperidin^l-yl)oxy)-
5-(4-((4-(1 -(oxetan-3-yl)piperidin-4-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI"1" (m/z):
[M+H]+ calcd for C31 H34FN704: 587.6; found: 588.3
1H NMR (400 MHz, DMSO-c/6) δ 10.30 (s, 1 H), 8.80 (s, 1 H), 8.64 - 8.54 (d, J = 10,8, 2H), 7.65 (dd, J = 9.1 , 6.0 Hz, 3H), 7.26 (d, J = 8.2 Hz, 2H), 5.14 - 4.90 (m, 2H), 4.68 (q, J = 6.2 Hz, 1 H), 4.49 (dt, J = 29.2, 6.3 Hz, 4H), 4.40 - 4.30 (m, 1 H), 4.24 - 3.37 (m, 3H), 4.35 - 3.35 (m, 2H), 3.17 (m, 1 H), 2.80 (m, 2H), 1.93 - 1.56 (m, 8H).
Example 306: 2-(((3R,4S)-3-fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4- (4-(tetrahydro-2H-pyran-4-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-
Figure imgf000315_0002
2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (100 mg, 0.18 mmol) was dissolved in dichloromethane (2.6 mL), N,N-Diisopropylethylamine (0.06 ml, 0.36 mmol), N- [(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminiumhexafluorophosphate N-oxide (102.36 mg, 0.27 mmol), glycolic acid (27.23 mg, 0.36 mmol) was added and the reaction was allowed to stir for 1 hour at room temperature. The mixture was diluted with dichloromethane and water. The aqueous phase was extracted three times with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via prep HPLC (0 - 40 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide 2-(((3R,4S)-3-fluoro-1 -(2- hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C H FN 04: 616.7; found: 617.2
1H NMR (400 MHz, DMSO-c/6) δ 10.12 (d, J = 17.9 Hz, 1 H), 8.74 (s, 1 H), 8.57 (d, J = 1 1 .3 Hz, 2H), 7.68 - 7.53 (m, 3H), 6.94 (s, 2H), 5.20 - 4.93 (m, 2H), 4.67 (q, J = 6.2 Hz, 1 H), 4.24 - 4.04 (m, 3H), 3.95 - 3.83 (m, 3H), 3.72 - 3.35 (m, 1 H), 3.19 - 3.04 (m, 6H), 2.67 - 2.52 (m, 4H), 2.51 - 2.32 (m, 2H), 1 .98 (s, 2H), 1 .74 (d, J = 13.6 Hz, 2H), 1 .41 (qd, J = 12.2, 4.5 Hz, 2H). Example 307: 2-(((3R,4S)-3-fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((3- fluoro-4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-
Figure imgf000316_0001
1-(2-fluoro-4-nitrophenyl)piperazine (2000 mg, 8.88 mmol), dihydro-2H-pyran-4(3H)-one (2667.15 mg, 26.64 mmol), sodium cyanoborohydride (1674.15 mg, 26.64 mmol) in methanol (68 ml) followed by zinc chloride (1815.77 mg, 13.32 mmol) was stirred at 48°C for 4 hours. The reaction was diluted with dichloromethane to make a 25% methanol/dichloromethane solution and the reaction was washed with water. The crude material was dried, filtered, concentrated and purified by flash chromatography (silica gel) to provide 1 -(2-fluoro-4-nitrophenyl)-4-(tetrahydro-2H-pyran-4-yl)piperazine. LCMS-
ESI+ (m/z): [M+H]+ calcd for C, H FNLO ■ 309.3; found: 310.9
1-(2-fluoro-4-nitrophenyl)-4-(tetrahydro-2H-pyran-4-yl)piperazine (2740 mg, 8.86 mmol), palladium (10%, 471 .32 mg, 0.44 mmol) on carbon in ethanol (12.6 ml) were combined in a PARR flask and shaken on the hydrogenator for 3h at 45 PSI. The reaction was filtered over celite and washed down with 25% methanol/dichloromethane, concentrated and provided 3-fluoro-4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1 -yl)aniline. LCMS-ESI+ (m/z): [M+H]+ calcd for C15H22FN30: 279.4; found: 279.9
3-fluoro-4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1 -yl)aniline (500 mg, 1 .79 mmol), 1 -(4- pyridinyl)piperazine (1 156.77 mg, 7.09 mmol), potassium carbonate (742.1 mg, 5.37 mmol) in dimethylformamide (10 mL) were combined, cooled to 0°C, followed by 2,4- dichloro-1 ,3,5-triazine (268.42 mg, 1 .79 mmol) in dimethylformamide (8 mL) and stirred at 0C. The reaction was stirred for 5 minutes, quenched with water, extracted with ethyl acetate, washed with water, and dried. The reaction extracted with 30% methanol/dichloromethane, washed with water, dried and purified by flash chromatography (silica gel) to provide 4-chloro-N-(3-fluoro-4-(4-(tetrahydro-2H-pyran-4- yl)piperazin-1 -yl)phenyl)-1 ,3,5-triazin-2-amine. LCMS-ESI+ (m/z): [M+H]+ calcd for C H CIFN O: 392.9; found: 393.4
A 2-5 mL microwave vial was charged with 4-chloro-N-(3-fluoro-4-(4-(tetrahydro-2H- pyran-4-yl)piperazin-1 -yl)phenyl)-1 ,3,5-triazin-2-amine (100 mg, 0.25 mmol), (3R,4S)- tert-butyl 4-(2-cyano-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)-3- fluoropiperidine-1 -carboxylate (136.33 mg, 0.31 mmol), 2M Sodium carbonate (0.23 ml), and Tetrakis(triphenylphosphine)palladium(0) (17.48 mg, 0.02 mmol) in dimethoxyethane (2.5 mL). The solution was degassed with nitrogen, irridated for 20 minutes at 150°C. The reaction was extracted with 30% methanol/dichloromethane, washed with water, dried, filtered and concentrated. The crude material was then purified by flash chromatography (silica gel) to provide (3R,4S)-tert-butyl 4-(2-cyano-4- (4-((3-fluoro-4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2- yl)phenoxy)-3-fluoropiperidine-1 -carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for
Figure imgf000317_0001
676.8; found: 677.3
(3R,4S)-tert-butyl 4-(2-cyano-4-(4-((3-fluoro-4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-1 -carboxylate ( 180 mg, 0.27 mmol) was dissolved in dichloromethane (1 .3 ml), trifluoroacetic acid (0.2 ml, 2.66 mmol) was added and the reaction was stirred at room temperature for 1 h. The reaction was cooled to 0°C, neutralized with saturated sodium bicarbonate, washed with water, dried, filtered and concentrated to provide 5-(4-((3-fluoro-4-(4-(tetrahydro-2H-pyran-4- yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-(((3R,4S)-3-fluoropiperidin-4- yl)oxy)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C30H34F2N8O2: 576.6; found:
577.1
5-(4-((3-fluoro-4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin- 2-yl)-2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)benzonitrile (104.70 mg, 0.18 mmol) was dissolved in dichloromethane (2.5 ml_), N,N-Diisopropylethylamine (0.06 ml, 0.36 mmol), N-[(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1 -ylmethylene]-N- methylmethanaminiumhexafluorophosphate N-oxide (103.83 mg, 0.27 mmol), glycolic acid (27.62 mg, 0.36 mmol) was added and the reaction was allowed to stir for 2 hours 30 minutes. The mixture was diluted with dichloromethane and water. The aqueous phase was extracted three times with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via prep HPLC (0 - 40 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide 2-(((3R,4S)-3-fluoro-1-(2-hydroxyacetyl)piperidin-4- yl)oxy)-5-(4-((3-fluoro-4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H36F2N804: 634.7; found: 635.3
1H NMR (400 MHz, DMSO-c/6) δ 10.45 (s, 1 H), 8.86 (s, 1 H), 8.77 (d, J = 16.3 Hz, 2H), 7.77-7.56 (m, 2H), 7.43 (s, 1 H), 7.04 (t, J = 16.4 Hz, 1 H), 5.22 - 4.93 (m, 2H), 4.67 (q, J = 6.2 Hz, 1 H), 4.45 - 4.05 (m, 3H), 3.95 - 3.83 (m, 3H), 3.71 - 3.44 (m, 2H), 3.39 (s, 1 H), 2.91 (s, 4H), 2.72 (s, 4H), 2.45 (s, 1 H), 2.07 - 1.80 (m, 2H), 1.80 -1.71 (m, 2H), 1.41 (qd, J = 12.2, 4.5 Hz, 2H). Example 308: 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5- (4-((4-(4-(oxetan-3-ylmethyl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-
Figure imgf000318_0001
Oxetane-3-carbaldehyde (977.1 1 mg, 1 1.35 mmol) in dichloromethane, 1-(4- nitrophenyl)piperazine (1 176.02 mg, 5.67 mmol) in dichloromethane, sodium triacetoxyborohydride (24055.12 mg, 1 13.5 mmol) were combined and stirred at room temperature for 2 hours. The reaction was concentrated, diluted with dichloromethane, and washed with sodium bicarbonate and stirred for 20 minutes. The organic layer was separated and washed with saturated sodium bicarbonate, dried, filtered, concentrated and purified by flash chromatography (silica gel) to provide 1-(4-nitrophenyl)-4-(oxetan- 3- ylmethyl)piperazine.
LCMS-ESI+ (m/z): [M+H]+ calcd for C14HigN303: 277.3; found: 278.1
1-(4-nitrophenyl)-4-(oxetan-3-ylmethyl)piperazine (820 mg, 2.96 mmol), Iron (1 155.99 mg, 20.7 mmol), ammonium chloride (1 107.15 mg, 20.7 mmol) were combined in water (14.8 mL) and ethanol (14.8 mL), heated to 80°C for 1 hour. The reaction was extracted with dichloromethane, washed with water, dried, filtered and concentrated to provide 4-
(4-(oxetan-3-ylmethyl)piperazin-1-yl)aniline. LCMS-ESI+ (m/z): [M+H]+ calcd for C14H21N30: 247.3; found: 248.0
4- (4-(oxetan-3-ylmethyl)piperazin-1-yl)aniline (360 mg, 1.46 mmol), potassium carbonate (603.48 mg, 4.37 mmol) in dichloromethane (7.5 mL) were combined, cooled to 0C, followed by 2,4-dichloro-1 ,3,5-triazine (218.28 mg, 1.46 mmol) in dichloromethane (7 mL) that was cooled to 0C before addition and stirred at 0°C. The reaction monitored at 5 minutes and then was subjected 2 times to 40 mg of more triazine and stirred for 10 minutes after each addition. The reaction was quenched with water, extracted with 30% methanol/dichloromethane and back extracted with water. 4- chloro-N-(4-(4-(oxetan-3-ylmethyl)piperazin-1 -yl)phenyl)-1 ,3,5-triazin-2-amine. LCMS-
ESI+ (m/z): [M+H]+ calcd for C17H21CIN60: 525.2; found: 525.8
A 2-5 mL microwave vial was charged with 4-chloro-N-(4-(4-(oxetan-3- ylmethyl)piperazin-1-yl)phenyl)-1 ,3,5-triazin-2-amine (100 mg, 0.28 mmol), (3R,4S)-tert- butyl 4-(2-cyano-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)-3- fluoropiperidine-1-carboxylate (148.43 mg, 0.33 mmol), 2M sodium carbonate (0.62 ml), Tetrakis(triphenylphosphine)palladium(0) (19.04 mg, 0.02 mmol) in 2.7 mL of dimethoxyethane, blown down with nitrogen gas, irridated for 20 minutes at 150°C. The reaction was extracted with dichloromethane, dried, filtered, concentrated and then purified by flash chromatography (silica gel) to provide (3R,4S)-tert-butyl 4-(2-cyano-4- (4-((4-(4-(oxetan-3-ylmethyl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenoxy)-3- fluoropiperidine-1-carboxylate. LCMS-ESI"1" (m/z): [M+H]+ calcd for C34H41FN804: 644.7; found: 645.4
(3R,4S)-tert-butyl 4-(2-cyano-4-(4-((4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-1-carboxylate (210 mg, 0.32 mmol) was dissolved in dichloromethane (1.5 ml), trifluoroacetic acid (0.25 ml, 3.19 mmol) was added and the reaction was stirred at room temperature for 45 minutes. The reaction
cooled to 0°C, neutralized with saturated sodium bicarbonate, diluted with 30% methanol/dichloromethane, washed with water, dried, filtered, and concentrated to provide 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-ylmethyl)piperazin-
1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C,QHMFNa02: 544.6; found: 545.1
2- (((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(1 -(oxetan-3-ylmethyl)piperidin-4- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (100 mg, 0.18 mmol) was dissolved in dichloromethane (2.6 mL),N,N-Diisopropylethylamine (0.06 ml, 0.37 mmol), N- [(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1 -ylmethylene]-N- methylmethanaminiumhexafluorophosphate N-oxide (105.19 mg, 0.28 mmol), (S)-2- hydroxypropanoic acid (33.14 mg, 0.37 mmol) was added and the reaction was allowed to stir for 1 hour at room temperature. The mixture was diluted with dichloromethane and water. The aqueous phase was extracted three times with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via prep HPLC (0 - 40 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide 2-(((3R,4S)-3-fluoro-1 -((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-ylmethyl)piperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile.
LCMS-ESI+ (m/z): [M+H]+ calcd for C33H38FN704: 615.7; found: 617.3
1H NMR (400 MHz, DMSO-c/6) δ 10.13 (d, J = 17.2 Hz, 1 H), 8.74 (s, 1 H), 8.57 (d, J = 12.2 Hz, 2H), 7.68 - 7.53 (m, 3H), 6.96 (d, J = 9.3 Hz, 2H), 5.17 - 4.94 (m, 3H), 4.66 (dd, J = 7.8, 5.8 Hz, 2H), 4.55 - 4.37 (m, 2H), 4.33 - 4.02 (m, 2H), 3.96 (d, J = 14.1 Hz, 2H), 3.74 - 3.53 (m, 1 H), 3.48 - 3.33 (m, 1 H), 3.31 - 3.02 (m, 6H), 2.77 - 2.62 (m, 2H), 1 .99 (d, J = 10.2 Hz, 1 H), 1 .84 (s, 1 H), 1 .30 - 1 .16 (m, 4H).
Example 309: 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5- (4-((4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-
Figure imgf000320_0001
1-(4-nitrophenyl)piperazine (2000 mg, 9.65 mmol), dihydro-2H-pyran-4(3H)-one (2898.7 mg, 28.95 mmol), sodium cyanoborohydride (1819.49 mg, 28.95 mmol) in methanol (74 ml) followed by zinc chloride (1973.41 mg, 14.48 mmol) was stirred at 48°C for 1 hour. The reaction was diluted with dichloromethane to make a 25% methanol/dichloromethane solution and the reaction was washed with water. The crude material was dried, filtered, concentrated and purified by flash chromatography (silica gel) to provide 1 -(4-nitrophenyl)-4-(tetrahydro-2H-pyran-4-yl)piperazine. LCMS-ESI+ (m/z): [M+H]+ calcd for C15H21 N30: 291 .4; found: 292.1
1 -(4-nitrophenyl)-4-(tetrahydro-2H-pyran-4-yl)piperazine (2810 mg, 9.64 mmol), palladium ( 10%, 513.21 mg, 0.48 mmol) on carbon in ethanol ( 14 ml) were combined in a PARR flask and shaken on the hydrogenator for overnight at 45 PSI . The reaction was filtered over celite and washed down with 25% methanol/dichloromethane, concentrated and provided 4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1 -yl)aniline. LCMS-ESI+ (m/z):
[M+H]+ calcd for C15H23N30: 261 .4; found: 262.1
4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1 -yl)aniline (1000 mg, 3.83 mmol), 1 -(4- pyridinyl)piperazine (1 156.77 mg, 7.09 mmol), potassium carbonate ( 1586.36 mg, 1 1 .48 mmol) in dichloromethane (19 mL) were combined, cooled to 0°C, followed by 2,4- dichloro-1 ,3,5-triazine (573.79 mg, 3.83 mmol) in DCM (19 mL) and stirred at 0°C. The reaction was subjected to additional solid 2,4-dichloro-1 ,3,5-triazine (1 14.76 mg, 0.77 mmol) and stirred for 5 minutes. The reaction was quenched with water, extracted with 30% methanol/dichloromethane, dried, filtered and concentrated to provide 4-chloro-N-
(4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1 -yl)phenyl)-1 ,3,5-triazin-2-amine. LCMS-ESI+ (m/z): [M+H]+ calcd for C18H23CIN60: 374.9; found: 375.5
A 2-5 mL microwave vial was charged with 4-chloro-N-(4-(4-(tetrahydro-2H-pyran-4- yl)piperazin-1 -yl)phenyl)-1 ,3,5-triazin-2-amine ( 100 mg, 0.27 mmol), (3R,4S)-tert-butyl 4- (2-cyano-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)-3-fluoropiperidine-1 - carboxylate (142.87 mg, 0.32 mmol), 2M Sodium carbonate (0.6 ml) , Tetrakis(triphenylphosphine)palladium(0) (18.32 mg, 0.02 mmol) in 2.63 mL of dimethoxyethane, blown down with nitrogen, irridated for 20 minutes at 150°C. The reaction was extracted with 30% methanol/dichloromethane, dried, filtered, concentrated and purified by flash chromatography (silica gel) to provide 2-(((3R,4S)-3-fluoro-1 -((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C H FN 04: 658.8; found: 659.4
(3R,4S)-tert-butyl 4-(2-cyano-4-(4-((4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-1 -carboxylate (210 mg, 0.32 mmol) was dissolved in dichloromethane (1 .5 ml), trifluoroacetic acid (0.25 ml, 3.19 mmol) was added and the reaction was stirred at room temperature for 45 minutes. The reaction cooled to 0°C, neutralized with saturated sodium bicarbonate, diluted with 30% methanol/dichloromethane washed with water, dried, filtered and concentrated to provide 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(tetrahydro-2H-pyran-4- yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z):
[M+H]+ calcd for C H FN O2I 558.7; found: 559.3
2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (100 mg, 0.18 mmol) was dissolved in dichloromethane (2.6 ml_), N,N-Diisopropylethylamine (0.06 ml, 0.36 mmol), N- [(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1 -ylmethylene]-N- methylmethanaminiumhexafluorophosphate N-oxide (102.36 mg, 0.27 mmol), (S)-2- hydroxypropanoic acid (32.25 mg, 0.36 mmol) was added and the reaction was allowed to stir for 1 hour at room temperature. The mixture was diluted with dichloromethane and water. The aqueous phase was extracted three times with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via prep HPLC (0 - 40 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide 2-(((3R,4S)-3-fluoro-1 -((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for Π Ή FN 04: 630.7; found: 631 .3
1H NMR (400 MHz, DMSO-c/6) δ 10.13 (d, J = 17.3 Hz, 1 H), 8.74 (s, 1 H), 8.67 - 8.50 (m, 2H), 7.72 - 7.44 (m, 3H), 6.96 (d, J = 9.1 Hz, 2H), 5.20 - 4.90 (m, 3H), 4.45 (dd, J = 7.8, 5.8 Hz, 2H), 3.90 (dt, J = 10.3, 6.7 Hz, 2H), 3.72-3.52 (m, 1 H), 3.10 (s, 5H), 2.62 (s, 4H), 2.48-2.45 (m, 2H), 2.02 - 1 .78 (m, 2H), 1 .75 (d, J = 7.4 Hz, 2H), 1 .50 - 1 .35 (m, 2H), 1.22 (dd, J = 6.5, 3.2 Hz, 3H).
Example 310: 2-(((3R,4S)-3-fluoro-1 -((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-
(4-((3-fluoro-4-(1-(oxetan-3-yl)piperidin-4-yl)phenyl)amino)-1,3,5-triazin-2- yl)benzonitrile
Figure imgf000322_0001
4-(2-fluoro-4-nitrophenyl)piperidine (300 mg, 1 .155 mmol), oxetan-3-one (248.8 mg, 3.45 mmol), sodium cyanoborohydride (216.95 mg, 3.45 mmol) in methanol (8.9 ml) followed by zinc chloride (235.3 mg, 1 .73 mmol) was stirred at 48C for overnight. The reaction was diluted with dichloromethane to make a 25% methanol/dichloromethane solution, washed with water, dried, filtered, concentrated and purified by flash chromatography (silica gel) to provide 4-(2-fluoro-4-nitrophenyl)-1 -(oxetan-3- yl)piperidine. LCMS-ESI+ (m/z): [M+H]+ calcd for C14H17N203: 280.3; found: 281 .1
4-(2-fluoro-4-nitrophenyl)-1 -(oxetan-3-yl)piperidine (310 mg, 1 .1 1 mmol), palladium (10%, 58.85 mg, 0.06 mmol) on carbon in ethanol (3 ml) were combined in a PARR flask and shaken on the hydrogenator for 2 hours at 45 PSI . The reaction was filtered over celite and washed down with 25% methanol/dichloromethane and concentrated to provide 3-fluoro-4-(1 -(oxetan-3-yl)piperidin-4-yl)aniline. LCMS-ESI+ (m/z): [M+H]+ calcd for C14H19FN20: 250.3; found: 251 .1
3-fluoro-4-( 1 -(oxetan-3-yl)piperidin-4-yl)aniline (276 mg, 1 .1 mmol), potassium carbonate (457.17 mg, 3.31 mmol) in dichloromethane (5.5 mL) were combined, cooled to 0°C, followed by 2,4-dichloro-1 ,3,5-triazine (165.36 mg, 1 .1 mmol) in dichloromethane (5.5 mL) that was cooled to 0C before addition and stirred at 0C. The reaction was quenched with water, extracted with 30% methanol/dichloromethane and back extracted with water. The organic layers were combined, dried, filtered, concentrated and purified by flash chromatography (silica gel) to provide 4-chloro-N-(4- (4-(oxetan-3-ylmethyl)piperazin-1 -yl)phenyl)-1 ,3,5-triazin-2-amine LCMS-ESI+ (m/z): [M+H]+ calcd for C17H19CIFN50: 363.8; found: 364.3
In a 5 ml microwave tube, combined 4-chloro-N-(3-fluoro-4-( 1 -(oxetan-3-yl)piperidin-4- yl)phenyl)-1 ,3,5-triazin-2-amine (70 mg, 0.19 mmol), 2-(((3R,4S)-3-fluoro-1 -((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzonitrile (96.57 mg, 0.23 mmol), dimethoxyethane (2 mL) and 2M Sodium carbonate solution in water (0.43 ml), tetrakis(triphenylphosphine)palladium (22.23 mg, 0.02 mmol) was added, blown down with nitrogen and the vial was sealed. The reaction mixture was heated in microwave at 150°C for 20 minutes. The mixture was diluted with 30% methanol/dichloromethane and water. The aqueous phase was extracted three times with 30% methanol/dichloromethane. The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via prep HPLC (0 - 70 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide 2-(((3R,4S)-3-fluoro-1 -((S)-2-hydroxypropanoyl)piperidin-4- yl)oxy)-5-(4-((3-fluoro-4-(1 -(oxetan-3-yl)piperidin-4-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H35FN704: 619.7; found: 620.3
1H NMR (400 MHz, DMSO-c/6) δ 10.30 (s, 1 H), 8.79 (s, 1 H), 8.63 - 8.53 (m, 2H), 7.64 (d, J = 9.1 Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H), 5.16 - 4.93 (m, 3H), 4.48 (dt, J = 29.7, 6.3 Hz, 4H), 4.25-3.90 (m, 2H), 3.46 - 3.26 (m, 2H), 3.26 - 3.1 1 (m, 1 H), 2.78 (s, 3H), 1.98- 1.60 (m, 8H), 1.19 (dd, J = 6.5, 3.2 Hz, 3H).
Example 311 : 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5- piperidin-4-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000324_0001
In a 5 ml microwave tube, combined 4-chloro-N-(4-(1-(oxetan-3-yl)piperidin-4- yl)phenyl)-1 ,3,5-triazin-2-amine (70 mg, 0.2 mmol), 2-(((3R,4S)-3-fluoro-1-((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzonitrile (101.6 mg, 0.24 mmol), dimethoxyethane (2 ml_) and 2M Sodium carbonate solution in water (0.46 ml), tetrakis(triphenylphosphine)palladium (23.39 mg, 0.02 mmol) was added, blown down with nitrogen and the vial was sealed. The reaction mixture was heated in microwave at 150°C for 20 minutes. The mixture was diluted with 30% methanol/dichloromethane and water. The aqueous phase was extracted three times with 30% methanol/dichloromethane. The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via prep HPLC (0 - 70 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4- yl)oxy)-5-(4-((4-(1-(oxetan-3-yl)piperidin-4-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H36FN704: 601.7; found: 602.2
1H NMR (400 MHz, DMSO-c/6) δ 10.30 (s, 1 H), 8.79 (s, 1 H), 8.63 - 8.53 (m, 2H), 7.64 (d, J = 9.1 Hz, 3H), 7.25 (d, J = 8.1 Hz, 2H), 5.16 - 4.93 (m, 3H), 4.48 (dt, J = 29.7, 6.3 Hz, 4H), 4.25-3.90 (m, 2H), 3.46 - 3.26 (m, 2H), 3.26 - 3.1 1 (m, 1 H), 2.78 (d, J = 10.7 Hz, 2H), 1.98 (s, 2H), 1.84 (t, J = 10.6 Hz, 4H), 1.76 - 1.58 (m, 2H), 1.19 (dd, J = 6.5, 3.2 Hz, 3H). Example 312: 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5- (4-((4-(4-(3-methyloxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-
Figure imgf000325_0001
1-fluoro-4-nitrobenzene (0.9 ml, 8.5 mmol), 1-(3-methyloxetan-3-yl)piperazine (1328.64 mg, 8.5 mmol), potassium carbonate (3526.15 mg, 25.51 mmol) in acetonitrile (13 ml) was stirred at 150°C for 2 overnights. The reaction was diluted with ethyl acetate, washed with water, dried, concentrated and purified by flash chromatography (silica gel) to provide 1-(3-methyloxetan-3-yl)-4-(4-nitrophenyl)piperazine. LCMS-ESI+ (m/z): [M+H]+ calcd for C14HigN303: 277.3; found: 278.0
1-(3-methyloxetan-3-yl)-4-(4-nitrophenyl)piperazine (2030 mg, 7.32 mmol), palladium (10%, 389.5 mg, 0.37 mmol) on carbon in ethanol (1 1 ml) were combined in a PARR flask and shaken on the hydrogenator for overnight at 45 PSI. The reaction was filtered over celite and washed down with 25% methanol/dichloromethane, concentrated to provide 4-(4-(3-methyloxetan-3-yl)piperazin-1-yl)aniline. LCMS-ESI+ (m/z): [M+H]+ calcd for C14H21N30: 247.3; found: 248.1
4-(4-(1-methylcyclobutyl)piperazin-1-yl)aniline (800 mg, 3.06 mmol), potassium carbonate (1269.09 mg, 9.18 mmol) in dichloromethane (15.5 mL) were combined, cooled to 0C, followed by 2,4-dichloro-1 ,3,5-triazine (459.03 mg, 3.06 mmol) in dichloromethane (15.5 mL) that was cooled to 0C before addition and stirred at 0°C for 5 minutes. The reaction was subjected to an additional 225 mg of 2,4-dichloro-1 ,3,5- triazine in dichloromethane (5 mL) and stirred for an additional 5 minutes. The reaction was quenched with water, extracted with 30% methanol/dichloromethane, dried, filtered, concentrated and purified by flash chromatography (silica gel) to provide 4-chloro-N-(4- (4-(3-methyloxetan-3-yl)piperazin-1-yl)phenyl)-1 ,3,5-triazin-2-amine. LCMS-ESI+ (m/z):
[M+H]+ calcd for C17H21CIN60: 360.8; found: 361.4
In a 5 ml microwave tube, combined 4-chloro-N-(4-(4-(3-methyloxetan-3-yl)piperazin-1- yl)phenyl)-1 ,3,5-triazin-2-amine (70 mg, 0.19 mmol), 2-(((3R,4S)-3-fluoro-1-((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzonitrile (97.37 mg, 0.23 mmol), dimethoxyethane (2 mL) and 2M Sodium carbonate solution in water (0.44 ml), tetrakis(triphenylphosphine)palladium (22.42 mg, 0.02 mmol) was added, blown down with nitrogen and the vial was sealed. The reaction mixture was heated in microwave at 150°C for 20 minutes. The mixture was diluted with 30% methanol/dichloromethane and water. The aqueous phase was extracted three times with 30% methanol/dichloromethane. The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via prep HPLC (0 - 70 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(3-methyloxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H37FN804: 616.7; found: 617.2
1H NMR (400 MHz, DMSO-c/6) δ 10.14 (d, J = 19.3 Hz, 1 H), 8.73 (s, 1 H), 8.62 - 8.50 (m, 2H), 7.59 (dd, J = 21.7, 8.9 Hz, 3H), 6.96 (d, J = 9.2 Hz, 2H), 5.16 - 4.93 (m, 3H), 4.45 (d, J = 5.6 Hz, 2H),4.53 - 3.5 (m, 2H), 4.14 (d, J = 5.6 Hz, 2H), 3.13 (d, J = 6.3 Hz, 4H), 2.43 (d, J = 6.3 Hz, 4H), 1.96 (d, J = 1 1.2 Hz, 2H), 1.32 - 1.14 (m, 7H), 0.91 - 0.76 (m, 1 H).
Example 313: 5-(4-((4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)phenyl)amino)-l,3,5-triazin-2-yl)-2- -hydroxypropanoyl)piperidin-4-yl)oxy)benzonitrile
Figure imgf000327_0001
1 -fluoro-4-nitrobenzene (0.75 ml, 7.09 mmol), 7-oxa-2-azaspiro[3.5]nonane oxalate salt (1525.19 mg, 7.09 mmol), potassium carbonate (2938.46 mg, 21 .26 mmol) in acetonitrile (1 1 ml) was stirred at 100°C for 2 overnights. The reaction was diluted with ethyl acetate, washed with water, dried and concentrated. The crude material was washed with ethyl acetate, filtered and dried to provide 2-(4-nitrophenyl)-7-oxa-2- azaspiro[3.5]nonane. LCMS-ESI"1" (m/z): [M+H]+ calcd for C13H16N203: 248.3; found: 249.1
2-(4-nitrophenyl)-7-oxa-2-azaspiro[3.5]nonane ( 1750 mg, 7.05 mmol), palladium (1 0% , 375.05 mg, 0.35 mmol) on carbon in ethanol (10 ml) were combined in a PARR flask and shaken on the hydrogenator for overnight at 45 PSI . The reaction was filtered over celite and washed down with 25% methanol/dichloromethane, concentrated to provide 4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)aniline. LCMS-ESI+ (m/z): [M+H]+ calcd for C„H N O: 218.3; found: 219.3
4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)aniline (800 mg, 3.66 mmol), potassium carbonate (1519.47 mg, 10.99 mmol) in dichloromethane ( 18 ml_) were combined, cooled to 0C, followed by 2,4-dichloro-1 ,3,5-triazine (549.59 mg, 3.66 mmol) in dichloromethane (18 ml_) that was cooled to 0°C before addition and stirred at 0C for 5 minutes. The reaction was quenched with water, extracted with 30% methanol/dichloromethane, dried, filtered, concentrated and purified by flash chromatography (silica gel) to provide N-(4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)phenyl)-4-chloro-1 ,3,5-triazin-2-amine. LCMS-
ESI+ (m/z): [M+H]+ calcd for C16H18CIN50: 331 .8; found: 332.6
In a 5 ml microwave tube, combined N-(4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)phenyl)-4- chloro-1 ,3,5-triazin-2-amine (65 mg, 0.2 mmol)), 2-(((3R,4S)-3-fluoro-1 -((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzonitrile (98.33 mg, 0.24 mmol), dimethoxyethane (2 ml_) and 2M Sodium carbonate solution in water (0.44 ml), tetrakis(triphenylphosphine)palladium (22.64 mg, 0.02 mmol) was added, blown down with nitrogen and the vial was sealed. The reaction mixture was heated in microwave at 150°C for 20 minutes. The mixture was diluted with 30% methanol/dichloromethane and water. The aqueous phase was extracted three times with 30% methanol/dichloromethane. The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via prep HPLC (0 - 70 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide 5-(4-((4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)-2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4- yl)oxy)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C31H34FN704: 587.6; found: 588.2 1H NMR (400 MHz, DMSO-c/6) δ 10.07 (d, J = 21.0 Hz, 1 H), 8.72 (s, 1 H), 8.67 - 8.45 (m, 2H), 7.64 (d, J = 9.1 Hz, 1 H), 7.49 (dd, J = 17.9, 8.5 Hz, 2H), 6.45 (dd, J = 11.5, 8.4 Hz, 2H), 5.24 - 4.90 (m, 3H), 4.59 - 4.30 (m, 2H), 4.28 - 3.86 (m, 1 H), 3.71 - 3.45 (m, 8H), 2.13 - 1.64 (m, 6H), 1.36 - 1.10 (m, 3H).
Example 314: 4-(4-((4-(3-cyano-4-(((3R,4S)-3-fluoro-1-((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)phenyl)-1,3,5-triazin-2- holine-2-carboxamide
Figure imgf000328_0001
1-fluoro-4-nitrobenzene (0.75 ml, 7.09 mmol), morpholine-2-carboxamide (1535.03 mg, 9.21 mmol), potassium carbonate (4897.44 mg, 35.44 mmol) in /V-Methyl-2-pyrrolidone (1 1 ml) was stirred at 100°C for 3 overnights. The reaction was diluted with ethyl acetate, washed with water, dried and concentrated. The crude was washed with ethyl acetate, filtered and dried to provide 4-(4-nitrophenyl)morpholine-2-carboxamide.
LCMS-ESI+ (m/z): [M+H]+ calcd for C11H13N304: 251.2; found: 252.1
1-(4-nitrophenyl)-4-(tetrahydro-2H-pyran-4-yl)piperazine (2810 mg, 9.64 mmol), palladium (10%, 513.21 mg, 0.48 mmol) on carbon in ethanol (14 ml) were combined in a PARR flask and shaken on the hydrogenator for overnight at 45 PSI. The reaction was filtered over celite and washed down with 25% methanol/dichloromethane, concentrated to provide 4-(4-aminophenyl)tetrahydro-2H-pyran-2-carboxamide.
LCMS-ESI+ (m/z): [M+H]+ calcd for C12H16N202: 220.3; found: 221.1
4-(4-aminophenyl)morpholine-2-carboxamide (500 mg, 2.26 mmol), potassium carbonate (936.96 mg, 6.78 mmol) in dichloromethane (1 1 mL) were combined, cooled to 0°C, followed by 2,4-dichloro-1 ,3,5-triazine (338.9 mg, 2.26 mmol) in dichloromethane (1 1 mL) that was cooled to OC before addition and stirred at OC for 5 minutes. The reaction was quenched with water, extracted with 30% methanol/dichloromethane, dried, filtered, concentrated and purified by flash chromatography (silica gel) to provide 4-(4-((4-chloro-1 ,3,5-triazin-2- yl)amino)phenyl)morpholine-2-carboxamide. LCMS-ESI+ (m/z): [M+H]+ calcd for
Figure imgf000329_0001
334.8; found: 335.4
In a 0.5-2 ml microwave tube, combined 4-(4-((4-chloro-1 ,3,5-triazin-2- yl)amino)phenyl)morpholine-2-carboxamide (35 mg, 0.1 mmol), 2-(((3R,4S)-3-fluoro-1- ((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzonitrile (52.48 mg, 0.13 mmol), dimethoxyethane (1 mL) and 2M Sodium carbonate solution in water (0.24 ml), tetrakis(triphenylphosphine)palladium (12.08 mg, 0.01 mmol) was added, blown down with nitrogen and the vial was sealed. The reaction mixture was heated in microwave at 150°C for 20 minutes. The mixture was diluted with 30% methanol/dichloromethane and water. The aqueous phase was extracted three times with 30% methanol/dichloromethane. The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via prep HPLC (0 - 70 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide 4-(4-((4-(3-cyano-4-(((3R,4S)-3-fluoro-1-((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)phenyl)-1 ,3,5-triazin-2-yl)amino)phenyl)morpholine-
2-carboxamide. LCMS-ESI+ (m/z): [M+H]+ calcd for C2gH31 FN804: 590.6; found: 591.1
1H NMR (400 MHz, DMSO-c/6) δ 10.18 (d, J = 18.1 Hz, 1 H), 8.75 (s, 1 H), 8.57 (d, J = 11.2 Hz, 2H), 7.63 (d, J = 9.5 Hz, 3H), 7.34 (d, J = 22.2 Hz, 2H), 6.99 (d, J = 8.5 Hz, 2H), 5.27 - 4.84 (m, 3H), 4.60 - 4.30 (m, 1 H), 4.24 - 3.88 (m, 4H), 3.71 (td, J = 1 1.2, 2.8 Hz, 2H), 3.52 - 3.33 (m, 2H), 2.67 (d, J = 33.1 Hz, 2H), 2.04 - 1.72 (m, 2H), 1.19 (dd, J = 6.5, 3.2 Hz, 3H).
Example 315: (R)-4-(4-((4-(3-cyano-4-(((3R,4S)-3-f luoro-1 -((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)phenyl)-1,3,5-triazin-2- yl)amino)phenyl)morpholine-2-carboxamide
Figure imgf000330_0001
4-(4-((4-(3-cyano-4-(((3R,4S)-3-fluoro-1 -((S)-2-hydroxypropanoyl)piperidin-4- yl)oxy)phenyl)-1 ,3,5-triazin-2-yl)amino)phenyl)morpholine-2-carboxamide was subjected to chiral HPLC chromatography (CHIRALCEL OD-H, ACN: methanol (90: 10)) to isolate (R)-4-(4-((4-(3-cyano-4-(((3R,4S)-3-fluoro-1 -((S)-2-hydroxypropanoyl)piperidin-4- yl)oxy)phenyl)-1 ,3,5-triazin-2-yl)amino)phenyl)morpholine-2-carboxamide.1H NMR (400 MHz, DMSO-d6) δ 10.16 (d, J = 16.3 Hz, 1 H), 8.74 (s, 1 H), 8.57 (d, J = 10.7 Hz, 2H), 7.63 (d, J = 9.6 Hz, 3H), 7.31 (d, J = 22.7 Hz, 2H), 6.97 (d, J = 8.5 Hz, 2H), 5.25 - 4.89 (m, 3H), 4.61 - 4.34 (m, 1 H), 4.28 - 3.86 (m, 4H), 3.71 (td, J = 1 1 .2, 2.8Hz, 2H), 3.52 - 3.41 (m, 2H), 2.70 (d, J = 33.1 Hz, 2H), 2.04 - 1 .72 (m, 2H), 1.19 (dd, J = 6.5, 3.2 Hz, 3H).
Example 316: (S)-4-(4-((4-(3-cyano-4-(((3R,4S)-3-f luoro-1 -((S)-2 hydroxypropanoyl)piperidin-4-yl)oxy)phenyl)-1 ,3,5-triazin-2- holine-2-carboxamide
Figure imgf000330_0002
4-(4-((4-(3-cyano-4-(((3R,4S)-3-fluoro-1 -((S)-2-hydroxypropanoyl)piperidin-4- yl)oxy)phenyl)-1 ,3,5-triazin-2-yl)amino)phenyl)morpholine-2-carboxamide was subjected to chiral HPLC chromatography (CHIRALCEL OD-H, ACN: methanol (90: 10)) to isolate (S)-4-(4-((4-(3-cyano-4-(((3R,4S)-3-fluoro-1 -((S)-2-hydroxypropanoyl)piperidin-4- yl)oxy)phenyl)-1 ,3,5-triazin-2-yl)amino)phenyl)morpholine-2-carboxamide.
1H NMR (400 MHz, DMSO-c 6) δ 10.16 (d, J = 16.5 Hz, 1 H), 8.74 (s, 1 H), 8.57 (d, J = 10.4 Hz, 2H), 7.63 (d, J = 9.6 Hz, 3H), 7.32 (d, J = 22.5 Hz, 2H), 6.97 (d, J = 8.5 Hz, 2H), 5.24 - 4.93 (m, 3H), 4.59 - 4.33 (m, 1 H), 4.23 - 3.89 (m, 4H), 3.71 (td, J = 1 1 .2, 2.8Hz, 2H), 3.51 - 3.33 (m, 2H), 2.70 (d, J = 33.1 Hz, 2H), 2.04 - 1.69 (m, 2H), 1.19 (dd, J = 6.4, 2.8 Hz, 3H).
Example 317: 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5- (4-((4-(tetrahydro-1 H-furo[3,4-c]pyrrol-5(3H)-yl)phenyl)amino)-1,3,5-triazin-2-
Figure imgf000331_0001
1-fluoro-4-nitrobenzene (0.75 ml, 7.09 mmol), hexahydro-1 H-furo[3,4-c]pyrrole (1378.49 mg, 9.21 mmol), potassium carbonate (4897.44 mg, 35.44 mmol) in /V-Methyl-2- pyrrolidone (1 1 ml) was stirred at 100°C for 3 overnights. The reaction was diluted with ethyl acetate, washed with water, dried, concentrated and purified by flash chromatography (silica gel) to provide 5-(4-nitrophenyl)hexahydro-1 H-furo[3,4-c]pyrrole
LCMS-ESI+ (m/z): [M+H]+ calcd for C12H14N203: 234.3; found: 235.1
5-(4-nitrophenyl)hexahydro-1 H-furo[3,4-c]pyrrole (1530 mg, 6.53 mmol), palladium (10%, 347.54 mg, 0.33 mmol) on carbon in ethanol (10 ml) were combined in a PARR flask and shaken on the hydrogenator for 1 hour at 45 PSI. The reaction was filtered over celite and washed down with 25% methanol/dichloromethane, and concentrated to provide 4-(tetrahydro-1 H-furo[3,4-c]pyrrol-5(3H)-yl)aniline. LCMS-ESI+ (m/z): [M+H]+ calcd for C12H16N20: 204.3; found: 205.1
4-(tetrahydro-1 H-furo[3,4-c]pyrrol-5(3H)-yl)aniline (500 mg, 2.45 mmol), potassium carbonate (1014.88 mg, 7.34 mmol) in dichloromethane (12 mL) were combined, cooled to 0°C, followed by 2,4-dichloro-1 ,3,5-triazine (367.08 mg, 2.45 mmol) in dichloromethane (12 mL) and stirred at 0°C for 5 minutes. The crude material was quenched with water, extracted with 30% methanol/dichloromethane, washed with water, dried, concentrated and purified by flash chromatography (silica gel) to provide 4- chloro-N-(4-(tetrahydro-1 H-furo[3,4-c]pyrrol-5(3H)-yl)phenyl)-1 ,3,5-triazin-2-amine.
LCMS-ESI+ (m/z): [M+H]+ calcd for C15H16CIN50: 317.8; found: 318.5
In a 2-5 ml microwave tube, combined 4-chloro-N-(4-(tetrahydro-1 H-furo[3,4-c]pyrrol- 5(3H)-yl)phenyl)-1 ,3,5-triazin-2-amine (70 mg, 0.22 mmol), 2-(((3R,4S)-3-fluoro-1-((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzonitrile (1 10.56 mg, 0.26 mmol), dimethoxyethane (2 ml_) and 2M Sodium carbonate solution in water (0.5 ml), tetrakis(triphenylphosphine)palladium (25.46 mg, 0.02 mmol) was added, blown down with nitrogen and the vial was sealed. The reaction mixture was heated in microwave at 150°C for 20 minutes. The mixture was diluted with 30% methanol/dichloromethane and water. The aqueous phase was extracted three times with 30% methanol/dichloromethane. The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via prep HPLC (0 - 60 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4- yl)oxy)-5-(4-((4-(tetrahydro-1 H-furo[3,4-c]pyrrol-5(3H)-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C30H32FN7O4: 573.6; found: 574.2
1H NMR (400 MHz, DMSO-c/6) δ 10.06 (d, J = 18.8 Hz, 1 H), 8.70 (d, J = 2.7 Hz, 1 H), 8.64 - 8.45 (m, 2H), 7.62 (d, J = 9.1 Hz, 1 H), 7.50 (dd, J = 16.4, 8.5 Hz, 2H), 6.64 (dd, J = 1 1.6, 8.5 Hz, 2H), 5.26 - 4.86 (m, 3H), 4.56 - 4.32 (m, 2H), 4.25 - 3.91 (m, 2H), 3.89 - 3.72 (m, 2H), 3.60 - 3.48 (m, 2H), 3.25 - 3.03 (m, 3H), 2.97 (q, J = 4.1 Hz, 2H), 1.98- 1.83 (m, 2H), 1.19 (dd, J = 6.6, 3.3 Hz, 3H). Example 318: 2-(((3R,4S)-3-fluoro-1-(1 H-pyrazole-5-carbonyl)piperidin-4-yl)oxy)-5- peridin-4-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000332_0001
2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(1-(oxetan-3-yl)piperidin-4- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (70 mg, 0.13 mmol) was dissolved in dichloromethane (2 ml_), N,N-Diisopropylethylamine (0.05 ml, 0.26 mmol), N- [(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminiumhexafluorophosphate N-oxide (75.58 mg, 0.2 mmol), 1 H- pyrazole-5-carboxylic acid (29.63 mg, 0.26 mmol) was added and the reaction was allowed to stir for 1 hour at room temperature. The mixture was diluted with 30% methanol/dichloromethane and water. The aqueous phase was extracted three times with 30% methanol/dichloromethane. The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via prep HPLC (0 - 60 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4- yl)oxy)-5-(4-((4-(tetrahydro-1 H-furo[3,4-c]pyrrol-5(3H)-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H34FN903: 623.7; found: 624.2
1H NMR (400 MHz, DMSO-c/6) δ 13.23 (d, J = 2.2 Hz, 1 H), 10.32 (s, 1 H), 8.79 (s, 1 H), 8.66 - 8.46 (m, 2H), 7.92 - 7.75 (m, 1 H), 7.65 (d, J = 9.2 Hz, 3H), 7.25 (d, J = 8.3 Hz, 2H), 6.60 (t, J = 2.2 Hz, 1 H), 5.28 - 4.83 (m, 3H), 4.53 (t, J = 2.2 Hz, 2H), 4.44 (t, J = 2.2 Hz, 2H), 4.38 - 4.19 (m, 1 H), 3.68 - 3.35 (m, 2H), 2.80 (d, J = 10.8 Hz, 2H), 2.13 - 1.53 (m, 10H).
Example 319: 2-(((3R,4S)-1-(2-(1 H-1,2,3-triazol-5-yl)acetyl)-3-fluoropiperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-
Figure imgf000333_0001
2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (50 mg, 0.09 mmol) was dissolved in dichloromethane (1.3 ml_), N,N-Diisopropylethylamine (0.03 ml, 0.19 mmol), N- [(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminiumhexafluorophosphate N-oxide (53.89 mg, 0.14 mmol), 2-(1 H- 1 ,2,3-triazol-5-yl)acetic acid (23.95 mg, 0.19 mmol) was added and the reaction was allowed to stir for 1 hour at room temperature. According to LCMS, the reaction was complete but allowed to run for 3 hours 30 minutes. The mixture was diluted with 30% methanol/dichloromethane and water. The aqueous phase was extracted three times with 30% methanol/dichloromethane. The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via prep HPLC (0 - 40 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide 2-(((3R,4S)-1-(2-(1 H-1 ,2,3-triazol-5-yl)acetyl)-3-fluoropiperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H34FN1103: 639.7; found: 640.2
1H NMR (400 MHz, DMSO-c 6) δ 10.16 (d, J = 18.8 Hz, 1 H), 8.75 (s, 1 H), 8.57 (d, J = 12.5 Hz, 2H), 7.74 - 7.47 (m, 4H), 6.97 (t, J = 9.3 Hz, 2H), 5.06 (d, J = 58.3 Hz, 2H), 4.57 (t, J = 6.5 Hz, 2H), 4.47 (t, J = 6.1 Hz, 2H), 4.39 (s, 1 H), 3.94 (d, J = 19.8 Hz, 2H), 3.86 - 3.56 (m, 1 H), 3.47 - 3.38 (m, 2H), 3.14 (m, 5H), 2.41 (dd, J = 6.0, 3.7 Hz, 2H), 1.91 (d, J = 37.7 Hz, 2H), 1 .24 (d, J = 3.3 Hz, 1 H).
Example 320: 2-(((3R,4S)-1-(2-(1 H-pyrazol-5-yl)acetyl)-3-fluoropiperidin-4-yl)oxy)-5- erazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000334_0001
2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (50 mg, 0.09 mmol) was dissolved in dichloromethane (1 .3 ml_), N,N-Diisopropylethylamine (0.03 ml, 0.19 mmol), N- [(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1 -ylmethylene]-N- methylmethanaminiumhexafluorophosphate A-oxide (53.89 mg, 0.14 mmol), 2-(1 H- pyrazol-5-yl)acetic acid (23.77 mg, 0.19 mmol) was added and the reaction was allowed to stir for 1 hour at room temperature. The mixture was diluted with 30% methanol/dichloromethane and water. The aqueous phase was extracted three times with 30% methanol/dichloromethane. The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via prep HPLC (0 - 40 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide 2-(((3R,4S)-1 -(2-(1 H-pyrazol-5-yl)acetyl)-3-fluoropiperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H35FN10O3: 638.7; found: 639.1
1H NMR (400 MHz, DMSO-c/6) δ 10.16 (d, J = 19.1 Hz, 1 H), 8.75 (s, 1 H), 8.58 (d, J = 12.4 Hz, 2H), 7.76 - 7.52 (m, 4H), 7.43 (s, 1 H), 6.99 (d, J = 9.2 Hz, 2H), 6.26 (td, J = 2.1 , 1 .2 Hz, 1 H), 5.33 - 4.89 (m, 4H), 4.57 (t, J = 6.5 Hz, 2H), 4.48 (t, J = 6.5 Hz, 2H), 4.41 (d, J = 27.5 Hz, 1 H), 4.23 - 3.99 (m, 1 H), 3.90-3.66 (m, 1 H), 3.53 - 3.38 (m, 2H), 3.22 - 3.12 (m, 4H), 2.41 (dd, J = 6.4, 3.4 Hz, 4H), 1 .95 (d, J = 49.2 Hz, 2H). Example 321 : 2-(((3R,4S)-3-fluoro-1-(3-methyl-1 H-pyrazole-5-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-
Figure imgf000335_0001
2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (50 mg, 0.09 mmol) was dissolved in dichloromethane (1 .3 mL), N,N-Diisopropylethylamine (0.03 ml, 0.19 mmol), N- [(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1 -ylmethylene]-N- methylmethanaminiumhexafluorophosphate N-oxide (53.89 mg, 0.14 mmol), 3-methyl- 1 H-pyrazole-5-carboxylic acid (23.77 mg, 0.19 mmol) was added and the reaction was allowed to stir for 1 hour at room temperature. The reaction was then subjected to 0.5 mL-1 mL of DMF until all of the precipitate went into solution. The reaction was allowed to stir overnight. The reaction was concentrated and then purified via prep HPLC (0 - 40 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide 2-(((3R,4S)-3-fluoro-1 - (3-methyl-1 H-pyrazole-5-carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-
1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for CJ-U . N 03: 638.7; found: 639.3
1H NMR (400 MHz, DMSO-c/6) δ 12.90 (s, 1 H), 10.15 (d, J = 18.5 Hz, 1 H), 8.74 - 8.45 (m, 2H), 7.82 - 7.51 (m, 3H), 6.97 (d, J = 9.2 Hz, 2H), 6.33 (s, 1 H), 5.24 - 4.80 (m, 2H), 4.56 (t, J = 6.5 Hz, 2H), 4.46 (t, J = 6.0 Hz, 2H), 4.35 - 4.22 (m, 1 H), 3.92 - 3.50 (m, 1 H), 3.44 (q, J = 6.3 Hz, 1 H), 3.13 (t, J = 4.9 Hz, 4H), 2.39 (t, J = 4.9 Hz, 4H), 2.45 (s, 3H), 2.20 - 1 .85 (m, 2H).
Example 322: 2-(((3R,4S)-1 -(4-chloro-1 H-pyrazole-5-carbonyl)-3-fluoropiperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-
Figure imgf000336_0001
2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (50 mg, 0.09 mmol) was dissolved in dichloromethane (1.3 mL), N,N-Diisopropylethylamine (0.03 ml, 0.19 mmol), Λ/- [(dimethylamino)-lH-l,2,3-triazolo-[4,5-b]pyridin-l-ylmethylene]-N- methylmethanaminiumhexafluorophosphate /V-oxide (53.89 mg, 0.14 mmol), 3-methyl-1 H- pyrazole-5-carboxylic acid (23.77 mg, 0.19 mmol) was added and the reaction was allowed to stir for 1 hour at room temperature. The reaction was then subjected to 0.5 mL-1 mL of DMF until all of the precipitate went into solution. The reaction was allowed to stir overnight. The reaction was then subjected to 0.5 mL-1 mL of DMF until all of the precipitate went into solution. The reaction was allowed to stir overnight. The reaction was concentrated and then purified via prep HPLC (0 - 40 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide 2-(((3R,4S)-1-(4-chloro-1 H-pyrazole-5-carbonyl)-3- fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H32CIFN10O3: 659.1 ; found: 659.3
1H NMR (400 MHz, DMSO-c/6) δ 10.14 (d, J = 6.0 Hz, 1 H), 8.73 (s, 1 H), 8.56 (d, J = 12.7 Hz, 2H), 8.05 (s, 1 H), 7.71 - 7.48 (m, 3H), 6.95 (t, J = 9.1 Hz, 2H), 5.33 - 4.81 (m, 2H), 4.56 (t, J = 6.5 Hz, 2H), 4.47 (t, J = 6.5 Hz, 2H), 4.41 - 4.25 (m, 1 H), 4.00 - 3.50 (m, 1 H), 3.44 (h, J = 6.4 Hz, 2H), 3.14 (m, 5H), 2.44 - 2.28 (m, 4H), 2.03 (d, J = 17.5 Hz, 2H).
Example 323: 2-(((3R,4S)-1 -(3-amino-4-chloro-1 H-pyrazole-5-carbonyl)-3- fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)- 1,3,5-triazin-2-yl)benzonitrile
Figure imgf000337_0001
2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (50 mg, 0.09 mmol) was dissolved in dichloromethane (1.3 mL), N,N-Diisopropylethylamine (0.2 ml, 1.13 mmol), N- [(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminiumhexafluorophosphate N-oxide (53.89 mg, 0.14 mmol), 3-amino-4- chloro-1 H-pyrazole-5-carboxylic acid (30.45 mg, 0.19 mmol) was added and the reaction was allowed to stir for 1 hour at room temperature. The reaction was then subjected to 0.5 mL-1 mL of DMF until all of the precipitate went into solution. The reaction was allowed to stir overnight. The reaction was concentrated and then purified via prep HPLC (0 - 40 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide 2-(((3R,4S)-1-(3-amino-4-chloro-1 H-pyrazole-5-carbonyl)-3-fluoropiperidin-4-yl)oxy)-5- (4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-
ESI+ (m/z): [M+H]+ calcd for Cg^CIFN^Os: 674.1 ; found: 674.2
1H NMR (400 MHz, DMSO-c/6) δ 12.16 (s, 1 H), 10.12 (d, J = 16.6 Hz, 1 H), 8.73 (s, 1 H), 8.56 (d, J = 10.2 Hz, 2H), 7.79 - 7.45 (m, 3H), 6.95 (s, 2H), 5.38 (s, 1 H), 5.27 - 4.82 (m, 2H), 4.58 (t, J = 6.0 Hz, 2H), 4.46 (t, J = 6.0 Hz, 2H), 4.38 - 4.18 (m, 1 H), 4.13 - 3.90 (m, 1 H), 3.80 - 3.35 (m, 2H), 3.20 - 3.05 (t, J = 4.8 Hz, 4H), 2.40 (t, J = 4.8 Hz, 4H), 2.10 - 1.80 (m, 2H).
Example 324: 2-(((3R,4S)-1 -(3-chloro-1 H-pyrazole-5-carbonyl)-3-fluoropiperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-
Figure imgf000337_0002
2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (50 mg, 0.09 mmol) was dissolved in dichloromethane (1 .3 mL), Ν,Ν-Diisopropylethylamine (0.2 ml, 1 .13 mmol), N- [(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1 -ylmethylene]-N- methylmethanaminiumhexafluorophosphate W-oxide (53.89 mg, 0.14 mmol), 3- chloro-1 H-pyrazole-5-carboxylic acid (27.62 mg, 0.19 mmol) was added and the reaction was allowed to stir for 1 hour at room temperature. The reaction was then subjected to 0.5 mL-1 mL of DMF until all of the precipitate went into solution. The reaction was allowed to stir overnight. The reaction was concentrated and then purified via prep HPLC (0 - 40 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide 2-(((3R,4S)-1 -(3-chloro-1 H-pyrazole-5-carbonyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-
(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+
(m/z): [M+H]+ calcd for Cg^CIFN^Os: 674.1 ; found: 674.2 1H NMR (400 MHz,
DMSO-c/6) 5 13.79 (s, 1 H), 10.12 (d, J = 17.9 Hz, 1 H), 8.73 (s, 1 H), 8.57 (d, J = 10.7 Hz, 2H), 7.73 - 7.43 (m, 3H), 6.95 (s, 2H), 6.70 (s, 1 H), 5.20-5.00 (m, 2H), 4.55 (t, J = 6.5 Hz, 2H), 4.46 (t, J = 6.1 Hz, 2H), 4.4-4.25 (m, 1 H), 3.42 (td, J = 1 1 .8, 1 1 .0, 5.5 Hz, 2H), 3.13 (s, 4H), 2.42 - 2.32 (m, 4H), 2.15-1 .80 (m, 2H), 1 .22 (d, J = 3.4 Hz, 1 H).
Example 325: 2-(((3R,4S)-3-fluoro-1 -(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((3- methoxy-4-(4-morpholinopiperidin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-
Figure imgf000338_0001
1-fluoro-2-methoxy-4-nitrobenzene (5000mg, 29.22 mmol), 4-(piperidin-4-yl)morpholine (4974 mg, 29.22 mmol), potassium carbonate (80764 mg, 58.44 mmol) in acetonitrile (45 ml) was stirred at 100°C for overnight. The reaction was diluted with ethyl acetate, washed with water, dried, concentrated and purified by flash chromatography (silica gel) to provide 4-(1 -(2-methoxy-4-nitrophenyl)piperidin-4-yl)morpholine. LCMS-ESI+ (m/z):
[M+H]+ calcd for C16H23N304: 321 .4; found: 322.0
4-(1 -(2-methoxy-4-nitrophenyl)piperidin-4-yl)morpholine (8470 mg, 26.36 mmol), palladium (10%, 4207 mg, 3.953 mmol) on carbon in ethanol (38 ml) were combined in a PARR flask and shaken on the hydrogenator for 1 hour at 45 PSI. The reaction was filtered over celite and washed down with 25% methanol/dichloromethane, and concentrated to provide 3-methoxy-4-(4-morpholinopiperidin-1-yl)aniline. LCMS-ESI+
(m/z): [M+H]+ calcd for C16H25N302: 291.4; found: 292.0
3-methoxy-4-(4-morpholinopiperidin-1-yl)aniline (2000 mg, 6.86 mmol) and potassium carbonate (2845.8 mg, 20.59 mmol) in dichloromethane (34 mL) were combined, cooled to 0°C, followed by 2,4-dichloro-1 ,3,5-triazine (1029.32 mg, 6.86 mmol) in dichloromethane (34 mL) and the reaction was stirred at 0°C for 5 minutes. The reaction was filtered, washed with dichloromethane. The filtrate was quenched with water, washed with water and dried to provide 4-chloro-N-(3-methoxy-4-(4- morpholinopiperidin-1-yl)phenyl)-1 ,3,5-triazin-2-amine.
LCMS-ESI+ (m/z): [M+H]+ calcd for CigH25CIN602: 590.0; found: 591.5
A 10-20 mL microwave vial was charged with (3R,4S)-tert-butyl 4-(2-cyano-4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)-3-fluoropiperidine-1-carboxylate (496.04 mg, 1.1 1 mmol), 4-chloro-N-(3-methoxy-4-(4-morpholinopiperidin-1-yl)phenyl)-1 ,3,5- triazin-2-amine (375 mg, 0.93 mmol), 2M Sodium carbonate (2.08 ml), Palladium- tetrakis(triphenylphosphine (63.62 mg, 0.06 mmol) in 10 mL of dimethoxyethane, blown down with nitrogen, irridated for 20 minutes at 150°C. The reaction was extracted with 30% methanol/dichloromethane, dried, filtered, concentrated and purified by flash chromatography (silica gel) to provide (3R,4S)-tert-butyl 4-(2-cyano-4-(4-((3-methoxy-4- (4-morpholinopiperidin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-
1- carboxylate.
LCMS-ESI+ (m/z): [M+H]+ calcd for C36H45FN805: 688.8; found: 689.4
(3R,4S)-tert-butyl 4-(2-cyano-4-(4-((3-methoxy-4-(4-morpholinopiperidin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-1-carboxylate (450 mg, 0.65 mmol) was dissolved in dichloromethane (3 ml), trifluoroacetic acid (0.5 ml, 6.53 mmol) was added and the reaction was stirred at room temperature for 1 h and then an additional 0.1 mL of TFA was added and the reaction was stirred for 10 minutes more. The reaction cooled to 0C, neutralized with saturated sodium bicarbonate, washed with water, dried, filtered and concentrated to provide 2-(((3R,4S)-3- fluoropiperidin-4-yl)oxy)-5-(4-((3-methoxy-4-(4-morpholinopiperidin-1-yl)phenyl)amino)-
1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C31H37FN803: 588.7; found: 589.3
2- (((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((3-methoxy-4-(4-morpholinopiperidin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (50 mg, 0.08 mmol) was dissolved in dimethylformamide (0.5 ml_), N,N-Diisopropylethylamine (0.03 ml, 0.17 mmol),
N-[(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminiumhexafluorophosphate Λ/oxide (48.57 mg, 0.13 mmol), 2- hydroxyacetic acid (12.92 mg, 0.17 mmol) was added and the reaction was allowed to stir for 1 hour at room temperature. The reaction was concentrated and then purified via prep HPLC (0 - 40 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide 2- (((3R,4S)-3-fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((3-methoxy-4-(4- morpholinopiperidin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for Cggh^FNgOs: 646.7; found: 647.3
1H NMR (400 MHz, DMSO-c/6) δ 10.22 (s, 1 H), 8.76 (s, 1 H), 8.66 - 8.50 (m, 2H), 7.74 - 7.54 (m, 2H), 7.16 (s, 1 H), 6.87 (d, J = 8.6 Hz, 1 H), 5.22 - 4.90 (m, 2H), 4.66 (s, 1 H), 4.42 - 4.03 (m, 4H), 4.00 - 3.60 (m, 4H), 3.60 - 3.50 (m, 5H), 3.42 - 3.32 (m, 3H), 3.23 - 3.04 (m, 1 H), 2.21 (dd, J = 9.2, 5.5 Hz, 2H), 2.06 - 1.73 (m, 5H), 1.65 - 1.42 (m, 2H).
Example 326: 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5- (4-((3-methoxy-4-(4-morpholinopiperidin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile
Figure imgf000340_0001
2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((3-methoxy-4-(4-morpholinopiperidin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (50 mg, 0.08 mmol) was dissolved in dimethylformamide (0.5 ml_), N,N-Diisopropylethylamine (0.03 ml, 0.17 mmol),
N-[(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminiumhexafluorophosphate N-oxide (48.57 mg, 0.13 mmol), (S)-2- hydroxypropanoic acid (15.3 mg, 0.17 mmol) was added and the reaction was allowed to stir for 1 hour at room temperature. The reaction was concentrated and then purified via prep HPLC (0 - 40 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((3-methoxy-4-
(4-morpholinopiperidin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C34H41FN805: 660.7; found: 661.3
1H NMR (400 MHz, DMSO-c/6) δ 10.23 (s, 1 H), 8.76 (s, 1 H), 8.67 - 8.51 (m, 2H), 7.63 (d, J = 9.0 Hz, 2H), 7.16 (d, J = 8.6 Hz, 1 H), 6.88 (d, J = 8.6 Hz, 1 H), 5.22 - 4.90 (m, 3H), 4.58 - 4.38 (m, 2H), 4.22 - 3.90 (m, 2H), 3.90 - 3.75 (m, 4H), 3.6-3.55 (m, 5H), 3.45 - 3.33 (m, 3H), 3.25-3.05 (m, 1 H), 2.20 (d, J = 1 1.7 Hz, 2H), 2.06 - 1.72 (m, 5H), 1.52 (d, J = 1 1.2 Hz, 2H), 1.19 (dd, J = 6.5, 2.7 Hz, 3H).
Example 327: 2-(((3R,4S)-1 -(2-cyanoacetyl)-3-f luoropiperidin-4-yl)oxy)-5-(4-((3- methoxy-4-(4-morpholinopiperidin-1-yl)phenyl)amino)-1,3,5-triazin-2-
Figure imgf000341_0001
2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((3-methoxy-4-(4-morpholinopiperidin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (50 mg, 0.08 mmol) was dissolved in dimethylformamide (0.5 ml_), N,N-Diisopropylethylamine (0.03 ml, 0.17 mmol),
N-[(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminiumhexafluorophosphate Λ/oxide (48.57 mg, 0.13 mmol), 2- cyanoacetic acid (14.45 mg, 0.17 mmol) was added and the reaction was allowed to stir for 1 hour at room temperature. The reaction was concentrated and then purified via prep HPLC (0 - 40 % acetonitrile in water, 0.1 % trifluoroacetic acid buffer) to provide 2- (((3R,4S)-1-(2-cyanoacetyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((3-methoxy-4-(4- morpholinopiperidin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C34H38FN904: 655.7; found: 656.3
1H NMR (400 MHz, DMSO-c/6) δ 10.23 (s, 1 H), 8.76 (s, 1 H), 8.68 - 8.54 (m, 2H), 7.62 (d, J = 9.0 Hz, 2H), 7.40-7.20 (m, 1 H), 6.87 (d, J = 8.5 Hz, 1 H), 5.29 - 4.92 (m, 2H), 4.40 - 4.30 (m, 1 H), 4.25 - 3.90 (m, 3H), 3.88-3.70 (m, 4H), 3.70 - 3.56 (m, 5H), 3.40- 3.34 (m, 3H), 2.20 (d, J = 1 1.4 Hz, 2H), 1.97 (d, J = 17.1 Hz, 2H), 1.82 (d, J = 12.3 Hz, 3H), 1.52 (q, J = 1 1.5 Hz, 3H).
Example 328: 3-fluoro-2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2- yl)benzonitrile
Figure imgf000342_0001
Stepl : Preparation of (3R,4S)-tert-butyl 4-(4-bromo-2-cyano-6-fluorophenoxy)-3- fluoropiperidine-1-carboxylate: PS-PPri3 resin (5.34 g, 20.4 mmol 4.4 equiv) was added to a dried 500 ml_ RBF that was then capped and flushed with nitrogen. The resin was suspended in 75 ml_ of anhydrous THF. After a period of 2 min, 5-bromo-3-fluoro-2- hydroxybenzonitrile (1 g, 4.63 mmol) dissolved in 38 ml_ of anhydrous THF was added in a single portion. The resultant suspension was mixed briefly, after which a solution of DEAD was added in a single portion. This mixture was then agitated on an orbital shaker for 30min, after which a solution of 3R,4R)-tert-butyl 3-fluoro-4- hydroxypiperidine-1-carboxylate (1.27 g, 5.79 mmol) in THF (38 ml) was added in a single portion. The reaction mixture was then stirred 3 h. Then another portion of DEAD was added. The stirring was maintained overnight. The resultant suspension was filtered, and the resin was washed with THF. The filtrate was evaporated in vacuum. Solids were dissolved in DCM and water was added. The organic phase was evaporated under reduced pressure and purified by silica gel column chromatography with EtOAc in hexanes to give the product.
Step2: Preparation of (3R,4S)-tert-butyl 4-(2-cyano-6-fluoro-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenoxy)-3-fluoropiperidine-1-carboxylate: (3R,4S)-tert- butyl 4-(4-bromo-2-cyano-6-fluorophenoxy)-3-fluoropiperidine-1-carboxylate (750 mg, 1.8 mmol), potassium acetate ( 530 mg, 5.4 mmol), bis(pinacolato)diboron (913 mg, 3.6 mmol), and Pd(dppf)CI2 (133 mg, 0.18 mmol) were combined in a sealed tube. 1.4- dioxane (25 ml_) was added and the mixture was heated at 90 °C overnight. After cooling down, the mixture was filtered through a pad of Celite, eluting with 1 ,4- dioxane. The filtrate was concentrated to dryness under reduced pressure and the residue was purified by a silica gel column with the ESCO system with 0-5% MeOH in CH2CI2 to give the product.
Step 3: Preparation of (3R,4S)-tert-butyl 4-(2-cyano-6-fluoro-4-(4-((4-(4-(oxetan-3- yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-1- carboxylate : To a mixture of the (3R,4S)-tert-butyl 4-(2-cyano-6-fluoro-4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)-3-methylpiperidine-1 -carboxylate (372 mg, 0.81 mmol), 4-chloro-N-(4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)-1 ,3,5-triazin-2-amine (280 mg, 0.81 mmol), and Pd(PPh3)4 (70 mg, 0.061 mmol) in 1 ,2-DME (4 mL) , was added 2M sodium carbonate solution (1 .82 mL). The mixture was run under microwave at 130 °C for 75 minutes. Then the reaction mixture was diluted with a mixture of DCM and MeOH (1 : 1 ), filtered through a pad of Celite. The biphasic filtrate was concentrated under reduced pressure. Ethanol was added and concentrated. The residue was passed over a silica gel column with 5-15% MeOH in CH2CI2 to give the product.
LCMS-ESI+ (m/z): [M+H]+ calcd for C33H38 F2N804: 649.3; found: 649.2
Step 4:Preparation of 3-fluoro-2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile: (3R,4S)- tert-butyl 4-(2-cyano-6-fluoro-4-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5- triazin-2-yl)phenoxy)-3-fluoropiperidine-1 -carboxylate (414 mg, 0.64 mmol) was taken up in DCM (8 mL) and treated with TFA (2 mL). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column eluting 0-20% MeOH in dichloromethane to give the product. LCMS-ESI+ (m/z): [M+H]+ calcd for C28H30 F2N8O2: 549.3; found: 549.2
Step 5: Preparation of 3-fluoro-2-(((3R,4S)-3-fluoro-1 -((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile: To a mixture of 3-fluoro-2-(((3R,4S)- 3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5- triazin-2-yl)benzonitrile (50 mg), (S)-2-hydroxypropanoic acid (16 mg) and TEA (45 mg) in DMF (3 mL) was added HATU (69 mg). The reaction mixture was stirred at room temperature overnight. The mixture was treated with water and extracted with DCM. The organic phase was dried over Na2S04, concentrated to dryness. The residue was purified by silica gel column chromatography using 5-20% MeOH in CH2CI2 as eluent to give the title compound. 1H NMR (400 MHz, DMSO-c 6) δ 10.22 (d, 1 H), 8.77 (d, 1 H), 8.53 - 8.24 (m, 2H), 7.55 (t, 2H), 6.95 (d, 2H), 5.02 (m, 2H), 4.90 (d, 2H), 4.56 (t, 2H), 4.46 (t, 3H), 4.24 - 3.81 (m, 2H), 3.60 (m, 1 H), 3.43 (m, 1 H), 3.14 (d, 4H), 2.40 (d, 4H),
2.13 - 1 .79 (m, 2H), 1 .12 (d, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C3 H34
F2N804: 621 .3; found: 621 .4 Example 329: 3-fluoro-2-(((3R,4S)-3-fluoro-1 -(2-hydroxyacetyl)piperidin-4-yl)oxy)- l)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000344_0001
To a mixture of 3-fluoro-2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (50 mg, 0.09 mmol), glycolic acid (14 mg, 0.18 mmol) and TEA (45 mg, 0.37 mmol) in DMF (3 mL) was added HATU (69 mg, 0.18 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was treated with water and extracted with DCM. The organic phase was dried over Na2S04, concentrated to dryness. The residue was purified by silica gel column with ESCO system using 5-20% MeOH in CH2CI2 as eluent to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 10.22 (d, 1 H), 8.77 (d, 1 H), 8.53 - 8.26 (m, 2H), 7.55 (t, 2H), 7.12 - 6.86 (m, 2H), 5.05 (s, 1 H), 4.89 (m, 1 H), 4.66 (s, 1 H), 4.56 (m, 2H), 4.46 (m, 2H), 4.24 - 3.99 (m, 3H), 3.93 (m, 1 H), 3.67 (d, 1 H), 3.52 - 3.37 (m, 1 H), 3.13 (m, 5H), 2.40 (m, 4H), 2.13 - 1.84 (m, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd for C3oH32 F2N8O4: 607.3; found: 607.4
Example 330: 2-(((3R,4S)-1 -(2-cyanoacetyl)-3-fluoropiperidin-4-yl)oxy)-3-f luoro-5- (4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000344_0002
3-fluoro-2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (35 mg, 0.064 mmol), HATU (48 mg, 0.128 mmol), TEA (32 mg, 0.26 mmol) and 2-cyanoacetic acid(1 1 mg, 0.128 mmol) were dissolved in DMF( 2ml_) and stirred at room temperature for 2hr. The mixture was diluted with DCM and extracted with water. The organic phase was evaporated and the residue was purified by preparative HPLC. The fractions were taken and extracted with DCM and washed aqueous NaHC03 solution. The organic phase was dried over Na2S04, filtered. The filtrate was evaporated under reduced pressure to give the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 10.28 (d, 1 H), 8.79 (s, 1 H), 8.53 - 8.32 (m, 2H), 7.59 (m, 2H), 7.14 - 6.92 (m, 2H), 5.07 (d, 1 H), 5.01 - 4.80 (m, 2H), 4.72 (m, 4H), 4.33 (m, 1 H), 4.25 - 3.93 (m, 3H), 3.72 - 3.52 (m, 2H), 3.27 (m, 2H), 3.01 (m, 4H),
2.25 - 1.78 (m, 4H). LCMS-ESI+ (m/z): [M+H]+ calcd for C3 H31 F2N903: 616.3; found: 616.4
Example 331 : 3-fluoro-2-(((3R,4S)-3-fluoro-1-(3-hydroxypropanoyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-
Figure imgf000345_0001
3-fluoro-2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (25 mg, 0.046 mmol), HATU (35 mg, 0.09 mmol), TEA (22 mg, 0.18 mmol) and 3-hydroxypropanoic acid (8 mg, 0.09 mmol) were dissolved in DMF( 2ml_) and stirred at room temperature for 2hr. The mixture was diluted with DCM and extracted with water. The organic phase was evaporated and the residue was purified by preparative HPLC. The fractions were taken and extracted with DCM and washed aqueous NaHC03 solution. The organic phase was dried over Na2S04, filtered. The filtrate was evaporated under reduced pressure to give the title compound. 1H NMR (400 MHz, DMSO-c/6) δ 10.28 (d, 1 H), 8.79 (s, 1 H), 8.54 - 8.27 (m, 2H), 7.60 (t, 2H), 7.04 (m, 2H), 5.02 (d, 1 H), 4.94 - 4.81 (m, 2H), 4.73 (m, 4H), 4.36 - 4.15 (m, 1 H), 4.08 (m, 1 H), 3.96 - 3.70 (m, 2H), 3.62 (m, 3H), 3.16 - 2.85 (m, 4H), 2.48
(m, 6H), 2.16 -1.76 (m, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd for C3 H34 F2N804:
620.3; found: 621.4 Example 332: 5-(4-((4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl)amino)-1 ,3,5-triazin-2-yl)-2- ((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile
Figure imgf000346_0001
To a suspension of 5-(4-chloro-1 ,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4- yl)oxy)benzonitrile (222 mg, 0.70 mmol) in DMF (4 mL) was treated with 4-(2-(pyrrolidin- 1-yl)ethoxy)aniline (145 mg, 0.70 mmol) and DIEA (0.18 g, 1.4 mmol) at room temperature. The mixture was stirred at room temperature for 15 min. The mixture was purified by preparative HPLC to give the title compound. 1 H NMR (400 MHz, DMSO- d6) δ 9.97 (s, 1 H), 8.76 (s, 1 H), 8.65 - 8.40 (m, 1 H), 7.67 (d, 2H), 7.54 (d, 1 H), 7.03 (d, 2H), 4.93 (m, 1 H), 4.29 (m, 2H), 3.94 - 3.77 (m, 3H), 3.71 - 3.40 (m, 7H), 3.12 (m, 2H),
2.04 (m, 3H), 1.88 (m, 2H), 1.68 (m, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd for C27H30
N603: 487.2; found: 487.3
Example 333: 2-(((3R,4S)-3-fluoro-1-((S)-2-oxooxazolidine-4-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile
Figure imgf000346_0002
2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (82 mg, 0.15 mmol), HATU (1 17 mg, 0.31 mmol), TEA (76 mg, 0.62 mmol) and (S)-2-oxooxazolidine-4-carboxylic acid (41 mg, 0.31 mmol) were dissolved in DMF( 4 mL) and stirred at room temperature for 2hr. The mixture was diluted with DCM and extracted with water. The organic phase was evaporated and the residue was purified by preparative HPLC. The fractions were taken and extracted with DCM and washed aqueous NaHC03 solution. The organic phase was dried over Na2S04, filtered. The filtrate was evaporated under reduced pressure to give the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 10.1 1 (d, 1 H), 8.73 (s, 1 H), 8.65 - 8.44 (m, 2H), 7.95 (d, 1 H), 7.71 - 7.42 (m, 3H), 6.95 (m, 2H), 5.22 - 4.93 (m, 2H), 4.86 (m, 1 H), 4.63 - 4.39 (m, 6H), 4.38 - 4.12 (m, 2H), 4.04 (m, 1 H), 3.44
(m, 1 H), 3.13 m, 5H), 2.40 (m, 4H), 1.99 (m, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H34 FN9O5: 644.3; found: 644.3
Example 334: 2-(((3R,4S)-1 -(3-amino-1 H-1 ,2,4-triazole-5-carbonyl)-3- fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)- 1,3,5-triazin-2-yl)benzonitrile
Figure imgf000347_0001
2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (70 mg, 0.13 mmol), HATU (100 mg, 0.26 mmol), DIEA (52 mg, 0.4 mmol) and 3-amino-1 H-1 ,2,4-triazole-5-carboxylic acid (34 mg, 0.26 mmol) were dissolved in DMF (4 mL) and stirred at room temperature for 2 hr. The mixture was diluted with DCM and extracted with water. The organic phase was dried over Na2S04 and concentrated. The residue was purified silica gel column with ESCO system with 5-20% MeOH in CH2CI2 to give the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 12.33 (d, J = 7.3 Hz, 1 H), 10.12 (d, J = 22.3 Hz, 1 H), 8.81 - 8.66 (m, 1 H), 8.66 - 8.42 (m, 2H), 7.71 - 7.34 (m, 3H), 6.95 (t, J = 9.2 Hz, 2H), 6.15 (s, 1 H), 5.26 - 4.85 (m, 2H), 4.51 (m , 4H), 4.17 (s, 1 H), 3.73 (m, 1 H), 3.60 (m, 1 H), 3.45 (m, 1 H), 3.12
(m, 4H), 2.41 (m, 4H), 2.12 - 1.79 (m, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd for C31 H33 FN-12O3: 641.3; found: 641.4 Example 335: N-((S)-1-((3R, 4S)-4-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenoxy)-3-f luoropiperidin-1 -yl)-1 -oxopropan-2- yl)acetamide
Figure imgf000348_0001
2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (60 mg, 0.1 1 mmol), HATU (86 mg, 0.23 mmol) , DIEA (44 mg, 0.34 mmol), and (S)-2-acetamidopropanoic acid (30 mg, 0.23 mmol) were dissolved in DMF (4 ml_) and stirred at room temperature overnight. The mixture was diluted with DCM and extracted with water. The organic phase was dried over Na2S04 and concentrated. The residue was purified by silica gel column chromatography with 5-20% MeOH in CH2CI2 to give the product. LCMS-ESI"1" (m/z): [M+H]+ calcd for C33H38 FN9O4: 644.3; found: 644.3
Example 336: 2-(((3R,4S)-3-f luoro-1 -(pyrazine-2-carbonyl)piperidin-4-yl)oxy)-5-(4- ((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000348_0002
2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(1-(oxetan-3-yl)piperidin-4- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (40 mg, 0.075 mmol) was dissolved in dimethylformamide (5 ml_), N,N-diisopropylethylamine (0.04 ml, 0.23 mmol), (1-
[Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (57 mg, 0.15 mmol), pyrazine-2-carboxylic acid (19 mg, 0.15 mmol) was added and the reaction was allowed to stir for 1 hour at room temperature. The mixture was diluted with 20% methanol/dichloromethane and water. The aqueous phase was extracted twice with 20% methanol/dichloromethane. The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via normal phase prep HPLC (0 - 25 % methanol/dichloromethane) to provide 2-(((3R,4S)-3-fluoro-1-(pyrazine-2- carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for CssHssFN^Os: 636.68; found: 637.17 1H NMR (300 MHz, DMSO-c/6) δ 10.15 (d, J = 18.2 Hz, 1 H), 8.86 (t, J = 1.3 Hz, 1 H), 8.82 - 8.65 (m, 3H), 8.65 - 8.43 (m, 2H), 7.79 - 7.41 (m, 3H), 6.97 (d, J = 8.7 Hz, 2H), 5.37 - 4.75 (m, 2H), 4.56 (t, J = 6.5 Hz, 2H), 4.46 (t, J = 6.0 Hz, 2H), 4.37 - 3.34 (m, 5H), 3.1 1 (t, J = 7.2 Hz, 4H), 2.43 (t, J = 23.6 Hz, 4H), 2.27 - 1.78 (m, 2H).
Example 337: 2-(((3R,4S)-3-fluoro-1 -(pyrimidine-4-carbonyl)piperidin-4-yl)oxy)-5- (4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000349_0001
This molecule was synthesized in the same manner as Example 336 except replacing with 4-pyrimidinecarboxilic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H33FN10O3: 636.68; found: 637.22. 1H NMR (300 MHz, DMSO-c/6) δ 10.14 (d, J = 19.8 Hz, 1 H), 9.26 (t, J = 1.6 Hz, 1 H), 8.98 (dd, J = 5.1 , 2.6 Hz, 1 H), 8.73 (s, 1 H), 8.55 (dd, J = 13.3, 5.0 Hz, 2H), 7.83 - 7.42 (m, 4H), 6.95 (t, J = 8.7 Hz, 2H), 5.35 - 4.84 (m, 2H), 4.55 (t, J = 6.5 Hz, 2H), 4.45 (t, J = 6.0 Hz, 2H), 4.39 - 3.20 (m, 5H), 3.12 (bs, 4H), 2.39 (t, J = 4.8 Hz, 4H), 2.24 - 1.80 (m, 2H).
Example 338: 2-(((3R,4S)-3-fluoro-1 -(pyridazine-4-carbonyl)piperidin-4-yl)oxy)-5-(4- ((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000350_0001
This molecule was synthesized in the same manner Example 336 except replacing with
4-pyridazinecarboxilic acid. LCMS-ESI"1" (m/z): [M+H]+ calcd for C33H33FN10O3: 636.68; found: 637.22. 1H NMR (300 MHz, DMSO-c/6) δ 10.14 (d, J = 20.3 Hz, 1 H), 9.49 - 9.15 (m, 2H), 8.73 (s, 1 H), 8.68 - 8.42 (m, 2H), 7.76 (ddd, J = 15.9, 5.3, 2.3 Hz, 1 H), 7.69 - 7.42 (m, 3H), 6.95 (t, J = 8.7 Hz, 2H), 5.32 - 4.81 (m, 2H), 4.55 (t, J = 6.5 Hz, 2H), 4.45 (t, J = 6.0 Hz, 2H), 3.93 - 3.18 (m, 5H), 3.18 - 2.95 (m, 4H), 2.39 (t, J = 6.1 , 4H), 2.04 (m, 2H).
Example 339: 2-(((3R,4S)-1 -(3-aminopyrazine-2-carbonyl)-3-fluoropiperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2- yl)benzonitrile
Figure imgf000350_0002
This molecule was synthesized in the same manner as Example 336 except replacing with 3-amino-2-pyrazinecarboxilic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H34FN11 O3: 651.69; found: 652.27. 1H NMR (300 MHz, DMSO-c/6) δ 10.15 (d, J = 18.8 Hz, 1 H), 8.83 - 8.41 (m, 2H), 8.05 (dd, J = 2.6, 1.5 Hz, 1 H), 7.78 (d, J = 2.5 Hz, 1 H), 7.70 - 7.44 (m, 3H), 6.97 (d, J = 9.2 Hz, 2H), 6.54 (m, 3H), 5.40 - 4.72 (m, 2H), 4.56 (t, J = 6.5 Hz, 2H), 4.46 (t, J = 6.0 Hz, 2H), 4.35 - 3.52 (m, 2H), 3.52 - 3.21 (m, 3H), 3.13 (t, J = 6.0 Hz, 4H), 2.39 (t, J = 4.9 Hz, 4H), 1.94 (m, 2H).
Example 340: 2-(((3R,4S)-1 -(6-aminopyrazine-2-carbonyl)-3-fluoropiperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2- yl)benzonitrile
Figure imgf000351_0001
This molecule was synthesized in the same manner as Example 336 except replacing with 6-amino-2-pyrazinecarboxilic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H34FN11 O3: 651.69; found: 652.32. 1H NMR (300 MHz, DMSO-d6) δ 10.12 (d, J = 18.0 Hz, 1 H), 8.72 (s, 1 H), 8.56 (d, J = 10.7 Hz, 2H), 7.91 (s, 1 H), 7.80 (d, J = 3.0 Hz, 1 H), 7.73 - 7.43 (m, 3H), 6.94 (t, J = 7.8 Hz, 2H), 6.69 (s, 2H), 5.32 - 4.79 (m, 1 H), 4.55 (t, J = 6.5 Hz, 2H), 4.50 (m, 1 H), 4.45 (t, J = 6.0 Hz, 2H), 4.34 - 3.88 (m, 1 H), 3.83 - 3.33 (m, 3H), 3.21 - 2.98 (m, 4H), 2.47 - 2.30 (m, 5H), 2.20 - 1.80 (m, 2H).
Example 341 : 2-(((3R,4S)-1 -(5-aminopyrazine-2-carbonyl)-3-fluoropiperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2- yl)benzonitrile
Figure imgf000351_0002
This molecule was synthesized in the same manner as Example 336 except replacing with 5-amino-2-pyrazinecarboxilic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H34FN11 O3: 651.69; found: 652.27. 1H NMR (300 MHz, DMSO-c/6) δ 10.12 (d, J = 16.3 Hz, 1 H), 8.73 (s, 1 H), 8.56 (d, J = 1 1.0 Hz, 2H), 8.24 (s, 1 H), 7.89 - 7.71 (m, 1 H), 7.71 - 7.41 (m, 3H), 6.97 (bs, 4H), 5.14 (d, J = 21.6 Hz, 1 H), 4.55 (t, J = 6.5 Hz, 2H), 4.46 (t, J = 6.0 Hz, 2H), 4.40 (m, 1 H), 4.29 - 3.48 (m, 1 H), 3.48 - 3.36 (m, 3H), 3.21 - 2.99 (m, 4H), 2.47 - 2.29 (m, 4H), 2.00 (s, 2H).
Example 342: 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5- (4-((4-(3-hydroxy-3-methylazetidin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile
Figure imgf000352_0001
Stepl : 1-(4-((4-chloro-1,3,5-triazin-2-yl)amino)phenyl)-3-methylazetidin-3-ol: 1-(4- aminophenyl)-3-methylazetidin-3-ol (680mg, 4mmol) and potassium carbonate (1.581 g, 11 mmol) were charged to a RB-flask under nitrogen and dimethylformamide (15ml_) was added and the suspension was cooled to 0°C using an ice bath. 2,4-dichloro-1 ,3,5- triazine (572mg, 4mmol) was placed into a 50ml_ vial and dissolved in dimethylformamide (5ml_) and cooled to 0°C for 10min. The triazine was then added via syringe to the suspension over 2min and allowed to react at 0°C for 5min. Water (100ml_) and 20% methanol/dichloromethane (100ml_) was then added and the organic layer was washed with saturated sodium bicarbonate (1 x 50ml_) and brine (1 x 50ml_) and then dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via normal phase prep HPLC (15-85 % ethyl acetate/hexanes) to provide 1 -(4-((4-chloro-1 ,3,5-triazin-2-yl)amino)phenyl)-3-methylazetidin-3-ol.
Step 2: (3R,4S)-tert-butyl 4-(2-cyano-4-(4-((4-(3-hydroxy-3-methylazetidin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenoxy)-3-f luoropiperidine-1 -carboxylate: 1 -(4- ((4-chloro-1 ,3,5-triazin-2-yl)amino)phenyl)-3-methylazetidin-3-ol (89mg, 0.31 mmol), (3R,4S)-tert-butyl 4-(2-cyano-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)-3- fluoropiperidine-1-carboxylate (150mg, 0.36mmol), sodium carbonate (129mg, 1.24mmol) and Tetrakis(triphenylphosphine)palladium(0) (35mg, 0.03mmol) were all placed into a microwave reaction vessel and to that was added dimethoxyethane (3ml_) and water (2ml_) and then placed in a microwave reactor at 150°C for 20min. Water (100ml_) and 20% methanol/dichloromethane (100ml_) was then added and the organic layer was washed with saturated sodium bicarbonate (1 x 50ml_) and brine (1 x 50ml_) and then dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via normal phase prep HPLC (0-20% methanol/dichloromethane) to provide (3R,4S)-tert-butyl 4-(2-cyano-4-(4-((4-(3-hydroxy-3-methylazetidin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-1-carboxylate.
Step 3: 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(3-hydroxy-3-methylazetidin- 1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile: 4-(2-cyano-4-(4-((4-(3-hydroxy-3- methylazetidin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-1- carboxylate (1 18mg, 0.21 mmol) was dissolved in dichloromethane (5ml_) and to that was added trifluoroacetic acid (1 ml_) and was allowed to react for 1 hr at room temperature. The reaction was then concentrated under reduced pressure and to the residue was added saturated sodium bicarbonate and 20% methanol/dichloromethane and the extracted organic layer was washed with saturated sodium bicarbonate (1 x 50ml_) and brine (1 x 50ml_) and then dried over sodium sulfate and concentrated under reduced pressure to provide 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(3-hydroxy- 3-methylazetidin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile which was used directly in the next reaction.
Step 4: 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4- (3-hydroxy-3-methylazetidin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile: 2-
(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(3-hydroxy-3-methylazetidin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (76mg, 0.16mmol), (1- [Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (91 mg, 0.24mmol), L-(+)-lactic acid (29mg, 0.32mmol) and N,N- diisopropylethylamine (0.056mL, 0.32mmol) were all added to a 100ml_ flask and dissolved in dimethylformamide (5ml_) and allowed to react at room temperature for 1 hour. Water (100ml_) and 20% methanol/dichloromethane (100ml_) was then added and the organic layer was washed with saturated sodium bicarbonate (1 x 50ml_) and brine (1 x 50ml_) and then dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via normal phase prep HPLC (0-20% methanol/dichloromethane) to provide 2-(((3R,4S)-3-fluoro-1 -((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4-(3-hydroxy-3-methylazetidin-1 - yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C28H3oFN704: 547.58; found: 548.22. 1H NMR (300 MHz, DMSO-c/6) δ 10.05 (d, J = 20.3 Hz, 1 H), 8.72 (s, 1 H), 8.63 - 8.41 (m, 2H), 7.63 (d, J = 9.1 Hz, 1 H), 7.49 (dd, J = 18.0, 8.3 Hz, 2H), 6.46 (t, J = 9.8 Hz, 2H), 5.48 (s, 1 H), 5.30 - 4.78 (m, 3H), 4.64 - 3.84 (m, 3H), 3.84 - 3.64 (m, 2H), 3.64 - 3.47 (m, 2H), 3.47 - 3.03 (m, 2H), 1 .90 (m, 2H), 1 .46 (s, 3H), 1 .34 - 1 .16 (m, 3H).
Example 343: 2-(((3R,4S)-3-fluoro-1 -(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((1 - methyl-1 H-indazol-6-yl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000354_0001
This molecule was synthesized in the same manner as Example 342 except starting with 1 -methyl-1 H-indazol-6-amine and substituting glycolic acid for L-(+)-lactic acid.
LCMS-ESI+ (m/z): [M+H]+ calcd for C25H23FN803: 502.50; found: 503.07. 1H NMR (300 MHz, DMSO-c/6) δ 10.61 (s, 1 H), 8.88 (s, 1 H), 8.75 - 8.54 (m, 2H), 8.37 (s, 1 H), 7.98 (d, J = 0.9 Hz, 1 H), 7.68 (dd, J = 17.7, 8.9 Hz, 2H), 7.32 (d, J = 8.7 Hz, 1 H), 5.25 - 4.56 (m, 3H), 4.49 - 3.78 (m, 6H), 3.77 - 3.15 (m, 2H), 2.16 - 1 .56 (m, 2H).
Example 344: 2-(((3R,4S)-3-fluoro-1 -((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5- (4-((1 -methyl-1 H-indazol-6-yl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000354_0002
This molecule was synthesized in the same manner as Example 342 except starting with 1-methyl-1 H-indazol-6-amine. LCMS-ESI"1" (m/z): [M+H]+ calcd for C26H25FN8O3: 516.53; found: 517.07. 1H NMR (300 MHz, DMSO-c/6) δ 10.59 (s, 1 H), 8.87 (s, 1 H), 8.76 - 8.50 (m, 2H), 8.37 (s, 1 H), 7.97 (d, J = 0.9 Hz, 1 H), 7.80 - 7.53 (m, 2H), 7.31 (d, J = 8.7 Hz, 1 H), 5.31 - 4.82 (m, 3H), 4.59 - 4.27 (m, 1 H), 4.27 - 3.80 (m, 4H), 3.77 - 3.03 (m, 2H), 2.13 - 1.65 (m, 2H), 1.34 - 1.1 1 (m, 3H).
Example 345: 2-(((3R,4S)-1-(2,4-dimethyl-1 H-imidazole-5-carbonyl)-3- fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)- 1,3,5-triazin-2-yl)benzonitrile
Figure imgf000355_0001
This molecule was synthesized in the same manner as Example 336 except replacing with 2,5-dimethylimidazole-4-carboxilic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C34H37FN10O3: 652.72; found: 653.22. 1H NMR (300 MHz, DMSO-c/6) δ 1 1.94 (s, 1 H), 10.14 (d, J = 15.9 Hz, 1 H), 8.74 (s, 1 H), 8.58 (d, J = 10.6 Hz, 2H), 7.59 (dd, J = 23.5, 10.8 Hz, 3H), 6.97 (s, 2H), 5.30 - 4.80 (m, 3H), 4.57 (t, J = 6.5 Hz, 2H), 4.51 (t, J = 6.5 Hz, 2H), 3.58 - 3.36 (m, 1 H), 3.29 - 3.00 (m, 6H), 2.41 (t, J = 4.7 Hz, 4H), 2.31 (s, 3H), 2.23 (s, 3H), 2.05 (m, 3H).
Example 346: 5-(4-((1,3-dimethyl-1 H-indazol-6-yl)amino)-1,3,5-triazin-2-yl)-2- (((3R,4S)-3-fluoro-1 -(2-hydroxyacetyl)piperidin-4-yl)oxy)benzonitrile
Figure imgf000356_0001
This molecule was synthesized in the same manner as Example 342 except starting with 1 ,3-dimethyl-1 H-indazol-6-amine and substituting glycolic acid for L-(+)-lactic acid.
LCMS-ESI+ (m/z): [M+H]+ calcd for C26H25FN803: 516.53; found: 517.12. 1H NMR (300 MHz, DMSO-c/6) δ 10.59 (s, 1 H), 8.88 (s, 1 H), 8.76 - 8.47 (m, 2H), 8.30 (s, 1 H), 7.65 (d, J = 8.9 Hz, 2H), 7.28 (d, J = 8.7 Hz, 1 H), 5.32 - 4.57 (m, 3H), 4.51 - 4.00 (m, 3H), 3.95 (d, J = 7.6 Hz, 3H), 3.79 - 2.94 (m, 22H), 2.44 (s, 3H), 1 .90 (m, 2H).
Example 347: 5-(4-((1 ,3-dimethyl-1 H-indazol-6-yl)amino)-1 ,3,5-triazin-2-yl)-2- (((3R,4S)-3-fluoro-1 -((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)benzonitrile
Figure imgf000356_0002
This molecule was synthesized in the same manner as Example 342 except starting with 1 ,3-dimethyl-1 H-indazol-6-amine. LCMS-ESI"1" (m/z): [M+H]+ calcd for C27H27FN803: 530.55; found: 531 .17. 1 H NMR (300 MHz, DMSO-c/6) δ 10.59 (s, 1 H), 8.87 (s, 1 H), 8.74 - 8.51 (m, 2H), 8.12 (m, 1 H), 7.65 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 8.6 Hz, 1 H), 5.29 - 4.79 (m, 3H), 4.46 (dt, J = 1 1 .0, 6.7 Hz, 1 H), 4.25 - 3.83 (m, 4H), 3.83 - 2.99 (m, 2H), 2.46 (s, 3H), 1 .91 (m, 2H), 1 .35 - 1 .09 (m, 3H).
Example 348: 2-(((3R,4S)-1 -(2,3-dihydroxypropanoyl)-3-fluoropiperidin-4-yl)oxy)-5- (4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000357_0001
Step 1 : 2-(((3R,4S)-1-(2,2-dimethyl-1,3-dioxolane-4-carbonyl)-3-fluoropiperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2- yl)benzonitrile
The title compound was synthesized in the same manner as Example 336 except replacing with 2,2-dimethyl-1 ,3-dioxolane-4-carboxylic acid.
Step 2: 2-(((3R,4S)-1-(2,3-dihydroxypropanoyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4- (4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile: 2- (((3R,4S)-1-(2,2-dimethyl-1 ,3-dioxolane-4-carbonyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4- (4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (150mg, 0.23mmol) was dissolved in tetrahydrofuran (18ml_) and to that was added HCI (1 M, 2.0ml_) and the reaction was allowed to proceed for 18 hours. Following day the sample was concentrated and redissolved in 20% methanol/dichloromethane and basified using saturated sodium bicarbonate (2 x 50ml_), washed with brine (1 x 50ml_) and dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via normal phase prep HPLC (0 - 25 % methanol/dichloromethane) to provide 2-(((3R,4S)- 1-(2,3-dihydroxypropanoyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-
1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile as a racemate. LCMS-ESI+ (m/z): [M+H]+ calcd for C3iH35FN805: 618.66; found: 619.27. 1H NMR (300 MHz, DMSO-c/6) δ 10.12 (d, J = 17.3 Hz, 1 H), 8.73 (s, 1 H), 8.56 (d, J = 10.6 Hz, 2H), 7.58 (dd, J = 23.5, 10.4 Hz, 3H), 6.95 (s, 2H), 5.74 - 4.63 (m, 3H), 4.55 (t, J = 6.5 Hz, 2H), 4.46 (t, J = 6.0 Hz, 2H), 4.41 - 3.83 (m, 4H), 3.78 - 3.34 (m, 3H), 3.13 (m, 4H), 2.40 (m, J = 5.0 Hz, 4H), 1.91 (m, 2H). Example 349: 2-(((3R,4S)-3-fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((1- isopropyl-1H-pyrazol-4-yl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000358_0001
This molecule was synthesized in the same manner as Example Example 342 except starting with 1-isopropyl-1H-pyrazol-4-amine and substituting glycolic acid for L-(+)-lactic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C23H25FN803: 480.49; found: 481.18. 1H NMR (300 MHz, DMSO-c6) δ 10.28 (d, J = 7.8 Hz, 1 H), 8.75 (d, J = 29.5 Hz, 1 H), 8.66 - 8.44 (m, 2H), 7.99 (dd, J = 14.5, 0.7 Hz, 1H), 7.74 - 7.48 (m, 2H), 5.28 - 4.84 (m, 2H), 4.50 (dp, J= 11.3, 6.6 Hz, 1 H), 4.41 - 3.81 (m, 3H), 3.42 (m, 3H), 2.09 - 1.70 (m, 2H), 1.42 (dd, J= 13.9, 6.6 Hz, 6H).
Example 350: 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5- (4-((1-isopropyl-1H-pyrazol-4-yl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000358_0002
This molecule was synthesized in the same manner as Example 342 except starting with 1-isopropyl-1H-pyrazol-4-amine. LCMS-ESI+ (m/z): [M+H]+ calcd for C24H27FN8O3: 494.52; found: 495.17.1H NMR (300 MHz, DMSO-c/6) δ 10.28 (d, J = 7.6 Hz, 1H), 8.75 (d, J = 29.5 Hz, 1 H), 8.64 - 8.44 (m, 2H), 7.99 (d, J = 14.7 Hz, 1 H), 7.79 - 7.34 (m, 2H), 5.04 (d, J = 48.3 Hz, 2H), 4.67 - 4.25 (m, 2H), 4.25 - 3.82 (m, 1H), 3.82 - 2.89 (m, 3H), 2.18-1.65 (m, 2H), 1.42 (dd, J= 14.0, 6.7 Hz, 6H), 1.32- 1.08 (m, 3H). Example 351 : 5-(4-((1 -ethyl-1 H-pyrazol-4-yl)amino)-1 ,3,5-triazin-2-yl)-2-(((3R,4S)-3- fluoro-1 -((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)benzonitrile
Figure imgf000359_0001
This molecule was synthesized in the same manner as Example 342 except starting with 1 -ethyl-1 H-pyrazol-4-amine. LCMS-ESI"1" (m/z): [M+H]+ calcd for C23H25FN8O3: 480.49; found: 481 .18. 1H NMR (300 MHz, DMSO-c/6) δ 9.58 (s, 1 H), 8.63 (d, J = 1 .1 Hz, 1 H), 8.34 (d, J = 2.3 Hz, 1 H), 8.28 (dd, J = 9.0, 2.3 Hz, 1 H), 8.03 (s, 1 H), 7.75 - 7.38 (m, 2H), 7.06 (d, J = 1 .2 Hz, 1 H), 5.23 - 4.79 (m, 3H), 4.64 - 4.26 (m, 1 H), 4.1 1 (q, J = 7.2 Hz, 3H), 3.75 - 2.98 (m, 2H), 2.12 - 1 .66 (m, 2H), 1 .35 (t, J = 7.2 Hz, 3H), 1 .28 - 1.12 (m, 3H).
Example 352: 5-(4-((1 -(2,2-difluoroethyl)-1 H-pyrazol-4-yl)amino)-1 ,3,5-triazin-2-yl)- 2-(((3R,4S)-3-fluoro-1 -((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)benzonitrile
Figure imgf000359_0002
This molecule was synthesized in the similar manner as Example 342 except starting with 1 -(2,2-difluoroethyl)-1 H-pyrazol-4-amine and replacing the boronate for 2-(((3R,4S)- 3-fluoro-1 -((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzonitrile in the microwave Suzuki reaction. LCMS-ESI+ (m/z):
[M+H]+ calcd for C23H23F3N803: 516.48; found: 517.12. 1 H NMR (300 MHz, DMSO-c/6) δ 10.39 (d, J = 2.2 Hz, 1 H), 8.78 (d, J = 30.7 Hz, 1 H), 8.67 - 8.47 (m, 2H), 8.10 (d, J = 6.7 Hz, 1 H), 7.81 - 7.53 (m, 2H), 6.70 - 6.02 (m, 1 H), 5.35 - 4.79 (m, 3H), 4.64 (qd, J = 15.0, 3.8 Hz, 2H), 4.52 - 4.27 (m, 1 H), 4.24 - 2.94 (m, 2H), 1.90 (d, J = 42.5 Hz, 2H), 1.19 (dt, J = 6.6, 3.2 Hz, 3H).
Example 353: 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5- (4-((1 -(oxetan-3-yl)-1 H-pyrazol-4-yl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000360_0001
This molecule was synthesized in the same manner as Example 342 except starting with 1-(oxetan-3-yl)-1 H-pyrazol-4-amine and replacing the boronate for 2-(((3R,4S)-3- fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzonitrile in the microwave Suzuki reaction. LCMS-ESI+ (m/z): [M+H]+ calcd for C24H25FN804: 508.50; found: 509.12. 1H NMR (300 MHz, DMSO-c/6) δ 10.39 (d, J = 3.0 Hz, 1 H), 8.77 (d, J = 29.3 Hz, 1 H), 8.69 - 8.45 (m, 2H), 8.12 (dd, J = 4.6, 0.7 Hz, 1 H), 7.78 (d, J = 37.7 Hz, 1 H), 7.62 (d, J = 9.1 Hz, 1 H), 5.79 - 5.43 (m, 1 H), 5.26 - 4.96 (m, 3H), 4.89 (tt, J = 10.3, 6.7 Hz, 4H), 4.46 (dt, J = 1 1.7, 6.8 Hz, 1 H), 4.26 - 3.78 (m, 1 H), 3.77 - 3.27 (m, 2H), 1.90 (d, J = 45.1 Hz, 2H), 1.40 - 1.04 (m, 3H). Example 354: 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5- (4-((1-(tetrahydro-2H-pyran-4-yl)-1 H-pyrazol-4-yl)amino)-1,3,5-triazin-2- yl)benzonitrile
Figure imgf000360_0002
This molecule was synthesized in the same manner as Example 342 except starting with 1-(tetrahydro-2H-pyran-4-yl)-1 H-pyrazol-4-amine and replacing the boronate for 2- (((3R^S)-3-fluoro-1 -((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4,4,5,5-tetramethyl-
1 ,3,2-dioxaborolan-2-yl)benzonitrile in the microwave Suzuki reaction. LCMS-ESI+
(m/z): [M+H]+ calcd for C26H29FN804: 536.56; found: 537.12. 1 H NMR (300 MHz, DMSO-c/e) δ 10.32 (d, J = 4.8 Hz, 1 H), 8.75 (d, J = 27.9 Hz, 1 H), 8.67 - 8.46 (m, 2H), 8.03 (d, J = 13.1 Hz, 1 H), 7.81 - 7.50 (m, 2H), 5.33 - 4.84 (m, 3H), 4.44 (m, 2H), 4.26 - 3.80 (m, 2H), 3.53 - 3.15 (m, 5H), 1 .96 (m, 6H), 1.19 (dt, J = 6.3, 3.4 Hz, 3H).
Example 355: 2-(((3R,4S)-3-fluoro-1 -((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-
(4-((4-(4-hydroxy-4-methylpiperidin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile
Figure imgf000361_0001
This molecule was synthesized in the same manner as Example 342 except starting with 1 -(4-aminophenyl)-4-methylpiperidin-4-ol. LCMS-ESI+ (m/z): [M+H]+ calcd for C3oH34FN704: 575.63; found: 576.27. 1H NMR (300 MHz, DMSO-c/6) δ 10.08 (d, J = 17.6 Hz, 1 H), 8.89 - 8.38 (m, 3H), 7.58 (dd, J = 24.8, 10.4 Hz, 3H), 6.95 (d, J = 8.8 Hz, 2H), 5.32 - 4.71 (m, 3H), 4.45 (d, J = 10.0 Hz, 1 H), 4.26 (m, 2H), 3.80 - 3.43 (m, 1 H), 3.45 - 3.22 (m, 5H), 3.1 1 (ddt, J = 1 1 .9, 8.9, 3.9 Hz, 3H), 2.10 - 1 .67 (m, 2H), 1 .55 (t, J = 5.6 Hz, 3H), 1 .38 - 1 .01 (m, 4H).
Example 356: 2-(((3R,4S)-3-f luoro-1 -(1 H-pyrazole-4-carbonyl)piperidin-4-yl)oxy)-5- (4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000362_0001
This molecule was synthesized in the same manner as Example 336 except replacing with (1 /-/)-pyrazole-4carboxilic acid. LCMS-ESI"1" (m/z): [M+H]+ calcd for C32H33FN10O3: 624.67; found: 625.17. 1H NMR (300 MHz, DMSO-c/6) δ 13.22 (s, 1 H), 10.14 (d, J = 18.2 Hz, 1 H), 8.73 (s, 1 H), 8.57 (d, J = 1 1.1 Hz, 2H), 8.10 (s, 1 H), 7.87 - 7.68 (m, 1 H), 7.68 - 7.42 (m, 3H), 6.95 (t, J = 8.9 Hz, 2H), 5.74 (s, 1 H), 5.41 - 4.76 (m, 2H), 4.56 (t, J = 6.5 Hz, 2H), 4.46 (t, J = 6.0 Hz, 2H), 4.41 - 3.90 (m, 2H), 3.90 - 3.35 (m, 2H), 3.23 - 2.95 (m, 4H), 2.39 (t, J = 4.9 Hz, 4H), 2.01 (s, 2H).
Example 357: 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5- (4-((4-((R)-3-hydroxypiperidin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000362_0002
This molecule was synthesized in the same manner as Example Example 342 except starting with (R)-1-(4-aminophenyl)piperidin-3-ol. LCMS-ESI+ (m/z): [M+H]+ calcd for C29H32FN704: 561.25; found: 562.00. 1H NMR (300 MHz, DMSO-c/6) δ 10.14 (d, J = 18.4 Hz, 1 H), 8.88 - 8.37 (m, 2H), 7.77 - 7.35 (m, 3H), 6.93 (t, J = 9.0 Hz, 2H), 5.33 - 4.89 (m, 3H), 4.83 (d, J = 4.4 Hz, 1 H), 4.62 - 3.78 (m, 3H), 3.75 - 3.03 (m, 3H), 2.81 - 2.52 (m, 1 H), 2.14 - 1.38 (m, 5H), 1.24 (dtd, J = 15.3, 6.6, 6.1 , 2.9 Hz, 6H). Example 358: 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-
(4-((5-fluoro-6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)amino)-1,3,5-triazin-2- yl)benzonitrile
Figure imgf000363_0001
This molecule was synthesized in the same manner as Example 342 except starting with 5-fluoro-6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-amine. LCMS-ESI+ (m/z):
[M+H]+ calcd for C3oH3oF2N904: 621.64; found: 622.82. 1H NMR (300 MHz, DMSO-c/6) δ 10.43 (s, 1 H), 8.82 (s, 1 H), 8.56 (s, 1 H), 8.39 (s, 1 H), 7.99 (dd, J = 14.9, 2.2 Hz, 1 H), 7.65 (d, J = 8.9 Hz, 1 H), 5.31 - 4.80 (m, 3H), 4.54 (t, J = 6.5 Hz, 2H), 4.46 (t, J = 6.0 Hz, 2H), 4.29 - 3.00 (m, 8H), 2.45 - 2.31 (m, 4H), 1.98 (d, J = 7.7 Hz, 2H), 1.19 (dt, J = 7.6, 3.9 Hz, 3H).
Example 359: 2-((1-((S)-2-hydroxypropanoyl)azepan-4-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000363_0002
This molecule was synthesized in the same manner as Example 342 except replacing with 2-(azepan-4-yloxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H38N8O4: 598.70; found: 599.22. 1H NMR (300 MHz, DMSO-c/6) δ 10.13 (s, 1 H), 8.72 (s, 1 H), 8.55 (d, J = 9.4 Hz, 2H), 7.73 - 7.35 (m, 3H), 6.96 (d, J = 8.1 Hz, 2H), 5.04 - 4.73 (m, 2H), 4.55 (t, J = 6.5 Hz, 2H), 4.44 (dt, J = 13.0, 6.2 Hz, 3H), 3.85 - 3.35 (m, 5H), 3.12 (d, J = 5.5 Hz, 4H), 2.40 (t, J = 5.0 Hz, 4H), 1.90 (s, 5H), 1.19 (dd, J = 6.5, 2.5 Hz, 3H). Example 360: 5-(4-((1-ethyl-1 H-pyrazol-4-yl)amino)-1,3,5-triazin-2-yl)-2-(((3R,4S)-3- fluoro-1 -(2-hydroxyacetyl)piperidin-4-yl)oxy)benzonitrile
Figure imgf000364_0001
This molecule was synthesized in the same manner as Example 342 except starting with 1-ethyl-1 H-pyrazol-4-amine and substituting glycolic acid for L-(+)-lactic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C22H23FN8O3: 466.47; found: 467.23. 1H NMR (300 MHz, DMSO-c/6) δ 10.29 (d, J = 4.7 Hz, 1 H), 8.75 (d, J = 28.8 Hz, 1 H), 8.66 - 8.45 (m, 2H), 7.98 (dd, J = 8.4, 0.8 Hz, 1 H), 7.76 - 7.45 (m, 2H), 5.04 (d, J = 49.5 Hz, 2H), 4.66 (q, J = 6.1 Hz, 1 H), 4.47 - 3.82 (m, 4H), 3.79-3.25 (m, 3H), 1.70 - 2.1 (m, 2H), 1.37 (dt, J = 13.3, 7.3 Hz, 3H). Example 361 : 5-(4-((1-(2,2-difluoroethyl)-1 H-pyrazol-4-yl)amino)-1,3,5-triazin-2-yl)- 2-(((3R,4S)-3-fluoro-1 -(2-hydroxyacetyl)piperidin-4-yl)oxy)benzonitrile
Figure imgf000364_0002
This molecule was synthesized in the same manner as Example 342 except starting with 1-(2,2-difluoroethyl)-1 H-pyrazol-4-amine and substituting glycolic acid for L-(+)- lactic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C22H21 NF3N8O3: 502.45; found: 503.07. 1H NMR (300 MHz, DMSO-c/6) δ 10.37 (s, 1 H), 8.77 (d, J = 30.5 Hz, 1 H), 8.68 - 8.43 (m, 2H), 8.09 (d, J = 6.0 Hz, 1 H), 7.82 - 7.51 (m, 2H), 6.72 - 6.05 (dtt, 1 H), 5.04 (d, J = 48.7 Hz, 2H), 4.79 - 4.49 (m, 3H), 4.48 - 3.80 (m, 4H), 3.79 - 3.03 (m, 1 H), 1.90 (m, 2H).
Example 362: 5-(4-((4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenyl)am triazin-2-yl)-2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4- yl)oxy)benzonitrile
Figure imgf000365_0001
Step 1 : Preparation of 3-(4-nitrophenyl)-8-oxa-3-azabicyclo[3.2.1]octane To 4- fluoro nitrobenzene (200 mg, 1.42 mmol) and 8-oxa-3-azabicyclo[3.2.1 ]octane (320 mg, 2.83 mmol) dissolved in DMSO (6 mL) was added potassium carbonate (294 mg, 2.14 mmol). The reaction mixture was heated at 90 °C for 1 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to give 3-(4-nitrophenyl)-8-oxa-3- azabicyclo[3.2.1]octane.
Step 2: Preparation of 4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)aniline: 3-(4- nitrophenyl)-8-oxa-3-azabicyclo[3.2.1]octane (242 mg, 1.03 mmol) dissolved in ethanol (4 mL) was treated with ammonium formate (390 mg, 6.19 mmol) and 10% Pd/C (1 10 mg, 0.103 mmol). The reaction mixture was heated at 60 °C for 30 min. After cooling to room temperature, the reaction mixture was filtered, washed with methanol. The filtrate was concentrated to give 4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)aniline.
Step 3: Preparation of N-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenyl)-4-chloro- 1,3,5-triazin-2-amine: 4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)aniline (100 mg, 0.490 mmol) was dissolved in methanol (2 mL) and cooled to 0 °C. Triethyl amine (90 μί, 0.646 mmol) was then added, followed by 2,4-dichloro-1 ,3,5-triazine (73 mg, 0.487 mmol). The reaction mixture was allowed to warm to room temperature. After 30 min, the reaction mixture was concentrated. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated to give N-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenyl)-4-chloro-1 ,3,5- triazin-2-amine.
Step 4: Preparation of 5-(4-((4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenyl)amino)- 1 ,3,5-triazin-2-yl)-2-fluorobenzonitrile: N-(4-(8-oxa-3-azabicyclo[3.2.1 ]octan-3- yl)phenyl)-4-chloro-1 ,3,5-triazin-2-amine (47 mg, 0.148 mmol) was dissolved in dioxane (4 ml_) and the reaction mixture was degassed with argon. 2-fluoro-5-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (37 mg, 0.150 mmol) was then added, followed by [1 ,1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) dichloromethane (12 mg, 0.015 mmol), and 2M sodium carbonate solution (240 μΙ_, 0.480 mmol). The reaction mixture was heated at 90 °C. After 30 min, the reaction mixture was cooled to room temperature and concentrated. The residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated to give 5-(4-((4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)-2-fluorobenzonitrile.
Step 5: Preparation of (3R,4S)-tert-butyl 4-(4-(4-((4-(8-oxa-3-azabicyclo[3.2.1]octan- 3-yl)phenyl)amino)-1,3,5-triazin-2-yl)-2-cyanophenoxy)-3-fluoropiperidine-1- carboxylate
Terf-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (1 1 mg, 0.050 mmol) dissolved in DMF (2 mL) was cooled to 0 °C and treated with 60% sodium hydride (2 mg, 0.050 mmol). After stirring at 0 °C for 20 min, 5-(4-((4-(8-oxa-3-azabicyclo[3.2.1]octan-3- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-fluorobenzonitrile (16 mg, 0.040 mmol) dissolved in DMF (500 μΙ_) was added dropwise. The reaction mixture was warmed at 45 °C for 2 h. After cooling to room temperature, the reaction was quenched by addition of water and then extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to give (3R,4S)-tert-butyl 4-(4-(4-((4-(8-oxa-3-azabicyclo[3.2.1 ]octan-3-yl)phenyl)amino)- 1 ,3,5-triazin-2-yl)-2-cyanophenoxy)-3-fluoropiperidine-1-carboxylate.
Step 6: Preparation of 5-(4-((4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenyl)amino)- 1,3,5-triazin-2-yl)-2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)benzonitrile: (3R,4S)-tert- butyl 4-(4-(4-((4-(8-oxa-3-azabicyclo[3.2.1 ]octan-3-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2- cyanophenoxy)-3-fluoropiperidine-1-carboxylate (12 mg, 0.020 mmol) dissolved in DCM (1 mL) was treated with trifluoroacetic acid (40 μΙ_, 0.523 mmol). The reaction mixture was stirred at room temperature for 30 min and then concentrated to give 5-(4-((4-(8- oxa-3-azabicyclo[3.2.1]octan-3-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-(((3R,4S)-3- fluoropiperidin-4-yl)oxy)benzonitrile. Step 7: Preparation of 5-(4-((4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenyl)amino)- 1,3,5-triazin-2-yl)-2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4- yl)oxy)benzonitrile: 5-(4-((4-(8-oxa-3-azabicyclo[3.2.1 ]octan-3-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)-2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)benzonitrile (15 mg, 0.030 mmol) dissolved in DCM (1 mL) was treated with HATU (14 mg. 0.037 mmol), (S)-2- hydroxypropanoic acid (3.5 mg, 0.039 mmol), and N,N-diisopropylethylamine (80 μΙ_, 0.459 mmol). The reaction mixture was stirred at room temperature for 30 min. It was then diluted with dichloromethane and washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by HPLC to give the title compound. 1H NMR (400 MHz, dmso) δ 10.08 (d, J = 24.8 Hz, 1 H), 8.72 (s, 1 H), 8.56 (s, 1 H), 7.62 (d, J = 9.2 Hz, 1 H), 7.53 (d, J = 18.5 Hz, 2H), 6.84 (s, 2H), 5.19 - 4.93 (m, 2H),4.97 (s, 1 H), 4.43 (d, J = 15.3 Hz, 2H), 4.16-3.92 (m, 4H), 3.16 (s, 2H), 2.77 (d, J = 1 1.1 Hz, 2H), 1.97 (s, 2H), 1.82 (s, 4H), 1.19 (dd, J = 6.4, 3.8 Hz, 3H). LCMS-ESr (m/z): [M+H]+ calcd for C30H32FN7O4: 574.3; found: 574.3.
Example 363: 5-(4-((4-(1 ,4-oxazepan-4-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2- (((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)benzonitrile
Figure imgf000367_0001
The title compound was synthesized in the same manner as Example 362 using 1 ,4- oxazepane . 1H NMR (400 MHz, DMSO-d6) δ 10.00 (d, J = 29.2 Hz, 1 H), 8.69 (s, 1 H), 8.63 - 8.46 (m, 2H), 7.61 (d, J = 9.1 Hz, 1 H), 7.47 (dd, J = 31.0, 8.5 Hz, 2H), 6.77 (d, J = 1 1.5 Hz, 2H), 5.03 (d, J = 48.0 Hz, 2H), 4.53 - 4.28 (m, 2H), 4.21 - 3.87 (m, 2H), 3.71 (s, 2H), 3.55 (s, 6H), 1.93 (d, J = 32.7 Hz, 5H), 1.19 (dd, J = 6.5, 3.8 Hz, 3H). LCMS- ESI+ (m/z): [M+H]+ calcd for C29H32FN704: 562.2; found: 562.2.
Example 364: 5-(4-((4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)-2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4- yl)oxy)benzonitrile
Figure imgf000368_0001
The title compound was synthesized in the same manner as Example 362 using 2-oxa- 6-azaspiro[3.3]heptane. 1H NMR (400 MHz, DMSO-d6) δ 10.08 (d, J = 24.8 Hz, 1 H), 8.72 (s, 1 H), 8.56 (s, 1 H), 7.62 (d, J = 9.2 Hz, 1 H), 7.53 (d, J = 18.5 Hz, 2H), 6.84 (s, 2H), 5.19 - 4.93 (m, 2H), 4.43 (d, J = 15.3 Hz, 2H), 4.26 (m, 2H), 3.16 (s, 2H), 2.77 (d, J
= 1 1.1 Hz, 2H), 1.97 (s, 2H), 1.82 (s, 4H), 1.19 (dd, J = 6.4, 3.8 Hz, 3H). LCMS-ESI+
(m/z): [M+H]+ calcd for C29H30FN7O4: 560.2; found: 560.1.
Example 365: 5-(4-((4-(2-oxa-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)-2-(((3R,4S)-3-fluoro-1 -((S)-2-hydroxypropanoyl)piperidin-4- yl)oxy)benzonitrile
Figure imgf000368_0002
The title compound was synthesized in the same manner as Example 362 using 2-oxa- 7-azaspiro[3.5]nonane. 1H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1 H), 8.76 (s, 1 H), 8.67 - 8.46 (m, 2H), 7.63 (dd, J = 12.5, 7.7 Hz, 3H), 7.15 (s, 2H), 5.18 - 4.87 (m, 3H), 4.53 - 4.41 (m, 1 H), 4.35 (s, 4H), 4.16-4.01 (m, 4H), 3.17 (s, 4H), 1.96 (s, 4H), 1.84 (s,
1 H), 1.19 (dd, J = 6.5, 3.0 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C31 H34FN704: 588.3; found: 588.4. Example 366: 5-(4-((4-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)phenyl)am triazin-2-yl)-2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4- yl)oxy)benzonitrile
Figure imgf000369_0001
The title compound was synthesized in the same manner as Example 362 using 2-oxa- 7-azaspiro[3.5]nonane. 1H NMR (400 MHz, DMSO-d6) δ 10.09 (d, J = 27.5 Hz, 1 H), 8.71 (d, J = 12.9 Hz, 1 H), 8.56 (q, J = 1 1.0, 10.2, 10.2 Hz, 2H), 7.61 (d, J = 9.2 Hz, 1 H), 7.56 (d, J = 9.4 Hz, 2H), 6.64 (s, 2H), 5.21 - 4.88 (m, 3H), 4.46 (dq, J = 13.4, 6.8, 6.6, 6.6 Hz, 2H), 4.36 - 4.07 (m, 5H), 3.40 - 3.07 (m, 3H), 2.66 (d, J = 7.3 Hz, 1 H), 1.91 (dd, J = 54.0, 7.1 Hz, 3H), 1.19 (dd, J = 6.4, 4.0 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C29H30FN7O4: 560.2; found: 560.2.
Example 367: 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5- (4-((3-fluoro-4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1,3,5-triazin-2- yl)benzonitrile
Figure imgf000369_0002
The title compound was synthesized in the same manner as Example 362 using 1- (oxetan-3-yl)piperazine and 1 ,2-difluoro-4-nitrobenzene instead of 4-fluoro nitrobenzene and 8-oxa-3-azabicyclo[3.2.1]octane. 1H NMR (400 MHz, DMSO-d6) δ 10.49 (d, J = 51.4 Hz, 2H), 8.58 (d, J = 7.5 Hz, 3H), 7.82 - 7.59 (m, 3H), 7.52 - 7.37 (m, 2H), 7.22 - 6.93 (m, 3H), 5.21 - 4.96 (m, 3H), 4.75 (d, J = 5.9 Hz, 4H), 4.55 - 4.29 (m, 3H), 4.24 - 3.82 (m, 4H), 1.91 (d, J = 57.5 Hz, 4H), 1.25 - 1.15 (m, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C31 H34F2N804: 621.3; found: 621.4.
Example 368: 2-(((3R,4S)-3-fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4- (4-(oxetan-3-yl)piperazin-1 -yl)-3-(trifluoromethyl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile
Figure imgf000370_0001
The title compound was synthesized in the same manner as Example 362 using 1- (oxetan-3-yl)piperazine and 1-fluoro-4-nitro-2-(trifluoromethyl)benzene. 1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 2H), 8.88 (s, 1 H), 8.66 - 8.47 (m, 2H), 7.93 (s, 2H), 7.63 (t, J = 10.1 , 10.1 Hz, 2H), 5.19 - 4.94 (m, 3H), 4.72 (s, 4H), 4.25 - 4.03 (m, 5H), 3.93 (s, 2H), 3.60 (m, 2H ), 3.09 (s, 4H), 1.98 (s, 1 H). LCMS-ESI+ (m/z): [M+H]+ calcd for C31 H32F4N804: 657.3; found: 657.4.
Example 369: 5-((4-(3-cyano-4-(((3R,4S)-3-fluoro-1-((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)phenyl)-1,3,5-triazin-2-yl)amino)-2-(4- (oxetan-3-yl)piperazin-1 -yl)benzonitrile
Figure imgf000370_0002
The title compound was synthesized in the same manner as Example 362 using 1- (oxetan-3-yl)piperazine and 2-fluoro-5-nitrobenzonitrile. 1H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1 H), 8.85 (s, 1 H), 8.57 (d, J = 8.5 Hz, 2H), 8.13 (s, 1 H), 7.93 (s, 1 H), 7.63 (d, J = 9.3 Hz, 1 H), 7.30 (s, 1 H), 5.22 - 4.97 (m, 3H), 4.79 - 4.39 (m, 6H), 4.04-3.92 (m, 4H), 3.60 (m, 2H), 3.17 (s, 4H), 1.98 (s, 2H), 1.19 (dd, J = 6.4, 3.4 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H34FN904: 628.3; found: 628.4.
Example 370: 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5- (4-((4-(4-(oxetan-3-yl)piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-1,3,5-triazin- 2-yl)benzonitrile
Figure imgf000371_0001
The title compound was synthesized in the same manner as Example 362 using 1- (oxetan-3-yl)piperazine and 1-fluoro-4-nitro-2-(trifluoromethyl)benzene. 1H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1 H), 8.85 (s, 1 H), 8.57 (d, J = 8.5 Hz, 2H), 8.13 (s, 1 H), 7.93 (s, 1 H), 7.63 (d, J = 9.3 Hz, 1 H), 5.22 - 4.97 (m, 3H), 4.79 - 4.39 (m, 6H), 4.03 (m, 4H), 3.59 (m, 2H), 3.17 (s, 5H), 1.98 (s, 2H), 1.19 (dd, J = 6.4, 3.4 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H34F4N804: 671.3; found: 671.4.
Example 371 : 5-(4-((3-(difluoromethyl)-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1,3,5-triazin-2-yl)-2-(((3R,4S)-3-fluoro-1-((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)benzonitrile
Figure imgf000371_0002
The title compound was synthesized in the same manner as Example 362 using 1- (oxetan-3-yl)piperazine and 2-(difluoromethyl)-1-fluoro-4-nitrobenzene. 1H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1 H), 8.85 (s, 1 H), 8.60 (d, J = 7.4 Hz, 2H), 7.76 (s, 2H), 7.70 - 7.52 (m, 2H), 7.42 (d, J = 8.7 Hz, 2H), 5.14 (d, J = 27.7 Hz, 2H), 4.75 (s, 4H), 4.50 - 4.22 (m, 4H), 4.22 - 3.83 (m, 4H), 3.16 - 2.95 (m, 4H), 2.29 (s, 2H), 1.97 (s, 2H), 1.28 - 1.14 (m, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H35F3N804: 653.3; found: 653.3.
Example 372: 2-(((3R,4S)-3-fluoro-1-((S)-5-oxopyrrolidine-2-carbonyl)piperidin-4- yl)oxy)-5-(4-((3-fluoro-4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1,3,5-triazin- 2-yl)benzonitrile
Figure imgf000372_0001
The title compound was synthesized in the same manner as Example 362 using 1- (oxetan-3-yl)piperazine and 1 ,2-difluoro-4-nitrobenzene. 1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1 H), 8.83 (s, 1 H), 8.58 (d, J = 8.3 Hz, 2H), 7.79 - 7.61 (m, 3H), 7.47 (s, 1 H), 7.15 (t, J = 9.4, 9.4 Hz, 1 H), 5.07 (d, J = 48.9 Hz, 3H), 4.77 (d, J = 6.3 Hz, 4H), 4.68 - 4.30 (m, 4H), 4.04 (m, 2H), 3.08 (s, 5H), 2.21 (s, 2H), 2.09 (t, J = 8.2, 8.2 Hz, 2H), 2.00 (s, 4H). LCMS-ESr (m/z): [M+H]+ calcd for C33H35F2N904: 660.3; found: 660.4.
Example 373: 2-(((3R,4S)-3-fluoro-1-(1 H-1,2,3-triazole-5-carbonyl)piperidin-4- yl)oxy)-5-(4-((3-fluoro-4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1,3,5-triazin- 2-yl)benzonitrile
Figure imgf000372_0002
The title compound was synthesized in the same manner as Example 362 using 1- (oxetan-3-yl)piperazine and 1 ,2-difluoro-4-nitrobenzene. 1H NMR (400 MHz, DMSO- d6) δ 1 H NMR (400 MHz, dmso) δ 10.41 (s, 1 H), 8.83 (s, 1 H), 8.63 - 8.51 (m, 3H), 7.75 - 7.59 (m, 3H), 7.46 (s, 2H), 7.13 (s, 2H), 5.17 (d, J = 24.5 Hz, 5H), 4.72 (s, 6H), 4.54 (s, 4H), 3.06 (s, 4H). LCMS-ESI+ (m/z): [M+H]+ calcd for C31 H31 F2N1 103: 644.3; found: 644.2.
Example 374: 2-(((3R,4S)-3-fluoro-1 -((S)-5-oxopyrrolidine-2-carbonyl)piperidin-4- yl)oxy)-5-(4-((2-fluoro-4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin- 2-yl)benzonitrile
Figure imgf000373_0001
The title compound was synthesized in the same manner as Example 362. 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1 H), 8.76 (s, 1 H), 8.52 (s, 2H), 7.72 (d, J = 20.5 Hz, 2H), 7.61 (d, J = 8.8 Hz, 1 H), 7.09 (dd, J = 10.4, 2.8 Hz, 1 H), 7.06 - 6.92 (m, 1 H), 5.73 (s, 1 H), 5.05 (d, J = 51.2 Hz, 2H), 4.79 - 4.66 (m, 4H), 4.59 (ddd, J = 13.2, 9.1 , 3.9 Hz, 2H), 4.38 (d, J = 17.2 Hz, 2H), 3.83 (d, J = 14.3 Hz, 2H), 3.32 (dd, J = 18.7, 12.1 Hz, 2H), 3.05 (s, 4H), 2.31 (q, J = 10.6, 10.6, 10.1 Hz, 2H), 2.16 - 2.02 (m, 2H), 2.02 - 1.71
(m, 3H).). LCMS-ESI+ (m/z): [M+H]+ calcd for C33H35F2N904: 660.3; found: 660.3.
Example 375: 2-(((3R,4S)-3-fluoro-1 -((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5- (4-((2-fluoro-4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile
Figure imgf000374_0001
The title compound was synthesized in the same manner as Example 362. 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1 H), 8.76 (s, 1 H), 8.52 (s, 2H), 7.76 (s, 1 H), 7.60 (d, J = 8.9 Hz, 1 H), 7.14 - 6.92 (m, 2H), 5.73 (s, 3H), 5.21 - 4.94 (m, 3H), 4.72 (m, 4H), 4.58 - 4.30 (m, 4H), 3.04 (s, 4H), 2.00 - 1.80 (m, 2H), 1.19 (d, J = 6.5 Hz, 4H). LCMS-ESI+
(m/z): [M+H]+ calcd for C31 H34F2N804: 621.3; found: 621.3.
Example 376: 2-(((3R,4S)-3-fluoro-1 -(1 -(2-hydroxyethyl)-1 H-1 ,2,3-triazole-4- carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)- 1,3,5-triazin-2-yl)benzonitrile
Figure imgf000374_0002
2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (38 mg, 0.072 mmol) suspended in DCM (1 mL) was treated with HATU (33 mg. 0.087 mmol), 1-(2-hydroxyethyl)-1 H-1 ,2,3- triazole-4-carboxylic acid (14 mg, 0.089 mmol), and N,N-diisopropylethylamine (60 μΙ_, 0.344 mmol). The reaction mixture was stirred at room temperature for 30 min. It was then diluted with dichloromethane and washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by HPLC to give the title compound. 1H NMR (400 MHz, dmso) δ 10.20 (s, 1 H), 8.75 (s, 1 H), 8.58 (dd, J = 9.0, 2.1 Hz, 1 H), 8.51 (s, 2H), 7.64 (d, J = 9.3 Hz, 3H), 7.04 (s, 2H), 5.15 (s, 3H), 4.75 (d, J = 6.0 Hz, 5H), 4.44 (t, J = 5.3, 5.3 Hz, 3H), 3.80 (t, J = 5.4, 5.4 Hz, 2H), 2.98 (s, 5H), 2.05 (m, 4H). LCMS-ESI+ (m/z): [M+H]+ calcd for C33H36FN1 104: 670.3; found: 670.4.
Example 377: 2-(((3R,4S)-1-(2-(4H-1,2,4-triazol-4-yl)acetyl)-3-fluoropiperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2- yl)benzonitrile
Figure imgf000375_0001
The title compound was synthesized in the same manner as Example 376 using 2-(4H- 1 ,2,4-triazol-4-yl)acetic acid instead of 1-(2-hydroxyethyl)-1 H-1 ,2,3-triazole-4-carboxylic acid. 1H NMR (400 MHz, dmso) δ 10.20 (s, 1 H), 8.75 (s, 1 H), 8.58 (dd, J = 9.0, 2.1 Hz, 1 H), 8.51 (s, 2H), 7.64 (d, J = 9.3 Hz, 4H), 7.04 (s, 3H), 5.15 (m, 6H), 4.75 (d, J = 6.0 Hz, 5H), 4.44 (t, J = 5.3, 5.3 Hz, 3H), 3.80 (t, J = 5.4, 5.4 Hz, 2H), 2.98 (s, 5H). LCMS- ESI+ (m/z): [M+H]+ calcd for C32H34FN1 103: 640.3; found: 640.3.
Example 378: 5-(4-((3-chloro-4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5- triazin-2-yl)-2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4- yl)oxy)benzonitrile
Figure imgf000375_0002
The title compound was synthesized in the same manner as Example 362 starting from 1-(oxetan-3-yl)piperazine and 2-chloro-1-fluoro-4-nitrobenzene except the reduction of the nitro group to the aniline was carried out by the following procedure. 1-(2-chloro-4- nitrophenyl)-4-(oxetan-3-yl)piperazine (155 mg, 0.521 mmol) suspended in ethanol (4 ml_) was treated with a solution of ammonium chloride (143 mg, 2.673 mmol) in 1.5 ml_ water followed by iron powder (232 mg, 4.154 mmol). The reaction mixture was heated at 90 °C for 2 h. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved in saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated to give 3-chloro-4-(4-(oxetan-3-yl)piperazin-1- yl)aniline .
1H NMR (400 MHz, dmso) δ 10.47 (s, 1 H), 8.84 (s, 1 H), 8.58 (d, J = 8.0 Hz, 2H), 8.01 (s, 2H), 7.64 (d, J = 9.1 Hz, 2H), 7.26 (s, 2H), 5.13 (d, J = 23.9 Hz, 3H), 4.73 (s, 5H), 4.46 (d, J = 6.5 Hz, 4H), 1.98 (s, 3H), 1.26 (s, 2H), 1.25 - 1.16 (m, 4H). LCMS-ESI+ (m/z): [M+H]+ calcd for C31 H34CIFN804: 637.3; found: 637.4.
Example 379: 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5- (4-((6-(4-(oxetan-3-yl)piperazin-1 -yl)pyridin-3-yl)amino)-1,3,5-triazin-2- yl)benzonitrile
Figure imgf000376_0001
The title compound was synthesized in the same manner as Example 362 starting from 6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-amine. 1H NMR (400 MHz, dmso) δ 10.21 (d, J = 23.9 Hz, 1 H), 8.76 (s, 1 H), 8.64 - 8.45 (m, 2H), 7.94 (m, 2H), 7.62 (d, J = 9.2 Hz, 1 H), 7.04 (m, 2H), 5.18 - 4.93 (m, 3H), 4.75 (d, J = 6.6 Hz, 4H), 4.54 - 4.28 (m, 4H), 4.20 - 3.88 (m, 4H), 1.97 (s, 2H), 1.83 (s, 1 H), 1.30 - 1.12 (m, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C30H34FN9O4: 604.3; found: 604.4.
Example 380: Ethyl 3-((4-(3-cyano-4-(((3R,4S)-3-fluoro-1-((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)phenyl)-1,3,5-triazin-2-yl)amino)benzoate
Figure imgf000377_0001
The title compound was synthesized in the same manner as Example 362 starting from ethyl 3-aminobenzoate 1H NMR (400 MHz, dmso) δ 10.57 (s, 1 H), 8.87 (s, 1 H), 8.62 (m, 2H), 7.94 (s, 1 H), 7.66 (dd, J = 22.4, 8.6 Hz, 2H), 7.52 (t, J = 7.9, 7.9 Hz, 1 H), 5.21 - 4.97 (m, 3H), 4.47 (dt, J = 13.1 , 6.4, 6.4 Hz, 2H), 4.35 (q, J = 7.2, 7.2, 7.2 Hz, 3H), 4.25 - 3.87 (m, 4H), 2.01 - 1.80 (m, 2H), 1.32 (t, J = 7.1 , 7.1 Hz, 3H), 1.19 (dd, J = 6.5, 3.8 Hz, 2H). LCMS-ESr (m/z): [M+H]+ calcd for C27H27FN605: 535.2; found: 535.1.
Example 381 : 2-(((3R,4S)-3-fluoro-1-((S)-5-oxopyrrolidine-2-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-((S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5- triazin-2-yl)benzonitrile
Figure imgf000377_0002
Step 1 : (S)-tert-butyl 2-methylpiperazine-1-carboxylate (800 mg, 3.99 mmol) dissolved in 1 ,2-dichloroethane (20 mL) was treated with 3-oxetanone (200 μΙ_, 3.43 mmol). The reaction mixture was stirred at room temperature for 1 h before sodium triacetoxyborohydride (1.10 g, 5.19 mmol) was added in portions. The reaction mixture was stirred at room temperature for 30 min. It was then diluted with dichloromethane and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated to give (S)-tert-butyl 2-methyl-4-(oxetan-3-yl)piperazine-1-carboxylate.
Step 2: (S)-tert-butyl 2-methyl-4-(oxetan-3-yl)piperazine-1-carboxylate (1000 mg, 3.90 mmol) dissolved in dichloromethane (15 ml_) was treated with trifluoroacetic acid (7.0 ml_, 91.5 mmol). The reaction mixture was stirred at room temperature for 1 h and then concentrated. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate, filtered and concentrated to give (S)-3-methyl-1-(oxetan-3-yl)piperazine.
The title compound was then synthesized in the same manner as Example 362 starting from (S)-3-methyl-1-(oxetan-3-yl)piperazine. 1H NMR (400 MHz, dmso) δ 10.26 (s, 1 H), 8.81 (s, 1 H), 8.24 (s, 1 H), 7.81 - 7.60 (m, 3H), 7.50 (d, J = 9.1 Hz, 2H), 6.97 (s, 4H), 4.98 (s, 3H), 4.72 (s, 4H), 4.61 - 4.37 (m, 3H), 4.35 - 4.05 (m, 3H), 3.89 (d, J = 13.8 Hz, 2H), 2.28 (s, 1 H), 2.19 - 2.02 (m, 2H), 1.91 (d, J = 18.4 Hz, 4H), 1.07 (s, 3H). LCMS- ESI+ (m/z): [M+H]+ calcd for C34H38FN904: 656.3; found: 656.3.
Example 382: 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5- (4-((6-(2-hydroxypropan-2-yl)pyridin-3-yl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000378_0001
Step 1 : Preparation of 2-bromo-5-(2, 2,5, 5-tetramethyl-1 , 2, 5-azadisilolidin-1-yl)pyridine: 6-bromopyridin-3-amine (2.24g, 12.95 mmol) , bis(dimethylaminodimethylsilyl)ethane (5.12 ml_, 18.14mmol) and Zinc Iodide (0.1 1g, 0.345 mmol) were applied to a 100 ml_ sealed tube and the mixture was heated up to 140°C for overnight. After cooling to room temperature, the mixture was quenched with saturated aqueous amino chloride solution (PH~7) and extracted with ethyl acetate for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to provide the desired material as a white solid. 1H NMR (300 MHz, DMSO-c/6) δ 7.92 (d, J = 3.6 Hz, 1 H), 7.41 (d, J = 8.7 Hz, 1 H), 7.22 (dd, J = 3.0 Hz, J = 8.4 Hz, 1 H), 0.84 (S, 4H), 0.22 (t, J = 3.6 Hz, 12H). Step 2: Preparation of 2-(5-aminopyridin-2-yl)propan-2-ol: 2-bromo-5-(2, 2,5,5- tetramethyl-1 ,2,5-azadisilolidin-1-yl)pyridine (635 mg, 2 mmol) was dissolved in Tetrahydrofuran (12 ml_) and cooled to -78°C. nBuLi solution (1.6M in hexane, 1.9 ml_) was added drop wise and the resulting bright yellow solution was stirred at -78°C for 1 h. Then acetone (0.5 ml_, 6.8 mmol) was added and the reaction mixture was stirred at - 78°C for another 1 h. After that time, water (5.5 ml_) was added and dry-ice bath was removed. The reaction mixture was allowed to warm up to room temperature, followed by addition of 1 M HCI solution (4 ml_), and stir for 15 minutes. Reaction mixture was quenched with saturated sodium bicarbonate solution (PH~8) and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to provide the desired material as light green oil.
LCMS-ESI+ (m/z): [M+H]+ calcd for C8H13N20: 153.2; found: 153.1.
Step 3: Preparation of 2-(5-((4-chloro-1 ,3,5-triazin-2-yl)amino)pyridin-2-yl)propan-2-ol: To a solution of 2,4-dichloro-1 ,3,5-triazine in Ν,Ν-dimethylformamide (1 ml_) at 0°C, 2-(5- aminopyridin-2-yl)propan-2-ol (50 mg) in Ν,Ν-dimethylformamide (1 ml_) was added drop wise and the reaction mixture was stirred at 0°C for 1 h. After this time, the reaction was quenched with saturated sodium bicarbonate solution (PH~8) and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the desired material. Use as crude for next step. LCMS-ES (m/z): [M+H]+ calcd for CnH13CIN50: 266.7; found: 266.1.
Step 4: Preparation of (3R,4S)-tert-butyl 4-(4-bromo-2-cyanophenoxy)-3- fluoropiperidine-1 -carboxylate: (3R,4S)-tert-butyl 3-f luoro-4-hydroxypiperidine-1 - carboxylate (3.6 g, 16.4 mmol) was dissolved in /VJv-Dimethylacetamide (40 ml_) and sodium hydrides was added in a single portion and stirred at room temperature for 30 minutes. A solution of 5-bromo-2-fluorobenzonitrile (3.0g, 15.1 mmol) in N,N- Dimethylacetamide (14ml_) was added to the above reaction mixture drop wise. N,N- dimethylformamide (40 ml_) was added to make all material into solution. The reaction mixture was stirred at room temperature for 30 minutes and was quenched with saturated sodium bicarbonate solution (PH~8), extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to provide the desired material as light yellow solid. 1H NMR (300 MHz, DMSO-c 6) δ 8.02 (d, J = 2.7 Hz, 1 H), 7.85 (dd, J = 9.0, 2.4 Hz, 1 H), 7.39 (d, J = 8.7 Hz, 1 H), 4.99 (m, 2H), 4.04 (m, 1 H), 3.78 (m, 1 H), 3.30 (m, 2H), 1.85 (m, 2H), 1.31 (s, 9H).
Step 5: Preparation of 5-bromo-2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)benzonitrile: (3R,4S)-tert-butyl 4-(4-bromo-2-cyanophenoxy)-3-fluoropiperidine-1-carboxylate (1.03 g, 2.58 mmol) was dissolved in dichloromethane (25 ml_) , trifluoroacetic acid (4.8 ml_, 62.4 mmol) was added drop wise and the reaction mixture was stirred at room temperature for 30 minutes. After this time, the reaction was quenched with saturated sodium bicarbonate solution (PH~8), extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude was used for next step. LCMS-EST (m/z): [M+H]+ calcd for Ci2H13BrFN20: 300.1 ; found: 300.2.
Step 6: Preparation of 5-bromo-2-(((3R,4S)-3-fluoro-1-((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)benzonitrile: 5-bromo-2-(((3R,4S)-3-fluoropiperidin- 4-yl)oxy)benzonitrile (824 mg, 2.76 mmol) and L-(+)-Lactic acid (248 mg, 2.76 mmol) were taken up as suspension in Ν,Ν-dimethylformamide (20ml_). The mixture was treated successively with N,N-diisopropylethylamine (1.44 ml_, 8.26 mmol) and N- [(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminiumhexafluorophosphate N-oxide (HATU, 1.57 g, 4.1 mmol). The mixture was stirred for 2 hours at room temperature and then purified by flash chromatography (silica gel) to provide the desired material. LCMS-ESI+ (m/z): [M+H]+ calcd for C15H17BrFN203: 372.2; found: 372.6.
Step 7: Preparation of 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4- yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile: To 5-bromo-2- (((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)benzonitrile (0.596 g, 1.6 mmol) in 1 ,4-Dioxane (9 ml_) was added bis(pinacolato)diboron (0.61 g, 2.4 mmol), Potassium acetate (0.47 g, 4.8 mmol), and Pd(dppf)CI2 (0.13 g, 0.16 mmol). The reaction was heated to 1 10 °C for 1 h. The reaction mixture was filtered through a pad of Celite diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to provide the desired material. LCMS-ESI+ (m/z): [M+H]+ calcd for C21 H29BFN2O5: 419.2; found: 419.1.
Step 8: Preparation of 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4- yl)oxy)-5-(4-((6-(2-hydroxypropan-2-yl)pyridin-3-yl)amino)-1 ,3,5-triazin-2-yl)benzonitrile: A suspension of 2-(5-((4-chloro-1 ,3,5-triazin-2-yl)amino)pyridin-2-yl)propan-2-ol (90 mg, 0.34 mmol) and 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (198 mg, 0.47 mmol) in 1 ,2- Dimethoxyethane (4 ml_) was treated with 2M sodium carbonate solution (0.67 ml_, 1.36 mmol) and Tetrakis(triphenylphosphine)palladium (39 mg, 0.034 mmol). The mixture was heated in a microwave reactor for 30 minutes at 130°C. The cooled reaction mixture was quenched with water and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to give the desired product as off-white solid. LCMS-ESI+ (m/z): [M+H]+ calcd for C26H29FN7O4: 522.5; found: 522.2. 1 H NMR (300 MHz, DMSO-d6) δ 10.46 (s, 1 H), 8.83 (s, 1 H), 8.89 - 8.70 (br, 1 H), 8.59 (m, 2H), 8.13 (m, 2H), 7.66 (m, 1 H), 5.18 (m, 4H), 4.51 (m, 3H), 3.71 (m, 1 H), 3.28 (m, 1 H), 1.99 (m, 2H), 1.43 (s, 6H), 1.20 (dd, J = 6.3, 2.4 Hz, 3H). Example 383: 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5- (4-((4-((R)-3-(hydroxymethyl)morpholino)phenyl)amino)-1,3,5-triazin-2-
Figure imgf000381_0001
Step 1 : Preparation of (R)-(4-(4-nitrophenyl)morpholin-3-yl)methanol: A mixture of 4- Fluoronitrobenzene (0.69 ml_, 6.5 mmol), (R)-morpholin-3-ylmethanol hydrochloride (1.99 g, 13 mmol), and potassium carbonate (3.64 g, 26 mmol) in N,N- dimethylformamide (15 ml_) was stirred at 100 °C for 15 hours. After cooling to room temperature, the mixture was partitioned between ethyl acetate and water. The mixture was extracted three times with ethyl acetate. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to provide the desired material. LCMS-ESI+ (m/z):
[M+H]+ calcd for C11 H15N2O4: 239.2; found: 239.1.
Step 2: Preparation of (R)-(4-(4-aminophenyl)morpholin-3-yl)methanol: In a Parr bottle, A mixture of (R)-(4-(4-nitrophenyl)morpholin-3-yl)methanol (0.77 g, 3 mmol) in ethanol (40 mL.) was treated with 10 % palladium on charcoal (150 mg). The bottle was placed on Parr-shaker under an atmosphere of hydrogen gas at 35-40PSI and shake for 30 minutes. The catalyst was removed by filtration through a pad of Celite diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure to provide the desired material. LCMS-ESI+ (m/z): [M+H]+ calcd for CiiHi7N202: 209.2; found: 209.1. Step 3: Preparation of (R)-(4-(4-((4-chloro-1 ,3,5-triazin-2-yl)amino)phenyl)morpholin-3- yl)methanol: To a solution of 2,4-dichloro-1 ,3,5-triazine (252 mg, 1.68 mmol) in dichloromethane (6 mL) at 0°C, (R)-(4-(4-aminophenyl)morpholin-3-yl)methanol (350 mg, 1.68 mmol) in dichloromethane (10 mL) was added drop wise, followed by N,N- Diisopropylethylamine (0.44 mL, 2.6 mmol). The reaction mixture was stirred at 0°C for 20 minutes. After this time, the reaction was quenched with saturated sodium bicarbonate solution (PH~8) and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the desired material. Use as crude for next step. LCMS-ESI+ (m/z): [M+H]+ calcd for Ci4Hi7CIN502: 322.7; found: 322.1.
Step 4: Preparation of 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4- yl)oxy)-5-(4-((4-((R)-3-(hydroxymethyl)morpholino)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile: A suspension of (R)-(4-(4-((4-chloro-1 ,3,5-triazin-2- yl)amino)phenyl)morpholin-3-yl)methanol (65 mg, 0.20 mmol) and 2-(((3R,4S)-3-fluoro-
1- ((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-
2- yl)benzonitrile (101 mg, 0.24 mmol) in 1 ,2-Dimethoxyethane (3 mL) was treated with 2M sodium carbonate solution (0.40 mL, 0.81 mmol) and Tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol). The mixture was heated in a microwave reactor for 30 minutes at 130 °C. The cooled reaction mixture was quenched with water and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to give the desired product as yellow solid. LCMS-ESI+ (m/z): [M+H]+ calcd for C29H33FN7O5: 578.6; found: 578.2. 1 H NMR (300 MHz, DMSO-d6) δ 10.15 (m, 1 H), 8.63 (s, 1 H), 8.51 (m, 2H), 7.58 (m, 3H), 6.95 (m, 2H), 5.12 (m, 3H), 4.68 (s, 1 H), 4.50 (m, 5H), 3.70 (m, 4H), 3.45 (m, 1 H), 3.23 (m, 4H), 1.99 (m, 2H), 1.20 (dd, J = 6.3, 3.0 Hz, 3H).
Example 384: 2-(((3R,4S)-3-fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4- holino)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000383_0001
Step 1 : Preparation of 5-bromo-2-(((3R,4S)-3-fluoro-1-(2-hydroxyacetyl)piperidin-4- yl)oxy)benzonitrile: 5-bromo-2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)benzonitrile (772 mg, 2.58 mmol) and Glycolic acid (392mg, 5.16 mmol) were taken up as suspension in N,N- dimethylformamide (20ml_). The mixture was treated successively with N,N- diisopropylethylamine (1.35 ml_, 7.75 mmol) and N-[(dimethylamino)-1 H-1 ,2,3-triazolo- [4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (HATU, 1.96 g, 5.16 mmol). The mixture was stirred for 2 hours at room temperature and then purified by flash chromatography (silica gel) to provide the desired material. LCMS-ESI+ (m/z): [M+H]+ calcd for C14H15BrFN203: 358.1 ; found: 358.0.
Step 2: Preparation of 2-(((3R,4S)-3-fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile: To 5-bromo-2-(((3R,4S)-3- fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)benzonitrile (0.76 g, 2.1 mmol) in 1 ,4- Dioxane (15 ml_) was added bis(pinacolato)diboron (0.81 g, 3.2 mmol), Potassium acetate (0.63 g, 6.4 mmol), and Pd(dppf)CI2 (0.17 g, 0.2 mmol). The reaction was heated to 110 °C for 1 h. The reaction mixture was filtered through a pad of Celite diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to provide the desired material. LCMS-ESI+ (m/z): [M+H]+ calcd for C20H27BFN2O5: 405.2; found: 405.1.
Step 3: A suspension of (R)-(4-(4-((4-chloro-1 ,3,5-triazin-2-yl)amino)phenyl)morpholin-3- yl)methanol (65 mg, 0.20 mmol) and 2-(((3R,4S)-3-fluoro-1-(2-hydroxyacetyl)piperidin- 4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (91 mg, 0.23 mmol) in 1 ,2-Dimethoxyethane (3 mL) was treated with 2M sodium carbonate solution (0.40 mL, 0.81 mmol) and Tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol). The mixture was heated in a microwave reactor for 30 minutes at 130 °C. The cooled reaction mixture was quenched with water and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to give the desired product as yellow solid. LCMS-ESI+ (m/z): [M+H]+ calcd for C28H3i FN705: 564.6; found: 564.6. 1 H NMR (300 MHz, DMSO-d6) δ 10.13 (m, 1 H), 8.72 (s, 1 H), 8.58 (m, 2H), 7.64 (m, 3H), 6.89 (m, 2H), 5.12 (m, 2H), 4.68 (m, 2H), 4.35 (m, 6H), 3.70 (m, 5H), 3.23 (m, 4H), 2.02 (m, 2H).
Example 385: 5-(4-((3,3-dimethyl-2-oxoindolin-6-yl)amino)-1 ,3,5-triazin-2-yl)-2- droxypropanoyl)piperidin-4-yl)oxy)benzonitrile
Figure imgf000384_0001
Step 1 : Preparation of 6-((4-chloro-1 ,3,5-triazin-2-yl)amino)-3,3-dimethylindolin-2-one: To a solution of 2,4-dichloro-1 ,3,5-triazine (300 mg, 2 mmol) in dichloromethane (15 mL) at 0°C, (R)-(4-(4-aminophenyl)morpholin-3-yl)methanol (352 mg, 2 mmol) in dichloromethane (5 mL) was added drop wise, followed by N,N-Diisopropylethylamine (0.52 mL, 3 mmol). The reaction mixture was stirred at 0°C for 20 minutes. After this time, the reaction was quenched with saturated sodium bicarbonate solution (PH~8) and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the desired material. Use as crude for next step. LCMS-ESI+ (m/z): [M+H]+ calcd for C13H13CIN50: 290.7; found: 290.1.
Step 2: Preparation of 5-(4-((3,3-dimethyl-2-oxoindolin-6-yl)amino)-1 ,3,5-triazin-2-yl)-2- (((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)benzonitrile: A suspension of 6-((4-chloro-1 ,3,5-triazin-2-yl)amino)-3,3-dimethylindolin-2-one (59 mg, 0.20 mmol) and 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (103 mg, 0.24 mmol) in 1 ,2- Dimethoxyethane (3 mL) was treated with 2M sodium carbonate solution (0.41 mL, 0.82 mmol) and Tetrakis(triphenylphosphine)palladium (24 mg, 0.02 mmol). The mixture was heated in a microwave reactor for 30 minutes at 130 °C. The cooled reaction mixture was quenched with water and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to give the desired product as white solid. LCMS-ESI+ (m/z): [M+H]+ calcd for C28H29FN7O4: 546.6; found: 546.2. 1 H NMR (300 MHz, DMSO-d6) δ 10.34 (m, 2H), 8.81 (s, 1 H), 8.61 (d, J = 6.9 Hz, 2H), 7.64 (d, J = 9.0 Hz, 1 H), 7.45 (s, 1 H), 7.25 (m, 2H), 5.16 (m, 3H), 4.48 (m, 2H), 3.70 (m, 1 H), 3.38 (m, 1 H), 3.29 (m, 1 H), 1.98 (m, 2H), 1.24 (m, 9H).
Example 386: 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5- l)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000385_0001
Step 1 : Preparation of 2-(4-((4-chloro-1 ,3,5-triazin-2-yl)amino)pyridin-2-yl)propan-2-ol: To a solution of 2,4-dichloro-1 ,3,5-triazine (390 mg, 2.6 mmol) in N,N- dimethylformamide (3 mL) at room temperature, 2-(4-aminopyridin-2-yl)propan-2-ol (304 mg, 2 mmol) in N,N-dimethylformamide (3 mL) was added drop wise and the reaction mixture was heated at 50°C for 30 minutes. After this time, the reaction was cooled and quenched with saturated sodium bicarbonate solution (PH~8) and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to give the desired material. LCMS-ESI+ (m/z): [M+H]+ calcd for CiiHi3CIN50: 266.7; found: 266.1.
Step 2: Preparation of 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4- yl)oxy)-5-(4-((2-(2-hydroxypropan-2-yl)pyridin-4-yl)amino)-1 ,3,5-triazin-2-yl)benzonitrile: A suspension of 2-(4-((4-chloro-1 ,3,5-triazin-2-yl)amino)pyridin-2-yl)propan-2-ol (80 mg, 0.30 mmol) and 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (132 mg, 0.32 mmol) in 1 ,2- Dimethoxyethane (4 ml_) was treated with 2M sodium carbonate solution (0.60 ml_, 1.2 mmol) and Tetrakis(triphenylphosphine)palladium (35 mg, 0.030 mmol). The mixture was heated in a microwave reactor for 30 minutes at 130 °C. The cooled reaction mixture was quenched with water and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to give the desired product as off-white solid. LCMS-ESI+ (m/z): [M+H]+ calcd for C26H29FN7O4: 522.7; found: 523.0. 1 H NMR (300 MHz, DMSO-d6) δ 10.72 (s, 1 H), 8.94 (s, 1 H), 8.68 (m, 2H), 8.39 (d, J = 5.4 Hz, 1 H), 8.25 (br, 1 H), 7.65 (m, 2H), 5.21 (m, 4H), 4.51 (m, 3H), 3.71 (m, 1 H), 3.28 (m, 1 H), 2.0 (m, 2H), 1.45 (m, 6H), 1.21 (dd, J = 6.3, 3.0 Hz, 3H).
Example 387: 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-
(4-((4-((S)-3-(hydroxymethyl)morpholino)phenyl)amino)-1,3,5-triazin-2-
Figure imgf000386_0001
Step 1 : Preparation of (S)-(4-(4-nitrophenyl)morpholin-3-yl)methanol: This compound was prepared by the same procedure as Example 383, step 1 , using (S)-morpholin-3- ylmethanol (1.00 g, 8.56 mmol), fluoronitrobenzene (0.45 ml, 4.26 mmol), and potassium carbonate (1.76 g, 15.8 mmol) in N,N-dimethylformamide (14 ml_). LCMS- ESI+ (m/z): [M+H]+ calcd for C11H15N204: 239.2; found: 239.1.
Step 2: Preparation of (S)-(4-(4-aminophenyl)morpholin-3-yl)methanol: This compound was prepared by the same procedure as Example 383, step 2, using (S)-(4-(4- nitrophenyl)morpholin-3-yl)methanol (300 mg, 1.26 mmol), 10 % palladium on charcoal
(50 mg) in ethanol (30 ml_). LCMS-ESI+ (m/z): [M+H]+ calcd for CnH^C^: 209.2; found: 209.1.
Step 3: Preparation of (S)-(4-(4-((4-chloro-1 ,3,5-triazin-2-yl)amino)phenyl)morpholin-3- yl)methanol: This compound was prepared by the same procedure as Example 383, step 3, using (S)-(4-(4-aminophenyl)morpholin-3-yl)methanol (230 mg, 1.1 mmol), 2,4- dichloro-1 ,3,5-triazine (165 mg, 1.1 mmol) and N,N-Diisopropylethylamine (0.29 mL, 2.0 mmol) in dichloromethane (10 mL). LCMS-ESI+ (m/z): [M+H]+ calcd for C14H17CIN5O2: 322.7; found: 322.1.
Step 4: Preparation of 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4- yl)oxy)-5-(4-((4-((S)-3-(hydroxymethyl)morpholino)phenyl)amino)-1 ,3,5-triazin-2-yl)- benzonitrile: This compound was prepared by the same procedure as Example 383, step 4, using (S)-(4-(4-((4-chloro-1 ,3,5-triazin-2-yl)amino)phenyl)morpholin-3- yl)methanol (354 mg, 0.88 mmol), 2-(((3R,4S)-3-fluoro-1-((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzonitrile (368 mg, 0.88 mmol), 2M sodium carbonate solution (1.76 mL, 3.52 mmol) and Tetrakis(triphenylphosphine)palladium (102 mg, 0.088 mmol) in 1 ,2- Dimethoxyethane (9 mL) . LCMS-ESI+ (m/z): [M+H]+ calcd for C29H33FN7O5: 578.6; found: 578.2. 1 H NMR (300 MHz, DMSO-d6) δ 10.19 (m, 1 H), 8.73 (s, 1 H), 8.54 (m, 2H), 7.64 (m, 3H), 6.90 (m, 2H), 5.07 (m, 3H), 4.70 (m, 2H), 4.04 (m, 3H), 3.57 (m, 4H), 3.22 (m, 6H), 1.99 (m, 2H), 1.20 (dd, J = 6.3, 3.3 Hz, 3H).
Example 388: 2-(((3R,4S)-3-fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((6- (2-hydroxypropan-2-yl)pyridin-3-yl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000387_0001
A suspension of 2-(5-((4-chloro-1 ,3,5-triazin-2-yl)amino)pyridin-2-yl)propan-2-ol (100 mg, 0.38 mmol) and 2-(((3R,4S)-3-fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (167 mg, 0.41 mmol) in 1 ,2- Dimethoxyethane (4 mL) was treated with 2M sodium carbonate solution (0.75 mL, 1.50 mmol) and Tetrakis(triphenylphosphine)palladium (43 mg, 0.038 mmol). The mixture was heated in a microwave reactor for 30 minutes at 130 °C. The cooled reaction mixture was quenched with water and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C25H27FN7O4: 508.5; found: 508.2. 1 H NMR (300 MHz, DMSO-d6) δ 10.47 (s, 1 H), 8.83 (m, 2H), 8.59 (d, J = 7.8 Hz, 2H), 8.10 (m, 1 H), 7.67 (d, J = 9.3 Hz, 2H), 5.19 (m, 4H), 4.42 (m, 3H), 3.87 (m, 1 H), 3.30 (m, 2H), 1.99 (m, 2H), 1.52 (m, 6H).
Example 389: 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5- (4-((3-methoxy-4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-
Figure imgf000388_0001
Step 1 : Preparation of 4-chloro-N-(3-methoxy-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)- 1 ,3,5-triazin-2-amine: To a solution of 2,4-dichloro-1 ,3,5-triazine (150 mg, 1 mmol) in dichloromethane (4 mL) at 0°C, 3-methoxy-4-(4-(oxetan-3-yl)piperazin-1-yl)aniline (263 mg, 1 mmol) in dichloromethane (6 mL) was added drop wise, followed by N, NiDiisopropylethylamine (0.26 mL, 1.5 mmol). The reaction mixture was stirred at 0°C for 10 minutes, then at room temperature for 1.5 hr. After this time, the reaction was quenched with saturated sodium bicarbonate solution (PH~8) and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the desired material. Use as crude for next step. LCMS-ESI+ (m/z): [M+H]+ calcd for C17H22CIN602: 377.7; found: 377.1.
Step 2: Preparation of 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4- yl)oxy)-5-(4-((3-methoxy-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile: A suspension of 4-chloro-N-(3-methoxy-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)-1 ,3,5-triazin-2-amine (73 mg, 0.194 mmol) and 2-(((3R,4S)-3-fluoro-1-((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzonitrile (97 mg, 0.233 mmol) in 1 ,2-Dimethoxyethane (2 mL) was treated with 2M sodium carbonate solution (0.39 mL, 0.78 mmol) and Tetrakis(triphenylphosphine)palladium (22 mg, 0.019 mmol). The mixture was heated in a microwave reactor for 25 minutes at 135 °C. The cooled reaction mixture was quenched with water and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H38FN805: 633.7; found: 633.9. 1 H NMR (300 MHz, DMSO-d6) δ 10.23 (m, 1 H), 8.77 (s, 1 H), 8.61 (m, 2H), 7.65 (d, J = 9.3 Hz, 2H), 7.37 (m, 1 H), 6.90 (m, 1 H), 5.18 (m, 3H), 4.56 (m, 2H), 4.47 (m, 3H), 4.41 (m, 2H), 3.84 (m, 3H), 3.47 (m, 1 H), 3.31 (m, 1 H), 2.96 (br, 4H), 2.39 (br, 4H), 1.99 (m, 2H), 1.20 (dd, J = 6.3, 2.7 Hz, 3H).
Example 390: 2-(((3R,4S)-1 -(3-aminoisonicotinoyl)-3-fluoropiperidin-4-yl)oxy)-5-(4- -1-yl)phenyl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000389_0001
2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (50 mg, 0.094 mmol) and 3- aminoisonicotinic acid (26 mg, 0.19 mmol) were taken up as suspension in dichloromethane (1 ml_) and Ν,Ν-dimethylformamide (1 ml_). The mixture was treated successively with /V,/V-diisopropylethylamine (0.05 ml_, 0.28 mmol) and N- [(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1 -ylmethylene]-N- methylmethanaminiumhexafluorophosphate W-oxide (HATU, 72 mg, 0.19 mmol). The mixture was stirred for 25 minutes at room temperature and then purified by flash chromatography (silica gel) to provide 2-(((3R,4S)-1-(3-aminoisonicotinoyl)-3- fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C34H36FN10O3: 651.7; found: 651.3.
Example 391 : 2-(((3R,4S)-1 -(4-amino-1 H-pyrazole-5-carbonyl)-3-fluoropiperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2-
Figure imgf000390_0001
2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile (50 mg, 0.094 mmol) and 4-amino-1 H- pyrazole-5-carboxylic acid (24 mg, 0.19 mmol) were taken up as suspension in dichloromethane (1 mL) and Ν,Ν-dimethylformamide (1 ml_). The mixture was treated successively with /V,/V-diisopropylethylamine (0.05 mL, 0.28 mmol) and N- [(dimethylamino)-1 H-1 ,2,3-triazolo-[4,5-b]pyridin-1 -ylmethylene]-N- methylmethanaminiumhexafluorophosphate W-oxide (HATU, 72 mg, 0.19 mmol). The mixture was stirred for 4 hr at room temperature and then purified by flash chromatography (silica gel) to provide 2-(((3R,4S)-1-(3-aminoisonicotinoyl)-3- fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5- triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H35FN11 O3: 640.7; found: 640.1. 1 H NMR (300 MHz, DMSO-d6) δ 12.6 (s, 1 H), 10.18 (m, 1 H), 8.73 (s, 1 H), 8.59 (m, 2H), 7.66 (m, 3H), 7.14 (s, 1 H), 6.99 (m, 2H), 5.15 (m, 3H), 4.60 (m, 4H), 4.47 (m, 2H), 4.43-3.60 (br, 1 H), 3.45 (m, 1 H), 3.31 (m, 1 H), 3.14 (m, 4H), 2.92 (br, 1 H), 2.41 (m, 4H), 2.01 (m, 2H).
Example 392: 2-(((3R,4S)-3-fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((3- methoxy-4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)amino)-1 ,3,5-triazin-2- yl)benzonitrile
Figure imgf000390_0002
A suspension of 4-chloro-N-(3-methoxy-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1 ,3,5- triazin-2-amine (73 mg, 0.194 mmol) and 2-(((3R,4S)-3-fluoro-1-(2- hydroxyacetyl)piperidin-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzonitrile (86 mg, 0.213 mmol) in 1 ,2-Dimethoxyethane (2 mL) was treated with 2M sodium carbonate solution (0.39 mL, 0.78 mmol) and Tetrakis(triphenylphosphine)palladium (22 mg, 0.019 mmol). The mixture was heated in a microwave reactor for 20 minutes at 135 °C. The cooled reaction mixture was quenched with water and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to give the desired. LCMS-ESr (m/z): [M+H]+ calcd for C3iH36FN805: 619.7; found: 619.2. 1 H NMR (300 MHz, DMSO-d6) δ 10.24 (m, 1 H), 8.77 (s, 1 H), 8.61 (m, 2H), 7.64 (d, J = 8.7 Hz, 2H), 7.38-7.15 (br, 1 H), 6.90 (m, 1 H), 5.12 (m, 2H), 4.67 (m, 1 H), 4.56 (m, 2H), 4.47 (m, 2H), 3.84 (m, 3H), 4.41-4.00 (m, 2H), 4.00-3.50 (m, 4H), 3.47 (m, 1 H), 3.28-3.10 (br, 1 H), 2.96 (br, 4H), 2.85-2.50 (br, 1 H), 2.39 (br, 1 H), 1.99 (m, 2H).
Example 393: 5-(4-((3-(difluoromethoxy)-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1,3,5-triazin-2-yl)-2-(((3R,4S)-3-fluoro-1-(2- -4-yl)oxy)benzonitrile
Figure imgf000391_0001
Step 1 : Preparation of 1-(2-(difluoromethoxy)-4-nitrophenyl)-4-(oxetan-3-yl)piperazine: A mixture of 2-(difluoromethoxy)-1-fluoro-4-nitrobenzene (1g, 4.83 mmol), 1-(oxetan-3- yl)piperazine (1.43g, 10 mmol), and potassium carbonate (2.66 g, 19 mmol) in N,N- dimethylformamide (30 mL) was stirred at 100 °C for 2 hours. After cooling to room temperature, the mixture was quenched with water and sonicated. The resulting solid was filtered and dried under vacuum to provide the desired material. LCMS-ESI+ (m/z):
[M+H]+ calcd for C14H18F2N304: 330.3; found: 330.5.
Step 2: Preparation of 3-(difluoromethoxy)-4-(4-(oxetan-3-yl)piperazin-1-yl)aniline: In a Parr bottle, A mixture of 1-(2-(difluoromethoxy)-4-nitrophenyl)-4-(oxetan-3-yl)piperazine (1.76 g, 4.8 mmol) in ethanol (60 mL) and ethyl acetate (25 mL) was treated with 10 % palladium on charcoal (170 mg). The bottle was placed on Parr-shaker under an atmosphere of hydrogen gas at 35-40PSI and shake for 40 minutes. The catalyst was removed by filtration through a pad of Celite diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure to provide the desired material. LCMS-
ESI+ (m/z): [M+H]+ calcd for C14H20F2N3O2: 300.3; found: 300.1.
Step 3: Preparation of 4-chloro-N-(3-(difluoromethoxy)-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)-1 ,3,5-triazin-2-amine: To a solution of 2, 4-dichloro-1 ,3,5-triazine (300 mg, 2 mmol) in dichloromethane (10 mL) at 0°C, 3-(difluoromethoxy)-4-(4-(oxetan-3- yl)piperazin-1-yl)aniline (623 mg, 2 mmol) in dichloromethane (5 mL) was added drop wise, followed by N,N-Diisopropylethylamine (0.52 mL, 3 mmol). The reaction mixture was stirred at 0°C for 1 hr. After this time, the reaction was quenched with saturated sodium bicarbonate solution (PH~8) and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the desired material. Use as crude for next step. LCMS-ESI+ (m/z): [M+H]+ calcd for C17H2oCIF2N602: 413.8; found: 413.6.
Step 4: Preparation of 5-(4-((3-(difluoromethoxy)-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1 ,3,5-triazin-2-yl)-2-(((3R,4S)-3-fluoro-1-(2-hydroxyacetyl)piperidin-4- yl)oxy)benzonitrile: A suspension of 4-chloro-N-(3-(difluoromethoxy)-4-(4-(oxetan-3- yl)piperazin-1-yl)phenyl)-1 ,3,5-triazin-2-amine (93 mg, 0.194 mmol) and 2-(((3R,4S)-3- fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzonitrile (86 mg, 0.213 mmol) in 1 ,2-Dimethoxyethane (2 mL) was treated with 2M sodium carbonate solution (0.39 mL, 0.78 mmol) and Tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol). The mixture was heated in a microwave reactor for 20 minutes at 135 °C. The cooled reaction mixture was quenched with water and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for Cs^FsNeOs: 655.6; found: 655.3. 1 H NMR (300 MHz, DMSO-d6) δ 10.40 (m, 1 H), 8.81 (s, 1 H), 8.59 (m, 2H), 7.83-7.25 (m, 3H), 7.12 (d, J = 8.7 Hz, 1 H), 5.12 (m, 2H), 4.67 (m, 1 H), 4.57 (m, 2H), 4.46 (m, 2H), 4.40-3.53 (m, 3H), 3.47 (m, 1 H), 3.28 (m, 1 H), 2.98 (m, 4H), 2.40 (m, 4H), 1.98 (m, 2H).
Example 394: 2-(((3R,4S)-3-fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((3- methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile
Figure imgf000393_0001
Step 1 : Preparation of 1-(2-methyl-4-nitrophenyl)-4-(oxetan-3-yl)piperazine: A mixture of 1-fluoro-2-methyl-4-nitrobenzene (1.16 mL, 10 mmol), 1-(oxetan-3-yl)piperazine (1.42g, 10 mmol), and potassium carbonate (5.5 g, 40 mmol) in N,N-dimethylformamide (60 mL) was stirred at 100 °C for overnight. After cooling to room temperature, the mixture was partitioned between ethyl acetate and water. The mixture was extracted three times with ethyl acetate. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to provide the desired material. LCMS-ESI+ (m/z): [M+H]+ calcd for C14H2oN303: 278.3; found: 278.6.
Step 2: Preparation of 3-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)aniline: In a Parr bottle, A mixture of 1-(2-methyl-4-nitrophenyl)-4-(oxetan-3-yl)piperazine (2 g, 7.2 mmol) in ethanol (60 mL) and ethyl acetate (20 mL) was treated with 10 % palladium on charcoal (260 mg). The bottle was placed on Parr-shaker under an atmosphere of hydrogen gas at 35-40PSI and shake for 40 minutes. The catalyst was removed by filtration through a pad of Celite diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure to provide the desired material. LCMS-ESI+ (m/z):
[M+H]+ calcd for C14H22N30: 248.3; found: 248.1.
Step 3: Preparation of 4-chloro-N-(3-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)- 1 ,3,5-triazin-2-amine: To a solution of 2,4-dichloro-1 ,3,5-triazine (300 mg, 2 mmol) in dichloromethane (10 mL) at 0°C, 3-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)aniline (515 mg, 2 mmol) in dichloromethane (4 mL) was added drop wise, followed by N,N- Diisopropylethylamine (0.52 mL, 3 mmol). The reaction mixture was stirred at 0°C for 30 minutes. After this time, the reaction was quenched with saturated sodium bicarbonate solution (pH~8) and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the desired material. Use as crude for next step. LCMS-ESI+ (m/z): [M+H]+ calcd for Ci7H22CIN60: 361.8; found: 361.6. Step 4: Preparation of 2-(((3R,4S)-3-fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4- ((3-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1 ,3,5-triazin-2-yl)benzonitrile: A suspension of 4-chloro-N-(3-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1 ,3,5- triazin-2-amine (77 mg, 0.194 mmol) and 2-(((3R,4S)-3-fluoro-1-(2- hydroxyacetyl)piperidin-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzonitrile (86 mg, 0.213 mmol) in 1 ,2-Dimethoxyethane (2 ml_) was treated with 2M sodium carbonate solution (0.39 ml_, 0.78 mmol) and Tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol). The mixture was heated in a microwave reactor for 20 minutes at 135 °C. The cooled reaction mixture was quenched with water and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C3iH36FN804: 603.6; found: 603.3. 1 H NMR (300 MHz, DMSO-d6) δ 10.21 (m, 1 H), 8.76 (s, 1 H), 8.57 (m, 2H), 7.64 (m, 3H), 7.06 (d, J = 8.4 Hz, 1 H), 5.13 (m, 2H), 4.67 (m, 1 H), 4.56 (m, 2H), 4.48 (m, 2H), 4.40- 3.81 (m, 3H), 3.91 (m, 1 H), 3.21 (m, 1 H), 2.84 (m, 4H), 2.41 (m, 4H), 2.25 (s, 3H), 1.96 (m, 2H), 1.21 (s, 1 H). Example 395: 5-(4-((3-(difluoromethoxy)-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)amino)-1,3,5-triazin-2-yl)-2-(((3R,4S)-3-fluoro-1-((S)-2- din-4-yl)oxy)benzonitrile
Figure imgf000394_0001
A suspension of 4-chloro-N-(3-(difluoromethoxy)-4-(4-(oxetan-3-yl)piperazin-1- yl)phenyl)-1 ,3,5-triazin-2-amine (216 mg, 0.45 mmol) and 2-(((3R,4S)-3-fluoro-1-((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzonitrile (188 mg, 0.45 mmol) in 1 ,2-Dimethoxyethane (4.5 ml_) was treated with
2M sodium carbonate solution (0.90 ml_, 1.8 mmol) and
Tetrakis(triphenylphosphine)palladium (52 mg, 0.045 mmol). The mixture was heated in a microwave reactor for 15 minutes at 135 °C. The cooled reaction mixture was quenched with water and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for
Figure imgf000395_0001
669.7; found: 669.4. 1 H NMR (300 MHz, DMSO-d6) δ 10.40 (m, 1 H), 8.81 (s, 1 H), 8.59 (m, 2H), 7.83-7.25 (m, 3H), 7.13 (d, J = 8.7 Hz, 1 H), 5.12 (m, 3H), 4.57 (m, 2H), 4.47 (m, 3H), 4.40-3.80 (br, 1 H), 3.75-3.50 (br, 1 H), 3.47 (m, 1 H), 3.21 (m, 1 H), 2.98 (m, 4H), 2.40 (m, 4H), 1 .97 (m, 2H), 1 .20 (m, 3H).
Example 396: 2-(((3R,4S)-3-fluoro-1-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-
(4-((3-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)amino)-1,3,5-triazin-2-
A suspension of 4-chloro-N-(3-methyl-4-(4-(oxetan-3-yl)piperazin-1 -yl)phenyl)-1 ,3,5- triazin-2-amine (88 mg, 0.22 mmol) and 2-(((3R,4S)-3-fluoro-1 -((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzonitrile (93 mg, 0.22 mmol) in 1 ,2-Dimethoxyethane (2.2 mL) was treated with 2M sodium carbonate solution (0.45 mL, 0.88 mmol) and Tetrakis(triphenylphosphine)palladium (26 mg, 0.022 mmol). The mixture was heated in a microwave reactor for 20 minutes at 135 °C. The cooled reaction mixture was quenched with water and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H38FN8O4: 617.7; found: 617.9. 1 H NMR (300 MHz, DMSO-d6) δ 10.21 (m, 1 H), 8.76 (s, 1 H), 8.58 (m, 2H), 7.65-7.50 (m, 3H), 7.06 (d, J = 9.0 Hz, 1 H), 5.02 (m, 3H), 4.57 (m, 2H), 4.48 (m, 3H), 4.40-3.80 (br, 1 H), 3.75-3.50 (br, 1 H), 3.47 (m, 1 H), 3.20 (m, 2H), 2.87 (m, 4H), 2.41 (m, 4H), 2.25 (s, 3H), 1.97 (m, 2H), 1.20 (dd, J = 6.3, 2.4 Hz, 3H).
Example 397: 2-(((3R,4S)-3-fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((2- (2-hydroxypropan-2-yl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)benzonitrile
Figure imgf000396_0001
A suspension of 2-(4-((4-chloro-1 ,3,5-triazin-2-yl)amino)pyridin-2-yl)propan-2-ol (141 mg, 0.53 mmol) and 2-(((3R,4S)-3-fluoro-1-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile (217 mg, 0.54 mmol) in 1 ,2- Dimethoxyethane (5ml_) was treated with 2M sodium carbonate solution (1.1 ml_, 2.1 mmol) and Tetrakis(triphenylphosphine)palladium (61 mg, 0.053 mmol). The mixture was heated in a microwave reactor for 20 minutes at 130 °C. The cooled reaction mixture was quenched with water and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to give the desired product as off-white solid. LCMS-ESI+ (m/z): [M+H]+ calcd for C25H27FN7O4: 508.5; found: 508.2. 1 H NMR (300 MHz, DMSO-d6) δ 10.71 (s, 1 H), 8.94 (s, 1 H), 8.66 (m, 2H), 8.39 (d, J = 5.8 Hz, 1 H), 8.25 (br, 1 H), 7.65 (m, 2H), 5.19 (m, 3H), 4.68 (m, 1 H), 4.39-3.81 (m, 4H), 3.80-3.40 (br, 1 H), 3.38 (m, 1 H), 3.21 (m, 1 H), 1.99 (m, 2H), 1.45 (m, 6H).
Example 398: 2-(((3R,4S)-l-((S)-2,3-dihydroxypropanoyl)-3-fluoropiperidin-4- yl)oxy)-5-(4-((4-(((3R,4S)-3-fluoro-l-methylpiperidin-4-yl)oxy)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
Figure imgf000397_0001
A solution of 5-(4-((4-(((3 ;4S)-3-fluoro-l-methylpiperidin-4-yl)oxy)phenyl)amino)-l,3;5-triazin- 2-yl)-2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)benzonitrile hydrochloride (102 mg, 0.196 mmol) in 1.5 mL DMF was treated with L-glyceric acid (25 mg, 0.23 mmol), DIEA (134 uL, 0.78 mmol) and HATU (89 mg, 0.23 mmol) and stirred for 30 min at rt for 30 min. The reaction mixture was then treated with TFA (92 uL, 1.17 mmol) and diluted with 3 mL MeCN and 4 mL water. Purification by RP-HPLC provided 2-(((3R,4S)-l-((S)-2,3-dihydroxypropanoyl)-3-fluoropiperidin- 4-yl)oxy)-5-(4-((4-(((3R,4S)-3-fluoro-l-methylpiperidin-4-yl)oxy)phenyl)amino)-l,3,5-triazin-2- yl)benzonitrile (16 mg) as a yellow solid. :H NMR (400 MHz, DMSO-d6) δ 10.22 (d, J = 18.9 Hz, 1H), 9.79 (bs, 1H), 8.73 (s, 1H), 8.62 - 8.40 (m, 2H), 7.70 - 7.49 (m, 3H), 7.03 (m, 2H), 5.08 (d, J = 29.8 Hz, 3H), 4.92 (s, 1H), 4.80 - 4.44 (m, 2H), 4.39 - 4.20 (m, 2H), 4.15 - 3.82 (m, 2H), 3.61 - 3.44 (m, 5H), 3.17 - 3.01 (m, 2H), 2.75 (s, 3H), 2.23 - 1.72 (m, 4H). ES/MS 610.36 (M+H+).
Example 399: (ff)-2-(5-hydroxy-2-oxopiperidin-l-yl)-5-(4-((3-methoxy-4-(4-(oxetan-3- yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000397_0002
To a solution of 5-hydroxypiperidin-2-one (74.8 mg, 0.650 mmol) in DMF (4 mL) was added potassium t-butoxide (109 mg, 0.975 mmol) at 0 °C. The reaction mixture was allowed to stir for
1 hour. To the reaction mixture was added a solution of 2-fluoro-5-(4-((3-methoxy-4-(4-(oxetan- 3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile in DMF (2mL) at room temperature. The reaction mixture was brought to 80 °C and heated overnight. The solvent was concentrated under reduced pressure and dissolved in 0.1%TFA in 1:1 H20:MeCN and purified by preparative HPLC to afford product (R)-2-(5-hydroxy-2-oxopiperidin-l-yl)-5-(4-((3-methoxy-4- (4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l;3;5-triazin-2-yl)benzonitrile. :H NM (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.83 (s, 1H), 8.64 (d, J = 1.8 Hz, 1H), 8.60 - 8.50 (m, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.49 (s, 1H), 7.18 (s, 1H), 6.97 (s, 1H), 4.76 (d, J = 6.4 Hz, 4H), 4.59 (t, J = 7.2 Hz, 1H),
4.48 (s, 1H), 3.88 (s, 2H), 3.22 - 3.13 (m, 2H), 3.09 (s, 2H), 3.03 - 2.94 (m, 4H), 2.94 (s, 3H), 2.00 {d, J = 8.0 Hz, 2H), 1.22 (s, 2H), 0.83 (s, 1H).
LCMS-ES (m/z): [M+H]+ calcd for 0,9Η32Ν804: 557.6; found: 557.3
Example 400: 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)- 5-(4-((4-(((3R,4S)-3-fluoro-l-methylpiperidin-4-yl)oxy)phenyl)amino)-l,3,5-triazin- 2-yl)benzonitrile
Figure imgf000399_0001
A solution of 5-(4-((4-(((3R,4S)-3-fluoro-l-methylpiperidin-4-yl)oxy)phenyl)amino)- l,3,5-triazin-2-yl)-2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)benzonitrile hydrochloride (102 mg, 0.196 mmol) in 1.5 mL DMF was treated with L-lactic acid (156 mg, 1.73 mmol), DIEA (134 uL, 0.78 mmol) and HATU (89 mg, 0.23 mmol) and stirred for 30 min at rt for 30 min. The reaction mixture was then treated with TFA (92 uL, 1.17 mmol) and diluted with 3 mL MeCN and 4 mL water. Purification by RP-HPLC provided 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4- (((3R,4S)-3-fluoro-l-methylpiperidin-4-yl)oxy)phenyl)amino)-l,3,5-triazin-2- yl)benzonitrile (32 mg) as a yellow solid. ¾ NMR (400 MHz, DMSO-d6) 10.24 (d, J = 17.7 Hz, 1H), 8.77 (s, 1H), 8.66 - 8.47 (m, 2H), 7.73 - 7.57 (m, 4H), 7.06 (s, 3H), 5.20 - 4.95 (m, 3H), 4.67 (s, 6H), 4.54 - 4.11 (m, 1H), 4.10 - 3.87 (m, 1H), 3.69 - 3.58 (m, 1H), 3.42 - 3.08 (m, 2H), 2.15 - 1.78 (m, 4H), 1.19 (t, J = 6.6 Hz, 3H). ES/MS 594.4 (M+H+). Example 401 : 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-
5-(4-((4-(((3R,4S)-3-fluoro-l-(oxetan-3-yl)piperidin-4-yl)oxy)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
Figure imgf000400_0001
A solution of 5-(4-((4-(((3R,4S)-3-fluoro-l-(oxetan-3-yl)piperidin-4- yl)oxy)phenyl)amino)-l,3,5-triazin-2-yl)-2-(((3R,4S)-3-fluoropiperidin-4- yl)oxy)benzonitrile (260 mg, 0.46 mmol) in 4 mL DMF was treated with L-lactic acid (46 mg, 0.51 mmol), HATU (210 mg, 0.55 mmol), and DIEA (158 uL, 0.92 mmol) and stirred for 30 min at rt. The reaction mixture was then treated with TFA (142 uL, 1.84 mmol) and diluted with 3 mL MeCN and 4 mL water. Purification by RP-HPLC provided 2-(((3R,4S)-l-((S)-2,3-dihydroxypropanoyl)-3-fluoropiperidin-4-yl)oxy)-5-(4- ((4-(((3R,4S)-3-fluoro-l-methylpiperidin-4-yl)oxy)phenyl)amino)-l,3,5-triazin-2- yl)benzonitrile as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.24 (d, J = 17.6 Hz, 1H), 8.77 (s, 1H), 8.65 - 8.45 (m, 2H), 7.74 - 7.52 (m, 4H), 7.06 (s, 2H), 5.35 - 4.89 (m, 3H), 4.67 (s, 6H), 4.55 - 4.27 (m, 2H), 4.22 - 3.87 (m, 2H), 3.63 (dd, J = 28.7, 14.6 Hz, 1H), 3.45 - 3.10 (m, 2H), 2.23 - 1.74 (m, 4H), 1.20 (dt, J = 6.4, 2.4 Hz, 4H). ES/MS 636.6 (M+H+).
Example 402 : 2-(((3R,4S)-3-fluoro-l-(2-methoxyacetyl)piperidin-4-yl)oxy)-5-(4-((3- fluoro-4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2- yl)benzonitrile
Figure imgf000401_0001
A solution 2-(((3R,4S)-3 -fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3 -yl)piperazin- 1 - yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (100 mg, 0.18 mmol), 2-methoxyacetic acid (20 mg, 0.22 mmol) in 2 mL DMF was treated with HATU (83 mg, 0.22 mmol) and TEA (76 uL, 0.55 mmol) and stirred at room temperature for lh. The reaction was then diluted with water and MeCN and purified by RP-HPLC to provide 2-(((3R,4S)-3- fluoro-l-((2S,4R)-4-fluoro-5-oxopyrrolidine-2-carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.83 (s, 1H), 8.64 - 8.51 (m, 2H), 7.75 (dd, J = 14.8, 2.4 Hz, 1H), 7.64 (d, J = 9.4 Hz, 1H), 7.47 (s, 1H), 7.14 (t, J = 9.3 Hz, 1H), 5.19 - 4.91 (m, 3H), 4.76 (d, J = 6.4 Hz, 5H), 4.39 (m, 2H), 4.27 - 3.88 (m, 4H), 3.73 (d, J = 13.8 Hz, 1H), 3.66 - 3.32 (m, 2H), 3.28 (s, 3H), 3.26 - 2.68 (m, 3H), 1.91 (m, 3H). ES/MS 621.4 (M+H+).
Example 403 : 2-(((3R,4S)-3-fluoro-l-((2S,4R)-4-hydroxy-5-oxopyrrolidine-2- carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)- l,3,5-triazin-2-yl)benzonitrile
Figure imgf000401_0002
A solution 2-(((3R,4S)-3 -fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3 -yl)piperazin- 1 - yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (100 mg, 0.19 mmol) and (2S,4R)-4- hydroxy-5-oxopyrrolidine-2-carboxylic acid (33 mg, 0.23 mmol) in 2 mL DMF was treated with HATU (107 mg, 0.28 mmol) and TEA (79 uL, 0.57 mmol) and stirred at room temperature for lh. The reaction was then diluted with water and MeCN and purified by RP-HPLC to provide 2-(((3R,4S)-3-fluoro-l-((2S,4R)-4-hydroxy-5- oxopyrrolidine-2-carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.19 (d, J = 22.3 Hz, 1H), 8.75 (s, 1H), 8.66 - 8.44 (m, 2H), 7.90 (d, J = 23.2 Hz, 1H), 7.63 (d, J = 9.3 Hz, 4H), 7.04 (s, 2H), 5.20 - 4.95 (m, 3H), 4.76 (m, 5H), 4.65 - 4.52 (m, 1H), 4.40 (m, 1H), 4.17 (m, 1H), 4.02 (dt, J = 17.2, 8.3 Hz, 1H), 3.84 (d, J = 14.0 Hz, 1H), 3.69 - 2.57 (m, 7H), 2.36 - 1.71 (m, 4H). ES/MS 658.4 (M+H+). Example 404: 2-(((3R,4S)-l-(2-cyanoacetyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((3- fluoro-4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2- yl)benzonitrile
Figure imgf000402_0001
A solution 2-(((3R,4S)-3 -fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3 -yl)piperazin- 1 - yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (100 mg, 0.18 mmol) 2-cyanoacetic acid (19 mg, 0.22 mmol) in 2 mL DMF was treated with HATU (83 mg, 0.22 mmol) and TEA (76 uL, 0.55 mmol) and stirred at room temperature for lh. The reaction was then diluted with water and MeCN and purified by RP-HPLC to provide 2-(((3R,4S)-3- fluoro-l-((2S,4R)-4-fluoro-5-oxopyrrolidine-2-carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.83 (s, 1H), 8.65 - 8.50 (m, 2H), 7.75 (dd, J = 14.8, 2.4 Hz, 1H), 7.69 - 7.58 (m, 1H), 7.47 (s, 1H), 7.22 - 7.08 (m, 1H), 5.22 - 4.92 (m, 2H), 4.76 (d, J = 6.7 Hz, 4H), 4.40 (m, 1H), 4.23 - 3.82 (m, 4H), 3.73 - 2.64 (m, 9H), 2.09 - 1.78 (m, 3H). ES/MS 616.4 (M+H+). Example 405: 2-(((3R,4S)-3-fluoro-l-((2S,4R)-4-fluoro-5-oxopyrrolidine-2- carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)- l,3,5-triazin-2-yl)benzonitrile
Figure imgf000403_0001
A solution 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (100 mg, 0.19 mmol) and (2S,4R)-4- fluoro-5-oxopyrrolidine-2-carboxylic acid (67 mg, 0.23 mmol) in 2 mL DMF was treated with HATU (107 mg, 0.28 mmol) and TEA (79 uL, 0.57 mmol) and stirred at room temperature for lh. The reaction was then diluted with water and MeCN and purified by RP-HPLC to provide 2-(((3R,4S)-3-fluoro-l-((2S,4R)-4-fluoro-5- oxopyrrolidine-2-carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.19 (d, J = 23.5 Hz, 1H), 8.75 (s, 1H), 8.66 - 8.39 (m, 3H), 7.63 (dd, J = 9.9, 4.7 Hz, 3H), 7.04 (s, 2H), 5.21 - 4.93 (m, 2H), 4.84 - 4.65 (m, 6H), 4.41 (d, J = 25.5 Hz, 1H), 4.18 (d, J = 13.2 Hz, 1H), 3.97 - 2.64 (m, 10H), 2.44 - 2.23 (m, 2H), 2.09 - 1.72 (m, 3H). ES/MS 660.4 (M+H+).
Example 406: 2-(((3R,4S)-3-fluoro-l-((2S,4S)-4-fluoro-5-oxopyrrolidine-2- carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)- l,3,5-triazin-2-yl)benzonitrile
Figure imgf000403_0002
A solution 2-(((3R,4S)-3 -fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3 -yl)piperazin- 1 - yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (100 mg, 0.19 mmol) and (2S,4S)-4- fluoro-5-oxopyrrolidine-2-carboxylic acid (33 mg, 0.23 mmol) in 2 mL DMF was treated with HATU (86 mg, 0.23 mmol) and TEA (39 uL, 0.28 mmol) and stirred at room temperature for lh. The reaction was then diluted with water and MeCN and purified by RP-HPLC to provide -(((3R)-3-fluoro-l-((2S,4S)-4-fluoro-5-oxopyrrolidine- 2-carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)- l,3,5-triazin-2-yl)benzonitrile as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.18 (d, J = 24.7 Hz, 1H), 8.75 (s, 1H), 8.65 - 8.50 (m, 2H), 8.46 (d, J = 15.3 Hz, 1H), 7.63 (m, 3H), 7.04 (s, 3H), 5.21 - 4.94 (m, 3H), 4.76 (d, J = 6.4 Hz, 5H), 4.48 (dd, J = 64.7, 22.1 Hz, 3H), 4.27 - 4.03 (m, 1H), 4.02 - 3.23 (m, 3H), 3.22 - 2.54 (m, 5H), 2.09 - 1.71 (m, 4H). ES/MS 660.33 (M+H+).
Example 407: 2-(((3R,4S)-3-fluoro-l-((S)-l-methyl-5-oxopyrrolidine-2- carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)- l,3,5-triazin-2-yl)benzonitrile
Figure imgf000404_0001
A solution 2-(((3R,4S)-3 -fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3 -yl)piperazin- 1 - yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (100 mg, 0.19 mmol) and (S)-l-methyl- 5-oxopyrrolidine-2-carboxylic acid (30 mg, 0.21 mmol) in 3 mL DMF was treated with HATU (83 mg, 0.22 mmol) and TEA (51 uL, 0.37 mmol) and stirred at room temperature for lh. The reaction was then diluted with water and MeCN and purified by RP-HPLC to provide 2-(((3R,4S)-3-fluoro-l-((S)-l-methyl-5-oxopyrrolidine-2- carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)- l,3,5-triazin-2-yl)benzonitrile as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.19 (d, J = 22.0 Hz, 1H), 8.75 (s, 1H), 8.65 - 8.47 (m, 2H), 7.64 (d, J = 9.2 Hz, 3H), 7.05 (s, 2H), 5.22 - 4.98 (m, 3H), 4.85 - 4.72 (m, 5H), 4.67 (td, J = 9.4, 8.8, 4.8 Hz, 1H), 4.40 (m, 2H), 4.29 - 4.08 (m, 1H), 4.08 - 2.70 (m, 6H), 2.61 (m, 3H), 2.35 - 2.12 (m,43H), 2.12 - 1.71 (m, 4H). ES/MS 656.5 (M+H+).
Example 408: 2-(((3R,4S)-3-fluoro-l-((S)-l-methyl-5-oxopyrrolidine-2- carbonyl)piperidin-4-yl)oxy)-5-(4-((3-fluoro-4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000405_0001
A solution 5 -(4-((3 -fluoro-4-(4-(oxetan-3 -yl)piperazin- 1 -yl)phenyl)amino)- 1 ,3 ,5 -triazin- 2-yl)-2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)benzonitrile (100 mg, 0.19 mmol) and (S)- l-methyl-5-oxopyrrolidine-2-carboxylic acid (29 mg, 0.20 mmol) in 3 mL DMF was treated with HATU (83 mg, 0.22 mmol) and TEA (51 uL, 0.37 mmol) and stirred at room temperature for lh. The reaction was then diluted with water and MeCN and purified by RP-HPLC to provide 2-(((3R,4S)-3-fluoro-l-((S)-l-methyl-5-oxopyrrolidine- 2-carbonyl)piperidin-4-yl)oxy)-5-(4-((3-fluoro-4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.83 (s, 1H), 8.58 (d, J = 8.5 Hz, 2H), 7.75 (dd, J = 14.8, 2.4 Hz, 1H), 7.66 (d, J = 9.3 Hz, 1H), 7.46 (s, 1H), 7.14 (t, J = 9.3 Hz, 1H), 5.22 - 4.95 (m, 3H), 4.82 - 4.61 (m, 6H), 4.51 - 3.68 (m, 5H), 3.68 - 2.65 (m, 5H), 2.61 (m, 3H), 2.34 - 2.12 (m, 3H), 2.06 - 1.70 (m, 4H). ES/MS 677.4(M+H+).
Example 409: 2-(((3R,4S)-l-((S)-2,3-dihydroxypropanoyl)-3-fluoropiperidin-4- yl)oxy)-5-(4-((3-fluoro-4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-
2-yl)benzonitrile
Figure imgf000406_0001
A solution 5 -(4-((3 -fluoro-4-(4-(oxetan-3 -yl)piperazin- 1 -yl)phenyl)amino)- 1 ,3 ,5 -triazin- 2-yl)-2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)benzonitrile (155 mg, 0.28 mmol) and (S)- glyceric acid (40 mg, 0.31 mmol) in4 mL DMF was treated with HATU (118 mg, 0.31 mmol) and TEA 118 uL, 0.85 mmol) and stirred at room temperature for lh. The reaction was then diluted with water and MeCN and purified by RP-HPLC to provide 2- (((3R)-l-((S)-2,3-dihydroxypropanoyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((3-fluoro-4-(4- (oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.78 (s, 1H), 8.59 - 8.44 (m, 2H), 7.70 (dd, J = 14.9, 2.4 Hz, 1H), 7.59 (d, J = 9.2 Hz, 1H), 7.42 (s, 1H), 7.09 (t, J = 9.3 Hz, 1H), 5.19 - 4.86 (m, 3H), 4.70 (d, J = 6.2 Hz, 5H), 4.58 - 3.80 (m, 5H), 3.80 - 2.64 (m, 10H), 1.87 (d, J = 43.6 Hz, 3H). ES/MS 637.4 (M+H+).
Example 410: 2-(((3R,4S)-3-fluoro-l-((2S,4S)-4-hydroxy-5-oxopyrrolidine-2- carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)- l,3,5-triazin-2-yl)benzonitrile
Figure imgf000406_0002
A solution 2-(((3R,4S)-3 -fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3 -yl)piperazin- 1 - yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (150 mg, 0.28 mmol) and (2S,4S)-4- hydroxy-5-oxopyrrolidine-2-carboxylic acid (45 mg, 0.31 mmol) in 2 mL DMF was treated with HATU (129 mg, 0.34 mmol) and TEA (157 uL, 0.11 mmol) and stirred at room temperature for lh. The reaction was then diluted with water and MeCN and purified by RP-HPLC to provide 2-(((3R,4S)-3-fluoro-l-((2S,4S)-4-hydroxy-5- oxopyrrolidine-2-carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.14 (d, J = 24.0 Hz, 1H), 8.70 (s, 1H), 8.62 - 8.40 (m, 2H), 7.84 (d, J = 19.5 Hz, 1H), 7.58 (d, J = 9.1 Hz, 2H), 7.00 (s, 3H), 5.02 (m, 3H), 4.71 (d, J = 6.4 Hz, 5H), 4.40 (m, 1H), 4.24 - 3.87 (m, 3H), 3.78 (s, 1H), 3.61 - 3.21 (m, 4H), 3.19 - 2.70 (m, 4H), 2.60 (ddd, J = 19.7, 15.6, 8.2 Hz, 2H), 1.97 (m, 2H), 1.81 - 1.45 (m, 1H). ES/MS 658.3 (M+H+).
Example 411 : 2-(((2S,4S,5R)-5-fluoro-2-methyl-l-((R)-5-oxopyrrolidine-2- carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)- l,3,5-triazin-2-yl)benzonitrile
Figure imgf000407_0001
A solution of 2-(((2S,4S,5R)-5-fluoro-2-methylpiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan- 3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (55 mg, 0.10 mmol) and (R)-5-oxopyrrolidine-2-carboxylic acid (14 mg, 0.11 mmol) in 1 mL DMF was treated with HATU (42 mg, 0.11 mmol) and DIEA (35 uL, 0.20 mmol) and stirred at room temperature overnight. The reaction was then diluted with water and MeCN and purified by RP-HPLC to provide 2-(((2S,5R)-5-fluoro-2-methyl-l-((R)-5- oxopyrrolidine-2-carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.18 (m, 1H), 8.75 (s, 1H), 8.58 (d, J = 9.2 Hz, 2H), 8.52 (m, 1H), 7.72 - 7.54 (m, 4H), 7.05 (s, 2H), 5.31 - 5.15 (m, 1H), 5.15 - 4.90 (m, 2H), 4.76 (d, J = 6.5 Hz, 4H), 4.74 - 4.64 (m, 2H), 4.62 - 4.27 (m, 2H), 4.27 - 2.63 (m, 7H), 2.39 - 1.79 (m, 5H), 1.38 - 1.20 (m, 3H). ES/MS 656.4 (M+H+). Example 412: 2-(((2S,4S,5R)-5-fluoro-l-((R)-2-hydroxypropanoyl)-2- methylpiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)- l,3,5-triazin-2-yl)benzonitrile
Figure imgf000408_0001
A solution of 2-(((2S,4S,5R)-5-fluoro-2-methylpiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan- 3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (85 mg, 0.16 mmol) and d-lactic acid (15 mg, 0.17 mmol) in 1 mL DMF was treated with HATU (65 mg, 0.17 mmol) and DIEA (54 uL, 0.31 mmol) and stirred at room temperature for lh. The reaction was then diluted with water and MeCN and purified by RP-HPLC to provide 2- (((2S,5R)-5-fluoro-l-((R)-2-hydroxypropanoyl)-2-methylpiperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.18 (d, J = 24.1 Hz, 1H), 8.75 (s, 1H), 8.67 - 8.34 (m, 2H), 7.64 (s, 3H), 7.05 (s, 2H), 5.30 - 4.90 (m, 4H), 4.84 - 4.65 (m, 5H), 4.60 - 4.23 (m, 4H), 4.18 - 2.69 (m, 5H), 2.22 - 1.85 (m, 3H), 1.35 (d, J = 6.8 Hz, 2H), 1.29 - 1.11 (m, 5H). ES/MS 617.4(M+H+).
Example 413 : 2-(((3R,4S)-3-fluoro-l-(6-oxo-l,6-dihydropyridine-2- carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)- l,3,5-triazin-2-yl)benzonitrile
Figure imgf000409_0001
A solution 2-(((3R,4S)-3 -fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3 -yl)piperazin- 1 - yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (126 mg, 0.24 mmol) and 6-oxo-l,6- dihydropyridine-2-carboxylic acid (36 mg, 0.26 mmol) in 2 mL DMF was treated with HATU (108 mg, 0.29 mmol) and DIEA (60 uL, 0480 mmol) and stirred at room temperature for lh. The reaction was then diluted with water and MeCN and purified by RP-HPLC to provide 2-(((3R,4S)-3-fluoro-l-(2-oxoimidazolidine-4-carbonyl)piperidin- 4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2- yl)benzonitrile as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.18 (d, J = 24.7 Hz, 1H), 8.75 (s, 1H), 8.66 - 8.44 (m, 3H), 8.29 - 8.19 (m, 1H), 7.71 - 7.48 (m, 4H), 7.00 (m, 4H), 5.27 - 4.89 (m, 3H), 4.83 - 4.58 (m, 6H), 4.59 - 4.11 (m, 2H), 4.04 - 3.19 (m, 2H), 3.10 (s, 6H), 2.02 (m, 2H). ES/MS 652.4 (M+H+).
Example 414: 2-(((3R,4S)-3-fluoro-l-(2-oxoimidazolidine-4-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2- yl)benzonitrile
Figure imgf000409_0002
A solution of 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (55 mg, 0.10 mmol) and (±)-2-oxoimidazolidine-4-carboxylic acid (15 mg, 0.11 mmol) in 1 mL DMF was treated with HATU (42 mg, 0.11 mmol) and DIEA (35 uL, 0.20 mmol) and stirred at room temperature for lh. The reaction was then diluted with water and MeCN and purified by RP-HPLC to provide 2: 2-(((3R,4S)-3-fluoro-l-(2-oxoimidazolidine-4- carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin- 1 -yl)phenyl)amino)- l,3,5-triazin-2-yl)benzonitrile as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.18 (d, J = 22.2 Hz, 1H), 8.75 (s, 1H), 8.57 (m, 2H), 7.59 (m, 2H), 7.02 (m, 3H), 6.40 (bs, 1H), 6.23 (bs, 1H), 5.24 - 4.97 (m, 3H), 4.76 (d, J = 6.3 Hz, 5H), 4.61 (ddd, J = 14.5, 9.7, 4.8 Hz, 1H), 4.38 (m, 2H), 4.24 - 3.97 (m, 1H), 3.74 (m, 1H), 3.67 - 3.22 (m, 4H), 3.04 (m, 4H), 1.89 (m, 3H).. ES/MS 643.4 (M+H+).
Example 415: 2-(((2S,4S,5R)-5-fluoro-l-((S)-2-hydroxypropanoyl)-2- methylpiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)- l,3,5-triazin-2-yl)benzonitrile
Figure imgf000410_0001
A solution of 1-lactic acid (10 mg, 0.11 mmol) in 1 mL DMF was treated with HATU (42 mg, 0.11 mmol), 2-(((2S,4S,5R)-5-fluoro-2-methylpiperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (55 mg, 0.10 mmol) and DIEA (35 uL, 0.20 mmol) and stirred at room temperature for 2h. After 2h a premixed solution of 1-lactic acid (19 mg, 0.22 mmol) and HATU (89 mg, 0.24 mmol) in 1 mL DMF and added and the mixturw stirred for an additional hour. A solution of 252 uL of 2N NaOH in 1 mL MeOH was then added and the mixture stirred for 5 min. 40 mL of TFA was added and the reaction diluted with water and purified by RP-HPLC to provide 2-(((2S,5R)-5-fluoro- 1 -((S)-2-hydroxypropanoyl)-2-methylpiperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3 -yl)piperazin- 1 -yl)phenyl)amino)- 1 ,3 ,5 -triazin-2- yl)benzonitrile as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.18 (d, J = 25.8 Hz, 1H), 8.75 (s, 1H), 8.68 - 8.45 (m, 2H), 7.65 (d, J = 9.3 Hz, 2H), 7.04 (s, 3H), 5.31 - 5.14 (m, 1H), 5.30 - 4.84 (m, 2H), 4.84 - 4.68 (m, 5H), 4.55 - 4.15 (m, 3H), 4.08 - 3.57 (m, 3H), 3.52 - 2.65 (m, 6H), 2.21 - 1.83 (m, 2H), 1.40 - 1.15 (m, 5H). ES/MS 617.4(M+H+).
Example 416: 2-(((2S,4S,5R)-5-fluoro-2-methyl-l-((S)-5-oxopyrrolidine-2- carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)- l,3,5-triazin-2-yl)benzonitrile
Figure imgf000411_0001
A solution of 2-(((2S,4S,5R)-5-fluoro-2-methylpiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan- 3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (55 mg, 0.10 mmol) and (S)-5-oxopyrrolidine-2-carboxylic acid (14 mg, 0.11 mmol) in 1 mL DMF was treated with HATU (42 mg, 0.11 mmol) and DIEA (35 uL, 0.20 mmol) and stirred at room temperature overnight. The reaction was then diluted with water and MeCN and purified by RP-HPLC to provide 2-(((2S,5R)-5-fluoro-2-methyl-l-((S)-5-oxopyrrolidine- 2-carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin- 1 -yl)phenyl)amino)- l,3,5-triazin-2-yl)benzonitrile as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.18 (m, 1H), 8.75 (s, 1H), 8.58 (d, J = 9.2 Hz, 2H), 8.52 (m, 1H), 7.72 - 7.54 (m, 4H), 7.05 (s, 2H), 5.31 - 5.15 (m, 1H), 5.15 - 4.90 (m, 2H), 4.76 (d, J = 6.5 Hz, 4H), 4.74 - 4.64 (m, 2H), 4.62 - 4.27 (m, 2H), 4.27 - 2.63 (m, 8H), 2.39 - 1.79 (m, 5H), 1.38 - 1.20 (m, 3H). ES/MS 656.4 (M+H+).
Example 417: 2-(((3R,4S)-l-(3-cyanopropanoyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan- 3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000412_0001
Step-1: To solution of 2,4-dichloro-l,3,5-triazine (2.5 g, 16.67 mmol ) in DMF (100 mL) at 0 C under nitrogen atmosphere was added solution of 4-(4-(oxetan-3-yl)piperazin-l-yl)aniline (3.5 g, 15.1 mmol) in DMF (120 mL) over 5 minutes. The reaction mixture was stirred at 0 C for lh and the solvent concentrated to dryness under reduced pressure. Crude product was added 40%MeOH\DCM and sonicated for 2 minutes to bring solid particles in to solution. The crude product was adsorbed on silica gel and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel [Method, 10-60% B over 15 min (A = DCM, B = 20% MeOH/DCM)] to afford product. LCMS-ESI+ (m/z): [M+H]+ calcd for C16H19CIN60: 347.1 found:347.3.
Step-2. A mixture of 4-chloro-N-(4-(4-(oxetan-3-yl)piperazin- l -yl)phenyl)-l ,3,5-triazin- 2-amine (lg, 2.88 mmol), 2-fluoro-5-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2- yl)benzonitrile (0.783g, 3.17 mmol) and Pd(PPh3)4 (0.25g, 0.21 mmol) was taken up in 1,2-DME (24 mL) in a 100 mL round bottom flask. To well stirred mixture was added solution of sodium carbonate (1.375 g 12.98 mmol) in water (12 mL). The mixture heated at 95 °C for 4h (500 mg scale was done under microwave irradiation at 120 C for 30 min). The reaction mixture was diluted with 30% MeOH/DCM (50 mL) and filtered through short pad of silica gel and washed with 30% MeOH/DCM (10 mL x 2). The filtrate was adsorbed on silica gel and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel to afford 2-fluoro-5- (4-((4-(4-(oxetan-3-yl)piperazin-l -yl)phenyl)amino)-l ,3,5-triazin-2-yl)benzonitrile
LCMS-ESI+ (m/z): [M+H]+ calcd for C23H22FN70: 432.2; found:432.3. XH NMR (400 MHz, DMSO-i/6) δ 10.20 (d, J = 21.0 Hz, 1H), 8.77 (s, 1H), 8.65 (d, J = 10.8 Hz, 2H), 7.72 (s, 1H), 7.64 - 7.43 (m, 2H), 6.96 (t, J = 10.8 Hz, 2H), 4.55 (t, J= 6.5 Hz, 2H), 4.46 (t, J= 6.0 Hz, 2H), 3.47-3.40 (m, 1H), 3.13 (d, J= 6.6 Hz, 4H), 2.46 - 2.32 (m, 4H). Step-3: (3R,4S)-tert-butyl 3-fluoro-4-hydroxypiperidine-l-carboxylate (430 mg, 2.29 mmol) was added Me-THF (20 mL) under argon atmosphere and cooled at 0 C. To well stirred solution was added potassium tert-butoxide at one portion and stirred for 30 minutes. To well stirred solution was added 2-fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3;5-triazin- 2-yl)benzonitrile (900 mg, 2.09 mmol) and warmed to room temperature over 10 min. The reaction was heated at 80 C overnight. The reaction was quenched with minimum amount of water and diluted with 10% MeOH/DCM to make clear solution. The crude product was adsorbed on silica gel and purified by flash column chromatography on silica gel gel [Method, 0- 50% B over 15 min (A = DCM, B = 20% MeOH/DCM)] to afford (3R,4S)-tert-butyl 4-(2-cyano-4- (4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)phenoxy)-3- fluoropiperidine-l-carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H39FN804: 631.3; found : 631.4
Step-4: (3R,4S)-tert-butyl 4-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)- l,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-l-carboxylate (90 mg, 0.15 mmol) was dissolved in 20% TFA/DCM (5 mL) and stirred at room temperature for lh. The solvent was concentrated under reduced pressure to afford 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile. The dried residue was used for next step without purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C28H31FN802: 531.2; found : 531.4 Step-5: To solution of 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin- l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (65 mg, 0.12 mmol), 3-cyanopropanoic acid (20 mg, 0.24 mmol), HATU (58 mg, 0.24 mmol) in DMF (3 mL) was added DIPEA (0.26 mL) in a 25 mL round bottom flask and flushed with argon gas. This reaction mixture was stirred at room temperature overnight. The solvent was concentrated and the crude product purified via prep HPLC (5-95% acetonitrile in water, 0.1% trifluoroacetic acid buffer) to isolate 2-(((3R,4S)-l-(3- cyanopropanoyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C31H36FN904: 612.3: found:612.3 :H NMR (400 MHz, DMSO-d6) δ 10.19 (d, J = 20.3 Hz, 1H), 8.75 (s, 1H), 8.63 - 8.46 (m, 2H), 7.63 (t, J = 8.8 Hz, 3H), 7.14 - 6.90 (m, 2H), 5.24 - 4.92 (m, 3H), 4.75 (d, J = 6.6 Hz, 5H), 4.55 - 4.26 (m, 2H), 4.25 - 3.81 (m, 4H), 3.74 - 3.49 (m, 1H), 3.31 (ddt, J = 24.2, 18.0, 12.8 Hz, 2H), 3.19 - 2.83 (m, 4H), 2.10 - 1.79 (m, 2H). Example 418: 5-(4-((l-(tert-butyl)-lH-pyrazol-4-yl)amino)-l,3,5-triazin-2-yl)-2-(((3R,4S)-3- fluoro-l-(5-methyl-4H-l,2,4-triazole-3-carbonyl)piperidin-4-yl)oxy)benzonitrile
Figure imgf000414_0001
The title compound was prepared by coupling 5-(4-((l-(tert-butyl)-lH-pyrazol-4-yl)amino)-l,3,5- triazin-2-yl)-2-(((3R;4S)-3-fluoropiperidin-4-yl)oxy)benzonitrile with 5-methyl-4H-l,2,4-triazole-
3-carboxylic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for CjeHjsFN Oj: 546.2: found :546.1 :H NMR (400 MHz, DMSO-d6) δ 10.27 (d, J = 21.1 Hz, 1H), 8.75 (d, J = 40.2 Hz, 1H), 8.57 (dd, J = 7.9, 5.8 Hz, 2H), 8.04 (d, J = 39.8 Hz, 1H), 7.71 - 7.49 (m, 2H), 7.39 - 7.22 (m, 1H), 7.19 - 7.06 (m, 1H), 5.29 - 4.91 (m, 2H), 4.65 (d, J = 89.6 Hz, 1H), 4.29 (d, J = 13.5 Hz, 1H), 3.92 - 3.18 (m, 2H), 2.37 (s, 3H), 2.15 - 1.82 (m, 2H), 1.53 (d, J = 18.3 Hz, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C26H28FN 02: 546.2: found:546.1
Example 419: 5-(4-((l-(tert-butyl)-lH-pyrazol-4-yl)amino)-l,3,5-triazin-2-yl)-2-(((3R,4S)-l-((S)- 2,3-dihydroxypropanoyl)-3-fluoropiperidin-4-yl)oxy)benzonitrile
Figure imgf000415_0001
The title compound was prepared by coupling 5-(4-((l-(tert-butyl)-lH-pyrazol-4-yl)amino)-l,3,5- triazin-2-yl)-2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)benzonitrile with (S)-2,3-dihydroxypropanoic acid. LCMS-ESI+ (m/z): [M+H]+ ca led for C25H29FN804: 525.2: found :525.1 :H NMR (400 MHz, DMSO-d6) δ 10.27 (d, J = 21.3 Hz, 1H), 8.75 (d, J = 40.2 Hz, 1H), 8.64 - 8.49 (m, 2H), 8.04 (d, J = 39.6 Hz, 1H), 7.71 - 7.53 (m, 2H), 5.03 (d, J = 55.4 Hz, 3H), 4.48 - 4.24 (m, 2H), 3.94 (d, J = 6.8 Hz, 1H), 3.80 - 3.18 (m, 5H), 1.92 (d, J = 44.0 Hz, 2H), 1.53 (d, J = 18.4 Hz, 9H).
Example 420: 5-(4-((l-(tert-butyl)-lH-pyrazol-4-yl)amino)-l,3,5-triazin-2-yl)-2-(((3R,4S)-3- fluoro-l-(2-hydroxyacetyl)piperidin-4-yl)oxy)benzonitrile
Figure imgf000415_0002
The title compound was prepared by coupling 5-(4-((l-(tert-butyl)-lH-pyrazol-4-yl)amino)-l,3,5- triazin-2-yl)-2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)benzonitrile with 2-hydroxyacetic acid. LCMS-
ESI+ (m/z): [M+H]+ calcd for
Figure imgf000415_0003
495.2: found :495.1 1H NMR (400 MHz, DMSO-d6) δ 10.27 (d, J = 21.7 Hz, 1H), 8.75 (d, J = 40.2 Hz, 1H), 8.63 - 8.48 (m, 2H), 8.04 (d, J = 39.0 Hz, 1H), 7.70 - 7.53 (m, 2H), 5.23 - 4.92 (m, 2H), 4.66 (s, 1H), 4.42 - 3.82 (m,3H), 3.75 - 3.04 (m, 3H), 2.06 - 1.75 (m, 2H), 1.53 (d, J = 18.2 Hz, 9H). Example 421: 2-((l-methyl-2-oxohexahydropyrimidin-5-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000416_0001
To a solution of 5-hydroxy-l-methyltetrahydropyrimidin-2(lH)-one (36 mg, 0.28 mmol) in DMF (4 mL) was added potassium t-butoxide (47 mg, 0.42 mmol) at 0 °C. The reaction mixture was allowed to stir for 1 hour. To the reaction mixture was added 2-fluoro-5-(4-((4-(4-(oxetan-3- yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (60 mg, 0.14 mmol) at room temperature. The reaction mixture was brought to 80 °C and heated overnight. The solvent was concentrated and the crude product purified via prep HPLC (5-95% acetonitrile in water, 0.1% trifluoroacetic acid buffer) to isolate product 2-((l-methyl-2-oxohexahydropyrimidin-5-yl)oxy)-
5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+
(m/z): [M+H]+ calcd for C28H31N903: 542.2: found :542.4
Example 422: 2-((l-methyl-6-oxopiperidin-3-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000417_0001
The title compound was prepared following the same procedure reported in Example 421 by coupling 2-fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3;5-triazin-2- yl)benzonitrile with 5-hydroxy-l-methylpiperidin-2-one instead of 5-hydroxy-l- methyltetrahydropyrimidin-2(lH)-one. LCMS-ESI+ (m/z): [M+H]+ calcd for 0,9Η32Ν803: 541.2: found :541.4
Example 423: 2-(((3R,4S)-3-fluoro-l-((R)-3-fluoropyrrolidine-l-carbonyl)piperidin-4-yl)oxy)-5- (4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000417_0002
To solution of 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (50 mg, 0.1 mmol) in DMF (3 mL) was activated with DIPE (66 uL) and generated HCI gas was flushed with argon balloon. To stirred solution was added (R)-3-fluoropyrrolidine hydrochloride salt (71 mg, 0.56 mmol) followed by phosgene ( 15% in Toluene 250 uL) at once and stirred at room temperature for 3h. Solvent was concentrated and the crude product purified via prep HPLC (5-95% acetonitrile in water, 0.1% trifluoroacetic acid buffer) to isolate 2-(((3R,4S)-3-fluoro-l-((R)-3-fluoropyrrolidine-l- carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(o^
2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H37F2N903: 646.3: found:646.4 :H NM (400 MHz, DMSO-d6) δ 10.18 (d, J = 21.7 Hz, 1H), 8.74 (s, 1H), 8.65 - 8.43 (m, 2H), 7.60 (d, J = 9.2 Hz, 2H), 7.03 (s, 3H), 5.41 - 4.84 (m, 3H), 4.82 - 4.57 (m, 5H), 4.42 (s, 1H), 3.93 - 3.58 (m, 2H), 3.55 - 3.26 (m, 6H), 3.20 - 2.86 (m, 7H), 2.12 - 1.85 (m, 5H).
Example 424: 2-(((3R,4S)-3-fluoro-l-(pyrrolidine-l-carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000418_0001
The title compound was prepared following the same procedure reported in Example 423 by coupling 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile with pyrrolidine instead of (R)-3- fluoropyrrolidine. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H38FN9O3: 628.3: found :628.4 :H NMR (400 MHz, DMSO-d6) δ 10.19 (d, J = 23.9 Hz, 1H), 8.75 (s, 1H), 8.66 - 8.42 (m, 2H), 7.64 (d, J = 9.2 Hz, 2H), 7.04 (s, 3H), 5.31 - 5.01 (m, 4H), 4.75 (d, J = 6.6 Hz, 6H), 4.55 - 4.00 (m, 5H), 3.99 - 3.62 (m, 2H), 3.59 - 3.36 (m, 2H), 3.34 - 2.72 (m, 6H), 2.31 - 1.68 (m, 4H).
Example 425: 2-(((3R,4S)-3-fluoro-l-((R)-3-hydroxypyrrolidine-l-carbonyl)piperidin-4-yl)oxy)- 5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000419_0001
The title compound was prepared following the same procedure reported in Example 423 by coupling 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile with (R)-pyrrolidin-3-ol instead of (R)-3- fluoropyrrolidine. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H38FN904: 644.3: found :644.4. :H NMR (400 MHz, DMSO-d6) δ 10.23 - 10.13 (m, 1H), 8.75 (s, 1H), 8.60 - 8.49 (m, 2H), 7.60 (d, J = 10.2 Hz, 3H), 7.04 (s, 2H), 5.23 - 4.84 (m, 3H), 4.75 (d, J = 6.4 Hz, 5H), 4.42 (s, 1H), 4.19 (p, J = 4.2 Hz, 1H), 3.89 - 3.60 (m, 2H), 3.54 - 3.22 (m, 7H), 3.11 (td, J = 12.4, 11.6, 5.4 Hz, 4H), 2.07 - 1.58 (m, 6H).
Example 426: 2-(((3R,4S)-3-fluoro-l-((S)-3-hydroxypyrrolidine-l-carbonyl)piperidin-4-yl)oxy)- 5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000419_0002
The title compound was prepared following the same procedure reported in Example 423 by coupling 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile with (S)-pyrrolidin-3-ol instead of (R)-3- fluoropyrrolidine. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H38FN904: 644.3: found :644.4 Example 427: (3R,4S)-4-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5- triazin-2-yl)phenoxy)-3-fluoro-N-(2-methoxyethyl)piperidine-l-carboxamide.
Figure imgf000420_0001
The title compound was prepared following the same procedure reported in Example 423 by coupling 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile with 2-methoxyethanamine instead of (R)-3- fluoropyrrolidine. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H38FN904: 632.3: found :632.4
Example 428: (3R,4S)-4-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5- triazin-2-yl)phenoxy)-3-fluoro-N-(2-hydroxyethyl)-N-methylpiperidine-l-carboxamide
Figure imgf000420_0002
The title compound was prepared following the same procedure reported in Example 423 by coupling 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile with 2-(methylamino)ethanol instead of (R)-3- fluoropyrrolidine. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H38FN904: 632.3: found :632.4 Example 429: (3R,4S)-4-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5- triazin-2-yl)phenoxy)-3-fluoro-N-(2-hydroxyethyl)piperidine-l-carboxamide
Figure imgf000421_0001
The title compound was prepared following the same procedure reported in Example 423 by coupling 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile with 2-aminoethanol instead of (R)-3- fluoropyrrolidine. LCMS-ESI+ (m/z): [M+H]+ calcd for C31H36FN904: 618.3: found:618.4 :H NMR (400 MHz, DMSO-d6) δ 10.18 (d, J = 22.5 Hz, 1H), 8.75 (s, 1H), 8.65 - 8.42 (m, 2H), 7.60 (d, J = 9.2 Hz, 2H), 7.04 (s, 3H), 6.62 (t, J = 5.4 Hz, 1H), 5.18 - 4.84 (m, 3H), 4.84 - 4.61 (m, 5H), 4.41 (s, 1H), 3.97 (dt, J = 133, 6.9 Hz, 1H), 3.80 - 3.26 (m, 9H), 3.13 (dq, J = 36.2, 6.5, 6.0 Hz, 4H), 1.88 (d, J = 5.7 Hz, 2H).
Example 430: Cis 2-((3,3-difluoro-l-(2-hydroxyacetyl)-5-methylpiperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000421_0002
Stepl: Synthesis of cis and trans mixture of tert-butyl 4-(2-cyano-4-(4-((4-(4-(oxetan-3- yl)piperazin-l-yl)phenyl)amino)-l,3;5-triazin-2-yl)phenoxy)-3;3-difluoro-5-methylpiperidine-l- carboxylate: tert-butyl 3,3-difluoro-4-hydroxy-5-methylpiperidine-l-carboxylate (262 mg, 1.04 mmol) was added Me-THF (12 mL) under argon atmosphere and cooled at 0 C. To well stirred solution was added potassium tert-butoxide (117 mg, 1.04 mmol) at one portion and stirred for 30 minutes. To well stirred solution was added 2-fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (300 mg, 0.7 mmol) and warmed to room temperature over 5 min and heated at 80 C overnight. The reaction was quenched with minimum amount of water and diluted with 10% MeOH/DCM to make clear solution. The crude product was adsorbed on silica gel and purified by flash column chromatography on silica gel [Method, 0-50% B over 15 min (A = DCM, B = 20% MeOH/DCM)] to afford mixture of 4isomers. This was subjected for second purification by flash column chromatography on silica gel [Method, 0-40% B over 25 min (A = DCM, B = 20% MeOH/DCM)] to isolate the products which was tentatively assigned as cis and trans mixture of enantiomers. Cis and trans isomers: LCMS- ESI+ (m/z): [M+H]+ calcd for C34H4oF2N804: 663.3: found :663.2. Tentatively assigned mixture of cis enantiomers was subjected for Boc-deprotection followed by coupling with 2-hydroxyacetic acid to afford the title compound. LCMS-ESI+ (m/z): [M+H]+ calcd for C31H36 FN904: 621.3: found :621.3. :H NM (400 MHz, DMSO-d6) δ 10.21 (d, J = 23.5 Hz, 1H), 8.75 (s, 1H), 8.66 - 8.46 (m, 2H), 7.88 - 7.45 (m, 3H), 7.04 (s, 2H), 5.30 (s, 1H), 4.74 (s, 5H), 4.50 (s, 1H), 4.17 (dt, J = 33.2, 15.9 Hz, 3H), 3.64 (d, J = 13.1 Hz, 6H), 3.19 - 2.72 (m, 5H), 2.23 (d, J = 53.3 Hz, 1H ), 0.98 (d, J = 6.7 Hz, 3H).
Example 431: trans-2-((3,3-difluoro-l-((S)-2-hydroxypropanoyl)-5-methylpiperidin-4-yl)oxy)-5- (4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000423_0001
Tentatively assigned mixture of trans isomers from step 1 of Example 430 was subjected for Boc deprotection followed by coupling with (S)-2-hydroxypropanoic acid to afford the title compound. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H36 F2N804: 635.2: found :635.4 :H NM (400 MHz, DMSO-d6) δ 10.22 (d, J = 23.4 Hz, 1H), 8.76 (s, 1H), 8.67 - 8.45 (m, 2H), 7.62 (d, J = 10.0 Hz, 3H), 7.06 (d, J = 10.8 Hz, 2H), 5.29 - 4.90 (m, 2H), 4.75 (d, J = 6.3 Hz, 5H), 4.59 - 4.05 (m, 3H), 3.28 - 2.67 (m, 6H), 2.07 (d, J = 74.5 Hz, 1H), 1.50 - 1.36 (m, 1H), 1.28 - 1.13 (m, 3H), 1.00 (d, J = 6.1 Hz, 3H).
Example 432: trans-2-((3,3-difluoro-l-(2-hydroxyacetyl)-5-methylpiperidin-4-yl)oxy)-5-(4-((4- (4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000423_0002
Tentatively assigned mixture of trans isomers from step 1 of Example 430 was subjected for Boc-deprotection followed by coupling with 2-hydroxyacetic acid to give the title compound.
LCMS-ESI+ (m/z): [M+H]+ calcd for C3iH36 FN904: 621.3: found :621.3
:H NMR (400 MHz, DMSO-d6) δ 10.22 (d, J = 25.0 Hz, 1H), 8.76 (s, 1H), 8.75 - 8.46 (m, 2H), 7.62 (d, J = 12.9 Hz, 3H), 7.06 (d, J = 10.9 Hz, 2H), 5.35 - 5.05 (m, 1H), 4.75 (s,5H), 4.45 - 4.04 (m,3H), 3.82 (d, J = 13.9 Hz, 1H), 3.54 (s, 7H), 3.28 - 2.63 (m, 4H), 2.08 (d, J = 79.9 Hz, 1H), 0.98 (d, J = 6.8 Hz, 3H). Example 433: 2-(((3R,4S)-l-((R)-2-aminopropanoyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000424_0001
The title compound was prepared by coupling 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile with (R)-2-((tert- butoxycarbonyl)amino)propanoic acid followed by Boc-deprotection. LCMS-ESI"1" (m/z): [M+H]+ calcd for C31H36 FN903: 602.3: found :602.4
Example 434: 2-(((3R,4S)-l-((R)-2-aminopropanoyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000424_0002
The title compound was prepared by coupling 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile with (R)-2-((tert- butoxycarbonyl)amino)propanoic acid followed by Boc-deprotection. LCMS-ESI+ (m/z): [M+H]+ calcd for C31H36 FN903: 602.3: found :602.4. :H NMR (400 MHz, DMSO-d6) δ 10.19 (d, J = 26.7 Hz, 1H), 8.76 (s, 1H), 8.67 - 8.43 (m, 2H), 8.10 (d, J = 7.5 Hz, 3H), 7.64 (t, J = 8.7 Hz, 2H), 7.04 (s, 2H), 5.28 - 5.00 (m, 3H), 4.84 - 4.66 (m, 5H), 4.56 - 4.30 (m, 3H), 4.19 (dd, J = 31.7, 14.4 Hz, 1H), 3.95 - 3.48 (m, 1H), 3.44 - 3.22 (m, 2H), 3.15 (s, 5H), 2.13 - 1.73 (m, 2H), 1.33 (dd, J = 14.1, 6.8 Hz, 3H).
Example 435: (R)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)-2- ((l-(5-oxo-2,5-dihydro-lH-l,2,4-triazole-3-carbonyl)pyrrolidin-3-yl)oxy)benzonitrile
Figure imgf000425_0001
The title compound was prepared by coupling ( )-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl (phenyl )amino)-l,3,5-triazin-2-yl)-2-(pyrrol id in-3-yloxy)benzonitrile with 5-oxo-2,5-dihydro- lH-l,2,4-triazole-3-carboxylic acid. LCMS-ESI+ (m/z): [M+H]+ ca led for C3oH31N1104: 610.3: found :610.4
Example 436: 2-(((3R,4S)-3-fluoro-l-((5-oxo-2,5-dihydro-lH-l,2,4-triazol-3- yl)methyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
Figure imgf000425_0002
2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl (phenyl )amino)- l,3,5-triazin-2-yl)benzonitrile (70 mg, 0.13 mmol) were added 5-(chloromethyl)-lH-l,2,4-triazol- 3(18 mg, 0.13 mmol), IPA (4 mL), and DIPE (0.3 mL) sequentially. The generated HCI gas was flushed with argon balloon and the reaction mixture was heated at 80 °C for 30 minutes. The reaction was cooled to room temperature and the yellow solid was filtered and dried to afford product 2-(((3R,4S)-3-fluoro-l-((5-oxo-2,5-dihydro-lH-l,2,4-triazol-3-yl)methyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile.
LCMS-ESI+ (m/z): [M+H]+ calcd for C31H34FN1103: 628.2: found:628.4
Example 437: 2-(((3R,4S)-3-fluoro-l-(5-oxo-2,5-dihydro-lH-l,2,4-triazole-3-carbonyl)piperidin- 4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000426_0001
The title compound was prepared by coupling 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile with 5-oxo-2,5-dihydro- lH-l,2,4-triazole-3-carboxylic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C31H32 FN 04: 642.3: found :642.4 :H NMR (400 MHz, DMSO-d6) δ 11.99 (d, J = 6.0 Hz, 2H), 10.21 (s, 1H), 10.15 (s, 1H), 8.61 - 8.50 (m, 2H), 7.63 (d, J = 9.2 Hz, 3H), 7.05 (s, 2H), 5.26 - 4.86 (m, 4H), 4.77 (d, J = 6.4 Hz, 5H), 4.65 - 4.35 (m, 2H), 4.22 (d, J = 13.0 Hz, 1H), 3.88 (dd, J = 31.2, 14.9 Hz, 1H), 3.53 (td, J = 31.9, 13.1 Hz, 2H), 3.24 (s, 1H), 3.13 - 2.91 (m, 3H), 2.07 (d, J = 13.1 Hz, 2H).
Example 438: Trans-2-((l-(2-hydroxyacetyl)-3-(trifluoromethyl)piperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000427_0001
Stepl: Synthesis of cis and trans mixture of :tert-butyl 4-(2-cyano-4-(4-((4-(4-(oxetan-3- yl)piperazin-l-yl)phenyl)amino)-l,3;5-triazin-2-yl)phenoxy)-3-(trifluoromethyl)piperidine-l- carboxylate: tert-butyl 4-hydroxy-3-(trifluoromethyl)piperidine-l-carboxylate (262 mg, 0.97 mmol) was added Me-THF (12 mL) under argon atmosphere and cooled at 0 C. To well stirred solution was added potassium tert-butoxide (109 mg, 0.97 mmol) at one portion and stirred for 30 minutes. To well stirred solution was added 2-fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (300 mg, 0.69 mmol) and warmed to room temperature over 5 min and heated at 80 C overnight. The reaction was quenched with minimum amount of water and diluted with 10% MeOH/DCM to make clear solution. The crude product was adsorbed on sil ica gel and purified by flash column chromatography on silica gel [Method, 0-50% B over 15 min (A = DCM, B = 20% MeOH/DCM)] to afford mixture of isomers. This was subjected for second purification by flash column chromatography on silica gel [Method, 0-40% B over 25 min (A = DCM, B = 20% MeOH/DCM)] to isolate cis and trans isomers
(tentatively assigned structures). LCMS-ESI+ (m/z): [M+H]+ calcd for C34H39F3N804: 681.3: found :681.2
Step2: The tentatively assigned trans-isomer mixture from Step 1 was subjected for Boc- deprotection followed by coupling with 2-hydroxyacetic acid to afford the title compound. LCMS-ESI+ (m/z): [M+H]+ calcd for C31H33 F3N804: 639.3: found :639.2
:H NM (400 MHz, DMSO-d6) δ 10.19 (d, J = 19.6 Hz, 1H), 8.75 (s, 1H), 8.66 - 8.41 (m, 2H), 7.62 (d, J = 9.8 Hz, 3H), 7.04 (d, J = 8.6 Hz, 2H), 5.38 (d, J = 5.0 Hz, 1H), 4.75 (d, J = 6.4 Hz, 5H), 4.58 - 4.30 (m, 2H), 4.29 - 4.07 (m, 3H), 4.02 - 3.48 (m, 5H), 3.26 (t, J = 13.2 Hz, 2H), 2.97 (d, J = 69.7 Hz, 4H), 2.10 - 1.66 (m, 2H). Example 439: cis-2-((l-(2-hydroxyacetyl)-3-(trifluoromethyl)piperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000428_0001
The tentatively assigned cis-isomer mixture from Step 1 of Example 438 was subjected to Boc- deprotection followed by coupling with 2-hydroxyacetic acid and purification gave the title compound. LCMS-ESI+ (m/z): [M+H]+ calcd for C31H33 F3N804: 639.3: found:639.2. :H NM (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.75 (s, 1H), 8.59 (d, J = 9.3 Hz, 1H), 8.54 - 8.31 (m, 1H), 7.62 (d, J = 9.9 Hz, 3H), 7.04 (d, J = 11.8 Hz, 2H), 5.39 (s, 1H), 4.74 (s, 5H), 4.50 (s, 1H), 4.16 (d, J = 15.9 Hz, 2H), 3.35 (s, 9H), 3.03 (s, 3H), 2.65 (s, 1H), 1.87 (d, J = 104.6 Hz, 2H).
Example 440: 2-(((4S,5R)-5-fluoro-3,3-dimethylpiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000428_0002
Stepl: Preparation of tert-butyl 4-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl (phenyl )amino)-l,3,5-triazin-2-yl)phenoxy)-5-f I uoro-3,3-dimethylpiperidine-l-carboxylate: tert-butyl 5-fluoro-4-hydroxy-3,3-dimethylpiperidine-l-carboxylate (401 mg, 1.62 mmol) was added Me-THF (16 mL) under argon atmosphere and cooled at 0 C. To well stirred solution was added potassium tert-butoxide (182 mg, 1.62 mmol) at one portion and stirred for 30 minutes. To well stirred solution was added 2-fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (500 mg, 1.15 mmol) and warmed to room temperature over 5 min. The reaction was heated at 80 C overnight. The reaction was quenched with minimum amount of water and diluted with 10% MeOH/DCM to make clear solution. The crude product was adsorbed on silica gel and purified by flash column chromatography on silica gel [Method, 0-50% B over 15 min (A = DCM, B = 20% MeOH/DCM)] to afford tert-butyl 4-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl (phenyl )amino)-l,3,5-triazin- 2-yl)phenoxy)-5-fluoro-3,3-dimethylpiperidine-l-carboxylate as mixture of cis enantiomers. Step 2: The mixture of cis enantiomers were separated by chiral separation using chiral column chromatography to afford the two peaks were tentatively assigned as (4S,5 )-tert-butyl 4-(2- cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl (phenyl )amino)-l,3,5-triazin-2-yl)phenoxy)-5- fluoro-3,3-dimethylpiperidine-l-carboxylate and (4R,5S)-tert-butyl 4-(2-cyano-4-(4-((4-(4- (oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3;5-triazin-2-yl)phenoxy)-5-fluoro-3;3- dimethylpiperidine-l-carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for
Figure imgf000429_0001
659.3: found :659.2
Step 3: (4S,5R)-tert-butyl 4-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l;3;5- triazin-2-yl)phenoxy)-5-fluoro-3,3-dimethylpiperidine-l-carboxylate from step 1 was subjected for Boc-deprotection followed by purification gave the title compound. LCMS-ESI"1" (m/z): [M+H]+ calcd for C3oH35FN802: 559.3: found:559.2
Example 441: 2-(((4S,5R)-5-fluoro-3,3-dimethyl-l-(l-methyl-lH-l,2,3-triazole-4- carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
Figure imgf000429_0002
(4S,5R)-tert-butyl 4-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l;3;5-triazin- 2-yl)phenoxy)-5-fluoro-3,3-dimethylpiperidine-l-carboxylate from Exampl4 440 step 1 was subjected for Boc-deprotection followed by coupling with l-methyl-lH-l,2,3-triazole-4- carboxylic acid to afford 2-(((4S;5R)-5-fluoro-3;3-dimethyl-l-(l-methyl-lH-l;2;3-triazole-4- carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl (phenyl )amino)-l,3,5-triazin-
2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C34H38 FN 03: 668.3: found:668.2 :H NMR (400 MHz, DMSO-d6) δ 10.20 (d, J = 21.1 Hz, 1H), 8.76 (s, 1H), 8.67 - 8.43 (m, 3H), 7.64 (t, J = 12.2 Hz, 3H), 7.05 (s, 2H), 5.30 - 5.03 (m, 1H), 4.92 (d, J = 22.1 Hz, 1H), 4.76 (d, J = 6.7 Hz, 5H), 4.52 - 4.13 (m, 2H), 4.08 (s, 4H), 3.99 - 3.64 (m, 3H), 3.15 (s, 6H), 1.04 (dd, J = 31.0, 17.8 Hz,6H).
Example 442: 2-(((4S,5R)-5-fluoro-3,3-dimethyl-l-(lH-pyrazole-5-carbonyl)piperidin-4-yl)oxy)- 5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000430_0001
(4S,5R)-tert-butyl 4-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin- 2-yl)phenoxy)-5-fluoro-3,3-dimethylpiperidine-l-carboxylate was subjected for Boc- deprotection followed by coupling with lH-pyrazole-5-carboxylic acid to afford 2-(((4S,5R)-5- fluoro-3,3-dimethyl-l-(lH-pyrazole-5-carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for 653.3: found :653.2 :H NMR (400 MHz, DMSO-d6) δ 10.19 (d, J = 20.7 Hz, 1H), 8.75 (s, 1H), 8.54 (ddd, J = 19.7, 8.0, 1.7 Hz, 2H), 7.86 - 7.70 (m, 1H), 7.71 - 7.45 (m, 4H), 7.05 (s, 2H), 6.74 - 6.54 (m, 1H), 5.14 (d, J = 47.6 Hz, 1H), 4.92 (d, J = 20.9 Hz, 1H), 4.77 (d, J = 6.6 Hz, 4H), 4.45 (s, 2H), 4.18 (t, J = 15.9 Hz, 1H), 3.92 - 3.62 (m, 3H), 3.42 (d, J = 49.4 Hz, 1H), 3.15 (s, 6H), 1.23 - 0.81 (m, 6H).
Example 443: 2-(((4S,5R)-5-fluoro-l-(3-hydroxypropanoyl)-3,3-dimethylpiperidin-4-yl)oxy)-5- (4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000431_0001
(4S,5R)-tert-butyl 4-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin- 2-yl)phenoxy)-5-fluoro-3,3-dimethylpiperidine-l-carboxylate was subjected for Boc- deprotection followed by coupling with 2-hydroxypropionic acid to afford 2-(((4S,5R)-5-fluoro-l- (3-hydroxypropanoyl)-3,3-dimethylpiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H39FN804: 631.3: found :631.2 :H NMR (400 MHz, DMSO-d6) δ 10.19 (d, J = 22.0 Hz, 1H), 8.75 (s, 1H), 8.68 - 8.44 (m, 2H), 7.75 - 7.49 (m, 3H), 7.05 (d, J = 8.4 Hz,2H), 5.08 (dd, J = 48.2, 22.9 Hz, 1H), 4.86 (d, J = 21.7 Hz, 1H), 4.75 (d, J = 6.2 Hz, 5H), 4.13 - 3.70 (m, 5H), 3.72 - 3.46 (m, 3H), 3.30 - 2.82 (m, 6H), 2.73 - 2.51 (m, 2H), 1.17 - 0.84 (m, 6H).
Example 444: 2-(((4R,5S)-5-fluoro-3,3-dimethyl-l-((S)-5-oxopyrrolidine-2-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000432_0001
(4 ,5S)-tert-butyl 4-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l;3;5-triazin- 2-yl)phenoxy)-5-fluoro-3,3-dimethylpiperidine-l-carboxylate was subjected for Boc- deprotection followed by coupling with (S)-5-oxopyrrolidine-2-carboxylic acid to afford 2- (((4R,5S)-5-fluoro-3;3-dimethyl-l-((S)-5-oxopyrrolidine-2-carbonyl)piperidin-4-yl)oxy)-5-(4-((4-
(4-(oxetan-3-yl)piperazin-l-yl (phenyl )amino)-l,3;5-triazin-2-yl)benzonitrile. LCMS-ESI"1" (m/z):
[M+H]+ calcd for C35H4oFN904: 670.3.3: found:670.4
Example 445: 2-(((4S,5R)-5-fluoro-3,3-dimethyl-l-((S)-5-oxopyrrolidine-2-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000432_0002
(4S,5R)-tert-butyl 4-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l;3;5-triazin-
2-yl)phenoxy)-5-fluoro-3,3-dimethylpiperidine-l-carboxylate was subjected for Boc- deprotection followed by coupling with (S)-5-oxopyrrolidine-2-carboxylic acid to afford 2- (((4S,5R)-5-fluoro-3;3-dimethyl-l-((S)-5-oxopyrrolidine-2-carbonyl)piperidin-4-yl)oxy)-5-(4-((4-
(4-(oxetan-3-yl)piperazin-l-yl (phenyl )amino)-l,3,5-triazin-2-yl)benzonitrile. LCMS-ESI"1" (m/z):
[M+H]+ calcd for C35H4oFN904: 670.3: found:670.4 :H NMR (400 MHz, DMSO-d6) δ 10.31 - 10.07 (m, 1H), 8.75 (s, 1H), 8.56 (q, J = 12.8, 11.8 Hz, 2H), 7.74 (s, 1H), 7.69 - 7.48 (m, 3H), 7.04 (s, 2H), 5.12 (dd, J = 48.3, 14.4 Hz, 1H), 4.87 (d, J = 20.4 Hz, 1H), 4.82 - 4.69 (m, 5H), 4.63 (ddd, J = 21.0, 8.8, 4.1 Hz, 1H), 4.34 (d, J = 83.5 Hz, 2H), 4.00 - 3.34 (m, 4H), 3.15 (s, 5H), 2.34 (ddt, J = 16.1, 12.5, 6.6 Hz, 1H), 2.16 - 2.00 (m, 2H), 2.00 - 1.76 (m, 1H), 1.19 - 0.87 (m, 7H).
Example 446: 2-((5,5-difluoro-6-oxopiperidin-3-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000433_0001
The title compound was prepared by coupling 2-fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl (phenyl )amino)-l,3,5-triazin-2-yl)benzonitrile with 3,3-difluoro-5-hydroxypiperidin-2-one.
LCMS-ESI+ (m/z): [M+H]+ calcd for C28H28F2N803: 563.2: found:563.3
Example 447: 2-((5,5-difluoro-6-oxopiperidin-3-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzamide
Figure imgf000434_0001
The title compound 2-((5,5-difluoro-6-oxopiperidin-3-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin- l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzamide was isolated as byproduct from example 32. LCMS-ESI+ (m/z): [M+H]+ calcd for C28H3oF2N804: 581.2: found:581.2
Example 448: 2-(((3R,4S)-3-fluoro-l-(l-(2-hydroxyethyl)-lH-pyrazole-5-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000434_0002
The title compound was prepared by coupling 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile with l-(2- hydroxyethyl)-lH-pyrazole-5-carboxylic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C 7FN 669.3: found :669.4 Example 449: 2-(((4R,5S)-l-(2-cyanoacetyl)-5-fluoro-3,3-dimethylpiperidin-4-yl)oxy)-5-(4-((4- (4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000435_0001
(4R,5S)-tert-butyl 4-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l;3;5-triazin- 2-yl)phenoxy)-5-fluoro-3,3-dimethylpiperidine-l-carboxylate was subjected for Boc- deprotection followed by coupling with 2-cyanoacetic acid to afford the title compound after purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H36FN903: 626.3: found :626.4
Example 450: 2-(((4S,5R)-l-(2-cyanoacetyl)-5-fluoro-3,3-dimethylpiperidin-4-yl)oxy)-5-(4-((4- (4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000435_0002
(4S,5R)-tert-butyl 4-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l;3;5-triazin- 2-yl)phenoxy)-5-fluoro-3,3-dimethylpiperidine-l-carboxylate was subjected for Boc- deprotection followed by coupling with 2-cyanoacetic acid, followed by reverse phase purification gave the title compound. LCMS-ESI+ (m/z): [M+H]+ calcd for CssHseFNgOs: 626.3: found :626.4. :H NMR (400 MHz, DMSO-d6) δ 10.18 (d, J = 22.0 Hz, 1H), 8.75 (s, 1H), 8.66 - 8.43 (m, 2H), 7.73 - 7.46 (m, 3H ), 7.04 (d, J = 9.4 Hz, 2H), 5.13 (dd, J = 47.1, 18.5 Hz, 1H), 4.99 - 4.81 (m, 1H), 4.81 - 4.64 (m, 5H), 4.30 - 3.95 (m, 3H), 3.86 - 3.60 (m, 3H), 3.42 (d, J = 14.4 Hz, 2H), 3.22 - 2.88 (m, 5H), 1.15 - 0.89 (m, 6H).
Example 451: 2-(((3R,4S)-3-fluoro-l-(3-methyl-lH-l,2,4-triazole-5-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000436_0001
The title compound was prepared by coupling 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile with 3-methyl-lH- l,2,4-triazole-5-carboxylic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H34FNii03: 640.3: found :640.6 :H NMR (400 MHz, DMSO-d6) δ 10.18 (d, J = 20.6 Hz, 1H), 8.75 (s, 1H), 8.64 - 8.46 (m, 2H), 7.61 (t, J = 10.3 Hz, 4H), 7.03 (d, J = 9.5 Hz, 2H), 5.26 - 5.02 (m, 3H), 4.75 (d, J = 6.4 Hz, 5H), 4.60 - 4.20 (m, 2H), 3.79 (s, 1H), 3.61 - 3.20 (m, 3H), 3.19 - 2.86 (m, 5H), 2.36 (s, 3H), 2.13 - 1.83 (m, 2H).
Example 452: (S)-2-((3,3-difluoro-l-(3-methyl-lH-l,2,4-triazole-5-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile.
Figure imgf000437_0001
The title compound was prepared by coupling (S)-2-((3,3-difluoropiperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile with 3-methyl-lH- l,2,4-triazole-5-carboxylic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for CszHssFzN Os: 658.3: found :658.4 :H NM (400 MHz, DMSO-d6) δ 10.20 (d, J = 20.6 Hz, 1H), 8.76 (s, 1H), 8.69 - 8.45 (m, 2H), 7.64 (dd, J = 26.0, 11.8 Hz, 4H), 7.04 (s, 2H), 5.43 (d, J = 8.8 Hz, 1H), 4.85 - 4.62 (m, 4H), 4.51 - 4.18 (m, 2H), 4.13 - 3.47 (m, 7H), 3.04 (s, 5H), 2.38 (d, J = 3.7 Hz, 3H), 2.20 (s, 1H), 1.96 (d, 7 = 20.7 Hz, 1H).
Example 453: 5-(4-((l-(difluoromethyl)-lH-pyrazol-4-yl)amino)-l,3,5-triazin-2-yl)-2-(((3R,4S)- 3-fluoropiperidin-4-yl)oxy)benzonitrile
Figure imgf000437_0002
Step-1: To solution of 2,4-dichloro-l,3,5-triazine (1.46 g, 9.77 mmol ) in DMF (9 mL) at 0 C under nitrogen atmosphere were added DIPEA (2.6 mL), solution of l-(difl uoromethyl)-lH- pyrazol-4-amine (1 g, 7.5 mmol) in DMF (9 mL) at once. The reaction mixture was stirred at 0 C for lh and at room temperature for 2h. Solvent was concentrated to dryness under reduced pressure. The crude product was dissolved in 10% MeOH\DCM. The crude product was adsorbed on silica gel and solvent was concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel [Method, 10-60% B over 15 min (A = DCM, B = 20% MeOH/DCM)] to afford product 4-chloro-N-(l-(difluoromethyl)-lH- pyrazol-4-yl)-l,3,5-triazin-2-amine. LCMS-ESI+ (m/z): [M+H]+ calcd for C7H5CIF2N6: 247.0 found :347.2.
Step-2: A mixture of 4-chloro-N-(l-(difluoromethyl)-lH-pyrazol-4-yl)-l,3,5-triazin-2- amine (500 mg, 2.02 mmol), 2-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzonitrile (551 mg, 2.2 mmol) and Pd(PPh3)4 (117 mg, 0.1 mmol) was taken up in
1,2-DME (10 mL) in a 12 mL microwave vial. To this mixture was added solution of sodium carbonate (644 mg 6.08 mmol) in water (5 mL). The mixture heated at 120 °C for 30 minutes. The reaction mixture was diluted with 30% MeOH/DCM (50 mL) and filtered through short pad of silica gel and washed with 30% MeOH/DCM (20 mL x 2). The filtrate was adsorbed on silica gel and solvent was concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel to afford 5-(4-((l-(difluoromethyl)-lH-pyrazol-4-yl)amino)-l,3,5-triazin-2-yl)-2- fluorobenzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for Ci4H8F3 7: 332.1; found:332.2 Step-3: (3 ,4S)-tert-butyl 3-fluoro-4-hydroxypiperidine-l-carboxylate (450 mg, 1.36 mmol) was added Me-THF (20 mL) under argon atmosphere and cooled at 0 C. To well stirred solution was added potassium tert-butoxide (213 mg, 1.9 mmol) at one portion and stirred for 30 minutes. To well stirred solution was added 5-(4-((l-(difluoromethyl)-lH-pyrazol-4-yl)amino)-l,3,5- triazin-2-yl)-2-fluorobenzonitrile (450 mg, 1.35 mmol) and warmed to room temperature over 10 min. The reaction was heated at 80 C overnight. The reaction was quenched with minimum amount of water and diluted with 10% MeOH/DCM to make clear solution. The crude product was adsorbed on silica gel and purified by flash column chromatography on silica gel [Method, 0-50% B over 15 min (A = DCM, B = 20% MeOH/DCM)] to afford (3R,4S)-tert-butyl 4-(2-cyano-4- (4-((l-(difluoromethyl)-lH-pyrazol-4-yl)amino)-l,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-l- carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for Ο^Η^ΝίΑ: 531.2; found : 631.4
Step-4: (3R,4S)-tert-butyl 4-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)- l,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-l-carboxylate (60 mg, 0.11 mmol) was dissolved in 20% TFA/DCM (5 mL) and stirred at room temperature for lh. The solvent was concentrated under reduced pressure to afford 5-(4-((l-(difluoromethyl)-lH-pyrazol-4-yl )amino)-l,3,5-triazin- 2-yl)-2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C19H17F3N80: 431.2: found:431.3 Example 454: 5-(4-((l-(difluoromethyl)-lH-pyrazol-4-yl)amino)-l,3,5-triazin-2-yl)-2-(((3R,4S)- 3-fluoro-l-(2-hydroxyacetyl)piperidin-4-yl)oxy)benzonitrile
Figure imgf000439_0001
To solution of 5-(4-((l-(difluoromethyl)-lH-pyrazol-4-yl)amino)-l;3;5-triazin-2-yl)-2-(((3 ;4S)-3- fluoropiperidin-4-yl)oxy)benzonitrile (Example 42) (48 mg, 0.11 mmol), 2-hydroxyacetic acid ( 17 mg, 0.22 mmol), HATU (53 mg, 0.22 mmol) in DMF (4 mL) was added DIPEA (0.24 mL) in a 25 mL round bottom flask and flushed with argon gas. This reaction mixture was stirred at room temperature overnight. Solvent was concentrated and the crude product purified via prep HPLC (5-95% acetonitrile in water, 0.1% trifluoroacetic acid buffer) to isolate 5-(4-((l- (difluoromethyl)-lH-pyrazol-4-yl)amino)-l,3,5-triazin-2-yl)-2-(((3R,4S)-3-fluoro-l-(2- hydroxyacetyl)piperidin-4-yl)oxy)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for C2iH19F3N803: 489.2: found :489.3. :H NMR (400 MHz, DMSO-d6) δ 10.55 (d, J = 6.3 Hz, 1H), 8.83 (d, J = 41.4 Hz, 1H), 8.66 - 8.52 (m, 2H), 8.42 (d, J = 2.8 Hz, 1H), 8.03 - 7.76 (m, 2H), 7.63 (d, J = 9.2 Hz, 1H), 5.30 - 4.85 (m, 2H), 4.41 - 3.81 (m, 3H), 3.73 - 3.34 (m, 3H), 3.14 (t, J = 11.9 Hz, 1H), 2.07 - 1.66 (m, 2H).
Example 455: 5-(4-((l-(difluoromethyl)-lH-pyrazol-4-yl)amino)-l,3,5-triazin-2-yl)-2-(((3R,4S)- 3-fluoro-l-(3-hydroxypropanoyl)piperidin-4-yl)oxy)benzonitrile
Figure imgf000440_0001
The title compound was prepared by coupling 5-(4-((l-(difluoromethyl)-lH-pyrazol-4-yl)amino)- l,3,5-triazin-2-yl)-2-(((3 ,4S)-3-fluoropiperidin-4-yl)oxy)benzonitrile with 3-hydroxypropanoic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C22H21F3N803: 503.2: found:503.3. :H NMR (400 MHz, DMSO-d6) δ 10.55 (d, J = 6.8 Hz, 1H), 8.83 (d, J = 41.4 Hz, 1H), 8.66 - 8.51 (m, 2H), 8.42 (d, J = 3.3 Hz, 1H), 8.05 - 7.56 (m, 3H), 5.26 - 4.84 (m, 2H), 4.40 - 3.74 (m, 2H), 3.62 (q, J = 9.0, 7.8 Hz, 4H), 3.08 (t, J = 11.6 Hz, 1H), 2.56 (dt, J = 16.8, 7.4 Hz,2H), 2.08 - 1.67 (m, 2H).
Example 456: 5-(4-((l-(difluoromethyl)-lH-pyrazol-4-yl)amino)-l,3,5-triazin-2-yl)-2-(((3R,4S)- l-((S)-2,3-dihydroxypropanoyl)-3-fluoropiperidin-4-yl)oxy)benzonitrile
Figure imgf000440_0002
The title compound was prepared by coupling 5-(4-((l-(difluoromethyl)-lH-pyrazol-4-yl)amino)- l,3,5-triazin-2-yl)-2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)benzonitrile with (S)-2,3- dihydroxypropanoic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C22H21F3N804: 519.2: found :519.3 :H NMR (400 MHz, DMSO-d6) δ 10.55 (d, J = 7.2 Hz, 1H), 8.84 (d, J = 41.5 Hz, 1H), 8.67 - 8.50 (m, 2H), 8.42 (d, J = 3.7 Hz, 1H), 8.07 - 7.76 (m,lH), 7.73 - 7.49 (m, 1H), 7.36 - 7.03 (m, 1H), 5.27 - 4.89 (m, 4H), 4.65 (d, J = 40.8 Hz, 1H), 4.35 (d, J = 34.0 Hz, 2H), 3.93 (s, 1H), 3.82 - 3.31 (m, 3H), 1.98 (s, 2H). Example 457: 5-(4-((l-(difluoromethyl)-lH-pyrazol-4-yl)amino)-l,3,5-triazin-2-yl)-2-(((3R,4S)- 3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)benzonitrile
Figure imgf000441_0001
The title compound was prepared by coupling 5-(4-((l-(difluoromethyl)-lH-pyrazol-4-yl)amino)- l,3,5-triazin-2-yl)-2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)benzonitrile with (S)-2- hydroxypropanoic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C22H21F3N803: 503.2: found:503.3 :H NMR (400 MHz, DMSO-d6) δ 10.55 (d, J = 6.5 Hz, 1H), 8.83 (d, J = 41.4 Hz, 1H), 8.64 - 8.50 (m, 2H), 8.42 (d, J = 3.4 Hz, 1H), 8.07 - 7.75 (m, 2H), 7.72 - 7.56 (m, 1H), 5.24 - 4.90 (m, 2H), 4.68 - 3.82 (m, 4H), 3.77 - 3.07 (m, 2H), 1.91 (d, J = 55.7 Hz, 2H), 1.19 (dd, J = 6.5, 4.0 Hz, 3H).
Example 458: 5-(4-((l-(tert-butyl)-lH-pyrazol-4-yl)amino)-l,3,5-triazin-2-yl)-2-(((3R,4S)-3- fluoro-l-(3-hydroxypropanoyl)piperidin-4-yl)oxy)benzonitrile
Figure imgf000441_0002
The title compound was prepared by coupling 5-(4-((l-(tert-butyl)-lH-pyrazol-4-yl)amino)-l,3,5- triazin-2-yl)-2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)benzonitrile with 3-hydroxypropanoic acid.
LCMS-ESI+ (m/z): [M+H]+ calcd for C25H29FN803: 509.2: found :509.3 :H NMR (400 MHz, DMSO- d6) δ 10.35 - 9.98 (m, 1H), 8.75 (d, J = 40.3 Hz, 1H), 8.64 - 8.48 (m, 2H), 8.04 (d, J = 39.8 Hz, 1H), 7.74 - 7.52 (m,lH ), 7.38 - 7.01 (m, 1H ), 5.30 - 4.86 (m, 2H), 4.40 - 3.73 (m, 4H), 3.63 (t, J = 6.6 Hz, 2H), 3.47 - 2.94 (m, 1H), 2.77 - 2.50 (m, 2H), 2.11 - 1.73 (m, 2H), 1.53 (d, J = 18.3 Hz, 9H).
Example 459: 5-(4-((l-(tert-butyl)-lH-pyrazol-4-yl)amino)-l,3,5-triazin-2-yl)-2-(((3R,4S)-l-(2- cyanoacetyl)-3-fluoropiperidin-4-yl)oxy)benzonitrile
Figure imgf000442_0001
The title compound was prepared by coupling 5-(4-((l-(tert-butyl)-lH-pyrazol-4-yl)amino)-l,3,5- triazin-2-yl)-2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)benzonitrile with 2-cyanoacetic acid. LCMS- ESI+ (m/z): [M+H]+ calcd for C25H26FN902: 504.2: found :504.3 :H NMR (400 MHz, DMSO-d6) δ 10.27 (d, J = 22.4 Hz, 1H), 8.75 (d, J = 40.3 Hz, 1H), 8.62 - 8.51 (m, 2H), 8.04 (d, J = 38.6 Hz, 1H), 7.72 - 7.55 (m, 2H), 5.26 - 4.91 (m, 2H), 4.44 - 3.79 (m, 3H), 3.74 - 3.14 (m, 3H), 2.09 - 1.77 (m, 2H), 1.53 (d, J = 18.1 Hz, 9H).
Example 460: 2-(((S)-3,3-difluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4-((R)- 2-(hydroxymethyl)morpholino)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000442_0002
The title compound was prepared following a similar procedure reported in Example 218 using ( )-(4-(4-aminophenyl)morpholin-2-yl)methanol, (S)-tert-butyl 3,3-difluoro-4- hydroxypiperidine-l-carboxylate and (S)-2-hydroxypropanoic acid. :H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.75 (s, 1H), 8.60 (m, 2H), 7.69-7.59 (m, 3H), 6.99-6.91 (m, 2H), 5.37 (s, 1H), 5.22 (d, J = 6.9 Hz, 1H), 4.76 (t, J = 5.7 Hz, 1H), 4.57 - 4.39 (m, 1H), 4.17 (s, 1H), 4.08 - 3.70 (m, 3H), 3.69 - 3.36 (m, 4H), 3.04 - 2.87 (m, 1H), 2.64 (s, 1H), 2.44-2.35 (m, 2H), 2.23 - 1.68 (m, 3H), 1.20
(d, J = 6.3 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd. for C29H31F2N705: 596.2; found:596.2.
Example 461: 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxy-3-methylbutanoyl)piperidin-4-yl)oxy)-5-(4- ((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000443_0001
To a solution of 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (50 mg, 0.09 mmol), (S)-2-hydroxy-3- methylbutanoic acid (14 mg, 0.11 mmol), HATU (72 mg, 0.18 mmol) in 6 ml of DMF, TEA (38 mg, 0.38 mmol) was added. This reaction mixture was stirred at room temperature for 2 hrs. DCM and water were added and organic layer was extracted and evaporated to dryness. Solids were re-dissolved in acetonitrile and then purified via preparative HPLC (5-65% acetonitrile in water, 0.1% trifluoroacteic acid buffer). Fractions containing desired product were collected and DCM and a saturated aqueous solution of NaHC03 were added. Organics were collected dried over magnesium sulfate and evaporated under reduced pressure to yield 2-(((3R,4S)-3-fluoro-l-((S)- 2-hydroxy-3-methylbutanoyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile. :H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.73 (s, 1H), 8.67 - 8.39 (m, 2H), 7.58 (dd, J = 26.8, 11.7 Hz, 3H), 6.99-6.88 (m, 2H), 5.23 - 5.01 (m, 2H ), 4.86 (s, 1H), 4.55 (t, J = 6.5 Hz, 2H), 4.46 (t, J = 6.0 Hz, 3H), 4.06 (dd, J = 13.2, 6.0 Hz, 3H), 3.43 (p, J = 6.3 Hz, 2H), 3.18-3.09 (m, 4H), 2.40 (t, J = 4.9 Hz, 4H), 2.07 - 1.72 (m, 3H ), 0.93 - 0.78 (m, 6H). LCMS-ESI+ (m/z): [M+H]+ calcd for C33H39FN804 Exact Mass: 631.3 found :631.2.
Example 462 : 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4
5-(4-((4-(4-(oxetan-3-yl)-2-oxopiperazin-l-yl)phenyl)amino)-l,3,5-triazin-2- yl)benzonitrile.
Figure imgf000444_0001
To a mixture of tert-butyl 3-oxopiperazine-l-carboxylate (2.0 gr, 9.9 mmol), l-iodo-4- nitrobenzene (2.2 gr, 8.9 mmol), Cs2C03 (2.0 gr, 14.9 mmol), 4,5-Bis(diphenylphosphino)-9,9- dimethylxanthene (346 mg, 0.59 mmol) and Pd(OAc)2 (89 mg, 0.4 mmol) in argon atmosphere was added 15 ml of de-gassed 1,4-dioxane. The mixture was stirred in a heating block under argon atmosphere for 2 h at 104 °C. Water was added and it was extracted with DCM. Organic layer was dried over Mg2S04 and evaporated under reduced pressure to dryness to yield tert- butyl 4-(4-nitrophenyl)-3-oxopiperazine-l-carboxylate.
The following steps for the synthesis of the title compound was taken from the procedure reported in Example 241 using the compound tert-butyl 4-(4-nitrophenyl)-3-oxopiperazine-l- carboxylate, shown above, and (S)-2-hydroxypropanoic acid. :H NM (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.80 (s, 1H), 8.68 - 8.48 (m, 2H), 7.74 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 9.5 Hz, 1H), 7.32 (d, J = 8.2 Hz, 2H), 5.24 - 4.86 (m, 3H), 4.58 (t, J = 6.6 Hz, 2H), 4.53 - 4.29 (m, 3H), 4.11 (dd, 7 = 35.8, 10.0 Hz, 2H), 3.62 (dt, = 30.6, 5.8 Hz, 3H ), 3.13 (d, J = 16.7 Hz, 4H), 2.71 (dd, J = 6.1, 4.7
Hz, 2H), 2.03-1.92 (m, 2H), 1.19 (dd, J = 6.5, 4.3 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C31H33FN8O5 Exact Mass: 617.3 found :617.2 Example 463: 2-(((3R,4S)-3-fluoro-l-(2-hydroxy-2-(l-methyl-lH-pyrazol-4-yl)acetyl)piperidin- 4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000445_0001
The title compound was prepared following a similar procedure reported in Example 461 using a racemic mixture of 2-hydroxy-2-(l-methyl-lH-pyrazol-4-yl)acetic acid. LCMS-ESI"1" (m/z): [M+H]+ calcd for C34H37FN10O4 Exact Mass: 669.3 found :669.2.
Example 464: 2-(((3R,4S)-3-fluoro-l-((R)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000445_0002
The title compound was prepared following a similar procedure reported in Example 461 using ( )-2-hydroxypropanoic acid. :H NMR (400 MHz, DMSO-d6) δ 10.12 (d, J = 24.7 Hz, 1H), 8.73 (s, 1H), 8.65 - 8.47 (m, 2H), 7.59 (dd, J = 27.5, 11.0 Hz, 3H), 6.99-6.91 (m, 2H), 5.22 - 4.86 (m, 3H), 4.55 (t, J = 6.5 Hz, 2H), 4.47 (q, J = 6.7, 6.1 Hz, 3H), 3.92 (d, J = 14.0 Hz, 2H), 3.43 (q, 7 = 6.3 Hz, 2H), 3.20-3.11 (m, 5H), 2.40 (t, J = 5.1 Hz, 4H), 1.91 (d, J = 59.0 Hz, 2H), 1.27 - 1.10 (m,
3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C31H35FN804 Exact Mass: 603.3 found:603.2 Example 465: 2-(((3R,4S)-3-fluoro-l-((R)-2-hydroxy-3-methylbutanoyl)piperidin-4-yl)oxy)-5-(4- ((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000446_0001
The title compound was prepared following a similar procedure reported in Example 461 using
( )-2-hydroxy-3-methylbutanoic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H39FN804 Exact Mass: 631.3 found:631.2
Example 466: 2-(((3R,4S)-3-fluoro-l-((S)-5-oxopyrrolidine-2-carbonyl)piperidin- yl)oxy)-5-(4-((4-((R)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)phenyl)amino) l,3,5-triazin-2-yl)benzonitrile
Figure imgf000446_0002
To a stirred solution of l-fiuoro-4-nitrobenzene (1.1 g, 8.0 mmol) in D SO under a nitrogen atmosphere was added {R)-ortahydropyrazlno[2,l-c][l,.4]oxazlrie (1.2 g, 9 rrsmoi) followed by TEA (3ml, 23 mmol). The mixture was stirred at 140 C for 48 h, and then cooled to room temperature. The mixture was then poured into water and extracted with DC . The combined organic layers were washed with brine, dried over magnesium sulfate, concentrated in vacuo to obtain {R)-8-(4-nltrophenyi)oci3hydropyrazino[2.,l [.l,4]oxazine. The following steps for the synthesis of the title compound was taken from the procedure reported in Example 241 using the compound (R)-8-(4-nitrophenyl)octahydropyrazino[2,l- c] [l,4]oxazine, shown above, and (S)-5-oxopyrrolidine-2-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.74 (s, 1H), 8.65 - 8.49 (m, 2H), 7.85 - 7.44 (m, 4H), 6.95 (s, 2H), 5.11 (d, J = 23.0 Hz, 2H), 4.61 (ddd, J = 15.8, 8.9, 3.8 Hz, 1H), 4.47 - 4.05 (m, 2H), 3.95 - 3.67 (m, 3H), 3.67 - 3.41 (m, 4H), 3.20 - 2.99 (m, 2H), 2.96 - 2.60 (m, 4H), 2.41 - 1.70 (m, 8H). LCMS-ESI+
(m/z): [M+H]+ calcd. for C33H36FN904 Exact Mass: 642.3 found :642.3
Example 467: 2-(((3R,4S)-l-(2-cyanoacetyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-((R)-2- (hydroxymethyl)morpholino)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000447_0001
The title compound was prepared following a similar procedure reported in Example 218 using (R)-(4-(4-aminophenyl)morpholin-2-yl (methanol, (3R,4S)-tert-butyl 3-fluoro-4- hydroxypiperidine-l-carboxylate and 2-cyanoacetic acid. :H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.74 (s, 1H), 8.57 (d, J = 12.2 Hz, 2H), 7.69 - 7.49 (m, 3H), 6.99-6.82 (m, 2H), 5.24 - 4.67 (m, 3H), 4.46 - 3.81 (m, 5H), 3.72 - 3.36 (m, 8H), 2.41 (d, J = 11.9 Hz, 2H), 1.94 (d, J = 56.9 Hz,
2H). LCMS-ESI+ (m/z): [M+H]+ calcd for C29H29FN804: 573.2; found :573.2 Example 468: 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-
5-(4-((4-((R)-3-(hydroxymethyl)-4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5- triazin-2- l nz nitril
Figure imgf000448_0001
To a stirred solution of l-fluoro-4-nitrobenzene (1.1 g.8.0 mmo! in DM50 under a nitrogen atmosphere was added (Ri-tert-butyl 2-(hydroxymethyi)piperazine-l-carboxyiate (1.2 g. 9 mmol) followed by DiPEA (3 ml, 23 rnoi . The mixture was stirred at 140 °C for 24 h, and then cooled to room temperature. The mixture was then poured into water and extracted with DC . The combined organic layers were washed with brine, dried over magnesium sulfate, concentrated in vacuo to obtain R)-tert-butyi 2-{hydroxymethyl)-4-{4-nltrophenyi)plperazine-l- carboxylate,
The following steps for the synthesis of the title compound was taken from the procedure reported in Example 241 using the compound (R)-tert-butyl 2-(hydroxymethyl)-4-(4- nitrophenyl)piperazine-l-carboxylate, shown above, and (S)-2-hydroxypropanoic acid. 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.74 (s, 1H), 8.56 (d, J = 17.2 Hz, 2H), 7.59 (dd, J = 28.7, 13.7 Hz, 3H), 6.95 (s, 2H), 5.23 - 4.87 (m, 3H), 4.63 - 4.27 (m, 3H), 4.24 - 3.81 (m, 2H), 3.76 - 3.39 (m, 4H), 3.18 (dd, J = 21.6, 11.1 Hz, 4H), 2.74 - 2.55 (m, 2H ), 2.36 - 1.72 (m, 7H), 1.23 (s,
3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H37FN805 Exact Mass: 633.3 found :633.3
Example 469: 2-(((S)-3,3-difluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4-((R)-3- (hydroxymethyl)-4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000449_0001
The title compound was prepared following a similar procedure reported in Example 468 using (S)-tert-butyl 3,3-difluoro-4-hydroxypiperidine-l-carboxylate. :H NM (400 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.74 (s, 1H), 8.57 (d, J = 20.0 Hz, 2H), 7.61 (dd, J = AAA, 14.6 Hz, 3H), 6.99-6.88 (m, 2H), 5.30 (d, J = 55.9 Hz, 2H), 4.70 - 4.38 (m, 2H), 4.17 (s, 1H), 3.89 - 3.40 (m, 7H), 3.22 - 3.04 (m, 3H), 2.68 (d, J = 13.4 Hz, 2H), 2.42 - 1.75 (m, 7H), 1.21 (d, J = 6.4 Hz, 3H). LCMS-
ESI+ (m/z): [M+H]+ calcd for C32H36F2N805 Exact Mass: 651.3 found :651.3
Example 470: 2-(((3R,4S)-3-fluoro-l-((S)-3-hydroxybutanoyl)piperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000449_0002
The title compound was prepared following a similar procedure reported in Example 461 using (S)-3-hydroxybutanoic acid. :H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.70 (s, 1H), 8.63 - 8.40 (m, 2H), 7.57 (d, J = 9.2 Hz, 3H), 7.00 (s, 2H), 5.16 - 4.82 (m, 3H), 4.71 (d, J = 6.3 Hz, 4H), 4.49 - 4.18 (m, 2H), 3.95 (h, J = 6.2 Hz, 3H), 3.1-2.85 (m, 5H), 2.41 - 2.22 (m, 4H), 2.00 -
1.62 (m, 4H), 1.04 (t, J = 6.3 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H37FN804 Exact Mass: 617.3 found :617.3 Example 471: 2-(((3R,4S)-3-fluoro-l-((R)-3-hydroxybutanoyl)piperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000450_0001
The title compound was prepared following a similar procedure reported in Example 461 using ( )-3-hydroxybutanoic acid. :H NMR (400 MHz, DMSO-d6) δ 10.14 (d, J = 23.4 Hz, 1H), 8.70 (s, 1H), 8.63 - 8.41 (m, 2H), 7.57 (d, J = 9.1 Hz, 3H), 7.00 (s, 2H), 5.16 - 4.87 (m, 3H), 4.71 (d, J = 6.2 Hz, 4H), 4.34 (d, J = 44.5 Hz, 2H), 4.13 - 3.90 (m, 4H), 3.36 - 2.78 (m, 7H), 2.67 - 2.47 (m, 2H),
2.37 - 2.15 (m, 1H), 2.05 - 1.59 (m, 2H), 1.08 (dd, J = 30.6, 6.2 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H37FN804 Exact Mass: 617.3 found :617.3
Example 472: 2-(((3R,4S)-3-fluoro-l-(3-hydroxyoxetane-3-carbonyl)piperidin-4-yl)oxy)-5-(4- ((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2- yl)benzonitrile
Figure imgf000450_0002
The title compound was prepared following a similar procedure reported in Example 461 using 3-hydroxyoxetane-3-carboxylic acid. :H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.74 (s, 1H), 8.65 - 8.45 (m, 2H), 7.61 (d, J = 9.3 Hz, 3H), 7.11-6.95 (m, 2H), 5.24 - 4.66 (m, 8H), 4.57 - 4.24 (m, 4H), 3.88-3.5 (m, 3H), 3.59-2.9 (m, 4H), 3.28-2.92 (s, 5H), 1.96 (d, J = 4.7 Hz, 2H).LCMS-ESI+ (m/z): [M+H]+ calcd for C32H35FN805 Exact Mass: 631.3 found :631.3
Example 473: 2-(((3R,4S)-3-fluoro-l-(oxazole-5-carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000451_0001
The title compound was prepared following a similar procedure reported in Example 461 using and oxazole-5-carboxylic acid. :H NM (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.75 (s, 1H), 8.58 (d, J = 9.7 Hz, 3H), 7.83 - 7.51 (m, 4H), 7.11-7.00 (m, 2H), 5.51-5.01 (m, 2H), 4.71-4.32 (m, 7H),
3.92-3.62 (m, 5H), 3.31-2.88 (m, 6H), 2.16 - 1.79 (m, 1H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H32FN904 Exact Mass: 626.3 found :626.3
Example 474: 2-(3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((2- methoxypyridin-4-yl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000451_0002
The title compound was prepared following a similar procedure reported in Example
218 using 2-methoxypyridin-4-amine, (3R,4S)-tert-butyl 3-fluoro-4-hydroxypiperidine-l- carboxylate and (S)-2-hydroxypropanoic acid. :H NM (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.58 (d, J = 9.4 Hz, 3H), 8.03 (s, 1H), 7.66 (d, J = 9.0 Hz, 1H), 7.45-7.29 (m, 2H), 5.34 - 4.80 (m, 3H), 4.52-4.40 (m, 1H), 4.20-4.10 (m, 2H), 3.83 (s, 3H), 3.62 (dd, J = 29.4, 14.6 Hz, 1H), 2.12-1.85 (m,
3H), 1.29 - 1.12 (m, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for
Figure imgf000452_0001
Exact Mass: 494.3 found : 494.2
Example 475: 2-(((3R,4S)-3-fluoro-l-((S)-morpholine-3-carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000452_0002
The title compound was prepared following a similar procedure reported in Example 461 using
(S)-morpholine-3-carboxylic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for
Figure imgf000452_0003
Exact Mass: 644.3 found :644.3.
Example 476: 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4-(l- methyl-2-oxo-l,2-dihydropyridin-4-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000452_0004
To a mixture of l-methyl-4-{4,.4,5i5-tetrarnethyi-l,3/2-dioxaborolan-2-yl)pyridln-2{lH)-one (204 mg,. 0.87 mmol), potassium carbonate (241 mg, 1.7 mmol), 4,5- Pd(tippf)CLCH2C!2 (80 mg, 0.01 mmo!) and 4-bromoaniline (150 mg, 0.87 mmol) in argon atmosphere was added 6 ml of degassed mixture of solvents (1,4-dioxane and water 2:1). The mixture was stirred in a heating block under argon atmosphere for 1 h at 104 °C. Water was added and it was extracted with DCM. Organic layer was dried over Mg2S04 and evaporated under reduced pressure to dryness to yield 4-(4-aminophenyl)-l-methylpyridin-2(lH)-one.
The following steps for the synthesis of the title compound was taken from the procedure reported in Example 218 using the compound 4-(4-aminophenyl)-l-methylpyridin- 2(lH)-one, shown above, (3R,4S)-tert-butyl 3-fluoro-4-hydroxypiperidine-l-carboxylate and (S)- 2-hydroxypropanoic acid. :H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.87 (s, 1H), 8.61 (d, J = 7.3 Hz, 2H), 7.90 (d, J = 8.7 Hz, 2H), 7.75 (t, J = 7.6 Hz, 3H), 7.64 (d, J = 9.5 Hz, 1H), 6.68 (d, J = 2.1 Hz, 1H), 6.59 (dd, J = 7.1, 2.1 Hz, 1H), 5.27 - 4.89 (m, 3H), 4.56 - 4.23 (m, 1H), 4.21 - 3.62 (m,
2H), 3.43 (s, 3H ), 3.40 - 3.09 (m, 1H), 2.09 - 1.63 (m, 3H), 1.30 - 1.11 (m, 3H). LCMS-ESI+ (m/z):
[M+H]+ calcd for C3oH28FN704 Exact Mass: 570.2 found :570.3
Example 477: 2-(((3R,4S)-3-fluoro-l-(oxazole-4-carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000453_0001
The title compound was prepared following a similar procedure reported in Example 461 using oxazole-4-carboxylic acid. :H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.76 (s, 1H), 8.68 - 8.49 (m, 4H), 7.62 (dd, J = 34.1, 11.9 Hz, 3H), 7.05-6.82 (m, 2H), 5.33 - 4.79 (m, 3H), 4.58 (t, J = 6.5 Hz, 2H), 4.49 (t, J = 6.0 Hz, 3H), 3.57 (s, 1H), 3.46 (p, J = 6.2 Hz, 1H), 3.16 (d, J = 5.4 Hz, 5H), 2.43
(t, J = 4.9 Hz, 4H), 2.17 - 1.78 (m, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H32FN904 Exact Mass: 626.3 found :626.3. Example 478: (3R,4S)-4-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5- triazin-2-yl)phenoxy)-3-fluoro-N-hydroxypiperidine-l-carboxamide
Figure imgf000454_0001
To a stirred soiution of 2-({{3R.4S5-3-fluo!Opiperidin-4-yl oxy)-5-{4-((4-(4-(oxet3n-3-yl piperazin- l-y!)phenyi}am!no!-l,3,5-triazin-2-yi !benion!tri!e [96 mg, 0,18 mmo!) in THF was added TEA (0.25 ml, 2.0 rnmcti), O-f tert-bLityldimethylsily!Jhydroxyiarnine (29 mg, 0,19 mrno! followed by triphosgene (48 mg, 0.16 mmol). The mixture was heated at 60 °C for 1 hr. and then cooled to room temperature. The mixture was then poured into water, DCM and a saturated aqueous soiution of NaHC03 and extracted. The combined organic layers were concentrated in vacuo to obtain (3R,4S)-N-({tert-butyidimethyls!lyl)oxy)-4-(2-cyano-4-(4-((4-(4-(oxetari-3-yl)pipera2!n-l- yi)phenyi)amino)-l,3,5-triazin-2-yi)phenoxy)-3-fl uoropiperidine-l-carboxamide.
{3R,4S)-N-{{tert-buty!dlmethylsily15oxy)-4-(2-cy^
yiJphenylJarninoJ- l^/S-triazin^-y!jphenoxyJ-S-f!uorop!peridine-l-carboxamide was dissolved with a mixture of DCM and TFA and stirred at room temperature for lhr. Reaction mixture was evaporated under reduced pressure and solids were purified via preparative HPLC (5-65% acetonitrile in water, 0.1% trifluoroacteic acid buffer). Fractions containing desired product were collected and DCM and a saturated aqueous solution of NaHC03 were added. Organics were collected dried over magnesium sulfate and evaporated under reduced pressure to yield (3R,4S)-4-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2- yl)phenoxy)-3-fluoro-N-hydroxypiperidine-l-carboxamide. :H NMR (400 MHz, DMSO-d6) δ 10.3- 10.2 (m, 1H), 9.18 (s, 1H), 8.75 (s, 1H), 8.57 (d, J = 9.4 Hz, 2H), 8.11 (s, 1H), 7.60 (t, J = 12.3 Hz, 2H), 6.97 (s, 2H), 5.07 (d, J = 22.2 Hz, 3H), 4.58 (t, J = 6.5 Hz, 2H ), 4.48 (t, J = 6.0 Hz, 2H), 4.01 (dt, J = 14.1, 7.2 Hz, 1H), 3.72-3.38 (m, 2H), 3.32-3.25 (m, 4H), 2.47 - 2.36 (m, 5H), 1.91 (d, J = 5.8 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C29H32FN904 Exact Mass: 590.3 found :590.2. Example 479: 2-(((S)-l-((S)-2,3-dihydroxypropanoyl)-3,3-difluoropiperidin-4-yl)oxy)-5-(4-((2- methoxypyridin-4-yl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000455_0001
The title compound was prepared following a similar procedure reported in Example
218 using 2-methoxypyridin-4-amine, (S)-tert-butyl 3,3-difluoro-4-hydroxypiperidine-l- carboxylate and (S)-2,3-dihydroxypropanoic acid. :H NM (400 MHz, DMSO-d6) δ 10.7 (s, 1H), 8.96 (s, 1H), 8.68 - 8.55 (m, 2H), 8.07 (d, J = 5.7 Hz, 1H ), 7.78 - 7.67 (m, 1H), 7.43 - 7.30 (m, 2H), 5.32 (d, J = 68.1 Hz, 2H), 4.75 (s, 1H), 4.29 (d, J = 81.4 Hz, 2H), 3.92-3.79 (m, 4H), 3.70 - 3.41 (m, 3H), 2.08 (d, J = 72.2 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C24H23F2N705 Exact Mass: 528.2 found : 528.1
Example 480: 2-(((3R,4S)-3-fluoro-l-(pyridin-2-yl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile.
Figure imgf000455_0002
To a solution of 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (50 mg, 0.094 mmol) in 4ml of DMSO, was added 2-bromopyridine (15 mg, 0.094 mmol), Cul (2 mg, 0.009 mmol), 2- isobutyrylcyclohexanone (16mg, 0.094mmol) and K2C03 (26mgs, 0.188mmol). reaction mixture was heated at 60 C in a heating block for 2hr. Reaction mixture loaded into a preparative HPLC system (5-65% acetonitrile in water, 0.1% trifluoroacteic acid buffer). Fractions containing desired product were collected and DCM and a saturated aqueous solution of NaHC03 were added. Organics were collected dried over magnesium sulfate and evaporated under reduced pressure to yield 2-(((3R,4S)-3-fluoro-l-(pyridin-2-yl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd. for C33H34FN9O2 Exact Mass: 608.3 found :608.3.
Example 481: 2-(((S)-l-acetyl-3,3-difluoropiperidin-4-yl)oxy)-5-(4-((4-(S- methylsulfonimidoyl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000456_0001
Step 1: Preparation of 4-(/V-(tert-butoxycarbonyl)-S-methylsulfonimidoyl)nitrobenzene: A solution of (fi,S)-S-(4-nitrophenyl)-S-methylsulfoximide (Enamine, 0.50 g, 2.5 mmol) in tert- butanol (18 mL) was treated with di-ieri-butyl dicarbonate (1.1 g, 5.0 mmol) followed by potassium tert-butoxide (0.56 g, 5.0 mmol). The resulting mixture was heated for 2 days in a sealed vessel on 98 °C heating block. After being allowed to cool to room temperature, the mixture was partitioned between ethyl acetate and water. The pH was adjusted to 3 by the addition of 10 % aqueous citric acid solution. The aqueous phase was extracted three times with ethyl acetate. The combined organics were washed once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to provide the desired material. LCMS-ESI+ (m/z): [M+H]+ calcd for C12H17N205S 301.1; found: 300.6
Step 2: Preparation of 4-(7V-(tert-butoxycarbonyl)-S-methylsulfonimidoyl)aniline:
A suspension of 4-(N-(tert-butoxycarbonyl)-5'-methylsulfonimidoyl)nitrobenzene (0.75 g, 2.5 mmol) in methanol was added to a stirred suspension of 20 % palladium hydroxide on carbon in methanol (15 mL). Ammonium formate (0.78 g, 12 mmol) was added in a single portion. The mixture was heated at 80 °C for 3 hours. After cooling to room temperature, an additional portion of ammonium formate (1 g) was added. The mixture was heated overnight at 90 °C. After cooling to room temperature, the mixture was filtered through a pad of Celite diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide the desired material. LCMS-ESI+ (m/z): [M+H]+ calcd for C12H19 2O3S 271.1 ; found:
270.8
Step 3: Preparation of 4-chloro-iV-(4-(S-methyWV-(tert- butoxycarbonyl)sulfonimidoyl)phenyl)-l,3,5-triazin-2-amine
To a solution of 2,4-dichloro-l,3,5-triazine (0.38 g, 2.6 mmol) in N,N- dimethylformamide (DMF, 5 mL) at 0 °C were added N,N-diisopropylethylamine (DIEA, 0.46 mL, 2.7 mmol), followed by a solution of 4-(N-(tert-butoxycarbonyl)-5'- methylsulfonimidoyl)aniline (0.60 g, 2.2 mmol) in DMF (6 mL). The mixture was stirred at 0 °C for 5 minutes and then allowed to warm to room temperature. The mixture was partitioned between ethyl acetate and half-saturated aqueous sodium hydrogen carbonate solution. The layers were separated and aqueous phase was extracted twice with ethyl acetate. The combined extracts were washed once each with water and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to provide 4-chloro-N-(4-(5'-methyl-N- (tert-butoxycarbonyl)sulfonimidoyl)phenyl)-l,3,5-triazin-2-amine. LCMS-ESI"1" (m/z): [M+H]+ calcd for Ci5H19Cl 503S 384.1; found: 383.7
Step 4: Preparation of 2-(((S)-l-acetyl-3,3-difluoropiperidin-4-yl)oxy)-5-(4-((4-(7V- (l-tert-butoxylcarbonyl)-S-methylsulfonimidoyl)phenyl)amino)-l,3,5-triazin-2- yl)benzonitrile : A mixture of crude (5)-2-((l-acetyl-3,3-difluoropiperidin-4-yl)oxy)-5- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile (preparation described in Example 301, 0.84 mmol) was taken up in 1,2-dimethoxy ethane (4 mL) and was added to a microwave vial containing 4-chloro-N-(4-(5-methyl-N-(tert- butoxycarbonyl)sulfonimidoyl)phenyl)-l,3,5-triazin-2-amine (0.27 g, 0.71 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.06 g, 7.5 mol%). 2 M aqueous sodium carbonate solution (1.6 mL) was added. The mixture was irradiated in a microwave for 75 minutes at 130 °C. The mixture was diluted with ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The combined extracts were concentrated, and the residue was purified by flash chromatography (silica gel) to provide the desired product. LCMS-ESI"1" (m/z): [M-C02-isobutylene+H]+ calcd for C24H24F2 7O3S 528.2; found: 528.3
Step 5: Preparation of 2-(((S)-l-acetyl-3,3-difluoropiperidin-4-yl)oxy)-5-(4-((4-(S- methylsulfonimidoyl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile: A solution of 2- (((5)-l-acetyl-3,3-difluoropiperidin-4-yl)oxy)-5-(4-((4-(N-(l-tert-butoxylcarbonyl)-5'- methylsulfonimidoyl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (85 mg, 0.14 mmol) in dichloromethane (2 mL) was treated with trifluoroacetic acid (0.52 mL, 7 mmol). After standing overnight at room temperature, the mixture was concentrated to dryness under pressure. The residue was purified by preparative HPLC (5 - 50 % acetonitrile in water, 0.1% trifluoroacetic acid buffer) to furnish 2-(((5)-l-acetyl-3,3-difluoropiperidin- 4-yl)oxy)-5-(4-((4-(5,-methylsulfonimidoyl)phenyl)amino)-l,3,5-triazin-2- yl)benzonitrile.
LCMS-ESI"1" (m/z): [M+H]+ calcd for C24H24F2 7O3S 528.2; found: 528.3 ¾ NMR
(400 MHz, DMSO-i/6) δ 1 1.04 (s, 1H), 9.04 (s, 1H), 8.76 - 8.68 (m, 2H), 8.21 (m, 2H), 8.13 (m, 2H), 7.75 (dd, J = 9.4, 3.8 Hz, 1H), 5.44 (m, 1H), 4.13 (m, 1H), 4.03 - 3.75 (m, 2H), 3.73 (s, 3H), 3.57 (m, 1H), 2.29 - 2.09 (m, 1H), 2.15 (s, 1.5H), 2.12 (s, 1.5H), 2.09 - 1.82 (m, 1H). Example 482 : 2-(((S)-3,3-difluoro-l-formylpiperidin-4-yl)oxy)-5-(4-((4-(S- amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000459_0001
Step 1: Preparation of 2-(((S)-3,3-difluoro-l-formylpiperidin-4-yl)oxy)-5-(4-((4-(iV- (l-tert-butoxylcarbonyl)-S-methylsulfonimidoyl)phenyl)amino)-l,3,5-triazin-2- yl)benzonitrile: A mixture of (5,)-2-((3,3-difluoro-l-formylpiperidin-4-yl)oxy)-5- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile (preparation described in Example 303, 0.56 mmol) was taken up in 1 ,2-dimethoxyethane (3 mL) and was added to a microwave vial containing 4-chloro-N-(4-(5'-methyl-N-(tert- butoxycarbonyl)sulfonimidoyl)phenyl)-l,3,5-triazin-2-amine (0.26 g, 0.68 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.05 g, 7.5 mol%). 2 M aqueous sodium carbonate solution (0.8 mL) was added. The mixture was irradiated in a microwave for 75 minutes at 130 °C. The mixture was diluted with ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The combined extracts were concentrated, and the residue was purified by flash chromatography (silica gel) to provide the desired product. LCMS-ESI+ (m/z): [M-C02-isobutylene+H]+ calcd for C23H22F2 7O3S 514.1; found: 514.3
Step 2: Preparation of 2-(((S)-3,3-difluoro-l-formylpiperidin-4-yl)oxy)-5-(4-((4-(S- methylsulfonimidoyl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile: A solution of 2-
(((5)-3,3-difluoro-l-formylpiperidin-4-yl)oxy)-5-(4-((4-(N-(l-tert-butoxylcarbonyl)-5'- methylsulfonimidoyl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (195 mg, 0.32 mmol) in dichloromethane (4 mL) was treated with trifluoroacetic acid (2.1 mL, 27 mmol).
After standing for three hours at room temperature, the mixture was concentrated to dryness under pressure. The residue was purified by preparative HPLC (5 - 50 % acetonitrile in water, 0.1% trifluoroacetic acid buffer) to furnish 2-(((5)-3,3-difluoro-l- formylpiperidin-4-yl)oxy)-5-(4-((4-(S-m
2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C23H22F2 7O3S 514.1; found: 514.3 ¾ NMR (400 MHz, DMSO-i/6) δ 11.01 (s, 1H), 9.03 (s, 1H), 8.79 - 8.63 (m, 2H), 8.21 (d, J = 5.5 Hz, 1H), 8.19 - 8.08 (m, 4H), 7.80 - 7.68 (m, 1H), 5.49 (td, J = 8.5, 4.0 Hz, 1H), 4.15 - 3.99 (m, 1H), 3.99 - 3.66 (m, 2H), 3.63 (s, 3H), 3.61 - 3.42 (m, 2H), 2.31 - 2.09 (m, 1H), 2.09 - 1.82 (m, 1H).
Example 483: 2-(((3ff,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((3- methoxy-4-(methylsulfonyl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000460_0001
Step 1: Preparation of 4-chloro-iV-(3-methoxy-4-(methylsulfonyl)phenyl)-l,3,5- triazin-2-amine: To a solution of 2,4-dichloro-l,3,5-triazine (0.21 g, 1.4 mmol) in N,N- dimethylformamide (DMF, 3 mL) at 0 °C were added N,N-diisopropylethylamine (DIEA, 0.24 mL, 1.4 mmol), followed by 4-methanesulfonyl-3-methoxyaniline (Combi- Blocks, 0.25 g, 1.2 mmol). The mixture was stirred at 0 °C for 5 minutes and then allowed to warm to room temperature. After three hours of stirring at room temperature, the mixture was partitioned between ethyl acetate and half-saturated aqueous sodium hydrogen carbonate solution. The layers were separated and aqueous phase was extracted twice with ethyl acetate. The combined extracts were washed once each with water and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with isopropanol to provide the desired material. LCMS-ESI"1" (m/z): [M+H]+ calcd for C1 1H12CIN4O3S 315.0; found: 315.9 Step 2: Preparation of (3/?,4S)-tert-butyl 4-(2-cyano-4-(4-((3-methoxy-4- (methylsulfonyl)phenyl)amino)-l,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-l- carboxylate: (3R,45)-tert-butyl 4-(2-cyano-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenoxy)-3-fluoropiperidine-l-carboxylate (preparation described in Example 293, 0.70 mmol) was taken up in 1, 2 -dimethoxy ethane (3 mL) and was added to a microwave vial containing 4-chloro-N-(3-methoxy-4-(methylsulfonyl)phenyl)-l,3,5-triazin-2-amine (0.20 g, 0.64 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.06 g, 7.5 mol%). 2 M aqueous sodium carbonate solution (0.9 mL) was added. The mixture was irradiated in a microwave for 75 minutes at 130 °C. The mixture was diluted with ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The combined extracts were concentrated, and the residue was purified by flash chromatography (silica gel) to provide the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C28H32F 6O6S
599.2; found: 599.0
Step 3: Preparation of 2-(((3/?,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((3-methoxy-4- (methylsulfonyl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile hydrochloride:
(3R,45)-tert-butyl 4-(2-cyano-4-(4-((3-methoxy-4-(methylsulfonyl)phenyl)amino)-l,3,5- triazin-2-yl)phenoxy)-3-fluoropiperidine-l-carboxylate (77 mg, 0.13 mmol) was taken up in 4N HCl/dioxanes (5 mL). The resulting suspension was heated briefly to reflux and then allowed to cool to room temperature. The suspension was homogenized with dichloromethane (3 mL). The mixture was allowed to stand at room temperature for 2 hours before being concentrated under reduced pressure to provide the desired material.
LCMS-ESI+ (m/z): [M+H]+ calcd for C23H24F 604S 499.2; found: 499.3
Step 4: Preparation of 2-(((3/?,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4- yl)oxy)-5-(4-((3-methoxy-4-(methylsulfonyl)phenyl)amino)-l,3,5-triazin-2- yl)benzonitrile: 2-(((3R,45)-3-fluoropiperidin-4-yl)oxy)-5-(4-((3-methoxy-4- (methylsulfonyl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile hydrochloride (0.13 mmol) and L-(+)-lactic acid (Sigma Aldrich, 32 mg, 0.36 mmol) were taken up in N,N- dimethylformamide (2 mL). The mixture was treated successively with N,N- diisopropylethylamine (90 μί, 0.52 mmol) and N-[(dimethylamino)-lH-l,2,3-triazolo- [4,5-b]pyridin-l-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (HATU, 98 mg, 0.26 mmol). The mixture remained at room temperature overnight. The mixture was concentrated to dryness under reduced pressure, the residue taken up in pyridine (1.5 mL), and treated with concentrated ammonium hydroxide solution (0.25 mL). The mixture was heated at 50 °C for 3 hours before being concentrated to dryness under reduced pressure. The residue was purified by prep HPLC (5 - 85 % acetonitrile in water, 0.1% trifluoroacetic acid buffer) to provide 2-(((3R,45)-3-fluoro-l-((5)-2- hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((3 -methoxy-4-
(methylsulfonyl)phenyl)amino)- 1 ,3 ,5-triazin-2-yl)benzonitrile. LCMS-ESI"1" (m/z):
[M+H]+ calcd for C26H28F 606S: 571.2; found: 571.1 1H NMR (400 MHz, DMSO- d6) δ 10.82 (s, 1H), 8.99 (s, 1H), 8.71 (d, J = 2.2 Hz, 1H), 8.67 (dd, J = 9.0, 2.2 Hz, 1H), 7.99 (br, 1H), 7.82 (d, J = 8.6 Hz, 1H), 7.70 (d, J = 9.1 Hz, 1H), 7.55 (br, 1H), 5.33 - 4.97 (m, 2H), 4.60 - 4.35 (m, 2H), 4.27 - 3.95 (m, 1H), 4.06 (s, 3H), 3.69 - 3.32 (m, 2H), 3.26 (s, 3H), 3.22 (m, 1H), 2.10 - 1.83 (m, 2H), 1.25 (dd, J = 6.5, 3.9 Hz, 3H).
Example 484: 4-(4-(methylsulfonyl)phenyl)-N-(4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)-l,3,5-triazin-2-amine, trifluoroacetic acid salt
Figure imgf000462_0001
A suspension of crude 4-chloro-N-(4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)-l,3,5- triazin-2 -amine (approximately 0.89 mmol), 4-(methylsulfonyl)phenylboronic acid (Sigma Aldrich, 0.28 g, 1.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.08 g, 7.5 mol%) in ethanol/toluene (1 : 1, 10 mL) was treated with 2 M aqueous sodium carbonate solution . The mixture was irradiated in a microwave reactor for 75 minutes at 130 °C. The mixture was diluted with ethyl acetate and water and filtered through a disposable fritted pad of Celite diatomaceous earth. The aqueous phase was extracted four times with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, concentrated to dryness under reduced pressure. The residue was purified by prep HPLC (5 - 80 % acetonitrile in water, 0.1% trifluoroacetic acid buffer) to provide the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C23H27 6O3S: 467.2; found: 467.3
Example 485: -CCCS.R^S^S-fluoro-l-Cl-meth l-lH-l^^-triazole^- carbonyl)piperidin-4-yl)oxy)-5-(4-((3-methyl-4-(l-methylpiperidin-4- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000463_0001
Step 1: Preparation of 5-bromo-2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)benzonitrile hydrochloride: (3R,4S)-tert-butyl 4-(4-bromo-2-cyanophenoxy)-3-fluoropiperidine-l- carboxylate (preparation given in example 382, 0.37 g, 0.93 mmol) was taken up in hydrogen chloride solution (4 M in dioxanes, 9.3 mL, 37 mmol). The mixture was allowed to stand at room temperature overnight and was then concentrated to dryness under reduced pressure to give the desired material. LCMS-ESI"1" (m/z): [M+H]+ calcd for C^H^BrF^O: 299.0; found: 299.1
Step 2: Preparation of 5-bromo-2-(((3 ?,4S)-3-fluoro-l-(l-methyl-lH-l,2,3-triazole- 4-carbonyl)piperidin-4-yl)oxy)benzonitrile: 1 -methyl- 1Η-1, 2,3 -triazole-4-carboxylic acid (Aurum Pharmtech LLC, 71 mg, 0.56 mmol) was added to a solution of 5-bromo-2- (((3R,4S)-3-fluoropiperidin-4-yl)oxy)benzonitrile hydrochloride in N,N- dimethylformamide (2.5 mL). The mixture was treated with N,N-diisopropylethylamine (0.41 mL, 2.3 mmol) followed by N-[(dimethylamino)-lH-l,2,3-triazolo-[4,5-b]pyridin- l-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (HATU, 0.36 g, 0.93 mmol). The mixture was left to stir overnight at room temperature and then was purified by flash chromatography (silica gel) to provide a semi-solid which was taken up as a suspension in dichloromethane and filtered through a plug of Celite diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure to provide the desired material. LCMS-ESI"1" (m/z): [M+H]+ calcd for Ci6H16BrFN502: 408.0; found: 408.1
Step 3: Preparation of 2-(((3 ?,4S)-3-fluoro-l-(l-methyl-lH-l,2,3-triazole-4- carbonyl)piperidin-4-yl)oxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzonitrile: A mixture of 5-bromo-2-(((3R,45)-3-fluoro-l-(l-methyl-lH-l,2,3- triazole-4-carbonyl)piperidin-4-yl)oxy)benzonitrile (0.19 g, 0.46 mmol), bis(pinacolato)diboron (0.23 g, 0.92 mmol), potassium acetate (0.14 g, 1.4 mmol), and [l, -bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.03 g, 10 mol%) in 1,4- dioxane (3 mL) was heated in a microwave reactor for 20 minutes at 150 °C. The mixture was filtered through a pad of Celite diatomaceous earth and concentrated to dryness under reduced pressure to provide the desired material, which was carried forward without further purification. LCMS-ESI"1" (m/z): [M+H]+ calcd for Ci6H16BrFN502: 408.0; found: 408.1
Step 4: Preparation of tert-butyl 4-(4-((4-(3-cyano-4-(((3JR,4S)-3-fluoro-l-(l- methyl-lH-l,2,3-triazole-4-carbonyl)piperidin-4-yl)oxy)phenyl)-l,3,5-triazin-2- yl)amino)-2-methylphenyl)piperidine-l-carboxylate : A mixture of tert-butyl 4-(4-((4- chloro-l,3,5-triazin-2-yl)amino)-2-methylphenyl)piperidine-l-carboxylate (preparation described in example 303, 0.19 g, 0.46 mmol), crude 2-(((3R,45)-3-fluoro-l-(l-methyl- lH-l,2,3-triazole-4-carbonyl)piperidin-4-yl)oxy)-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzonitrile (0.46 mmol assumed), and tetrakis(triphenylphosphine)palladium(0) (0.04 g, 7.5 mol%) in 1,2-dimethoxy ethane (DME, 3 mL) was treated with 2 M aqueous sodium carbonate solution (0.65 mL). The mixture was irradiated for 75 minutes in a microwave reactor at 130 °C. After cooling, the biphasic mixture was separated. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel) to provide tert-butyl 4-(4-((4-(3-cyano-4-(((3R,45)- 3-fluoro-l-(l -methyl- 1H- 1,2, 3-triazole-4-carbonyl)piperidin-4-yl)oxy)phenyl)-l, 3,5- triazin-2-yl)amino)-2-methylphenyl)piperidine-l-carboxylate. LCMS-ESI"1" (m/z): [M+H]+ calcd for C36H42F io04: 697.3; found: 696.9
Step 5: Preparation of 2-(((3 ?,4S)-3-fluoro-l-(l-methyl-lH-l,2,3-triazole-4- carbonyl)piperidin-4-yl)oxy)-5-(4-((3-methyl-4-(piperidin-4-yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile: A solution of tert-butyl 4-(4-((4-(3-cyano-4-(((3R,45)-3- fluoro- 1 -( 1 -methyl- 1H- 1 ,2,3 -triazole-4-carbonyl)piperidin-4-yl)oxy)phenyl)- 1,3,5- triazin-2-yl)amino)-2-methylphenyl)piperidine-l-carboxylate (53 mg, 0.08 mmol) in dichloromethane (2 mL) was treated with trifluoroacetic acid (0.26 mL, 3.4 mmol). After two hours at room temperature, the mixture was added to dilute ammonium hydroxide solution. The basic mixture was extracted five times with dichloromethane. The combined organics were dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure to give the desired material. LCMS-ESI"1" (m/z):
[M+H]+ calcd for C31 H34F 10O2: 597.3; found: 597.4
Step 6: Preparation of 2-(((3 ?,4S)-3-fluoro-l-(l-methyl-lH-l,2,3-triazole-4- carbonyl)piperidin-4-yl)oxy)-5-(4-((3-methyl-4-(l-methylpiperidin-4- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile, trifluoroacetic acid salt: A solution of 2-(((3R,45)-3 -fluoro- 1 -( 1 -methyl- 1H- 1 ,2,3 -triazole-4-carbonyl)piperidin-4-yl)oxy)-5- (4-((3-methyl-4-(piperidin-4-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (38 mg, 0.06 mmol) in methanol (3 mL) was treated with 37% formalin solution (19 uL, 0.26 mmol). After five minutes, sodium tri(acetoxy)borobydride (67 mg, 0.32 mmol) was added, and the mixture was allowed to stand at room temperature overnight before being treated with 1 M sodium hydroxide solution (0.5 mL). The mixture was concentrated to dryness under reduced pressure and purified by prep HPLC (5 - 85 % acetonitrile in water, 0.1% trifluoroacetic acid buffer) to provide the desired product as a trifluoroacetic acid salt. LCMS-ESI"1" (m/z): [M+H]+ calcd for C32H36F io02: 61 1.3; found: 61 1.4
¾ NMR (400 MHz, DMSO-i/6) δ 10.29 (s, 1H), 9.37 (s, 1H), 8.82 (s, 1H), 8.66 - 8.57 (m, 2H), 8.54 (s, 1H), 7.68 (d, J = 9.5 Hz, 1H), 7.59 (d, J= 8.5 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 5.13 (m, 2H), 4.65 - 4.30 (m, 1H), 4.10 (s, 3H), 3.86 (m, 1H), 3.53 (d, J = 1 1.9 Hz, 3H), 3.31 - 3.08 (m, 2H), 2.98 (m, 1H), 2.82 (d, J= 4.7 Hz, 3H), 2.36 (bs, 4H), 2.18 - 2.00 (m, 2H), 1.96 - 1.75 (m, 4H).
Example 486: 2-(((3 ?,45)-3-fluoro-l-((5)-2-hydroxypropanoyl)piperidin-4-yl)oxy)- 5-(4-((3-(2-hydroxypropan-2-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000465_0001
Step 1: Preparation of 2-(3-((4-chloro-l,3,5-triazin-2-yl)amino)phenyl)propan-2-ol To a solution of 2,4-dichloro-l,3,5-triazine (0.54 g, 3.6 mmol) in N,N- dimethylformamide (DMF, 6 mL) at 0 °C were added N,N-diisopropylethylamine (DIEA, 0.62 mL, 3.6 mmol), followed by a solution 2-(3-aminophenyl)propan-2-ol
(Enamine, 0.45 g, 3.0 mmol) in DMF (4 mL, then 2 mL rinsate). The mixture was stirred at 0 °C for 20 minutes and then allowed to warm to room temperature. After four hours, the mixture was partitioned between ethyl acetate and water. The layers were separated, and aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to provide 2-(3-((4- chloro-l,3,5-triazin-2-yl)amino)phenyl)propan-2-ol. LCMS-ESI+ (m/z): [M+H]+ calcd for C12H14CIN4O 265.1 ; found: 265.1
Step 2: Preparation of (3ff,4S)-tert-butyl 4-(2-cyano-4-(4-((3-(2-hydroxypropan-2- yl)phenyl)amino)-l,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-l-carboxylate
(3R,45)-tert-butyl 4-(2-cyano-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)- 3-fluoropiperidine-l-carboxylate (preparation described in Example 293, 1.0 mmol) was taken up in 1,2-dimethoxyethane (4 mL) and was added to a microwave vial containing 2-(3-((4-chloro-l,3,5-triazin-2-yl)amino)phenyl)propan-2-ol (0.27 g, 1.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.09 g, 7.5 mol%). 2 M aqueous sodium carbonate solution (2.0 mL) was added. The mixture was irradiated in a microwave for 75 minutes at 130 °C. The mixture was diluted with ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to provide the desired material, which was carried on without further purification. LCMS-
ESI+ (m/z): [M+H]+ calcd for C29H34F 604 549.3; found: 549.1 Step 3: Preparation of 2-(((3ff,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((3-(2-hydroxypropan-2- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
A solution of crude (3R,45)-tert-butyl 4-(2-cyano-4-(4-((3-(2-hydroxypropan-2- yl)phenyl)amino)-l,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-l-carboxylate in dichloromethane (10 mL) was added to vigorously stirred 85 % aqueous phosphoric acid at room temperature. The mixture was stirred vigorously for 10 minutes. The aqueous phase was diluted with water and cooled in an ice-water bath. 50 % w/w aqueous sodium hydroxide solution was added dropwise to ~ pH 8. The mixture was extracted three times with dichloromethane. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel) to provide the desired material. LCMS-
ESI+ (m/z): [M+H]+ calcd for C24H26F 602 449.2; found: 449.1
Step 4: Preparation of 2-(((3/?,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-
((3-(2-hydroxypropan-2-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile 2-(((3R;4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((3-(2-hydroxypropan-2-yl)phenyl)amino)-l;3;5- triazin-2-yl)benzonitrile (48 mg, 0.10 mmol) and L-(+)-lactic acid (Sigma Aldrich, 14 mg, 0.16 mmol) were taken up in /V,/V-dimethylformamide (2 mL). The mixture was treated successively with /V,/V-diisopropylethylamine (93 μΐ, 0.54 mmol) and /V-[(dimethylamino)-lH-l;2;3-triazolo- [4;5-b]pyridin-l-ylmethylene]-N-methylmethanaminiumhexafluorophosphate /V-oxide (HATU, 61 mg, 0.16 mmol). The mixture stirred at room temperature for one hour. The mixture was concentrated to dryness under reduced pressure. The residue was purified by prep HPLC (5 - 70 % acetonitrile in water, 0.1% trifluoroacetic acid buffer) to provide 2-(((3/?,4S)-3-fluoro-l- ((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((3-(2-hydroxypropan-2-yl (phenyl )amino)- l,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C27H30FN6O4: 521.2; found : 521.1 !H NM (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.86 (s, 1H), 8.67 (m, 2H), 8.13 (bs, 1H),
7.72 - 7.60 (m, 1H), 7.50 (s, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 5.30 - 4.96 (m, 4H), 4.63 - 4.34 (m, 1H), 4.25 - 3.56 (m, 1H), 3.43 - 3.23 (m, 1H), 2.04 (m, 1H), 1.94 - 1.80 (m, 1H), 1.52 (s, 6H), 1.35 - 1.18 (m, 3H).
Example 487: 2-(((3 ?,45)-3-fluoro-l-((5)-2-hydroxypropanoyl)piperidin
5-(4-((3-methyl-4-(l-methylpiperidin-4-yl)phenyl)amino)-l,3,5-triazin-2-
Figure imgf000468_0001
Step 1: Preparation of 4-(2-methyl-4-nitrophenyl)-l,2,3,6-tetrahydropyridine hydrochloride:
A solution of ieri-butyl 4-(2-methyl-4-nitrophenyl)-5,6-dihydropyridine-l(2H)-carboxylate (preparation described in example 303, 4.8 g, 15 mmol) in toluene (20 mL) was treated dropwise with 4 N hydrogen chloride in dioxanes (20 mL, 80 mmol). After 30 minutes of stirring at room temperature, the resulting precipitate was collected by filtration. The solid was washed with diethyl ether and dried under house vacuum to provide the desired material.
LCMS-ESI+ (m/z): [M+H]+ calcd for C-^H-^^C^: 219.1; found: 219.0 Step 2: Preparation of 2-(trimethylsilyl)ethyl 4-(2-methyl-4-nitrophenyl)-5,6- dihydropyridine-l(2H)-carboxylate : A suspension of 4-(2-methyl-4-nitrophenyl)- 1,2,3, 6-tetrahydropyridine hydrochloride (3.6 g, 14 mmol) in dichloromethane (60 mL), stirred in an ice-water bath, was treated successively dropwise with N,N- diisopropylethylamine (12 mL, 71 mmol) and a solution of N-[2- (trimethylsilyl)ethoxycarbonyloxy]succinimide (4.4 g, 17 mmol) in dichloromethane (20 mL). The cooling bath was allowed to expire, allowing the mixture to regain room temperature. The mixture was concentrated almost to dryness under reduced pressure. The residue was partitioned between water and ethyl acetate. The aqueous phase was extracted twice with ethyl acetate and once with diethyl ether. The combined extracts were washed twice with water and once with saturated aqueous sodium chloride solution and then were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to provide the desired material, which was carried forward without further purification. LCMS-ESI+ (m/z): [M-2CH2+H]+ calcd for c16H23N2°4si: 335.1 ; found: 335.0
Step 3: Preparation of 2-(trimethylsilyl)ethyl 4-(4-amino-2- methylphenyl)piperidine-l-carboxylate: A solution of crude 2-(trimethylsilyl)ethyl 4- (2-methyl-4-nitrophenyl)-5,6-dihydropyridine-l(2H)-carboxylate (14 mmol assumed) in methanol (75 mL) was degassed before the addition of 10 % palladium on carbon (500 mg). The suspension was shaken for four hours under 50 psi of hydrogen. The mixture was filtered through a pad of Celite diatomaceous earth, eluting with methanol. The filtrate was concentrated to dryness under reduced pressure to provide the desired material, which was carried forward without further purification. LCMS-ESI"1" (m/z): [M+H]+ calcd for Ci 8H3 iN202Si: 335.2; found: 334.9
Step 4: Preparation of 2-(trimethylsilyl)ethyl 4-(4-((4-chloro-l,3,5-triazin-2- yl)amino)-2-methylphenyl)piperidine-l-carboxylate: To a solution of 2,4-dichloro-
1,3,5-triazine (2.6 g, 17 mmol) in N,N-dimethylformamide (DMF, 40 mL) at 0 °C were added N,N-diisopropylethylamine (DIEA, 3.1 mL, 18 mmol), followed by a solution of crude 2-(trimethylsilyl)ethyl 4-(4-amino-2-methylphenyl)piperidine-l-carboxylate (14 mmol assumed) in DMF (10 mL then 10 mL rinsate). The mixture was stirred at 0 °C for 20 minutes and then allowed to warm to room temperature. The mixture was partitioned between ethyl acetate and water. The layers were separated and aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed once each with water and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to provide 2- (trimethylsilyl)ethyl 4-(4-((4-chloro-l,3,5-triazin-2-yl)amino)-2- methylphenyl)piperidine- 1 -carboxylate. LCMS-ESI"1" (m/z): [M+H]+ calcd for c21H31clN5°2si 448-2; found: 447·9
Step 5: Preparation of (3 ?,4S)-tert-butyl 4-(2-cyano-4-(4-((3-methyl-4-(l-((2- (trimethylsilyl)ethoxy)carbonyl)piperidin-4-yl)phenyl)amino)-l,3,5-triazin-2- yl)phenoxy)-3-fluoropiperidine-l-carboxylate: (3R,45)-tert-butyl 4-(2-cyano-4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)-3-fluoropiperidine-l -carboxylate (preparation described in Example 293, 1.7 mmol) was taken up in 1,2-dimethoxyethane (8 mL) and was added to a microwave vial containing 2-(trimethylsilyl)ethyl 4-(4-((4- chloro- 1, 3, 5-triazin-2-yl)amino)-2-methylphenyl)piperi dine- 1 -carboxylate (0.75 g, 1.7 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.15 g, 7.5 mol%). 2 M aqueous sodium carbonate solution (3.3 mL) was added. The mixture was irradiated in a microwave for 75 minutes at 130 °C. The mixture was diluted with ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to provide the desired material, which was carried forward without further purification. LCMS-ESI"1" (m/z): [M+H]+ calcd for C38H5oF 705Si 732.4; found:
732.2
Step 5: Preparation of (3R,4S)-tert-butyl 4-(2-cyano-4-(4-((3-methyl-4-(piperidin-4- yl)phenyl)amino)-l,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-l-carboxylate
A solution of crude (3R,4S)-tert-butyl 4-(2-cyano-4-(4-((3-methyl-4-(l-((2- (trimethylsilyl)ethoxy)carbonyl)piperidin-4-yl)phenyl)amino)- 1 ,3 ,5-triazin-2- yl)phenoxy)-3-fluoropiperidine-l-carboxylate (1.7 mmol assumed) in N,N- dimethylformamide (6 mL) was treated with cesium fluoride (3.0 g, 20 mmol). The mixture was heated at 100 °C for three hours and then was allowed to cool to room temperature. The mixture was filtered through a pad of Celite diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography (silica gel) to provide the desired material. LCMS-ESI"1" (m/z): [M+H]+ calcd for C32H39FN7O3 588.3; found: 588.2
Step 6: Preparation of (3 ?,4S)-tert-butyl 4-(2-cyano-4-(4-((3-methyl-4-(l- methylpiperidin-4-yl)phenyl)amino)-l,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine- 1-carboxylate: A solution of (3R,45)-tert-butyl 4-(2-cyano-4-(4-((3-methyl-4-(l- methylpiperidin-4-yl)phenyl)amino)-l,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-l- carboxylate (0.28 g, 0.47 mmol) in methanol (3 mL) was treated with 37% formalin solution (140 uL, 1.9 mmol). After five minutes, sodium tri(acetoxy)borohydride (0.50 g, 2.3 mmol) was added, and the mixture was allowed to stand at room temperature for 20 minutes before being concentrated under reduced pressure. The residue was treated with 1 M sodium hydroxide solution (3 mL) and extracted four times with dichloromethane. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to provide the desired material, which was carried forward without further purification. LCMS-ESI"1" (m/z): [M+H]+ calcd for C33H41 FN7O3 602.3; found: 602.3
Step 7: Preparation of 2-(((3 ?,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((3-methyl-4-(l- methylpiperidin-4-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile dihydrochloride A solution of (3R,45)-tert-butyl 4-(2-cyano-4-(4-((3-methyl-4-(l-methylpiperidin-4- yl)phenyl)amino)-l,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-l-carboxylate (0.26 g, 0.44 mmol) in dichloromethane (4 mL) was treated with 4 N hydrogen chloride in dioxane (10 mL, 40 mmol). The resulting suspension was allowed to stand overnight at room temperature before being concentrated under reduced pressure to provide the desired material. LCMS-ESI+ (m/z): [M+H]+ calcd for C28H33F 7O 502.3; found:
502.5
Step 8: Preparation of 2-(((3 ?,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4- yl)oxy)-5-(4-((3-methyl-4-(l-methylpiperidin-4-yl)phenyl)amino)-l,3,5-triazin-2- yl)benzonitrile, trifluoroacetic acid salt: A mixture of 2-(((3R,45)-3-fluoropiperidin-4- yl)oxy)-5-(4-((3-methyl-4-(l-methylpiperidin-4-yl)phenyl)amino)-l,3,5-triazin-2- yl)benzonitrile dihydrochloride (55 mg, 0.1 1 mmol) and N,N-diisopropylethylamine (96 μί, 0.55 mmol) in N,N-dimethylformamide (2 mL) was treated successively with L-(+)- lactic acid (Sigma Aldrich, 15 mg, 0.17 mmol) and N-[(dimethylamino)-lH- 1,2,3- triazolo-[4,5-b]pyridin-l-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N- oxide (HATU, 63 mg, 0.17 mmol). The mixture stirred at room temperature for one hour. The mixture was concentrated to dryness under reduced pressure. The residue was purified by prep HPLC (5 - 70 % acetonitrile in water, 0.1% trifluoroacetic acid buffer) to provide 2-(((3R,45)-3-fluoro-l-((5)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((3- methyl-4-( 1 -methylpiperidin-4-yl)phenyl)amino)- 1 ,3 ,5-triazin-2-yl)benzonitrile, trifluoroacetic acid salt. LCMS-ESI+ (m/z): [M+H]+ calcd for C31 H37FN7O3 : 574.3; found: 574.4 XH NMR (400 MHz, DMSO-i¾) δ 10.32 (br, 1H), 9.44 (bs, 1H), 8.81 (s, 1H), 8.67 - 8.55 (m, 2H), 7.66 (d, J= 9.3 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 5.26 - 4.94 (m, 2H), 4.48 (m, 1H), 4.26 - 3.91 (m, 2H), 3.64 - 3.25 (m, 1H), 3.52 (d, J= 11.9 Hz, 2H), 3.13 (m, 2H), 2.97 (m, 1H), 2.82 (d, J= 4.7 Hz, 3H), 2.36 (bs, 4H), 2.09 - 1.69 (m, 6H), 1.21 (dd, J= 6.4, 4.1 Hz, 3H).
Example 488 : 2-(((3 ?,4S)-l-(2-cyanoacetyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((3- methyl-4-(l-methylpiperidin-4-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000471_0001
The title compound was prepared and purified in the manner of Example 487 (2- (((3R,45)-3-fluoro-l-((5)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((3-methyl-4-(l- methylpiperidin-4-yl)phenyl)amino)- 1 ,3 ,5-triazin-2-yl)benzonitrile, trifluoroacetic acid salt) by substituting cyanoacetic acid for L-(+)-lactic acid. LCMS-ESI"1" (m/z): [M+H]+ calcd for C31 H34FN8O2: 569.3; found: 569.4 XH NMR (400 MHz, DMSO-i¾) δ 10.33
(br, 1H), 9.43 (br, 1H), 8.81 (s, 1H), 8.65 - 8.48 (m, 2H), 7.65 (dd, J = 9.6, 1.8 Hz, 1H), 7.58 (d, J= 8.5 Hz, 1H), 7.15 (d, J= 8.4 Hz, 1H), 5.26 - 4.93 (m, 2H), 4.37 (dt, J= 14.4, 6.9 Hz, 1H), 4.29 - 3.84 (m, 3H), 3.75 - 3.58 (m, 1H), 3.54 (m, 2H), 3.48 - 3.20 (m, 1H), 3.13 (q, J = 11.4 Hz, 2H), 3.03 - 2.89 (m, 1H), 2.82 (d, J = 4.7 Hz, 3H), 2.36 (s, 4H), 2.10 - 1.97 (m, 1H), 1.86 (m, 4H). Example 489: 2-(((3 ?,4S)-3-fluoro-l-(2-methoxyacetyl)piperidin-4-yl)oxy)-5-(4-((3- methyl-4-(l-methylpiperidin-4-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000472_0001
The title compound was prepared and purified in the manner of Example 487: (2- (((3R,45,)-3-fluoro-l-((5,)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((3-methyl-4-(l- methylpiperidin-4-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile, trifluoroacetic acid salt) by substituting methoxyacetic acid for L-(+)-lactic acid. LCMS-ESI"1" (m/z):
[M+H]+ calcd for C31 H37FN7O3 : 574.3; found: 574.5 XH NMR (400 MHz, DMSO-i¾) δ 10.32 (br, 1H), 9.40 (bs, 1H), 8.81 (s, 1H), 8.68 - 8.51 (m, 2H), 7.65 (d, J = 9.4 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 5.23 - 4.93 (m, 2H), 4.36 (m, 1H), 4.20 (m, 1H), 4.08 (m, 1H), 3.99 (m, 1H), 3.75 (d, J = 14.1 Hz, 1H), 3.52 (d, J = 11.7 Hz, 2H), 3.30 (s, 3H), 3.13 (q, J = 11.1 Hz, 2H), 2.96 (m, 1H), 2.82 (d, J = 4.6 Hz, 3H), 2.36 (br, 4H), 2.10 - 1.69 (m, 6H). Example 490: -CCCS.R^S^S-fluoro-l-CS-meth MH-l^^-triazole-S- carbonyl)piperidin-4-yl)oxy)-5-(4-((3-methyl-4-(l-methylpiperidin-4- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000473_0001
The title compound was prepared and purified in the manner of Example 487: (2- (((3R,45)-3-fluoro-l-((5)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((3-methyl-4-(l- methylpiperidin-4-yl)phenyl)amino)- 1 ,3 ,5-triazin-2-yl)benzonitrile, trifluoroacetic acid salt) by substituting 5-methyl-lH-l,2,4,-triazole-3-carboxylic acid (Aurum Pharmtech) for L-(-)-lactic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H36F io02: 611.3; found: 611.5 XH NMR (400 MHz, DMSO-i/6) δ 10.32 (br, 1H), 9.41 (br, 1H), 8.81 (s, 1H), 8.67 - 8.54 (m, 2H), 7.66 (d, J= 9.1 Hz, 1H), 7.59 (d, J= 8.9 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 5.30 - 4.93 (m, 2H), 4.55 - 4.31 (m, 3H), 3.80 (m, 1H), 3.41 (m, 3H), 3.21 - 2.88 (m, 4H), 2.82 (d, J = 4.6 Hz, 3H), 2.44 - 2.30 (m, 6H), 2.29 - 2.12 (m, 1H), 2.12 - 1.61 (m, 4H).
Example 491: 3-((2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)- l,3,5-triazin-2-yl)phenoxy)methyl)oxetane-3-carbonitrile
Figure imgf000473_0002
Potassium tert-butoxide (100 mg, 0.88 mmol) was added to a solution of 3- (hydroxymethyl)oxetane-3-carbonitrile (Enamine, 100 mg, 0.88 mmol) in tetrahydrofuran (5 mL). The resulting suspension was stirred at room temperature for 30 minutes before the addition of 2-fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (Example 87, 100 mg, 0.23 mmol). The mixture was heated overnight at 60 °C. The mixture was purified by flash chromatography (silica gel) to provide the desired product. LCMS-ESI"1" (m/z): [M+H]+ calcd for C28H29 8O3 : 525.2; found: 525.3 Example 492: 2-(((3 ?,4S)-3-fluoro-l-(2-methoxyacetyl)piperidin-4-yl)oxy)-5-(4-((4- (l-formylpiperidin-4-yl)-3-methylphenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000474_0001
Step 1: Preparation of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,6- tetrahydropyridine hydrochloride: Acetyl chloride (10 mL, 150 mmol) was added to methanol, which was cooled in an ice-water bath, tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-5,6-dihydropyridine-l(2H)-carboxylate (Advanced ChemBlocks, Inc., 3.0 g, 9.7 mmol) was added to the solution in a single portion. The mixture was removed from the bath and allowed to regain room temperature. Dichloromethane (approximately 20 mL) was added to homogenize the mixture, which was left overnight at room temperature. Concentration under reduced pressure provided the desired material.
LCMS-ESI"1" (m/z): [M+H]+ calcd for Ci 1 H21 B O2: 210.2; found: 210.1
Step 2: Preparation of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6- dihydropyridine-l(2H)-carbaldehyde: To a suspension of 4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-l,2,3,6-tetrahydropyridine hydrochloride (2.4 g, 9.7 mmol), 1-ethyl- 3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.5 g, 16 mmol), 4- dimethylaminopyridine (0.59 g, 4.9 mmol) in dichloromethane (80 niL) were added successively N,N-diisopropylethylamine (8.4 mL, 49 mmol) and formic acid (0.92 mL, 24 mmol). The reaction mixture stirred at room temperature overnight. The crude reaction mixture was diluted with dichloromethane and saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with three times with dichloromethane. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to provide the desired product. LCMS-ESI"1" (m/z): [M+H]+ calcd for C1 2H21 B O3 : 238.2; found: 238.1
Step 3: Preparation of 4-(2-methyl-4-nitrophenyl)-5,6-dihydropyridine-l(2H)- carbaldehyde: A mixture of 2-bromo-5-nitrotoluene (.19 g, 8.8 mmol), crude 4- (4,4,5, 5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine- l (2H)-carbaldehyde (2.3 g, 9.7 mmol), tetrakis(triphenylphosphine)palladium(0) (0.61 g, 6 mol%), 2 M aqueous sodium carbonate solution (13 mL), and 1,4-dioxane (30 mL) was heated at 90 °C for 3 hours. The reaction mixture was allowed to cool to room temperature. The mixture was diluted with ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel) to provide the desired material. LCMS-ESI"1" (m/z): [M+H]+ calcd for Ci 3H15 203 : 247.1 ; found: 246.9
Step 4: Preparation of 4-(4-amino-2-methylphenyl)piperidine-l-carbaldehyde: A solution of 4-(2-methyl-4-nitrophenyl)-5,6-dihydropyridine- l(2H)-carbaldehyde (2.6 g, 1 1 mmol) in methanol (25 mL) was degassed and then treated with 10 % palladium on carbon (260 mg). The suspension was shaken under 50 psi hydrogen overnight and then filtered through a bed of Celite diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure, and the residue was taken up in methanol (25 mL), degassed, and treated with 10 % palladium on carbon (260 mg). The suspension was shaken under 50 psi hydrogen overnight and then filtered through a bed of Celite diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure to provide the desired material. LCMS-ESI"1" (m/z): [M+H]+ calcd for C1 3H1 9N2O: 219.1 ; found: 219.1
Step 5: Preparation of 4-(4-((4-chloro-l,3,5-triazin-2-yl)amino)-2- methylphenyl)piperidine-l-carbaldehyde: To a solution of 2,4-dichloro-l,3,5-triazine
(1.3 g, 8.6 mmol) in N,N-dimethylformamide (DMF, 25 mL) at 0 °C were added N,N- diisopropylethylamine (DIEA, 1.5 mL, 8.6 mmol), followed by a solution of 4-(4-amino- 2-methylphenyl)piperidine-l-carbaldehyde (1.7 g, 7.8 mmol) in DMF (5 mL). The mixture was stirred at 0 °C for 5 minutes and then allowed to warm to room temperature. After one hour of stirring, the mixture was partitioned between ethyl acetate and water. The layers were separated and aqueous phase was extracted twice with ethyl acetate. The combined extracts were washed once each with water and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to provide the desired material. LCMS-ESI"1" (m/z):
[M+H]+ calcd for Ci6Hi9Cl 50 332.1; found: 332.2
Step 6: Preparation of (3/?, S)-tert-butyl 4-(2-cyano-4-(4-((4-(l-formylpiperidin-4- yl)-3-methylphenyl)amino)-l,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-l- carboxylate: A solution of crude (3R,45)-tert-butyl 4-(2-cyano-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenoxy)-3-fluoropiperidine-l-carboxylate (preparation described in Example 293, 1.5 mmol) in 1,2-dimethoxyethane (8 mL) was added to a mixture of 4-(4-((4-chloro-l,3,5-triazin-2-yl)amino)-2-methylphenyl)piperidine-l- carbaldehyde (0.65 g, 2.0 mmol), [1, 1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.11 g, 10 mol%), and potassium carbonate (0.85 g, 6.1 mmol). Water (3 mL) was added, and the mixture was heated for 75 minutes at 105 °C. After cooling to room temperature, the mixture was diluted with ethyl acetate and saturated aqueous sodium chloride solution and then filtered through a pad of Celite diatomaceous earth. The aqueous phase was extracted three times with ethyl acetate. The combined organic extracts were concentrated under reduced pressure to provide the crude desired material, which was carried forward without further purification.: LCMS-ESI"1" (m/z): [M+H]+ calcd for C33H39FN7O4
616.3; found: 616.0
Step 7: Preparation of 2-(((3 ?,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(l- formylpiperidin-4-yl)-3-methylphenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
A solution of crude (3R,45)-tert-butyl 4-(2-cyano-4-(4-((4-(l-formylpiperidin-4-yl)-3- methylphenyl)amino)- 1 ,3,5-triazin-2-yl)phenoxy)-3 -fluoropiperidine- 1 -carboxylate (1.5 mmol assumed) in dichloromethane (25 mL) was treated with trifluoroacetic acid (5 mL).The mixture was left at room temperature for 30 minutes before being concentrated to dryness. The residue was purified by flash chromatography (silica gel) to provide the desired material: LCMS-ESI+ (m/z): [M+H]+ calcd for C28H31 F 7O2 516.2; found: 516.3
Step 8: Preparation of 2-(((3 ?,4S)-3-fluoro-l-(2-methoxyacetyl)piperidin-4-yl)oxy)- 5-(4-((4-(l-formylpiperidin-4-yl)-3-methylphenyl)amino)-l,3,5-triazin-2- yl)benzonitrile: 2-(((3R,45)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(l-formylpiperidin-4- yl)-3-methylphenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (50 mg, 0.10 mmol) and methoxyacetic acid (11 uL, 0.15 mmol) were taken up in N,N-dimethylformamide (2 mL). The mixture was treated successively with N,N-diisopropylethylamine (80 μΐ,, 0.49 mmol) and N-[(dimethylamino)-lH-l,2,3-triazolo-[4,5-b]pyridin-l-ylmethylene]-N- methylmethanaminiumhexafluorophosphate N-oxide (HATU, 55 mg, 0.15 mmol). The mixture remained at room temperature overnight. The mixture was concentrated to dryness under reduced pressure and purified by prep HPLC (5 - 70 % acetonitrile in water, 0.1% trifluoroacetic acid buffer) to provide the desired product. LCMS-ESI"1"
(m/z): [M+H]+ calcd for C3 iH35F 704 588.3; found: 588.4 ¾ NMR (400 MHz,
DMSO-i/6) δ 10.25 (m, 1H), 8.80 (s, 1H), 8.64 - 8.49 (m, 2H), 8.04 (s, 1H), 7.65 (d, J = 9.0 Hz, 1H), 7.52 (d, J= 8.2 Hz, 1H), 7.19 (d, J= 8.4 Hz, 1H), 5.23 - 4.94 (m, 2H), 4.60 (br, 6H), 4.33 (m, 1H), 4.20 (m, 1H), 4.15 - 3.91 (m, 1H), 3.78 (m, 2H), 3.65 - 3.34 (m, 1H), 3.30 (d, J= 1.7 Hz, 3H), 3.16 (m, 1H), 2.99 (t, J= 12.0 Hz, 1H), 2.71 (td, J= 12.9, 3.0 Hz, 1H), 2.36 (s, 3H), 2.09 - 1.91 (m, 1H), 1.75 (m, 2H).
Example 493: 2-(((3 ?,45)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)- 5-(4-((4-(l-formylpiperidin-4-yl)-3-methylphenyl)amino)-l,3,5-triazin-2- yl)benzonitrile
Figure imgf000477_0001
The title compound was prepared and purified in the manner of Example 492: 2- (((3R,45)-3 -fluoro- 1 -(2-methoxyacetyl)piperidin-4-yl)oxy)-5-(4-((4-( 1 -formylpiperidin- 4-yl)-3-methylphenyl)amino)-l,3,5-triazin-2-yl)benzonitrile by substituting L-(+)-lactic acid for methoxyacetic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C31 H35FN7O4: 588.3; found: 588.3 ¾ NMR (400 MHz, DMSO-i¾) δ 10.25 (m, 1H), 8.80 (s, 1H), 8.59 (d, J= 9.2 Hz, 2H), 8.04 (s, 1H), 7.65 (d, J= 9.0 Hz, 1H), 7.57 - 7.46 (m, 1H), 7.19 (d, J = 8.4 Hz, 1H), 5.41 (br, 6H), 5.25 - 4.93 (m, 2H), 4.48 (m, 1H), 4.38 - 4.28 (m, 1H), 4.25 - 3.90 (m, 1H), 3.87 - 3.75 (m, 1H), 3.64 (dd, J= 29.1, 14.4 Hz, 1H), 3.33 (m, 1H), 3.24 - 3.11 (m, 1H), 2.99 (t, J = 12.1 Hz, 1H), 2.71 (td, J = 12.8, 2.9 Hz, 1H), 2.36 (s, 3H), 2.00 (m, 1H), 1.75 (m, 2H), 1.21 (dd, J= 6.4, 4.5 Hz, 3H).
Example 494: 2-cyano-iV-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-l- l)phenyl)amino)-l,3,5-triazin-2-yl)phenyl)acetamide
Figure imgf000478_0001
Step 1: Preparation of 2-amino-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile: A mixture of 4-chloro-N-(4-(4- (oxetan-3-yl)piperazin-l-yl)phenyl)-l,3,5-triazin-2-amine (1.1 g, 3.1 mmol), 2-amino-5- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile (preparation described in example 37, 0.75 g, 3.1 mmol), [1, 1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.15 g, 7 mol%), and potassium carbonate (1.7 g, 12 mmol) in 1,4-dioxane (15 mL) and water (6 mL) was heated for 30 minutes at 100 °C. After cooling, the mixture was purified by flash chromatography
(silica gel) to provide the desired product. LCMS-ESI"1" (m/z): [M+H]+ calcd for
C23H25N80: 429·2; found: 429·2
Step 2: Preparation of 2-cyano-iV-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)phenyl)acetamide: A mixture of 2-amino-5-(4- ((4-(4-(oxetan-3-yl)piperazin- 1 -yl)phenyl)amino)- 1 ,3 ,5-triazin-2-yl)benzonitrile (84 mg, 0.20 mmol) and cyanoacetic acid (36 mg, 0.43 mmol) in pyridine (1 mL) was treated with 1-propanephosphonic anhydride solution (~ 50 % in N,N-dimethylformamide, 0.25 uL) and heated overnight at 80 °C. After concentration, the mixture was first purified by flash chromatography (silica gel) and then by preparative HPLC (5 - 60 % acetonitrile in water, 0.1% trifluoroacetic acid buffer) to provide the desired material as a trifluoroacetic acid salt. LCMS-ESI+ (m/z): [M+H]+ calcd for C26H26N9O2: 496.2; found: 496.3 XH
NMR (400 MHz, DMSO-i¾) δ 10.83 (s, 1H), 10.28 (d, J = 14 Hz, 1H), 8.80 (s, 1H), 8.71 - 8.53 (m, 2H), 7.94 (d, J = 8.6 Hz, 1H), 7.75 - 7.52 (m, 2H), 7.16 - 7.00 (m, 2H), 4.78 (dd, J= 6.5, 3.2 Hz, 4H), 4.46 (bs, 1H), 4.11 (s, 2H), 4.00 - 2.76 (br, 8H).
Example 495: 7V-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)- henyl)propionamide
Figure imgf000479_0001
The title compound was prepared from 2-amino-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile in the manner of the Example 494 by substituting propionic acid for cyanoacetic acid. It was first purified by flash chromatography (silica gel) and then by preparative HPLC (5 - 60 % acetonitrile in water, 0.1% trifluoroacetic acid buffer) to provide the desired material as a trifluoroacetic acid salt. LCMS-ESI+ (m/z): [M+H]+ calcd for C26H26N9O2: 496.2; found: 496.3
Example 496: 7V-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)- l,3,5-triazin-2-yl)phenyl)-3,3,3-trifluoropropanamide
Figure imgf000479_0002
The title compound was prepared from 2-amino-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile in the manner of the Example 494 by substituting 3,3,3-trifluoropropionic acid for cyanoacetic acid. It was first purified by flash chromatography (silica gel) and then by preparative HPLC (5 - 60 % acetonitrile in water, 0.1% trifluoroacetic acid buffer) to provide the desired material as a trifluoroacetic acid salt. LCMS-ESI+ (m/z): [M+H]+ calcd for C26H26F3N8O2: 539.2; found: 496.3
1H MR (400 MHz, DMSO-i¾) δ 10.81 (s, 1H), 10.28 (d, J= 12.1 Hz, 1H), 8.81 (s, 1H), 8.76 - 8.53 (m, 2H), 7.93 (s, 1H), 7.75 - 7.52 (m, 2H), 7.08 (m, 2H), 4.78 (m, 4H), 4.46 (bs, 1H), 3.99 (br, 4H), 3.72 (q, J= 11.0 Hz, 2H), 3.06 (br, 4H).
Example 497: 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4- (piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000480_0001
Step 1: tert-butyl 4-(4-((4-chloro-l,3,5-triazin-2-yl)amino)phenyl)piperazine-l- carboxylate: Tert-butyl 4-(4-aminophenyl)piperazine-l-carboxylate (1260 mg, 4.54 mmol) in 8 mL of DCM was combined with N,N-diisopropylethylamine (3.14 ml, 18.03 mmol) and then cooled to 0 °C. 2,4-dichloro-l,3,5-triazine (681.27 mg, 4.54 mmol) in 10 mL of DCM was cooled to 0 °C and then added to the cooled mixture. The reaction then stirred for 5 minutes. The reaction was incomplete. The reaction was subjected to an additional 200 mg of triazine in DCM and stirred for 5 more minutes. According to
LCMS, the reaction was complete. The reaction was washed with saturated sodium bicarbonate, extracted with 25% MeOH/DCM, dried, filtered and concentrated to provide tert-butyl 4-(4-((4-chloro- 1 ,3 ,5-triazin-2-yl)amino)phenyl)piperazine- 1 - carboxylate.
Step 2: (S)-tert-butyl 4-(4-((4-(3-cyano-4-(((3R,4S)-3-fluoro-l-((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)phenyl)-l,3,5-triazin-2-yl)amino)phenyl)-3- methylpiperazine-l-carboxylate: In a microwave tube, tert-butyl 4-(4-((4-chloro-l,3,5-triazin-2- yl)amino)phenyl)piperazine-l-carboxylate (80 mg, 0.2 mmol), 2-(((3R,4S)-3-fluoro-l-((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzonitrile (102.73 mg, 0.25 mmol), were combined in DME (2 mL) and 2M Sodium carbonate solution in water (0.46 ml), tetrakis(triphenylphosphine)palladium (23.65 mg, 0.02 mmol) was added, blown down with nitrogen and the vial was sealed, and heated in the microwave at 135°C for 20 minutes. The reaction was washed with water, extracted with 20% methanol/dichloromethane, dried, filtered and concentrated. The reaction was pushed forward to the next step assuming 100% yield of(S)-tert-butyl 4-(4-((4-(3-cyano-4-(((3R,4S)-3-fluoro-l- ((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)phenyl)-l,3,5-triazin-2-yl)amino)phenyl)-3- methylpiperazine-l-carboxylate .
Step 3: 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4-(piperazin- l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile: In a RBF, (S)-tert-butyl 4-(4-((4-(3-cyano-4- (((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)phenyl)-l,3,5-triazin-2- yl)amino)phenyl)-3-methylpiperazine-l-carboxylate (65 mg, 0.1 mmol) was dissolved in DCM (0.5 ml), trifluoroacetic acid (0.02 ml, 0.2 mmol) was added and the reaction was stirred at rt for 2h, an additional 2 equivalence of TFA was added and the reaction was stirred for overnight. The reaction cooled to 0 °C, neutralized with saturated sodium bicarbonate, washed with water, dried, filtered and concentrated. The residue was purified by reverse phase chromatography to provide 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4-(piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (26.3 mg, 24%). LCMS-ESI+ (m/z): [M+H]+ calcd for C28H31FN803: 546.25; found : 547.19. :H NMR (300 MHz, DMSO-d6) δ 10.06 (d, J = 16.01 Hz, 1H), 8.73 (s, 1H), 8.55 (d, J = 9.05 Hz, 2H), 7.53 - 6.85 (m, 5H), 6.95 (s, 2H), 5.20 - 4.90 (m, 3H), 4.50 - 3.87 (m, 3H), 3.70 - 3.50 (m, 1H), 3.40 - 3.30 (m, 1H), 3.0 (s, 4H), 2.80 (s, 4H), 2.0-1.65 (m, 2H), 1.2 (dd, J = 9.04, 2.78, 3H).
Example 498: 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4-(4- methylpiperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000482_0001
2-(((3 ,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4-(piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (22.8 mg, 0.04 mmol) was dissolved in methanol (2 ml), Formaldehyde solution 37%, Formalin (0.01 ml, 0.17 mmol) was added and the reaction was stirred for 5 minutes, followed by the addition of sodium triacetoxyborohydrlde (44.2 mg, 0.21 mmol). The reaction was allowed to stir at room temperature for 2 hours. The reaction was quenched with IN NaOH, extracted with 25% methanol/dichloromethane, dried, filtered and concentrated. The crude material was purified by reverse phase to provide 2-(((3R,4S)-3-fluoro- l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4-(4-methylpiperazin-l-yl (phenyl )amino)- l,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C29H33FN803: 560.27; found : 561.30. :H NMR (300 MHz, DMSO-d6) δ 10.06 (d, J = 16.01 Hz, 1H), 8.73 (s, 1H), 8.55 (d, J = 9.05 Hz, 2H), 7.53 - 6.85 (m, 5H), 6.95 (s, 2H), 5.20 - 4.90 (m, 3H), 4.50 - 3.87 (m, 3H), 3.70 - 3.50 (m, 1H), 3.40 - 3.30 (m, 1H), 3.15 (s, 4H), 2.45 (m, 4H), 2.20 (s, 1H), 2.0-1.65 (m, 2H), 1.2 (dd, J = 9.04, 2.78, 3H).
Example 499: 5-(4-((4-((S)-2,4-dimethylpiperazin-l-yl)-3-methoxyphenyl)amino)-l,3,5-triazin- 2-yl)-2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)benzonitrile
Figure imgf000482_0002
Step 1: (S)-tert-butyl 4-(2-methoxy-4-nitrophenyl)-3-methylpiperazine-l-carboxylate 1-Fluoro- 2-methoxy-4-nitrobenzene (2000 mg, 11.69 mmol), (S)-tert-butyl 3-methylpiperazine-l- carboxylate (2340.71 mg, 11.69 mmol), potassium carbonate (4845.75 mg, 35.06 mmol) in NMP (18 ml) was stirred at 100 °C for 3 overnights. The reaction was diluted with EtOAc, washed with water, dried and concentrated. The crude was washed with EtOAc, filtered and dried to provide (S)-tert-butyl 4-(2-methoxy-4-nitrophenyl)-3-methylpiperazine-l-carboxylate.
Step 2: (S)-tert-butyl 4-(4-((4-chloro-l,3,5-triazin-2-yl)amino)-2-methoxyphenyl)-3- methylpiperazine-l-carboxylate: (S)-tert-butyl 4-(4-amino-2-methoxyphenyl)-3- methylpiperazine-l-carboxylate (1000 mg, 3.11 mmol) in 6 mL of DCM was combined with N,N- Diisopropylethylamine (1.63 ml, 9.33 mmol) and then cooled to 0°C. 2,4-dichloro-l,3,5-triazine (466.58 mg, 3.11 mmol) in 10 mL of DCM was cooled to 0°C and then added to the cooled mixture. The reaction then stirred for 5 minutes. The reaction was subjected to an additional 150 mg of triazine in DCM and stirred for 5 more minutes. The reaction was washed with saturated sodium bicarbonate, extracted with 25% MeOH/DCM, dried, filtered and concentrated to provide (S)-tert-butyl 4-(4-((4-chloro-l,3,5-triazin-2-yl)amino)-2- methoxyphenyl)-3-methylpiperazine-l-carboxylate.
Step 3: (S)-tert-butyl 4-(4-((4-(3-cyano-4-(((3R,4S)-3-fluoro-l-((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)phenyl)-l,3,5-triazin-2-yl)amino)-2-methoxyphenyl)-3- methylpiperazine-l-carboxylate: Tert-butyl 4-(4-((4-chloro-l,3,5-triazin-2- yl)amino)phenyl)piperazine-l-carboxylate (80 mg, 0.2 mmol) and 2-(((3 ,4S)-3-fluoro-l-((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzonitrile (102.73 mg, 0.25 mmol) were combined in DME (2 mL) and 2M Sodium carbonate solution in water (0.46 ml), tetrakis(triphenylphosphine)palladium (23.65 mg, 0.02 mmol) was added, blown down with nitrogen and the vial was sealed. The reaction mixture was heated in microwave at 135°C for 20 minutes. The reaction was extracted with 25% MeOH/DCM and water, dried, filtered and concentrated. The crude mixture was purified by flash chromatography on silica gel to provide (S)-tert-butyl 4-(4-((4-(3-cyano-4-(((3R,4S)-3- fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)phenyl)-l,3,5-triazin-2-yl)amino)-2- methoxyphenyl)-3-methylpiperazine-l-carboxylate. Step 4: 5-(4-((4-((S)-2,4-dimethylpiperazin-l-yl)-3-methoxyph
(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)benzonitrile: 2-(((3R,4S)-3- fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((3-methoxy-4-((S)-2-methylpiperazin- l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (34.9 mg, 0.06 mmol) was dissolved in methanol (3 ml), Formaldehyde solution 37%, Formalin (0.01 ml, 0.15 mmol) was added and the reaction was stirred for 5 minutes, followed by the addition of sodium triacetoxyborohydride 95% (62.62 mg, 0.3 mmol) and the reaction was allowed to stir at room temperature for 2h. The reaction was quenched with IN NaOH, extracted with 25% methanol/dichloromethane, dried, filtered and concentrated. The crude mixture was purified by flash chromatography on silica gel to provide 5-(4-((4-((S)-2,4-dimethylpiperazin-l-yl)-3- methoxyphenyl)amino)-l,3,5-triazin-2-yl)-2-(((3 ,4S)-3-fluoro-l-((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for C31H37FN804: 604.29; found : 605.19. :H NMR (300 MHz, DMSO-d6) δ 10.11 (m, 1H), 8.73 (s, 1H), 8.55 (m, 2H), 7.64 - 6.90 (m, 3H), 6.94 (s, 2H), 5.21 - 4.90 (m, 3H), 4.50 - 3.92 (m, 3H), 3.75 - 3.50 (m, 1H), 3.09 (s, 4H), 2.45 (m, 3H), 2.20 (s, 3H), 2.0-1.70 (m, 2H ), 1.2 (d, J = 6.27, 3H).
Example 500: 5-(4-((4-((S)-2,4-dimethylpiperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)-2- (((3R,4S)-3-fluoro-l-(2-hydroxyacetyl)piperidin-4-yl)oxy)benzonitrile
Figure imgf000484_0001
This molecule was synthesized in the same manner as Example 499 except starting with (S)-2,4- dimethyl-l-(4-nitrophenyl)piperazine and substituting glycolic acid for L-(+)-lactic acid. LCMS- ESI"1" (m/z): [M+H]+ calcd for C28H31FN803: 560.27; found : 561.06. :H NMR (300 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.91 (s, 1H), 8.75 - 8.73 (m, 2H), 7.82-7.74 (m, 3H), 7.08 (s, 2H), 5.31-5.15 (m, 2H), 4.86-4.82 (m, 1H), 4.54-4.07 (m, 4H), 3.88-3.53 (m, 1H), 3.34 - 3.25 (m, 2H), 3.20-3.10 (m, 1H), 2.95-2.70 (m, 3H), 2.49-2.37 (m, 3H), 2.31-2.10 (m, 2H), 1.40 (s, 1H), 1.28-1.56 (m, 3H). Example 501: 5-(4-((4-((S)-2,4-dimethylpiperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)-2- (((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)benzonitrile
Figure imgf000485_0001
This molecule was synthesized in the same manner as Example 499 except starting with (S)-2,4- dimethyl-l-(4-nitrophenyl)piperazine. LCMS-ESI+ (m/z): [M+H]+ calcd for C3oH35FN803: 574.28; found : 575.09. :H NM (300 MHz, DMSO-d6) δ 10.30 (m, IH), 8.92 (s, IH), 8.77 - 8.74 (m, 2H), 7.83-7.75 (m, 3H), 7.09 (s, 2H), 5.31-5.15 (m, 3H), 4.69-4.00 (m, 2H), 3.45-3.33 (m, IH), 3.20- 3.10 (m, IH), 2.95 - 2.72 (m, 3H), 2.67-2.38 (m, IH), 2.38 (s, 3H), 2.31-2.17 (m, 2H), 1.41-1.37 (m, 4H), 1.18-1.16 (m, IH).
Example 502: 5-(4-((l-ethyl-lH-l,2,3-triazol-4-yl)amino)-l,3,5-triazin-2-yl)-2-(((3R,4S)-3- fluoro-l-(2-hydroxyacetyl)piperidin-4-yl)oxy)benzonitrile
Figure imgf000485_0002
This molecule was synthesized in the same manner as Example 342 except starting with 1-ethyl- lH-l,2,3-triazol-4-amine and substituting glycolic acid for L-(+)-lactic acid. LCMS-ESI"1" (m/z):
[M+H]+ calcd for C21H22FN903: 467.18; found : 468.18. :H NMR (300 MHz, DMSO-d6) δ 11.06 (s, IH), 8.84 (d, J = 16.7 Hz, IH), 8.62 (s, 2H), 8.41 (d, J = 37.59 Hz, IH), 7.63 (s, IH), 5.13-4.97 (m, 2H), 4.71-4.65 (m, IH), 4.47-4.33 (m, 3H), 4.21-3.92 (m, 3H), 3.70-3.34 (m, 2H), 2.72-2.49 (m, IH), 2.07-1.82 (m, 2H), 1.51-1.45 (m, 3H). Example 503: 5-(4-((2-ethyl-2H-l,2,3-triazol-4-yl)amino)-l,3,5-triazin-2-yl)-2-(((3R,4S)-3- fluoro-l-(2-hydroxyacetyl)piperidin-4-yl)oxy)benzonitrile
Figure imgf000486_0001
This molecule was synthesized in the same manner as Example 342 except starting with 2-ethyl-
2H-l,2,3-triazol-4-amine and substituting glycolic acid for L-(+)-lactic acid. LCMS-ESI"1" (m/z):
[M+H]+ calcd for C21H22FN903: 467.18; found : 468.20. :H NM (300 MHz, DMSO-d6) δ 11.09 (s, IH), 8.84 (s, IH), 8.63-8.59 (m, 2H), 8.15-8.01 (m, IH), 7.65 (d, J = 9.74, IH), 5.19-4.97 (m, 2H), 4.71-4.64 (m, IH), 4.40-4.35 (m, 3H), 4.20-3.94 (m, 3H), 3.71-3.86 (m, IH), 3.33-3.15 (m, IH), 1.99-1.85 (m, 2H), 1.45 (t, J = m, 3H).
Example 504: 2-(((3R,4S)-3-fluoro-l-((S)-tetrahydrofuran-2-carbonyl)piperidin-4-yl)oxy)-5-(4- ((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000486_0002
This molecule was synthesized in the same manner as Example 336 except starting with (S)- tetrahydrofuran-2-carboxylic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H37FN804: 628.29; found : 629.42. :H NMR (300 MHz, DMSO-d6) δ 10.16-10.11 (s, IH ), 8.74 (s, IH), 8.59 - 8.56 (m,
2H), 7.64-7.57 (m, 3H), 6.96 (s, IH), 5.13-4.97 (m, 2H), 4.76-4.67 (m, IH), 4.57 (dt, J = 41.61, 6.45, 4H), 4.20-3.92 (m, 2H), 3.82 - 3.77 (m, 2H), 3.48-3.30 (m, 2H), 3.14 (s, 5H), 2.41 (s, 4H), 2.13-1.96 (m, 4H), 1.87-1.81 (m, 2H).
Example 505: 2-(((3R,4S)-3-fluoro-l-((R)-tetrahydrofuran-2-carbonyl)piperidin-4-yl)oxy)-5-(4- ((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000487_0001
This molecule was synthesized in the same manner as Example 336 except starting with (S)- tetrahydrofuran-2-carboxylic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H37FN804: 628.29; found : 629.42. :H NM (300 MHz, DMSO-d6) δ 10.16-10.11 (s, 1H), 8.74 (s, 1H), 8.59 - 8.56 (m, 2H), 7.64-7.57 (m, 3H), 6.96 (s, 1H), 5.13-4.97 (m, 2H), 4.76-4.67 (m, 1H), 4.57 (dt, J = 41.61, 6.45, 4H), 4.20-3.92 (m, 2H), 3.82 - 3.77 (m, 2H), 3.48-3.30 (m, 2H), 3.14 (s, 5H), 2.41 (s, 4H), 2.13-1.96 (m, 4H), 1.87-1.81 (m, 2H).
Example 506: 2-(((3R,4S)-3-fluoro-l-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((l-(2- hydroxyethyl)-lH-pyrazol-4-yl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000487_0002
This molecule was synthesized in the same manner as Example 342 except starting with l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-lH-pyrazol-4-amine. Also, with the final step being: 5-(4-((l -(2-((tert-butyldimethylsilyl)oxy)ethyl)- lH-pyrazol-4-yl)amino)- 1 ,3,5- triazin-2-yl)-2-(((3R,4S)-3-fluoro-l-(2-hydroxyacetyl)piperidin-4-yl)oxy)benzonitrile (80 mg, 0.13 mmol) was dissolved in THF (13.4 mL), cooled to 0°C, 1M Tetrabutylammonium fluoride solution 1.0 M in THF in THF (0.16 ml) was added dropwise and the reaction was allowed to stir for 45 minutes. The reaction was quenched with iced water, extracted with DCM. The organic layer was combined, washed, dried and filtered. Solvent was removed by vacuum to provide 2-(((3R,4S)-3-fluoro-l-(2- hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((l-(2-hydroxyethyl)-lH-pyrazol-4-yl)amino)- l,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C22H23F 804: 482.18; found: 483.23. ¾ NMR (300 MHz, DMSO-i¾) δ 10.32 (s, 1H), 8.81 (s, 1H), 8.71 (s, 1H), 8.65 - 8.50 (m, 1H), 7.95 (d, J = 10.56, 1H), 7.69-7.59 (m, 2H), 5.31-4.68 (m, 4H), 4.36-3.77 (m, 4H), 3.75-3.71 (m, 2H), 3.66-3.78 (m, 1H), 3.15-3.05 (m, 1H), 2.07-1.85 (m, 2H), 1.23 (s, 1H). Example 507: 5-(4-((lH-pyrazol-4-yl)amino)-l,3,5-triazin-2-yl)-2-(((3R,4S)-3-fluoro-l-(2- hydroxyacetyl)piperidin-4-yl)oxy)benzonitrile
Figure imgf000488_0001
This molecule was synthesized in the same manner as Example 342 except starting with l-(2-
((tert-butyldimethylsilyl)oxy)ethyl)-lH-pyrazol-4-amine. LCMS-ESI+ (m/z) : [M+H]+ calcd for C20H19FN8O3: 438.16; found : 439.23. :H NMR (300 MHz, DMSO-d6) δ 12.75 (s, 1H), 8.81 (d, J = 11.21 Hz, 1H), 8.80-8.55 (m, 3H), 8.02-7.61 (m, 3H), 7.69-7.59 (m, 2H), 5.31-4.68 (m, 4H), 4.36- 3.77 (m, 4H), 3.75-3.71 (m, 2H), 3.66-3.78 (m, 1H), 3.15-3.05 (m, 1H), 2.07-1.85 (m, 2H), 1.23 (s, 1H). Example 508: 5-(4-((4-((S)-2,4-dimethylpiperazin-l-yl)-3-methoxyphenyl)amino)-l,3,5-triazin- 2-yl)-2-(((3R,4S)-3-fluoro-l-(2-hydroxyacetyl)piperidin-4-yl)oxy)benzonitrile
Figure imgf000489_0001
This molecule was synthesized in the same manner as Example 499 except starting with l-(2- ((tert-butyldimethylsilyl)oxy)ethyl)-lH-pyrazol-4-amine and substituting glycolic acid for L-(+)- lactic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C3oH35FN804: 590.28; found: 591.40. :H NM (300 MHz, DMSO-d6) δ 10.28 (m, 1H), 8.79 (s, 1H), 8.62-8.57 (m, 2H), 7.64 - 6.94 (m, 2 H), 6.94 (s, 2H), 5.19 - 4.97 (m, 2H), 4.70 - 4.64 (m, 1H), 4.45-3.45 (m, 8H), 3.60-3.35 (m, 3H), 3.20-3.0 (m, 2H), 3.09-2.72 (m, 2H), 2.40-3.76 (m, 1H), 2.20(s, 1H), 1.98-1.70 (m, 2H), 0.83 (d, J= 6.45 Hz, 3H).
Example 509: 2-(((3R,4S)-l-((S)-2,3-dihydroxypropanoyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4- (l-(oxetan-3-yl)piperidin-4-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000489_0002
This molecule was synthesized in the same manner as Example 318 except substituting (S)-2,3- dihydroxypropanoic acid for lH-pyrazole-5-carboxylic acid. LCMS-ESI"1" (m/z): [M+H]+ calcd for C32H36FN705: 617.28; found: 618.43. :H NMR (300 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.78 (s, 1H), 8.59 (d, J = 7.65 Hz, 2H), 7.66 (t, J = 7.65 Hz, 3H), 7.26 (d, J = 7.65 Hz, 2H), 5.19-4.98 (m, 2H), 4.83-4.62 (m, IH), 4.57-4.32 (m, 4H), 4.32-3.85 (m, 2H), 3.80-3.50 (m, 5H), 3.85-3.75 (d, J = 10.44 Hz, 2H), 2.16 - 1.60 (m, 8H), 1.22 (s, IH).
Example 510: 2-(((3R,4S)-l-((S)-2,3-dihydroxypropanoyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((6- (4-(oxetan-3-yl)piperazin-l-yl)pyridin-3-yl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000490_0001
This molecule was synthesized in the same manner as Example 336 except starting with 2- fluoro-5-nitropyridine and substituting (S)-2,3-dihydroxypropanoic acid for pyrazine-2- carboxylic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C3oH34FN905: 619.27; found: 620.37. :H NM (300 MHz, DMSO-d6) δ 10.13 (m, IH), 8.74 (s, IH), 8.60-8.35 (m, 3H), 7.85 (s, IH), 7.63 (d, J = 9.74 Hz, 2H), 5.19-5.16 (m, 2H), 5.00-4.97 (m, IH), 4.76-4.13 (m, 5H), 3.80-3.30 (m, 9H), 2.45- 2.25 (m, 5H), 2.18-1.80 (m,2H).
Example 511: 2-(((3R,4S)-l-((S)-2,3-dihydroxypropanoyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((5- methoxy-6-(4-(oxetan-3-yl)piperazin-l-yl)pyridin-3-yl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000490_0002
This molecule was synthesized in the same manner as Example 336 except starting with 2- fluoro-3-methoxy-5-nitropyridine and substituting (S)-2,3-dihydroxypropanoic acid for pyrazine-
2-carboxylic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C31H36FN906: 649.28; found : 650.38. :H NM (300 MHz, DMSO-d6) δ 10.28 (m, 1H), 8.80 (s, 1H), 8.60-8.56 (m, 2H), 8.12 (s, 1H), 7.86- 7.63 (m, 2H), 5.28-4.98 (m, 3H), 4.80-4.32 (m, 7H), 4.13-3.80 (m, 5H), 3.70-3.36 (m, 4H), 2.38 (s, 4H), 2.18-1.80 (m,2H).
Example 512: 2-(((3R,4S)-l-((S)-2,3-dihydroxypropanoyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((l- (2-hydroxy-2-methylpropyl)-lH-pyrazol-4-yl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000491_0001
This molecule was synthesized in the same manner as Example 342 except starting with l-(4- amino-lH-pyrazol-l-yl)-2-methylpropan-2-ol and substituting (S)-2,3-dihydroxypropanoic acid for L-(+)-lactic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C25H29FN805: 540.22; found: 541.30. :H NMR (300 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.82-8.56 (m, 3H), 8.01 (m, 1H), 7.66 - 7.58 (m, 2H), 5.19-4.96 (m, 3H), 7.73-7.69 (m, 2H), 4.40-4.32 (m, 1H), 4.20-3.85 (m, 3H), 3.75-3.35 (m, 2H), 2.15-1.70 (m, 2H), 1.08 (d, J = 12.89 Hz, 6H).
Example 513: 2-(((3R,4S)-l-((S)-2,3-dihydroxypropanoyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((5- methyl-6-(4-(oxetan-3-yl)piperazin-l-yl)pyridin-3-yl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000492_0001
This molecule was synthesized in the same manner as Example 336 except starting with 2- fluoro-3-methyl-5-nitropyridine and substituting (S)-2,3-dihydroxypropanoic acid for pyrazine-2- carboxylic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C31H36FN905: 633.28; found: 634.38. :H NM (300 MHz, DMSO-d6) δ 10.28 (s, IH), 8.79 (s, IH), 8.57 - 8.36 (m, 3H), 7.89 (s, IH), 7.65 (d, J = 9.38 Hz, IH), 5.18-4.80 (m, 7H), 4.20-3.35 (m, 3H), 3.06 (s, 5H), 2.42 (s, 5H), 2.26 (s, 5H), 2.16 - 1.78 (m, 2H).
Example 514: 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((5- methoxy-6-(4-(oxetan-3-yl)piperazin-l-yl)pyridin-3-yl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000492_0002
This molecule was synthesized in the same manner as Example 336 except starting with 2- fluoro-3-methoxy-5-nitropyridine and substituting L-(+)-lactic acid for pyrazine-2-carboxylic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C31H36FN905: 633.28; found : 634.41. :H NMR (300 MHz, DMSO-d6) δ 10.28 (m, IH), 8.80 (s, IH), 8.60-8.56 (m, 2H ), 8.12 (s, IH), 7.86-7.63 (m, 2H), 5.28-4.98 (m, 3H), 4.80-4.32 (m, 7H), 4.13-3.80 (m, 5H), 3.70-3.36 (m, 4H), 2.38 (s, 4H), 2.18- 1.80 (m, 2H).
4yu Example 515: 2-(((3R,4S)-l-((S)-2,3-dihydroxypropanoyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4- ((S)-2,4-dimethylpiperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000493_0001
This molecule was synthesized in the same manner as Example 499 except starting with (S)-2,4- dimethyl-l-(4-nitrophenyl)piperazine and substituting (S)-2,3-dihydroxypropanoic acid for L-(+)- lactic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C3oH35FN804: 590.28; found: 591.36. :H NM (300 MHz, DMSO-d6) δ 10.11 (m, IH), 8.74 (s, IH), 8.59-8.56 (m, 2H), 7.64 - 7.40 (m, 3H), 6.91 (s, 2H), 5.16 - 4.87 (m, 3H), 4.75 - 4.55 (m, IH), 4.45-3.68 (m, 8H), 3.67-3.35 (m, 4H), 3.25-3.10 (m, IH), 3.05-2.90 (m, IH), 2.80-2.70 (m, IH), 2.60-2.50 (m, IH), 2.35-2.25 (m, IH), 2.15-2.05 (m, IH), 2.03-1.80 (m, 2H), 1.08-0.92 (m, 3H).
Example 516: 5-(4-((3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-7-yl)amino)-l,3,5-triazin-2-yl)-2- (((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)benzonitrile
Figure imgf000493_0002
This molecule was synthesized in the same manner as Example 342 except starting with 3,4- dihydro-2H-pyrido[3,2-b] [l,4]oxazin-7-amine. LCMS-ESI+ (m/z): [M+H]+ calcd for C26H26FN804: 520.20; found : 521.33. :H NMR (300 MHz, DMSO-d6) δ 10.03 (m, IH), 8.72 (s, IH), 8.58-8.50 (m, 2H), 7.96-7.32 (m, 3H), 6.61 (s, 1H), 5.20 - 4.92 (m, 3H), 4.28- 4.55 (m, 1H), 4.22-4.05 (m, 3H), 3.37 (s, 2H), 2.05-1.70 (m, 2H), 1.19 (m, 3H).
Example 517: 5-(4-((3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)amino)-l,3,5-triazin-2-yl)-2- (((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)benzonitrile
Figure imgf000494_0001
This molecule was synthesized in the same manner as Example 342 except starting with 3,4- dihydro-2H-benzo[b] [l,4]oxazin-6-amine. LCMS-ESI+ (m/z): [M+H]+ calcd for C26H26FN704: 519.20; found : 520.33. :H NMR (300 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.72 (s, 1H), 8.59 - 8.57 (m, 2H), 7.62 (d, J = 9.05 Hz, 1H), 7.03 (s, 1H), 6.79 (s, 1H), 6.60 (d, J = 9.04 Hz, 1H), 6.00-5.85 (m, 1H), 5.22 - 4.92 (m, 3), 4.65-4.30 (m, 1H), 4.20- 3.90 (m, 4H), 3.30-3.10 (m, 4H), 2.08-1.75 (m, 2H), 1.30-1.15 (m, 3H).
Example 518: 2-(((3R,4S)-l-((S)-2,3-dihydroxypropanoyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4- ((R)-l,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000494_0002
This molecule was synthesized in the same manner as Example 342 except starting with (R)-3- (4-aminophenyl)-l,4-dimethylpiperazin-2-one. LCMS-ESI+ (m/z): [M+H]+ calcd for C3oH33FN804: 588.26; found : 589.39. 610.33 (s, 1H), 8.79 (s, 1H), 8.60-8.57 (m, 2H), 7.65 - 7.62 (m, 3H), 7.26 (d, J = 7.66, 2H), 5.12 - 4.95 (m, 3H), 4.02 - 4.30 (m, 1H), 3.65-3.52 (m, 2H), 3.28-3.10 (m, 3H), 3.05-2.95 (m, 1H), 2.82 (s, 3H), 2.60-2.50 (m, 1H), 2.05 (s, 3H), 2.03-1.75 (m, 2H), 1.22-1.70 (m, 3H).
Example 519: 2-(((S)-3,3-difluoro-l-((S)-2-oxooxazolidine-4-carbonyl)piperidin-4-yl)oxy)-5-(4- ((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000495_0001
(S)-2-((3,3-difluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (30 mg, 0.055 mmol), HATU (42 mg, 0.11 mmol), DIEA (22 mg, 0.16 mmol) and (S)-2-oxooxazolidine-4-carboxylic acid (15 mg, 0.11 mmol) were dissolved in DMF( 1.5 mL) and stirred at room temperature for 2hr. The mixture was treated with water and extracted with DCM. The organic phase was dried over Na2S04, concentrated to dryness. The residue was purified by silica gel column chromatography using 0-15% MeOH in CH2C12 as eluent to give the product. ¾ NMR (400 MHz, DMSO-d6) δ 10.13 (d, 1H), 8.74 (s, 1H), 8.58 (t, 2H), 7.98 (d, 1H), 7.74 - 7.41 (m, 3H), 6.96 (d, 2H), 5.38 (s, 1H), 4.90 (m, 1H), 4.51 (m, 4H), 4.35 - 4.02 (m, 2H), 3.96 - 3.62 (m, 3H), 3.55 - 3.38 (m, 2H), 3.13 (s, 4H), 2.39 (d, 4H), 2.27 - 1.72
(m, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H33 F2N905: 662.26; found: 662.39 Example 520: 2-(((S)-3,3-difluoro-l-((R)-2-oxothiazolidine-4-carbonyl)piperidin-4-yl)oxy)-5-(4- ((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000496_0001
(S)-2-((3 ,3 -difluoropiperidin-4-yl)oxy)-5 -(4-((4-(4-(oxetan-3 -yl)piperazin- 1 - yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (30 mg, 0.065 mmol), HATU (42 mg, 0.11 mmol), DIEA (22 mg, 0.16 mmol) and (R)-2-oxothiazolidine-4-carboxylic acid (16 mg, 0.1 1 mmol) were dissolved in DMF (1.5 mL) and stirred at room temperature for 2 hr. The mixture was treated with water and extracted with DCM. The organic phase was dried over Na2S04, concentrated to dryness. The residue was purified by silica gel column chromatography using 0-15% MeOH in CH2CI2 as eluent to give the product. XH NMR (400 MHz, DMSO-d6) δ 10.14 (d, 1H), 8.74 (s, 1H), 8.66 - 8.49 (m, 2H), 8.22 (d, 1H), 7.67 (t, 1H), 7.63 - 7.47 (m, 2H), 6.97 (d, 2H), 5.39 (s, 1H), 4.96 (m, 1H), 4.56 (t, 2H), 4.46 (t, 2H), 4.36 - 3.91 (m, 1H), 3.86 - 3.65 (m, 3H), 3.63 - 3.39 (m, 2H), 3.38 - 3.31 (m, 1H), 3.13 (s, 4H), 2.40 (t, 4H), 2.28 - 1.75 (m, 2H). LCMS-ESI+ (m/z):
[M+H]+ calcd for C32H33F2N9O4S: 678.3; found: 678.3
Example 521: 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-3-methyl-5- (4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000497_0001
Step 1 : Preparation of (3R,4S)-tert-butyl 4-(4-bromo-2-cyano-6-methylphenoxy)-3- fluoropiperidine-l-carboxylate: PS-PPI13 resin (8.16 g, 31.1 mmol, 4.4 equiv) was added to a dried 500 mL RBF that was then capped and flushed with nitrogen. The resin was suspended in 110 mL of anhydrous THF. After a period of 2 min, 5-bromo-2- hydroxy-3-methylbenzonitrile (1.5 g, 7.07 mmol) dissolved in 60 mL of anhydrous THF was added in a single portion. The resultant suspension was mixed briefly, after which a solution of DEAD (1.97 g, 11.3 mmol) was added in a single portion. This mixture was then stirred for 30min, after which a solution of (3R,4R)-tert-butyl 3-fluoro-4- hydroxypiperidine-l-carboxylate (1.94 g, 8.84 mmol) in THF (60 mL) was added in a single portion. The reaction mixture was then stirred 3 h. Then another portion of DEAD was added. The stirring was maintained overnight. The resultant suspension was filtered, and the resin was washed with THF. The filtrate was evaporated in vacuum. Solids were dissolved in DCM and water was added. The organic phase was evaporated under reduced pressure and purified by silica gel column chromatography with EtOAc in hexanes to give the product.
Step 2: Preparation of (3R,4S)-tert-butyl 4-(2-cyano-6-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)-3-fluoropiperidine-l-carboxylate:
(3R,4S)-tert-Butyl 4-(4-bromo-2-cyano-6-methylphenoxy)-3-fluoropiperidine-l- carboxylate (1.91 g, 4.62 mmol), potassium acetate (1.36 g, 13.86 mmol), bis(pinacolato)diboron (2.347 g, 9.24 mmol), and Pd(dppf)Cl2 (343 mg, 0.462 mmol) were combined in a sealed tube. 1.4-Dioxane (50 mL) was added and the mixture was heated at 90 °C overnight. After cooling down, the mixture was filtered through a pad of Celite, eluting with 1,4-dioxane. The filtrate was concentrated to dryness under reduced pressure and the residue was purified by a silica gel column with 0-30% EtOAc in hexanes to give the product. Step 3: Preparation of (3R,4S)-tert-butyl 4-(2-cyano-6-methyl-4-(4-((4-(4-(oxetan-3- yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-l- carboxylate: To a mixture of the (3R,4S)-tert-butyl 4-(2-cyano-6-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)-3-fluoropiperidine-l-carboxylate (1.25g, 2.7 mmol), 4-chloro-N-(4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)-l,3,5-triazin-2-amine (945 mg, 2.7 mmol), and Pd(PPh3)4 (236 mg, 0.204 mmol) in 1,2-DME (12 mL) , was added 2M sodium carbonate solution (6.1 mL ). The mixture was run under microwave at 130 °C for 75 minutes. Then the reaction mixture was diluted with a mixture of DCM and MeOH (1 : 1), filtered through a pad of Celite. The biphasic filtrate was concentrated under reduced pressure. Ethanol was added and concentrated. The residue was passed over a silica gel column with 5-15% MeOH in CH2C12 to give the product. LCMS-ESI"1"
(m/z): [M+H]+ calcd for C34H41 FN804: 645.3; found: 645.5
Step 4: Preparation of 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-3-methyl-5-(4-((4-(4- (oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile: (3R,4S)- tert-butyl 4-(2-cyano-6-methyl-4-(4-((4-(4-(oxetan-3 -yl)piperazin- 1 -yl)phenyl)amino)- l,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-l-carboxylate (670 mg, 1.04 mmol) was taken up in DCM (12 mL) and treated with TFA (3 mL). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the residue was used for next step. LCMS-ESI"1" (m/z): [M+H]+ calcd for C29H33F 802: 545.3; found: 545.2
Step 5 : 2-(((3 R,4S)-3 -fluoropiperidin-4-yl)oxy)-3 -methyl-5 -(4-((4-(4-(oxetan-3 - yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (128 mg, 0.24 mmol), HATU (179 mg, 0.47 mmol) , DIEA (91 mg, 0.71 mmol), and (S)-2-hydroxypropanoic acid (42 mg, 0.47 mmol) were dissolved in DMF (4 mL) and stirred at room temperature for 2 h. The mixture was treated with water and extracted with DCM. The organic phase was dried over Na2S04, concentrated to dryness. The residue was purified by silica gel column chromatography using 5-20% MeOH in CH2CI2 as eluent to give the product. XH NMR (400 MHz, DMSO-d6) δ 10.17 (d, 1H), 8.76 (s, 1H), 8.57 - 8.31 (m, 2H), 7.56 (m, 2H), 7.16 - 6.83 (m, 3H), 5.74 (s, 1H), 5.10 - 4.88 (m, 2H), 4.78 - 4.61 (m, 1H), 4.56 (t, 2H), 4.46 (t, 2H), 4.26 (d, 1H), 4.03 (d, 1H), 3.52 - 3.38 (m, 1H), 3.24 - 3.03 (m, 4H),
2.89 (d, 1H), 2.39 (d, 7H), 2.00 (m, 2H), 1.24 - 1.11 (m, 3H). LCMS-ESI"1" (m/z): [M+H]+ calcd for C32H37F 804: 617.3; found: 617.4 Example 522: 2-(((3R,4S)-3-fluoro-l-(2-hydroxyacetyl)piperidin-4-yl)oxy)-3-methyl-5-(4-((4-(4- (oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000499_0001
2-(((3R,4S)-3-Fluoropiperidin-4-yl)oxy)-3-methyl-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (128 mg, 0.24 mmol), HATU (179 mg, 0.47 mmol) , DIEA (91 mg, 0.71 mmol), and glycolic acid (36 mg, 0.47 mmol) were dissolved in DMF (4 mL) and stirred at room temperature for 2 h. The mixture was treated with water and extracted with DCM. The organic phase was dried over a2S04, concentrated to dryness. The residue was purified by silica gel column chromatography using 5-20% MeOH in CH2C12 as eluent to give the product. XH NMR (400 MHz, DMSO-d6) δ 10.17 (d, 1H), 8.75 (s, 1H), 8.58 - 8.31 (m, 1H), 7.66 - 7.41 (m, 1H), 6.96 (d, 1H), 5.74 (s, 2H), 4.97 (d, 1H), 4.76 - 4.60 (m, 2H), 4.56 (m, 2H), 4.46 (t, 2H), 4.28 (d, 1H), 4.21 - 3.92 (m, 2H), 3.74 (d, 1H), 3.44 (m, 2H), 3.14 (d, 4H), 2.88 (m, 1H), 2.39 (m, 7H), 2.10 - 1.86 (m, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd for C3 iH35F 804:
603.3; found: 603.4
Example 523: 2-(((3R,4S)-3-fluoro-l-((4S,5R)-5-methyl-2-oxooxazolidine-4-carbonyl)piperidin- 4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000499_0002
2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (131 mg, 0.27 mmol), HATU (188 mg, 1.1 mmol), DIEA (96 mg, 0.74 mmol) and (4S,5R)-5-methyl-2-oxooxazolidine-4- carboxylic acid (72 mg, 0.49 mmol) were dissolved in DMF (4 mL) and stirred at room temperature for 2hr. The reaction mixture was concentrated to dryness and the residue was purified by silica gel column with 5-20% MeOH in (¾(¾ to give the product as a yellowish solid. XH NMR (400 MHz, DMSO-d6) δ 10.13 (d, 1H), 8.74 (s, 1H), 8.65 - 8.48 (m, 2H), 7.90 (d, 1H), 7.69 - 7.47 (m, 4H), 6.96 (s, 2H), 5.23 - 4.95 (m, 3H), 4.70 - 4.34 (m, 4H), 4.31 - 4.03 (m, 1H), 3.77 (d, 1H), 3.67 - 3.37 (m, 2H), 3.13 (m, 4H), 2.40 (s, 4H), 2.04-1.81 (m, 2H), 1.36 (m, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C33H36F 905: 658.3; found: 658.4
Example 524: 2-(((3R,4S)-3-fluoro-l-((4S,5S)-5-methyl-2-oxooxazolidine-4-carbonyl)piperidin- 4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrH
2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (129 mg, 0.24 mmol), HATU (185 mg, 0.49 mmol), DIEA (94 mg, 0.73 mmol) and (4S,5S)-5-methyl-2-oxooxazolidine-4- carboxylic acid (71 mg, 0.31 mmol) were dissolved in DMF( 4 mL) and stirred at room temperature for 2hr. The mixture was concentrated to dryness and the residue was purified by silica gel column with 5-20 MeOH in (¾(¾ to give the product. XH NMR (400 MHz, DMSO-d6) δ 10.11 (d, 1H), 8.73 (s, 1H), 8.65 - 8.44 (m, 2H), 7.68 - 7.48 (m, 4H), 6.95 (s, 2H), 5.23 - 4.79 (m, 4H), 4.86 (m, m 1H), 4.63 - 4.39 (m, 4H), 4.38 - 4.12 (m, 2H), 3.44 (t, 1H), 3.13 (s, 4H), 2.40 (t, 4H), 181-1.99 (m, , 2H), 1.22 (m, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C33H36F 905: 658.3; found: 658.4
Example 525: 2-(((3R,4S)-3-fluoro-l-(2-oxo-2,3-dihydrooxazole-4-carbonyl)piperidin
5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000501_0001
3 -Fluoro-2-(((3 R,4S)-3 -fluoropiperidin-4-yl)oxy)-5 -(4-((4-(4-(oxetan-3 -yl)piperazin- 1 - yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (91 mg, 0.172 mmol), HATU (130 mg, 0.34 mmol), DIEA (67 mg, 0.52 mmol) and 2-oxo-2,3-dihydrooxazole-4-carboxylic acid (45 mg, 0.343 mmol) were dissolved in DMF (4 mL) and stirred at room temperature overnight. The mixture was concentrated and the residue was purified by silica gel column with 5-20 % MeOH in CH2C12 to give the product. ¾ NMR (400 MHz, DMSO- de) δ 11.19 (s, 1H), 10.12 (d, , 1H), 8.82 - 8.66 (m, 1H), 8.65 - 8.46 (m, 2H), 7.73 - 7.61 (m, 2H), 7.57 (t, 3H), 6.95 (s, 2H), 5.03-5.15 (m, 2H), 4.56 (t, 2H), 4.46 (t, 2H), 4.38 (s, 2H), 4.15 (s, 1H), 3.44 (m, 1H), 3.13 (s, 4H), 2.40 (t, 4H), 2.12 - 1.78 (m, 2H). LCMS-
ESI+ (m/z): [M+H]+ calcd for C32H32 FN905: 642.3; found: 642.3
Example 526: 2-(((3R,4S)-l-(3,4-dimethyl-lH-pyrazole-5-carbonyl)-3-fluoropiperidin-4-yl)oxy)- 5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000502_0001
3 -Fluoro-2-(((3 R,4S)-3 -fluoropiperidin-4-yl)oxy)-5 -(4-((4-(4-(oxetan-3 -yl)piperazin- 1 - yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (85 mg, 0.16 mmol), HATU (122 mg, 0.32 mmol), DIEA (62 mg, 0.48 mmol) and 3,4-dimethyl-lH-pyrazole-5-carboxylic acid (45 mg, 0.32 mmol) were dissolved in DMF (4 mL) and stirred at room temperature overnight. The mixture was concentrated and the residue was purified by silica gel column with 5-20 % MeOH in CH2C12 to give the product. ¾ NMR (400 MHz, DMSO- d6) δ 12.65 (s, 1H), 10.13 (d, 1H), 8.73 (s, 1H), 8.65 - 8.42 (m, 2H), 7.71 - 7.40 (m, 4H), 7.07 - 6.83 (m, 3H), 5.23 - 4.92 (m, 2H), 4.51 (m, 4H), 4.21 (m, 1H), 3.73 (m, 1H), 3.52 - 3.39 (m, 1H), 3.13 (s, 4H), 2.40 (s, 4H), 2.15 (s, 3H), 1.95 (m, 5H). LCMS-ESI+ (m/z):
[M+H]+ calcd for C34H37 FN10O3: 653.3; found: 653.5
Example 527: 2-(((3R,4S)-3-fluoro-l-(4-methyl-lH-imidazole-2-carbonyl)piperidin-4-yl)oxy)-5- (4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000502_0002
3 -Fluoro-2-(((3 R,4S)-3 -fluoropiperidin-4-yl)oxy)-5 -(4-((4-(4-(oxetan-3 -yl)piperazin- 1 - yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (82 mg, 0.15 mmol), HATU (117 mg, 0.31 mmol), TEA (76 mg, 0.62 mmol) and 4-methyl-lH-imidazole-2-carboxylic acid (41 mg, 0.31 mmol) were dissolved in DMF( 4 mL) and stirred at room temperature overnight. The mixture was concentrated and the residue was purified by silica gel column with 5-20 % MeOH in CH2C12 to give the product. XH NMR (400 MHz, DMSO- d6) δ 12.63 (m, 1H), 10.12 (d, 1H), 8.83 - 8.34 (m, 2H), 7.83 - 7.33 (m, 4H), 6.76 (d, 1H), 5.91 - 5.55 (m, 1H), 5.37 (s, 1H), 5.08 (m, 3H), 4.51 (m, 4H), 4.30 (d, 1H), 3.79 (m, 1H), 3.43 (m,lH), 3.13 (s, 4H), 2.40 (t, 4H), 2.15 (s, 3H), 1.65-1.98 (m, 2H).
LCMS-ESI+ (m/z): [M+H]+ calcd for C33H35 FNi0O3: 639.3; found: 639.2
Example 528: 2-(((3R,4S)-3-fluoro-l-(4-methyl-lH-pyrazole-5-carbonyl)piperidin-4-yl)oxy)-5- (4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000503_0001
3 -Fluoro-2-(((3 R,4S)-3 -fluoropiperidin-4-yl)oxy)-5 -(4-((4-(4-(oxetan-3 -yl)piperazin- 1 - yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (82 mg, 0.15 mmol), HATU (117 mg, 0.31 mmol), TEA (76 mg, 0.62 mmol) and 4-methyl-lH-pyrazole-5-carboxylic acid (41 mg, 0.31 mmol) were dissolved in DMF( 4 mL) and stirred at room temperature overnight. The mixture was concentrated and the residue was purified by silica gel column with 5-20 % MeOH in CH2C12 to give the product. ¾ NMR (400 MHz, DMSO- d6) δ 12.87 (s, 1H), 10.12 (d, 1H), 8.73 (d, 1H), 8.65 - 8.42 (m, 2H), 7.58 (m, 4H), 6.95 (s, 2H), 5.30 - 4.84 (m, 3H), 4.55 (t, 2H), 4.46 (t, 2H), 4.22 (m, 1H), 3.87 - 3.60 (m,
1H), 3.43 (t, 1H), 3.13 (d, 4H), 2.40 (t, 4H), 2.15 - 1.82 (m, 5H). LCMS-ESI+ (m/z):
[M+H]+ calcd for C33H35 FNi ()03: 639.3; found: 639.3 Example 529: 2-(((3R,4S)-3-fluoro-l-((S)-4-oxoazetidine-2-carbonyl)piperidin-4-yl)oxy)-5-(4- ((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000504_0001
3 -Fluoro-2-(((3 R,4S)-3 -fluoropiperidin-4-yl)oxy)-5 -(4-((4-(4-(oxetan-3 -yl)piperazin- 1 - yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (82 mg, 0.15 mmol), HATU (117 mg, 0.31 mmol), TEA (76 mg, 0.62 mmol) and (S)-4-oxoazetidine-2-carboxylic acid (41 mg, 0.31 mmol) were dissolved in DMF (4 mL) and stirred at room temperature for 2hr. The mixture was diluted with DCM and extracted with water. The organic phase was concentrated and the residue was purified by silica gel column with 5-20 % MeOH in CH2Cl2 to give the product. ¾ NMR (400 MHz, DMSO-d6) δ 10.12 (d, 1H), 8.73 (s, 1H), 8.64 - 8.45 (m, 2H), 8.25 (d, 1H), 7.69 - 7.43 (m, 4H), 6.95 (t, 2H), 5.21 - 4.87 (m, 2H), 4.55 (t, , 2H), 4.47 (t, 2H), 4.39 - 4.27 (m, 1H), 4.16 (d, 1H), 3.98 (m, 1H), 3.74 - 3.38 (m, 2H), 3.13 (s, 4H), 2.92 - 2.68 (m, 1H), 2.40 (t, 4H), 2.12 - 1.68 (m, 2H).
LCMS-ESI+ (m/z): [M+H]+ calcd for C32H34 FN9O4: 628.3; found: 628.3
Example 530: 2-(((3R,4S)-3-fluoro-l-((R)-2-oxothiazolidine-4-carbonyl)piperidin-4-yl)oxy)-5-(4- ((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000505_0001
3 -Fluoro-2-(((3 R,4S)-3 -fluoropiperidin-4-yl)oxy)-5 -(4-((4-(4-(oxetan-3 -yl)piperazin- 1 - yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (82 mg, 0.15 mmol), HATU (117 mg, 0.31 mmol), TEA (76 mg, 0.62 mmol) and (R)-2-oxothiazolidine-4-carboxylic acid (41 mg, 0.31 mmol) were dissolved in DMF (4 mL) and stirred at room temperature for 2hr. The mixture was diluted with DCM and extracted with water. The organic phase was concentrated and the residue was purified by silica gel column with 5-20 % MeOH in CH2Cl2 to give the product. ¾ NMR (400 MHz, DMSO-d6) δ 10.12 (d, 1H), 8.73 (s, 1H), 8.64 - 8.46 (m, 2H), 8.19 (d, 1H), 7.71 - 7.44 (m, 2H), 6.95 (s, 1H), 5.74 (s, 1H), 5.22 - 4.96 (m, 1H), 4.92 (m, 1H), 4.55 (m, 2H), 4.46 (m, 2H), 4.15 (t, 1H), 3.84 (d, 1H), 3.77 - 3.52 (m, 2H), 3.39 - 3.30 (m, 4H), 3.13 (m, 4H), 2.40 (t, 4H), 1.98 - 1.83 (m,
2H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H34 FN9O4S: 660.2; found: 660.3
Example 531: (R)-5-(4-((3-methoxy-4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5- triazin-2-yl)-2-((6-oxopiperidin-3-yl)oxy)benzonitrile
Figure imgf000505_0002
Step 1. To solution of 2,4-dichloro-l,3,5-triazine (370 mg, 2.47 mol) in DMF (20 mL) at 0 °C was added solution of 3-methoxy-4-(4-(oxetan-3-yl)piperazin-l-yl)aniline (500 mg, 1.90 mmol) in DMF (20 mL). The reaction mixture was stirred at 0 °C for 30 min. Reaction completed and the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel to afford 4-chloro-N-(3-methoxy-4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)-l,3,5-triazin-2-amine. LCMS-ESI+ (m/z) : [M+H]+ calcd for C17H21CIN602: 377.1; found : 377.3.
Step 2. To a solution of 4-chloro-N-(3-methoxy-4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)-l,3,5- triazin-2-amine (525 mg, 1.39 mmol), 2-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzonitrile, (379 mg, 1.53 mmol), and tetrakis(triphenylphosphine)palladium(0) (80 mg, 0.070 mmol) in DME (9 mL) was added a solution of sodium carbonate (443 mg, 4.18 mmol) in water (5 mL). The mixture was heated at 120 °C for 35 min by microwave. The mixture was diluted with 30% MeOH in CH2CI2 and filtered through a short pad of silica gel which was washed with 30% MeOH in CH2CI2. The mixture was adsorbed onto silica gel, and solvent was removed under reduced pressure. The slurry was loaded onto silica gel and purified by flash column chromatography to afford 2-fluoro-5-(4-((3-methoxy-4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C24H24FN702: 462.2; found : 462.3.
Step 3. To a solution of 5-hydroxypiperidin-2-one (74.8 mg, 0.650 mmol) in DMF (4 mL) was added potassium t-butoxide (109 mg, 0.975 mmol) at 0 °C. The reaction mixture was allowed to stir for 1 hour. To the reaction mixture was added a solution of 2-fluoro-5-(4-((3-methoxy-4-(4- (oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile in DMF (2mL) at room temperature. The reaction mixture was brought to 80 °C and heated overnight. The solvent was concentrated under reduced pressure and dissolved in 0.1%TFA in 1: 1 H20:MeCN and purified by preparative HPLC to afford product (R)-5-(4-((3-methoxy-4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)-2-((6-oxopiperidin-3-yl)oxy)benzonitrile. :H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.79 (s, 1H), 8.60 (s, 1H), 8.57 (d, J = 2.2 Hz, 1H), 7.71 (s, 1H), 7.58 (d, J = 8.9 Hz, 1H), 7.46 (s, 1H), 7.20 (s, 1H), 6.97 (d, J = 8.7 Hz, 1H), 5.17 - 5.07 (m, 2H), 4.76 (d, J = 6.5 Hz, 2H), 4.48 (s, 1H), 3.95 (s, 1H), 3.87 (s, 3H), 3.52 (s, 3H), 3.36 (d, J = 13.7 Hz, 1H), 3.15 (s, 1H), 2.41 - 2.17 (m, 5H), 2.10 (d, J = 6.9 Hz, 4H).
LCMS-ES (m/z): [M+H]+ calcd for C29H32N804: 557.6; found: 557.7 Example 532: (R)-5-(4-((3-methyl-4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l;3;5-triazin- 2-yl)-2-((6-oxopiperidin-3-yl)oxy)benzonitrile
Figure imgf000507_0001
Step 1. To a stirred solution of l-fluoro-2-methyl-4-nitrobenzene (1.50 g, 9.67 mmol) in DMF (50 mL) in a sealed tube was added l-(oxetan-3-yl)piperazine (1.65 g, 11.6 mmol) and potassium carbonate (5.35 g, 38.7 mmol) at room temperature. The reaction mixture was brought to 100 °C and heated overnight. The solvent was removed under reduced pressure. The reaction was quenched with water, and extracted with EtOAc (3x50 mL) followed by CH2CI2 (2x50 mL) and dried over Na2S04. The organic phase was loaded onto silica gel and purified by flash column chromatography to afford l-(2-methyl-4-nitrophenyl)-4-(oxetan-3-yl)piperazine. LCMS-ESr (m/z): [M+H]+ calcd for C14H19N303: 278.1; found : 278.3.
Step 2. To a stirred solution of l-(2-methyl-4-nitrophenyl)-4-(oxetan-3-yl)piperazine (1.56 g, 5.34 mmol) in EtOH (50 mL) was added 10% Pd/C under a hydrogen atmosphere at room temperature. Reaction mixture was stirred overnight and filtered through a pad of Cel ite and washed with CH2CI2. Solvent was removed under reduced pressure to produce 3-methyl-4-(4- (oxetan-3-yl)piperazin-l-yl)aniline LCMS-ESI+ (m/z): [M+H]+ calcd for C14H21N30: 248.2; found : 248.4.
Step 3. 4-chloro-N-(3-methyl-4-(4-(oxetan-3-yl)piperazin-l-yl (phenyl )-l,3,5-triazin-2-a mine was prepared following the same procedure reported in Example 531 by coupling 3-methyl-4-(4- (oxetan-3-yl)piperazin-l-yl)aniline to 2,4-dichloro-l,3,5-triazine instead of 3-methoxy-4-(4- (oxetan-3-yl)piperazin-l-yl)aniline to afford product. LCMS-ESI+ (m/z): [M+H]+ calcd for C17H21CIN60: 361.2; found : 361.3.
Step 4. 2-fluoro-5-(4-((3-methyl-4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l;3;5-triazin-2- yl)benzonitrile was prepared following the same procedure reported in Example 531 by coupling 2-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile with 4-chloro-N- (3-methyl-4-(4-(oxetan-3-yl)piperazin-l-yl (phenyl )-l, 3, 5-triazin-2-amine instead of 4-chloro-N- (3-methoxy-4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)-l,3,5-triazin-2-amine to afford product. LCMS-ES (m/z): [M+H]+ calcd for C24H24FN70: 446.2; found: 446.4. Step 5. ( )-5-(4-((3-methyl-4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l;3;5-triazin-2-yl)-2- ((6-oxopiperidin-3-yl)oxy)benzonitrile was prepared following the same procedure reported in Example 531 by coupling 5-hydroxypiperidin-2-one with 2-fluoro-5-(4-((3-methyl-4-(4-(oxetan- 3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile instead of 2-fluoro-5-(4-((3- methoxy-4-(4-(oxetan-3-yl)piperazin-l-yl (phenyl )amino)-l,3,5-triazin-2-yl)benzonitrile to afford product. LCMS-ES (m/z): [M+H]+ calcd for C29H32N803: 541.3; found : 541.4. :H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.78 (s, 1H), 8.58 (d, J = 8.6 Hz, 1H), 7.66 (s, 1H), 7.58 (d, J = 9.4 Hz, 1H), 7.46 (s, 1H), 7.10 (d, J = 8.7 Hz, 1H), 5.12 (s, 1H), 4.83 - 4.72 (m, 4H), 4.55 - 4.48 (m, 1H), 3.52 (d, J = 14.2 Hz, 2H), 3.20 (s, 1H), 3.11 (s, 1H), 3.01 (s, 1H), 2.87 (s, 1H), 2.71 (s, 1H ), 2.41 - 2.16 (m, 6H), 2.10 (s, 4H), 2.05 (s, 2H ).
Example 533: 2-(((3R,4S)-3-fluoro-l-(3-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((3-methyl- 4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000508_0001
To a solution of 2-(((3R;4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((3-methyl-4-(4-(oxetan-3- yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (62 mg, 0.113 mmol) in DMF (4 mL) was added 3-hydroxypropanoic acid (61 mg, 1.36 mmol), N,N-diisopropylethylamine (175 mg, 1.36 mmol), l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, N-[(Dimethylamino)-lH-l,2,3-triazolo-[4,5-b]pyridin-l-ylmethylene]-N- methylmethanaminium hexafluorophosphate N-oxide (79.8 mg, 0.339 mmol) at room temperature and stirred overnight. Solvent was removed under reduced pressure, and crude was dissolved in 0.1%TFA in 1:3 H20:MeCN and purified by preparative HPLC to afford 2- (((3 ,4S)-3-fluoro-l-(3-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((3-methyl-4-(4-(oxetan-3- yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile LCMS-ESI+ (m/z): [M+H]+ calcd for C32H37FN804: 617.3; found : 617.5. :H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.78 (s, 1H), 8.58 (d, J = 8.5 Hz, 2H), 7.59 (dd, J = 32.9, 8.7 Hz, 3H), 7.10 (d, J = 8.6 Hz, 1H), 5.25 - 4.88 (m, 2H), 4.89 - 4.67 (m, 5H), 4.65 - 4.38 (m, 1H), 4.31 (s, 1H), 4.10 (s, 1H), 3.81 (d, J = 13.9 Hz, 1H), 3.70 - 3.30 (m, 4H), 3.11 (q, J = 41.8, 32.0 Hz, 5H), 2.52 (s, 2H), 2.29 (s, 3H), 1.85 (d, J = 93.9 Hz, 2H), 1.29 - 1.11 (m, 2H).
Example 534: 2-((2S,4R)-4-hydroxy-2-methylpyrrolidin-l-yl)-5-(4-((3-methyl-4-(4-(oxetan-3- yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000509_0001
A solution of 2-fluoro-5-(4-((3-methyl-4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile (60.0 mg, 0.135 mmol), N,N-diisopropylethylamine (17.4 mg, 0.135 mmol), and (3R,5S)-5-methylpyrrolidin-3-ol (17.0 mg, 0.168 mmol) in /-PrOH (3 mL) was heated by microwave irradiation to 150 °C for 3 hours. Solvent was removed under reduced pressure, and crude was dissolved in 0.1%TFA in 1:3 H20:MeCN and purified by preparative HPLC to afford 2-((2S,4R)-4-hydroxy-2-methylpyrrolidin-l-yl)-5-(4-((3-methyl-4-(4-(oxetan-3- yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C29H34N802: 527.3; found : 527.3.
:H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.69 (s, 1H), 8.45 (s, 1H), 8.32 (dd, J = 9.2, 2.2 Hz, 1H), 7.54 (d, J = 8.5 Hz, 2H ), 7.08 (d, J = 8.5 Hz, 1H), 7.02 (d, J = 9.3 Hz, 1H), 4.83 - 4.71 (m, 4H), 4.50 (s, 1H), 4.41 - 4.32 (m, 2H), 4.01 (dd, J = 10.9, 4.1 Hz, 1H), 3.95 (s, 1H), 3.15 (s, 8H), 2.29 (s, 3H), 2.13 (dd, J = 12.9, 7.0 Hz, 2H), 1.79 (ddd, J = 12.6, 8.0, 4.5 Hz, 2H), 1.21 (d, J = 6.0 Hz, 3H).
Example 535: 2-(((3R,4S)-3-fluoro-l-((S)-5-oxopyrrolidine-2-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-((S)-3-methyl-4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
Figure imgf000510_0001
Step 1: Preparation of (S)-tert-butyl 2-methyl-4-(4-nitrophenyl)piperazine-l- carboxylate: To 4-fluoro nitrobenzene (697 mg, 4.940 mmol) and (S)-tert-butyl 2- methylpiperazine-l-carboxylate (1650 mg, 8.239 mmol) dissolved in DMSO (37 mL) was added potassium carbonate (1050 mg, 7.597 mmol). The reaction mixture was heated at 90 °C for lh. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to give (S)-tert-butyl 2-methyl-4-(4-nitrophenyl)piperazine-l- carboxylate.
Step 2: Preparation of (S)-3-methyl-l-(4-nitrophenyl)piperazine: (S)-tert-butyl 2- methyl-4-(4-nitrophenyl)piperazine-l-carboxylate (500 mg, 1.556 mmol) dissolved in DCM (15 mL) was treated with trifluoroacetic acid (2200 μϊ^, 28.75 mmol). The reaction mixture was stirred at room temperature for lh and then concentrated. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The layers were separated. The organic layer was concentrated to give (S)-3 -methyl- 1 -(4- nitrophenyl)piperazine.
Step 3: Preparation of (S)-2-methyl-4-(4-nitrophenyl)-l-(oxetan-3-yl)piperazine: (S)-3 -methyl- l-(4-nitrophenyl)piperazine (283 mg, 1.279 mmol) dissolved in 1,2- dichloroethane (10 mL) was treated with 3-oxetanone (70 μΐ^, 1.092 mmol). The reaction mixture was stirred at room temperature for 1 h before sodium triacetoxyborohydride (353 mg, 1.666 mmol) was added. The reaction mixture was heated at 55 °C for 2h. It was then diluted with dichloromethane and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated to give (S)-2-methyl-4-(4- nitrophenyl)- 1 -(oxetan-3 -yl)piperazine.
Step 4: Preparation of (S)-4-(3-methyl-4-(oxetan-3-yl)piperazin-l-yl)aniline: (S)-2- methyl-4-(4-nitrophenyl)-l -(oxetan-3 -yl)piperazine (220 mg, 0.793 mmol) dissolved in ethanol (7 mL) was treated with ammonium formate (300 mg, 4.78 mmol) and 10% Pd/C (85 mg, 0.080 mmol). The reaction mixture was heated at 60 °C for lh. After cooling to room temperature, the reaction mixture was filtered, washed with methanol. The filtrate was concentrated to give (S)-4-(3-methyl-4-(oxetan-3-yl)piperazin-l-yl)aniline.
Step 5: Preparation of (S)-4-chloro-N-(4-(3-methyl-4-(oxetan-3-yl)piperazin-l- yl)phenyl)-l,3,5-triazin-2-amine: (S)-4-(3-methyl-4-(oxetan-3-yl)piperazin-l-yl)aniline (184 mg, 0.744 mmol) was dissolved in methanol (6 mL) and cooled to 0 °C. Triethyl amine (100 μί, 0.717 mmol) was then added, followed by 2,4-dichloro-l,3,5-triazine (1 10 mg, 0.733 mmol). The reaction mixture was allowed to warm to room temperature. After 30 min, the reaction mixture was concentrated. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated to give (S)-4-chloro-N-(4-(3-methyl-4-(oxetan-3- yl)piperazin- 1 -yl)phenyl)- 1 ,3 ,5-triazin-2-amine.
Step 6: Preparation of (3R,4S)-tert-butyl 4-(2-cyano-4-(4-((4-((S)-3-methyl-4- (oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)phenoxy)-3- fluoropiperidine-l-carboxylate: (S)-4-chloro-N-(4-(3-methyl-4-(oxetan-3-yl)piperazin- l-yl)phenyl)-l,3,5-triazin-2-amine (214 mg, 0.593 mmol) was dissolved in dioxane (5 mL) and the reaction mixture was degassed with argon. (3R,4S)-tert-butyl 4-(2-cyano-4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)-3-fluoropiperidine-l-carboxylate (270 mg, 0.605 mmol) was then added, followed by [1, 1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane (45 mg, 0.055 mmol), and 2M sodium carbonate solution (930 μί, 1.860 mmol). The reaction mixture was heated at 90 °C. After 3h, the reaction mixture was cooled to room temperature and concentrated. The residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to give (3R,4S)-tert-butyl 4-(2-cyano-4-(4-((4- ((S)-3 -methyl-4-(oxetan-3-yl)piperazin- 1 -yl)phenyl)amino)- 1 ,3 ,5-triazin-2-yl)phenoxy)- 3-fluoropiperidine-l-carboxylate.
Step 7: Preparation of 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-((S)-3-methyl-4-(oxetan-
3- yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile: (3 ,4S)-tert-butyl 4-(2-cyano-
4- (4-((4-((S)-3-methyl-4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)ph fluoropiperidine-l-carboxylate (290 mg, 0.450 mmol) dissolved in DCM (4 mL) was treated with trifluoroacetic acid (850 μΐ, 11.11 mmol). The reaction mixture was stirred at room temperature for 30 min and then concentrated. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The layers were separated. The organic layer was concentrated to give 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-((S)-3-methyl-4- (oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile.
Step 8: Preparation of 2-(((3R,4S)-3-fluoro-l-((S)-5-oxopyrrolidine-2-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-((S)-3-methyl-4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2- yl)benzonitrile: 2-(((3R;4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-((S)-3-methyl-4-(oxetan-3- yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (90 mg, 0.165 mmol) dissolved in DCM (3 mL) was treated with HATU (75 mg. 0.197 mmol), (S)-5-oxopyrrolidine-2-carboxylic acid (26 mg, 0.201 mmol), and N,N-diisopropylethylamine ( 100 μΐ, 0.574 mmol). The reaction mixture was stirred at room temperature for 30 min. It was then diluted with dichloromethane and washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by HPLC to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 10.18 (d, J = 23.4 Hz, 1H), 8.75 (s, 1H), 8.62 - 8.48 (m, 2H), 7.73 (d, J = 20.9 Hz, 1H), 7.63 (d, J = 9.1 Hz, 3H), 7.04 (s, 2H), 5.19 - 5.06 (m, 2H ), 5.01 (t, J = 6.6 Hz, 1H), 4.94 - 4.73 (m, 3H), 4.73 - 4.54 (m, 3H), 4.39 (m, 1H), 4.25 - 4.06 (m, 2H), 3.84 (m, 2H ), 3.32 (m, 1H), 3.14 - 2.94 (m, 2H), 2.79 (s, 1H), 2.31 (m, 1H), 2.17 - 2.04 (m, 2H), 1.98 (m, 1H), 1.95 - 1.74 (m, 1H),
1.18 (d, J = 6.5 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C34H38FN904: 656.3; found : 656.2. Example 536: 2-(((3R,4S)-3-fluoro-l-((S)-5-oxopyrrolidine-2-carbonyl)piperidin-4- yl)oxy)-5-(4-((3-methyl-4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
Figure imgf000513_0001
The title compound was synthesized in the same manner as Example 535 using l-(oxetan-3- yl)piperazine and l-fluoro-2-methyl-4-nitrobenzene. :H NM (400 MHz, DMSO-d6) δ 10.26 (s, IH), 8.78 (s, IH), 8.62 - 8.54 (m, 2H), 7.71 (s, IH), 7.69 - 7.61 (m, IH), 7.55 (d, J = 8.0 Hz, IH), 7.10 (d, J = 8.6 Hz, IH), 5.20 - 5.06 (m, 2H), 5.01 (s, IH), 4.60 (ddd, J = 14.1, 8.7, 3.8 Hz, IH), 4.49 (s, IH), 4.38, (m, IH), 4.13 (m, IH), 3.84 (m, IH), 2.30 (m, 2H ), 2.09 (m, 3H), 2.00 (m, 2H), 1.86 (m, 3H). LCMS-ESI+ (m/z) : [M+H]+ calcd for C34H38FN904: 656.3; found: 656.3.
Example 537: N-(5-((4-(3-cyano-4-(((3R,4S)-3-fluoro-l-((S)-5-oxopyrrolidine-2- carbonyl)piperidin-4-yl)oxy)phenyl)-l,3,5-triazin-2-yl)amino)pyridin-2- yl)acetamide
Figure imgf000513_0002
The title compound was synthesized in the same manner as Example 535 using N-(5- aminopyridin-2-yl)acetamide. :H NMR (400 MHz, DMSO-d6) δ 10.47 (s, IH), 10.42 (s, IH), 8.82 (s, IH), 8.65 - 8.52 (m, 3H), 8.10 (s, 2H), 7.76 - 7.62 (m, 2H), 5.10 (d, J = 23.8 Hz, 2H), 5.01 (s, IH), 4.60 (s, 2H), 4.38 (s, IH), 4.19 (d, J = 14.5 Hz, 2H), 3.84 (d, J = 14.7 Hz, IH), 2.31 (t, J = 15.2 Hz, 3H), 2.10 (s, 1H), 2.08 (d, J = 3.9 Hz, 5H), 1.99 (s, 3H).. LCMS-ESI+ (m/z): [M+H]+ calcd for C27H26FN904: 560.2; found: 560.2.
Example 538: 5-(4-((6-ethoxypyridin-3-yl)amino)-l,3,5-triazin-2-yl)-2-(((3R,4S)-3- fluoro-l-((S)-5-oxopyrrolidine-2-carbonyl)piperidin-4-yl)oxy)benzonitrile
Figure imgf000514_0001
The title compound was synthesized in the same manner as Example 535 using 6-ethoxypyridin- 3-amine. :H NM (400 MHz, DMSO-d6) δ 10.26 (d, J = 16.3 Hz, 1H), 8.78 (s, 1H), 8.63 - 8.35 (m, 3H), 7.98 (dd, J = 8.9, 2.8 Hz, 1H), 7.72 (d, J = 21.4 Hz, 1H), 7.64 (d, J = 9.1 Hz, 1H), 6.83 (s, 1H), 5.10 (m, 2H), 5.00 (m, 1H), 4.65 - 4.54 (m, 1H), 4.39 (s, 1H), 4.28 (d, J = 7.2 Hz, 2H), 4.11 (s, 1H), 3.32 (m, 1H), 3.05 (m, 1H), 2.30 (m, 1H), 2.09 (m, 2H), 1.99 (m,lH), 1.31 (t, J = 7.0 Hz, 3H). LCMS- ESI+ (m/z): [M+H]+ calcd for C27H27FN804: 547.2; found : 547.1.
Example 539 : 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)- 5-(4-((3-(morpholinomethyl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000514_0002
The title compound was synthesized in the same manner as Example 535 using 3-
(morpholinomethyl)aniline. :H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 9.89 (s, 1H), 8.86 (s,
1H), 8.64 - 8.56 (m, 2H), 7.92 (s, 1H), 7.79 (s, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.24 (d, J = 7.5 Hz, 1H), 5.21 - 4.93 (m, 3H), 4.46 (m, 1H), 4.37 (m, 3H), 3.96 (m, 3H), 3.62 (m, 1H), 3.16 (m, 3H), 1.97 (m, 2H), 1.84 (m, 1H ), 1.20 (m, 3H), 1.07 - 1.01 (m, 1H). LCMS-ESI+ (m/z): [M+H]+ calcd for C29H32FN704: 562.3; found : 562.3.
Example 540: N-(5-((4-(3-cyano-4-(((3R,4S)-3-fluoro-l-((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)phenyl)-l,3,5-triazin-2-yl)amino)pyridin-2- yl)acetamide
Figure imgf000515_0001
The title compound was synthesized in the same manner as Example 535. :H NM (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 10.40 (s, 1H), 8.77 (s, 1H), 8.59 (s, 1H), 8.53 (d, J = 9.6 Hz, 2H), 8.07 (d, J = 23.9 Hz, 2H), 7.59 (m, 2H), 7.33 - 7.27 (m, 1H), 5.07 (m, 2H), 4.93 (s, 1H), 3.89 (m, 1H), 3.10
(m, 1H), 2.03 (s, 3H), 1.93 (m, 2H), 1.25 (m, 1H), 1.14 (m, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C25H25FN804: 521.2; found : 521.3.
Example 541 : 5-(4-((6-ethoxypyridin-3-yl)amino)-l,3,5-triazin-2-yl)-2-(((3R,4S)-3- fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)benzonitrile
Figure imgf000515_0002
The title compound was synthesized in the same manner as Example 535. :H NMR (400 MHz, DMSO-d6) δ 10.28 (d, J = 18.7 Hz, 1H), 8.78 (s, 1H), 8.56 (d, J = 31.4 Hz, 3H), 7.98 (dd, J = 8.9, 2.8 Hz, 1H), 7.63 (d, J = 9.4 Hz, 1H), 6.84 (s, 1H), 5.17 - 4.94 (m, 3H), 4.28 (s, 2H), 4.15 (m,lH), 3.35 (m, 1H), 1.98 (m, 2H), 1.81 (s, 1H), 1.36 - 1.25 (m, 5H), 1.19 (t, J = 5.5 Hz, 3H). LCMS-ESI+ (m/z) : [M+H]+ calcd for C25H26FN704: 508.2; found : 508.2.
Example 542 : 2-(((3R,4S)-3-fluoro-l-((S)-5-oxopyrrolidine-2-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-((R)-3-methyl-4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
Figure imgf000516_0001
The title compound was synthesized in the same manner as Example 535 using (R)-2-methyl-l- (oxetan-3-yl)piperazine and 4-fluoroaniline. :H NMR (400 MHz, DMSO-d6) δ 10.18 (d, J = 22.9 Hz, 1H), 8.75 (s, 1H), 8.61 - 8.50 (m, 2H), 7.73 (d, J = 20.8 Hz, 1H), 7.63 (d, J = 9.1 Hz, 3H), 7.04 (s, 2H), 5.11 (m, 2H), 5.01 (m, 1H), 4.84 (m, 2H), 4.76 (m, 1H), 4.73 - 4.54 (m, 4H), 4.43 (m, 1H), 4.19 (m, 2H), 3.40 - 3.27 (m, 2H), 3.04 (m, 2H), 2.36 - 2.25 (m, 1H), 2.15 - 2.06 (m, 2H), 1.99 (m,
2H), 1.91 (m, 1H), 1.19 (m, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C34H38FN904: 656.3; found : 656.4.
Example 543 : 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)- 5-(4-((6-((2-methoxyethyl)amino)pyridin-3-yl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000516_0002
The title compound was synthesized in the same manner as Example 535 using N-(2- methoxyethyl)-5-nitropyridin-2-amine. :H NM (400 MHz, DMSO-d6) δ 10.35 (s, 1H ), 8.82 (s, 1H), 8.63 - 8.49 (m, 2H), 8.32 (d, J = 2.4 Hz, 1H), 8.00 (s, 1H), 7.61 (s, 1H), 7.03 (d, J = 9.3 Hz, 1H), 5.20 - 4.94 (m, 3H), 4.53 - 4.41 (m, 1H), 4.35 (m, 1H), 3.93 (m, 2H), 3.56 - 3.45 (m, 4H), 3.29 (s, 3H), 3.18 (m, 1H), 1.97 (m, 2H), 1.82 (m, 1H), 1.19 (m, 3H). LCMS-ESI+ (m/z) : [M+H]+ calcd for C26H29FN804: 537.2; found: 537.3.
Example 544: 2-(((3R,4S)-3-fluoro-l-((S)-5-oxopyrrolidine-2-carbonyl)piperidin yl)oxy)-5-(4-((3-methoxy-4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
Figure imgf000517_0001
The title compound was synthesized in the same manner as Example 535 starting with 1- fluoro-2-methoxy-4-nitrobenzene and l-(oxetan-3-yl)piperazine. :H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.79 (s, 1H), 8.62 - 8.56 (m, 2H), 8.27 (s, 2H), 7.77 - 7.61 (m, 2H), 6.96 (d, J = 8.6 Hz, 1H), 5.13 (s, 2H), 4.74 (m, 4H), 4.59 (m, 2H), 4.37 (s, 2H), 4.17 (s, 3H), 3.60 (m, 7H), 3.32 (m,
4H), 3.22 - 3.03 (m, 4H), 2.09 (m, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd for C34H38FN905: 672.3; found : 672.4.
Example 545 : 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)- 5-(4-(isoindolin-5-ylamino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000518_0001
Step 1: Preparation of tert-butyl 5-((4-chloro-l,3,5-triazin-2-yl)amino)isoindoline- 2-carboxylate: Tert-butyl 5-aminoisoindoline-2-carboxylate (220 mg, 0.939 mmol) was dissolved in methanol (6 mL) and cooled to 0 °C. Triethyl amine (160 μϊ^, 1.148 mmol) was then added, followed by 2,4-dichloro-l,3,5-triazine (138 mg, 0.920 mmol). The reaction mixture was allowed to warm to room temperature. After 30 min, the reaction mixture was concentrated. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated to give tert-butyl 5-((4-chloro-l,3,5-triazin-2-yl)amino)isoindoline-2-carboxylate.
Step 2: Preparation of 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile: (3R,4S)-tert-butyl 4-(2-cyano-4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)-3-fluoropiperidine-l-carboxylate (307 mg, 0.688 mmol) dissolved in DCM (7 mL) was treated with trifluoroacetic acid (1300 μϊ^, 16.99 mmol). The reaction mixture was stirred at room temperature for 1 h and then concentrated. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The layers were separated. The organic layer was concentrated to give 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)benzonitrile.
Step 3: Preparation of 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4- yl)oxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile: 2-(((3R,4S)-3- fluoropiperidin-4-yl)oxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile (190 mg, 0.549 mmol) dissolved in DCM (5 mL) was treated with HATU (244 mg. 0.642 mmol), (S)-2-hydroxypropanoic acid (64 mg, 0.710 mmol), and N,N- diisopropylethylamine (260 μί, 1.493 mmol). The reaction mixture was stirred at room temperature for 30 min. It was then diluted with dichloromethane and washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to give 2-(((3R,4S)-3-fluoro-l- ((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)benzonitrile.
Step 4: Preparation of tert-butyl 5-((4-(3-cyano-4-(((3R,4S)-3-fluoro-l-((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)phenyl)-l,3,5-triazin-2-yl)amino)isoindoline-
2- carboxylate: Tert-butyl 5-((4-chloro-l,3,5-triazin-2-yl)amino)isoindoline-2- carboxylate (65 mg, 0.187 mmol) was dissolved in dioxane (2 mL) and the reaction mixture was degassed with argon. 2-(((3R,4S)-3-fluoro-l-((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzonitrile (76 mg, 0.182 mmol) was then added, followed by [Ι, - Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane (14 mg, 0.017 mmol), and 2M sodium carbonate solution (290 μϊ^, 0.580 mmol). The reaction mixture was heated at 90 °C. After 30 min, the reaction mixture was cooled to room temperature and concentrated. The residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography to give tert-butyl 5-((4-(3-cyano-4-(((3R,4S)-
3- fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)phenyl)-l,3,5-triazin-2- yl)amino)isoindoline-2-carboxylate.
Step 5: Preparation of 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4- yl)oxy)-5-(4-(isoindolin-5-ylamino)-l,3,5-triazin-2-yl)benzonitrile: Tert-butyl 5-((4- (3-cyano-4-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)phenyl)- l,3,5-triazin-2-yl)amino)isoindoline-2-carboxylate (31 mg, 0.051 mmol) dissolved in DCM (1 mL) was treated with trifluoroacetic acid (100 μϊ^, 1.307 mmol). The reaction mixture was stirred at room temperature for 1 h and then concentrated. The residue was purified by HPLC to give the title compound. XH NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 9.32 (s, 1H), 8.84 (s, 1H), 8.59 (d, J = 7.6 Hz, 1H), 7.86 (s, 1H), 7.68 (s, 1H), 7.62 (d, J = 9.4 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 6.49 (s, 2H), 5.10 (s, 2H), 4.97 (s, 2H),
4.51 (d, J = 23.2 Hz, 4H), 1.98 (s, 3H), 1.25 - 1.17 (m, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C26H26FN703: 504.2; found: 504.3. Example 546 : 2-(((3R,4S)-3-fluoro-l-(2-methoxyacetyl)piperidin-4-yl)oxy)-5-(4-((4- (4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000520_0001
The title compound was synthesized in the same manner as Example 535 using 2- methoxyacetic acid. :H NM (400 MHz, DMSO-d6) δ 10.18 (d, J = 21.4 Hz, 1H), 8.75 (s, 1H), 8.62 - 8.49 (m, 2H), 7.61 (d, J = 9.2 Hz, 3H), 7.04 (s, 2H), 5.18 - 5.05 (m, 2H), 4.97 (m, 1H), 4.75 (m, 4H), 4.33 (m, 2H), 4.18 (m, 2H), 4.14 - 3.95 (m, 5H), 3.73 (m, 2H), 3.28 (s, 3H), 3.13 (m, 2H), 1.97 (m, 2H), 1.83 (m, 1H). LCMS-ESI+ (m/z): [M+H]+ calcd for C31H35FN804: 603.3; found : 603.4.
Example 547: 2-(((3R,4S)-3-fluoro-l-((S)-2-methoxypropanoyl)piperidin-4-yl)oxy)- 5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000520_0002
The title compound was synthesized in the same manner as Example 535 using (S)-2- methoxypropanoic acid. :H NMR (400 MHz, DMSO-d6) δ 10.19 (d, J = 22.4 Hz, 1H), 8.75 (s, 1H), 8.62 - 8.50 (m, 2H), 7.62 (m, 3H), 7.05 (m, 2H), 5.11 (m, 2H), 4.99 (m, 1H), 4.77 (d, J = 6.4 Hz, 4H), 4.44 (m, 2H), 4.34 - 4.13 (m, 4H), 3.41 - 3.25 (m, 2H), 3.20 (s, 3H), 3.09 (m, 2H), 1.99 (m,
2H), 1.92 (m, 1H), 1.22 (m, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H37FN804: 617.3; found : 617.4. Example 548: 2-(((3R,4S)-3-fluoro-l-((S)-5-oxopyrrolidine-3-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2- yl)benzonitrile
Figure imgf000521_0001
The title compound was synthesized in the same manner as Example 535 using (S)-5- oxopyrrolidine-3-carboxylic acid. :H NM (400 MHz, DMSO-d6) δ 10.13 (d, J = 23.5 Hz, 1H), 8.70 (s, 1H), 8.57 - 8.43 (m, 2H), 7.56 (dd, J = 14.8, 7.9 Hz, 4H), 6.99 (m, 2H), 5.05 (m, 2H), 4.93 (m, 1H), 4.70 (m, 4H), 4.36 (m, 1H), 4.15 (m, 1H), 3.78 (m, 2H), 3.68 - 3.51 (m, 2H), 3.21 (m, 4H), 2.62 (m, 1H), 2.33 - 2.24 (m, 3H), 1.92 (m, 2H), 1.72 (m, 1H). LCMS-ESI+ (m/z): [M+H]+ calcd forC33H36FN904: 642.3; found : 642.4.
Example 549: 2-(((3R,4S)-3-fluoro-l-(2-(methylsulfonyl)acetyl)piperidin-4-yl)oxy)- 5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000521_0002
The title compound was synthesized in the same manner as Example 535 using 2-
(methylsulfonyl)acetic acid. :H NMR (400 MHz, DMSO-d6) δ 10.19 (d, J = 21.8 Hz, 1H), 8.75 (s,
1H), 8.63 - 8.49 (m, 2H), 7.62 (d, J = 9.6 Hz, 3H), 7.05 (s, 2H), 5.13 (m, 3H), 4.98 (m, 1H), 4.76 (d, J = 6.2 Hz, 4H), 4.56 (s, 1H), 4.38 (m, 2H), 4.18 - 4.09 (m, 1H), 3.94 (m, 4H), 3.10 (d, J = 10.5 Hz,
3H), 2.04 - 1.93 (m, 2H), 1.89 (m, 1H). LCMS-ESI+ (m/z): [M+H]+ calcd for C31H35FN805S: 651.2; found : 651.4.
Example 550: 2-(((3R,4S)-3-fluoro-l-(3-hydroxycyclobutanecarbonyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2- yl)benzonitrile
Figure imgf000522_0001
The title compound was synthesized in the same manner as Example 535 using 3- hydroxycyclobutanecarboxylic acid. :H NM (400 MHz, DMSO-d6) δ 10.15 (d, J = 29.2 Hz, 1H), 8.74 (s, 1H), 8.63 - 8.46 (m, 2H), 7.61 (d, J = 9.1 Hz, 3H), 7.03 (m, 2H), 5.06 (m, 2H ), 4.94 (m, 1H), 4.73 (m, 4H), 4.34 (m, 1H), 4.17 - 4.08 (m, 3H), 3.97 (m, 1H), 3.02 (m, 2H), 2.79 (m, 1H), 2.35 (m,
2H), 2.05 (m, 1H), 1.94 (m, 2H), 1.77 (m, 1H ). LCMS-ESI+ (m/z): [M+H]+ calcd for C33H37FN804: 629.3; found : 629.4.
Example 551: 2-(((3R,4S)-3-fluoro-l-(2-oxopyrrolidine-3-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2- yl)benzonitrile
Figure imgf000523_0001
The title compound was synthesized in the same manner as Example 535 using 2- oxopyrrolidine-3-carboxylic acid. :H NM (400 MHz, DMSO-d6) δ 10.18 (d, J = 21.8 Hz, IH), 8.76 (s, IH), 8.60 - 8.53 (m, 2H), 7.83 - 7.80 (m, IH), 7.63 - 7.54 (m, 3H), 7.05 (m, 2H), 5.15 (m, 2H), 5.10 (m, IH), 4.93 (m, IH), 4.75 (m, 5H), 4.39 (m, 3H), 4.09 - 3.89 (m, 4H), 3.50 (m, 2H), 3.32 -
3.14 (m, 2H), 2.40 (m, IH), 2.08 (m, 2H), 1.95 (m, IH). LCMS-ESI+ (m/z): [M+H]+ calcd for C33H36FN904: 642.3; found: 642.7.
Example 552 : 2-(((3R,4S)-3-fluoro-l-((R)-5-oxopyrrolidine-3-carbonyl)piperidin- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2- yl)benzonitrile
Figure imgf000523_0002
The title compound was synthesized in the same manner as Example 535 using (R)-5- oxopyrrolidine-3-carboxylic acid. :H NMR (400 MHz, DMSO-d6) δ 10.18 (d, J = 23.0 Hz, IH), 8.75 (s, IH), 8.61 - 8.49 (m, 2H), 7.68 - 7.54 (m, 4H), 7.04 (s, 2H), 5.10 (m, 2H), 4.98 (m, IH), 4.76 (m, 4H), 4.44 (m, 2H), 4.20 (m, 2H), 3.84 (m, 3H ), 3.72 - 3.58 (m, 3H), 3.57 - 3.27 (m, 4H), 2.36 (m,
2H), 1.99 (m, 2H), 1.79 (m, IH). LCMS-ESI+ (m/z): [M+H]+ calcd for C33H36FN904: 642.3; found : 642.4. Example 553: 2-(((3R,4S)-3-fluoro-l-(3-hydroxy-3-methylbutanoyl)piperidin-4-yl)oxy)-5-(4-((4- (4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000524_0001
The title compound was synthesized in the same manner as Example 535 using 3-hydroxy-3- methylbutanoic acid. :H NM (400 MHz, DMSO-d6) δ 10.18 (d, J = 22.1 Hz, 1H), 8.75 (s, 1H), 8.58 - 8.52 (m, 2H), 7.62 (m, 3H), 7.05 (m, 2H), 5.16 (m, 3H), 4.99 (m, 1H), 4.76 (m, 4H), 4.41 (m, 2H), 4.15 (m, 2H), 3.97 - 3.73 (m, 4H), 3.51 - 3.27 (m, 3H), 2.63 (m, 1H ), 2.02 - 1.92 (m, 2H),
1.81 (m, 1H), 1.16 (s, 6H), 1.11 (m, 1H). LCMS-ESI+ (m/z): [M+H]+ calcd for C33H39FN804: 631.3; found : 631.4.
Example 554: 5-(4-((4-(lH-imidazol-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)-2- (((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)benzonitrile
Figure imgf000524_0002
The title compound was synthesized in the same manner as Example 535 starting with 4-( lH- imidazol-l-yl)aniline. :H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 9.49 (s, 1H), 8.89 (s, 1H), 8.61 (m, 1H), 8.20 (s, 1H), 8.00 (d, J = 8.7 Hz, 2H), 7.83 (m, 3H), 7.64 (d, J = 9.3 Hz, 1H), 5.17 (m, 2H), 4.98 (s, 1H), 4.51 - 4.42 (m, 1H), 4.36 (m, 1H), 4.16 (m, 1H), 4.05 (m, 1H), 3.94 (m, 1H), 2.03 - 1.92 (m, 2H), 1.83 (m, IH), 1.19 (m, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C27H25FN803: 529.2; found : 529.3.
Example 555: 2-(((3R,4S)-l-((S)-2,3-dihydroxypropanoyl)-3-fluoropiperidin-4- yl)oxy)-5-(4-((4-morpholinophenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000525_0001
The title compound was synthesized in the same manner as Example 535 using (S)-2,3- dihydroxypropanoic acid. :H NM (400 MHz, DMSO-d6) δ 10.14 (d, J = 20.3 Hz, IH), 8.74 (s, IH), 8.56 (m, 2H), 7.63 - 7.58 (m, 3H), 6.97 (m, 2H), 5.09 (m, 2H), 4.97 (m, IH), 4.38 (m, 2H), 4.12 (m, IH), 3.93 (m, IH), 3.75-3.72 (m, 4H), 3.59 (m, IH), 3.56 - 3.48 (m, IH), 3.48 - 3.40 (m, 2H), 3.08 (m, 2H), 1.97 (m, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C28H30FN7O5: 564.2; found : 564.3.
Example 556: 2-(((3R,4S)-l-((S)-2,3-dihydroxypropanoyl)-3-fluoropiperidin-4- yl)oxy)-5-(4-((2-fluoro-4-morpholinophenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000525_0002
The title compound was synthesized in the same manner as Example 535 starting with 4-(3- fluoro-4-nitrophenyl)morpholine. :H NMR (400 MHz, DMSO-d6) δ 9.79 (d, J = 27.4 Hz, IH), 8.72 (m, IH), 8.58 (s, IH), 8.39 (s, IH), 7.59 (m, IH), 7.31 (m, IH), 6.87 (m, IH), 6.78 (m, IH), 5.08 (m, 2H), 4.96 (s, IH), 4.39 (m, 2H), 4.12 (m, IH), 3.92 (m, IH), 3.74-3.72 (m, 4H), 3.59 (m, IH), 3.51
(m, IH ), 3.44 (m, 2H), 3.31 (m, 2H), 1.96 (m, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C28H29F2N705: 582.2; found : 582.3.
Example 557: 2-(((3R,4S)-3-fluoro-l-(2-hydroxy-3-methoxypropanoyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2- yl)benzonitrile
Figure imgf000526_0001
The title compound was synthesized in the same manner as Example 535 using 2-hydroxy-3- methoxypropanoic acid. :H NM (400 MHz, DMSO-d6) δ 10.18 (d, J = 22.3 Hz, IH), 8.75 (s, IH), 8.62 - 8.49 (m, 2H), 7.61 (m, 3H), 7.04 (s, 2H), 5.13 (m, 2H), 4.95 (s, IH), 4.76 (m, 4H), 4.51 (m, 2H), 4.45 (m, 2H), 4.14 (m, 2H), 3.96 (m, 2H), 3.56 - 3.36 (m, 6H), 1.98 (m, 2H), 1.85 (m, IH).
LCMS-ESI+ (m/z): [M+H]+ calcd for C32H37FN805: 633.3; found : 633.4.
Example 558: 2-(((3R,4S)-l-(2-cyanoacetyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((3-methoxy-4-(4- (oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000527_0001
Step 1 : Preparation of (3R,4S)-tert-butyl 4-(2-cyano-4-(4-((3-methoxy-4-(4-(oxetan-3- yl)piperazin- 1 -yl)phenyl)amino)- 1 ,3 ,5-triazin-2-yl)phenoxy)-3 -fluoropiperidine- 1 - carboxylate: A suspension of 4-chloro-N-(3-methoxy-4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)-l,3,5-triazin-2-amine (170 mg, 0.406 mmol) and (3R,4S)-tert-butyl 4-(2- cyano-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)-3-fluoropiperidine-l- carboxylate (190 mg, 0.426 mmol) in 1,2-Dimethoxyethane (4 mL) was treated with 2M sodium carbonate solution (0.82 mL, 1.62 mmol) and Tetrakis(triphenylphosphine)palladium (47 mg, 0.04 mmol). The mixture was heated in a microwave reactor for 20 minutes at 135 °C. The cooled reaction mixture was quenched with water and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to give the desired product as yellow solid. LCMS-ESI+ (m/z): [M+H]+ calcd for C34H42F 8O5: 661.7; found: 661.4. Step 2: Preparation of 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((3-methoxy-4-(4- (oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile: (3R,4S)-tert- butyl 4-(2-cyano-4-(4-((3-methoxy-4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)- l,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-l-carboxylate (52.3 mg, 0.08 mmol) was taken up in dichloromethane (1 mL) and treated with trifluoroacetic acid (0.12 mL, 1.64 mmol). After 30 minutes, the mixture was quenched with saturated sodium bicarbonate (PH ~ 8) and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude was used for next step. LCMS-ESI+ (m/z): [M+H]+ calcd for C29H34F 8O3: 561.6; found: 561.2.
Step 3: Preparation of 2-(((3R,4S)-l-(2-cyanoacetyl)-3-fluoropiperidin-4-yl)oxy)-5-(4- ((3-methoxy-4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2- yl)benzonitrile:
2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((3-methoxy-4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (40 mg, 0.071 mmol) and 2-cyanoacetic acid (13.8 mg, 0.16 mmol) were taken up as suspension in dichloromethane (1 mL). The mixture was treated successively with N,N-diisopropylethylamine (0.03 mL, 0.17 mmol) and N-[(dimethylamino)-lH-l,2,3-triazolo-[4,5-b]pyridin-l-ylmethylene]-N- methylmethanaminiumhexafluorophosphate N-oxide (HATU, 47 mg, 0.12 mmol). The mixture was stirred for 2 hour at room temperature and then purified by reverse phase chromatography (CI 8) to provide the desired product as yellow solid. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H35FN9O4: 628.7; found: 628.3. 1H NMR (300 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.78 (s, 1H), 8.61 (m, 2H), 7.64 (d, J = 9.0 Hz, 2H), 7.29 (br, 1H), 6.90 (d, J = 8.1 Hz, 1H), 5.13 (m, 2H), 4.56 (m, 2H), 4.52 (m, 2H), 4.35 (m, 1H), 4.17-3.95 (br, 3H), 3.84 (m, 3H), 3.61 (m, 1H), 3.47 (m, 1H), 2.96 (m, 4H), 2.39 (m, 4H), 2.01 (m, 2 H), 1.21 (s, 1H).
Example 559 : 2-(((3R,4S)-l-(2-amino-lH-imidazole-5-carbonyl)-3-fluoropiperidin-
4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-
Figure imgf000528_0001
2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (50 mg, 0.094 mmol) and 2-amino-lH- imidazole-5-carboxylic acid (23.95 mg, 0.19 mmol) were taken up as suspension in N,N- dimethylformamide (3mL). The mixture was treated successively with N,N- diisopropylethylamine (0.05 mL, 0.28 mmol) and -[(dimethylamino)-lH-l,2,3-triazolo- [4,5-b]pyridin-l-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (HATU, 72 mg, 0.19 mmol). The mixture was stirred for 2 hr at room temperature. Another portion of 2-amino-lH-imidazole-5-carboxylic acid (10.7 mg, 0.08 mmol), N,N-diisopropylethylamine (0.05 mL, 0.28 mmol) and N-[(dimethylamino)-lH-l,2,3- triazolo- [4,5 -b]pyridin- 1 -ylmethylene] -N-methylmethanaminiumhexafluorophosphate N-oxide (HATU, 68 mg, 0.18 mmol) were added and the reaction mixture was stirred at room temperature for overnight. After that time, the reaction mixture was quenched with water and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel), and by reverse column (CI 8) to give the desired product as bright yellow solid. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H35FN11O3: 640.7; found: 640.3. 1H NMR (300 MHz, DMSO-d6) δ 10.28 (S, 1H), 10.15 (m, 1H), 8.73 (s, 1H), 8.58 (d, J = 8.7 Hz, 2H), 7.64 (m, 3H), 7.06 (m, 3H), 5.40 (s, 1H), 5.10 (m, 2H), 4.57 (m, 2H), 4.48 (m, 2H), 3.45 (m, 1H), 3.13 (m, 4H), 2.40 (m, 4H), 1.96 (br, 2H), 1.43 (m, 1H), 1.21 (s, 2H), 0.82 (m, 1H).
Example 560: (S)-2-((3,3-difluoro-l-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((3- methoxy-4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-
Figure imgf000529_0001
Step 1: Preparation of (S)-tert-butyl 4-(2-cyano-4-(4-((3-methoxy-4-(4-(oxetan-3- yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)phenoxy)-3,3-difluoropiperidine-l- carboxylate: A suspension of 4-chloro-N-(3-methoxy-4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)-l,3,5-triazin-2-amine (336 mg, 0.802 mmol) and (S)-tert-butyl 4-(2-cyano-4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)-3,3-difluoropiperidine-l- carboxylate (373 mg, 0.802 mmol) in 1, 2 -Dimethoxy ethane (8 mL) was treated with 2M sodium carbonate solution (1.61 mL, 3.2 mmol) and Tetrakis(triphenylphosphine)palladium (93 mg, 0.08 mmol). The mixture was heated in a microwave reactor for 15 minutes at 145 °C. The cooled reaction mixture was quenched with water and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to give the desired product as yellow solid. LCMS-ESI+ (m/z): [M+H]+ calcd for C34H4iF2 805: 679.7; found: 679.8. Step 2: Preparation of (S)-2-((3,3-difluoropiperidin-4-yl)oxy)-5-(4-((3-methoxy-4-(4- (oxetan-3 -yl)piperazin- 1 -yl)phenyl)amino)- 1 ,3 ,5-triazin-2-yl)benzonitrile: (S)-tert-butyl 4-(2-cyano-4-(4-((3-methoxy-4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5- triazin-2-yl)phenoxy)-3,3-difluoropiperidine-l-carboxylate (1 10 mg, 0.162 mmol) was taken up in dichloromethane (2 mL) and treated with trifluoroacetic acid (0.248 mL, 3.24 mmol). After 40 minutes, the mixture was quenched with saturated sodium bicarbonate (PH ~ 8) and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting yellow oil was used for next step. LCMS-ESI+ (m/z): [M+H]+ calcd for C29H33F2 803 579.6; found: 579.3.
Step 3: Preparation of (S)-2-((3,3-difluoro-l-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4- ((3-methoxy-4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2- yl)benzonitrile: (S)-2-((3,3-difluoropiperidin-4-yl)oxy)-5-(4-((3-methoxy-4-(4-(oxetan-3- yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (47mg, 0.08 mmol) and Glycolic acid (12.3 mg, 0.16 mmol) were taken up as suspension in dichloromethane (1 mL). The mixture was treated successively with N,N-diisopropylethylamine (0.04 mL, 0.24 mmol) and N-[(dimethylamino)-lH-l,2,3-triazolo-[4,5-b]pyridin-l-ylmethylene]-N- methylmethanaminiumhexafluorophosphate N-oxide (HATU, 46 mg, 0.12 mmol). The mixture was stirred for 2 hour at room temperature and then purified by reverse phase chromatography (CI 8) to provide the desired product as yellow solid. LCMS-ESI+ (m/z): [M+H]+ calcd for CsiHssFz sOj: 637.7; found: 637.2. 1H NMR (300 MHz, DMSO-d6) δ 10.26 (br, 1H), 8.78 (s, 1H), 8.62 (m, 2H), 7.68-7.10 (br, 3H), 6.90 (m, 1H), 5.48-4.80 (br, 1H), 4.54 (m, 2H), 4.45 (m, 2H), 4.20-3.90 (br, 3H), 3.84-3.55 (br, 5H), 3.45 (m, 1H), 2.96 (m, 4H), 2.39 (m, 4H), 2.01 (m, 2 H). Example 561 : 2-(((S)-3,3-difluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-
5-(4-((3-methoxy-4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-
Figure imgf000531_0001
(S)-2-((3,3-difluoropiperidin-4-yl)oxy)-5-(4-((3-methoxy-4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (47mg, 0.08 mmol) and L-lactic acid (14.6 mg, 0.16 mmol) were taken up as suspension in dichloromethane (1 mL). The mixture was treated successively with N,N-diisopropylethylamine (0.04 mL, 0.24 mmol) and N-[(dimethylamino)- 1 H- 1 ,2,3 -triazolo-[4,5-b]pyridin- 1 -ylmethylene]-N- methylmethanaminiumhexafluorophosphate N-oxide (HATU, 46 mg, 0.12 mmol). The mixture was stirred for 2 hour at room temperature and then purified by reverse phase chromatography (CI 8) to provide the desired product as yellow solid. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H37F2 805: 651.7; found: 651.3. 1H NMR (300 MHz, DMSO-d6) δ 10.26 (br, 1H), 8.78 (s, 1H), 8.62 (m, 2H), 7.68-7.10 (br, 3H), 6.90 (m, 1H), 5.38 (br, 1H), 5.23 (d, J = 7.2 Hz, 1H), 4.54 (m, 2H), 4.54 (m, 3H), 4.20-3.45 (br, 7H), 3.47 (m, 1H), 2.96 (m, 4H), 2.39 (m, 4H), 2.14 (m, 2 H), 1.21 (m, 3H).
Example 562: 2-(((3R,4S)-3-fluoro-l-(3-hydroxypropanoyl)piperidin-4-yl)oxy)-5- (4-((3-methoxy-4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2- yl)benzonitrile
Figure imgf000532_0001
2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((3-methoxy-4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (40 mg, 0.071 mmol) and 3- hydroxypropanoic acid (30% in water, 42.85 mg, 0.14 mmol) in were taken up as suspension in Ν,Ν-dimethylformamide (1 mL). The mixture was treated successively with N,N-diisopropylethylamine (0.04 mL, 0.21 mmol) and N-[(dimethylamino)-lH- 1 ,2,3 -triazolo-[4,5 -b]pyridin- 1 -ylmethylene] -N- methylmethanaminiumhexafluorophosphate N-oxide (HATU, 41 mg, 0.11 mmol). The mixture was stirred for 2 hour at room temperature and then purified by reverse phase chromatography (CI 8) to provide the desired product as yellow solid. LCMS-ESI+ (m/z): [M+H]+ calcd C32H38F 8O5: 633.7; found: 633.3. 1H NMR (300 MHz, DMSO- d6) δ 10.26 (br, 1H), 8.78 (s, 1H), 8.62 (m, 2H), 7.65 (d, J = 9.3 Hz, 2H), 7.49-7.17 (br, 1H), 6.91 (d, J = 9.3 Hz, 1H), 5.14 (m, 2H), 4.57 (m, 3H), 4.44 (m, 2H), 4.20-4.10 (br, 1H), 3.85 (m, 3H), 3.67 (m, 2H), 3.48 (m, 1H), 3.10 (m, 1H), 2.97 (m, 4H), 2.57 (m, 1H), 2.40 (m, 4H), 1.97 (m, 2 H), 1.23 (m, 2H), 0.86 (m, 1H).
Example 563 : 2-(((3R,4S)-3-fluoro-l-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4-((4- -triazin-2-yl)benzonitrile
Step 1 : Preparation of N-(4-chloro-l,3,5-triazin-2-yl)-4-methylthiazol-5-amine: To a solution of 2,4-dichloro-l,3,5-triazine (165mg, 1.1 mmol) in dichloromethane (6 mL) at 0°C, 4-methylthiazol-5-amine HCl salt (187.09 mg, 1 mmol) in dichloromethane (2 mL +2mL wash) was added, followed by N,N-Diisopropylethylamine (0.61 mL, 3.5 mmol). The reaction mixture was stirred at 0°C for 15 minutes. After this time, the reaction was quenched with saturated sodium bicarbonate solution (PH~8) and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to give the desired product as yellow solid. LCMS- ESI+ (m/z): [M+H]+ calcd for C7H7CIN5S: 228.7; found: 228.0. 1H NMR (300 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.80 (d, J = 6 Hz, 1H), 8.66 (s, 1H), 2.31 (s, 3H).
Step 2: Preparation of 2-(((3R,4S)-3-fluoro-l-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4- ((4-methylthiazol-5-yl)amino)-l,3,5-triazin-2-yl)benzonitrile: A suspension of N-(4- chloro-l,3,5-triazin-2-yl)-4-methylthiazol-5-amine (90 mg, 0.395 mmol) and 2- (((3R,4S)-3-fluoro-l-(2-hydroxyacetyl)piperidin-4-yl)oxy)-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzonitrile (176 mg, 0.435 mmol) in 1,2-Dimethoxyethane (2 mL) was treated with 2M sodium carbonate solution (2 mL, 4.0 mmol) and Tetrakis(triphenylphosphine)palladium (38 mg, 0.033 mmol). The mixture was heated at 125 °C for lh. The cooled reaction mixture was quenched with water and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to give the desired product as yellow solid. LCMS- ESI+ (m/z): [M+H]+ calcd for C2iH21F 703S: 470.5; found: 470.1. 1H NMR (300 MHz, DMSO-d6) δ 10.78 (br, 1H), 8.86 (m, 2H), 8.64 (m, 2H), 8.10 (m, 1H), 5.14 (m, 2H), 4.69 (m, 1H), 4.41-3.85 (br, 3H), 3.78-3.20 (m, 1H), 3.08 (m, 1H), 2.40 (m, 3H), 1.98 (m, 2H), 1.22 (m, 1H).
Example 564: 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)- 5-(4-((3-(hydroxymethyl)-l-methyl-lH-pyrazol-4-yl)amino)-l,3,5-triazin-2- yl)benzonitrile
Figure imgf000534_0001
Step 1 : Preparation of methyl 4-((4-chloro-l,3,5-triazin-2-yl)amino)-l-methyl-lH- pyrazole-3-carboxylate: To a solution of 2,4-dichloro-l,3,5-triazine (667 mg, 4.45 mmol) in dichloromethane (30 mL) at 0°C, methyl 4-amino-l -methyl- lH-pyrazole-3- carboxylate (0.62 g, 4 mmol) in dichloromethane (5 mL + 5 mL wash) was added, followed by N,N-Diisopropylethylamine (1.05 mL, 6 mmol). The reaction mixture was stirred at 0°C for 2 h. After this time, the reaction was quenched with saturated sodium bicarbonate solution (PH~8) and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to give the desired product as white solid. LCMS-ESI+ (m/z): [M+H]+ calcd for C9H10ClN6O2: 269.7; found: 269.0.
Step 2: Preparation of (3R,4S)-tert-butyl 4-(2-cyano-4-(4-((3-(methoxycarbonyl)-l- methyl- lH-pyrazol-4-yl)amino)- 1,3, 5-triazin-2-yl)phenoxy)-3-fluoropiperidine- 1 - carboxylate: A suspension of methyl 4-((4-chloro-l,3,5-triazin-2-yl)amino)-l-methyl- lH-pyrazole-3 -carboxylate (166 mg, 0.62 mmol) and (3R,4S)-tert-butyl 4-(2-cyano-4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)-3-fluoropiperidine-l -carboxylate (279mg, 0.63 mmol) in 1 ,2-Dimethoxyethane (6 mL) was treated with 2M sodium carbonate solution (2.4 mL, 4.8 mmol) and Tetrakis(triphenylphosphine)palladium (75 mg, 0.065 mmol). The mixture was heated in at 115 °C for 30 minutes. The cooled reaction mixture was quenched with water and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to give the desired product as yellow solid. LCMS-ESI+ (m/z): [M+H]+ calcd for C26H30F 8O5: 553.6; found: 553.2. Step 3: Preparation of methyl 4-((4-(3-cyano-4-(((3R,4S)-3-fluoropiperidin-4- yl)oxy)phenyl)- 1, 3, 5-triazin-2-yl)amino)-l -methyl- lH-pyrazole-3-carboxylate: (3R,4S)- tert-butyl 4-(2-cyano-4-(4-((3-(methoxycarbonyl)-l -methyl- lH-pyrazol-4-y l)amino)- l,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-l-carboxylate (330 mg, 0.597 mmol) was taken up in dichloromethane (12 mL) and treated with trifluoroacetic acid (1.2 mL, 15.68 mmol). After 30 minutes, the mixture was quenched with saturated sodium bicarbonate (PH ~ 8) and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude was used for next step. LCMS-ESI+ (m/z): [M+H]+ calcd for C2iH22F 803: 453.4; found: 453.2.
Step 4: Preparation of 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((3- (hydroxymethyl)- 1 -methyl- lH-pyrazol-4-yl)amino)- 1,3, 5-triazin-2-yl)benzonitrile: methyl 4-((4-(3-cyano-4-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)phenyl)-l,3,5-triazin-2- yl)amino)-l -methyl- lH-pyrazole-3-carboxylate (250mg, 0.47mmol) was dissolved in THF (7 mL) and the reaction mixture was cooled to 0°C. Lithium Aluminum Hydride (1M solution in THF, 1.57 m, 1.57 mmol) was added drop wise. The reaction mixture was stirred at 0°C for lh and was monitored with LC_MS for completion. Then the mixture was quenched with 0.2 mL H20, 0.2 mL IN NaOH and 0.2 mL water sequentially and stirred at room temperature for lh. Small amount of sodium sulfate and Celite were added and filtered. The filtrate was evaporated and purified by flash chromatography (silica gel) to give the desired product as white solid. LCMS-ESI+ (m/z): [M+H]+ calcd for C20H22FN8O2: 425.4; found: 425.2.
Step 5: Preparation of 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4- yl)oxy)-5-(4-((3 -(hydroxymethyl)- 1 -methyl- 1 H-pyrazol-4-yl)amino)- 1 ,3 ,5-triazin-2- yl)benzonitrile: 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((3-(hydroxymethyl)-l- methyl-lH-pyrazol-4-yl)amino)-l,3,5-triazin-2-yl)benzonitrile (52 mg, 0.12 mmol) and L-lactic acid (22.1 mg, 0.24 mmol) were taken up as suspension in N,N- dimethylformamide (1.5 mL). The mixture was treated successively with N,N- diisopropylethylamine (0.07 mL, 0.40 mmol) and N-[(dimethylamino)-lH-l,2,3-triazolo- [4,5-b]pyridin-l-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (HATU, 73 mg, 0.19 mmol). The mixture was stirred for 1 hour at room temperature and then purified by reverse phase chromatography (CI 8) to provide the desired product as pale yellow solid. LCMS-ESI+ (m/z): [M+H]+ calcd for C23H26F 804: 497.5; found: 497.2. 1H NMR (300 MHz, DMSO-d6) δ 9.59 (d, J = 20.7 Hz, 1H), 8.77 (d, J = 12.3 Hz, 1H), 8.62 (m, 2H), 8.06 (d, J = 29.1 Hz, 1H), 7.64 (m, 1H), 5.12 (m, 4H), 4.49 (m, 4H), 4.29-3.90 (br, 1H), 3.85 (d, J = 16.5 Hz, 3H), 3.75-3.32 (br, 1H), 3.25 (m, 1H), 1.99 (br, 2H), 1.22 (m, 3H).
Example 565: 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-
5-(4-((5-(hydroxymethyl)-l-methyl-lH-pyrazol-4-yl)amino)-l,3,5-triazin-2- yl)benzonitrile
Figure imgf000536_0001
Step 1: Preparation of methyl 4-((4-chloro-l,3,5-triazin-2-yl)amino)-l-methyl-lH- pyrazole-5-carboxylate: To a solution of 2,4-dichloro-l,3,5-triazine (665 mg, 4.43 mmol) in dichloromethane (30 mL) at 0°C, methyl 4-amino-l -methyl- lH-pyrazole-5- carboxylate (0.62 g, 4 mmol) in dichloromethane (5 mL + 5 mL wash) was added, followed by N,N-Diisopropylethylamine (1.05 mL, 6 mmol). The reaction mixture was stirred at 0°C for 30 minutes. After this time, the reaction was quenched with saturated sodium bicarbonate solution (PH~8) and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to give the desired product as white solid. LCMS-ESI+ (m/z): [M+H]+ calcd for C9HioCl 602: 269.7; found: 269.1.
Step 2: Preparation of (3R,4S)-tert-butyl 4-(2-cyano-4-(4-((5-(methoxycarbonyl)-l- methyl- lH-pyrazol-4-yl)amino)-l ,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine- 1 - carboxylate: A suspension of methyl 4-((4-chloro-l,3,5-triazin-2-yl)amino)-l-methyl- lH-pyrazole-5-carboxylate (135 mg, 0.50 mmol) and (3R,4S)-tert-butyl 4-(2-cyano-4-
(4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)-3-fluoropiperidine-l -carboxylate
(225 mg, 0.54 mmol) in 1,2-Dimethoxy ethane (5 mL) was treated with 2M sodium carbonate solution (2 mL, 4 mmol) and Tetrakis(triphenylphosphine)palladium (60 mg, 0.052 mmol). The mixture was heated in at 1 15 °C for 40 minutes. The cooled reaction mixture was quenched with water and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to give the desired product as yellow solid. LCMS-ESI+ (m/z): [M+H]+ calcd for C26H30F 8O5: 553.6; found: 553.3.
Step 3: Preparation of methyl 4-((4-(3-cyano-4-(((3R,4S)-3-fluoropiperidin-4- yl)oxy)phenyl)- 1, 3, 5-triazin-2-yl)amino)-l -methyl- lH-pyrazole-5-carboxylate: (3R,4S)- tert-butyl 4-(2-cyano-4-(4-((5-(methoxycarbonyl)- 1 -methyl- 1 H-pyrazol-4-yl)amino)- l,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-l-carboxylate (100 mg, 0.181 mmol) was taken up in dichloromethane (3 mL) and treated with trifluoroacetic acid (0.35 mL, 4.58 mmol). After 60 minutes, the mixture was quenched with saturated sodium bicarbonate (PH ~ 8) and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude was used for next step. LCMS-ESI+ (m/z): [M+H]+ calcd for C2iH22FN803 453.4; found: 453.3.
Step 4: Preparation of 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((5- (hydroxymethyl)- 1 -methyl- lH-pyrazol-4-yl)amino)- 1,3, 5-triazin-2-yl)benzonitrile:
methyl 4-((4-(3-cyano-4-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)phenyl)-l,3,5-triazin-2- yl)amino)-l-methyl-lH-pyrazole-5-carboxylate (81.9 mg, 0.181 mmol) was dissolved in THF (2 mL) and the reaction mixture was cooled to 0°C. Lithium Aluminum Hydride (1M solution in THF, 0.54 m, 0.54 mmol) was added drop wise. The reaction mixture was stirred at 0°C for 20 minutes. Then the mixture was quenched with 0.2 mL water, 0.2 mL IN NaOH and 0.2 mL water sequentially and stirred at room temperature for lh. Small amount of sodium sulfate and Celite were added and filtered. The filtrate was evaporated and purified by flash chromatography (silica gel) to give the desired product as white solid. LCMS-ESI+ (m/z): [M+H]+ calcd for C2oH22F 802: 425.4; found: 425.2. Step 5: Preparation of 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4- yl)oxy)-5-(4-((5-(hydroxymethyl)- 1 -methyl- 1 H-pyrazol-4-yl)amino)- 1 ,3 ,5-triazin-2- yl)benzonitrile: 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((5-(hydroxymethyl)-l- methyl-lH-pyrazol-4-yl)amino)-l,3,5-triazin-2-yl)benzonitrile (25.2 mg, 0.06 mmol) and L-lactic acid (15 mg, 0.167 mmol) were taken up as suspension in N,N- dimethylformamide (0.5 mL). The mixture was treated successively with N,N- diisopropylethylamine (0.03 mL, 0.18 mmol) and -[(dimethylamino)-lH-l,2,3-triazolo- [4,5-b]pyridin-l-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide (HATU, 34 mg, 0.09 mmol). The mixture was stirred for 1 hour at room temperature and then purified by reverse phase chromatography (CI 8) to provide the desired product as pale yellow solid. LCMS-ESI+ (m/z): [M+H]+ calcd for
Figure imgf000538_0001
497.5; found: 497.3. 1H NMR (300 MHz, DMSO-d6) δ 9.76 (d, J = 34.2 Hz, 1H), 8.72 (m, 1H), 8.60 (m, 2H), 7.75 (m, 2H), 5.12 (m, 4H), 4.56 (m, 4H), 4.17-3.93 (br, 1H), 3.84 (m, 3H), 3.70-3.45 (br, 1H), 3.26 (m, 1H), 1.99 (br, 2H), 1.21 (m, 3H).
Example 566: 5-(4-((l,5-dimethyl-lH-pyrazol-4-yl)amino)-l,3,5-triazin-2-yl)-2-
(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)benzonitrile
Figure imgf000538_0002
Step 1 : Preparation of 4-chloro-N-(l,5-dimethyl-lH-pyrazol-4-yl)-l,3,5-triazin-2-amine: To a solution of 2,4-dichloro-l,3,5-triazine (363 mg, 2.42 mmol) in dichloromethane (10 mL) at 0°C, l,5-dimethyl-lH-pyrazol-4-amine, diHCl salt (412.5 mg, 2.24 mmol) was added, followed by N,N-Diisopropylethylamine (1.34 mL, 7.7 mmol). The reaction mixture was stirred at 0°C for 60 minutes. After this time, the reaction was quenched with saturated sodium bicarbonate solution (PH~8) and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to give the desired product as white solid. LCMS-ESI+ (m/z): [M+H]+ calcd for C8H10C1N6: 225.7; found: 225.1.
Step 2: Preparation of (3R,4S)-tert-butyl 4-(2-cyano-4-(4-((l,5-dimethyl-lH-pyrazol-4- yl)amino)-l,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-l-carboxylate: A suspension of methyl 4-chloro-N-(l,5-dimethyl-lH-pyrazol-4-yl)-l,3,5-triazin-2-amine (112 mg, 0.50 mmol) and (3R,4S)-tert-butyl 4-(2-cyano-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenoxy)-3-fluoropiperidine-l-carboxylate (234 mg, 0.525 mmol) in 1,2- Dimethoxyethane (5 mL) was treated with 2M sodium carbonate solution (1.99 mL, 3.98 mmol) and Tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol). The mixture was heated in at 115 °C for 30 minutes. The cooled reaction mixture was quenched with water and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to give the desired product as yellow solid. LCMS-ESI+ (m/z): [M+H]+ calcd for C25H30F 8O3: 509.6; found: 509.4.
Step 3: Preparation of 5-(4-((l,5-dimethyl-lH-pyrazol-4-yl)amino)-l,3,5-triazin-2-yl)-2- (((3R,4S)-3-fluoropiperidin-4-yl)oxy)benzonitrile: (3R,4S)-tert-butyl 4-(2-cyano-4-(4- (( 1 ,5 -dimethyl- 1 H-pyrazol-4-yl)amino)- 1 ,3 ,5 -triazin-2-yl)phenoxy)-3 -fluoropiperidine- 1-carboxylate (100 mg, 0.197 mmol) was taken up in dichloromethane (2mL) and treated with trifluoroacetic acid (0.38 mL, 4.97 mmol). After 60 minutes, the mixture was quenched with saturated sodium bicarbonate (PH ~ 8) and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude was used for next step. LCMS-ESI+ (m/z): [M+H]+ calcd for C20H22F 8O 409.4; found: 409.3.
Step 4: Preparation of 5-(4-((l,5-dimethyl-lH-pyrazol-4-yl)amino)-l,3,5-triazin-2-yl)-2- (((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)benzonitrile: 5-(4- ((l,5-dimethyl-lH-pyrazol-4-yl)amino)-l,3,5-triazin-2-yl)-2-(((3R,4S)-3- fluoropiperidin-4-yl)oxy)benzonitrile (80.5 mg, 0.197 mmol) and L-lactic acid (35.5 mg, 0.394 mmol) were taken up as suspension in N,N-dimethylformamide (2 mL). The mixture was treated successively with N,N-diisopropylethylamine (0.11 mL, 0.632 mmol) and N-[(dimethylamino)-lH-l,2,3-triazolo-[4,5-b]pyridin-l-ylmethylene]-N- methylmethanaminiumhexafluorophosphate N-oxide (HATU, 112.4 mg, 0.296 mmol). The mixture was stirred for 1 hour at room temperature and then purified by reverse phase chromatography (CI 8) to provide the desired product as pale yellow solid. LCMS- ESI+ (m/z): [M+FTJ+ calcd for C23H26F 8O3: 481.5; found: 481.3. 1H NMR (300 MHz, DMSO-d6) δ 9.73 (d, J = 47.4 Hz, 1H), 8.70 (d, J = 9.3 Hz, 1H), 8.59 (d, J = 34.2 Hz, 1H), 8.57 (m, 1H), 7.65 (m, 2H), 5.13 (m, 3H), 4.55-3.90 (br, 3H), 3.74 (d, J = 6.9 Hz, 3H), 3.70-3.40 (br, 1H), 3.30 (m, 1H), 2.21 (d, J = 12.9 Hz, 3H), 1.98 (br, 2H), 1.23 (m, 3H). Example 567: 2-(((3R,4S)-l-((S)-2,3-dihydroxypropanoyl)-3-fluoropiperidin-4- yl)oxy)-5-(4-((l,5-dimethyl-lH-pyrazol-4-yl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000540_0001
5-(4-((l,5-dimethyl-lH-pyrazol-4-yl)amino)-l,3,5-triazin-2-yl)-2-(((3R,4S)-3- fluoropiperidin-4-yl)oxy)benzonitrile (70 mg, 0.171 mmol) and dihydroxypropanoic acid (36 mg, 0.34 mmol) were taken up as suspension in N,N- dimethylformamide (2 mL). The mixture was treated successively with N,N- diisopropylethylamine (0.10 mL, 0.574 mmol) and N-[(dimethylamino)-lH-l,2,3- triazolo- [4,5 -b]pyridin- 1 -ylmethylene] -N-methylmethanaminiumhexafluorophosphate N-oxide (HATU, 97.8 mg, 0.257 mmol). The mixture was stirred for 1 hour at room temperature and then purified by reverse phase chromatography (CI 8) to provide the desired product as pale yellow solid. LCMS-ESI+ (m/z): [M+H]+ calcd for C23H26F 804: 497.5; found: 497.3. 1H NMR (300 MHz, DMSO-d6) δ 9.74 (d, J = 47.4 Hz, 1H), 8.70 (d, J = 9.3 Hz, 1H), 8.59 (m, 2H), 7.65 (m, 2H), 5.11-3.90 (br, 5H), 3.74 (d, J = 6.9 Hz, 3H), 3.70-3.35 (br, 2H), 3.25-3.00 (br, 1H), 2.40-2.20 (br, 1H), 2.21 (d, J = 12.3 Hz, 3H), 1.98 (br, 2H), 1.23 (s, 1H).
Example 568: 5-(4-((l-ethyl-3-methyl-lH-pyrazol-4-yl)amino)-l,3,5-triazin-2-yl)-2- (((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)benzonitrile
Figure imgf000541_0001
Step 1 : Preparation of 4-chloro-N-(l-ethyl-3-methyl-lH-pyrazol-4-yl)-l,3,5-triazin-2- amine: To a solution of 2,4-dichloro-l,3,5-triazine (330 mg, 2.2 mmol) in dichloromethane (15 mL) at 0°C, l-ethyl-3 -methyl- lH-pyrazol-4-amine (250.34 mg, 2 mmol) was added, followed by N,N-Diisopropylethylamine (0.523 mL, 3 mmol). The reaction mixture was stirred at 0°C for 40 minutes. After this time, the reaction was quenched with saturated sodium bicarbonate solution (PH~8) and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to give the desired product as red solid. LCMS-ESI+ (m/z): [M+H]+ calcd for C9H12C1N6: 239.7; found: 239.1.
Step 2: Preparation of (3R,4S)-tert-butyl 4-(2-cyano-4-(4-(( l-ethyl-3 -methyl- 1H- pyrazol-4-yl)amino)-l,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-l-carboxylate: A suspension of 4-chloro-N-(l-ethyl-3-methyl-lH-pyrazol-4-yl)-l,3,5-triazin-2-amine (1 19 mg, 0.50 mmol) and (3R,4S)-tert-butyl 4-(2-cyano-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenoxy)-3-fluoropiperidine-l-carboxylate (245.5 mg, 0.55 mmol) in 1,2-Dimethoxy ethane (4 mL) was treated with 2M sodium carbonate solution (1.99 mL, 3.98 mmol) and Tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol). The mixture was heated in at 115 °C for 30 minutes. The cooled reaction mixture was quenched with water and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to give the desired product as white solid. LCMS-ESI+ (m/z): [M+H]+ calcd for C26H32F 8O3: 523.6; found: 523.4. Step 3: Preparation of 5-(4-((l-ethyl-3-methyl-lH-pyrazol-4-yl)amino)-l,3,5-triazin-2- yl)-2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)benzonitrile: (3R,4S)-tert-butyl 4-(2-cyano-4- (4-(( 1 -ethyl-3 -methyl- 1 H-pyrazol-4-yl)amino)- 1 ,3 ,5-triazin-2-yl)phenoxy)-3 - fluoropiperidine-l-carboxylate (256.5 mg, 0.49 mmol) was taken up in dichloromethane (5 mL) and treated with trifluoroacetic acid (0.8 mL, 10.5 mmol). After 20 minutes, the mixture was quenched with saturated sodium bicarbonate (PH ~ 8) and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude was used for next step. LCMS-ESI+ (m/z): [M+H]+ calcd for C2iH24F 80 423.5; found: 423.3.
Step 4: Preparation of 5-(4-((l-ethyl-3-methyl-lH-pyrazol-4-yl)amino)-l,3,5-triazin-2- yl)-2-(((3R,4S)-3-fluoro- 1 -((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)benzonitrile: 5- (4-(( 1 - ethy 1-3 -methyl- 1 H-pyrazol-4-yl)amino)- 1 ,3 ,5 -triazin-2-y l)-2-(((3 R,4S)-3 - fluoropiperidin-4-yl)oxy)benzonitrile (85 mg, 0.2 mmol) and L-lactic acid (36.3 mg, 0.42 mmol) were taken up as suspension in N,N-dimethylformamide (2 mL). The mixture was treated successively with N,N-diisopropylethylamine (0.104 mL, 0.597 mmol) and N- [(dimethylamino)- 1 H- 1 ,2,3 -triazolo-[4,5 -b]pyridin- 1 -ylmethylene] -N- methylmethanaminiumhexafluorophosphate N-oxide (HATU, 114.8 mg, 0.30 mmol). The mixture was stirred for 45 minutes at room temperature and then purified by reverse phase chromatography (CI 8) to provide the desired product as pale yellow solid. LCMS- ESI+ (m/z): [M+H]+ calcd for C24H28F 803: 495.5; found: 495.3. 1H NMR (300 MHz, DMSO-d6) δ 9.75 (d, J = 38.1 Hz, 1H), 8.72 (d, J = 3.0 Hz, 1H), 8.62 (m, 2H), 7.98 (d, J = 35.1 Hz, 1H), 7.64 (m, 1H), 5.12-4.13 (br, 5H), 4.20-3.40 (br, 4H), 3.28 (m, 1H), 2.13 (d, J = 2.4 Hz, 3H), 1.98 (br, 2H), 1.41 (m, 3H), 1.21 (m, 3H).
Example 569: 5-(4-((l-ethyl-3-methyl-lH-pyrazol-4-yl)amino)-l,3,5-triazin-2-yl)-2- -3-fluoro-l-(2-hydroxyacetyl)piperidin-4-yl)oxy)benzonitrile
Figure imgf000542_0001
5-(4-((l-ethyl-3-methyl-lH-pyrazol-4-yl)amino)-l,3,5-triazin-2-yl)-2-(((3R,4S)-3- fluoropiperidin-4-yl)oxy)benzonitrile (85 mg, 0.2 mmol) and Glycolic acid (30.6 mg, 0.4 mmol) were taken up as suspension in N,N-dimethylformamide (2 rnL). The mixture was treated successively with N,N-diisopropylethylamine (0.104 mL, 0.597 mmol) and N- [(dimethylamino)- 1 H- 1 ,2,3 -triazolo-[4,5 -b]pyridin- 1 -ylmethylene] -N- methylmethanaminiumhexafluorophosphate N-oxide (HATU, 114.8 mg, 0.30 mmol). The mixture was stirred for 60 minutes at room temperature and then purified by reverse phase chromatography (CI 8) to provide the desired product as pale yellow solid. LCMS- ESI+ (m/z): [M+H]+ calcd for C23H26F 803: 481.5; found: 481.6. 1H NMR (300 MHz, DMSO-d6) δ 9.75 (d, J = 38.1 Hz, 1H), 8.72 (d, J = 3.0 Hz, 1H), 8.61 (m, 2H), 7.98 (d, J = 35.1 Hz, 1H), 7.64 (m, 1H), 5.13-4.25 (br, 3H), 4.15-3.40 (br, 6H), 3.20 (br, 1H), 2.13 (d, J = 1.8 Hz, 3H), 1.98 (br, 2H), 1.41 (m, 3H).
Example 570: 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)- mino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000543_0001
Step 1 : Preparation of N-(4-chloro-l,3,5-triazin-2-yl)-2-methylthiazol-5-amine: To a solution of 2,4-dichloro-l,3,5-triazine (333 mg, 2.2 mmol) in dichloromethane (15 mL) at 0°C, 2-methylthiazol-5-amine (230 mg, 2.01 mmol) was added, followed by N,N- Diisopropylethylamine (0.53 mL, 3.02 mmol). The reaction mixture was stirred at 0°C for 15 minutes. After this time, the reaction was quenched with saturated sodium bicarbonate solution (PH~8) and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to give the desired product as yellow solid. LCMS-ESI+ (m/z): [M+H]+ calcd for C7H7CIN5S: 228.7; found: 228.5.
Step 2: Preparation of 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4- yl)oxy)-5-(4-((2-methylthiazol-5-yl)amino)-l,3,5-triazin-2-yl)benzonitrile: A suspension of N-(4-chloro-l,3,5-triazin-2-yl)-2-methylthiazol-5-amine (228 mg, 1.0 mmol) and 2- (((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile (460 mg, 1.1 mmol) in 1,2- Dimethoxyethane (10 mL) was treated with 2M sodium carbonate solution (3.8 mL, 7.6 mmol) and Tetrakis(triphenylphosphine)palladium (115.7 mg, 0.1 mmol). The mixture was heated at 125 °C for 45 minutes. The cooled reaction mixture was quenched with water and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel), then reverse phase (CI 8) to give the desired product as yellow solid. LCMS-ESI+ (m/z): [M+H]+ calcd for C22H23F 703S: 484.5; found: 484.6. 1H NMR (300 MHz, DMSO-d6) δ 1 1.47 (br, 1H), 8.88 (m, 1H), 8.71 (m, 2H), 7.72 (m, 1H), 7.42 (S, 1H), 5.13 (m, 3H), 4.48-3.90 (br, 3H), 3.80-3.45 (br, 1H), 3.15 (m, 1H), 2.61 (m, 3H), 1.99 (br, 2H), 1.22 (m, 3H).
Example 571 : 5-(4-((2,4-dimethylthiazol-5-yl)amino)-l,3,5-triazin-2-yl)-2-(((3R,4S)- panoyl)piperidin-4-yl)oxy)benzonitrile
Figure imgf000544_0001
Step 1 : Preparation N-(4-chloro-l,3,5-triazin-2-yl)-2,4-dimethylthiazol-5-amine: To a solution of 2,4-dichloro-l,3,5-triazine (0.825 mg, 5.5 mmol) in dichloromethane (50 mL) at 0°C, 2,4-dimethylthiazol-5-amine (0.64 g, 5 mmol) was added, followed by N,N- Diisopropylethylamine (1.31 mL, 17.5 mmol). The reaction mixture was stirred at 0°C for 20 minutes. After this time, the reaction was quenched with saturated sodium bicarbonate solution (PH~8) and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to give the desired product as red solid. LCMS-ESI+ (m/z): [M+H]+ calcd for C8H9C1N5S: 242.7; found: 242.3.
Step 2: Preparation of (3R,4S)-tert-butyl 4-(2-cyano-4-(4-((2,4-dimethylthiazol-5- yl)amino)-l,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-l-carboxylate: A suspension of N-(4-chloro-l,3,5-triazin-2-yl)-2,4-dimethylthiazol-5-amine (144 mg, 0.596 mmol) and (3R,4S)-tert-butyl 4-(2-cyano-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)- 3-fluoropiperidine-l-carboxylate (269.9 mg, 0.605 mmol) in 1,2-Dimethoxyethane (6 mL) was treated with 2M sodium carbonate solution (1.2 mL, 2.4 mmol) and Tetrakis(triphenylphosphine)palladium (72 mg, 0.062 mmol). The mixture was heated in at 125 °C for 40 minutes. The cooled reaction mixture was quenched with water and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to give the desired product as white solid. LCMS- ESI+ (m/z): [M+H]+ calcd for
Figure imgf000545_0001
526.6; found: 526.3.
Step 3 : Preparation of 5-(4-((2,4-dimethylthiazol-5-yl)amino)-l,3,5-triazin-2-yl)-2- (((3R,4S)-3-fluoropiperidin-4-yl)oxy)benzonitrile: (3R,4S)-tert-butyl 4-(2-cyano-4-(4- ((2,4-dimethylthiazol-5-yl)amino)-l,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-l- carboxylate (60 mg, 0.108 mmol) was taken up in dichloromethane (1.5 mL) and treated with trifluoroacetic acid (0.175 mL, 2.29 mmol). After 20 minutes, the mixture was quenched with saturated sodium bicarbonate (PH ~ 8) and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude was used for next step. LCMS-ESI+ (m/z): [M+H]+ calcd for C2oH21FN7OS 426.5; found: 426.3.
Step 4: Preparation of 5-(4-((2,4-dimethylthiazol-5-yl)amino)-l,3,5-triazin-2-yl)-2- (((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)benzonitrile: 5-(4- ((2,4-dimethylthiazol-5-yl)amino)-l,3,5-triazin-2-yl)-2-(((3R,4S)-3-fluoropiperidin-4- yl)oxy)benzonitrile (40 mg, 0.094 mmol) and L-lactic acid (18 mg, 0.2 mmol) were taken up as suspension in Ν,Ν-dimethylformamide (1 mL). The mixture was treated successively with N,N-diisopropylethylamine (0.052 mL, 0.3 mmol) and N- [(dimethylamino)- 1H- 1 ,2,3 -triazolo-[4,5-b]pyridin- 1 -ylmethylene]-N- methylmethanaminiumhexafluorophosphate N-oxide (HATU, 57 mg, 0.15 mmol). The mixture was stirred for 60 minutes at room temperature and then purified by reverse phase chromatography (C I 8) to provide the desired product as pale yellow solid. LCMS- ESI+ (m/z): [M+H]+ calcd for
Figure imgf000546_0001
498.6; found: 498.3. 1H NMR (300 MHz, DMSO-d6) δ 10.59 (br, 1H), 8.81 (m, 1H), 8.59 (m, 2H), 7.66 (m, 1H), 5.12 (m, 3H), 4.47-3.50 (br, 2H), 3.37 (m, 1H), 3.15 (m, 1H), 2.57 (m, 3H), 2.27 (m, 3H), 1.98 (br, 2H), 1.21 (m, 4H).
Example 572 : 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)- -(4-((4-(hydroxymethyl)thiazol-5-yl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000546_0002
Step 1 : Preparation of ethyl 5-((4-chloro-l,3,5-triazin-2-yl)amino)thiazole-4-carboxylate: To a solution of 2,4-dichloro-l,3,5-triazine (330.5 mg, 2.2 mmol) in dichloromethane (15 mL) at 0°C, ethyl 5-aminothiazole-4-carboxylate (345 mg, 2 mmol) was added, followed by N,N-Diisopropylethylamine (0.523 mL, 3 mmol). The reaction mixture was stirred at 0°C for 30 minutes. Then more 2,4-dichloro-l,3,5-triazine (300 mg, 2 mmol) was added and the reaction mixture was stirred at room temperature overnight. After this time, the reaction was quenched with saturated sodium bicarbonate solution (PH~8) and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to give the desired product as white solid. LCMS-ESI+ (m/z): [M+H]+ calcd for C9H9C1N502S: 286.7; found: 286.1.
Step 2: Preparation of ethyl 5-((4-(4-(((3R,4S)-l-(tert-butoxycarbonyl)-3- fluoropiperidin-4-yl)oxy)-3-cyanophenyl)-l,3,5-triazin-2-yl)amino)thiazole-4- carboxylate: A suspension of ethyl 5-((4-chloro-l,3,5-triazin-2-yl)amino)thiazole-4- carboxylate (308.6 mg, 1.08 mmol) and (3R,4S)-tert-butyl 4-(2-cyano-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)-3-fluoropiperidine-l-carboxylate (495 mg, 1.1 mmol) in 1,2-Dimethoxy ethane (1 1 mL) was treated with 2M sodium carbonate solution (2.2 niL, 4.4 mmol) and Tetrakis(triphenylphosphine)palladium (132 mg, 0.114 mmol). The mixture was heated in at 125 °C for 40 minutes. The cooled reaction mixture was quenched with water and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel) to give the desired product as yellow solid. LCMS-ESI+ (m/z): [M+H]+ calcd for C26H29FN705S: 570.6; found: 570.3.
Step 3: Preparation of (3R,4S)-tert-butyl 4-(2-cyano-4-(4-((4-(hydroxymethyl)thiazol-5- yl)amino)-l,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-l-carboxylate: ethyl 5-((4-(4- (((3R,4S)-l-(tert-butoxycarbonyl)-3-fluoropiperidin-4-yl)oxy)-3-cyanophenyl)- 1,3,5- triazin-2-yl)amino)thiazole-4-carboxylate (310 mg, 0.19 mmol) was dissolved in THF (8 mL) and the reaction mixture was cooled to 0°C. Lithium Aluminum Hydride (1M solution in THF, 1.67 mL, 1.67 mmol) was added drop wise. The reaction mixture was stirred at 0°C for 20 minutes. Then the mixture was quenched with 0.3 mL water, 0.2 mL IN NaOH and 0.3 mL water sequentially and stirred at room temperature for lh. Small amount of sodium sulfate and Celite were added and filtered. The filtrate was evaporated and purified by flash chromatography (silica gel) to give the desired product as white solid. LCMS-ESI+ (m/z): [M+H]+ calcd for C24H26FN704S: 528.6; found: 528.3. Step 4: Preparation of 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4- (hydroxymethyl)thiazol-5-yl)amino)-l,3,5-triazin-2-yl)benzonitrile: (3R,4S)-tert-butyl 4- (2-cyano-4-(4-((4-(hydroxymethyl)thiazol-5-yl)amino)-l,3,5-triazin-2-yl)phenoxy)-3- fluoropiperidine-l-carboxylate (50 mg, 0.095 mmol) was taken up in dichloromethane (1 mL) and treated with trifluoroacetic acid (0.145 mL, 1.90 mmol). After 20 minutes, the mixture was quenched with saturated sodium bicarbonate (PH ~ 8) and extracted with dichloromethane for three times. The combined extracts were washed once with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude was used for next step. LCMS-ESI+ (m/z): [M+H]+ calcd for C19H19FN702S 428.5; found: 428.2.
Step 5: Preparation of 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4- yl)oxy)-5-(4-((4-(hydroxymethyl)thiazol-5-yl)amino)-l,3,5-triazin-2-yl)benzonitrile: Preparation of 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(hydroxymethyl)thiazol- 5-yl)amino)-l,3,5-triazin-2-yl)benzonitrile (30 mg, 0.07 mmol) and L-lactic acid (17 mg, 0.189 mmol) were taken up as suspension in Ν,Ν-dimethylformamide (1 mL). The mixture was treated successively with N,N-diisopropylethylamine (0.05 mL, 0.28 mmol) and N-[(dimethylamino)- 1 H- 1 ,2,3 -triazolo-[4,5-b]pyridin- 1 -ylmethylene]-N- methylmethanaminiumhexafluorophosphate N-oxide (HATU, 54 mg, 0.142 mmol). The mixture was stirred for 2 hour at room temperature and then purified by reverse phase chromatography (CI 8) to provide the desired product as pale yellow solid. LCMS-ESI+ (m/z): [M+H]+ calcd for C22H23F 704S: 500.5; found: 500.3. 1H NMR (300 MHz, DMSO-d6) δ 10.71 (br, 1H), 8.87 (m, 4H), 7.68 (m, 1H), 5.11 (m, 4H), 4.70 (m, 2H), 4.43-3.90 (br, 3H), 3.51 (br, 1H), 3.15 (m, 1H), 1.99 (br, 2H), 1.21 (m, 3H).
Example 573: 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4-(4- ((S)-2-hydroxypropyl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000548_0001
Stepl: (S)-l-(4-(4-nitrophenyl)piperazin-l-yl)propan-2-ol: l-(4-nitrophenyl)piperazine (l.Og, 4.83mmol) was charged into a 20mL pressure vessel and was suspended in 5mL DMF and to that was added (S)-2-methyloxirane (5mL, 71.4mmol, 14.8equivs) and the reaction was sealed and heated at 100°C for six hours. LCMS showed complete conversion and the reaction was cooled to room temperature, followed by concentration on a rotary evaporator. The crude was dissolved in 10% methanol/dichloromethane and washed lxlOOmL saturated sodium bicarbonate, lxlOOmL brine and dried over sodium sulfate. The crude was filtered, concentrated on a rotary evaporator and flashed on an ISCO purification system using a gradient of 0-20% methanol/dichloromethane. (S)-l-(4-(4-nitrophenyl)piperazin-l-yl)propan-2- ol was isolated as a colorless syrup, (977mg, 76%).
Step 2: (S)-l-(4-(4-aminophenyl)piperazin-l-yl)propan-2-ol: (S)-l-(4-(4-nitrophenyl)piperazin-l- yl)propan-2-ol (600mg, 2.26mmol) was dissolved in lOOmL of 1:1 ethyl acetate and ethanol and to that was added lOOmg of wet palladium on carbon and then placed into a Parr vessel and hydrogenated with 60psi hydrogen pressure for six hours. LCMS showed complete reduction and the vessel was removed and the reaction solution was filtered through a pad of Celite® and then concentrated on a rotary evaporator. The sample solidified under vacuum to yield (S)-l- (4-(4-aminophenyl)piperazin-l-yl)propan-2-ol as a light yellow crystalline solid (505mg, 95%). Step 3: (S)-l-(4-(4-((4-chloro-l,3;5-triazin-2-yl)amino)phenyl)piperazin-l-yl)propan-2-ol: To a 250 round-bottomed flask was charged (S)-l-(4-(4-aminophenyl)piperazin-l-yl)propan-2-ol (300mg, 1.27mmol), 2,4-dichloro-l,3,5-triazine (191mg, l,27mmol) and potassium carbonate (3.0 equivs, 3.82mmol, 528mg) and to that was added 5mL dimethylacetamide precooled to 0°C. After 15 min LCMS showed the reaction to be complete and lOOmL water was added to the reaction and the crude was extracted into lOOmL 5% methanol/dichloromethane. The sample was washed IxlOOmL saturated sodium bicarbonate, IxlOOmL brine and dried over sodium sulfate. The crude solution was filtered, concentrated on a rotary evaporator and flashed on an ISCO system using a gradient of 0-20% methanol/dichloromethane. The desired product (S)-l-(4-(4-((4-chloro-l,3,5-triazin-2-yl)amino)phenyl)piperazin-l-yl)propan-2-ol was recovered as a light yellow solid (252mg, 57%).
Step 4: (3 ,4S)-tert-butyl 4-(2-cyano-4-(4-((4-(4-((S)-2-hydroxypropyl)piperazin-l- yl (phenyl )amino)-l,3,5-triazin-2-yl)phenoxy)-3-f I uoropiperidine-l-carboxylate: (S)-l-(4-(4-((4- chloro-l,3,5-triazin-2-yl)amino)phenyl)piperazin-l-yl)propan-2-ol (355mg, 1.02mmol), (3R,4S)- tert-butyl 4-(2-cyano-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)-3- fluoropiperidine-l-carboxylate (l.lequiv, 500mg, 1.21mmol) and tetrakis-triphenylphosphine- palladium[0] (0.1%, 118mg) were added to a round-bottomed flask and to that was added 20mL dimethoxyethane and lOmL 2N sodium carbonate and the reaction was allowed to proceed at 125°C for lhr. LCMS showed reaction complete and after cooling to room temperature the crude solution was transferred to a separatory funnel and to that was added lOOmL water and lOOmL 10% methanol/dichloromethane. The crude sample was extracted into the organic layer which was then dried over sodium sulfate, filtered and concentrated on a rotary evaporator and flashed on an ISCO using a gradient of 0-25% methanol/dichloromethane. The desired product (3R,4S)-tert-butyl 4-(2-cyano-4-(4-((4-(4-((S)-2-hydroxypropyl)piperazin-l-yl)phenyl)amino)- l,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-l-carboxylate was obtained as an off-white foam (440mg, 68%).
Step 5: 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-((S)-2-hydroxypropyl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile: (3R,4S)-tert-butyl 4-(2-cyano-4-(4-((4-(4-((S)-2- hydroxypropyl)piperazin-l-yl)phenyl)amino^
carboxylate (82mg, 0.13mmol) was dissolved in 9.0mL dichloromethane and to that was added l.OmL trifluoroacetic acid and the sample was stirred at room temperature for two hours. LCMS showed complete deprotection of the Boc-group and all solvent was removed. The crude was dissolved in lOOmL 10% methanol/dichloromethane and free-based by washing 2xl00mL saturated sodium bicarbonate, lxlOOmL brine and dried over sodium sulfate. The sample was filtered, concentrated on a rotary evaporator and dried on high vacuum to yield the desired product 2-(((3 ,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-((S)-2-hydroxypropyl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile as an off-white solid (69mg, 80%). Step 6: 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-((S)-2-hydroxypropyl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (50mg, 0.094mmol) was dissolved in 5mL dimethylformamide and to that was added (S)-lactic acid (188uL of a 1M solution in dimethylformamide, 2equivs), l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (HATU, 2equivs, 0.188mmol, 71mg) and diisopropylethylamine (DIEA, 3equivs, 0.28mmol, 49uL) and allowed to react at room temperature for two hours. LCMS showed completion and lOOmL of water and lOOmL of 10% methanol/dichloromethane were added and the crude was extracted into organic. The organic layer was dried over sodium sulfate, concentrated on a rotary evaporator and flashed on an ISCO 0-25% methanol/dichloromethane yielding the desired target 2-(((3R,4S)-3-fluoro-l-((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4-(4-((S)-2-hydroxypropyl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile as a light yellow solid. :H NMR (300 MHz, DMSO-d6) δ 10.13 (d, J = 16.6 Hz, 1H), 8.74 (s, 1H), 8.57 (d, J = 10.7 Hz, 2H), 7.79 - 7.37 (m, 3H), 6.95 (s, 2H), 5.33 - 4.78 (m, 3H), 4.61 - 3.45 (m, 5H), 3.45 - 3.21 (m, 12H), 3.11 (bs, 4H), 2.53 (bs, 4H), 2.34 (m, 2H), 2.07 - 1.67 (m, 2H), 1.44 - 1.13 (m, 3H), 1.06 (d, J = 6.1 Hz, 3H). LCMS- ESI+ (m/z): [M+H]+ calcd for C 31 H 37 FN 8 O 4 : 604.3; ' found: 605.5.
Example 574: 2-(((3R,4S)-l-((S)-2,3-dihydroxypropanoyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((l- isopropyl-lH-pyrazol-4-yl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000551_0001
2-(((3 ,4S)-3-fluoropiperidin-4-yl)oxy)-5-^
yljbenzonitrile (44mg, 0.104mmol, lequiv) was dissolved in 5mL dimethylformamide and to that was added diisopropylethylamine (DIEA, 3equivs, 0.312mmol, 54uL), (S)-2,3- dihydroxypropanoic acid (2equivs, 22mg, 0.208mmol) and (l-[bis(dimethylamino)methylene]- lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (HATU, 2equivs, 0.208mmol, 79mg) and the reaction was allowed to proceed for two hours. After which time LCMS showed complete consumption of the free piperidine and the reaction was quenched by the addition of lOOmL water. The crude was extracted into lOOmL of 10% methanol/dichloromethane and was then dried over sodium sulfate. The crude solution was then filtered, concentrated on a rotary evaporator and then flashed on silica gel employing an ISCO purification system using a gradient of 0-30% methanol/dichloromethane. The desired 2-(((3R,4S)-l-((S)-2,3-dihydroxypropanoyl)-3- fluoropiperidin-4-yl)oxy)-5-(4-((l-isopropyl-lH-pyrazol-4-yl)amino)-l,3,5-triazin-2- yl)benzonitrile was recovered as a light yellow solid. :H NMR (300 MHz, DMSO-d6) δ 10.31 (d, J = 7.3 Hz, 1H ), 9.02 - 8.44 (m, 3H), 8.01 (d, J = 14.6 Hz, 1H), 7.81 - 7.40 (m, 2H ), 5.34 - 4.84 (m,
3H), 4.87 - 3.85 (m, 4H), 3.75-3.34 (m, 3H), 2.51 (bs, 2H), 2.00 (bs, 2H), 1.44 (m, 6H). LCMS-ESI+ (m/z): [M+H]+ calcd for 24H2yFNg04: 510.2; found: 511.2.
Example 575: 2-(((3R,4S)-l-((S)-2,3-dihydroxypropanoyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((3- methyl-4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000552_0001
Step 1: 2-(((3R,4S)-l-(2,2-dimethyl-l,3-dioxolane-4-carbonyl)-3-fluoropiperi^^
((3-methyl-4-(4-(oxetan-3-yl)piperazin-l-yl (phenyl )amino)-l,3,5-triazin-2-yl)benzonitrile: 2- (((3R;4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((3-methyl-4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (lOOmg, 0.184mmol, lequiv) was dissolved in 5mL dimethylformamide and to that was added racemic 2,2-dimethyl-l,3-dioxolane-4- carboxylic acid (2equivs, 54mg, 0.367mmol), diisopropylethylamine (DIEA, 3equivs, 96uL, 0.551mmol) and (l-[bis(dimethylamino)methylene]-lH-l;2;3-triazolo[4;5-b]pyridinium 3-oxid hexafluorophosphate) (HATU, 2equivs, 140mg, 0.367mmol) and the reaction allowed to proceed for two hours. LCMS showed reaction complete and lOOmL water was then added to quench the reaction. The crude was extracted into lOOmL of 10% methanol/dichloromethane and then dried over sodium sulfate. The crude solution was then filtered, concentrated on a rotary evaporator and then flashed on silica gel employing an ISCO purification system using a gradient of 0-15% methanol/dichloromethane yielding 84mg of the racemic ketal (68%) as a light yellow solid.
Step 2: 2-(((3R;4S)-l-(2;2-dimethyl-l;3-dioxolane-4-carbonyl)-3-fluoropiperidin-4-yl)oxy)-5-(4- ((3-methyl-4-(4-(oxetan-3-yl)piperazin-l-yl (phenyl )amino)-l,3,5-triazin-2-yl)benzonitrile (84mg, 0.125mmol) was dissolved in 9.0mL dichloromethane and to that was added ImL trifluoroacetic acid and allowed to react for two hours at room temperature. LCMS confirmed the complete deprotection of the ketal and all solvent was removed on a rotary evaporator. The crude was then dissolved in 10% methanol/dichloromethane and was washed with lOOmL saturated sodium bicarbonate and then dried on sodium sulfate. The sample was then filtered, concentrated and purified on silica gel employing an ISCO purification system using a gradient of 0-30% methanol/dichloromethane. The desired racemic diol 2-(((3R,4S)-l-(2,3- dihydroxypropanoyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((3-methyl-4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (71mg, 90%) was recovered as a light yellow solid. :H NMR (300 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.78 (s, 1H), 8.58 (d, J = 8.2 Hz, 2H), 7.81 - 7.34 (m, 3H), 7.06 (d, J = 8.6 Hz, 1H), 5.36 - 4.65 (m, 4H), 4.57 (t, J = 6.5 Hz, 2H), 4.47 (t, J = 6.1 Hz, 3H), 4.05 (d, J = 59.3 Hz, 2H), 3.87 - 3.38 (m, 3H), 3.37 - 3.09 (m, 2H), 2.86 (bs, 4H), 2.50 -
2.34 (bs, 3H), 2.27 (bs, 4H), 1.99 (s, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd for 32H37FNgOs: 632.3; found : 633.4. Step 3: The above compound from Step 2, 2-(((3R,4S)-l-(2,3-dihydroxypropanoyl)-3- fluoropiperidin-4-yl)oxy)-5-(4-((3-methyl-4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile was dissolved in (methanol) and purified on chiral column (Chiralpak IC) using gradient (MTBE:MeOH, 90: 10) to the ttile compound as light yellow solid ( later eluting isomer) :H NMR (300 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.77 (s, 1H), 8.58 (d, J = 8.2 Hz, 2H), 7.82 - 7.30 (m, 3H), 7.05 (d, J = 8.6 Hz, 1H), 5.31 - 4.85 (m, 3H), 4.80 - 4.22 (m, 5H), 4.08 (q, J = 5.3 Hz, 1H), 3.96 (d, J = 13.2 Hz, 1H), 3.86 - 3.21 (m, 4H), 2.85 (bs, 4H), 2.42 (bs, 4H ), 2.26 (s, 3H), 1.98
(s, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H37FNg05: 632.3; found : 633.0.
Example 576: 2-(((3R,4S)-l-((R)-2,3-dihydroxypropanoyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((3- methyl-4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000553_0001
The compound from Example 575, 2-(((3R,4S)-l-(2,3-dihydroxypropanoyl)-3-fluoropiperidin-4- yl)oxy)-5-(4-((3-methyl-4-(4-(oxetan-3-yl)piperazin-l-yl (phenyl jam ino)-l,3,5-triazin-2- yl)benzonitrile was dissolved in methanol and purified on chiral column (Chiralpak IC) using gradient (MTBE:MeOH, 90:10) to yield the title compound (first eluting (R)-enantiomer) as light yellow solid. :H NMR (300 MHz, DMSO-d6) δ 10.18 (d, J = 16.6 Hz, 1H), 8.77 (s, 1H), 8.58 (d, J = 7.8 Hz, 2H), 7.84 - 7.31 (m, 3H), 7.05 (d, J = 8.6 Hz, 1H), 5.30 - 4.66 (m, 3H), 4.56 (t, J = 6.5 Hz, 2H), 4.51 - 3.86 (m, 4H), 3.48 (p, J = 6.2, 5.6 Hz, 2H), 3.20 (dd, J = 22.3, 8.0 Hz, 1H), 2.84 (d, J = 4.9 Hz, 4H), 2.49 - 2.32 (m, 4H), 2.26 (s, 3H), 2.13 - 1.71 (m, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd for C H FN 0 : 632.3; found: 633.0.
Example 577: 2-(((S)-l-((S)-2,3-dihydroxypropanoyl)-3,3-difluoropiperidin-4-yl)oxy)-5-(4-((3- methoxy-4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000554_0001
(S)-2-((3,3-difluoropiperidin-4-yl)oxy)-5-(4-((3-methoxy-4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (88mg, 0.152mmol, lequiv) was dissolved in 5mL dimethylformamide and to that was added diisopropylethylamine (DIEA, 3equivs, 0.456mmol, 79uL), (S)-2,3-dihydroxypropanoic acid (2equivs, 32mg, 0.304mmol) and (1- [bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (HATU, 2equivs, 0.304mmol, 116mg) and the reaction was allowed to proceed for two hours. After which time LCMS showed complete consumption of the free piperidine and the reaction was quenched by the addition of lOOmL water. The crude was extracted into lOOmL of 10% methanol/dichloromethane and was then dried over sodium sulfate. The crude solution was then filtered, concentrated on a rotary evaporator and then flashed on silica gel employing an ISCO purification system using a gradient of 0-30% methanol/dichloromethane. The desired 2-(((S)-l-((S)-2,3-dihydroxypropanoyl)-3,3- difluoropiperidin-4-yl)oxy)-5-(4-((3-methoxy-4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)- l,3,5-triazin-2-yl)benzonitrile was recovered as a light yellow solid. :H NM (300 MHz, DMSO- d6) δ 10.24 (d, J = 23.5 Hz, 1H), 8.79 (s, 1H), 8.62 (d, J = 8.1 Hz, 2H), 7.69 (d, J = 9.2 Hz, 1H), 7.29 (d, J = 56.8 Hz, 2H), 6.91 (d, J = 8.5 Hz, 1H), 5.57 - 5.06 (m, 2H), 4.79 (d, J = 15.4 Hz, 1H), 4.67 - 3.98 (m, 6H), 3.86 (s, 3H), 3.72 - 3.41 (m, 5H), 2.99 (s, 4H), 2.72 - 2.29 (m, 4H), 2.18 (s, 1H), 1.41 - 1.09 (m, 1H). LCMS-ESI+ (m/z): [M+H]+ calcd for C H, F N O ■ 666.3; found: 667.2.\ Example 578: 2-(((3R,4S)-l-((S)-2,3-dihydroxypropanoyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((3- methoxy-4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000555_0001
Step 1: 2-(((3 ;4S)-l-(2;3-dihydroxypropanoyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((3-methoxy-4-
(4-(oxetan-3-yl)piperazin-l-yl (phenyl )amino)-l, 3, 5-triazin-2-yl)benzonitrile was prepared following very similar procedure to Example 575. :H NMR (300 MHz, DMSO-d6) δ 10.21 (d, J = 24.2 Hz, 1H), 8.78 (s, 1H), 8.69 - 8.48 (m, 2H), 7.64 (d, J = 9.0 Hz, 2H), 7.20 (s, 1H), 6.90 (d, J = 8.5 Hz, 1H), 5.32 - 5.02 (m, 2H), 5.02 - 4.66 (m, 2H), 4.55 (t, J = 6.5 Hz, 2H), 4.50 - 4.23 (m, 3H), 3.85
(s, 2H), 3.45 (m, 4H), 2.97 (bs, 4H), 2.40 (bs, 4H), 1.95 (m, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd for C H FN O : 648.3; found: 649.7.
Step 2: The racemic mixture was then separated by chiral column Chromatography to give the title compound. :H NMR (300 MHz, DMSO-d6) δ 10.22 (d, J = 24.6 Hz, 1H), 8.78 (s, 1H), 8.70 - 8.45 (m, 2H), 7.64 (d, J = 9.0 Hz, 1H), 7.29 (d, J = 54.8 Hz, 2H ), 6.90 (d, J = 8.5 Hz, 1H), 5.36 - 4.86 (m, 3H), 4.81 - 4.22 (m, 7H), 4.22 - 3.68 (m, 3H), 3.68 - 3.35 (m, 3H), 3.31 (m, 2H), 2.97 (s, 4H),
2.40 (s, 4H), 1.94 (d, J = 25.2 Hz, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H37FNgOg: 648.3; found : 649.5.
Example 579: 2-(((3R,4S)-l-((R)-2,3-dihydroxypropanoyl)-3-fluoropiperidin-4- yl)oxy)-5-(4-((3-methoxy-4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
Figure imgf000556_0001
The racemic compound from Example 578 (step 1), was dissolved in (methanol) and purified on chiral column (Chiralpak IC) using gradient (MTBE:MeOH, 90: 10) to yield the title compound as light yellow solid
:H NM (300 MHz, DMSO-d6) δ 10.22 (d, J = 23.3 Hz, 1H), 8.78 (s, 1H), 8.69 - 8.45 (m, 2H), 7.64 (d, J = 9.0 Hz, 1H), 7.29 (d, J = 55.9 Hz, 2H), 6.90 (d, J = 8.6 Hz, 1H), 5.31 - 4.64 (m, 4H), 4.55 (t, J = 6.5 Hz, 2H), 4.49 - 3.63 (m, 7H), 3.63 - 3.37 (m, 2H), 3.31 (m, 1H), 2.98 (s, 4H), 2.44 (d, J = 23.1
Hz, 4H), 1.94 (d, J = 25.6 Hz, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd for 32H37FNgOg: 648.3; found :
649.5.
Example 580: 2-(((4S)-l-(2,3-dihydroxypropanoyl)-3,3-difluoropiperidin-4-yl)oxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000556_0002
The title compound was synthesized in the same manner as Example 575. :H NMR (300 MHz, DMSO-d6) δ 10.15 (d, J = 16.3 Hz, 1H), 8.75 (s, 1H), 8.69 - 8.45 (m, 2H), 7.78 - 7.39 (m, 3H), 6.96 (s, 2H), 5.37 (m, 1H), 5.22 (d, J = 7.1 Hz, 1H), 4.75 (m, 1H), 4.56 (t, J = 6.5 Hz, 2H), 4.50 - 4.31 (m,
3H), 3.85 (m, 1H), 3.73 - 3.36 (m, 2H), 3.14 (s, 4H), 2.48 - 2.31 (bs, 4H), 2.13 (m, 2H). LCMS-ESI+
(m/z): [M+H]+ calcd for C H F N O : 636.3; found: 637.0. Example 581: 2-(((S)-l-((S)-2,3-dihydroxypropanoyl)-3,3-difluoropiperidin-4-yl)oxy)-5-(4-((4- (4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000557_0001
Racemic Example 580 was dissolved in (MeOH) and purified on chiral column (Chiralpak IC) using gradient (MTBE:MeOH, 90: 10) to yield the tile compound (second eluting isomer) as light yellow solids. :H NMR (300 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.76 (s, 1H), 8.68 - 8.44 (m, 2H), 7.82 - 7.43 (m, 3H), 6.97 (s, 2H), 5.32 (d, J = 35.4 Hz, 2H), 4.76 (s, 1H), 4.57 (t, J = 6.5 Hz, 2H), 4.48 (t, J = 6.1 Hz, 2H), 4.41 (bs, 1H), 4.18 (s, 1H), 3.85 (s, 1H), 3.71 - 3.37 (m, 3H), 3.15 (s, 4H), 2.41 (t, J = 5.0 Hz, 4H), 2.22 (d, J = 31.7 Hz, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd for C H F N O : 636.3; found: 637.0.
Example 582: 2-(((S)-l-((R)-2,3-dihydroxypropanoyl)-3,3-difluoropiperidin-4-yl)oxy)-5-(4-((4- (4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000557_0002
acemic Example 580 was dissolved in (MeOH) and purified on chiral column (Chiralpak IC) using gradient (MTBE:MeOH, 90:10) to yield the tile compound (first eluting isomer) as light yellow solids :H NMR (300 MHz, DMSO-d6) δ 10.16 (d, J = 16.2 Hz, 1H), 8.76 (s, 1H), 8.60 (d, J = 10.2 Hz, 2H), 7.79 - 7.39 (m, 3H), 6.97 (s, 2H), 5.38 (s, 1H), 5.23 (d, J = 7.1 Hz, 1H), 4.77 (s, 1H), 4.57 (t, J = 6.5 Hz, 2H), 4.48 (t, J = 6.0 Hz, 2H), 4.40 (d, J = 6.3 Hz, 1H), 4.32 - 3.77 (m, 1H), 3.77 -
3.38 (m, 4H), 3.26 - 3.00 (m, 4H), 2.41 (t, J = 5.0 Hz, 4H), 2.02 (d, J = 84.1 Hz, 2H). LCMS-ESI+
(m/z): [M+H]+ calcd for 31H34F2Ng05: 636.3; found: 637.0.
Example 583: 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(2- hydroxyethyl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000558_0001
2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(2-hydroxyethyl)piperazin-l-yl (phenyl )amino)- l,3,5-triazin-2-yl)benzonitrile (50mg, 0.096mmol, lequiv) was charged to a lOOmL round- bottomed flask and then dissolved in 5mL dimethylformamide. To that solution was added diisopropylethylamine (DIEA, 3equivs, 50uL, 0.289mmol), (S)-lactic acid (2equivs, 193uL of a 1M solution in dimethylformamide) and (l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate) (HATU, 2equivs, 223mg, 0.193mmol) and allowed to react for two hours. LCMS confirmed completion of the reaction and lOOmL 10% methanol/dichloromethane and lOOmL water were then added and the crude sample was extracted into the organic layer. The organic layer was then dried over sodium sulfate, filtered, concentrated on a rotary evaporator and flash chromatographed on silica gel employing an ISCO system and using a gradient of 0-25% methanol/dichloromethane. The desired 2- (((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(2- hydroxyethyl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile was obtained (25mg, 44%) as a light yellow solid.
:H NMR (300 MHz, DMSO-d6) δ 10.12 (d, J = 16.8 Hz, 1H), 8.74 (s, 1H), 8.57 (d, J = 11.3 Hz, 2H), 7.77 - 7.40 (m, 3H), 6.95 (s, 2H), 5.28 - 4.88 (m, 3H), 4.62 - 4.28 (m, 1H), 4.28 - 3.83 (m, 2H), 3.53 (q, J = 6.0 Hz, 2H), 3.32 (m, 3H), 3.09 (d, J = 5.9 Hz, 4H), 2.56 (t, J = 5.0 Hz, 4H), 2.43 (t, J =
6.2 Hz, 2H), 2.14 - 1.63 (m, 2H), 1.20 (dd, J = 6.7, 2.8 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C H FN O : 590.3; found: 590.8.
Example 584: 2-(((3R,4S)-l-((S)-2,3-dihydroxypropanoyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4- (4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000559_0001
Racemic 2-(((3R,4S)-l-(2;3-dihydroxypropanoyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan- 3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile was prepared in similar manner to Example 575 and then was purified on a chiral column (Chiralpak IC) using gradient (MTBE:MeOH, 90: 10) to afford the title compound. :H NMR (300 MHz, DMSO-d6) δ 10.13 (d, J = 17.0 Hz, 1H), 8.74 (s, 1H), 8.57 (d, J = 11.0 Hz, 2H), 7.81 - 7.40 (m, 3H), 6.96 (s, 2H), 5.80 - 5.29 (m, 1H), 5.29 - 4.66 (m, 3H), 4.57 (t, J = 6.5 Hz, 3H), 4.51 - 3.86 (m, 5H), 3.87 - 3.35 (m, 3H),
3.14 (s, 4H ), 2.50 - 2.30 (m, 4H), 1.99 (s, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd for 31H35FNg05:
618.3; found : 619.3.
Example 585: 2-(((3R,4S)-l-((R)-2,3-dihydroxypropanoyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4- (4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000560_0001
acemic 2-(((3R;4S)-l-(2,3-dihydroxypropanoyl)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan- 3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile was prepared in similar manner to Example 575 and then was purified on a chiral column (Chiralpak IC) using gradient (MTBE:MeOH, 90: 10) to afford the title compound.
:H NMR (300 MHz, DMSO-d6) δ 10.13 (d, J = 16.9 Hz, 1H), 8.74 (s, 1H), 8.57 (d, J = 10.4 Hz, 2H), 7.78 - 7.37 (m, 3H), 6.96 (s, 2H), 5.33 - 4.64 (m, 4H), 4.56 (t, J = 6.5 Hz, 2H), 4.50 - 3.83 (m, 4H),
3.82 - 3.35 (m, 4H), 3.26 - 3.02 (m, 4H), 2.50 - 2.29 (m, 4H), 2.17 - 1.70 (m, 2H). LCMS-ESI+
(m/z): [M+H]+ calcd for C H FN O : 618.3; found: 619.3.
31 35 8 5 '
Example 586: 2-(((3R,4S)-l-(2-cyanopropanoyl)-3-fluoropiperidin-4-yl)oxy)-5-(4- ((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
To a solution of 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (35 mgs, 0.07 mmol) in DMF (1.0 mL) was added 2-cyanopropanoic acid (13 mgs, 0.13 mmol), HATU (50 mgs, 0.13 mmol) and DIPEA (0.02 mL, 0.13 mmol). The above reaction mixture was stirred at room temperature for 2 h, evaporated under reduced pressure and purified via preparative HPLC (5-65% acetonitrile in water, 0.1% trifluoroacteic acid buffer) to yield the title compound. LCMS-ESI+ (m/z)
C32H34FN903: 612.3; found: 612.3.
Example 587: 2-(((3R,4S)-l-(l-cyanocyclopropanecarbonyl)-3-fluoropiperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2- yl)benzonitrile
Figure imgf000561_0001
The title compound was synthesized in the same manner as Example 586. LCMS-ESI+ (m/z) [M+H]+ calcd for C33H34FN903: 624.2; found : 624.3.
Example 588: 2-(((3R,4S)-3-fluoro-l-((2S,4S)-4-hydroxypyrrolidine-2 carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)- l,3,5-triazin-2-yl)benzonitrile
Figure imgf000561_0002
The title compound was synthesized in the same manner as Example 586. LCMS-ESI+ (m/z) [M+H]+ calcd for C33H38FN904: 644.3; found : 644.1. Example 589: 2-(((3R,4S)-3-fluoro-l-((2S,4R)-4-hydroxypyrrolidine-2- carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)- l,3,5-triazin-2-yl)benzonitrile
Figure imgf000562_0001
The title compound was synthesized in the same manner as Example 586. LCMS-ESI"1" (m/z) :
[M+H]+ calcd for C33H38FN904: 644.3; found : 644.1.
Example 590 : 3-(((S)-l-((S)-2-hydroxypr opanoyl)pyrrolidin-3-yl)methoxy)-5-(4-((4- (4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000562_0002
The title compound was synthesized in the same manner as Example 134 using (S)-tert- butyl 3-(hydroxymethyl)pyrrolidine-l-carboxylate instead of tert-butyl 4- hydroxypiperidine-l-carboxylate. LCMS-ESI"1" (m/z): [M+H]+ calcd for C31H36N804: 585.4; found: 585.2. Example 591 : (S)-3-((l-(2-hydroxyacetyl)pyrrolidin-3-yl)methoxy)-5-(4-((4-(4- (oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000563_0001
The title compound was synthesized in the same manner as Example 134 using using (S)-tert- butyl 3-(hydroxymethyl)pyrrolidine-l-carboxylate instead of tert-butyl 4-hydroxypiperidine-l- carboxylate and using Glycolic acid instead of (S)-2-hydroxypropanoic acid . LCMS-ESI"1" (m/z):
[M+H]+ calcd for C30H34N8O4: 571.3; found: 571.1.
Examples 592-610: The following examples were prepared using general procedure described below: A solution of corresponding alcohol (3 equiv) in THF (3 mL) was stirred in an ice-water bath under an atmosphere of Argon. Potassium tert-butoxide (1.0 M, 3 equiv) was added in a single portion and the mixture was stirred at 0 °C for 30 minutes, and then 2-fluoro-5-(4-((4-(4- (oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile was added (1 equiv). The mixture was stirred for 2hr at rt After the mixture cooled to room temperature, water was added, and mixture evaporated under reduced pressure. Solids were purified via preparative HPLC (5-65% acetonitrile in water, 0.1% trifluoroacetic acid buffer) to yield the final product.
M+ H
Example Formula-Parent
Structure M calcd found
592 C28H29N902 523.6 524.3
593 C36H39N904 661.8 662.5
Figure imgf000564_0001
©·-"¾
594 C28H30N8O3 526.6 527.2
595 C35H37N904 647.7 648.3
Figure imgf000564_0002
Figure imgf000565_0001
Figure imgf000566_0001
Figure imgf000567_0001
Figure imgf000568_0001
Example 611: 2-(((3R,4S) -fluoro-l-(pyridin-3-yl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile.
Figure imgf000569_0001
The title compound was prepared following a similar procedure reported in Example
480 using 3-bromopyridine. LCMS-ESI+ (m/z): [M+H]+ calcd. for C33H34FN902 Exact Mass: 608.3 found:608.3.
Example 612: 2-(((3R,4S)-3-fluoro-l-(3-methyl-l,2,4-oxadiazole-5-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000569_0002
The title compound was prepared following a similar procedure reported in Example 461 using 3-methyl-l,2,4-oxadiazole-5-carboxylic acid. :H NM (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.73 (s, 1H), 8.66 - 8.45 (m, 2H), 7.68 - 7.61 (m, 1H), 7.61 - 7.48 (m, 2H), 6.99-6.92 (m, 2H), 5.32- 5.15 (m, 2H), 4.55 (t, J = 6.5 Hz, 2H), 4.46 (t, J = 6.0 Hz, 2H), 4.31 (d, J = 14.1 Hz, 1H), 4.13 - 3.69 (m, 1H), 3.65 - 3.38 (m, 2H), 3.19-3.10 (m, 4H), 2.44 (d, J = 2.4 Hz, 3H), 2.40 (t, J = 4.9 Hz, 4H),
2.04 (ddd, J = 55.6, 30.8, 12.6 Hz, 2H). LCMS-ESI+ (m/z): [M+H]+ calcd for C32H33FN10O4 Exact Mass: 641.3 found : 641.3
Example 613: 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)amino)-5-(4-((4-(4- (oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile.
Figure imgf000570_0001
A solution of a 2-fluoro-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile (500 mg, 1.16 mmol), DIPEA (0.26 gr, 2.3 mmol) in DMSO was stirred in a heating block at 120 C for 24 h. After the mixture cooled to room temperature, water was added, and formed solids were filtered out, washed with diethyl-ether to yield (3R,4S)-tert- butyl 4-((2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl (phenyl )amino)-l, 3, 5-triazin-2- yl (phenyl )amino)-3-fluoropiperidine-l-carboxylate.
Oily material from previous step was dissolved with DCM and TFA. Reaction mixture was stirred at room temperature for lhr. Reaction mixture was evaporated under reduced pressure and solids were suspended in a saturated aqueous solution of NaHC03 and extracted with DCM. Organic phase was collected dried over magnesium sulfate and evaporated under reduced pressure to yield 2-(((3R,4S)-3-fluoropiperidin-4-yl)amino)-5-(4-((4-(4-(oxetan-3- yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile. To a solution of 2-(((3R,4S)-3-fluoropiperidin-4-yl)amino)-5-(4-((4-(4-(oxetan-3- yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (30 mg, 0.05 mmol), (S)-2- hydroxypropanoic acid (5 mg, 0.05 mmol), HATU (43 mgs, 0.11 mmol) in DMF (3 mL) was added TEA (23 mg, 0.23 mmol) in a 100 ml rbf. This reaction mixture was stirred at room temperature for lhr. Water was added and desired product was extracted with DCM. Organic layer was dried over Mg2S04 and evaporated under reduced pressure to dryness. Solids re-dissolved in acetonitrile and purified via preparative HPLC (5-65% acetonitrile in water, 0.1% trifluoroacteic acid buffer) to yield 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)amino)-5-(4-
((4-(4-(oxetan-3-yl)piperazin-l-yl (phenyl )amino)-l,3,5-triazin-2-yl)benzonitrile. LCMS-ESI"1" (m/z): [M+H]+ calcd for C31H36FN903: 602.3; found: 602.3
Example 614: 2-(((3R,4S)-3-fluoro-l-(3-hydroxyazetidine-3-carbonyl)piperidin-4-yl)oxy)-5-(4- ((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000571_0001
To a solution of 2-(((3R,4S)-3-fluoropiperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-l-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile (190 mg, 0.36 mmol), l-(tert- butoxycarbonyl)-3-hydroxyazetidine-3-carboxylic acid (86 mg, 0.39 mmol), HATU (204 mg, 0.54 mmol) in 4 ml of DMF, TEA (54 mg, 0.54 mmol) was added. This reaction mixture was stirred at room temperature for 2 hrs. Water was added to induce precipitation. Solids filtered out to obtain tert-butyl 3-((3R,4S)-4-(2-cyano-4-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl)phenyl)amino)- l,3,5-triazin-2-yl)phenoxy)-3-fluoropiperidine-l-carbonyl)-3-hydroxyazetidine-l-carboxylate.
Solids from previous step were dissolved with DCM and TFA. Reaction mixture was stirred at room temperature for lhr. Reaction mixture was evaporated under reduced pressure. Solids re-dissolved in acetonitrile and purified via preparative HPLC (5-65% acetonitrile in water, 0.1% trifluoroacteic acid buffer) to yield 2-(((3R,4S)-3-fluoro-l-(3-hydroxyazetidine-3- carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l-yl (phenyl )amino)-l,3,5-triazin-
2-yl)benzonitrile. LCMS-ESI+ (m/z): [M+H]+ calcd for C32H36FN904: 630.3; found: 630.3
Example 615: 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4-((R)- pyrrolidin-2-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000572_0001
To a solution of N-Boc-pyrrolidine ( 500 mg, 2.9 mmol ) and (-)-sparteine (684mg, 2.9 mmol) in MTBE (12 ml) at -78°C was added s-BuLi (1.4M in cyclohexane, 1.2ml, 2.9 mmol) drop- wise keeping the temperature below - 68 C. The resulting solution was aged for 3h at -74 C. A solution of ZnCI2 (1.9 M in ether, 238mg, 1.75 mmol) was added drop-wise to the reaction mixture with rapid stirring keeping the temperature below -68 C. The resulting light suspension was Aged at -74 C for 30min and then warmed to 20 C. The resulting homogeneous solution was aged for 30 minutes at 20 C and then was charged with aryl-bromide (416mg, 2.4 mmol) followed by Pf(OAc)2 (12mg, 0.12 mmol) and 'Βυ2Ρ-ΗΒΡ4 (29mg, 0.14mmol) in one portion. The mixture was aged overnight at room temperature. The resulting mixture was filtered over celite and washed with MTBE. The filtrate was washed with 1M HCI solution and then twice with water. The organic layer was dried over Mg2S04 and evaporated under reduced pressure to yiled (R)-tert-butyl 2-(4-aminophenyl (pyrrol id ine-l-carboxylate.
To a solution of 2,4-dichloro-l,3,5-triazine (228 mg, 1.5 mmol) in DMF at 0 °C (flushed with Argon) was added a solution of (R)-tert-butyl 2-(4-aminophenyl)pyrrolidine-l-carboxylate (400mg, 1.5 mmol) in DMF over 15 min and stirred in an ice-bath for lh. Water was added to the reaction mixture and product was extracted with DCM. Organic layer was dried over Mg2S04 and evaporated to dryness to yield (R)-tert-butyl 2-(4-((4-chloro-l,3,5-triazin-2- yl)amino)phenyl (pyrrol idine-l-carboxylate.
To (R)-tert-butyi 2-{4-{{4-chloro-l,3..5-triazin-2-yi)amino)phenyi)pyrToiidine-l- carboxylate (455 mg. 1.2 mmoi), 2-{{i3R/4S -3-fiuoro-l-((S5-2-hydroxyp;Opanoyl)p!peridin-4- yi)oxy!-5-{4,4,5,5-tetramethyl-l,3..2-dioxaboroian-2-yi)benzonitri!e (556mg. 1.3 mmoi). PdidppfjC!jCi- C (lllmg, O.lSmmo!) and potassium carbonate (334mg. 2.4 mmoi) mixture in argon atmosphere was added a mixture of de-gassed solvents (1,4-dioxane and water 2 :1 ). The mixture was heated under argon atmosphere at 104 "C for 60 in in a heating block. After cooiing at room temperature, water was added and product was extracted with DCM. Organic layer was dried over Mg2S04 and evaporated to dryness to yield (R)-tert-butyl 2-(4-((4-(3-cyano- 4-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)phenyl)-l;3;5-triazin-2- yl)amino)phenyl (pyrrol idine-l-carboxylate.
(R)-tert-butyl 2-(4-((4-(3-cyano-4-(((3R,4S)-3-fluoro-l-((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)phenyl)-l,3,5-triazin-2-yl)amino)phenyl (pyrrol id ine-1- carboxylate was dissolved with DCM and TFA. Reaction mixture was stirred at room temperature for lhr. Reaction mixture was evaporated under reduced pressure and solids were suspended in a saturated aqueous solution of NaHC03 and extracted with DCM. Organic phase was collected dried over magnesium sulfate and evaporated under reduced pressure. Solids re- dissolved in acetonitrile and purified via preparative HPLC (5-65% acetonitrile in water, 0.1% trifluoroacteic acid buffer) to yield 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4- yl)oxy)-5-(4-((4-((R)-pyrrolidin-2-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile. :H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.85 (s, 1H), 8.66 - 8.52 (m, 2H), 7.83 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 9.2 Hz, 1H), 7.49 (d, J = 8.2 Hz, 2H), 6.51 (s, 1H), 5.38-4.92 (m, 3H), 4.61 - 4.29 (m, 3H), 4.23 - 3.84 (m, 2H), 3.12-3.22 (m, 1H), 2.42-2.29 (m, 2H), 2.15-1.76 (m, 6H), 1.19 (dd, J = 6.6, 3.7 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C28H3oFN703: 532.3; found : 532.3
Example 616: 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4-((R)- l-(oxetan-3-yl)pyrrolidin-2-yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000574_0001
To a mixture of 2-({{3R,4S)-3-fluoro-l-{(S)-2-hydroxypropanoyi)piperidin-4-yi)oxy)-5-{4- {{4-{(R}-pyrro!idin-2-yl)phenyi)amino)-l,3/5-irlazln-2-y!)benzonitrile {30mg, 0.05 rrsmoi), zinc chloride {IGmg, 0.07 mrnol), ctxetan--3-one (40 rng, 0,05rnmoi) in methanol was added NaBH3CN (9mg, 0.07mmoi). The mixture was stirred at 75 °C for 2 hours. Reaction mixture was diluted with IN HCI in water and stirred at room temperature for 30min. To reaction mixture a saturated aqueous solution of NaHC03 and DCM were added. Organic phase was collected dried over magnesium sulfate and evaporated under reduced pressure. Solids re-dissolved in acetonitrile and purified via preparative HPLC (5-65% acetonitrile in water, 0.1% trifluoroacteic acid buffer) to yield 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4- ((R)-l-(oxetan-3-yl)pyrrolidin-2-yl)phenyl)amino)-l,3;5-triazin-2-yl)benzonitrile. :H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.82 (s, 1H), 8.56 (d, J = 7.2 Hz, 2H), 7.82 (s, 2H), 7.59 (d, J = 9.4 Hz, 1H), 7.50 (s, 2H), 4.99 (d, J = 50.4 Hz, 3H), 4.74 - 4.49 (m, 3H), 4.45-4.22 (m, 4H), 4.16 - 3.78
(m, 3H), 3.22-3.10 (m, 3H), 2.42-2.05 (m, 6H), 1.14 (dd, J = 6.6, 3.9 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C31H34FN704: 588.3; found: 588.3.
Example 617: 2-(((3R,4S)-3-fluoro-l-((R)-2-hydroxy-3- methoxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000575_0001
The title compound was separated from Example 557 via chiral HPLC. LCMS-ESI"1" (m/z): [M+H]+ calcd for C32H37FN805: 633.3; found : 633.4.
Example 618: 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxy-3- methoxypropanoyl)piperidin-4-yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-triazin-2-yl)benzonitrile
Figure imgf000575_0002
The title compound was separated from Example 557 via chiral HPLC. :H NM (400 MHz, DMSO-d6) δ 10.08 (d, J = 24.5 Hz, 1H), 8.68 (s, 1H), 8.49 (m, 3H), 7.56 (m, 3H), 6.91 (m, 3H), 5.26 (m, 1H), 5.04 (m, 3H), 4.41 (m, 4H), 3.91 (m, 2H), 3.42 (m, 6H), 3.07 (m, 6H), 2.35 (m, 4H). LCMS- ESI"1" (m/z): [M+H]+ calcd for C32H37FN805: 633.3; found : 633.4.
Example 619: 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxypropanoyl)piperidin-4-yl)oxy)- 5-(4-((4-((R)-hexahydropyrazino[2,l-c] [l,4]oxazin-8(lH)-yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
Figure imgf000576_0001
The title compound was synthesized in the same manner as Example 535 starting with ( )- octahydropyrazino[2,l-c] [l,4]oxazine . :H NMR (400 MHz, DMSO-d6) δ 10.19 (d, J = 24.9 Hz, 1H), 8.75 (s, 1H), 8.64 - 8.47 (m, 2H), 7.62 (m, 3H), 7.03 (s, 2H), 5.12 (m, 2H), 4.97 (s, 1H), 4.47 (dt, J = 13.3, 6.5 Hz, 2H), 4.39 (m, 2H), 4.23 - 4.12 (m, 2H), 4.05 (m, 3H), 3.74 (m, 2H), 3.59 -
3.12 (m, 6H), 2.99 (m, 1H), 1.97 (s, 2H), 1.19 (m, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C31H35FN804: 603.3; found: 603.4.
Biological Assays:
TBK1 and ΙΚΚε:
Enzymatic activity of ΙΚΚε and TBK1 was measured using a homogeneous time resolved fluorescence resonance energy transfer (TR-FRET) assay that monitors enzyme dependent phosphorylation of a biotinylated serine/threonine peptide substrate. An increase in the amount of phopshorylated peptide results in an increase in TR-FRET signal. TBK1 and ΙΚΚε were expressed and purified as full length recombinant proteins. Detection reagents for the assay were purchased from Cisbio. TBK1 and ΙΚΚε enzymes were assayed under initial rate conditions in the presence of 2X Km ATP (40-80 μΜ) and 1 μΜ peptide, hepes (pH 7), 0.1 mM orthovanadate, 0.02% NaN3, 0.01 % BSA, 10mM MgCI2, 0.01 % (v/v) tritonX, 1 mM dithiothreitol, 0.5% (v/v) DMSO at the following concentrations for each enzyme: TBK1 at 2.5 nM and ΙΚΚε at 0.3 nM. After an assay reaction time of 240 minutes at 25°C, reactions were terminated with EDTA.
Amount of phosphorylated peptide was determined by the addition of 125 nM streptavidin XL665 and europium cryptate labeled anti-phospho monoclonal antibody and the resulting TR-FRET signal was recorded on an Envision plate reader (Ex: 340 nm; Em: 615/665 nm; 100με delay and 200με read window). Data was normalized based on a positive (1 μΜ Staurosporine) and negative (DMSO) controls and IC50 values calculated from the fit of the dose-response curves to a four-parameter equation. All IC50 values represent geometric mean values of a minimum of four determinations. These assays generally produced results within 3-fold of the reported mean. hJAK2: Enzymatic activity of hJAK2 was measured using a LANCE homogeneous time resolved fluorescence resonance energy transfer (TR-FRET) assay that monitors enzyme dependent phosphorylation of a biotinylated serine/threonine peptide substrate (PTK). An increase in the amount of phopshorylated peptide results in an increase in TR-FRET signal. hJAK2 was expressed and purified as full length recombinant proteins. Detection reagents for the assay were purchased from PerkinElmer. hJAK2 enzyme was assayed under initial rate conditions in the presence of 2X Km ATP (30 μΜ) and 1 μΜ peptide, 50 mM Tris-CI (pH 7.5), 10mM MgCI2, , 1 mM dithiothreitol, 0.01 % BSA, 0.05% (v/v) DMSO at the following concentration of enzyme: hJAK2 at 0.3 nM. After an assay reaction time of 40 minutes at 25°C, reactions were terminated with EDTA and LANCE Detection Buffer.
Amount of phosphorylated peptide was determined by the addition of 20 nM SA- APC and 1 nM europium cryptate labeled anti-phospho PTK monoclonal antibody PY66 and the resulting TR-FRET signal was recorded on an Envision plate reader (Ex: 340 nm; Em: 615/665 nm; 100με delay and 200με read window). Data was normalized based on a positive (1 μΜ Staurosporine) and negative (DMSO) controls and IC50 values calculated from the fit of the dose-response curves to a four-parameter equation. All IC50 values represent geometric mean values of a minimum of four determinations. These assays generally produced results within 3-fold of the reported mean.
Results:
Table 1 below depicts IKKs-IC50 (nM), TBK1-IC50 (nM) and JAK2 (nM) values or the compounds described herein.
Table 1
n-2-yl]- - - -yl]-
Figure imgf000579_0001
- n-2-yl]-
Figure imgf000580_0001
Figure imgf000581_0001
Figure imgf000582_0001
Figure imgf000583_0001
Figure imgf000584_0001
Figure imgf000585_0001
-
Figure imgf000586_0001
,3,5-
Figure imgf000587_0001
Figure imgf000588_0001
Figure imgf000589_0001
,3,5- -
Figure imgf000590_0001
Figure imgf000591_0001
Figure imgf000592_0001
- n-2-yl]-
Figure imgf000593_0001
Figure imgf000594_0001
Figure imgf000595_0001
Figure imgf000596_0001
Figure imgf000597_0001
Figure imgf000598_0001
Figure imgf000599_0001
Figure imgf000600_0001
Figure imgf000601_0001
i n-3-
Figure imgf000602_0001
Figure imgf000603_0001
Figure imgf000604_0001
Figure imgf000605_0001
n : no ata
Table 1 - Continued
Figure imgf000606_0001
TBK1 IKKe JAK2
Ex Structure Name
IC50 IC50 IC50
2-(((2S,4S,5R)-5-fluoro-l- (2-hydroxyacetyl)-2- methylpipe din-4-yl)oxy)-
115 12 21 1000 5-(4-((4-(4-(oxetan-3- yl)piperazin-l-
AAV yl (phenyl )amino)-l,3,5- triazin-2-yl)benzonitrile
2- (((S)-3,3-difluoro-l-((S)-5- oxopyrrolidine-2- carbonyl)piperidin-4-
116 2 1 146 yl)oxy)-5-(4-((4-(4-(oxetan-
3- yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
2-(((3R,4S)-3-fluoro-l-((S)- 6-oxopiperidine-2- carbonyl)piperidin-4-
117 3 4 342 yl)oxy)-5-(4-((4-(4-(oxetan- 3-yl)piperazin-l- yl (phenyl )amino)-l,3,5- triazin-2-yl)benzonitrile
2-(((3R,4S)-l-(l,l- dioxidoisothiazolidine-3- carbonyl)-3- fluoropiperidin-4-yl)oxy)-5-
118 7 11 284
(4-((4-(4-(oxetan-3- yl)piperazin-l- yl (phenyl )amino)-l,3,5- triazin-2-yl)benzonitrile
2-(((3R,4S)-3-fluoro-l-(2- hydroxyacetyl)piperidin-4- yl)oxy)-5-(4-((4-(4-
119 6 2 338 methylpiperazine-1- carbonyl (phenyl )amino)- l,3,5-triazin-2- yl)benzonitrile
Figure imgf000608_0001
triazin-2-yl)benzonitrile
Figure imgf000609_0001
triazin-2-yl)benzonitrile
Figure imgf000610_0001
Figure imgf000611_0001
Figure imgf000612_0001
TBK1 IKKe JAK2
Ex Structure Name
IC50 IC50 IC50
2- (((3 ,4S)-3-fluoro-l-(lH- pyrazole-5- carbonyl)piperidin-4-
145 2 1 219 yl)oxy)-5-(4-((4-(4-(oxetan-
3- yl)piperazin-l- yl (phenyl )amino)-l,3,5- triazin-2-yl)benzonitrile
Figure imgf000613_0001
2- (((3R,4S)-3-fluoro-l-(lH- imidazole-5- carbonyl)piperidin-4-
146 3 1 156 yl)oxy)-5-(4-((4-(4-(oxetan-
3- yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
2- (((3R,4S)-3-fluoro-l-(l- methyl-lH-l,2,3-triazole-4- carbonyl)piperidin-4-
147 3 1 184 yl)oxy)-5-(4-((4-(4-(oxetan-
3- yl)piperazin-l- yl (phenyl )amino)-l,3,5- triazin-2-yl)benzonitrile
2- ((3,3-difluoropipe din-4- yl)oxy)-5-(4-((4-(4-(oxetan-
148 3 23 242 3- yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
(S)-2-((3,3- difluoropiperidin-4-yl)oxy)-
5-(4-((4-(4-(oxetan-3-
149 49 229 330
yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
Figure imgf000614_0001
TBK1 IKKe JAK2
Ex Structure Name
IC50 IC50 IC50
2-(((S)-3,3-difluoro-l-((S)-2- hydroxypropanoyl)piperidi n-4-yl)oxy)-5-(4-((4-(4-
155 0 1 198
(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
2-(((R)-3,3-difluoro-l-((S)-2- hydroxypropanoyl)piperidi n-4-yl)oxy)-5-(4-((4-(4-
156 16 23 196
(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
2-((3,3-difluoro-l-((R)-2- hydroxypropanoyl)piperidi n-4-yl)oxy)-5-(4-((4-(4-
157 3 14 188
(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
2-(((S)-3,3-difluoro-l-((R)- 2- hydroxypropanoyl)piperidi
158 1 3 171 n-4-yl)oxy)-5-(4-((4-(4-
(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
2-(((R)-3,3-difluoro-l-((R)- 2- hydroxypropanoyl)piperidi
159 79 209 207 n-4-yl)oxy)-5-(4-((4-(4-
(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
Figure imgf000616_0001
TBK1 IKKe JAK2
Ex Structure Name
IC50 IC50 IC50
(S)-2-((3,3-difluoro-l-(lH- l,2,3-triazole-5- carbonyl)piperidin-4-
165 2 1 83 yl)oxy)-5-(4-((4-(4-(oxetan-
3-yl)piperazin-l- yl (phenyl )amino)-l,3,5- ill triazin-2-yl)benzonitrile
(S)-2-((3,3-difluoro-l-(4H- l,2,4-triazole-3- carbonyl)piperidin-4-
166 2 0 53 yl)oxy)-5-(4-((4-(4-(oxetan-
3-yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
(S)-2-((3,3-difluoro-l-( lH- imidazole-5- carbonyl)piperidin-4-
167 3 1 104 yl)oxy)-5-(4-((4-(4-(oxetan-
3-yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
2-(((2R,4S)-l-(2- hydroxyacetyl)-2- methylpiperidin-4-yl)oxy)-
168 15 61 877 5-(4-((4-(4-(oxetan-3- yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile.
2-(((2S,4S)-l-(2- hydroxyacetyl)-2- methylpipe din-4-yl)oxy)-
169 2 5 230 5-(4-((4-(4-(oxetan-3- yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile. TBK1 IKKe JAK2
Ex Structure Name
IC50 IC50 IC50
2-((l-(2-hydroxyacetyl)-3- methylpipe din-4-yl)oxy)-
170 3 8 255 5-(4-((4-(4-(oxetan-3- yl)piperazin-l- yl (phenyl )amino)-l,3,5- triazin-2-yl)benzonitrile
Figure imgf000618_0001
2- ((l-(2-hydroxyacetyl)- 2,6-dimethylpiperidin-4-
171 2 9 463 yl)oxy)-5-(4-((4-(4-(oxetan-
3- yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
2- ((3-(2-hydroxyacetyl)-3- azabicyclo[3.1.1]heptan-6-
172 72 676 1000 yl)oxy)-5-(4-((4-(4-(oxetan-
3- yl)piperazin-l- yl (phenyl )amino)-l,3,5- triazin-2-yl)benzonitrile
Figure imgf000618_0002
ON,—! 2- ((8-(2-hydroxyacetyl)-8- azabicyclo[3.2.1]octan-3-
173 92 218 265 yl)oxy)-5-(4-((4-(4-(oxetan-
3- yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
2-((l-(2-hydroxyacetyl)- 3,3-dimethylpiperidin-4-
174 4 4 160 yl)oxy)-5-(4-((4-(4-(oxetan- 3-yl)piperazin-l- JL yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile TBK1 IKKe JAK2
Ex Structure Name
IC50 IC50 IC50
(S)-2-((l-(2- hydroxyacetyl)-3,3- dimethylpiperidin-4-
175 4 5 397 yl)oxy)-5-(4-((4-(4-(oxetan- 3-yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
(R)-2-((l-(2-hydroxyacetyl)-
3,3-dimethylpiperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-
176 3 3 133
3-yl)piperazin-l- JL. JL J yl (phenyl )amino)-l,3,5- triazin-2-yl)benzonitrile o-\
2-((5-fluoro-l-(2- hydroxyacetyl)-3,3- dimethylpiperidin-4-
177 0 N^N 6 3 117 yl)oxy)-5-(4-((4-(4-(oxetan- HO^^F 3-yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
N
2- (((4R,5S)-5-fluoro-l-(2- hydroxyacetyl)-3,3- dimethylpiperidin-4-
178 2 1 49 yl)oxy)-5-(4-((4-(4-(oxetan-
3- yl)piperazin-l- yl (phenyl )amino)-l,3,5- triazin-2-yl)benzonitrile
2- (((4S,5R)-5-fluoro-l-(2- hydroxyacetyl)-3,3- dimethylpiperidin-4-
179 8 13 234 yl)oxy)-5-(4-((4-(4-(oxetan-
3- yl)piperazin-l- yl (phenyl )amino)-l,3,5- triazin-2-yl)benzonitrile
Figure imgf000619_0001
TBK1 IKKe JAK2
Ex Structure Name
IC50 IC50 IC50
2- ((5-fluoro-l-((S)-2- hydroxypropanoyl)-3,3- dimethylpiperidin-4-
180 0 N^N 11 17 317 yl)oxy)-5-(4-((4-(4-(oxetan-
3- yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile N
2-(((2S,4S)-l-((S)-2- hydroxypropanoyl)-2- methylpipe din-4-yl)oxy)-
181 10 20 432 5-(4-((4-(4-(oxetan-3- yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
2-(((2S,4S)-l-((R)-2- hydroxypropanoyl)-2- methylpipe din-4-yl)oxy)-
182 32 95 491 5-(4-((4-(4-(oxetan-3- yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
2-(((2R,4S)-l-((S)-2- hydroxypropanoyl)-2- methylpiperidin-4-yl)oxy)-
183 50 120 593 5-(4-((4-(4-(oxetan-3- yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
Figure imgf000620_0001
2-(((2R,4S)-l-((R)-2- hydroxypropanoyl)-2- methylpipe din-4-yl)oxy)-
184 103 277 1000 5-(4-((4-(4-(oxetan-3- A A yl)piperazin-l- yl)phenyl)amino)-l,3,5- ill triazin-2-yl)benzonitrile
Figure imgf000621_0001
Figure imgf000622_0001
Figure imgf000623_0001
Figure imgf000624_0001
Figure imgf000625_0001
Figure imgf000626_0001
Figure imgf000627_0001
Figure imgf000628_0001
Figure imgf000629_0001
Figure imgf000630_0001
triazin-2-yl)benzonitrile
Figure imgf000631_0001
Figure imgf000632_0001
triazin-2-yl)benzonitrile TBK1 IKKe JAK2
Ex Structure Name
IC50 IC50 IC50
2-(((R)-3,3-difluoro-l-((S)- 2- hydroxypropanoyl)piperidi n-4-yl)oxy)-5-(4-((4-((R)-3-
245 17 26 228
methyl-4-(oxetan-3- yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
2-(((S)-3,3-difluoro-l-((S)- 2- hydroxypropanoyl)pipe di n-4-yl)oxy)-5-(4-((4-((R)-3-
246 2 1 181
methyl-4-(oxetan-3- yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
2-(((R)-3,3-difluoro-l-((R)- 2- hydroxypropanoyl)piperidi n-4-yl)oxy)-5-(4-((4-((R)-3-
247 233 397 333
methyl-4-(oxetan-3- yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
2-(((S)-3,3-difluoro-l-((R)- 2- hydroxypropanoyl)piperidi n-4-yl)oxy)-5-(4-((4-((R)-3-
248 3 3 187
methyl-4-(oxetan-3- yl)piperazin-l- yl (phenyl )amino)-l,3,5- triazin-2-yl)benzonitrile
2-(((3R,4S)-3-fluoro-l-((S)- 2- hydroxypropanoyl)piperidi n-4-yl)oxy)-5-(4-((4-((S)-2-
249 3 2 389
methyl-4-(oxetan-3- yl)piperazin-l- ill yl (phenyl )amino)-l,3,5- triazin-2-yl)benzonitrile
Figure imgf000634_0001
triazin-2-yl)benzonitrile TBK1 IKKe JAK2
Ex Structure Name
IC50 IC50 IC50
2-(((3R,4S)-3-fluoro-l-(lH- l,2,3-triazole-5- carbonyl)piperidin-4- yl)oxy)-5-(4-((4-((S)-2-
255 4 2 227
methyl-4-(oxetan-3- yl)piperazin-l- ill yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
2-(((3R,4S)-3-fluoro-l-(lH- imidazole-5- carbonyl)piperidin-4- yl)oxy)-5-(4-((4-((S)-2-
256 3 1 144
methyl-4-(oxetan-3- yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
2-(((3R,4S)-3-fluoro-l-(lH- pyrazole-5- carbonyl)piperidin-4- yl)oxy)-5-(4-((4-((S)-2-
257 2 1 270
methyl-4-(oxetan-3- yl)piperazin-l- ill yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
2-(((S)-3,3-difluoro-l-(lH- l,2,3-triazole-5- carbonyl)piperidin-4- yl)oxy)-5-(4-((4-((S)-2-
258 3 1 98
methyl-4-(oxetan-3- yl)piperazin-l- ill yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
2-(((S)-3,3-difluoro-l-(lH- imidazole-5- carbonyl)piperidin-4- yl)oxy)-5-(4-((4-((S)-2-
259 3 1 66
methyl-4-(oxetan-3- yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
Figure imgf000636_0001
triazin-2-yl)benzonitrile TBK1 IKKe JAK2
Ex Structure Name
IC50 IC50 IC50
5-(4-((4-((2S,5R)-2,5- dimethyl-4-(oxetan-3- yl)piperazin-l- yl (phenyl )amino)-l, 3,5-
265 5 4 426
triazin-2-yl)-2-(((3R,4S)-3- fluoro-l-((S)-2- ill hydroxypropanoyl)piperidi n-4-yl)oxy)benzonitrile
2-(((3R,4S)-l-( l,2- dimethyl-lH-imidazole-5- carbonyl)-3- fluoropiperidin-4-yl)oxy)-5-
266 82 83 387
(4-((4-(4-(oxetan-3- yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
2- (((3R,4S)-3-fluoro-l-(l- methyl-lH-imidazole-5- carbonyl)piperidin-4-
267 120 264 404 yl)oxy)-5-(4-((4-(4-(oxetan-
3- yl)piperazin-l-
0AOCOA"J yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
2-((l,l-dioxidotetrahydro- 2H-thiopyran-4-yl)oxy)-5- (4-((3-fluoro-4-(4-(oxetan-
268 12 69 527
3-yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
2-(3-methoxyazetidin-l- yl)-5-(4-((4-(4-(oxetan-3-
269 13 25 219 yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
Figure imgf000638_0001
Figure imgf000639_0001
Figure imgf000640_0001
Figure imgf000641_0001
Figure imgf000642_0001
Figure imgf000643_0001
TBK1 IKKe JAK2
Ex Structure Name
IC50 IC50 IC50
Chiral
2-(((3 ,4S)-3- fluorotetrahydro-2H-pyran- 4-yl)oxy)-5-(4-((4
300 4 3 453
methylpiperidin-4- yl)phenyl)amino ,3,5- triazin-2-yl)benzonitrile
(S)-2 -acetyl-3,3- difluoropiperidin-4-yl)oxy)-
301 3 0 308 5-(4-((4-(piperidin-4- yl)phenyl)amino ,3,5- triazin-2-yl)benzonitrile
Chiral
(S)-2 -acetyl-3,3- difluoropiperidin-4-yl)oxy)-
302 2 0 174 5-(4-((4 -methylpiperidin- 4-yl)phenyl)amino ,3,5- triazin-2-yl)benzonitrile
(S)-2-((3,3-difluoro formylpiperidin-4-yl)oxy)-5-
303 1 0 290 (4-((3-methyl-4-(piperidin- 4-yl)phenyl)amino ,3,5- triazin-2-yl)benzonitrile
Figure imgf000644_0001
(S)-2-((3,3-difluoro formylpiperidin-4-yl)oxy)-5- (4-((3-methyl-4
304 2 0 1000
methylpiperidin-4- yl)phenyl)amino ,3,5- triazin-2-yl)benzonitrile
Figure imgf000645_0001
triazin-2-yl)benzonitrile TBK1 IKKe JAK2
Ex Structure Name
IC50 IC50 IC50
2-(((3R,4S)-3-fluoro-l-((S)- hydroxypropanoyljpiperidi
310 4 2 1000 n-4-yl)oxy)-5-(4-((3-fluoro- 4-(l-(oxetan-3-yl)piperidin- 4-yl (phenyl )amino)-l,3,5- triazin-2-yl)benzonitrile
2-(((3R,4S)-3-fluoro-l-((S)- hydroxypropanoyljpiperidi
311 3 1 1000 n-4-yl)oxy)-5-(4-((4-(l- (oxetan-3-yl)piperidin-4- yl (phenyl )amino)-l,3,5- triazin-2-yl)benzonitrile
2-(((3R,4S)-3-fluoro-l-((S)- 2- hydroxypropanoyl)piperidi n-4-yl)oxy)-5-(4-((4-(4-(3-
312 3 3 636
methyloxetan-3- yl)piperazin-l- yl (phenyl )amino)-l,3,5- triazin-2-yl)benzonitrile
5-(4-((4-(7-oxa-2- azaspiro[3.5] nonan-2- yl (phenyl )amino)-l,3,5-
313 4 2 375 triazin-2-yl)-2-(((3R,4S)-3- fluoro-l-((S)-2- hydroxypropanoyl)piperidi n-4-yl)oxy)benzonitrile
4-(4-((4-(3-cyano-4-
(((3R,4S)-3-fluoro-l-((S)-2-
NH2 "¾ ΝΗ hydroxypropanoyl)piperidi
314 O N ^N 3 1 609 n-4-yl)oxy)phenyl)-l,3,5- triazin-2- yl)amino)phenyl)morpholin
N e-2-carboxamide
Figure imgf000647_0001
triazin-2-yl)benzonitrile
Figure imgf000648_0001
Figure imgf000649_0001
TBK1 IKKe JAK2
Ex Structure Name
IC50 IC50 IC50
2- (((3R,4S)-l-(2- cyanoacetyl)-3- fluoropiperidin-4-yl)oxy)-3-
330 4 6 941 fluoro-5-(4-((4-(4-(oxetan-
3- yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
3-fluoro-2-(((3R,4S)-3- fluoro-l-(3- hydroxypropanoyl)piperidi
331 7 14 943 n-4-yl)oxy)-5-(4-((4-(4-
(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
5-(4-((4-(2-(pyrrolidin-l- yl)ethoxy)phenyl)amino)-
332 10 5 943 l,3,5-triazin-2-yl)-2- ((tetrahydro-2H-pyran-4- yl)oxy)benzonitrile
Figure imgf000650_0001
2-(((3R,4S)-3-fluoro-l-((S)-
2- oxooxazolidine-4- carbonyl)piperidin-4-
333 2 3 233 yl)oxy)-5-(4-((4-(4-(oxetan-
3- yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
2- (((3R,4S)-l-(3-amino-lH- l,2,4-triazole-5-carbonyl)-
3- fluoropiperidin-4-yl)oxy)-
334 16 2 80 5-(4-((4-(4-(oxetan-3- yl)piperazin-l- yl)phenyl)amino)-l,3,5-
CN ill triazin-2-yl)benzonitrile
Figure imgf000651_0001
Figure imgf000652_0001
yl)benzonitrile TBK1 IKKe JAK2
Ex Structure Name
IC50 IC50 IC50
2-(((3R,4S)-l-(2,4- dimethyl-lH-imidazole-5- carbonyl)-3- fluoropiperidin-4-yl)oxy)-5-
345 10 12 213
(4-((4-(4-(oxetan-3- yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
5-(4-((l,3-dimethyl-lH-
1 i indazol-6-yl)amino)-l,3,5- triazin-2-yl)-2-(((3R,4S)-3-
346 3 1 511
fluoro-l-(2- hydroxyacetyl)piperidin-4- yl)oxy)benzonitrile
5-(4-((l,3-dimethyl-lH-
/ 1 indazol-6-yl)amino)-l,3,5- triazin-2-yl)-2-(((3R,4S)-3-
347 4 5 1000
fluoro-l-((S)-2- hydroxypropanoyl)piperidi n-4-yl)oxy)benzonitrile
2-(((3R,4S)-l-(2,3- dihydroxypropanoyl)-3- fluoropiperidin-4-yl)oxy)-5-
348 4 3 162 (4-((4-(4-(oxetan-3- .X yl)piperazin-l-
H0J C0XJ yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
2-(((3R,4S)-3-fluoro-l-(2- hydroxyacetyl)piperidin-4- yl)oxy)-5-(4-((l-isopropyl-
349 2 2 98
lH-pyrazol-4-yl)amino)- l,3,5-triazin-2- yl)benzonitrile
Figure imgf000654_0001
yl)benzonitrile
Figure imgf000655_0001
Figure imgf000656_0001
n-4-yl)oxy)benzonitrile TBK1 IKKe JAK2
Ex Structure Name
IC50 IC50 IC50
5-(4-((4-(2-oxa-7- azaspiro[3.5] nonan-7- yl (phenyl )amino)-l, 3,5-
365 4 2 474 triazin-2-yl)-2-(((3R,4S)-3- fluoro-l-((S)-2- hydroxypropanoyl)piperidi n-4-yl)oxy)benzonitrile
5-(4-((4-(3-oxa-6- azabicyclo[3.1.1] heptan-6- yl (phenyl )amino)-l, 3,5-
366 3 2 531 triazin-2-yl)-2-(((3R,4S)-3- fluoro-l-((S)-2- hydroxypropanoyl)piperidi n-4-yl)oxy)benzonitrile
2-(((3R,4S)-3-fluoro-l-((S)- 2- hydroxypropanoyl)piperidi
367 3 2 1000 n-4-yl)oxy)-5-(4-((3-fluoro-
4-(4-(oxetan-3-yl)piperazin- l-yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
2- (((3R,4S)-3-fluoro-l-(2- hydroxyacetyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-
368 3 2 225 3- yl)piperazin-l-yl)-3- (trifluoromethyl (phenyl )am ino)-l,3,5-triazin-2- yl)benzonitrile
Figure imgf000657_0001
5-((4-(3-cyano-4-(((3R,4S)-
3-fluoro-l-((S)-2- hydroxypropanoyl)piperidi
369 3 3 718 n-4-yl)oxy)phenyl)-l,3,5- triazin-2-yl)amino)-2-(4-
(oxetan-3-yl)piperazin-l- yl)benzonitrile TBK1 IKKe JAK2
Ex Structure Name
IC50 IC50 IC50
2-(((3R,4S)-3-fluoro-l-((S)- 2- hydroxypropanoyl)piperidi
TS n-4-yl)oxy)-5-(4-((4-(4-
370 5 8 875 (oxetan-3-yl)piperazin-l- yi)-3-
(trifluoromethyl (phenyl jam ino)-l,3,5-triazin-2- yl)benzonitrile
5-(4-((3-(difluoromethyl)- 4-(4-(oxetan-3-yl)piperazin- 1-yl (phenyl )amino)-l, 3,5-
371 2 1 989 triazin-2-yl)-2-(((3R,4S)-3- fluoro-l-((S)-2- hydroxypropanoyl)piperidi n-4-yl)oxy)benzonitrile
2-(((3R,4S)-3-fluoro-l-((S)-
5-oxopyrrolidine-2- carbonyl)piperidin-4-
372 4 5 305 yl)oxy)-5-(4-((3-fluoro-4-(4-
(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
2-(((3R,4S)-3-fluoro-l-(lH- l,2,3-triazole-5- carbonyl)piperidin-4-
373 2 1 146 yl)oxy)-5-(4-((3-fluoro-4-(4-
(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
2-(((3R,4S)-3-fluoro-l-((S)-
5-oxopyrrolidine-2- carbonyl)piperidin-4-
374 1000 1000 1000 yl)oxy)-5-(4-((2-fluoro-4-(4-
(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5-
Figure imgf000658_0001
triazin-2-yl)benzonitrile TBK1 IKKe JAK2
Ex Structure Name
IC50 IC50 IC50
2-(((3R,4S)-3-fluoro-l-((S)- 2- hydroxypropanoyl)piperidi
375 1000 1000 1000 n-4-yl)oxy)-5-(4-((2-fluoro-
4-(4-(oxetan-3-yl)piperazin- l-yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
2- (((3R,4S)-3-fluoro-l-(l- (2-hydroxyethyl)-lH-l,2,3- triazole-4- carbonyl)piperidin-4-
376 5 3 127
yl)oxy)-5-(4-((4-(4-(oxetan-
3- yl)piperazin-l- yl (phenyl )amino)-l,3,5- triazin-2-yl)benzonitrile
2-(((3R,4S)-l-(2-(4H-l,2,4- triazol-4-yl (acetyl )-3- fluoropiperidin-4-yl)oxy)-5-
377 37 129 87 (4-((4-(4-(oxetan-3- yl)piperazin-l- yl (phenyl )amino)-l,3,5- triazin-2-yl)benzonitrile
5-(4-((3-chloro-4-(4- (oxetan-3-yl)piperazin-l- yl (phenyl )amino)-l,3,5-
378 2 2 173 triazin-2-yl)-2-(((3R,4S)-3- fluoro-l-((S)-2- hydroxypropanoyl)piperidi n-4-yl)oxy)benzonitrile
Figure imgf000659_0001
2-(((3R,4S)-3-fluoro-l-((S)- 2- hydroxypropanoyl)piperidi n-4-yl)oxy)-5-(4-((6-(4-
379 5 3 1000
(oxetan-3-yl)piperazin-l- yl)pyridin-3-yl)amino)- l,3,5-triazin-2- yl)benzonitrile TBK1 IKKe JAK2
Ex Structure Name
IC50 IC50 IC50
Ethyl 3-((4-(3-cyano-4- (((3R,4S)-3-fluoro-l-((S)-2- hydroxypropanoyl)piperidi
380 6 8 891
n-4-yl)oxy)phenyl)-l,3,5- triazin-2- yl)amino)benzoate
2-(((3R,4S)-3-fluoro-l-((S)-
5-oxopyrrolidine-2- carbonyl)piperidin-4- yl)oxy)-5-(4-((4-((S)-2-
381 1000 1000 1000
methyl-4-(oxetan-3- yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
2-(((3R,4S)-3-fluoro-l-((S)- 2- hydroxypropanoyl)piperidi n-4-yl)oxy)-5-(4-((6-(2-
382 3 3 1000
hydroxypropan-2- yl)pyridin-3-yl)amino)- l,3,5-triazin-2- yl)benzonitrile
2-(((3R,4S)-3-fluoro-l-((S)- 2- hydroxypropanoyl)piperidi
383 2 1 568 n-4-yl)oxy)-5-(4-((4-((R)-3-
(hydroxymethyl)morpholin o)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
2-(((3R,4S)-3-fluoro-l-(2- hydroxyacetyl)piperidin-4- yl)oxy)-5-(4-((4-((R)-3-
384 2 1 189
(hydroxymethyl)morpholin o)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
Figure imgf000661_0001
triazin-2-yl)benzonitrile TBK1 IKKe JAK2
Ex Structure Name
IC50 IC50 IC50
2-(((3R,4S)-l-(3- aminoisonicotinoyl)-3- fluoropiperidin-4-yl)oxy)-5-
390 65 165 37 (4-((4-(4-(oxetan-3- yl)piperazin-l- yl (phenyl )amino)-l,3,5- triazin-2-yl)benzonitrile
2-(((3R,4S)-l-(4-amino-lH- pyrazole-5-carbonyl)-3- fluoropiperidin-4-yl)oxy)-5-
391 6 9 122 (4-((4-(4-(oxetan-3- yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
2-(((3R,4S)-3-fluoro-l-(2- hydroxyacetyl)piperidin-4- yl)oxy)-5-(4-((3-methoxy-4-
392 5 1 26
(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
5-(4-((3-(difluoromethoxy)- 4-(4-(oxetan-3-yl)piperazin- 1-yl (phenyl )amino)-l, 3,5-
393 3 1 29 triazin-2-yl)-2-(((3R,4S)-3- fluoro-l-(2- hydroxyacetyl)piperidin-4- yl)oxy)benzonitrile
2-(((3R,4S)-3-fluoro-l-(2- hydroxyacetyl)piperidin-4- yl)oxy)-5-(4-((3-methyl-4-
394 2 1 64
(4-(oxetan-3-yl)piperazin-l- yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
Figure imgf000663_0001
yl)benzonitrile
Figure imgf000664_0001
Figure imgf000665_0001
Figure imgf000666_0001
TBK1 IKKe JAK2
Ex Structure Name
IC50 IC50 IC50
410 2 2 450 2-(((3R,4S)-3-fluoro-l-((2S,4S)-4- nydroxy-5-oxopyrrolidine-2-
Figure imgf000667_0001
carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-
(oxetan-3-yl)piperazin-l- yl (phenyl )amino)-l,3, 5-triazin-2- yl)benzonitrile
41 1 533 1000 1000
2-(((2S,4S,5R)-5-fluoro-2-methyl-l-((R)-5- oxopyrrolidine-2-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin- 1-yl (phenyl )amino)-l, 3, 5-triazin-2- yl)benzonitrile
412 43 202 1000 2-(((2S,4S,5R)-5-fluoro-l-((R)-2- nydroxypropanoyl)-2-methylpiperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin- 1-yl (phenyl )amino)-l, 3, 5-triazin-2- yl)benzonitrile
413 3 2 109
2-(((3R,4S)-3-fluoro-l-(6-oxo-l,6- dihydropy dine-2-carbonyl)pipe din-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin- 1-yl (phenyl )amino)-l, 3, 5-triazin-2- yl)benzonitrile
Figure imgf000668_0001
Figure imgf000669_0001
TBK1 IKKe JAK2
Ex Structure Name
IC50 IC50 IC50
423 16 55 681
2-(((3R,4S)-3-fluoro-l-((R)-3- fluoropyrrolidine-l-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin- 1-yl (phenyl )amino)-l, 3, 5-triazin-2- yl)benzonitrile
424 6 12 1000
2-(((3R,4S)-3-fluoro-l-(pyrrolidine-l- carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-
(oxetan-3-yl)piperazin-l- yl (phenyl )amino)-l,3, 5-triazin-2- yl)benzonitrile
425 7 21 590
I I 2-(((3R,4S)-3-fluoro-l-((R)-3- nydroxypyrrolidine-l-carbonyl)piperidin- 4-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-l-yl (phenyl )amino)-l, 3,5- triazin-2-yl)benzonitrile
426 79 201 1000
I I 2-(((3R,4S)-3-fluoro-l-((S)-3- nydroxypyrrolidine-l-carbonyl)piperidin- 4-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-l-yl (phenyl )amino)-l, 3,5- triazin-2-yl)benzonitrile
Figure imgf000671_0001
Figure imgf000672_0001
Figure imgf000673_0001
Figure imgf000674_0001
Figure imgf000675_0001
yl)benzonitrile TBK1 IKKe JAK2
Ex Structure Name
IC50 IC50 IC50
447 65 197 15
2-((5,5-difluoro-6-oxopiperidin-3-yl)oxy)- 5-(4-((4-(4-(oxetan-3-yl)piperazin-l- /I (phenyl )amino)-l,3,5-triazin-2- yl)benzamide
448 54 84 213 2-(((3R,4S)-3-fluoro-l-(l-(2- nydroxyethyl)-lH-pyrazole-5- ill carbonyl)piperidin-4-yl)oxy)-5-(4-((4-(4-
(oxetan-3-yl)piperazin-l- yl (phenyl )amino)-l,3, 5-triazin-2- yl)benzonitrile
449 35 59 443
2-(((4R,5S)-l-(2-cyanoacetyl)-5-fluoro-
3,3-dimethylpiperidin-4-yl)oxy)-5-(4-((4- ill (4-(oxetan-3-yl)piperazin-l- yl (phenyl )amino)-l,3, 5-triazin-2- yl)benzonitrile
450 3 3 48
2-(((4S,5R)-l-(2-cyanoacetyl)-5-fluoro-
3,3-dimethylpiperidin-4-yl)oxy)-5-(4-((4- ill (4-(oxetan-3-yl)piperazin-l- yl (phenyl )amino)-l,3, 5-triazin-2- yl)benzonitrile
Figure imgf000677_0001
Figure imgf000678_0001
Figure imgf000679_0001
Figure imgf000680_0001
Figure imgf000681_0001
Figure imgf000682_0001
Figure imgf000683_0001
Figure imgf000684_0001
Figure imgf000685_0001
Figure imgf000686_0001
trifluoropropanamide
Figure imgf000687_0001
Figure imgf000688_0001
TBK1 IKKe JAK2
Ex Structure Name
IC50 IC50 IC50
508 2 0 49 5-(4-((4-((S)-2,4-dimethylpiperazin-l-yl)-
3-methoxyphenyl)amino)-l,3,5-triazin-2- yl)-2-(((3R,4S)-3-fluoro-l-(2- nydroxyacetyl)piperidin-4- yl)oxy)benzonitrile
509 3 1 699 2-(((3R,4S)-l-((S)-2,3- dihydroxypropanoyl)-3-fluoropiperidin- 4-yl )oxy)-5-(4-((4-( l-(oxeta n-3- yl)piperidin-4-yl)phenyl)amino)-l,3,5-
Figure imgf000689_0001
triazin-2-yl)benzonitrile
510 4 2 1000 2-(((3R,4S)-l-((S)-2,3- dihydroxypropanoyl)-3-fluoropiperidin-
IT *NJI 4-yl)oxy)-5-(4-((6-(4-(oxetan-3- yl)piperazin-l-yl)pyridin-3-yl)amino)- l,3;5-triazin-2-yl)benzonitrile
51 1 4 2 1000 2- (((3R,4S)-l-((S)-2,3- dihydroxypropanoyl)-3-fluoropiperidin- 4-yl)oxy)-5-(4-((5-methoxy-6-(4-(oxetan-
3- yl)piperazin-l-yl)pyridin-3-yl)amino)- l,3;5-triazin-2-yl)benzonitrile
512 2 2 1000 2-(((3R,4S)-l-((S)-2,3- dihydroxypropanoyl)-3-fluoropiperidin- 4-y I )oxy )-5-(4-( ( l-( 2-hyd roxy-2- nethyl propyl )-lH-pyrazol-4-yl )amino)- l,3;5-triazin-2-yl)benzonitrile TBK1 IKKe JAK2
Ex Structure Name
IC50 IC50 IC50
513 2 1 517 2-(((3R,4S)-l-((S)-2,3- dihydroxypropanoyl)-3-fluoropiperidin-
4-yl)oxy)-5-(4-((5-methyl-6-(4-(oxetan-3- yl)piperazin-l-yl)pyridin-3-yl)amino)- l,3,5-triazin-2-yl)benzonitrile
514 3 3 1000 2-(((3R,4S)-3-fluoro-l-((S)-2- nydroxypropanoyl)piperidin-4-yl)oxy)-5-
(4-((5-methoxy-6-(4-(oxetan-3- yl)piperazin-l-yl)pyridin-3-yl)amino)-
Figure imgf000690_0001
l,3;5-triazin-2-yl)benzonitrile
515 2 0 355 2-(((3R,4S)-l-((S)-2,3- dihydroxypropanoyl)-3-fluoropiperidin- 4-yl)oxy)-5-(4-((4-((S)-2,4- dimethylpiperazin-l-yl (phenyl )amino)- l,3;5-triazin-2-yl)benzonitrile
516 6 10 1000 5-(4-((3,4-dihydro-2H-pyrido[3,2-
3][l,4]oxazin-7-yl)amino)-l,3,5-triazin-2- yl)-2-(((3R,4S)-3-fluoro-l-((S)-2-
Figure imgf000690_0002
nydroxypropanoyl)piperidin-4- yl)oxy)benzonitrile h
517 2 1 828 5-(4-((3,4-dihydro-2H-
3enzo[b][l,4]oxazin-6-yl)amino)-l,3,5- triazin-2-yl)-2-(((3R,4S)-3-fluoro-l-((S)-2- nydroxypropanoyl)piperidin-4- yl)oxy)benzonitrile TBK1 IKKe JAK2
Ex Structure Name
IC50 IC50 IC50
518 3 3 1000 2-(((3R,4S)-l-((S)-2,3- dihydroxypropanoyl)-3-fluoropiperidin- 4-yl)oxy)-5-(4-((4-((R)-l,4-dimethyl-3- oxopiperazin-2-yl (phenyl )amino)-l,3,5- triazin-2-yl)benzonitrile
519 2 1 184 2-(((S)-3,3-difluoro-l-((S)-2- oxooxazolidine-4-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin- 1-yl (phenyl )amino)-l,3,5-triazin-2- yl)benzonitrile
520 2 1 177 2-(((S)-3,3-difluoro-l-((R)-2- oxothiazolidine-4-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin- 1-yl (phenyl )amino)-l, 3, 5-triazin-2- yl)benzonitrile
521 16 39 1000 521: 2-(((3R,4S)-3-fluoro-l-((S)-2- nydroxypropanoyl)piperidin-4-yl)oxy)-3- methyl-5-(4-((4-(4-(oxetan-3- yl)piperazin-l-yl (phenyl )amino)-l, 3,5- triazin-2-yl)benzonitrile
522 14 28 1000 2-(((3R,4S)-3-fluoro-l-(2- nydroxyacetyl)piperidin-4-yl)oxy)-3- methyl-5-(4-((4-(4-(oxetan-3- yl)piperazin-l-yl (phenyl )amino)-l, 3,5- triazin-2-yl)benzonitrile TBK1 IKKe JAK2
Ex Structure Name
IC50 IC50 IC50
523 10 26 81 1 2-(((3R,4S)-3-fluoro-l-((4S,5R)-5-methyl- 2-oxooxazolidine-4-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin- 1-yl (phenyl )amino)-l,3,5-triazin-2- yl)benzonitrile
524 7 29 959 2-(((3R,4S)-3-fluoro-l-((4S,5S)-5-methyl- 2-oxooxazolidine-4-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin- 1-yl (phenyl )amino)-l,3,5-triazin-2- yl)benzonitrile
525 3 3 390 2-(((3R,4S)-3-fluoro-l-(2-oxo-2,3- dihydrooxazole-4-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin- 1-yl (phenyl )amino)-l, 3, 5-triazin-2- yl)benzonitrile
526 9 19 447 2-(((3R;4S)-l-(3;4-dimethyl-lH-pyrazole- 5-carbonyl)-3-fluoropiperidin-4-yl)oxy)- 5-(4-((4-(4-(oxetan-3-yl)piperazin-l- /I (phenyl )amino)-l,3,5-triazin-2- yl)benzonitrile
527 5 8 323 2-(((3R,4S)-3-fluoro-l-(4-methyl-lH- midazole-2-carbonyl)piperidin-4-yl)oxy)- 5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl (phenyl )amino)-l,3, 5-triazin-2- yl)benzonitrile
Figure imgf000693_0001
TBK1 IKKe JAK2
Ex Structure Name
IC50 IC50 IC50
533 4 7 88 2-(((3R,4S)-3-fluoro-l-(3- nydroxypropanoyl)piperidin-4-yl)oxy)-5- (4-((3-methyl-4-(4-(oxetan-3- yl)piperazin-l-yl (phenyl )am ino)-l,3,5- triazin-2-yl)benzonitrile
534 4 7 32
2-((2S,4R)-4-hydroxy-2-methyl pyrrol id in- l-yl)-5-(4-((3-methyl-4-(4-(oxetan-3- yl)piperazin-l-yl (phenyl )amino)-l, 3,5- triazin-2-yl)benzonitrile
535 3 3 904 2- (((3R,4S)-3-fluoro-l-((S)-5- oxopyrrolidine-2-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-((S)-3-methyl-4-(oxetan-
3- yl)piperazin-l-yl)phenyl)amino)-l,3,5- triazin-2-yl)benzonitrile
536 2 1 101 2-(((3R,4S)-3-fluoro-l-((S)-5- oxopyrrolidine-2-carbonyl)piperidin-4- yl)oxy)-5-(4-((3-methyl-4-(4-(oxetan-3- yl)piperazin-l-yl (phenyl )amino)-l, 3,5- triazin-2-yl)benzonitrile
537 8 18 1000 N-(5-((4-(3-cyano-4-(((3R,4S)-3-fluoro-l-
((S)-5-oxopyrrolidine-2- carbonyl)piperidin-4-yl)oxy)phenyl)- l,3,5-triazin-2-yl)amino)pyridin-2- yl)acetamide
Figure imgf000695_0001
Figure imgf000696_0001
yl)benzonitrile TBK1 IKKe JAK2
Ex Structure Name
IC50 IC50 IC50
548 21 96 353 2-(((3R,4S)-3-fluoro-l-((S)-5- oxopyrrolidine-3-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin- 1-yl (phenyl )amino)-l,3,5-triazin-2- yl)benzonitrile
549 4 11 179 2-(((3R,4S)-3-fluoro-l-(2- (methylsulfonyl)acetyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin- 1-yl (phenyl )amino)-l,3,5-triazin-2- yl)benzonitrile
550 11 36 750 2-(((3R,4S)-3-fluoro-l-(3- nydroxycyclobutanecarbonyl)piperidin- 4-yl)oxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-l-yl (phenyl )amino)-l, 3,5- triazin-2-yl)benzonitrile
551 16 92 799 2- (((3R,4S)-3-fluoro-l-(2-oxopyrrolidine-
3- carbonyl)piperidin-4-yl)oxy)-5-(4-((4- (4-(oxetan-3-yl)piperazin-l-
/I (phenyl )amino)-l,3,5-triazin-2- yl)benzonitrile
552 28 174 562 2-(((3R,4S)-3-fluoro-l-((R)-5- oxopyrrolidine-3-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin- 1-yl (phenyl )amino)-l, 3, 5-triazin-2- yl)benzonitrile
Figure imgf000698_0001
TBK1 IKKe JAK2
Ex Structure Name
IC50 IC50 IC50
558 2 2 26 2-(((3R,4S)-l-(2-cyanoacetyl)-3- fluoropipe din-4-yl)oxy)-5-(4-((3- nethoxy-4-(4-(oxetan-3-yl)piperazin-l- /I (phenyl )amino)-l,3,5-triazin-2- yl)benzonitrile
559 5 2 83 2-(((3R,4S)-l-(2-amino-lH-imidazole-5- carbonyl)-3-fluoropiperidin-4-yl)oxy)-5- (4-((4-(4-(oxetan-3-yl)piperazin-l- yl (phenyl )amino)-l,3, 5-triazin-2- yl)benzonitrile
560 Q 2 1 18 (S)-2-((3,3-difluoro-l-(2- nydroxyacetyl)piperidin-4-yl)oxy)-5-(4- ((3-methoxy-4-(4-(oxetan-3-yl)piperazin- 1-yl (phenyl )amino)-l, 3, 5-triazin-2- yl)benzonitrile
561 2 1 68 2-(((S)-3,3-difluoro-l-((S)-2- nydroxypropanoyl)piperidin-4-yl)oxy)-5- (4-((3-methoxy-4-(4-(oxetan-3- yl)piperazin-l-yl (phenyl )am ino)-l,3,5- triazin-2-yl)benzonitrile
562 3 6 1 10 2-(((3R,4S)-3-fluoro-l-(3- nydroxypropanoyl)piperidin-4-yl)oxy)-5- (4-((3-methoxy-4-(4-(oxetan-3-
Figure imgf000699_0001
yl)piperazin-l-yl (phenyl )amino)-l, 3,5- triazin-2-yl)benzonitrile TBK1 IKKe JAK2
Ex Structure Name
IC50 IC50 IC50
<x
563 5 3 1000
2-(((3R,4S)-3-fluoro-l-(2- nydroxyacetyl)pipe din-4-yl)oxy)-5-(4- ((4-methylthiazol-5-yl)amino)-l,3,5- triazin-2-yl)benzonitrile
564 92 109 1000 2-(((3R,4S)-3-fluoro-l-((S)-2- nydroxypropanoyl)piperidin-4-yl)oxy)-5-
(4-((3-(hydroxymethyl)-l-methyl-lH-
Figure imgf000700_0001
3yrazol-4-yl)amino)-l,3,5-triazin-2- yl)benzonitrile
\
565 90 126 1000 2-(((3R,4S)-3-fluoro-l-((S)-2- nydroxypropanoyl)piperidin-4-yl)oxy)-5-
(4-((5-(hydroxymethyl)-l-methyl-lH-
3yrazol-4-yl)amino)-l,3,5-triazin-2- yl)benzonitrile
566 14 33 1000 5-(4-((l dimethyl-lH-pyrazol-4- yl)amino)-lA5-triazin-2-yl)-2-(((3R,4S)-
3-fluoro-l-((S)-2-
Figure imgf000700_0002
nydroxypropanoyl)piperidin-4- yl)oxy)benzonitrile
\
567 3 7 1000 2-(((3R,4S)-l-((S)-2,3- dihydroxypropanoyl)-3-fluoropiperidin-
4-yl)oxy)-5-(4-((l;5-dimethyl-lH-pyrazol-
4-yl)amino)-l,3,5-triazin-2- yl)benzonitrile
Figure imgf000701_0001
TBK1 IKKe JAK2
Ex Structure Name
IC50 IC50 IC50
573 3 1 969 2-(((3R,4S)-3-fluoro-l-((S)-2- nydroxypropanoyl)piperidin-4-yl)oxy)-5-
(4-((4-(4-((S)-2-hydroxypropyl)piperazin- l-yl)phenyl)amino)-l,3,5-triazin-2-
Figure imgf000702_0001
yl)benzonitrile
~<
574 2 2 354
2-(((3R,4S)-l-((S)-2,3- dihydroxypropanoyl)-3-fluoropiperidin- 4-yl)oxy)-5-(4-((l-isopropyl-lH-pyrazol-4- yl)amino)-l,3,5-triazin-2-yl)benzonitrile
575 2 1 62 2-(((3R,4S)-l-((S)-2,3- dihydroxypropanoyl)-3-fluoropiperidin- 4-yl)oxy)-5-(4-((3-methyl-4-(4-(oxetan-3- yl)piperazin-l-yl (phenyl )am ino)-l,3,5-
Figure imgf000702_0002
triazin-2-yl)benzonitrile
576 2 2 56 2-(((3R,4S)-l-((R)-2,3- dihydroxypropanoyl)-3-fluoropiperidin- 4-yl)oxy)-5-(4-((3-methyl-4-(4-(oxetan-3- yl)piperazin-l-yl (phenyl )amino)-l, 3,5- triazin-2-yl)benzonitrile
577 2 1 57 2-(((S)-l-((S)-2,3-dihydroxypropanoyl)- 3,3-difluoropipe din-4-yl)oxy)-5-(4-((3- nethoxy-4-(4-(oxetan-3-yl)piperazin-l- /I (phenyl )amino)-l,3,5-triazin-2- yl)benzonitrile
Figure imgf000703_0001
yl)benzonitrile
Figure imgf000704_0001
yl)benzonitrile
Figure imgf000705_0001
TBK1 IKKe JAK2
Ex Structure Name
IC50 IC50 IC50
593 452 660 1000 2-((l-(l-methyl-2-oxo-l,2- dihydropy dine-4-carbonyl)pipe din-4-
Figure imgf000706_0001
yl)methoxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-l-yl (phenyl )amino)-l, 3,5- triazin-2-yl)benzonitrile
594 169 232 1000
5-(4-((4-(4-(oxetan-3-yl)piperazin-l-
/I (phenyl )a mino)-l,3,5-triazin-2-yl )-2-((5- oxopyrrolidin-2-yl)methoxy)benzonitrile
595 69 89 1000 2-((l-(l-methyl-2-oxo-l,2- dihydropy dine-4-carbonyl)pipe din-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin- 1-yl (phenyl )amino)-l, 3, 5-triazin-2- yl)benzonitrile
596 264 403 1000
2-((l-methyl-2-oxopiperidin-4- o yl)methoxy)-5-(4-((4-(4-(oxetan-3- yl)piperazin-l-yl (phenyl )amino)-l, 3,5- triazin-2-yl)benzonitrile
597 95 131 1000
5-(4-((4-(4-(oxetan-3-yl)piperazin-l- yl (phenyl )amino)-l,3,5-triazin-2-yl)-2-(2-
(5-oxopyrrolidin-3-yl)ethoxy)benzonitrile
Figure imgf000707_0001
Figure imgf000708_0001
Figure imgf000709_0001
TBK1 IKKe JAK2
Ex Structure Name
IC50 IC50 IC50
613 128 175 69 2-(((3R,4S)-3-fluoro-l-((S)-2- hydroxypropanoyl)piperidin-4-yl)amino)- 5-(4-((4-(4-(oxetan-3-yl)piperazin-l- /I (phenyl )amino)-l,3,5-triazin-2-
Figure imgf000710_0001
yl)benzonitrile.
614 25 45 268 2-(((3R,4S)-3-fluoro-l-(3- hydroxyazetidine-3-carbonyl)piperidin-4- yl)oxy)-5-(4-((4-(4-(oxetan-3-yl)piperazin- 1-yl (phenyl )amino)-l, 3, 5-triazin-2- yl)benzonitrile
615 4 1 1000
2-(((3R,4S)-3-fluoro-l-((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)-5- (4-((4-((R)-pyrrol id in-2-yl (phenyl )amino)- l,3,5-triazin-2-yl)benzonitrile
616 5 4 1000 2-(((3R,4S)-3-fluoro-l-((S)-2- hydroxypropanoyl)piperidin-4-yl)oxy)-5- (4-((4-((R)-l-(oxetan-3-yl)pyrrolidin-2- /I (phenyl )amino)-l,3,5-triazin-2- yl)benzonitrile
617 29 75 226 2-(((3R,4S)-3-fluoro-l-((R)-2-hydroxy-3- i methoxypropanoyl)pipe din-4-yl)oxy)-5-
.0X C 0J (4-((4-(4-(oxetan-3-yl)piperazin-l-
I I /I (phenyl )amino)-l,3,5-triazin-2- yl)benzonitrile TBK1 IKKe JAK2
Ex Structure Name
IC50 IC50 IC50
618 2 1 162 2-(((3R,4S)-3-fluoro-l-((S)-2-hydroxy-3- nethoxypropanoyl)piperidin-4-yl)oxy)-5-
(4-((4-(4-(oxetan-3-yl)piperazin-l-
/I (phenyl )amino)-l,3,5-triazin-2-
Figure imgf000711_0001
yl)benzonitrile
619 3 3 364 2-(((3R,4S)-3-fluoro-l-((S)-2- nydroxypropanoyl)piperidin-4-yl)oxy)-5-
(4-((4-((R)-hexahydropyrazino[2,l- c][l,4]oxazin-8(lH)-yl)phenyl)amino)- l,3;5-triazin-2-yl)benzonitrile
While the foregoing description describes specific embodiments and aspects, those with ordinary skill in the art will appreciate that various modifications and alternatives can be developed. Accordingly, the particular embodiments and aspects described above are meant to be illustrative only, and not to limit the scope of the invention, which is to be given the full breadth of the appended claims, and any and all equivalents thereof. Each of the foregoing references are hereby incorporated by reference.

Claims

A compound of formula (I):
Figure imgf000713_0001
(I)
wherein,
A is C6-io aryl or 5-10 membered heteroaryl; X1 is CR1 or N;
R1 is selected from the group consisting of H, Ci_6 alkyl, Ci_6 haloalkyl, -NRaRb, halogen, -CN, and -ORa;
R2 is selected from the group consisting of H, hydroxyl, Ci_6 alkyl, Ci_6 heteroalkyl, -NRaRb, halogen, -C(0)Ra, -C(0)ORa, -C(0)NRaRb, -OC(0)NRaRb, - NRaC(0)Rb, -NRaC(0)ORb, -S(O)0-2Rc, -S(0)2NRaRb, -NRaS(0)2Rb, C6_i0 aryl, C3-io cycloalkyi, 5-10 membered heteroaryl, 3-12 membered heterocyclyl and -O-R5, wherein each C-i alkyl, Ci-6 heteroalkyl, C6-io aryl, C3-io cycloalkyi, 5-10 membered heteroaryl and 3-12 membered heterocyclyl is optionally substituted with from one to five R20 groups; or R1 and R2 are taken together to form a fused C6 aryl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl or C5.6 cycloalkyi each optionally substituted with one to five R20 groups;
R3 is selected from the group consisting of H, Ci_6 alkyl, Ci_6 heteroalkyl, -NRaRb, halogen, -C(0)Ra, -C(0)ORa, -C(0)NRaRb, -OC(0)NRaRb, -NRaC(0)Rb, - NRaC(0)ORb, -S(0)o-2Rc, -S(0)(Rc)=NRb, -S(0)2F, -S(0)2NRaRb, -NRaS(0)2Rb, -N3, - CN, -N02, -ORa, C6-io aryl, C3-io cycloalkyi, 5-10 membered heteroaryl and 3-12 membered heterocyclyl wherein each Ci-6 alkyl, Ci-6 heteroalkyl, C6-io aryl, C3-10 cycloalkyi, 5-10 membered heteroaryl and 3-12 membered heterocyclyl is optionally substituted with 1-5 R20 groups; each R4 is independently selected from the group consisting of H , Ci_6 alkyl, Ci_6 heteroalkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, C2.6 alkenyl, C2.6 alkynyl, C6-io aryl, C3-io cycloalkyi, 5-10 membered heteroaryl and 3-12 membered heterocyclyl, -NRaRb, halogen, -C(0)Ra, -C(0)ORa, -C(0)NRaRb, -OC(0)NRaRb, -NRaC(0)Rb, - NRaC(0)ORb, -S(0)o-2Rc, -S(0)2NRaRb, -NRaS(0)2Rb, -N3, -CN, -N02 and -ORa, wherein each Ci-6 alkyl, Ci-6 heteroalkyl, C6-io aryl, C3-io cycloalkyi, 5-10 membered heteroaryl and 3-12 membered heterocyclyl is optionally substituted with from one to five R20 groups; or R3 and one R4 are taken together to form a fused C6 aryl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl or C5.6 cycloalkyi each optionally substituted with one to five R20 groups; R5 is H; or Ci-6 alkyl, Ci-6 haloalkyl, C6-io aryl, 5-10 membered heteroaryl, C3-i0 cycloalkyi, or 3-12 membered heterocyclyl, each of which is optionally substituted with from one to five R20 groups; n is 0-2; each R20 is independently Ci-6 alkyl, C3-io cycloalkyi, Ci-6 heteroalkyl, 3-12 membered heterocyclyl, C6-io aryl, 5-10 membered heteroaryl, halogen, oxo, -ORa, - C(0)Ra, -C(0)ORa, -C(0)NRaRb, -OC(0)NRaRb, -NRaRb, -NRaC(0)Rb, -NRaC(0)ORb, -S(O)0-2Ra, -S(0)(Rc)=NRb, -S(0)2NRaRb, -NRaS(0)2Rb, -N3, -CN, or -N02, or two R20 groups can join together to form a fused, spiro or bridged C3-i0 cylcloalkyl or 3-12 membered heterocyclyl; wherein each Ci-6 alkyl, C3-i0 cycloalkyi, d-e heteroalkyl, 3-12 membered heterocyclyl, C6-io aryl, 5-10 membered heteroaryl is optionally substituted with from one to five halogen, Ci_6 alkyl, d-e heteroalkyl, Ci_6 haloalkyl, oxo, imino, - ORa, -C(0)Ra, -C(0)ORa, -C(0)NRaRb, -OC(0)NRaRb, -NRaRb, -NRaC(0)Rb, - NRaC(0)ORb, -S(O)0-2Ra, -S(0)2NRaRb, -NRaS(0)2Rb, -N3, -CN, or -N02; each R21 is independently Ci-6 alkyl, C3-io cycloalkyi, d-e heteroalkyl, 3-12 membered heterocyclyl, C6-Ci0 aryl, 5-10 membered heteroaryl, hydroxyl, Ci_6 alkoxy, amino, -CN, -C(0)H, -C(0)NH2, -C(0)NH(Ci_6 alkyl), -C(0)N(Ci_6 alkyl)2, -COOH, - C(0)Ci-6 alkyl, -C(0)OCi-6 alkyl, or halogen; and each Ra and each Rb are independently H; or Ci-6 alkyl, C2-e alkenyl, C3-10 cycloalkyl, Ci_6 heteroalkyl, 3-12 membered heterocyclyl, C6-io aryl, 5-10 membered heteroaryl, each of which is optionally substituted with from one to five R21 ; or Ra and Rb together with the atoms to which they are attached form a 3-12 membered heterocyclyl optionally substituted with one to five R21 groups; each Rc is independently Ci-6 alkyl, C2-e alkenyl, C3-io cycloalkyl, Ci-6 heteroalkyl, 3- 12 membered heterocyclyl, C6-io aryl, 5-10 membered heteroaryl, each of which is optionally substituted with from one to five R21 ; or a pharmaceutically acceptable salt thereof.
A compound of claim 1 , having the following formula (la):
Figure imgf000715_0001
(la) wherein X2 is N or CR4. a pharmaceutically acceptable salt thereof.
3. A compound of claim 1 , having the following formula (lb):
Figure imgf000715_0002
(lb)
or a pharmaceutically acceptable salt thereof.
4. A compound of claim 1 , having the following formula (Ic):
Figure imgf000716_0001
(lc) or a pharmaceutically acceptable salt thereof.
5. A compound of claims 1-2, wherein X1 is CR1.
6. A compound of claims 1-2, wherein X1 is N.
7. A compound of claims 1-2, wherein X2 is CR4. 8. A compound of claims 1-2, wherein X2 is N.
9. A compound of claim 1 , wherein A is a 5-6 membered heteroaryl.
10. A compound of claim 1 , wherein A is phenyl.
11. A compound of any one of claims 1-10, wherein R3 comprises a piperazinyl group.
12. A compound of claim 1 1 , wherin the piperazinyl group is substituted with oxetanyl.
13. A compound of any one of claims 1-12, where
Figure imgf000717_0001
wherein,
m is 0-2; and
R20' is H , CN, oxo, CONRaxRbx, d-e alkyl, d-e heteroalkyl and d-e hydroxyalkyl; wherein Rax and Rbx are independently H; or Ci-6 alkyl, C2-e alkenyl, C3-io cycloalkyl, d-e heteroalkyl, 3-12 membered heterocyclyl, C6-io aryl, 5-10 membered heteroaryl, each of which is optionally substituted with from one to five groups selected from Ci_6 alkyl, C3-10 cycloalkyl, C1-6 heteroalkyl, 3-12 membered heterocyclyl, d-do aryl, 5-10 membered heteroaryl, hydroxyl, d-e alkoxy, amino, -CN, -C(0)H, -C(0)NH2, -C(0)NH(d-e alkyl), - C(0)N(d_6 alkyl)2, -COOH , -C(0)Ci_6 alkyl, -C(0)OCi_6 alkyl, or halogen.
14. A compound of claim 13, wherein m is 0.
15. A compound of claim 1 , wherein:
Figure imgf000717_0002
Figure imgf000717_0003
Figure imgf000718_0001
716
Figure imgf000719_0001
717
Figure imgf000720_0001
718
Figure imgf000721_0001
16. A compound of any one of claims 1 -10, wherien R3 is not H.
17. A compound of any one of claims 1 -10, wherein R4 is H.
18. A compound of claim 5, wherein R1 is H.
19. A compound of any one of claims 1-3 and 5-18, wherein R2 is -NRaRb.
20. A compound of claim 19, wherien Ra and Rb on R5 join together with the atoms to which they are attached form a 3-12 membered heterocyclyl which is optionally substituted with one to three of halo, hydroxyl, oxo, Ci_6 alkyl, Ci_6 alkoxy, Ci_6 haloalkyl, Ci-e haloalkoxy, CN, amino, or Ci-e alkylamino.
21 . A compound of any one of claims 1-3 and 5-18, wherein R2 is -O-R5
22. A compound of claim 4 or 21 , wherein R5 is selected from the group consisting of tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, oxetanylmethyl, 1 -(oxetan-3- yl)pyrrolidinyl, oxo-propanylnitrile-pyrrolinyl and piperidinyl.
23. A compound of claim 4 or 21 , wherein R5 is unsubstituted tetrahydropyranyl.
24. A compound of claim 1 , wherein R2 is N-pyrrolidinyloxy or N-piperidinyloxy
substituted with Ci_6 alkoxycarbonyl, hydroxyl Ci_6 alkylcarbonyl, hydroxyl 3-6 membered heterocyclyl, halo 3-6 membered heterocyclyl, C-i-6 alkoxycarbonyl, cyano C-i-6 alkylcabonyl or C3-e cycloalkyl-Ci.6 alkoxy.
25. A compound of claim 4 or 21-24, wherein the R5 group is substituted with one or two fluoro groups. 26. A compound of claim 4 or 21 , wherein R5 is:
Figure imgf000722_0001
Xa is a bond or C(Rx)(Ry), wherein Rx and Ry are independently selected from the group consisting of H, halo or methyl;
Xb and Xc are independently selected from the group consisting of H, halo or methyl;
Xd is selected from the group consisting of H; or Ci-6 alkyl, C2.6 alkenyl, C3-io
cycloalkyl, Ci-6 heteroalkyl, 3-12 membered heterocyclyl, C6-io aryl, 5-10 membered heteroaryl, each of which is optionally substituted with from one to five groups selected from Ci-6 alkyl, C3-10 cycloalkyl, d-e heteroalkyl, 3-12 membered heterocyclyl, Ce-C-io aryl, 5-10 membered heteroaryl, hydroxyl, C-i-6 alkoxy, amino, -CN, -C(0)H, -C(0)NH2, -C(0)NH(Ci_6 alkyl), -C(0)N(Ci_6 alkyl)2, -COOH, -C(0)Ci-6 alkyl, -C(0)OCi-6 alkyl, or halogen. 27. A compound of claim 26, wherein Xd is Ci_6 alkyl substituted with hydroxyl.
28. A compound of claim 26 or 27, wherein Xa is CH2.
29. A compound of claim 26-28, wherein Xb is fluoro.
30. A compound of any one of claims 4, 21 or 22 wherein R5 is substituted with one R20 group selected from Ci-6 alkoxycarbonyl, hydroxyl Ci-6 alkylcarbonyl, Ci-6 alkoxycarbonyl, cyano Ci-6 alkylcabonyl or C3.6 cycloalkyl-Ci_6 alkoxy.
Figure imgf000723_0001
Figure imgf000724_0001
Figure imgf000725_0001
Figure imgf000726_0001
724
Figure imgf000727_0001
725
Figure imgf000728_0001
Figure imgf000728_0002
726
Figure imgf000729_0001
Figure imgf000730_0001
Figure imgf000731_0001
Figure imgf000732_0001
Figure imgf000733_0001
Figure imgf000734_0001
Figure imgf000735_0001
Figure imgf000736_0001
Figure imgf000737_0001
or a pharmaceutically acceptable salt thereof.
33. A pharmaceutical composition comprising a compound of any one of claims 1-32, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
34. A compound of any one of claims 1-33, or a pharmaceutically acceptable salt
thereof, for use in therapy.
35. A compound of any one of claims 1-33, or a pharmaceutically acceptable salt
thereof, for use in therapy; a method of treating a subject having a disease or condition responsive to the inhibition of TBK1 , such as cancer; a method of treating a subject having a disease or condition responsive to the inhibition of ΙΚΚε; a method of treating a subject suffering from a RAS-dependent/mutant cancer, such as non-small cell lung cancer, colorectal cancer, pancreatic cancer, AML, and melanoma; a method of treating a subject suffering from breast or ovarian cancer; a method of treating a subject suffering from cancer resistant to HER2 and EGFR targeted therapies; or a method of treating a subject suffering from a disease selected from the group consisting of Rheumatoid arthritis (RA), Inflammatory bowel disease (IBD), Chronic obstructive pulmonary disease (COPD), Systemic lupus erythematosus (SLE), Polymositis, Systemic sclerosis, Type 2 diabetes, Obesity and Hepatic steatosis.
36. Use of a compound of any one of claims 1 -33, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament, for treating a subject having a disease or condition responsive to the inhibition of TBK1 , such as cancer; treating a subject having a disease or condition responsive to the inhibition of ΙΚΚε; treating a subject suffering from a RAS-dependent/mutant cancer, such as non-small cell lung cancer, colorectal cancer, pancreatic cancer, AML, and melanoma; treating a subject suffering from breast or ovarian cancer; a method of treating a subject suffering from cancer resistant to HER2 and EGFR targeted therapies; or treating a subject suffering from a disease selected from the group consisting of Rheumatoid arthritis (RA), Inflammatory bowel disease (IBD), Chronic obstructive pulmonary disease (COPD), Systemic lupus erythematosus (SLE), Polymositis, Systemic sclerosis, Type 2 diabetes, Obesity and Hepatic steatosis.
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