WO2022173849A1 - (hetero)arylamino-cyclohexyl-sulfonyl derivatives as ccr6 inhibitors - Google Patents

(hetero)arylamino-cyclohexyl-sulfonyl derivatives as ccr6 inhibitors Download PDF

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WO2022173849A1
WO2022173849A1 PCT/US2022/015844 US2022015844W WO2022173849A1 WO 2022173849 A1 WO2022173849 A1 WO 2022173849A1 US 2022015844 W US2022015844 W US 2022015844W WO 2022173849 A1 WO2022173849 A1 WO 2022173849A1
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membered
pyridin
hydrogen
alkyl
pharmaceutically acceptable
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French (fr)
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Wenge Zhong
Lei Wu
Song Feng
Xianqiang SUN
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Qilu Regor Therapeutics Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Definitions

  • Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation (reviewed in Schall, Cytokine, 3: 165-183 (1991), Schall, el al. , Curr Opin. Immunol. 6:865- 873 (1994) and Murphy, Rev. Immun., 12:593-633 (1994)).
  • chemokines in addition to stimulating chemotaxis, other changes can be selectively induced by chemokines in responsive cells, including changes in cell shape, transient rises in the concentration of intracellular free calcium ions ([Ca 2+ ]), granule exocytosis, integrin upregulation, formation of bioactive lipids (e.g., leukotrienes) and respiratory burst, associated with leukocyte activation.
  • the chemokines are early triggers of the inflammatory response, causing inflammatory mediator release, chemotaxis and extravasation to sites of infection or inflammation.
  • chemokines There are two main classes of chemokines, CXC (alpha) and CC (beta), depending on whether the first two cysteines are separated by a single amino acid (C-X-C) or are adjacent (C-C).
  • the alpha-chemokines such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP -2) and melanoma growth stimulatory activity protein (MGSA) are chemotactic primarily for neutrophils
  • beta-chemokines such as RANTES, MIP-la, MIP-lb, monocyte chemotactic protein-1 (MCP-1), MCP-2, MCP-3 and eotaxin are chemotactic for macrophages, T-cells, eosinophils and basophils (Deng, el al., Nature, 381:661-666 (1996)).
  • chemokines bind specific cell- surface receptors belonging to the family of G-protein- coupled seven-transmembrane-domain proteins (reviewed in Horuk, Trends Pharm. Sci., 15: 159-165 (1994)) which are termed "chemokine receptors.”
  • chemokine receptors On binding their cognate ligands, chemokine receptors transduce an intracellular signal through the associated trimeric G protein, resulting in a rapid increase in intracellular calcium concentration.
  • chemokine receptors There are at least eleven human chemokine receptors that bind or respond to beta-chemokines and at least seven human chemokine recepotrs that bind to the alpha chemokines.
  • CX3CR1 fractalkine receptor
  • Chemokine receptors have been implicated as being important mediators of inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.
  • CCR6 is known to be expressed primarily in B cells, IL-17 secreting T cells, regulatory T cells and dendritic cells and shows strong binding to its cognate ligand CCL20 (MIP-3a). It is expressed on approximately 30-60% of adult peripheral blood effector/memory CD4 + T cells. CCR6 is involved in leukocyte homing to inflamed tissue, particularly the skin and lungs and is co-expressed on almost all T cells that have a skin homing phenotype, the CLA + T cells. Thus CCR6 may be an important player in skin pathologies in which leukocytes participate.
  • CCR6 expression has been linked to psoriasis in the following manner.
  • a large majority of skin-homing CD4 + T cells in the peripheral blood express CCR6 with a greater degree of CCL20-mediated chemotaxis occurring in T cells isolated from psoriatic patients (Homey, et. al, JI, 2000).
  • IL-17 secreting cells are central agents in several inflammatory diseases. T cells, such as gd T cells and TH17 T cells produce IL-17 after activation.
  • the pathogenic effects of IL-17 have been associated with human diseases such as rheumatoid arthritis (Patel DD et.
  • CCR6 + T cells isolated from psoriatic patients preferentially secrete IL-17 A, IL-22, and TNFoc when compared to healthy controls (Kagami, et. al, J. Invest. Dermatol., 2010).
  • ccl20 mRNA was up-regulated in lesional psoriatic skin samples (Homey, et. al, JI, 2000; Val-Nosjean, et. al, JEM, 2000).
  • CCR6 knock-out mice were protected from IL-23 driven psoriasis.
  • CCR6 inhibitors for example, compounds of structural formula (I), pharmaceutically acceptable salts, stereoisomers, and pharmaceutical compositions thereof. It was unexpected to find that the compounds disclosed herein significantly improve solubility in vitro and have suitable plasma protein binding properties.
  • the present disclosure further provides methods of using the compounds disclosed herein (e.g ., compounds of structural formula (I)), pharmaceutically acceptable salts, stereoisomers, or pharmaceutical compositions thereof, to inhibit the activity of CCR6.
  • the present disclosure further provides methods for using the compounds disclosed herein (e.g., compounds of structural formula (I)), pharmaceutically acceptable salts, stereoisomers, or pharmaceutical compositions thereof, to treat a condition, disease or disorder modulated at least in part by CCR6.
  • the present disclosure provides a compound of formula (I), a pharmaceutically acceptable salt, or a stereoisomer thereof.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compounds disclosed herein (e.g., compounds of structural formula (I)), a pharmaceutically acceptable salt, or a stereoisomer thereof, as defined in any one of the embodiments described herein, in a mixture with at least one pharmaceutically acceptable carrier.
  • the present disclosure provides a compound of formula (I), a pharmaceutically acceptable salt, or a stereoisomer thereof, as defined in any one of the embodiments described herein, for use as a medicament.
  • the present disclosure provides a compound of formula (I), a pharmaceutically acceptable salt, or a stereoisomer thereof, as defined in any one of the embodiments described herein, for use in the treatment of a condition, disease or disorder modulated at least in part by CCR6, specifically in treating an autoimmune disease or condition.
  • the present disclosure provides a use of a compound of formula (I), a pharmaceutically acceptable salt, or a stereoisomer thereof, as defined in any one of the embodiments described herein, for the manufacture of a medicament for treating a condition, disease or disorder modulated at least in part by CCR6, specifically in treating an autoimmune disease or condition.
  • the present disclosure provides a compound represented by Formula (I): a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein:
  • Y is O or NR 7 ; wherein R 7 is hydrogen, Ci- 6 alkyl, or C3-6cycloalkyl; wherein said Ci- 6 alkyl or C3-6cycloalkyl is optionally substituted by one or more halogen or OH;
  • R 1 is hydrogen, halogen, -CN, -NO2, -C(0)0R a , -C(0)NR a R b , -S0 2 R a , -S0 2 NR a R b , -P(0)R a R b , -C(0)R a , Ci-4alkyl, or C 2- 4alkynyl; wherein said C 1-4 alkyl represented by R 1 is optionally substituted by one or more halogen, OR a , or NR a R b ;
  • X 1 is N or CR 2 ;
  • X 2 is N or CR 3 ;
  • X 3 is N or CR 4 ; wherein R 2 , R 3 , and R 4 are each independently hydrogen, halogen, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR a , -NR a R b , -C(0)R a , -C(0)0R a , -C(0)NR a R b , -S0 2 R a , -S0 2 NR a R b , -P(0)R a R b , -NR a C(0)R b , -NR a S0 2 R b , 3-12 membered carbocyclyl, or 3-12 membered heterocyclyl; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl,
  • 3-12 membered carbocyclyl, or 3-12 membered heterocyclyl represented by R 2 , R 3 , or R 4 is optionally substituted by one to four R d ;
  • R a and R b are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; or R a and R b together with the N or P atom to which they are attached, form 4-12 membered heterocyclyl or 5-10 membered heteroaryl; each R d is independently hydrogen, halogen, oxo (as appropriate), -CN,
  • Ci-ealkyl Ci-ealkyl, -OR a , -NR a R b , -C(0)R a , -C(0)0R a , -C(0)NR a R b , -S0 2 R a , -S0 2 NR a R b , -P(0)R a R b , -NR a C(0)R b , or -NR a S0 2 R b ;
  • R 5 is hydrogen, halogen, -CN, or C 1-6 alkyl
  • R 6 is halogen, -CN, -OR a , -NR a R b , or C 1-6 alkyl;
  • R 8 is halogen, -CN, -OR a , -NR a R b , or C 1-6 alkyl;
  • R 9 is selected from the group consisting of a) a moiety represented by formula (IA): wherein Ring A is phenyl or 5-6 membered heteroaryl optionally substituted by one or more R 10 ; b) a moiety represented by formula (IB): wherein Ring B is phenyl or 5-6 membered heteroaryl optionally substituted by one or more R 10 ; c) a moiety represented by formula (IC): wherein Ring C is phenyl or 5-6 membered heteroaryl optionally substituted by one or more R 10 ; and d) 7-11 membered bicyclic nitrogen containing heterocyclyl or 8-11 membered bicyclic nitrogen containing heteroaryl, wherein said heterocyclyl or heteroaryl represented by R 9 is optionally substituted with one to four R f ; wherein R 10 is hydrogen, halogen, -CN, -OR a , -P(0)R a R b , -NR a C(0)R b ,
  • L is a bond, -0-, -N(R 11 )-, or -C(R 12 )(R 13 )-;
  • R 11 is hydrogen, C 1-6 alkyl, 3-6 membered cycloalkyl, or 4-6 membered heterocyclyl; wherein said C 1-6 alkyl represented by R 11 is optionally substituted by halogen, -OR a , -NR a R b , -C(0)OR a , or -C(0)NR a R b ;
  • R 12 and R 13 are independently hydrogen, -OR a , -NR a R b , -C(0)OR a , -C(0)NR a R b , or C 1-6 alkyl; wherein said C 1-6 alkyl represented by R 12 or R 13 is optionally substituted by halogen, -OR a , -NR a R b , -C(0)OR a , or -C(0)NR a R b ;
  • Z is -CONH 2 , 4-11 membered carbocyclyl, 4-11 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein said 4-11 membered carbocyclyl,
  • R e in each occurrence, is C 1-6 alkyl, C 1-6 alkyleneOR', C 1-6 alkyleneN(R)(R ), oxo (as appropriate), -OR, -N(R ' )(R " ), -NR'C(0)R", C(0)OR', C(0)NR'R", or 3-6 membered cycloalkyl, wherein said C 1-6 alkyl is optionally substituted by C(0)OR', C(0)NR'R", or NR'C(0)R";
  • R 14 is Ci-ealkyl, -C 1-6 alkyleneOR', -Ci-6alkyleneN(R ' )(R “ ), -COOR', or -CON(R ' )(R “ ), wherein said C 1-6 alkyl is optionally substituted by -C(0)OR, -C(0)NRR , or -NRC(0)R ;
  • R 15 is -OR, -N(R)(R ), Ci-ealkyl, C 1-6 alkyleneOR', Ci-6alkyleneN(R ' )(R “ ), -COOR', -CON(R)(R ), or -NRC(0)R , wherein said C 1-6 alkyl is optionally substituted by -C(0)OR , -C(0)NRR , or -NR ' C(0)R " ;
  • R f is halogen, -CN, Ci-ealkyl, oxo, -N(R ' )(R " ), OR, -COOR', -NRC(0)R , or -CON(R)(R );
  • R and R in each occurrence, are independently hydrogen or C 1-6 alkyl; or R and R together with the N atom to which they are attached form 4-12 membered heterocyclyl or 5-10 membered heteroaryl; m is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and n is 0, 1, 2, 3, or 4.
  • the present disclosure provides a compound according to the first embodiment, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein Y is O, and the definitions of the other variables are provided in the first embodiment.
  • the present disclosure provides a compound according to the first embodiment, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein Y is NR 7 ; wherein R 7 is hydrogen or -CH3, and the definitions of the other variables are provided in the first embodiment.
  • the present disclosure provides a compound according to any one of the first through third embodiments, a pharmaceutically acceptable salt or a stereoisomer thereof, wherein
  • R 9 is a moiety represented by formula (A): wherein
  • U is CH or N
  • V is N or CR 10 ; wherein R 10 is hydrogen, halogen, -CN, -C(0)NR a R b , or C 1-6 alkyl; wherein R a or R b are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; and the definitions of the other variables are provided in the first through third embodiments.
  • the present disclosure provides a compound according to any one of the first through third embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
  • R 9 is a moiety represented by formula (B): wherein
  • U is CH or N
  • V is N or CR 10 ; wherein R 10 is hydrogen, halogen, -CN, -C(0)NR a R b , or C 1-6 alkyl; wherein R a or R b are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; and the definitions of the other variables are provided in the first through third embodiments.
  • the present disclosure provides a compound according to any one of the first through third embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
  • R 9 is a moiety represented by formula (C): wherein
  • U is CH or N
  • V is N or CR 10 ; wherein R 10 is hydrogen, halogen, -CN, -C(0)NR a R b , or C 1-6 alkyl; wherein R a or R b are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; and the definitions of the other variables are provided in the first through third embodiments.
  • the present disclosure provides a compound according to any one of the first through third embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R 9 is 7-11 membered bicyclic nitrogen containing heterocyclyl or 8-11 membered bicyclic nitrogen containing heteroaryl, wherein said heterocyclyl or heteroaryl represented by R 9 is optionally substituted with one to four R f ; and the definitions of the other variables are provided in the first through third embodiments.
  • the present disclosure provides a compound according to any one of the first through third embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
  • R 1 is halogen, -CN, -CF 3 , or -P(0)(CH 3 ) 2 ;
  • X 1 is N or CR 2 ; and R 2 is hydrogen;
  • X 2 is N
  • X 3 is N or CR 4 ; and R 4 is hydrogen or -C(0)OCH 3 ; R 5 is hydrogen, fluorine, or -CN; m is 0; and n is 0; and the definitions of the other variables are provided in the first through seventh embodiments.
  • the present disclosure provides a compound according to any one of the first through fourth and eighth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
  • R 9 is a moiety represented by formula (A);
  • U is CH or N
  • V is N or CR 10 ; wherein R 10 is hydrogen, halogen, -CN, -C(0)NR a R b ; wherein R a or R b are each independently selected from the group consisting of hydrogen, Ci-4alkyl, 3-8 membered carbocyclyl, 4-8 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl;
  • L is a bond, O, -N(R 11 )-, or -C(R 12 )(R 13 )-;
  • R 11 is hydrogen, Ci-4alkyl, 3-6 membered cycloalkyl, or 4-6 membered heterocyclyl;
  • R 12 and R 13 are independently hydrogen, -OR, -NRR , or Ci-4alkyl
  • Z is 4-6 membered carbocyclyl, 4-9 membered heterocyclyl, or 5-6 membered heteroaryl; wherein said 4-6 membered carbocyclyl, 4-9 membered heterocyclyl, or 5-6 membered heteroaryl represented by Z is optionally substituted by one to two R e ;
  • R e in each occurrence, is C 1-6 alkyl, -C 1-6 alkyleneOR', -C 1-6 alkyleneN(R)(R ), oxo (as appropriate), -OR, -N(R ' )(R “ ), -NR'C(0)R", -C(0)0R', -C(0)NR'R “ , or 3-6 membered cycloalkyl, wherein said C 1-6 alkyl is optionally substituted by -C(0)0R, -C(0)NRR , or -NR C(0)R ;
  • R and R in each occurrence, are independently hydrogen or Ci-4alkyl; or R and R together with the N atom to which they are attached form 5-8 membered heterocyclyl or 5-6 membered heteroaryl; and the definitions of the other variables are provided in the first through fourth and eighth embodiments.
  • the present disclosure provides a compound according to any one of the first through fourth, eighth, and ninth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
  • R 9 is a moiety represented by formula (A):
  • U is CH or N
  • V is N or CR 10 ; wherein R 10 is hydrogen or halogen;
  • L is a bond, -N(R 11 )-, or -C(R 12 )(R 13 )-;
  • R 11 is hydrogen or Ci-4alkyl
  • R 12 and R 13 are independently hydrogen, -OH, or Ci-4alkyl
  • Z is 4-6 membered carbocyclyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl; wherein said 4-6 membered carbocyclyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl represented by Z is optionally substituted by one to two R e ;
  • R e in each occurrence, is independently Ci-4alkyl, -NR'C(0)R", -Ci-4alkyleneOR',
  • R and R in each occurrence, are independently hydrogen or Ci-4alkyl; and the definitions of the other variables are provided in the first through fourth, eighth, and ninth embodiments.
  • the present disclosure provides a compound according to any one of the first through fourth and eighth through tenth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
  • R 9 is a moiety represented by formula (Al), (A2), or (A3): wherein
  • R 10 is hydrogen or halogen
  • L is a bond, -N(R 11 )-, or -C(R 12 )(R 13 )-; wherein R 11 is hydrogen or Ci-4alkyl;
  • R 12 and R 13 are independently hydrogen, -OH, or Ci-3alkyl
  • Z is 4-6 membered cycloalkyl, 4-6 membered saturated monocyclic heterocyclyl,
  • R e in each occurrence, is independently Ci-2alkyl, -NR'C(0)R",
  • Ci-2alkyleneOR' -OR, -N(R)(R ), or oxo (as appropriate);
  • R and R in each occurrence, are independently hydrogen or Ci-2alkyl; and the definitions of the other variables are provided in the first through fourth and eighth through tenth embodiments.
  • the present disclosure provides a compound according to the first through fourth and eighty through eleventh embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R 10 is hydrogen or fluoro;
  • L is a bond, -NH-, -N(CH 3 )-, or -CH(OH)-;
  • Z is cyclobutyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, azaspiro[3.3]heptanyl, or triazolyl; wherein said cyclobutyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, azaspiro[3.3]heptanyl, or triazolyl is optionally substituted by one to two R e ; and
  • R e in each occurrence, is -CH 3 , -OH, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , oxo (as appropriate), -NHC(0)CH 3 , -OCH 3 , or -CH2NH2; and the definitions of the other variables are provided in the eleventh embodiment.
  • the present disclosure provides a compound according to the any one of first, fourth, and eighth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
  • Y is NR 7 ; wherein R 7 is hydrogen or -CH 3 ;
  • R 9 is a moiety represented by formula (A);
  • Z is -CONH2; and the definitions of the other variables are provided in the first, fourth, and eighth embodiments.
  • the present disclosure provides a compound according to any one of the first through fourth and eighth through twelfth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R 9 is selected from the group consisting of
  • the present disclosure provides a compound according to any one of the first through third, fifth, and eighth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R 9 is a moiety represented by formula (B);
  • V is N
  • R 14 is C 1-4 alkyleneOR', C 1-6 alkyleneN(R)(R ' ), -COOR', or -CON(R ' )(R " ); and R and R , in each occurrence, are independently hydrogen or Ci-2alkyl; and the definitions of the other variables are provided in the first through third, fifth, and eighth embodiments.
  • the present disclosure provides a compound according to any one of the first through third, fifth, eighth, and fifteenth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R 9 is selected from the group consisting of , and the definitions of the other variables are provided in the first through third, fifth, eighth, and fifteenth embodiments.
  • the present disclosure provides a compound according to the any one of the first through third, sixth, and eighth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
  • R 9 is a moiety represented by formula (C);
  • V is N
  • R 15 is -OR ' or -N(R ' )(R ' );
  • R and R in each occurrence, are independently hydrogen or C 1-4 alky 1 ; and the definitions of the other variables are provided in the first through third, sixth, and eighth embodiments.
  • the present disclosure provides a compound according to the any one of the first through third, sixth, eighth, and seventeenth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R 9 is a moiety represented by formula (C);
  • V is N
  • R 15 is OH or N3 ⁇ 4; and the definitions of the other variables are provided in the first through third, sixth, and eighteenth embodiments.
  • the present disclosure provides a compound according to the any one of the first through third, seventh, and eighth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
  • R 9 is 8-10 membered bicyclic nitrogen containing heterocyclyl or 8-10 membered bicyclic nitrogen containing heteroaryl, wherein said heterocyclyl or heteroaryl represented by R 9 is optionally substituted with one to three R f ;
  • R f is halogen, Ci-4alkyl, oxo (as appropriate), -NH2, Ci-4alkoxy, or-COOH; and the definitions of the other variables are provided in the first through third, seventh, and eighth embodiments.
  • the present disclosure provides a compound according to the any one of the first through third, seventh, eighth, and ninteenth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R 9 is selected from the group consisting of
  • the present disclosure provides a compound according to the any one of the first through twentieth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
  • R 1 is -CF 3 ;
  • X 1 is CH
  • X 2 is N; X 3 is CH;
  • R 5 is hydrogen; m is 0; and n is 0; and the definitions of the other variables are provided in the first through twentieth embodiments.
  • the present disclosure provides a compound selected from the compounds disclosed in examples and Table 1, a pharmaceutically acceptable salt or a stereoisomer thereof.
  • halogen refers to fluoride, chloride, bromide, or iodide.
  • alkyl used alone or as part of a larger moiety, such as “alkoxy” or “haloalkyl” and the like, means saturated aliphatic straight-chain or branched monovalent hydrocarbon radical of formula -C n H(2n+i). Unless otherwise specified, an alkyl group typically has 1-6 carbon atoms, i.e. C 1-6 alkyl. As used herein, a “C 1-6 alkyl” group means a radical having from 1 to 6 carbon atoms in a linear or branched arrangement.
  • Examples include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert- butyl, n-pentyl, isopentyl, hexyl, and the like.
  • alkylene as used herein, means a straight or branched chain divalent hydrocarbon group of formula -C n H 2n -. Non-limiting examples include ethylene, and propylene.
  • alkenyl means an alkyl group in which one or more carbon/carbon single bond is replaced by a double bond.
  • alkynyl means an alkyl group in which one or more carbon/carbon single bond is replaced by a triple bond.
  • alkoxy means an alkyl radical attached through an oxygen linking atom, represented by -O-alkyl.
  • (Ci-4)alkoxy includes methoxy, ethoxy, propoxy, and butoxy.
  • carbocyclyl refers to any stable non-aromatic hydrocarbon ring having 3-12 membered carbocyclyl.
  • carbocyclyl is 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic or tricyclic hydrocarbon ring, any of which may be saturated, partially unsaturated, or unsaturated.
  • Any substitutable ring atom can be substituted ( e.g ., by one or more substituents).
  • carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, and cyclooctadienyl.
  • carbocyclyl is intended to include, bridged, fused, and spirocyclic rings. In a spirocyclic carbocyclyl, one atom is common to two different rings.
  • spirocyclic carbocyclyl is spiropentanyl.
  • the rings In a bridged carbocyclyl, the rings share at least two common non-adjacent atoms.
  • bridged carbocyclyls include bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hept-2-enyl, and adamantanyl.
  • two or more rings In a fused-ring carbocyclyl system, two or more rings may be fused together, such that two rings share one common bond.
  • Examples of two- or three-fused ring carbocyclyls include naphthalenyl, tetrahydronaphthalenyl (tetralinyl), indenyl, indanyl (dihydroindenyl), anthracenyl, phenanthrenyl, and decalinyl.
  • cycloalkyl refers to a cyclic, bicyclic, tricyclic, or polycyclic saturated hydrocarbon groups having 3 to 12 ring carbons. In one embodiment, cycloalkyl may have 3 to 7 ring cabons. Any substitutable ring atom can be substituted ( e.g ., by one or more substituents). Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl may include multiple fused and/or bridged rings.
  • Non-limiting examples of fused/bridged cycloalkyl include: bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.0]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo [3.2.1] octane, bicyclo[2.2.2]octane, and the like.
  • Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom).
  • spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro [2.6] nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like.
  • heterocyclyl refers to a radical of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone (“3-12 membered heterocyclyl”).
  • a heterocyclyl group is a 3-7 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-7 membered heterocyclyl”).
  • heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”); polycyclic ring systems include fused, bridged, or spiro ring systems).
  • Exemplary monocyclic heterocyclyl groups include azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepanyl, oxepanyl, thiepanyl, tetrahydropyridinyl, and the like.
  • Heterocyclyl polycyclic ring systems can include heteroatoms in one or more rings in the polycyclic ring system. Substituents may be present on one or more rings in the polycyclic ring system.
  • Spiro heterocyclyl refers to 5 to 12 membered polycyclic heterocyclyl with rings connected through one common carbon atom (called as spiro atom), wherein said rings have one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone, the remaining ring atoms being C, wherein one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system.
  • spiro heterocyclyl include, but are not limited to the following groups:
  • Fused heterocyclyl refers to a 5 to 12 membered polycyclic heterocyclyl group, wherein each ring in the group shares an adjacent pair of carbon atoms with another ring in the group, wherein one or more rings can contain one or more double bonds, but none of the rings has a completely conjugated p-electron system, and wherein said rings have one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone, the remaining ring atoms being C.
  • fused heterocyclyl include, but are not limited to the following groups:
  • Bridged heterocyclyl refers to a 5 to 12 membered polycyclic heterocyclyl group, wherein any two rings in the group share two disconnected atoms, the rings can have one or more double bonds but have no completely conjugated p-electron system, and the rings have one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone as ring atoms, the remaining ring atoms being C.
  • Representive examples of bridged heterocyclyl include, but are not limited to the following groups:
  • the carbocyclyl, the cycloalkyl, or the heterocyclyl may be unsubstituted, or be substituted with one or more substituents as valency allows, wherein the substituents can be independently selected from a number of groups such as oxo, -CN, halogen, alkyl and alkoxyl, opotionally, the alkyl substitution may be further substituted.
  • aryl refers to a 6 to 10 membered all-carbon monocyclic ring or a polycyclic fused ring (a “fused” ring system means that each ring in the system shares an adjacent pair of carbon atoms with other ring in the system) group, and has a completely conjugated p-electron system.
  • fused ring system means that each ring in the system shares an adjacent pair of carbon atoms with other ring in the system
  • aryl represents phenyl and naphthyl.
  • heteroaryl refers to a monocyclic or multicyclic aromatic hydrocarbon in which at least one of the ring carbon atoms has been replaced with a heteroatom independently selected from oxygen, nitrogen and sulfur.
  • the heteroaryl is based on a C5-10 aryl with one or more of its ring carbon atoms replaced by the heteroatom.
  • a heteroaryl group may be attached through a ring carbon atom or, where valency permits, through a ring nitrogen atom.
  • the heteroaryl may be unsubstituted, or be substituted with one or more substituents as valency allows with the substituents being independently selected from halogen, OH, alkyl, alkoxyl, and amino ( e.g ., NH2, NHalkyl, N(alkyl)2), optionally, the alkyl may be further substituted.
  • treating includes any effect, e.g., lessening, reducing, modulating, ameliorating, or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.
  • terapéuticaally effective amount refers to an amount of an agent (e.g., a compound described herein) effective to treat at least one symptom of a disease or disorder in a patient or subject.
  • the “therapeutically effective amount” of the agent for administration may vary based upon the desired activity, the disease state of the patient or subject being treated, the dosage form, method of administration, patient factors such as the patient's sex, genotype, weight and age, the underlying causes of the condition or disease to be treated, the route of administration and bioavailability, the persistence of the administered agent in the body, evidence of natriuresis and/or diuresis, the type of formulation, and the potency of the agent.
  • pharmaceutically-acceptable salt refers to a pharmaceutical salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, and is commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically-acceptable salts are well known in the art. For example, S. M. Berge et al. describes pharmacologically acceptable salts in J. Pharm. Sci., 1977, 66, 1-19.
  • compositions of any one of the formulae described above include acid addition and base salts.
  • Suitable pharmaceutically acceptable salts of the compounds disclosed herein include pharmaceutically acceptable salts with pharmaceutically acceptable acid(s).
  • Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, and sulfuric acids) and of organic acids (such as acetic, benzenesulfonic, benzoic, ethanesulfonic, methanesulfonic, and succinic acids).
  • Compounds of the present teachings with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s).
  • Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts).
  • the resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.
  • the compounds of any one of the formulae described above, and pharmaceutically acceptable salts thereof, may exist in unsolvated and solvated forms.
  • the compounds of any one of the formulae described above may exhibit one or more kinds of isomerism (e.g . optical, geometric or tautomeric isomerism). Such variation is implicit to the compounds of any one of the formulae described above defined as they are by reference to their structural features and therefore within the scope of the present disclosure.
  • Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are mirror images of each other. Diastereomers are stereoisomers having two or more chiral centers that are not identifcal and are not mirror images of each other.
  • a compound When a compound is designated by its chemical name (e.g., where the configuration is indicated in the chemical name by or “S”) or its structure (e.g., the configuration is indicated by “wedge” bonds) that indicates a single enantiomer, unless indicated otherwise, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as “enantiomerically pure”).
  • Optical purity is the weight in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers.
  • stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.
  • a disclosed compound having a chiral center is depicted by a structure without showing a configuration at that chiral center, the structure is meant to encompass the compound with the S configuration at that chiral center, the compound with the R configuration at that chiral center, or the compound with a mixture of the R and S configuration at that chiral center.
  • a disclosed compound having a chiral center is depicted by its chemical name without indicating a configuration at that chiral center with “S” or “R”, the name is meant to encompass the compound with the S configuration at that chiral center, the compound with the R configuration at that chiral center or the compound with a mixture of the R and S configuration at that chiral center.
  • Racemic mixture means 50% of one enantiomer and 50% of is corresponding enantiomer.
  • a compound with one chiral center is named or depicted without indicating the stereochemistry of the chiral center, it is understood that the name or structure encompasses both possible enantiomeric forms (e.g., both enantiomerically-pure, enantiomerically-enriched or racemic) of the compound.
  • geometric isomer means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a carbocyclic ring, or to a bridged bicyclic system.
  • Substituent atoms (other than hydrogen) on each side of a carbon- carbon double bond may be in an E or Z configuration according to the Cahn-Ingold-Prelog priority rules. In the “E” configuration, the substituents having the highest priorities are on opposite sides in relationship to the carbon-carbon double bond. In the “Z” configuration, the substituents having the highest priorities are oriented on the same side in relationship to the carbon-carbon double bond.
  • Substituents around a carbon-carbon double bond can also be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.
  • the arrangement of substituents around a carbocyclic ring can also be designated as “cis” or “trans.”
  • the term “cis” represents substituents on the same side of the plane of the ring, and the term “trans” represents substituents on opposite sides of the plane of the ring.
  • Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis/trans.”
  • tautomeric isomerism (“tautomerism”) can occur. This can take the form of proton tautomerism in compounds of any one of the formulae described above containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
  • geometric isomer When a geometric isomer is depicted by name or structure, it is to be understood that the named or depicted isomer exists to a greater degree than another isomer, that is that the geometric isomeric purity of the named or depicted geometric isomer is greater than 50%, such as at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. Geometric isomeric purity is determined by dividing the weight of the named or depicted geometric isomer in the mixture by the total weight of all of the geomeric isomers in the mixture.
  • Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
  • Chiral compounds of any one of the formulae described above (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from
  • a compound of the present disclosure is administered in an amount effective to treat a condition as described herein.
  • the compounds of the present disclosure can be administered as compound per se, or alternatively, as a pharmaceutically acceptable salt.
  • the compound per se or pharmaceutically acceptable salt thereof will simply be referred to as the compounds of the present disclosure.
  • the compounds of the present disclosure are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
  • the compounds of the present disclosure may be administered orally, rectally, vaginally, parenterally, or topically.
  • the compounds of the present disclosure may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the bloodstream directly from the mouth.
  • the compounds of the present disclosure may also be administered directly into the bloodstream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • the compounds of the present disclosure may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • the compounds of the present disclosure can also be administered intranasally or by inhalation.
  • the compounds of the present disclosure may be administered rectally or vaginally.
  • the compounds of the present disclosure may also be administered directly to the eye or ear.
  • the dosage regimen for the compounds of the present disclosure and/or compositions containing said compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus the dosage regimen may vary widely.
  • the total daily dose of a compound of the present disclosure is typically from about 0.001 to about 100 mg/kg (i.e., mg compound of the present disclosure per kg body weight) for the treatment of the indicated conditions discussed herein.
  • compositions may be provided in the form of tablets containing 0.1- 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient.
  • doses may range from about 0.01 to about 10 mg/kg/minute during a constant rate infusion.
  • Suitable subjects according to the present disclosure include mammalian subjects, including non-human mammal such as primates, rodents (mice, rats, hamsters, rabbits etc).
  • humans are suitable subjects. Human subjects may be of either gender and at any stage of development.
  • the present disclosure comprises pharmaceutical compositions.
  • Such pharmaceutical compositions comprise a compound of the present disclosure presented with a pharmaceutically acceptable carrier or excipient.
  • Other pharmacologically active substances can also be present.
  • pharmaceutically acceptable carrier or excipient includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof, and may include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol, or sorbitol in the composition.
  • Pharmaceutically acceptable substances such as wetting agents or minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the antibody or antibody portion.
  • compositions of present disclosure may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g ., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories.
  • liquid solutions e.g ., injectable and infusible solutions
  • dispersions or suspensions tablets, pills, powders, liposomes and suppositories.
  • the form depends on the intended mode of administration and therapeutic application.
  • compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans with antibodies in general.
  • One mode of administration is parenteral (e.g . intravenous, subcutaneous, intraperitoneal, intramuscular).
  • the antibody is administered by intravenous infusion or injection.
  • the antibody is administered by intramuscular or subcutaneous injection.
  • Oral administration of a solid dose form may be, for example, presented in discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present disclosure.
  • the oral administration may be in a powder or granule form.
  • the oral dose form is sub-lingual, such as, for example, a lozenge.
  • the compounds of any one of the formulae described above are ordinarily combined with one or more adjuvants.
  • Such capsules or tablets may contain a controlled release formulation.
  • the dosage forms also may comprise buffering agents or may be prepared with enteric coatings.
  • oral administration may be in a liquid dose form.
  • Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water).
  • Such compositions also may comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening), and/or perfuming agents.
  • the present disclosure comprises a parenteral dose form.
  • Parenter administration includes, for example, subcutaneous injections, intravenous injections, intraperitoneally, intramuscular injections, intrasternal injections, and infusion.
  • injectable preparations i.e., sterile injectable aqueous or oleaginous suspensions
  • suitable dispersing, wetting agents, and/or suspending agents may be formulated according to the known art using suitable dispersing, wetting agents, and/or suspending agents.
  • the present disclosure comprises a topical dose form.
  • Topical administration includes, for example, transdermal administration, such as via transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhalation administration.
  • Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams.
  • a topical formulation may include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.
  • Penetration enhancers may be incorporated - see, for example, Finnin and Morgan, J. Pharm. Set, 88:955-958, 1999.
  • Formulations suitable for topical administration to the eye include, for example, eye drops wherein the compound of present disclosure is dissolved or suspended in a suitable carrier.
  • a typical formulation suitable for ocular or aural administration may be in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline.
  • Other formulations suitable for ocular and aural administration include ointments, biodegradable (i.e., absorbable gel sponges, collagen) and non-biodegradable (/. ⁇ ? ., silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
  • a polymer such as crossed linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cehulosic polymer, for example, hydroxypropylmethylcehulose, hydroxyethylcehulose, or methylcehulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride.
  • a preservative such as benzalkonium chloride.
  • Such formulations may also be delivered by iontophoresis.
  • the compounds of the present disclosure are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant.
  • Formulations suitable for intranasal administration are typically administered in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane.
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the present disclosure comprises a rectal dose form.
  • rectal dose form may be in the form of, for example, a suppository. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • compositions of the present disclosure may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures.
  • the present disclosure provides methods of treating or preventing a CCR6-mediated condition or disease by administering to a subject having such a condition or disease, a therapeutically effective amount of any compound of the disclosure.
  • compounds for use in the present methods are those compounds provided above, as well as compounds specifically exemplified in the Examples below, and provided with specific structures herein.
  • the "subject” is defined herein to include animals such as mammals, including, but not limited to, primates ( e.g ., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In one embodiment, the subject is a human.
  • CCR6-mediated condition or disease refers to a condition or disease characterized by inappropriate, e.g., less than or greater than normal, CCR6 functional activity.
  • Inappropriate CCR6 functional activity might arise as the result of CCR6 expression in cells which normally do not express CCR6, increased CCR6 expression (leading to, e.g., inflammatory and immunoregulatory disorders and diseases) or decreased CCR6 expression.
  • Inappropriate CCR6 functional activity might also arise as the result of CCL20 secretion by cells which normally do not secrete CCL20, increased CCL20 expression (leading to, e.g., inflammatory and immunoregulatory disorders and diseases) or decreased CCL20 expression.
  • a CCR6-mediated condition or disease may be completely or partially mediated by inappropriate CCR6 functional activity.
  • a CCR6-mediated condition or disease is one in which modulation of CCR6 results in some effect on the underlying condition or disease (e.g ., a CCR6 antagonist results in some improvement in patient well-being in at least some patients).
  • terapéuticaally effective amount means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • diseases or conditions associated with inflammation, infection and cancer can be treated or prevented with the present compounds and compositions.
  • diseases or conditions including chronic diseases, of humans or other species can be treated with inhibitors of CCR6 function.
  • diseases or conditions include: (1) allergic diseases such as systemic anaphylaxis or hypersensitivity responses, drug allergies, insect sting allergies and food allergies, (2) inflammatory bowel diseases, such as Crohn's disease, ulcerative colitis, ileitis and enteritis, (3) vaginitis, (4) psoriasis and inflammatory dermatoses such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria and pruritus, Vitiligo (5) vasculitis, (6) spondyloarthropathies, (7) scleroderma, (8) asthma and respiratory allergic diseases such as allergic asthma, allergic rhinitis, hypersensitivity lung diseases and the like, (9) autoimmune diseases, such as rheuma
  • the disease or condition that the present methods are directed to treat is an autoimmune disease or condition.
  • the disease or condition in the present methods are directed to treat is a neurodegenerative or neuroinflammatory disorder in a human.
  • the disease or condition that the present methods are directed to treat is rheumatoid arthritis, juvenile arthritis, juvenile rheumatoid arthritis, systemic onset rheumatoid arthritis, pauciarticular rheumatoid arthritis, pauciarticular juvenile rheumatoid arthritis, polyarticular rheumatoid arthritis, enteropathic arthritis, juvenile Reiter's Syndrome, ankylosing spondylitis, juvenile ankylosing spondylitis, SEA Syndrome, reactive arthritis (reactive arthropathy), psoriatic arthropathy, juvenile enteropathic arthritis, polymyalgia rheumatica, enteropathic spondylitis, juvenile idiopathic arthritis (JIA), juvenile psoriatic arthritis, juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid
  • the disease or condition that the present methods are directed to treat is lupus, systemic lupus erythematosus, juvenile systemic lupus erythematosus, lupus nephritis, Sjogren's syndrome, scleroderma (systemic sclerosis), Raynaud's phenomenonjuvenile scleroderma, polymyositis, dermatomyositis, polymyositis- dermatomyositis, mixed connective tissue disease, sarcoidosis, fibromyalgia, vasculitis microscopic polyangiitis, vasculitis, eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss syndrome), granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis), polyarteritis nodosa, Henoch- Schonlein purpura, idi
  • the present methods are directed to the treatment of diseases or conditions selected from inflammatory bowel disease, Crohn's disease, or ulcerative colitis in a human.
  • the present methods are directed to the treatment of diseases or conditions selected from allergic diseases, psoriasis, skin conditions such as atopic dermatitis and asthma and scleroderma.
  • the disease or condition that the present methods are directed to treat is psoriasis, atopic dermatitis, eczema dermatitis, dermatitis, pruritus, alopecia, autoimmune alopecia, vitiligo, epidermal hyperplasia, juvenile dermatomyositis, or dermatomyositis .
  • modulation of CCR6 dependent regulatory T cell trafficking may be modulated to treat diseases or conditions including cancers, infectious diseases (viral infections, e.g., HIV infection, and bacterial infections) and immunosuppressive diseases such as organ transplant conditions and skin transplant conditions.
  • infectious diseases viral infections, e.g., HIV infection, and bacterial infections
  • immunosuppressive diseases such as organ transplant conditions and skin transplant conditions.
  • organ transplant conditions is meant to include bone marrow transplant conditions and solid organ (e.g., kidney, liver, lung, heart, pancreas or combination thereof) transplant conditions.
  • kits comprising the compound of any one of the formulae described above or pharmaceutical compositions comprising the compound of any one of the formulae described above of the present disclosure.
  • a kit may include, in addition to the compound of any one of the formulae described above, of the present disclosure or pharmaceutical composition thereof, diagnostic or therapeutic agents.
  • kits may also include instructions for use in a diagnostic or therapeutic method.
  • the kit includes the compound of any one of the formulae described above, or a pharmaceutical composition thereof and a diagnostic agent.
  • the kit includes the compound of any one of the formulae described above, or a pharmaceutical composition thereof.
  • the present disclosure comprises kits that are suitable for use in performing the methods of treatment described herein.
  • the kit contains a first dosage form comprising one or more of the compounds of the present disclosure in quantities sufficient to carry out the methods of the present disclosure.
  • the kit comprises one or more compounds of the present disclosure in quantities sufficient to carry out the methods of the present disclosure and a container for the dosage and a container for the dosage.
  • the compounds of any one of the formulae described above may be prepared by the general and specific methods described below, using the common general knowledge of one skilled in the art of synthetic organic chemistry. Such common general knowledge can be found in standard reference books such as Comprehensive Organic Chemistry, Ed. Barton and Ollis, Elsevier; Comprehensive Organic Transformations: A Guide to Functional Group Preparations, Larock, John Wiley and Sons; and Compendium of Organic Synthetic Methods, Vol. I- XII (published by Wiley-Interscience).
  • the starting materials used herein are commercially available or may be prepared by routine methods known in the art.
  • certain compounds contain primary amines or carboxylic acid functionalities which may interfere with reactions at other sites of the molecule if left unprotected. Accordingly, such functionalities may be protected by an appropriate protecting group which may be removed in a subsequent step.
  • Suitable protecting groups for amine and carboxylic acid protection include those protecting groups commonly used in peptide synthesis (such as N-t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and 9- fluorenylmethylenoxycarbonyl (Fmoc) for amines, and lower alkyl or benzyl esters for carboxylic acids) which are generally not chemically reactive under the reaction conditions described and can typically be removed without chemically altering other functionality in the any one of the formulae described above compounds.
  • Xantpho s 4,5 -B is (diphenylpho sphino) -9 , 9-dimethylxanthene Section 1
  • Step 1 To a solution of tert- butyl (/ran.s'-4-((4-biOmophcnyl)thio)cyclohcxyl)carbamatc (4.90 g, 12.68 mmol) in EA (10 mL) was added HC1/EA (4M, 25.0 mL).
  • Step 2 To a solution of trans-4-((4-bromophenyl)thio)cyclohexan-l -amine (HC1 salt, 3.60 g, 11.16 mmol) and A, A- d i i s o p ro p y 1 c t h y 1 a m i n c (4.33 g, 33.47 mmol, 5.83 mL) in DMF (40 mL) was added 2-fluoro-5-(trifluoromethyl)pyridine (2.21 g, 13.39 mmol).
  • Step 3 To a suspension of trans-N-(4-((4-bromophenyl)thio)cyclohexyl)-5-
  • Step 1 To solution of tert-butyl cw-A/-(4-hydroxycyclohexyl)carbamate (23.00 g, 106.83 mmol), methanesulfonic anhydride (26.05 g, 149.57 mmol) and DMAP (1.31 g, 10.68 mmol) in THF (460 mL) was added dropwise TEA (30.27 g, 299.13 mmol, 41.69 mL) at 0 °C. The mixture was stirred at this temperature for 30 minutes, allowed to warm to room temperature slowly and stirred overnight until the starting material was totally consumed.
  • Step 2 To a solution of cA-4-((tert-butoxycarbonyl)amino)cyclohexyl methanesulfonate (27.50 g, 93.74 mmol) and 4-bromobenzenethiol (17.72 g, 93.74 mmol) in DMF (400 mL) was added cesium carbonate (91.62 g, 281.21 mmol). The mixture was stirred at 100 °C for 3 hours, cooled to room temperature, diluted with water (800 mL) and extracted with ethyl acetate (500 mL x 3).
  • Step 3 To a solution of tert-butyl (trans-4-((4-bromophcnyl)thio)cyclohcxyl (carbamate (19.20 g, 49.70 mmol) in CH2CI2 (300 mL) was added 3-chlorobenzenecarboperoxoic acid (25.73 g, 149.09 mmol). The mixture was stirred at 25 °C for 2 hours until the starting material was totally consumed. The mixture was quenched with Na 2 S0 3 aqueous solution (200 mL, 1M) and extracted with CH2CI2 (150 mL x 3).
  • Step 4 To a solution of crude tert-butyl (trans- 4-((4- bromophenyl)sulfonyl)cyclohexyl)carbamate (14.0 g, 33.47 mmol) in EA (20 mL) was added HC1/EA (4M, 60 mL).
  • Step 5 To a solution of trans-4-((4-bromophenyl)sulfonyl)cyclohexan- 1-amine (HC1 salt, 12.80 g, 40.22 mmol) and A,A-diisopropylcthylaminc (15.60 g, 120.67 mmol, 21.02 mL) in DMF (60 mL) was added 2-fluoro-5-(trifluoromethyl)pyridine (7.97 g, 48.27 mmol). The mixture was stirred at 100 °C for 6 hours, cooled to room temperature, diluted with water (120 mL) and extracted with EA (200 mL x 2).
  • Step 6 To a suspension of trans-4- (4 - ((4 - b ro m o p h c n y 1 ) s u 1 fo n y 1 ) c y c 1 o h c x y 1 ) - 5 - (trifluoromethyl)pyridin-2-amine (6.30 g, 13.60 mmol) and potassium acetate (2.80 g, 28.56 mmol) in dioxane (65 mL) were added Pd(dppf)Cl2 (497.5 mg, 679.89 ⁇ mol ) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (3.63 g, 14.28 mmol).
  • Step 1 To a stirred solution of tert- butyl ⁇ trans- 4-((4- bromophenyl)sulfonyl)cyclohexyl)carbamate (2.0 g, 4.78 mmol) and 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.46 g, 5.74 mmol) in 1,4-dioxane (40 mL) were added potassium acetate (1.41 g, 14.34 mmol) and Pd(dppf)Cl2 (349.8 mg, 478.07 ⁇ mol).
  • Step 2 To a stirred solution of tert-butyl (trans-4-((4-(4,4,5,5-tctramcthyl- 1 ,3,2-dioxaborolan- 2-yl)phenyl)sulfonyl)cyclohexyl)carbamate (2.2 g, 4.73 mmol) and 4-chloropicolinamide (888.1 mg, 5.67 mmol) in mixed solvent of 1,4-dioxane (40 mL) and H2O (10 mL) were added potassium phosphate (3.01 g, 14.18 mmol) and Pd(dppf)Cl2 (345.9 mg, 472.70 ⁇ mol).
  • Step 3 To a stirred solution of tert- butyl (trans-4-((4-(2-carbamoylpyndin-4- yl)phenyl)sulfonyl)cyclohexyl)carbamate (2.0 g, 4.35 mmol) in DCM (40 mL) was added HC1/EA (4M, 20 mL). The mixture was stirred at 25 °C for 1 hour, and concentrated in vacuo to give 4-(4-((trans-4-aminocyclohcxyl)suironyl)phcnyl)picolinamidc (1.6 g, quantitative) as a white solid.
  • Step 4 To a stirred solution of 4-(4-((trans-4-aminocyclohcxyl)suironyl)phcnyl)picolinamidc (200 mg, 556.42 ⁇ mol) and 2,3-difluoro-5-(trifluoromethyl)pyridine (112.1 mg, 612.06 ⁇ mol, 76.2 ⁇ L) in DMF (4.0 mL) was added DIPEA (287.7 mg, 2.23 mmol, 387.7 ⁇ L). The mixture was stirred at 100 °C for 4 hours, diluted with water (10 mL) and extracted with EA (30 mL x 3).
  • Step 1 To a solution of 3-chloro-6-(trifluoromethyl)pyridazine (182.5 mg, 1.0 mmol) and l ra n ,v - 4 - ((4 - h ro in o p h c n y 1 ) s u 1 fo n y 1 ) c y c 1 o h c x a n - 1 - a m i n c (349.8 mg, 986.1 , HC1 salt) in ⁇ mol NMP (4 mL) was added DIPEA (318.6 mg, 2.5 mmol, 429.4 ⁇ L).
  • Step 2 To a solution of / ran s - A- (4 - ((4 - h ro m o p h c n y 1 ) s u 1 fo n y 1 ) c y c 1 o h c x y 1 ) - 6 -
  • Step 3 To a solution of 4-bromopyridine-2-carboxamide (86.5 mg, 430.2 ⁇ mo)l and trans-N- (4-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)cyclohexyl)-6- (trifluoromethyl)pyridazin-3-amine (330 mg, 645.3 ⁇ mo)l in dioxane/water (9 mL, 8/1) were added Pd(dppf)Cl2 (63.0 mg, 86.0 ⁇ mo)l and K2CO3 (178.4 mg, 1.3 mmol).
  • 5-Dimethylphosphoryl-2-fluoro-pyridine was synthesized as below: To a solution of 5-bromo- 2-fluoro-pyridine (2.0 g, 11.3 mmol, 1.2 mL), dimethylphosphine oxide (975.7 mg, 12.5 mmol) in dioxane (20 mL) were added palladium (II) acetate (510.2 mg, 2.2 mmol), XantPhos (2.0 g, 3.4 mmol) and potassium phosphate (4.8 g, 22.7 mmol). The mixture was stirred at 110 °C under N2 atmosphere for 16 hours, cooled to room temperature and filtered.
  • Step 1 To a solution of 4-bromopyridine-2-carboxamide (252.1 mg, 1.2 mmol) and int. 1 (400 mg, 836.1 ⁇ mol) in mixed solvent of dioxane (5 mL), ethanol (3 mL) and water (1 mL) were added Pd(dppf)Cl2 (91.8 mg, 125.4 ⁇ mo)l and potassium carbonate (346.7 mg, 2.5 mmol). The mixture was stirred at 110 °C under N2 atmosphere for 16 hours, cooled to room temperature and filtered through a Celite pad.
  • Step 2 To a mixture of 4-(4-((irans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)thio)phenyl)picolinamide (170 mg, 359.7 ⁇ mol ) and ammonium carbamate (70.2 mg, 899.4 ⁇ mo)l in methanol (10 mL) was added iodobenzene diacetate (231.7 mg, 719.5 ⁇ mo)l. The mixture was stirred at 25 °C for 15 minutes and concentrated in vacuo.
  • Example 7 SFC chiral separation of Example 7 provided enantiomers of 4-(4-(trans-4-((5- (trifluoromethyl)pyridin-2-yl)amino)cyclohexane-l-sulfonimidoyl)phenyl)picolinamide. The stereochemistry was not confirmed, and two products were arbitrarily assigned.
  • Example 7A LC-MS (ESI) [(M+H)+] : 504.1. Chiral-HPLC retention time: 2.428 min; ee value: > 99%.
  • Example 7B LC-MS (ESI) [(M+H)+] : 504.1. Chiral-HPLC retention time: 3.362 min; ee value: > 99%.
  • Step i To a mixture of / ⁇ ? / 7-butyl (7f ⁇ ms'-4-((4-bromophcnyl)thio)cyclohcxyl (carbamate (1.5 g, 3.9 mmol) and ammonium carbamate (909.3 mg, 11.7 mmol) in methanol (15 mL) was added iodobenzene diacetate (3.8 g, 11.7 mmol). The mixture was stirred at 25 °C for 30 minutes and concentrated in vacuo.
  • Step 2 To a solution of tert-butyl (/ran.s'-4-(4- bromophenylsulfonimidoyl)cyclohexyl)carbamate (1.3 g, 3.1 mmol) in DML (10 mL) was added NaH (60% dispersion in mineral oil, 211.8 mg, 5.3 mmol) at 0 °C. The mixture was stirred at 0 °C for 10 minutes, followed by the addition of iodomethane (455.4 mg, 3.2 mmol, 199.7 ⁇ L). The mixture was stirred at 20 °C for 3 hours., quenched with water (50 mL) and extracted with EtOAc (50 mL x 2).
  • Step 3 To a solution of tert- butyl ( / ran.s' - 4 - ( 4 - b ro m o - N- methylphenylsulfonimidoyl)cyclohexyl)carbamate (700 mg, 1.6 mmol) in DCM (5 mL) was added HC1/EA (4M, 15 mL).
  • Step 4 ⁇ To a solution of (iran5-4-aminocyclohexyl)(4-bromophenyl)(methylimino)-X 6 - sulfanone (560 mg, 1.5 mmol, HC1 salt) in DMF (8 mL) were added DIPEA (984.1 mg, 7.6 mmol, 1.3 mL) and 2-fluoro-5-(trifluoromethyl)pyridine (326.8 mg, 2.0 mmol). The mixture was stirred at 90 °C for 8 hours and concentrated in vacuo.
  • Step 5 To a solution of (4-bromophcnyl)(mcthylimino)(trans-4-((5-(tnfhioromcthyl)pyndin- 2-yl)amino)cyclohexyl)- X 6 -sulfanone (250 mg, 524.8 ⁇ mo)l and 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(l,3,2-dioxaborolane) (199.9 mg, 787.2 ⁇ mol ) in dioxane (10 mL) were added Pd(dppf)Cl2 (76.8 mg, 105.0 ⁇ mo)l and potassium acetate (206.0 mg, 2.1 mmol) under the atmosphere of N2.
  • Step 6 To a solution of 4-bromopyridine-2-carboxamide (107.5 mg, 535.0 ⁇ mol) and (methylimino)(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)(/ra775-4-((5- (trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)- X 6 -sulfanone (280 mg, 535.0 ⁇ mol ) in mixed solvent of dioxane (10 mL), ethanol (10 mL) and water (0.6 mL) were added Pd(dppf)Cl2 (78.3 mg, 107.
  • Step 1 To a solution of 6-bromoisoindolin-l-one (56.1 mg, 264.5 ⁇ mo)l and int. 3 (135 mg, 264.5 m mol) in mixed solvent of dioxane (6 mL), ethanol (6 mL) and water (0.5 mL) were added Pd(dppf)Cl2 (38.7 mg, 52.9 ⁇ mo)l and sodium carbonate (84.1 mg, 793.5 ⁇ mol). The mixture was stirred at 110 °C under N2 atmosphere for 5 hours, cooled to room temperature and filtered through a Celite pad.
  • Step 1 A mixture of 6-bromoisoindolin-l-one (100 mg, 442.34 miho ⁇ ), tetrakis(triphenylphosphine) palladium (153.4 mg, 132.70 ⁇ mo)l, int. 1 (253.9 mg, 530.81 pmol) and sodium carbonate (117.2 mg, 1.11 mmol) in dioxane/water (2 mL, 4/1) was stirred at 100 °C for 1 hour under N2 atmosphere, cooled to room temperature, and diluted with ethyl acetate (20 mL). The resulting mixture was washed with H2O (10 mL x 3). The organic layer was dried over anhydrous Na 2 S0 4 and filtered.
  • 6-bromoisoindolin-l-one 100 mg, 442.34 miho ⁇
  • tetrakis(triphenylphosphine) palladium 153.4 mg, 132.70 ⁇ mo)l
  • int. 1 25
  • Step 2 To a mixture of 7-(4-((irans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)thio)phenyl)-3,4-dihydroisoquinolin-l(27/)-one (120 mg, 241.17 ⁇ mo)l and ammonium carbamate (37.7 mg, 482.34 ⁇ mo)l in methanol (4 mL) was added iodobenzene diacetate (156.3 mg, 482.34 ⁇ mol). The mixture was stirred at 25 °C for 30 minutes and concentrated in vacuo.
  • Step 1 To a solution of 3 - b ro m o - 7 , 8 - d i h yd ro - 6 /7- L 6 - n a p h t h y ri d i n - 5 - o n c (88.1 mg, 388.0 pmol) and int. 3 (198 mg, 388.0 p mol) in mixed solvent of dioxane (15 mL), ethanol (15 mL) and water (3 mL) were added Pd(dppf)Cl2 (56.8 mg, 77.6 ⁇ mol) and sodium carbonate (82.2 mg, 775.9 ⁇ mo)l.
  • Step 1 To a solution of 3 - b ro m o - 7 , 8 - d i h yd ro - 6 //- 1 , 6 - n a p h t h y ri d i n - 5 - o n c (91.1 mg, 401.4 p mol) and int.
  • Step 2 To a mixture of 3-(4-((irans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohcxyl)thio)phcnyl)-7,8-di hydro- 1 ,6-naphthyridin-5(6//)-onc (120.0 mg, 240.7 pmol) and ammonium carbamate (37.6 mg, 481.4 ⁇ mo)l in methanol/DCM (4 mL, 3/1) was added iodobenzene diacetate (155.1 mg, 481.4 ⁇ mo)l. The mixture was stirred at 25 °C for 30 minutes and concentrated in vacuo.
  • Step 1 To a solution of 7-hromo-4/7-isoquinolinc- 1 ,3-dionc (22.4 mg, 93.5 p mol) and int.
  • Step 7 To a solution of 7-bromo-2T7-isoquinolin-l-one (35.1 mg, 156.7 ⁇ mo)l and int. 3 (80 mg, 156.7 ⁇ mol) in mixed solvent of dioxane (2.5 mL), ethanol (1 mL) and water (0.5 mL) were added Pd(dppf)Cl2 (17.2 mg, 23.5 ⁇ mo) l and potassium carbonate (65.0 mg, 470.2 ⁇ mo)l. The mixture was stirred at 110 °C under N2 atmosphere for 3 hours, cooled to room temperature and filtered through a Celite pad.
  • Step 1 To a solution of 7-bromo-3,4-dihydro-2//-isoquinolin-l-one (120 mg, 530.8 ⁇ mo)l in anhydrous DMF (5 mL) was added NaH (60% dispersion in mineral oil, 106.2 mg, 2.7 mmol) at 0 °C. The mixture was stirred at 0 °C for 10 minutes, and iodomethane (226.0 mg, 1.6 mmol, 99.1 ⁇ L) was added thereto. The mixture was stirred at 20 °C for 3 hours, quenched with water (50 mL) and extracted with EtOAc (50 mL x 2).
  • Step 2 To a solution of 7-bromo-2-mcthyl-3,4-dihydroisoquinolin- 1 (2/7)-onc (45 mg, 187.4 pmol) and int. 3 (90 mg, 176.3 ⁇ mo)l in mixed solvent of dioxane (65 mL), ethanol (6mL) and water (0.3 mL) were added Pd(dppf)Cl2 (25.8 mg, 35.3 ⁇ mo)l and sodium carbonate (56.1 mg, 529.0 ⁇ mol). The mixture was stirred at 110 °C under N2 atmosphere for 5 hours, cooled to room temperature and filtered through a Celite pad.
  • Step 1 To a solution of 6-bromo-3 ,4-di hydro-2/7-i soqui nol i n- 1 -one (35.4 mg, 156.7 m mol) and int. 3 (80 mg, 156.7 m mol) in mixed solvent of dioxane (2.5 mL), ethanol (2 mL) and water (1 mL) were added Pd(dppf)Cl2 (17.2 mg, 23.5 ⁇ mo)l and potassium carbonate (66.0 mg, 470.2 pmol). The mixture was stirred at 110 °C under N2 atmosphere for 3 hours, cooled to room temperature and filtered through a Celite pad.
  • Step 1 To a solution of 7-bromo-l,2,3,4-tetrahydroisoquinoline hydrochloride (54 mg, 220 miho ⁇ ) and int. 3 (112 mg, 0.2 mmol) in mixed solvent of dioxane (10 mL), ethanol (10 mL) and water (1 mL) were added Pd(dppf)Cl2 (32 mg, 44 ⁇ mo)l and sodium carbonate (140 mg, 1.3 mmol). The mixture was stirred at 110 °C under N2 atmosphere for 5 hours, cooled to room temperature and filtered through a Celite pad.
  • Step 1 To a solution of / ⁇ ? /7 -butyl 6-bromo-3,4-dihydiO-l /7-isoqui noli nc-2-carboxy late (137.6 mg, 440.9 ⁇ mol) and int. 3 (225 mg, 440.9 ⁇ mo)l in mixed solvent of dioxane (10 mL) and water (0.5 mL) were added Pd(dppf)Cl2 (64.5 mg, 88.2 ⁇ mo)l and potassium carbonate (182.9 mg, 1.3 mmol). The mixture was stirred at 110 °C under N2 atmosphere for 5 hours, cooled to room temperature and filtered through a Celite pad.
  • Step 2 To a solution of tert-butyl 6-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- y l)amino)cyclohcxyl)sul I ' ony l)phcnyl)-3,4-dihydroisoqui nol i nc-2( l /7)-carboxy late (115 mg, 186.8 ⁇ mol) in DCM (5 mL) was added HC1/EA (4M, 3 mL). The reaction mixture was stirred at room temperature for 12 hours and concentrated in vacuo.
  • Step 1 To a solution of methyl 4-bromopyridine-2-carboxylate (5 g, 23.1 mmol) in DCM (100 mL) was added 3-chlorobenzenecarboperoxoic acid (12.0 g, 69.4 mmol) at 0 °C. The mixture was stirred at 25 °C for 36 hours and quenched with NaHC0 3 aqueous solution (2M, 100 mL). The two phases were separated, and the organic phase was washed with Na 2 S 2 0 3 aqueous solution (2M, 100 mL) and brine (40 mL x 2), dried over anhydrous Na 2 S0 4 and filtered.
  • Step 2 To a solution of methyl 4-bromo-2-(methoxycarbonyl)pyridine 1-oxide (3.4 g, 14.6 mmol) in THF (40 mL) were added triethylamine (7.3 g, 71.8 mmol, 10.0 mL) and TFAA (3.7 g, 17.6 mmol, 2.5 mF) at 0 °C. The mixture was stirred at 25 °C for 3 hours and concentrated in vacuo.
  • Step 3 To a solution of methyl 4-bromo-6-oxo-l,6-dihydropyridine-2-carboxylate (1.3 g, 5.6 mmol) in methanol (20 mF) was added 2-(benzylamino)ethanol (931.8 mg, 6.2 mmol, 879.1 pF) at 25 °C. The mixture was stirred under reflux for 36 hours and concentrated in vacuo.
  • Step 4 To a solution of N-benzyl-4-bromo-/V-(2-hydroxyethyl)-6-oxo-l,6-dihydropyridine-2- carboxamide (3.5 g, 10.0 mmol) in DCM (50 mL) were added DIPEA (3.9 g, 29.9 mmol, 5.2 mL) and HATU (4.6 g, 12.0 mmol). The mixture was stirred at 25 °C for 40 hours, diluted with water (50 mL) and extracted with DCM (100 mL x 3). The combined organic layer was washed with brine (20 mL x 3), dried over anhydrous Na 2 SO 4 and filtered.
  • DIPEA 3.9 g, 29.9 mmol, 5.2 mL
  • HATU 4.6 g, 12.0 mmol
  • Step 5 To a solution of 2-bcnzyl-8-biOmo-3,4-dihydro-2/7-pyndo[ 1 ,2-aJpyrazinc- 1 ,6-dionc (2.3 g, 6.9 mmol) in toluene (50 mL) was added trifluoromethanesulfonic acid (5.2 g, 34.5 mmol, 3.0 mL). The mixture was stirred at 110 °C for 26 hours, cooled to room temperature and concentrated in vacuo. The residue was diluted with DCM (50 mL), washed with saturated NaHCCL aqueous solution (100 mL x 3), dried over anhydrous sodium sulfate, and filtered.
  • Step 6 To a stirred solution of int. 3 (100.0 mg, 195.93 ⁇ mo)l and 8 - b ro m o - 3 , 4 - d i h y d ro - 277- pyrido[l,2-(3]pyrazine-l,6-dione (57.2 mg, 235.12 ⁇ mo)l in mixed solvent of 1,4-dioxane (4.0 mL) and water (1 mL) was added potassium phosphate (124.8 mg, 587.80 ⁇ mo)l, RuPhos Pd G2 (15.2 mg, 19.59 ⁇ mo)l.
  • reaction mixture was stirred at 100 °C under N2 atmosphere for 2 hours, cooled to room temperature, diluted with EA (100 mL) and washed with brine (30 mL x 3). The organic phase was dried over anhydrousNa 2 SO 4 and filtered.
  • Step 1 To a stirred solution of int. 1 (187.5 mg, 391.87 p mol) and 8 - b ro m o - 3 , 4 - d i h y d ro - 2 /7- pyrido[l,2-(3]pyrazine-l,6-dione (142.9 mg, 587.80 ⁇ mo)l in mixed solvent of 1,4-dioxane (8 mL) and water (2 mL) was added potassium phosphate (249.6 mg, 1.18 mmol), RuPhos Pd G2 (30.5 mg, 39.19 ⁇ mo)l.
  • reaction mixture was stirred at 100 °C under N2 atmosphere for 2 hours, cooled to room temperature, diluted with EA (40 mL) and washed with brine (10 mL x 3). The organic phase was dried over anhydrousNa 2 SO 4 and filtered.
  • Step 2 To a solution of 8-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)thio)phenyl)-3 ,4-dihydro-2H-pyrido[ 1 ,2-aJpyrazinc- 1 ,6-dione (100 mg, 194.34 ⁇ mol) and ammonium carbamate (30.3 mg, 388.68 ⁇ mo)l in MeOH (3 mL) was added iodobenzene diacetate (125.2 mg, 388.68 ⁇ mo)l. The mixture was stirred at 25 °C for 0.5 hour and concentrated in vacuo.
  • Step 1 To a stirred solution of 7-bromo-2//-isoquinolin- 1 -one (2.00 g, 8.93 mmol) in MeCN/Water (22 mL, 10/1) was added selectfluor (3.48 g, 9.82 mmol). The reaction mixture was stirred at 30 °C overnight, diluted with 20 mL of water, and extracted with DCM (20 mL x 3). The combined organic layer was dried over anhydrous Na 2 SO 4 and filtered.
  • Step 2 To a stirred solution of 7-bromo-4-fluoro-3-hydroxyisoquinolin-l(2//)-one (1.50 g, 5.77 mmol) in DCM (15 mL) was added methanesulfonic acid (2.77 g, 28.84 mmol, 1.87 mL). The reaction mixture was stirred at room temperature overnight, diluted with DCM (20 mL) and washed with water (20 mL) and brine (20 mL). The organic phase was dried over anhydrousNa 2 SO 4 and filtered.
  • Step 3 To a stirred solution of 7-bromo-4- I ⁇ uoroi soqui nol i n- 1 (2/7)-onc (500.0 mg, 2.07 mmol) in MeCN/Water (22 mL, 10/1) was added selectfluor (804.4 mg, 2.27 mmol). The reaction mixture was stirred at 30 °C overnight, diluted with 20 mL of water, and extracted with DCM (20 mL x 3). The combined organic layer was dried over anhydrous Na 2 SO 4 and filtered.
  • Step 4 ⁇ To a stirred solution of 7-bromo-4,4-difluoro-3-hydroxy-3,4-dihydroisoquinolin- l(27/)-one (300.0 mg, 1.08 mmol) in DCM (10 mL) were added methanesulfonic acid (414.8 mg, 4.32 mmol, 280.3 ⁇ L) and triethyl silane (627.3 mg, 5.39 mmol, 861.7 ⁇ L). The reaction mixture was stirred at room temperature overnight, quenched with saturated sodium bicarbonate aqueous solution (15 mL), and extracted with DCM (30 mL x 3).
  • Step 5 A mixture of 7-bromo-4,4-difluoro-3,4-dihydroisoquinolin-l(27/)-one (50.0 mg, 190.80 ⁇ mol), int. 3 (97.4 mg, 190.80 ⁇ mo)l, Pd(PPh 3 ) 2 Cl 2 (25.0 mg, 35.66 ⁇ mo) l and K2CO3 (88.0 mg, 637.68 ⁇ mol) in dioxane/water (10 mL, 3/1) was stirred at 100 °C under N2 atmosphere for 4 hours, cooled to room temperature, diluted with ethyl acetate (20 mL) and washed with water (10 mL x 3).
  • Step 1 A mixture of 7-bromo-4,4-di I ⁇ uoro-3 ,4-di hydroi soqui nol i n- 1 (2/7)-onc (50 mg, 190.80 pmol), int. 1 (91.3 mg, 190.80 ⁇ mo)l, Pd(PPh3)2Cl2 (27 mg, 38.52 ⁇ mo)l and K2CO3 (79 mg, 572.46 ⁇ mol) in dioxane/water (6 mL, 2/1) was stirred at 100 °C under N2 atmosphere for 4 hours, cooled to room temperature, diluted with ethyl acetate (20 mL) and washed with water (10 mL x 3).
  • Step 2 To a mixture of 4,4-difluoro-7-(4-((/rarz5-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)thio)phenyl)-3,4-dihydroisoquinolin-l(2//)-one (30 mg, 56.23 ⁇ mo)l and ammonium carbamate (8.8 mg, 112.45 ⁇ mo)l in methanol (5 mL) was added iodobenzene diacetate (36.5 mg, 112.45 ⁇ mol).
  • Step 1 To a solution of 6-bromoisoindolin-l-one (56.1 mg, 264.5 ⁇ mo)l and int. 3 (135 mg, 264.5 ⁇ mol) in mixed solvent of dioxane (6 mL), ethanol (6 mL) and water (0.5 mL) were added Pd(dppf)Cl2 (38.7 mg, 52.9 ⁇ mo)l and sodium carbonate (84.1 mg, 793.5 ⁇ mol). The mixture was stirred at 110 °C under N2 atmosphere for 5 hours, cooled to room temperature and filtered through a Celite pad.
  • Step 1 To a solution of 6-bromoisoindolin-l-one (178.2 mg, 840.3 ⁇ mo)l and int. 1 (335 mg, 700.3 p mol) in mixed solvent of dioxane (10 mL), ethanol (10 mL) and water (0.5 mL) were added Pd(dppf)Cl2 (102.5 mg, 140.06 ⁇ mo)l and sodium carbonate (222.7 mg, 2.1 mmol). The mixture was stirred at 110 °C under N2 atmosphere for 7 hours, cooled to room temperature and filtered through a Celite pad.
  • Step 2 To a solution of 6-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)thio)phenyl)isoindolin-l-one (130 mg, 268.9 ⁇ mol) and ammonium carbamate (63.0 mg, 806.5 ⁇ mo)l in methanol (15 mL) was added PhI(OAc)2 (259.8 mg, 806.5 pmol). The reaction mixture was stirred at room temperature for 50 minutes and concentrated in vacuo.
  • Step 1 A solution of 5-bromopyridine-2,3-dicarboxylic acid (2.5 g, 10.2 mmol) in acetic anhydride (4 mL) was stirred at 120 °C for 3 hours. To the above mixture was added ammonia acetate (1.7 g, 22.4 mmol) at 25 °C. The resulting mixture was stirred at 100 °C for another 2 hours and concentrated in vacuo.
  • Step 2 To a solution of 3-bromo-57/-pyrrolo[3,4-h]pyridine-5,7(67/)-dione (1.4 g, 6.2 mmol) in methanol (100 mL) and DCM (100 mL) was added NaBH4 (186.6 mg, 4.9 mmol) at -40 °C. The mixture was stirred at -40 °C for 1 hour, quenched with HC1 aqueous solution (2M, 10 mL) and concentrated in vacuo.
  • Step 3 To a solution of 3-bromo-7-hydroxy-6,7-dihydro-5//-pyrrolo[3,4-h]pyridin-5-one (350.0 mg, 1.5 mmol) in DCM (1 mL) were added 2,2,2-trifluoroacetic acid (7.4 g, 64.9 mmol, 5 mL) and triethyl silane (3.6 g, 31.3 mmol, 5 mL). The mixture was stirred at 25 °C for 16 hours and concentrated in vacuo.
  • Step 4 ⁇ To a solution of 3-bromo-6,7-dihydro-57/-pyrrolo[3,4-h]pyridin-5-one (40.0 mg, 187.7 pmol) and int. 3 (80.4 mg, 187.7 ⁇ mo)l in mixed solvent of dioxane (5 mL) and water (0.5 mL) were added Pd(dppf)Cl2 (20.6 mg, 28.2 ⁇ mo)l and sodium carbonate (59.7 mg, 563.3 ⁇ mo)l. The mixture was stirred at 110 °C under N2 atmosphere for 8 hours, cooled to room temperature and filtered through a Celite pad.
  • Step 1 Under microwave conditions, a mixture of int. 2 (50.0 mg, 107.92 m mol), 8-methoxy- 1,2,3,4-tetrahydroisoquinoline (17.6 mg, 107.92 ⁇ mol), Pd2(dba)3 (14.8 mg, 16.2 ⁇ mol), RuPhos (10.1 mg, 21.6 ⁇ mo)l and CS2CO3 (105.3 mg, 324 ⁇ m)o iln dioxane (5 mL) was stirred at 100 °C under the atmosphere of N2 for 2 hours, cooled to room temperature, and filtered through a pad of Celite.
  • Step 1 To a solution of 4-iodo-2-methoxy-pyridine-3-carbaldehyde (410.0 mg, 1.6 mmol) and ethynyl(trimethyl) silane (306.2 mg, 3.1 mmol, 440.6 ⁇ L) in THF (5 mL) were added TEA (473.2 mg, 4.7 mmol, 651.8 ⁇ L), Cul (29.7 mg, 155.8 ⁇ mol ) and bis(triphenylphosphine)palladium(II) chloride (109.4 mg, 155.8 ⁇ mol).
  • Step 2 To a solution of 2-methoxy-4-(2-trimethylsilylethynyl) pyridine-3-carbaldehyde (200 mg, 857.1 ⁇ mol) in methanol (5 mL) was added NEL/MeOH (2M, 5 mL). The mixture was stirred at 50 °C for 3 hours and concentrated in vacuo to give l-methoxy-2,7-naphthyridine (130 mg, crude) as black oil.
  • Step 3 To a solution of l-methoxy-2,7-naphthyridine (220 mg, 1.4 mmol) in mixed solvent of methanol (2.5 mL) and acetic acid (1 mL) was added 10% Pd/C (100 mg). The mixture was degassed with Eb and stirred at 25 °C for 16 hours and filtered through a Celite pad. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with methanol in dichloromethane from 0 to 20%) to give 8-methoxy-l,2,3,4- tetrahydro-2,7-naphthyridine (200 mg, impure) as a red solid. LC-MS (ESI) [(M+H) + ]: 165.1.
  • Step 4 ⁇ A mixture of int. 2 (176.4 mg, 380.6 ⁇ mol), 8-methoxy-l,2,3,4-tetrahydro-2,7- naphthyridine (100.0 mg, 609.0 ⁇ mo)l, Pd2(dba)3 (34.8 mg, 38.1 ⁇ mo),l RuPhos (35.5 mg, 76.1 pmol) and CS 2 CO 3 (372.0 mg, 1.1 mmol) in dioxane (5 mL) was stirred at 110 °C under the atmosphere of N2 for 3 hours, cooled to room temperature, and filtered through a pad of Celite. The solid cake was washed with ethyl acetate (20 mL), and the combined filtrate was concentrated in vacuo.
  • Step 1 To a solution of iran,s'-/V-(4-((4-(8-methoxy-3,4-dihydro-2,7-naphthyridin-2(l//)- yl)phenyl)sulfonyl)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine (30.0 mg, 54.9 ⁇ mol) in DMF (5 mL) were added 4-methylbenzenesulfonic acid (9.5 mg, 54.9 ⁇ mol) and lithium chloride (2.3 mg, 54.9 ⁇ mo)l. The mixture was stirred at 120 °C for 1 hour and concentrated in vacuo.
  • 4-Bromo-3-fluorobenzenethiol was synthesized as below: To a stirred solution 4-bromo-3- fluoro-benzenesulfonyl chloride (2.0 g, 7.31 mmol, 1.08 mL) in toluene was added triphenylphosphine (7.67 g, 29.25 mmol). The reaction mixture was stirred at room temperature for 15 minutes, diluted with water (10 mL) and stirred for 10 minutes. The two phases were separated, and the organic phase was washed with 10% NaOH aqueous solution (25 mL x 2).
  • Step 1 Under microwave conditions, a mixture of trans-N- ⁇ 4- ⁇ 4- bromophenyl)thio)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine (131.3 mg, 304.50 ⁇ mo)l, 8-methoxy-l,2,3,4-tetrahydro-2,7-naphthyridine (50 mg, 304.50 ⁇ mol), Pd2(dba)3 (55.7 mg, 60.90 ⁇ mol), RuPhos (42.6 mg, 91.35 ⁇ mo)l and CS2CO3 (296.9 mg, 913.50 ⁇ m)o iln dioxane (10 mL) was stirred at 110 °C under the atmosphere of N2 for 2 hours, cooled to room temperature, and filtered through a pad of Celite.
  • Step 2 A mixture of irans-A-(4-((4-(8-rnethoxy-3,4-dihydro-2,7-naphthyridin-2(l//)- yl)phenyl)thio)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine (40 mg, 77.73 ⁇ mol), TsOH (20.2 mg, 388.65 ⁇ mo)l and LiCl (16.5 mg, 388.65 ⁇ mo)l in DMF (3 mL) was stirred at 120 °C for 2 hours and concentrated in vacuo.
  • Step 3 To a mixture of 7-(4-((irans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)thio)phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-l(2//)-one (25 mg,
  • Step 1 To a solution of 4-methylpyridine-3-carbonitrile (2.00 g, 16.93 mmol) in DMF (10 mL) was added DMF-DMA (6.04 g, 50.79 mmol). The reaction mixture was stirred at 110 °C in a sealed tube overnight and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with EA/PE from 0 to 100%) to give (£)-4-(2- (dimethylamino)vinyl)nicotinonitrile (1.80 g, 61% yield) as colorless oil. LC-MS (ESI) [(M+H) + ] : 174.2.
  • Step 2 To a solution of (E)-4-(2-(di methyl ami no) vinyl)nicotinonitrilc (1.80 g, 10.39 mmol) in acetic acid (10 mL) was added ammonium formate (5.24 g, 83.13 mmol). The mixture was stirred at 115 °C for 4 hours, cooled to room temperature, and diluted with 3 ⁇ 40 (10 mL), which was basified with ammonia hydroxide aqueous solution (20 mL) and then extracted with DCM (30 mL x 3). The organic phases were dried over anhydrous sodium sulfate and filtered.
  • Step 3 To a solution of 2,7-naphthyridin-l -amine (800.0 mg, 5.51 mmol) in acetic acid (10 mL) was added small portions of NaBPL (416.6 mg, 11.02 mmol). The resulting mixture was stirred at room temperature until completed, poured into ice, basified with ammonia hydroxide aqueous solution (20 mL) and then extracted with DCM (30 mL x 3). The organic layers were washed with water (50 mL), dried over anhydrous sodium sulfate, and filtered.
  • Step 4 ⁇ Under microwave conditions, a mixture of int. 2 (93.0 mg, 200.73 ⁇ mol), 5, 6,7,8- tetrahydro-2,7-naphthyridin-l -amine (30.0 mg, 201.08 ⁇ mol), Pd2(dba)3 (28.0 mg, 30.60 pmol), RuPhos (20.0 mg, 42.92 ⁇ mo)l and CS2CO3 (196.0 mg, 603.08 ⁇ m)o iln dioxane (5 mL) was stirred at 100 °C under the atmosphere of N2 for 2 hours, cooled to room temperature, and filtered through a pad of Celite.
  • Step 1 To a stirred solution of 7-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-l-amine (30 mg, 56.43 ⁇ mol) in acetic acid (3 mL) were added sodium nitrite (3.9 mg, 56.43 ⁇ mo)l and copper(I) cyanide (5.1 mg, 56.43 ⁇ mo)l. The resulting mixture was stirred at room temperature for 1 hour, basified with NaOH aqueous solution (10M, 9 mL) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with methanol/DCM from 0 to 20%) and prep-HPLC to give T-(4-((trans-4-((5-
  • Step 1 To a solution of 5-bromoisoquinolin-l-amine (49 mg, 220 ⁇ mol) and int. 3 (112 mg, 200 ⁇ mol) in mixed solvent of dioxane (10 mL), ethanol (10 mL) and water (1 mL) were added Pd(dppf)Cl2 (32 mg, 44 ⁇ mo)l and sodium carbonate (70 mg, 660 ⁇ mol). The mixture was stirred at 110 °C under N2 atmosphere for 5 hours, cooled to room temperature and filtered through a Celite pad.
  • Step 1 To a mixture of int. 3 (100 mg, 195.93 p mol) and 3-(3-bromophenyl)oxetan-3-amine hydrochloride (51.8 mg, 195.93 p mol) in mixed solvent of dioxane and H2O (4/1, 3.0 mL) were added potassium carbonate (81.2 mg, 587.80 ⁇ mo)l and Pd(dppf)Cl2 (14.3 mg, 19.59 ⁇ mo)l. The mixture was degassed with N2, and stirred at 100 °C under microwave conditions for an hour, until the starting material was totally consumed.
  • reaction mixture was filtered through a pad of silica gel, and washed with ethyl acetate (10 mL x 2). The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with EtOAc/petroleum ether, 0/1— 100%, v/v) and prep-HPLC to afford trans-N- (4-((3'-(3-aminooxetan-3-yl)-[l,r-biphenyl]-4-yl)sulfonyl)cyclohexyl)-5- (trifluoromethyl)pyridin-2-amine (18 mg, 19% yield) as a white solid.
  • Step 1 To a solution of 2,4-dibromopyridine (1.0 g, 4.22 mmol) in anhydrous toluene (15 mL) was added dropwise n-butyl lithium hexane solution (2.5M, 5.00 mmol, 2 mL) at -78 °C. The reaction mixture was stirred for 20 minutes at this temperature, followed by the dropwise addition of the solution of 2-methyl- V-(oxetan-3-ylidene)propane-2-sulfinamide (739.8 mg, 4.22 mmol) in 1 mL of anhydrous toluene.
  • Step 3 To a mixture of int. 3 (100 mg, 195.93 ⁇ mol) and 3-(4-bromo-2-pyridyl)oxetan-3- amine (44.9 mg, 169.09 ⁇ mo,l HC1 salt) in mixed solvent of dioxane and H2O (4/1, 3.0 mL) were added potassium carbonate (81.2 mg, 587.80 ⁇ mo)l and Pd(dppf)Cl2 (14.3 mg, 19.59 pmol). The mixture was degassed with N2, and stirred at 100 °C under microwave conditions for an hour, until the starting material was totally consumed.
  • Step 1 To a mixture of int. 1 (100 mg, 209.04 miho ⁇ ) and 3-(4-bromo-2-pyridyl)oxetan-3- amine (58.3 mg, 219.49 p mol, HC1 salt) in mixed solvent of dioxane and thO (4/1, 3.0 mL) were added potassium carbonate (86.7 mg, 627.12 ⁇ mo)l and Pd(dppf)Cl2 (15.3 mg, 20.90 pmol).
  • the mixture was degassed with N2, and stirred at 110 °C under microwave conditions for an hour, until the starting material was totally consumed.
  • the reaction mixture was filtered through a pad of silica gel, and washed with ethyl acetate (10 mL x 2).
  • Step 2 To a mixture of /ran.s-/V-(4-((4-(2-(3-aminooxctan-3-yl)pyridin-4- yl)phenyl)thio)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine (70 mg, 139.84 ⁇ mol) and ammonium carbamate (21.8 mg, 279.68 ⁇ mol ) in MeOH (3 mL) was added (diacetoxyiodo)benzene (90.1 mg, 279.68 ⁇ mol). The mixture was stirred at 25 °C for 15 minutes until the reaction was completed, and concentrated in vacuo.
  • Step 1 A mixture of 3-(4-bromo-2-pyridyl)oxetan-3-amine (100 mg, 376.60 p mol, HC1 salt) and 37% aqueous solution of formaldehyde (611.2 mg, 7.53 mmol) in mixed solvent of THF (3 mL) and DCM (2 mL) was stirred at 0 °C for 30 minutes, followed by the addition of sodium triacetoxyborohydride (119.7 mg, 564.90 p mol). The resulting mixture was stirred for an hour until the reaction was complete, diluted with thO (5 mL) and extracted with EA (10 mL x 2).
  • Step 2 To a mixture of int. 3 (40 mg, 78.37 ⁇ mol) and 3-(4-bromopyridin-2-yl)-A,A- dimethyloxetan-3-amine (20.2 mg, 78.37 ⁇ mo)l in mixed solvent of dioxane and EbO (4/1, 2.0 mL) were added potassium carbonate (32.5 mg, 235.12 ⁇ mo)l and Pd(dppf)Cl2 (5.73 mg, 7.84 pmol). The mixture was degassed with N2, and stirred at 110 °C under microwave conditions for 2 hours, until the starting material was totally consumed.
  • reaction mixture was filtered through a Celite pad, and the pad was washed with ethyl acetate (10 mL x 2).
  • the filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with methanol in dichloromethane from 0 to 20%) to afford trans-N- ⁇ 4-((4-(2-(3- (dimethylamino)oxetan-3-yl)pyridin-4-yl)phenyl)sulfonyl)cyclohexyl)-5- (trifluoromethyl)pyridin-2-amine (16 mg, 36% yield) as a white solid.
  • Step 1 To a solution of DIPEA (43.7 mg, 337.98 p mol, 58.9 ⁇ L) and acetyl chloride (9.7 mg, 123.93 p mol, 7.5 ⁇ L) in dichloromethane (10 mL) was added the solution of 3-(4- bromopyridin-2-yl)oxetan-3-amine (30 mg, 112.66 ⁇ mo)l in dichloromethane (2 mL) at 0 °C. The mixture was stirred at room temperature for an hour and concentrated in vacuo.
  • Step 2 A mixture of int. 3 (229.7 mg, 450.12 ⁇ mol), N-(3-(4-bromopyridin-2-yl)oxetan-3- yl)acetamide (122 mg, 450.12 ⁇ mol), Pd(dppf)Cl2 (65.9 mg, 90.02 ⁇ mo)l and K2CO3 (186.4 mg, 1.35 mmol) in dioxane/water (10 mL, 4/1) was stirred at 100 °C under N2 atmosphere for 4 hours, cooled to room temperature, diluted with ethyl acetate (30 mL) and washed with water (10 mL x 2).
  • Step 1 To a stirred mixture of N-(3-(4-bromopyridin-2-yl)oxetan-3-yl)-2-methylpropane-2- sulfinamide (80 mg, 240.06 ⁇ mo)l in anhydrous THF (3 mL) was added sodium hydride (60% dispersion in mineral oil) (14.4 mg, 360.10 ⁇ mo)l at 0 °C. The mixture was stirred at 0 °C for 15 minutes, followed by the addition of iodomethane (51.1 mg, 360.10 ⁇ mol, 22.4 ⁇ L).
  • Step 2 To a mixture of int. 3 (110 mg, 215.53 ⁇ mo)l and N-(3-(4-bromopyridin-2-yl)oxetan-
  • Step 3 To A/,2-dimethyl-iran,s'- V-(3-(4-(4-((4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)oxetan-3-yl)propane-2-sulfinamide (70 mg, 107.56 ⁇ mol) was added HCl/dioxane (3 mL) at 0 °C, and the mixture was stirred at this temperature for 30 minutes and concentrated in vacuo.
  • Step 1 To a solution of 2,4-dibromopyridine (1.5 g, 6.33 mmol) in anhydrous DCM (30 mL) was added dropwise n-butyl lithium ( 2.5M in THF, 2.8 mL) at -60 °C under N2 atmosphere. The reaction mixture was stirred for 15 minutes at this temperature, followed by the dropwise addition of / ⁇ ? / 7-butyl 3-oxoazetidine-l-carboxylate (1.08 g, 6.33 mmol). The resulting mixture was stirred at -60 °C for an hour and poured into saturated NH 4 CI aqueous solution (30 mL).
  • Step 2 To a stirred mixture of tert-butyl 3-(4-bromopyridin-2-yl)-3-hydroxyazetidine-l- carboxylate (0.5 g, 1.52 mmol) in anhydrous THF (8 mL) was added sodium hydride (60% dispersion in mineral oil) (72.9 mg, 1.82 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 minutes, followed by the addition of iodomethane (258.7 mg, 1.82 mmol, 113.5 ⁇ L). The reaction mixture was stirred at room temperature for 18 hours until the reaction was completed, quenched with H2O (8 mL), and extracted with EA (20 mL x 2).
  • Step 3 To a mixture of int. 3 (100 mg, 195.93 ⁇ mo)l and tert-butyl 3-(4-bromopyridin-2-yl)- 3-methoxyazetidine-l-carboxylate (74.0 mg, 215.53 ⁇ mo)l in mixed solvent of dioxane and H2O (4/1, 3.8 mL) were added potassium carbonate (81.2 mg, 587.80 m mol) and Pd(dppf)Cl2 (14.3 mg, 19.59 ⁇ mol). The mixture was degassed with N2, and stirred at 110 °C under microwave conditions for 2 hours, until the starting material was totally consumed.
  • reaction mixture was filtered through a Celite pad, and the pad was washed with ethyl acetate (10 mL x 2).
  • the filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with methanol in dichloromethane from 0 to 20%) to afford / ⁇ ?
  • Step 4 ⁇ To tert-butyl 3-mcthoxy-3-(4-(4-((trans-4-((5-(tnfhioromcthyl)pyndin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)azetidine-l-carboxylate (75 mg, 115.97 pmol) was added HCl/dioxane (3 mL) at 0 °C, and the mixture was stirred at this temperature for 30 minutes and concentrated in vacuo.
  • Step 1 The mixture of tert- butyl 3-(4-bromo-2-pyridyl)-3-methoxy-azetidine-l-carboxylate (180 mg, 524.45 p mol) in HCl/ethyl acetate (4M, 5 mL) was stirred at room temperature for 30 minutes and diluted with saturated sodium bicarbonate aqueous solution (5 mL).
  • Step 2 To a mixture of 4-bromo-2-(3-methoxyazetidin-3-yl)pyridine (100 mg, 411.35 ⁇ mo)l, sodium acetate (67.5 mg, 822.71 ⁇ mo)l and acetic acid (49.4 mg, 822.71 ⁇ mol, 47.1 ⁇ L) in dichloromethane (10 mL) was added formaldehyde (37% aqueous solution, 822.71 ⁇ mo,l 0.2 mL) at 25 °C.
  • the mixture was stirred at 25 °C for 45 minutes, followed by the addition of sodium triacetoxyborohydride (261.6 mg, 1.23 mmol) in one portion at 0-5 °C, and 10 minutes after the addition was stirred at 25 °C for another hour.
  • the reaction mixture was quenched with NaOH aqueous solution (0.5M, 2 mL), and two layers were separated. The aqueous layer was extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrousNa 2 SO 4 and filtered.
  • Step 3 A mixture of int. 3 (138.9 mg, 272.24 ⁇ mol), 4-bromo-2-(3-methoxy- 1 -methyl - azetidin-3-yl)pyridine (70 mg, 272.24 ⁇ mo)l Pd(dppf)Cl2 (39.8 mg, 54.45 ⁇ mo)l and K2CO3 (150.6 mg, 1.09 mmol) in dioxane/water (10 mL, 4/1) was stirred at 100 °C under N2 atmosphere for 4 hours, cooled to room temperature, diluted with ethyl acetate (30 mL) and washed with water (10 mL x 2).
  • Step 1 To a solution / ⁇ ? / 7-butyl 3-(4-bromo-2-pyridyl)-3-hydroxy-azetidine-l-carboxylate (500 mg, 1.52 mmol) in DCM (10 mL) was added HCl/dioxane (4M, 5 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 minutes and concentrated in vacuo.
  • Step 2 A mixture of int. 3 (222.8 mg, 436.54 ⁇ mo)l, 3-(4-bromo-2-pyridyl)azetidin-3-ol (100 mg, 436.54 ⁇ mol) Pd(dppf)Cl2 (63.9 mg, 87.31 ⁇ mo)l and K2CO3 (150.6 mg, 1.09 mmol) in dioxane/water (10 mL, 4/1) was stirred at 100 °C under N2 atmosphere for 4 hours, cooled to room temperature, diluted with ethyl acetate (30 mL) and washed with water (10 mL x 2). The organic layer was dried over anhydrous Na 2 S0 4 and filtered.
  • Step 1 To a mixture of 3-(4-bromopyridin-2-yl)azetidin-3-ol (80 mg, 349.23 ⁇ mo)l, sodium acetate (57.3 mg, 698.47 ⁇ mol) and acetic acid (41.9 mg, 698.47 ⁇ mol, 40.0 ⁇ L) in dichloromethane (10 mL) was added formaldehyde (37% aqueous solution, 822.71 ⁇ mo,l 0.2 mL) at 25 °C.
  • the mixture was stirred at 25 °C for 45 minutes, followed by the addition of sodium triacetoxyborohydride (222.1 mg, 1.05 mmol) in one portion at 0-5 °C, and 10 minutes after the addition was stirred at 25 °C for another hour.
  • the reaction mixture was quenched with NaOH aqueous solution (0.5M, 2 mL), and two layers were separated. The aqueous layer was extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrousNa 2 SO 4 and filtered.
  • Step 1 To a solution of 2,4-dibromopyridine (1.0 g, 4.22 mmol) in anhydrous dichloromethane (20 mL) was added n-butyl lithium (4.65 mmol, 1.86 mL, 2.5 mol/L in THF) at -60 °C under the atmosphere of N2. 15 minutes after completion of addition, oxetan-3-one (304.2 mg, 4.22 mmol, 271.6 ⁇ L) was added into the solution at -60 °C. The reaction mixture was stirred at - 60 °C for one hour and poured into saturated ammonium chloride aqueous solution (30 mL).
  • Step 2 A mixture of 3-(4-bromo-2-pyridyl)oxetan-3-ol (60.0 mg, 260.80 ⁇ mol), int. 3 (133.0 mg, 260.59 ⁇ mo)l, Pd(PPh 3 ) 2 Cl 2 (36.6 mg, 52.21 ⁇ mo) l and K2CO3 (108.0 mg, 782.61 ⁇ mo)l in dioxane/water (10 mL, 4/1) was stirred at 110 °C under N2 atmosphere for 4 hours, cooled to room temperature, diluted with ethyl acetate (30 mL) and washed with water (10 mL x 3).
  • Step 1 A mixture of 3-(4-bromo-2-pyridyl)oxetan-3-ol (60.0 mg, 260.80 ⁇ mol), int. 1 (124.8 mg, 260.80 ⁇ mo)l, Pd(PPh 3 ) 2 Cl 2 (36.6 mg, 52.21 ⁇ mo) l and K2CO3 (108.0 mg, 782.61 ⁇ mo)l in dioxane/water (10 mL, 4/1) was stirred at 110 °C under N2 atmosphere for 4 hours, cooled to room temperature, diluted with ethyl acetate (30 mL) and washed with water (10 mL x 2). The organic layer was dried over anhydrous Na 2 S0 4 and filtered.
  • Step 2 To a mixture of 3-(4-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)thio)phenyl)pyridin-2-yl)oxetan-3-ol (50.0 mg, 99.69 ⁇ mol ) and ammonium carbamate (23.5 mg, 301.01 ⁇ mol) in methanol (10 mL) was added iodobenzene diacetate (64.8 mg, 199.93 ⁇ mol). The mixture was stirred at 25 °C for 3 hours and concentrated in vacuo.
  • Step 1 To a solution of 3-(4-bromo-2-pyridyl)oxetan-3-ol (100 mg, 434.67 ⁇ mo)l in anhydrous THF (4 mL) was added NaH (60% dispersion in mineral oil, 15.0 mg, 652.01 ⁇ mol) at 0 °C under the atmosphere of N2. 30 minutes after completion of addition, iodomethane (67.9 mg, 478.14 ⁇ mol, 29.8 ⁇ L) was added thereto at 25 °C. The resulting mixture was stirred at 25 °C for 2 hours and poured into saturated NH4CI aqueous solution (10 mL).
  • Step 2 A mixture of 4-bromo-2-(3-methoxyoxetan-3-yl)pyridine (90 mg, 368.72 ⁇ mol), tetrakis(triphenylphosphine) palladium (85.2 mg, 73.74 ⁇ mo)l, int. 3 (207.0 mg, 405.60 ⁇ mo)l and sodium carbonate (97.7 mg, 921.81 ⁇ mo)l in dioxane/water (2 mL, 4/1) was stirred at 100 °C for 1 hour under N2 atmosphere, cooled to room temperature, and diluted with ethyl acetate (20 mL). The resulting mixture was washed with H2O (10 mL x 3).
  • Step 1 To a solution of 2,4-dibromopyridine (100 mg, 422.13 ⁇ mo)l in anhydrous THE (2 mL) was added n-BuLi (2.5M in THE, 0.2 mL) at -78 °C under the atmosphere of N2. 15 minutes after completion of addition, oxetane-3-carbaldehyde (40.0 mg, 464.35 p mol) was added thereto at -60 °C. The resulting mixture was stirred at -60 °C for one hour, and poured into saturated NH4CI aqueous solution (30 mL). The organic layer was separated, and the aqueous phase was extracted with DCM (20 mL x 3).
  • Step 2 A mixture of (4-bromopyridin-2-yl)(oxetan-3-yl)methanol (100 mg, 409.69 ⁇ mol), tetrakis(triphenylphosphine) palladium (94.7 mg, 81.94 ⁇ mo)l, int. 3 (209.1 mg, 409.69 ⁇ mo)l and sodium carbonate (108.6 mg, 1.02 mmol) in dioxane/water (2 mL, 4/1) was stirred at 100 °C for 1 hour under N2 atmosphere, cooled to room temperature, and diluted with ethyl acetate (20 mL). The resulting mixture was washed with H2O (10 mL x 3).
  • Step 1 To a solution of 2,4-dibromopyridine (1.19 g, 5.04 mmol) in anhydrous DCM (10 mL) was added nBuLi (2.2 M hexane solution, 2.52 mL) dropwise at -78 °C over 20 minutes. The resulting solution was stirred at the same temperature for 30 minutes, followed by the dropwise addition of cyclobutanone (353.3 mg, 5.04 mmol, 376.6 ⁇ L) over 5 minutes. The reaction mixture was stirred at -78 °C for 1 hour, allowed to warm to room temperature spontaneously, and quenched with saturated NH4CI aqueous solution (10 mL).
  • nBuLi 2.2 M hexane solution, 2.52 mL
  • Step 2 To a stirred solution of l-(4-bromo-2-pyridyl)cyclobutanol (107.3 mg, 470.24 ⁇ mo)l and int. 3 (200 mg, 391.87 ⁇ mo)l in mixed solvent of dioxane (4 mL) and H2O (0.5 mL) were added RuPhos Pd G2 (30.5 mg, 39.19 ⁇ mo)l and K3PO4 (249.5 mg, 1.18 mmol). The mixture was stirred at 100 °C for 2 hours under N2 atmosphere, cooled to room temperature, diluted with EA (50 mL) and washed with brine (20 mL x 2).
  • Step 1 To a solution of 4-bromo-2-fluoro-pyridine (200 mg, 1.14 mmol, 117.0 ⁇ L) and azetidin-3-amine (90.1 mg, 1.25 mmol) in n-butanol (4 mL) was added TEA (345.0 mg, 3.41 mmol, 475.2 ⁇ L). The mixture was stirred at 100 °C for 3 hours, cooled to room temperature, diluted with water (10 mL) and extracted with DCM (30 mL x 3). The organic layers were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 and filtered.
  • Step 2 To a stirred solution of l-(4-bromo-2-pyridyl)azetidin-3-amine (107.3 mg, 470.24 ⁇ mo)l and int. 3 (200 mg, 391.87 ⁇ mo)l in mixed solvent of dioxane (4 mL) and H2O (0.5 mL) were added RuPhos Pd G2 (30.5 mg, 39.19 ⁇ mo)l and K3PO4 (249.5 mg, 1.18 mmol). The mixture was stirred at 100 °C for 2 hours under N2 atmosphere, cooled to room temperature, diluted with EA (50 mL) and washed with brine (20 mL x 2).
  • Step 1 To a solution of 4-bromo-2-fluoro-pyridine (500 mg, 2.84 mmol, 292.4 ⁇ L) and tert- butyl 3-aminoazetidine-l-carboxylate (587.2 mg, 3.41 mmol) in DMF (10 mL) was added cesium carbonate (2.78 g, 8.52 mmol). The mixture was stirred at 100 °C for 16 hours, cooled to room temperature, diluted with H2O (10 mL) and EA (100 mL) and washed with and brine (20 mL x 4). The organic phase was dried over anhydrous Na 2 SO 4 and filtered.
  • Step 2 To a stirred solution of tert-butyl 3-((4-bromopyridin-2-yl)amino)azetidine-l- carboxylate (308.7 mg, 940.48 ⁇ mol) and int. 3 (400 mg, 783.74 ⁇ mo)l in mixed solvent of dioxane (8 mL) and H2O (1 mL) were added RuPhos Pd G2 (61.0 mg, 78.37 ⁇ mo)l and K3PO4 (499.1 mg, 2.35 mmol). The mixture was stirred at 100 °C for 2 hours under N2 atmosphere, cooled to room temperature, diluted with EA (100 mL) and washed with brine (20 mL x 3).
  • Step 3 A solution of tert- butyl 3-((4-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)amino)azetidine- 1-carboxylate (200 mg, 316.60 ⁇ mol) in HCl/dioxane (4M, 6 mL) was stirred at 25 °C for 16 hours and concentrated in vacuo. The residue was basified to pH to 8 with saturated NaHCO 3 aqueous solution, and extracted with EA (20 mL x 3).
  • Step 2 To a stirred solution of 4-bromo-N-(tetrahydrofuran-3-yl)pyridin-2-amine (114.3 mg, 470.24 ⁇ mol) and int. 3 (200 mg, 391.87 ⁇ mo)l in mixed solvent of dioxane (4 mL) and H2O (0.5 mL) were added RuPhos Pd G2 (30.5 mg, 39.19 ⁇ mo)l and K3PO4 (249.5 mg, 1.18 mmol). The mixture was stirred at 100 °C for 2 hours under N2 atmosphere, cooled to room temperature, diluted with EA (100 mL) and washed with brine (20 mL x 3).
  • Step 1 To a solution of 4-bromo-2-fluoro-pyridine (500 mg, 2.84 mmol, 292.4 ⁇ L) and tetrahydropyran-4-amine (344.8 mg, 3.41 mmol) in DMF (10 mL) was added cesium carbonate (2.78 g, 8.52 mmol). The mixture was stirred at 100 °C for 16 hours, cooled to room temperature, diluted with H2O (10 mL) and EA (100 mL) and washed with brine (20 mL x 4). The organic phase was dried over anhydrous Na 2 SO 4 and filtered.
  • Step 2 To a stirred solution of 4-Bromo-N-(tctrahydro-2H-pyran-4-yl)pyridin-2-aminc (120.9 mg, 470.24 ⁇ mol) and int. 3 (200 mg, 391.87 ⁇ mo)l in mixed solvent of dioxane (4 mL) and H 2 O (0.5 mL) were added RuPhos Pd G2 (30.5 mg, 39.19 ⁇ mo)l and K3PO4 (249.5 mg, 1.18 mmol). The mixture was stirred at 100 °C for 2 hours under N2 atmosphere, cooled to room temperature, diluted with EA (100 mL) and washed with brine (20 mL x 3).
  • Step 1 To a solution of 4-bromo-2-fluoro-pyridine (200 mg, 1.14 mmol, 117.0 ⁇ L) and oxetan- 3-amine (99.7 mg, 1.36 mmol) in DMF (5 mL) was added cesium carbonate (1.11 g, 3.41 mmol). The mixture was stirred at 100 °C for 3 hours, cooled to room temperature, diluted with H2O (10 mL) and EA (100 mL) and washed with brine (20 mL x 4). The organic phase was dried over anhydrous Na 2 SO 4 and filtered.
  • Step 2 To a stirred solution of 4-bromo-/V-(oxetan-3-yl)pyridin-2-amine (116.7 mg, 509.43 ⁇ mol) and int. 3 (200 mg, 391.87 ⁇ mo)l in mixed solvent of dioxane (4 mL) and H2O (0.5 mL) were added RuPhos Pd G2 (30.5 mg, 39.19 ⁇ mol) and K3PO4 (249.5 mg, 1.18 mmol). The mixture was stirred at 100 °C for 2 hours under N2 atmosphere, cooled to room temperature, diluted with EA (100 mL) and washed with brine (20 mL x 3).
  • Step 1 To a stirred mixture of 4-bromo-N-(oxetan-3-yl)pyridin-2-amine (180 mg, 785.77 m mol) in anhydrous DMF (10 mL) was added sodium hydride (60% dispersion in mineral oil, 47.1 mg, 1.18 mmol) at 0 °C. 20 min later, iodomethane (167.3 mg, 1.18 mmol, 73.4 ⁇ L) was added into the solution. The reaction mixture was stirred at 0 °C for an hour, quenched with 2 mL of water and concentrated in vacuo.
  • Step 2 A mixture of 4-bromo-N-methyl-N-(oxetan-3-yl)pyridin-2-amine (100 mg, 411.35 pmol), int. 3 (209.9 mg, 411.35 ⁇ mo)l, Pd(dppf)Cl2 (60.2 mg, 82.27 ⁇ mo)l and K2CO3 (141.9 mg, 1.03 mmol) in dioxane/water (10 mL, 4/1) was stirred at 100 °C for 4 hours, cooled to room temperature, diluted with ethyl acetate (30 mL) and washed with water (10 mL x 2). The organic layer was dried over anhydrous Na 2 S0 4 and filtered.
  • Step 1 To a mixture of 5-bromo-2-fluoro-aniline (500 mg, 2.63 mmol), oxetan-3-one (189.6 mg, 2.63 mmol, 169.3 ⁇ L) and sodium triacetoxyborohydride (1.12 g, 5.26 mmol) in dichloromethane (10 mL) was added molecular sieves (4 A, 1 g). The mixture was stirred at room temperature overnight and filtered through a pad of Celite. The solid cake was washed with DCM (20 mL) and the filtrate was concentrated in vacuo.
  • Step 2 A mixture of A- (5 - b ro m o - 2 - fl u o ro - p h c n y 1 ) o x c t a n - 3 - a m i n c (70 mg, 284.47 ), int.
  • Step 1 To a solution of 4-bromo-2-fluoro-pyridine (100 mg, 568.23 p mol, 58.5 ⁇ L) in acetonitrile (10 mL) were added 2-oxa-6-azaspiro[3.3]heptane (56.3 mg, 568.23 ⁇ mol) and K2CO3 (196.0 mg, 1.42 mmol). The reaction mixture was stirred at 75 °C overnight, cooled to room temperature, diluted with water (10 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was dried over anhydrous Na 2 SO 4 and filtered.
  • Step 2 A mixture of 6-(4-bromo-2-pyridyl)-2-oxa-6-azaspiro[3.3]heptane (70 mg, 274.39 pmol), int. 3 (140.0 mg, 274.39 ⁇ mo)l, Pd(dppf)Cl2 (40.1 mg, 54.88 ⁇ mo)l and K2CO3 (94.7 mg, 685.98 ⁇ mol) in dioxane/water (10 mL, 4/1) was stirred at 100 °C for 4 hours, cooled to room temperature, diluted with ethyl acetate (30 mL) and washed with water (10 mL x 2). The organic layer was dried over anhydrous Na 2 S0 4 and filtered.
  • Step 1 To a solution of oxetan-3-one (900 mg, 12.49 mmol, 803.6 ⁇ L) in nitromethane (10 mL) was added a catalytic amount of triethylamine (126.38 mg, 1.25 mmol, 174.1 ⁇ L) at room temperature. The reaction mixture was stirred for 2 hours and concentrated in vacuo to give crude 3-(nitromethyl)oxetan-3-ol (1.2 g, 72% yield) without further purifications. LC-MS (ESI) [(M+H) + ] : 134.2.
  • Step 2 To a stirred solution of 3-(nitromethyl)oxetan-3-ol (1.2 g, 9.02 mmol) in dichloromethane (10 mL) was added DAST (2.18 g, 13.53 mmol, 1.79 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour and quenched with saturated potassium bicarbonate aqueous solution (10 mL). The resulting mixture was exacted with DCM (30 mL x 3), and the organic phases were dried over anhydrous Na 2 SO 4 and filtered.
  • Step 3 To a stirred solution of 2,4-dibromopyridine (824 mg, 3.48 mmol) in anhydrous DCM (20 mL) was added n-butyl lithium (1.4 mL, 2.5 mol/L in THF) at -60 °C under the atmosphere of N2. 15 minutes after completion of addition 15 minutes, 3-(nitromethylene)oxetane (400 mg, 3.48 mmol) was added into the solution at -60 °C. The reaction mixture was stirred at -60 °C for one hour and poured into saturated ammonium chloride aqueous solution (30 mL). The organic layer was separated, washed with brine (20 mL), dried over anhydrous NaiSCE and filtered.
  • Step 4 ⁇ A mixture of 4-bromo-2-[3-(nitromethyl)oxetan-3-yl]pyridine (140 mg, 512.66 ⁇ mo)l, int. 3 (261.6 mg, 512.66 ⁇ mo)l, Pd(dppf)Cl2 (75.0 mg, 102.53 ⁇ mo)l and K2CO3 (212.2 mg, 1.54 mmol) in dioxane/water (10 mL, 4/1) was stirred at 100 °C under N2 atmosphere for 4 hours, cooled to room temperature, diluted with ethyl acetate (30 mL) and washed with water (10 mL x 2). The organic layer was dried over anhydrous Na 2 S0 4 and filtered.
  • Step 5 To a mixture of trans-A-(4-((4-(2-(3-(nitromethyl)oxetan-3-yl)pyridin-4- yl)phenyl)sulfonyl)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine (100 mg, 173.43 ⁇ mol) and zinc powder (2 g, 1.73 mmol) in methanol (10 mL) was added HO Ac (3 drops). The reaction mixture was stirred under the atmosphere of N2 at 80 °C for 4 hours and filtered through a pad of Celite.
  • Step 1 A mixture of 5-chloropyridazin-3-ol (500. 0 mg, 3.83 mmol) and phosphorus oxybromide (1.10 g, 3.83 mmol) in acetonitrile (5 mL) was stirred in a sealed tube at 80 °C for 4 hours, cooled to room temperature, quenched with saturated NaHC0 3 aqueous solution to adjust pH 9 ⁇ 10, and extracted with EtOAc (150 mL x 3). The combined organic layer was dried over anhydrous Na 2 SO 4 and filtered.
  • Step 2 To a solution of 3,5-dibromopyridazine (500.0 mg, 2.10 mmol) in anhydrous dichloromethane (20 mL) was added n-butyl lithium (2.52 mmol, 1 mL, 2.5 mol/L in THF) at -60 °C under the atmosphere of N2. 15 minutes after completion of addition, oxetan-3-one (15E5 mg, 2.10 mmol, 135.3 ⁇ L) was added into the solution at -60 °C. The reaction mixture was stirred at -60 °C for one hour and poured into saturated ammonium chloride aqueous solution (30 mL).
  • Step 3 A mixture of 3-(5-bromopyridazin-3-yl)oxetan-3-ol (50.0 mg, 216.41 ⁇ mol), int. 3 (110.0 mg, 215.53 ⁇ mo),l l,r-bis(triphenylphosphine)ferrocenepalladium(II) dichloride (31.7 mg, 43.31 ⁇ mo)l and K2CO3 (90.0 mg, 651.18 ⁇ mo)l in dioxane/water (10 mL, 4/1) was stirred at 110 °C under N2 atmosphere for 4 hours, cooled to room temperature, diluted with ethyl acetate (30 mL) and washed with water (10 mL x 2).
  • Step 1 To a mixture of 4-bromo-2-fluoro-pyridine (200 mg, 1.14 mmol) and 2/7-triazole (117.7 mg, 1.70 mmol) in DMF (2 mL) was added TEA (230.0 mg, 2.27 mmol). The reaction mixture was stirred at 110 °C for 1 hour, cooled to room temperature, and diluted with ethyl acetate (100 mL). The resulting mixture was washed with H2O (20 mL x 3). The organic layer was dried over anhydrous NaiSCE and filtered.
  • Step 2 A mixture of 4-bromo-2-(triazol-2-yl)pyridine (60 mg, 266.61 ⁇ mol ), tetrakis(triphenylphosphine) palladium (92.4 mg, 79.98 ⁇ mo)l, int. 3 (136.1 mg, 266.61 ⁇ mo)l and sodium carbonate (70.7 mg, 666.53 ⁇ mo)l in dioxane/water (2 mL, 4/1) was stirred at 100 °C for 1 hour under N2 atmosphere, cooled to room temperature, and diluted with ethyl acetate (20 mL). The resulting mixture was washed with H2O (10 mL x 3).
  • Step 1 A mixture of 4-bromo-2-fluoro-pyridine (600 mg, 3.41 mmol, 350.9 ⁇ L), 1 H-triazolc (235.5 mg, 3.41 mmol) and K2CO3 (1.18 g, 8.52 mmol) in acetonitrile (10 mL) was stirred at 100 °C for 4 hours and concentrated in vacuo.
  • Step 2 A mixture of 4-bromo-2-(triazol-2-yl)pyridine (70 mg, 311.05 ⁇ mo)l, int. 1 (148.8 mg, 311.05 ⁇ mol), Pd(PPh 3 ) 2 Cl 2 (44 mg, 62.77 ⁇ mo)l and K2CO3 (129 mg, 934.78 ⁇ mol) in dioxane/water (6 mL, 2/1) was stirred at 100 °C under N2 atmosphere for 4 hours, cooled to room temperature, diluted with ethyl acetate (20 mL) and washed with water (10 mL x 3). The organic layer was dried over anhydrous Na 2 S0 4 and filtered.
  • Step 3 To a mixture of trans-N-(4-((4-(2-(2H-1 ,2,3-triazol-2-yl)pyridin-4- yl)phenyl)thio)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine (50 mg, 100.69 ⁇ mol) and ammonium carbamate (15.7 mg, 201.10 ⁇ mo)l in methanol (5 mL) was added iodobenzene diacetate (65.3 mg, 201.47 ⁇ mol). The mixture was stirred at 25 °C for 5 hours and concentrated in vacuo.
  • Step 1 A mixture of sodium methoxide (147.6 mg, 2.73 mmol) and 4-bromopyridine-2- carbonitrile (500.0 mg, 2.73 mmol) in MeOH (10 mL) was stirred at room temperature for 2 hours. NH4CI (579.2 mg, 10.93 mmol) was added thereto. The reaction mixture was stirred at 25 °C overnight and concentrated in vacuo to give 4-bromopicolinimidamide (500 mg, 91% yield), which was used in the next step without further purifications. LC-MS (ESI) [(M+H) + ]: 199.8.
  • Step 2 A mixture of 4-bromopicolinimidamide (500.0 mg, 2.50 mmol) and formylhydrazide (180.13 mg, 3.00 mmol) in ethanol (10 mL) was stirred at 90 °C overnight and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate / PE from 0 to 50%) to give 4-bromo-2-(4H-l,2,4-triazol-3-yl)pyridine (250.0 mg, 44% yield) as a white solid.
  • Step 3 A mixture of 4-bromo-2-(4H-l,2,4-triazol-3-yl)pyridine (60 mg, 266.61 ⁇ mol), tetrakis(triphenylphosphine) palladium (30 mg, 25.96 ⁇ mo)l, int. 3 (163.29 mg, 319.94 ⁇ mo)l and sodium carbonate (70 mg, 660.44 ⁇ mo)l in dioxane/water (2 mL, 4/1) was stirred at 130 °C for 8 hours under N2 atmosphere, cooled to room temperature, and diluted with ethyl acetate (20 mL). The resulting mixture was washed with H2O (10 mL x 3).
  • Step 1 To a solution of 4-bromo-2-(4H-l,2,4-triazol-3-yl)pyridine (110 mg, 488.79 ⁇ mo)l and DMAP (59.7 mg, 488.79 p mol) in THF (10 mL) was added BociO. The reaction mixture was stirred at room temperature for 10 minutes and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with methanol/dichloromethane from 0 to 5%) to give tert-butyl 3-(4-bromopyridin-2-yl)-4H-l,2,4-triazole-4-carboxylate (90 mg, 57% yield) as a white solid. LC-MS (ESI) [(M+H) + ]: 325.2.
  • Step 2 A mixture of tert-butyl 3-(4-bromopyridin-2-yl)-4H-l,2,4-triazole-4-carboxylate (140.0 mg, 430.56 ⁇ mo)l, l,l'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (63.0 mg, 86.10 ⁇ mo)l, int.
  • Step 1 A mixture of 2,4-dibromopyridine (200 mg, 844.27 ⁇ mo)l, tert-butyl N-pyrrolidin-3- ylcarbamate (173.0 mg, 928.69 ⁇ mo)l, (lS,2S)-Nl,N2-dimethylcyclohexane- 1,2-diamine (60.0 mg, 422.13 ⁇ mo,l 66.6 ⁇ L), K3PO4 (179.2 mg, 844.27 ⁇ mo)l and Cul (48.2 mg, 253.28 ⁇ mo)l in dioxane (4 mL) was stirred at 105 °C for 1 hour under N2 atmosphere, cooled to room temperature, and diluted with ethyl acetate (20 mL).
  • Step 2 A mixture of tert- butyl (l-(4-bromopyridin-2-yl)pyrrolidin-3-yl)carbamate (120 mg, 350.64 ⁇ mol), tetrakis(triphenylphosphine) palladium (60.8 mg, 52.60 ⁇ mo)l, int. 3 (196.9 mg, 385.70 ⁇ mol) and sodium carbonate (92.9 mg, 876.60 ⁇ mo)l in dioxane/water (2 ruL, 4/1) was stirred at 100 °C for 1 hour under N2 atmosphere, cooled to room temperature, and diluted with ethyl acetate (20 ruL).
  • Step 3 To a solution of tert- butyl (l-(4-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate (100 mg, 154.86 pmol) in DCM (2 ruL) was added HCl/dioxane (4M, 2 ruL). The reaction mixture was stirred at room temperature for 30 minutes and concentrated in vacuo.
  • Step 1 To a stirred mixture of 2-bromo-4-chloro-pyridine (200 mg, 1.04 mmol), pyrrolidin-2- one (88.5 mg, 1.04 mmol) and K3PO4 (441.2 mg, 2.08 mmol) in 1,4-dioxane (4 mL) were added palladium acetate (7.0 mg, 31.18 ⁇ mo)l, l,l'-bis(diphenylphosphino)ferrocene (51.9 mg, 93.54 pmol). The mixture was stirred at 100 °C for 2 hours under N2 atmosphere, cooled to room temperature, diluted with EA (50 mL) and washed with brine (20 mL x 2).
  • Step 2 To a stirred solution of l-(4-chloropyridin-2-yl)pyrrolidin-2-one (92.5 mg, 470.24 ⁇ mo)l and int.
  • Step 1 To a stirred mixture of 2-bromo-4-chloro-pyridine (300 mg, 1.56 mmol), / ⁇ ? /7 -butyl N- (5-oxopyrrolidin-3-yl)carbamate (312.2 mg, 1.56 mmol) and K3PO4 (661.8 mg, 3.12 mmol) in 1,4-dioxane (6 mL) were added palladium acetate (10.5 mg, 46.77 ⁇ mol ), 1,1'- bis(diphenylphosphino)ferrocene (77.8 mg, 140.30 ⁇ mo)l.
  • Step 2 To a stirred solution of tert-butyl (l-(4-chloropyridin-2-yl)-5-oxopyrrolidin-3- yl)carbamate (219.9 mg, 705.36 ⁇ mo)l and int. 3 (300 mg, 587.80 ⁇ mo)l in mixed solvent of dioxane (8 mL) and H2O (1 mL) were added RuPhos Pd G2 (45.7 mg, 58.78 miho ⁇ ) and K3PO4 (374.3 mg, 1.76 mmol).
  • Step 3 To a stirred solution of tert- butyl (5-oxo-l-(4-(4-((trans-4-((5-(trifluoromethyl)pyridin- 2-yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate (150 mg, 227.37 ⁇ mol) in DCM (3 mL) was added TLA (518.5 mg, 4.55 mmol, 350.3 ⁇ L). The mixture was stirred at 25 °C for an hour and concentrated in vacuo. The residue was basified to pH 8- 9 with saturated sodium carbonate aqueous solution, and extracted with EA (20 mL x 3).
  • Step 1 To a solution of 4-bromo-2-methyl-pyridine (5.1 g, 29.65 mmol, 3.52 mL) and dimethyl carbonate (4.01 g, 44.47 mmol, 3.74 mL) in anhydrous THF (30 mL) was added LDA (2 M, 23.72 mL) at -78 °C over 30 minutes. The reaction mixture was allowed to warm to room temperature slowly and stirred overnight. The reaction mixture was quenched with saturated NH4CI aqueous solution (50 mL) at 0 °C and diluted with H2O (40 mL).
  • Step 2 To a solution of methyl 2-(4-bromo-2-pyridyl)acetate (1 g, 4.35 mmol) in anhydrous THF (10 mL) was added sodium hydride (60% dispersion in mineral oil, 249.8 mg, 6.52 mmol) in portions. The resulting mixture was stirred at 0 °C for 30 minutes, followed by the addition of the solution of tert-butyl A- (2 - b ro m o c t h y 1 ) c a r b a m a t c (1.17 g, 5.22 mmol) in anhydrous THF (10 mL) slowly.
  • Step 3 To methyl 2-(4-bromo-2-pyridyl)-4-(tert-butoxycarbonylamino)butanoate (200 mg, 535.85 ⁇ mol) was added HCl/dioxane (4M, 1 mL). The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was triturated in EA (5 mL) and PE (10 mL) and filtered to afford 3-(4-bromo-2-pyridyl)pyrrolidin-2-one (90 mg, 70% yield) as an off-white solid.
  • Step 4 ⁇ A mixture of 3-(4-bromo-2-pyridyl)pyrrolidin-2-one (133.3 mg, 555.6 ⁇ mol), int. 3 (283.5 mg, 555.6 ⁇ mo)l, Pd(dppf)Cl2 (123.6 mg, 168.8 ⁇ mo)l and K2CO3 (229.9 mg, 1665.9 pmol) in dioxane/water (20 mL, 4/1) was stirred at 100 °C for 4 hours, cooled to room temperature, diluted with ethyl acetate (100 mL) and washed with water (30 mL x 3). The organic layer was dried over anhydrous Na 2 S0 4 and filtered.
  • Step 1 To a suspension of Cu (2.64 g, 41.57 mmol) in DMSO (30 mL) was added ethyl 2- bromo-2,2-difluoro-acetate (4.22 g, 20.79 mmol, 2.67 mL). After the mixture was stirred at room temperature for 1 hour, 2-bromo-4-chloro-pyridine (2 g, 10.39 mmol) was added thereto. The resulting mixture was stirred at room temperature for 15 hours, diluted with saturated NH4CI aqueous solution (15 mL) and extracted with CH2CI2 (50 mL x 3).
  • Step 2 To a stirred solution of int. 3 (400 mg, 783.74 ⁇ mo)l and ethyl 2-(4-chloropyridin-2- yl)-2,2-difluoroacetate (221.6 mg, 940.48 ⁇ mo)l in mixed solvent of 1,4-dioxane (10 mL) and water (2 mL) was added potassium phosphate (499.1 mg, 2.35 mmol), RuPhos Pd G2 (61.0 mg, 78.37 ⁇ mo)l. The reaction mixture was stirred at 100 °C under N2 atmosphere for 2 hours, cooled to room temperature, diluted with EA (50 mL) and washed with brine (10 mL x 3).
  • Step 3 To a stirred solution of ethyl 2,2-difluoro-2-(4-(4-((trans-4-((5- (trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)acetate (50 mg, 85.68 ⁇ mol) in EtOH (2 mL) was added NaBH4 (6.5 mg, 171.36 ⁇ mo)l at 0 °C. The mixture was stirred at 0 °C for 2 hours, diluted with ice water (100 mL), and extracted with EA (50 mL x 3). The organic phase was dried over anhydrous Na 2 S0 4 and filtered.
  • Step 1 To a stirred solution of ethyl 2,2-difluoro-2-(4-(4-((trans-4-((5- (trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)ethan-l-ol (160 mg, 274.17 ⁇ mol) in THF (3 mL) was added LiOH aqueous solution (1.0M, 2.0 mL). The mixture was stirred at room temperature for 2 hours, acidified to pH 5 ⁇ 6 with 3M hydrochloric acid aqueous solution, and extracted with EA (30 mL x 3).
  • Step 1 To a solution of 2,2-difluoro-2-(4-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)acetic acid (300 mg, 540.04 ⁇ mol) and HATU (410.7 mg, 1.08 mmol) in DMF (3.0 mL) were added DIPEA (209.4 mg, 1.62 mmol, 282.2 ⁇ L) and NH4CI (86.7 mg, 1.62 mmol). The mixture was stirred at 25 °C for 16 hours, diluted with water (10 mL) and extracted with EA (30 mL x 2).
  • Step 1 To a stirred solution of ethyl 2-(4-chloropyridin-2-yl)-2,2-difluoroacetate (500 mg, 2.12 mmol) in EtOH (5 mL) was added NaBH4 (160.6 mg, 4.24 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 hours, diluted with ice water (100 mL), and extracted with EA (50 mL x 3). The organic phase was dried over anhydrous Na 2 S0 4 and filtered.
  • Step 2 To a stirred solution of 2-(4-chloropyridin-2-yl)-2,2-difluoroethan-l-ol (400 mg, 2.07 mmol) and pyridine (261.5 mg, 3.31 mmol, 267.4 ⁇ L) in acetonitrile (4 mL) was added Tf 2 O (641.3 mg, 2.27 mmol, 381.7 ⁇ L) at 0 °C. The mixture was stirred at 0 °C for 1 hour, and ammonium hydroxide aqueous solution (1 mL) was added thereto. The reaction mixture was stirred at room temperature overnight, diluted with water (10 mL), and extracted with EA (20 mL x 3).
  • Step 3 To a stirred solution of int. 3 (150 mg, 293.90 ⁇ mo)l and 2-(4-chloropyridin-2-yl)-2,2- difluoroethan-1 -amine (140 mg, 729.17 ⁇ mo)l in mixed solvent of 1,4-dioxane (4 mL) and water (0.5 mL) was added potassium phosphate (187.2 mg, 881.70 ⁇ mo)l, RuPhos Pd G2 (22.9 mg, 29.39 ⁇ mo)l. The reaction mixture was stirred at 100 °C under N2 atmosphere for 2 hours, cooled to room temperature, diluted with EA (50 mL) and washed with brine (10 mL x 3).
  • Step 1 To a stirred solution of 2-(4-chloropyridin-2-yl)-2,2-difluoroethan-l-ol (120 mg, 619.90 p mol) and pyridine (78.5 mg, 0.99 mmol, 80.2 ⁇ L) in acetonitrile (3 mL) was added Tf 2 0 (209.9 mg, 743.89 ⁇ mo,l 124.9 ⁇ L) at 0 °C. The mixture was stirred at 0 °C for 1 hour, and methylamine (21.2 mg, 681.89 ⁇ mol, 23.6 ⁇ L) was added thereto.
  • Step 2 A mixture of 2-(4-chloropyridin-2-yl)-2,2-difluoro-/V-methylethan-l -amine (60 mg, 290.39 ⁇ mol), tetrakis(triphenylphosphine) palladium (100.7 mg, 87.12 ⁇ mo)l, int. 3 (177.5 mg, 348.47 ⁇ mo)l and sodium carbonate (77.0 mg, 725.97 ⁇ mo)l in dioxane/water (2 mL, 4/1) was stirred at 100 °C for 1 hour under N 2 atmosphere, cooled to room temperature, and diluted with ethyl acetate (20 mL).
  • Step 1 A mixture of 4-chloropyridine-2-carbaldehyde (0.8 g, 5.65 mmol), 2-methylpropane-2- sulfinamide (685.0 mg, 5.65 mmol) and cesium carbonate (2.76 g, 8.48 mmol) in CH2CI2 (20 mL) was stirred at room temperature for 3 hours and filtered. The filtrate was concentrated in vacuo.
  • Step 2 To a solution of (£ ' )-A/-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2- sulfinamide (0.8 g, 3.27 mmol) and tetrabutylammonium difluorotriphenylsilicate (1.94 g, 3.60 mmol) in THF (20 mL) was added (trifluoromethyl) trimethylsilane (1.16 g, 8.17 mmol, 1.30 mL) at -78 °C under N2 atmosphere.
  • the reaction mixture was stirred at -20 °C for 1.5 hours, quenched with saturated ammonium chloride aqueous solution (15 mL), and diluted with ethyl acetate (15 mL) and water (15 mL). The two phases were separated, and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo.
  • Step 3 To a solution of N-(l-(4-chloropyridin-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2- sulfinamide (710 mg, 2.26 mmol) in MeOH (2.0 mL) was added HCl/dioxane (4M, 3.5 mL). The mixture was stirred at 25 °C for 1 hour and concentrated in vacuo to give l-(4- chloropyridin-2-yl)-2,2,2-trifluoroethan-l -amine (650 mg, crude, HC1 salt) as a white solid.
  • Step 4 ⁇ To a stirred solution of l-(4-chloropyridin-2-yl)-2, 2, 2-trifluoroethan- 1-amine (650 mg, crude, HC1 salt), pyridine (624.4 mg, 7.89 mmol, 638.4 ⁇ L) and DMAP (32.1 mg, 263.11 ⁇ mo)l in dioxane (20 mL) was added B0C2O (1.15 g, 5.26 mmol, 1.21 mL) over 10 minutes at 5 °C. The reaction mixture was stirred at room temperature overnight and diluted with EtOAc (50 mL) and water (30 mL). The two layers were separated, and the aqueous layer was extracted with EtOAc (40 mL x 2).
  • Step 5 Under microwave condition, the mixture of int. 3 (150 mg, 293.90 ⁇ mo)l, tert-butyl (1- (4-chloropyridin-2-yl)-2,2,2-trifluoroethyl)carbamate (91.3 mg, 293.90 ⁇ mol), Pd(dppf)Cl2 (21.5 mg, 29.39 ⁇ mo)l and potassium carbonate (81.2 mg, 587.80 ⁇ mo)l in dioxane/H2O (4/1, 3.0 mL) was stirred at 110 °C under N2 atmosphere for 2 hours, cooled to room temperature and filtered through a pad of silica gel.
  • Step 1 Under microwave condition, the mixture of int. 1 (200 mg, 418.08 ⁇ mo)l, tert-butyl (1- (4-chloropyridin-2-yl)-2,2,2-trifluoroethyl)carbamate (129.9 mg, 418.08 ⁇ mol), Pd(dppf)Cl2 (30.6 mg, 41.81 ⁇ mo)l and potassium carbonate (115.6 mg, 836.16 ⁇ mo)l in dioxane/HiO (4/1, 3.0 mL) was stirred at 110 °C under N2 atmosphere for 2 hours, cooled to room temperature and filtered through a pad of silica gel.
  • Step 2 To a mixture of tert-butyl (2,2,2-trifluoro-l-(4-(4-((trans-4-((5- (trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)thio)phenyl)pyridin-2-yl)ethyl)carbamate (240 mg, 382.99 ⁇ mo)l and ammonium carbamate (74.8 mg, 957.46 ⁇ mo)l in MeOH (5 mL) was added iodobenzene diacetate (246.7 mg, 765.97 ⁇ mo)l. The mixture was stirred at 25 °C for 15 minutes and concentrated in vacuo.
  • Step 3 To a stirred solution of tert-butyl (2,2,2-tnfluoiO- 1 -(4-(4-(/ran.s'-4-((5- (trifluoromethyl)pyridin-2-yl)amino)cyclohexane-l-sulfonimidoyl)phenyl)pyridin-2- yl)ethyl)carbamate (200 mg, 304.10 ⁇ mo)l in MeOH (6 mL) was added HCl/dioxane (4M, 6 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 hour and concentrated in vacuo.
  • Step 1 To a mixture of 4-chloropyridine-2-carbaldehyde (2.0 g, 14.13 mmol) and potassium carbonate (195.3 mg, 1.41 mmol) in DMF (10 mL) was added trimethyl(trifluoromethyl)silane (2.41 g, 16.95 mmol, 2.69 mL) dropwise. The mixture was stirred at 25 °C for 15 hours, diluted with water (20 mL) and extracted with EA (20 mL x 2). The organic layer was washed with brine (30 mL x 2) and concentrated in vacuo.
  • Step 2 Under microwave condition, the mixture of int. 3 (100 mg, 195.93 ⁇ mol), l-(4- chloropyridin-2-yl)-2,2,2-trifluoroethan-l-ol (43.5 mg, 205.73 ⁇ mo)l, Pd(dppf)Cl2 (14.3 mg, 19.59 ⁇ mol) and potassium carbonate (54.2 mg, 391.87 ⁇ mo)l in dioxane/HiO (4/1, 2.5 mL) was stirred at 110 °C under N2 atmosphere for 3 hours, cooled to room temperature and filtered through a pad of silica gel.
  • Step 1 Under microwave condition, the mixture of int. 1 (100 mg, 209.04 m mol), l-(4- chloropyridin-2-yl)-2,2,2-trifluoroethan-l-ol (46.4 mg, 219.49 m mol), Pd(dppf)Cl2 (15.3 mg, 20.90 ⁇ mol) and potassium carbonate (57.8 mg, 418.08 ⁇ mo)l in dioxane/HiO (4/1, 3.0 mL) was stirred at 110 °C under N2 atmosphere for 2.5 hours, cooled to room temperature and filtered through a pad of silica gel.
  • Step 2 To a mixture of 2,2,2-trifluoro-l-(4-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)thio)phenyl)pyridin-2-yl)ethan-l-ol (50 mg, 94.78 ⁇ mo)l and ammonium carbamate (18.5 mg, 236.96 ⁇ mo)l in MeOH (3 mL) was added iodobenzene diacetate (61.1 mg, 189.56 umol). The mixture was stirred at 25 °C for 15 minutes and concentrated in vacuo.
  • Step 1 To a mixture of 4-methylthiophene-2-carboxylic acid (1.5 g, 10.55 mmol) in acetic acid (15 mL) was added BR2 (1.85 g, 11.61 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes and concentrated in vacuo. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with H2O (10 mL x 3).
  • Step 2 A mixture of 5-bromo-4-methyl-thiophene-2-carboxylic acid (800 mg, 3.62 mmol) in SOCI2 (5 mL) was stirred at 80 °C for 60 minutes and concentrated in vacuo. To the residue was added NH3 ⁇ 2O (6 mL) at 0 °C, and the resulting mixture was stirred for 30 minutes at this temperature and filtered to give 5-bromo-4-methylthiophene-2-carboxamide (670 mg, 84% yield) as a yellow solid.
  • Step 3 A mixture of 5-bromo-4-methylthiophene-2-carboxamide (80 mg, 363.49 p mol), tetrakis(triphenylphosphine) palladium (126.0 mg, 109.05 ⁇ mo)l, int. 3 (222.6 mg, 436.19 pmol) and sodium carbonate (96.3 mg, 908.73 ⁇ mo)l in dioxane/water (2 mL, 4/1) was stirred at 100 °C for 1 hour under N2 atmosphere, cooled to room temperature, and diluted with ethyl acetate (20 mL). The resulting mixture was washed with H2O (10 mL x 3).
  • Step 2 To a mixture of 4-methyl-5-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)thio)phenyl)thiophene-2-carboxamide (50 mg, 101.92 ⁇ mol ) and ammonium carbamate (19.9 mg, 254.79 ⁇ mo)l in mixed solvent of MeOH (0.5 mL) and DCM (1 mL) was added iodobenzene diacetate (66.1 mg, 203.83 ⁇ mo)l. The mixture was stirred at room temperature for 1 hour and concentrated in vacuo.
  • the High control wells as 0% inhibition, and the low control wells contain reference compound at IOmM as 100% inhibition.
  • the concentrations and % inhibition values for tested compounds are plotted and the concentration of compound required for 50% inhibition
  • IC50 is determined with a Three-parameter logistic dose response equation.
  • the endpoint value (IC50) for the reference peptide/compound is evaluated in each experiment as a quality control measure. If the endpoint value is within 3-fold of the expected value, then the experiment is deemed acceptable.
  • the IC50 values are indicated as "++++”, for values less than or equal to 100 nM; "+++”, for higher values than “++++” but less than or equal to 1 for higher values than “+++” but less than or equal to 10 pM; and for greater than 10 pM, respectively.
  • Sample tubes are shaken for 1 hour (1000 rpm) at room temperature.
  • Samples are centrifuged (10 min - 12000 rpm) to precipitate un-dissolved particles. And transfer the supernatants to a new tube or plate.
  • Solution B (0.02 mM): Add 8 ⁇ L of Solution A into 192 ⁇ L of 0.05 M sodium phosphate buffer. The final DMSO concentration in Solution B is 4%.

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Abstract

The present disclosure provides a compound of Formula (I) a pharmaceutically acceptable salt, or a stereoisomer and their use in, e.g. treating a condition, disease or disorder modulated at least in part by CCR6. This disclosure also features compositions containing the same as well as methods of using and making the same.

Description

(HETERO)ARYLAMINO-CYCLOHEXYL-SULFONYL DERIVATIVES AS
CCR6 INHIBITORS
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of priority to International Patent Application No. PCT/CN2021/076461, filed on February 10, 2021. The entire contents of the aforementioned application are incorporated herein by reference.
BACKGROUND
Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation (reviewed in Schall, Cytokine, 3: 165-183 (1991), Schall, el al. , Curr Opin. Immunol. 6:865- 873 (1994) and Murphy, Rev. Immun., 12:593-633 (1994)). In addition to stimulating chemotaxis, other changes can be selectively induced by chemokines in responsive cells, including changes in cell shape, transient rises in the concentration of intracellular free calcium ions ([Ca2+]), granule exocytosis, integrin upregulation, formation of bioactive lipids (e.g., leukotrienes) and respiratory burst, associated with leukocyte activation. Thus, the chemokines are early triggers of the inflammatory response, causing inflammatory mediator release, chemotaxis and extravasation to sites of infection or inflammation.
There are two main classes of chemokines, CXC (alpha) and CC (beta), depending on whether the first two cysteines are separated by a single amino acid (C-X-C) or are adjacent (C-C). The alpha-chemokines, such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP -2) and melanoma growth stimulatory activity protein (MGSA) are chemotactic primarily for neutrophils, whereas beta-chemokines, such as RANTES, MIP-la, MIP-lb, monocyte chemotactic protein-1 (MCP-1), MCP-2, MCP-3 and eotaxin are chemotactic for macrophages, T-cells, eosinophils and basophils (Deng, el al., Nature, 381:661-666 (1996)). The chemokines bind specific cell- surface receptors belonging to the family of G-protein- coupled seven-transmembrane-domain proteins (reviewed in Horuk, Trends Pharm. Sci., 15: 159-165 (1994)) which are termed "chemokine receptors."
On binding their cognate ligands, chemokine receptors transduce an intracellular signal through the associated trimeric G protein, resulting in a rapid increase in intracellular calcium concentration. There are at least eleven human chemokine receptors that bind or respond to beta-chemokines and at least seven human chemokine recepotrs that bind to the alpha chemokines. Additionally CX3CR1 (fractalkine receptor) can bind to the fractalkine chemokine, which is distinguished by a series of three amino acids between the first two cysteines. Chemokine receptors, have been implicated as being important mediators of inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.
CCR6 is known to be expressed primarily in B cells, IL-17 secreting T cells, regulatory T cells and dendritic cells and shows strong binding to its cognate ligand CCL20 (MIP-3a). It is expressed on approximately 30-60% of adult peripheral blood effector/memory CD4+ T cells. CCR6 is involved in leukocyte homing to inflamed tissue, particularly the skin and lungs and is co-expressed on almost all T cells that have a skin homing phenotype, the CLA+ T cells. Thus CCR6 may be an important player in skin pathologies in which leukocytes participate.
CCR6 expression has been linked to psoriasis in the following manner. In humans, a large majority of skin-homing CD4+ T cells in the peripheral blood express CCR6 with a greater degree of CCL20-mediated chemotaxis occurring in T cells isolated from psoriatic patients (Homey, et. al, JI, 2000). IL-17 secreting cells are central agents in several inflammatory diseases. T cells, such as gd T cells and TH17 T cells produce IL-17 after activation. The pathogenic effects of IL-17 have been associated with human diseases such as rheumatoid arthritis (Patel DD et. al, Ann Rheum Dis 2013), multiple sclerosis (Zepp J, Wu L, and X Li Trends Immunol 2011), and psoriasis (Martin DA et. al., J Invest Dermatol 2012). Evidence strongly linking IL-17 with psoriasis include gene wide association studies that show strong association between psoriasis and genes upstream (IL-23) or downstream (NFKb) of IL-17 signaling pathways as well as efficacy in targeting IL-17 in a clinical setting (Martin DA et. al, J. Invest Dermat. 2012; Papp et. al, NEJM, 2012; Papp et. al, NEJM,
2012). In addition to enhanced CCL20-mediated chemotaxis, CCR6+ T cells isolated from psoriatic patients preferentially secrete IL-17 A, IL-22, and TNFoc when compared to healthy controls (Kagami, et. al, J. Invest. Dermatol., 2010). Lastly, ccl20 mRNA was up-regulated in lesional psoriatic skin samples (Homey, et. al, JI, 2000; Dieu-Nosjean, et. al, JEM, 2000). In mice, CCR6 knock-out mice were protected from IL-23 driven psoriasis. Thus, a multitude of evidence in both mice and men suggest a protective role for CCR6 blockade in psoriasis and psoriasis-like models.
Accordingly, there are needs to for new compunds that modulate CCR6 activity for the treatment of diseases and disorders, e.g. rheumatoid arthritis, multiple sclerosis, or psoriasis. SUMMARY
The present disclosure provides CCR6 inhibitors, for example, compounds of structural formula (I), pharmaceutically acceptable salts, stereoisomers, and pharmaceutical compositions thereof. It was unexpected to find that the compounds disclosed herein significantly improve solubility in vitro and have suitable plasma protein binding properties.
Figure imgf000004_0001
The present disclosure further provides methods of using the compounds disclosed herein ( e.g ., compounds of structural formula (I)), pharmaceutically acceptable salts, stereoisomers, or pharmaceutical compositions thereof, to inhibit the activity of CCR6.
The present disclosure further provides methods for using the compounds disclosed herein (e.g., compounds of structural formula (I)), pharmaceutically acceptable salts, stereoisomers, or pharmaceutical compositions thereof, to treat a condition, disease or disorder modulated at least in part by CCR6.
In one aspect, the present disclosure provides a compound of formula (I), a pharmaceutically acceptable salt, or a stereoisomer thereof.
In one aspect, the present disclosure provides a pharmaceutical composition comprising the compounds disclosed herein (e.g., compounds of structural formula (I)), a pharmaceutically acceptable salt, or a stereoisomer thereof, as defined in any one of the embodiments described herein, in a mixture with at least one pharmaceutically acceptable carrier.
In another aspect, the present disclosure provides a compound of formula (I), a pharmaceutically acceptable salt, or a stereoisomer thereof, as defined in any one of the embodiments described herein, for use as a medicament.
In another aspect, the present disclosure provides a compound of formula (I), a pharmaceutically acceptable salt, or a stereoisomer thereof, as defined in any one of the embodiments described herein, for use in the treatment of a condition, disease or disorder modulated at least in part by CCR6, specifically in treating an autoimmune disease or condition. In another aspect, the present disclosure provides a use of a compound of formula (I), a pharmaceutically acceptable salt, or a stereoisomer thereof, as defined in any one of the embodiments described herein, for the manufacture of a medicament for treating a condition, disease or disorder modulated at least in part by CCR6, specifically in treating an autoimmune disease or condition.
DETAILED DESCRIPTION
1. Compounds
In a first embodiment, the present disclosure provides a compound represented by Formula (I):
Figure imgf000005_0001
a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein:
Y is O or NR7; wherein R7 is hydrogen, Ci-6 alkyl, or C3-6cycloalkyl; wherein said Ci-6 alkyl or C3-6cycloalkyl is optionally substituted by one or more halogen or OH;
R1 is hydrogen, halogen, -CN, -NO2, -C(0)0Ra, -C(0)NRaRb, -S02Ra, -S02NRaRb, -P(0)RaRb, -C(0)Ra, Ci-4alkyl, or C2-4alkynyl; wherein said C 1-4 alkyl represented by R1 is optionally substituted by one or more halogen, ORa, or NRaRb;
X1 is N or CR2;
X2 is N or CR3;
X3 is N or CR4; wherein R2, R3, and R4 are each independently hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -ORa, -NRaRb, -C(0)Ra, -C(0)0Ra, -C(0)NRaRb, -S02Ra, -S02NRaRb, -P(0)RaRb, -NRaC(0)Rb, -NRaS02Rb, 3-12 membered carbocyclyl, or 3-12 membered heterocyclyl; wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl,
3-12 membered carbocyclyl, or 3-12 membered heterocyclyl represented by R2, R3, or R4 is optionally substituted by one to four Rd; wherein
Ra and Rb are each independently selected from the group consisting of hydrogen, C1-6alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; or Ra and Rb together with the N or P atom to which they are attached, form 4-12 membered heterocyclyl or 5-10 membered heteroaryl; each Rd is independently hydrogen, halogen, oxo (as appropriate), -CN,
Ci-ealkyl, -ORa, -NRaRb, -C(0)Ra, -C(0)0Ra, -C(0)NRaRb, -S02Ra, -S02NRaRb, -P(0)RaRb, -NRaC(0)Rb, or -NRaS02Rb;
R5 is hydrogen, halogen, -CN, or C1-6alkyl;
R6 is halogen, -CN, -ORa, -NRaRb, or C1-6alkyl;
R8 is halogen, -CN, -ORa, -NRaRb, or C1-6alkyl;
R9 is selected from the group consisting of a) a moiety represented by formula (IA):
Figure imgf000006_0001
wherein Ring A is phenyl or 5-6 membered heteroaryl optionally substituted by one or more R10; b) a moiety represented by formula (IB):
Figure imgf000006_0002
wherein Ring B is phenyl or 5-6 membered heteroaryl optionally substituted by one or more R10; c) a moiety represented by formula (IC):
Figure imgf000006_0003
wherein Ring C is phenyl or 5-6 membered heteroaryl optionally substituted by one or more R10; and d) 7-11 membered bicyclic nitrogen containing heterocyclyl or 8-11 membered bicyclic nitrogen containing heteroaryl, wherein said heterocyclyl or heteroaryl represented by R9 is optionally substituted with one to four Rf; wherein R10 is hydrogen, halogen, -CN, -ORa, -P(0)RaRb, -NRaC(0)Rb, -NRaS02Rb,
-NRaRb, -C(0)0Ra, -C(0)NRaRb, -S02Ra, -S02NRaRb, Ci-ealkyl, 3-12 membered carbocyclyl, or 3-12 membered heterocyclyl;
L is a bond, -0-, -N(R11)-, or -C(R12)(R13)-; wherein
R11 is hydrogen, C1-6alkyl, 3-6 membered cycloalkyl, or 4-6 membered heterocyclyl; wherein said C1-6alkyl represented by R11 is optionally substituted by halogen, -ORa, -NRaRb, -C(0)ORa, or -C(0)NRaRb;
R12 and R13 are independently hydrogen, -ORa, -NRaRb, -C(0)ORa, -C(0)NRaRb, or C1-6alkyl; wherein said C1-6alkyl represented by R12 or R13 is optionally substituted by halogen, -ORa, -NRaRb, -C(0)ORa, or -C(0)NRaRb;
Z is -CONH2, 4-11 membered carbocyclyl, 4-11 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein said 4-11 membered carbocyclyl,
4-11 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl represented by Z is optionally substituted by one to four Re; provided that when Z is -CONH2, Y is NR7; wherein Re, in each occurrence, is C1-6alkyl, C1-6alkyleneOR', C1-6alkyleneN(R)(R ), oxo (as appropriate), -OR, -N(R')(R"), -NR'C(0)R", C(0)OR', C(0)NR'R", or 3-6 membered cycloalkyl, wherein said C1-6alkyl is optionally substituted by C(0)OR', C(0)NR'R", or NR'C(0)R";
R14 is Ci-ealkyl, -C1-6alkyleneOR', -Ci-6alkyleneN(R')(R"), -COOR', or -CON(R')(R"), wherein said C1-6alkyl is optionally substituted by -C(0)OR, -C(0)NRR , or -NRC(0)R ;
R15 is -OR, -N(R)(R ), Ci-ealkyl, C1-6alkyleneOR', Ci-6alkyleneN(R')(R"), -COOR', -CON(R)(R ), or -NRC(0)R , wherein said C1-6alkyl is optionally substituted by -C(0)OR , -C(0)NRR , or -NR'C(0)R";
Rf is halogen, -CN, Ci-ealkyl, oxo, -N(R')(R"), OR, -COOR', -NRC(0)R , or -CON(R)(R );
R and R , in each occurrence, are independently hydrogen or C1-6alkyl; or R and R together with the N atom to which they are attached form 4-12 membered heterocyclyl or 5-10 membered heteroaryl; m is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and n is 0, 1, 2, 3, or 4.
In a second embodiment, the present disclosure provides a compound according to the first embodiment, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein Y is O, and the definitions of the other variables are provided in the first embodiment.
In a third embodiment, the present disclosure provides a compound according to the first embodiment, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein Y is NR7; wherein R7 is hydrogen or -CH3, and the definitions of the other variables are provided in the first embodiment.
In a fourth embodiment, the present disclosure provides a compound according to any one of the first through third embodiments, a pharmaceutically acceptable salt or a stereoisomer thereof, wherein
R9 is a moiety represented by formula (A):
Figure imgf000008_0001
wherein
U is CH or N; and
V is N or CR10; wherein R10 is hydrogen, halogen, -CN, -C(0)NRaRb, or C1-6alkyl; wherein Ra or Rb are each independently selected from the group consisting of hydrogen, C1-6alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; and the definitions of the other variables are provided in the first through third embodiments.
In a fifth embodiment, the present disclosure provides a compound according to any one of the first through third embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
R9 is a moiety represented by formula (B):
Figure imgf000008_0002
wherein
U is CH or N; and
V is N or CR10; wherein R10 is hydrogen, halogen, -CN, -C(0)NRaRb, or C1-6alkyl; wherein Ra or Rb are each independently selected from the group consisting of hydrogen, C1-6alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; and the definitions of the other variables are provided in the first through third embodiments.
In a sixth embodiment, the present disclosure provides a compound according to any one of the first through third embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
R9 is a moiety represented by formula (C):
Figure imgf000009_0001
wherein
U is CH or N; and
V is N or CR10; wherein R10 is hydrogen, halogen, -CN, -C(0)NRaRb, or C1-6alkyl; wherein Ra or Rb are each independently selected from the group consisting of hydrogen, C1-6alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; and the definitions of the other variables are provided in the first through third embodiments.
In a seventh embodiment, the present disclosure provides a compound according to any one of the first through third embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R9 is 7-11 membered bicyclic nitrogen containing heterocyclyl or 8-11 membered bicyclic nitrogen containing heteroaryl, wherein said heterocyclyl or heteroaryl represented by R9 is optionally substituted with one to four Rf; and the definitions of the other variables are provided in the first through third embodiments.
In an eighth embodiment, the present disclosure provides a compound according to any one of the first through third embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
R1 is halogen, -CN, -CF3, or -P(0)(CH3)2;
X1 is N or CR2; and R2 is hydrogen;
X2 is N;
X3 is N or CR4; and R4is hydrogen or -C(0)OCH3; R5 is hydrogen, fluorine, or -CN; m is 0; and n is 0; and the definitions of the other variables are provided in the first through seventh embodiments.
In a ninth embodiment, the present disclosure provides a compound according to any one of the first through fourth and eighth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
R9 is a moiety represented by formula (A);
Figure imgf000010_0001
U is CH or N;
V is N or CR10; wherein R10 is hydrogen, halogen, -CN, -C(0)NRaRb; wherein Ra or Rb are each independently selected from the group consisting of hydrogen, Ci-4alkyl, 3-8 membered carbocyclyl, 4-8 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl;
L is a bond, O, -N(R11)-, or -C(R12)(R13)-; wherein
R11 is hydrogen, Ci-4alkyl, 3-6 membered cycloalkyl, or 4-6 membered heterocyclyl;
R12 and R13 are independently hydrogen, -OR, -NRR , or Ci-4alkyl;
Z is 4-6 membered carbocyclyl, 4-9 membered heterocyclyl, or 5-6 membered heteroaryl; wherein said 4-6 membered carbocyclyl, 4-9 membered heterocyclyl, or 5-6 membered heteroaryl represented by Z is optionally substituted by one to two Re;
Re, in each occurrence, is C1-6alkyl, -C1-6alkyleneOR', -C1-6alkyleneN(R)(R ), oxo (as appropriate), -OR, -N(R')(R"), -NR'C(0)R", -C(0)0R', -C(0)NR'R", or 3-6 membered cycloalkyl, wherein said C1-6alkyl is optionally substituted by -C(0)0R, -C(0)NRR , or -NR C(0)R ;
R and R , in each occurrence, are independently hydrogen or Ci-4alkyl; or R and R together with the N atom to which they are attached form 5-8 membered heterocyclyl or 5-6 membered heteroaryl; and the definitions of the other variables are provided in the first through fourth and eighth embodiments.
In a tenth embodiment, the present disclosure provides a compound according to any one of the first through fourth, eighth, and ninth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
R9 is a moiety represented by formula (A):
Figure imgf000011_0001
U is CH or N;
V is N or CR10; wherein R10 is hydrogen or halogen;
L is a bond, -N(R11)-, or -C(R12)(R13)-; wherein
R11 is hydrogen or Ci-4alkyl;
R12 and R13 are independently hydrogen, -OH, or Ci-4alkyl;
Z is 4-6 membered carbocyclyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl; wherein said 4-6 membered carbocyclyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl represented by Z is optionally substituted by one to two Re;
Re, in each occurrence, is independently Ci-4alkyl, -NR'C(0)R", -Ci-4alkyleneOR',
-OR, Ci-4alkyleneN(R)(R ), -N(R)(R ), or oxo (as appropriate);
R and R , in each occurrence, are independently hydrogen or Ci-4alkyl; and the definitions of the other variables are provided in the first through fourth, eighth, and ninth embodiments.
In an eleventh embodiment, the present disclosure provides a compound according to any one of the first through fourth and eighth through tenth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
R9 is a moiety represented by formula (Al), (A2), or (A3):
Figure imgf000011_0002
wherein
R10 is hydrogen or halogen;
L is a bond, -N(R11)-, or -C(R12)(R13)-; wherein R11 is hydrogen or Ci-4alkyl;
R12 and R13 are independently hydrogen, -OH, or Ci-3alkyl;
Z is 4-6 membered cycloalkyl, 4-6 membered saturated monocyclic heterocyclyl,
7 membered saturated bicyclic heterocyclyl, or 5 membered heteroaryl; wherein said 4-6 membered cycloalkyl, 4-6 membered saturated monocyclic heterocyclyl, 7 membered saturated bicyclic heterocyclyl, or 5 membered heteroaryl represented by Z is optionally substituted by one to two Re; and
Re, in each occurrence, is independently Ci-2alkyl, -NR'C(0)R",
Ci-2alkyleneOR', -OR, -N(R)(R ), or oxo (as appropriate);
R and R , in each occurrence, are independently hydrogen or Ci-2alkyl; and the definitions of the other variables are provided in the first through fourth and eighth through tenth embodiments.
In a twelfth embodiment, the present disclosure provides a compound according to the first through fourth and eighty through eleventh embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R10 is hydrogen or fluoro;
L is a bond, -NH-, -N(CH3)-, or -CH(OH)-;
Z is cyclobutyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, azaspiro[3.3]heptanyl, or triazolyl; wherein said cyclobutyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, azaspiro[3.3]heptanyl, or triazolyl is optionally substituted by one to two Re; and
Re, in each occurrence, is -CH3, -OH, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, oxo (as appropriate), -NHC(0)CH3, -OCH3, or -CH2NH2; and the definitions of the other variables are provided in the eleventh embodiment.
In a thirteenth embodiment, the present disclosure provides a compound according to the any one of first, fourth, and eighth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
Y is NR7; wherein R7 is hydrogen or -CH3;
R9 is a moiety represented by formula (A);
Figure imgf000012_0001
L is a bond; and
Z is -CONH2; and the definitions of the other variables are provided in the first, fourth, and eighth embodiments.
In a forteenth embodiment, the present disclosure provides a compound according to any one of the first through fourth and eighth through twelfth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R9 is selected from the group consisting of
Figure imgf000013_0001
The definitions of the other variables are provided in the first through fourth and eighth through twelfth embodiments.
In a fifteenth embodiment, the present disclosure provides a compound according to any one of the first through third, fifth, and eighth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R9 is a moiety represented by formula (B);
Figure imgf000014_0001
U is CH;
V is N;
R14 is C1-4alkyleneOR', C1-6alkyleneN(R)(R'), -COOR', or -CON(R')(R"); and R and R , in each occurrence, are independently hydrogen or Ci-2alkyl; and the definitions of the other variables are provided in the first through third, fifth, and eighth embodiments.
In a sixteenth embodiment, the present disclosure provides a compound according to any one of the first through third, fifth, eighth, and fifteenth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R9 is selected from the group consisting of
Figure imgf000014_0002
, and the definitions of the other variables are provided in the first through third, fifth, eighth, and fifteenth embodiments.
In a seventeenth embodiment, the present disclosure provides a compound according to the any one of the first through third, sixth, and eighth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
R9 is a moiety represented by formula (C);
Figure imgf000014_0003
U is CH;
V is N; and
R15 is -OR' or -N(R')(R'); and
R and R , in each occurrence, are independently hydrogen or C1-4alky 1 ; and the definitions of the other variables are provided in the first through third, sixth, and eighth embodiments.
In an eighteenth embodiment, the present disclosure provides a compound according to the any one of the first through third, sixth, eighth, and seventeenth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R9 is a moiety represented by formula (C);
Figure imgf000015_0001
U is CH;
V is N; and
R15 is OH or N¾; and the definitions of the other variables are provided in the first through third, sixth, and eighteenth embodiments.
In a ninteenth embodiment, the present disclosure provides a compound according to the any one of the first through third, seventh, and eighth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
R9 is 8-10 membered bicyclic nitrogen containing heterocyclyl or 8-10 membered bicyclic nitrogen containing heteroaryl, wherein said heterocyclyl or heteroaryl represented by R9 is optionally substituted with one to three Rf; and
Rf is halogen, Ci-4alkyl, oxo (as appropriate), -NH2, Ci-4alkoxy, or-COOH; and the definitions of the other variables are provided in the first through third, seventh, and eighth embodiments.
In a twentieth embodiment, the present disclosure provides a compound according to the any one of the first through third, seventh, eighth, and ninteenth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R9 is selected from the group consisting of
Figure imgf000016_0001
The definitions of the other variables are provided in the first through third, seventh, eighth, and ninteenth embodiments.
In a twenty-first embodiment, the present disclosure provides a compound according to the any one of the first through twentieth embodiments, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
R1 is -CF3;
X1 is CH;
X2 is N; X3 is CH;
R5 is hydrogen; m is 0; and n is 0; and the definitions of the other variables are provided in the first through twentieth embodiments. In one embodiment, the present disclosure provides a compound selected from the compounds disclosed in examples and Table 1, a pharmaceutically acceptable salt or a stereoisomer thereof.
2. Definitions
The term “halogen,” as used herein, refers to fluoride, chloride, bromide, or iodide.
The term “alkyl” used alone or as part of a larger moiety, such as “alkoxy” or “haloalkyl” and the like, means saturated aliphatic straight-chain or branched monovalent hydrocarbon radical of formula -CnH(2n+i). Unless otherwise specified, an alkyl group typically has 1-6 carbon atoms, i.e. C1-6alkyl. As used herein, a “C1-6alkyl” group means a radical having from 1 to 6 carbon atoms in a linear or branched arrangement. Examples include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert- butyl, n-pentyl, isopentyl, hexyl, and the like.
The term “alkylene” as used herein, means a straight or branched chain divalent hydrocarbon group of formula -CnH2n-. Non-limiting examples include ethylene, and propylene.
The term “alkenyl” means an alkyl group in which one or more carbon/carbon single bond is replaced by a double bond.
The term “alkynyl” means an alkyl group in which one or more carbon/carbon single bond is replaced by a triple bond.
The term “alkoxy” means an alkyl radical attached through an oxygen linking atom, represented by -O-alkyl. For example, “(Ci-4)alkoxy” includes methoxy, ethoxy, propoxy, and butoxy.
The term “carbocyclyl” refers to any stable non-aromatic hydrocarbon ring having 3-12 membered carbocyclyl. In one embodiment, carbocyclyl is 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic or tricyclic hydrocarbon ring, any of which may be saturated, partially unsaturated, or unsaturated. Any substitutable ring atom can be substituted ( e.g ., by one or more substituents). Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, and cyclooctadienyl. In one embodiment, carbocyclyl is intended to include, bridged, fused, and spirocyclic rings. In a spirocyclic carbocyclyl, one atom is common to two different rings. An example of a spirocyclic carbocyclyl is spiropentanyl. In a bridged carbocyclyl, the rings share at least two common non-adjacent atoms. Examples of bridged carbocyclyls include bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hept-2-enyl, and adamantanyl. In a fused-ring carbocyclyl system, two or more rings may be fused together, such that two rings share one common bond. Examples of two- or three-fused ring carbocyclyls include naphthalenyl, tetrahydronaphthalenyl (tetralinyl), indenyl, indanyl (dihydroindenyl), anthracenyl, phenanthrenyl, and decalinyl.
The term “cycloalkyl” refers to a cyclic, bicyclic, tricyclic, or polycyclic saturated hydrocarbon groups having 3 to 12 ring carbons. In one embodiment, cycloalkyl may have 3 to 7 ring cabons. Any substitutable ring atom can be substituted ( e.g ., by one or more substituents). Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl may include multiple fused and/or bridged rings. Non-limiting examples of fused/bridged cycloalkyl include: bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.0]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo [3.2.1] octane, bicyclo[2.2.2]octane, and the like. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro [2.6] nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like.
The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone (“3-12 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 3-7 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-7 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”); polycyclic ring systems include fused, bridged, or spiro ring systems). Exemplary monocyclic heterocyclyl groups include azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepanyl, oxepanyl, thiepanyl, tetrahydropyridinyl, and the like. Heterocyclyl polycyclic ring systems can include heteroatoms in one or more rings in the polycyclic ring system. Substituents may be present on one or more rings in the polycyclic ring system.
Spiro heterocyclyl refers to 5 to 12 membered polycyclic heterocyclyl with rings connected through one common carbon atom (called as spiro atom), wherein said rings have one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone, the remaining ring atoms being C, wherein one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Representive examples of spiro heterocyclyl include, but are not limited to the following groups:
Figure imgf000019_0001
Fused heterocyclyl refers to a 5 to 12 membered polycyclic heterocyclyl group, wherein each ring in the group shares an adjacent pair of carbon atoms with another ring in the group, wherein one or more rings can contain one or more double bonds, but none of the rings has a completely conjugated p-electron system, and wherein said rings have one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone, the remaining ring atoms being C. Representive examples of fused heterocyclyl include, but are not limited to the following groups:
Figure imgf000019_0002
Bridged heterocyclyl refers to a 5 to 12 membered polycyclic heterocyclyl group, wherein any two rings in the group share two disconnected atoms, the rings can have one or more double bonds but have no completely conjugated p-electron system, and the rings have one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone as ring atoms, the remaining ring atoms being C. Representive examples of bridged heterocyclyl include, but are not limited to the following groups:
Figure imgf000020_0001
Generally, the carbocyclyl, the cycloalkyl, or the heterocyclyl may be unsubstituted, or be substituted with one or more substituents as valency allows, wherein the substituents can be independently selected from a number of groups such as oxo, -CN, halogen, alkyl and alkoxyl, opotionally, the alkyl substitution may be further substituted.
The term “aryl” refers to a 6 to 10 membered all-carbon monocyclic ring or a polycyclic fused ring (a “fused” ring system means that each ring in the system shares an adjacent pair of carbon atoms with other ring in the system) group, and has a completely conjugated p-electron system. Representive examples of aryl are phenyl and naphthyl.
The term “heteroaryl,” as used herein, refers to a monocyclic or multicyclic aromatic hydrocarbon in which at least one of the ring carbon atoms has been replaced with a heteroatom independently selected from oxygen, nitrogen and sulfur. Preferably, the heteroaryl is based on a C5-10 aryl with one or more of its ring carbon atoms replaced by the heteroatom. A heteroaryl group may be attached through a ring carbon atom or, where valency permits, through a ring nitrogen atom. Generally, the heteroaryl may be unsubstituted, or be substituted with one or more substituents as valency allows with the substituents being independently selected from halogen, OH, alkyl, alkoxyl, and amino ( e.g ., NH2, NHalkyl, N(alkyl)2), optionally, the alkyl may be further substituted.
The symbol
Figure imgf000020_0002
as used herein, refers to the point where the moiety attaches.
As used herein, the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating, or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.
The term “therapeutically effective amount” refers to an amount of an agent (e.g., a compound described herein) effective to treat at least one symptom of a disease or disorder in a patient or subject. The “therapeutically effective amount” of the agent for administration may vary based upon the desired activity, the disease state of the patient or subject being treated, the dosage form, method of administration, patient factors such as the patient's sex, genotype, weight and age, the underlying causes of the condition or disease to be treated, the route of administration and bioavailability, the persistence of the administered agent in the body, evidence of natriuresis and/or diuresis, the type of formulation, and the potency of the agent. Pharmaceutically Acceptable Salts
The term “pharmaceutically-acceptable salt” refers to a pharmaceutical salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, and is commensurate with a reasonable benefit/risk ratio. Pharmaceutically-acceptable salts are well known in the art. For example, S. M. Berge et al. describes pharmacologically acceptable salts in J. Pharm. Sci., 1977, 66, 1-19.
Pharmaceutically acceptable salts of the compounds of any one of the formulae described above include acid addition and base salts.
Included in the present teachings are pharmaceutically acceptable salts of the compounds disclosed herein. Compounds having basic groups can form pharmaceutically acceptable salts with pharmaceutically acceptable acid(s). Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric, and sulfuric acids) and of organic acids (such as acetic, benzenesulfonic, benzoic, ethanesulfonic, methanesulfonic, and succinic acids). Compounds of the present teachings with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts).
Pharmaceutically acceptable salts of compounds of any one of the formulae described above may be prepared by one or more of three methods:
(i) by reacting the compound of any one of the formulae described above with the desired acid or base;
(ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of any one of the formulae described above or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or
(iii) by converting one salt of the compound of any one of the formulae described above to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.
All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised. The compounds of any one of the formulae described above, and pharmaceutically acceptable salts thereof, may exist in unsolvated and solvated forms.
Stereoisomers and Other Variations
The compounds of any one of the formulae described above may exhibit one or more kinds of isomerism ( e.g . optical, geometric or tautomeric isomerism). Such variation is implicit to the compounds of any one of the formulae described above defined as they are by reference to their structural features and therefore within the scope of the present disclosure.
Compounds having one or more chiral centers can exist in various stereoisomeric forms, i.e., each chiral center can have an R or S configuration, or can be a mixture of both. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are mirror images of each other. Diastereomers are stereoisomers having two or more chiral centers that are not identifcal and are not mirror images of each other.
When a compound is designated by its chemical name (e.g., where the configuration is indicated in the chemical name by
Figure imgf000022_0001
or “S”) or its structure (e.g., the configuration is indicated by “wedge” bonds) that indicates a single enantiomer, unless indicated otherwise, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as “enantiomerically pure”). Optical purity is the weight in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers.
When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.
When two stereoisomers are depicted by their chemical names or structures, and the chemical names or structures are connected by an “and”, a mixture of the two stereoisomers is intended.
When two stereoisomers are depicted by their chemical names or structures, and the names or structures are connected by an “or”, one or the other of the two stereoisomers is intended, but not both.
When a disclosed compound having a chiral center is depicted by a structure without showing a configuration at that chiral center, the structure is meant to encompass the compound with the S configuration at that chiral center, the compound with the R configuration at that chiral center, or the compound with a mixture of the R and S configuration at that chiral center. When a disclosed compound having a chiral center is depicted by its chemical name without indicating a configuration at that chiral center with “S” or “R”, the name is meant to encompass the compound with the S configuration at that chiral center, the compound with the R configuration at that chiral center or the compound with a mixture of the R and S configuration at that chiral center.
Racemic mixture means 50% of one enantiomer and 50% of is corresponding enantiomer. When a compound with one chiral center is named or depicted without indicating the stereochemistry of the chiral center, it is understood that the name or structure encompasses both possible enantiomeric forms (e.g., both enantiomerically-pure, enantiomerically-enriched or racemic) of the compound. When a compound with two or more chiral centers is named or depicted without indicating the stereochemistry of the chiral centers, it is understood that the name or structure encompasses all possible diasteriomeric forms (e.g., diastereomerically pure, diastereomerically enriched and equimolar mixtures of one or more diastereomers (e.g., racemic mixtures) of the compound.
The term “geometric isomer” means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a carbocyclic ring, or to a bridged bicyclic system. Substituent atoms (other than hydrogen) on each side of a carbon- carbon double bond may be in an E or Z configuration according to the Cahn-Ingold-Prelog priority rules. In the “E” configuration, the substituents having the highest priorities are on opposite sides in relationship to the carbon-carbon double bond. In the “Z” configuration, the substituents having the highest priorities are oriented on the same side in relationship to the carbon-carbon double bond.
Substituents around a carbon-carbon double bond can also be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond. The arrangement of substituents around a carbocyclic ring can also be designated as “cis” or “trans.” The term “cis” represents substituents on the same side of the plane of the ring, and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis/trans.”
Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism (“tautomerism”) can occur. This can take the form of proton tautomerism in compounds of any one of the formulae described above containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
When a geometric isomer is depicted by name or structure, it is to be understood that the named or depicted isomer exists to a greater degree than another isomer, that is that the geometric isomeric purity of the named or depicted geometric isomer is greater than 50%, such as at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. Geometric isomeric purity is determined by dividing the weight of the named or depicted geometric isomer in the mixture by the total weight of all of the geomeric isomers in the mixture.
Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.
Conventional techniques for the preparation/isolation of individual enantiomers/ diastereomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of any one of the formulae described above contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person. Chiral compounds of any one of the formulae described above (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from
0 to 5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture. Chiral chromatography using sub-and supercritical fluids may be employed. Methods for chiral chromatography useful in some embodiments of the present disclosure are known in the art (see, for example, Smith, Roger M., Loughborough University, Loughborough, UK; Chromatographic Science Series (1998), 75 (Supercritical Fluid Chromatography with Packed Columns), pp. 223-249 and references cited therein). Columns can be obtained from Chiral Technologies, Inc, West Chester, Pa., USA, a subsidiary of Daicel® Chemical Industries, Ltd., Tokyo, Japan.
It must be emphasized that the compounds of any one of the formulae described above have been drawn herein in a single tautomeric form, all possible tautomeric forms are included within the scope of the present disclosure.
3. Administration and Dosing
Typically, a compound of the present disclosure is administered in an amount effective to treat a condition as described herein. The compounds of the present disclosure can be administered as compound per se, or alternatively, as a pharmaceutically acceptable salt. For administration and dosing purposes, the compound per se or pharmaceutically acceptable salt thereof will simply be referred to as the compounds of the present disclosure.
The compounds of the present disclosure are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The compounds of the present disclosure may be administered orally, rectally, vaginally, parenterally, or topically.
The compounds of the present disclosure may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the bloodstream directly from the mouth.
In another embodiment, the compounds of the present disclosure may also be administered directly into the bloodstream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
In another embodiment, the compounds of the present disclosure may also be administered topically to the skin or mucosa, that is, dermally or transdermally. In another embodiment, the compounds of the present disclosure can also be administered intranasally or by inhalation. In another embodiment, the compounds of the present disclosure may be administered rectally or vaginally. In another embodiment, the compounds of the present disclosure may also be administered directly to the eye or ear.
The dosage regimen for the compounds of the present disclosure and/or compositions containing said compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus the dosage regimen may vary widely. In one embodiment, the total daily dose of a compound of the present disclosure is typically from about 0.001 to about 100 mg/kg (i.e., mg compound of the present disclosure per kg body weight) for the treatment of the indicated conditions discussed herein.
For oral administration, the compositions may be provided in the form of tablets containing 0.1- 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient. Intravenously, doses may range from about 0.01 to about 10 mg/kg/minute during a constant rate infusion.
Suitable subjects according to the present disclosure include mammalian subjects, including non-human mammal such as primates, rodents (mice, rats, hamsters, rabbits etc).
In one embodiment, humans are suitable subjects. Human subjects may be of either gender and at any stage of development.
4. Pharmaceutical Compositions
In another embodiment, the present disclosure comprises pharmaceutical compositions. Such pharmaceutical compositions comprise a compound of the present disclosure presented with a pharmaceutically acceptable carrier or excipient. Other pharmacologically active substances can also be present.
As used herein, “pharmaceutically acceptable carrier or excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof, and may include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol, or sorbitol in the composition. Pharmaceutically acceptable substances such as wetting agents or minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the antibody or antibody portion.
The compositions of present disclosure may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions ( e.g ., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. The form depends on the intended mode of administration and therapeutic application.
Typical compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans with antibodies in general. One mode of administration is parenteral ( e.g . intravenous, subcutaneous, intraperitoneal, intramuscular). In another embodiment, the antibody is administered by intravenous infusion or injection. In yet another embodiment, the antibody is administered by intramuscular or subcutaneous injection.
Oral administration of a solid dose form may be, for example, presented in discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present disclosure. In another embodiment, the oral administration may be in a powder or granule form. In another embodiment, the oral dose form is sub-lingual, such as, for example, a lozenge. In such solid dosage forms, the compounds of any one of the formulae described above are ordinarily combined with one or more adjuvants. Such capsules or tablets may contain a controlled release formulation. In the case of capsules, tablets, and pills, the dosage forms also may comprise buffering agents or may be prepared with enteric coatings.
In another embodiment, oral administration may be in a liquid dose form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water). Such compositions also may comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening), and/or perfuming agents.
In another embodiment, the present disclosure comprises a parenteral dose form.
“Parenteral administration” includes, for example, subcutaneous injections, intravenous injections, intraperitoneally, intramuscular injections, intrasternal injections, and infusion. Injectable preparations (i.e., sterile injectable aqueous or oleaginous suspensions) may be formulated according to the known art using suitable dispersing, wetting agents, and/or suspending agents.
In another embodiment, the present disclosure comprises a topical dose form.
“Topical administration” includes, for example, transdermal administration, such as via transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. A topical formulation may include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of present disclosure are administered by a transdermal device, administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.
Penetration enhancers may be incorporated - see, for example, Finnin and Morgan, J. Pharm. Set, 88:955-958, 1999.
Formulations suitable for topical administration to the eye include, for example, eye drops wherein the compound of present disclosure is dissolved or suspended in a suitable carrier. A typical formulation suitable for ocular or aural administration may be in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (i.e., absorbable gel sponges, collagen) and non-biodegradable (/.<?., silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cehulosic polymer, for example, hydroxypropylmethylcehulose, hydroxyethylcehulose, or methylcehulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.
For intranasal administration or administration by inhalation, the compounds of the present disclosure are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant. Formulations suitable for intranasal administration are typically administered in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
In another embodiment, the present disclosure comprises a rectal dose form. Such rectal dose form may be in the form of, for example, a suppository. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
Other carrier materials and modes of administration known in the pharmaceutical art may also be used. Pharmaceutical compositions of the present disclosure may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures.
The above considerations in regard to effective formulations and administration procedures are well known in the art and are described in standard textbooks. Formulation of drugs is discussed in, for example, Hoover, John E., Remington’ s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1975; Liberman et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe et al., Eds., Handbook of Pharmaceutical Excipients (3rd Ed.), American Pharmaceutical Association, Washington, 1999.
5. Method of Treatment
In one aspect, the present disclosure provides methods of treating or preventing a CCR6-mediated condition or disease by administering to a subject having such a condition or disease, a therapeutically effective amount of any compound of the disclosure. In one embodiment, compounds for use in the present methods are those compounds provided above, as well as compounds specifically exemplified in the Examples below, and provided with specific structures herein. The "subject" is defined herein to include animals such as mammals, including, but not limited to, primates ( e.g ., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In one embodiment, the subject is a human.
As used herein, the phrase "CCR6-mediated condition or disease" and related phrases and terms refer to a condition or disease characterized by inappropriate, e.g., less than or greater than normal, CCR6 functional activity. Inappropriate CCR6 functional activity might arise as the result of CCR6 expression in cells which normally do not express CCR6, increased CCR6 expression (leading to, e.g., inflammatory and immunoregulatory disorders and diseases) or decreased CCR6 expression. Inappropriate CCR6 functional activity might also arise as the result of CCL20 secretion by cells which normally do not secrete CCL20, increased CCL20 expression (leading to, e.g., inflammatory and immunoregulatory disorders and diseases) or decreased CCL20 expression. A CCR6-mediated condition or disease may be completely or partially mediated by inappropriate CCR6 functional activity. However, a CCR6-mediated condition or disease is one in which modulation of CCR6 results in some effect on the underlying condition or disease ( e.g ., a CCR6 antagonist results in some improvement in patient well-being in at least some patients).
The term "therapeutically effective amount" means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
Diseases and conditions associated with inflammation, infection and cancer can be treated or prevented with the present compounds and compositions. In one group of embodiments, diseases or conditions, including chronic diseases, of humans or other species can be treated with inhibitors of CCR6 function. These diseases or conditions include: (1) allergic diseases such as systemic anaphylaxis or hypersensitivity responses, drug allergies, insect sting allergies and food allergies, (2) inflammatory bowel diseases, such as Crohn's disease, ulcerative colitis, ileitis and enteritis, (3) vaginitis, (4) psoriasis and inflammatory dermatoses such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria and pruritus, Vitiligo (5) vasculitis, (6) spondyloarthropathies, (7) scleroderma, (8) asthma and respiratory allergic diseases such as allergic asthma, allergic rhinitis, hypersensitivity lung diseases and the like, (9) autoimmune diseases, such as rheumatoid arthritis, juvenile arthritis, juvenile rheumatoid arthritis, systemic onset rheumatoid arthritis, pauciarticular rheumatoid arthritis, pauciarticular juvenile rheumatoid arthritis, polyarticular rheumatoid arthritis, enteropathic arthritis, juvenile Reiter's Syndrome, ankylosing spondylitis, juvenile ankylosing spondylitis, SEA Syndrome, reactive arthritis (reactive arthropathy), psoriatic arthropathy, juvenile enteropathic arthritis, polymyalgia rheumatica, enteropathic spondylitis, juvenile idiopathic arthritis (JIA), juvenile psoriatic arthritis, juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, giant cell arteritis, or secondary osteoarthritis from inflammatory diseases in a human, (10) graft rejection (including allograft rejection and graft-v-host disease), and (11) other diseases in which undesired inflammatory responses are to be inhibited, such as atherosclerosis, myositis, neurodegenerative diseases (e.g., Alzheimer's disease), encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis, chronic obstructive pulmonary disease, sinusitis, Behcet's syndrome and gout.
In one embodiment, the disease or condition that the present methods are directed to treat is an autoimmune disease or condition.
In one embodiment, the disease or condition in the present methods are directed to treat is a neurodegenerative or neuroinflammatory disorder in a human. In one embodiment, the disease or condition that the present methods are directed to treat is rheumatoid arthritis, juvenile arthritis, juvenile rheumatoid arthritis, systemic onset rheumatoid arthritis, pauciarticular rheumatoid arthritis, pauciarticular juvenile rheumatoid arthritis, polyarticular rheumatoid arthritis, enteropathic arthritis, juvenile Reiter's Syndrome, ankylosing spondylitis, juvenile ankylosing spondylitis, SEA Syndrome, reactive arthritis (reactive arthropathy), psoriatic arthropathy, juvenile enteropathic arthritis, polymyalgia rheumatica, enteropathic spondylitis, juvenile idiopathic arthritis (JIA), juvenile psoriatic arthritis, juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, giant cell arteritis, or secondary osteoarthritis from inflammatory diseases in a human.
In one embodiment, the disease or condition that the present methods are directed to treat is lupus, systemic lupus erythematosus, juvenile systemic lupus erythematosus, lupus nephritis, Sjogren's syndrome, scleroderma (systemic sclerosis), Raynaud's phenomenonjuvenile scleroderma, polymyositis, dermatomyositis, polymyositis- dermatomyositis, mixed connective tissue disease, sarcoidosis, fibromyalgia, vasculitis microscopic polyangiitis, vasculitis, eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss syndrome), granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis), polyarteritis nodosa, Henoch- Schonlein purpura, idiopathic thrombocytopenic thrombotic purpura, juvenile vasculitis, polyarteritis nodossa (also known as panarteritis nodosa, periarteritis nodosa, Kussmaul disease, Kussmaul-Maier disease or PAN), serum sickness, Myasthenia gravis, Takayasu's arteritis, Behpet's syndrome, Kawasaki's disease (mucocutaneous lymph node syndrome), Buerger's disease (thromboangiitis obliterans), Vogt-Koyanagi-Harada syndrome, Addison's disease, Hashimoto's thyroiditis, sclerosing cholangitis, membranous glomerulopathy, polymyositis, myositis, atherosclerosis, autoimmune hemolytic anemia, autoimmune orchitis, or Goodpasture's disease in a human.
In one embodiment, the present methods are directed to the treatment of diseases or conditions selected from inflammatory bowel disease, Crohn's disease, or ulcerative colitis in a human.
In one embodiment, the present methods are directed to the treatment of diseases or conditions selected from allergic diseases, psoriasis, skin conditions such as atopic dermatitis and asthma and scleroderma.
In one embodiment, the disease or condition that the present methods are directed to treat is psoriasis, atopic dermatitis, eczema dermatitis, dermatitis, pruritus, alopecia, autoimmune alopecia, vitiligo, epidermal hyperplasia, juvenile dermatomyositis, or dermatomyositis .
In another group of embodiments, modulation of CCR6 dependent regulatory T cell trafficking may be modulated to treat diseases or conditions including cancers, infectious diseases (viral infections, e.g., HIV infection, and bacterial infections) and immunosuppressive diseases such as organ transplant conditions and skin transplant conditions. The term "organ transplant conditions" is meant to include bone marrow transplant conditions and solid organ (e.g., kidney, liver, lung, heart, pancreas or combination thereof) transplant conditions.
6. Kits
Another aspect of the present disclosure provides kits comprising the compound of any one of the formulae described above or pharmaceutical compositions comprising the compound of any one of the formulae described above of the present disclosure. A kit may include, in addition to the compound of any one of the formulae described above, of the present disclosure or pharmaceutical composition thereof, diagnostic or therapeutic agents.
A kit may also include instructions for use in a diagnostic or therapeutic method. In some embodiments, the kit includes the compound of any one of the formulae described above, or a pharmaceutical composition thereof and a diagnostic agent. In other embodiments, the kit includes the compound of any one of the formulae described above, or a pharmaceutical composition thereof.
In yet another embodiment, the present disclosure comprises kits that are suitable for use in performing the methods of treatment described herein. In one embodiment, the kit contains a first dosage form comprising one or more of the compounds of the present disclosure in quantities sufficient to carry out the methods of the present disclosure. In another embodiment, the kit comprises one or more compounds of the present disclosure in quantities sufficient to carry out the methods of the present disclosure and a container for the dosage and a container for the dosage.
7. Preparation
The compounds of any one of the formulae described above, may be prepared by the general and specific methods described below, using the common general knowledge of one skilled in the art of synthetic organic chemistry. Such common general knowledge can be found in standard reference books such as Comprehensive Organic Chemistry, Ed. Barton and Ollis, Elsevier; Comprehensive Organic Transformations: A Guide to Functional Group Preparations, Larock, John Wiley and Sons; and Compendium of Organic Synthetic Methods, Vol. I- XII (published by Wiley-Interscience). The starting materials used herein are commercially available or may be prepared by routine methods known in the art.
In the preparation of the compounds of any one of the formulae described above, it is noted that some of the preparation methods described herein may require protection of remote functionality ( e.g ., primary amine, secondary amine, carboxyl in any one of the formulae described above precursors). The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. The need for such protection is readily determined by one skilled in the art. The use of such protection/deprotection methods is also within the skill in the art. For a general description of protecting groups and their use, see Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.
For example, certain compounds contain primary amines or carboxylic acid functionalities which may interfere with reactions at other sites of the molecule if left unprotected. Accordingly, such functionalities may be protected by an appropriate protecting group which may be removed in a subsequent step. Suitable protecting groups for amine and carboxylic acid protection include those protecting groups commonly used in peptide synthesis (such as N-t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and 9- fluorenylmethylenoxycarbonyl (Fmoc) for amines, and lower alkyl or benzyl esters for carboxylic acids) which are generally not chemically reactive under the reaction conditions described and can typically be removed without chemically altering other functionality in the any one of the formulae described above compounds.
The Schemes described below are intended to provide a general description of the methodology employed in the preparation of the compounds of the present disclosure. Some of the compounds of the present present disclosure may contain single or multiple chiral centers with the stereochemical designation ( R ) or (5). It will be apparent to one skilled in the art that all of the synthetic transformations can be conducted in a similar manner whether the materials are enantioenriched or racemic. Moreover, the resolution to the desired optically active material may take place at any desired point in the sequence using well known methods such as described herein and in the chemistry literature. EXAMPLES
Abbreviations
DAST Diethylamino sulfur trifluoride
DCM Dichloromethane
DIPEA N,N-Diisopropylethylamine
DMAP 4-Dimethylaminopyridine
DMF N,N-dimethylformamide
DMF-DMA N,N-dimethylformamide dimethyl acetal
DMSO Dimethyl sulfoxide
Dppf 1 , 1 '-Bis(diphenylphosphino)ferrocene
EA Ethyl acetate
EtOH Ethanol
EtOAc Ethyl acetate
HATU N-[(Dimethylamino)-lH-l,2,3-triazolo-[4,5-b]pyridin-l-ylmethylene]-N methylmethanaminium hexafluorophosphate N-oxide HPLC High performance liquid chromatography
Int Intermediate
LC-MS Liquid chromatography - mass spectrometry
MeOH Methanol
NMP N-Methyl-2-pyrrolidinone
Pd(dppf)Cl2 Dichloro[l,l'-bis(diphenylphosphino)ferrocene]palladium Pd2(dba)3 Tris(dibenzylideneacetone) dipalladium
PE Petroleum ether
Prep Preparative
Ruphos 2-Dicyclohexylphosphino-2’ ,6’ -diisopropoxy- 1 , 1 ’-biphenyl
Ruphos Pd G2 (2’-Amino-[l,l’-biphenyl]-2-yl)(dicyclohexy(2’,6’-diisopropoxy-[l,l’- biphenyl] -2-yl)phosphoranyl)palladium(II) chloride TEA Triethylamine
THF Tetrahydrofuran
Tf Triflate
Ts Tosyl
Xantpho s 4,5 -B is (diphenylpho sphino) -9 , 9-dimethylxanthene Section 1
General methods and preparations
The compounds, including those of general formula (I), intermediates and specific examples are prepared through the synthetic methods described herein. In the experimental procedures, the modifications to reaction conditions, such as, temperature, concentration of solutions, volume of solvents, application of microwave conditions, duration of the reaction or combinations thereof, are envisioned as part of the present disclosure, and besides specifically mentioned acids, bases, reagents, coupling reagents, solvents, etc., alternative suitable acids, bases, reagents, coupling reagents, solvents etc. may be used and are included within the scope of the present disclosure. All possible geometrical isomers, stereoisomers, salt forms are envisioned within the scope of present disclosure.
Section 2. Synthetic Procedure for Preparing Intermediates
Int. 1
Figure imgf000035_0001
Trans -A-(4-((4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)phenyl)thio)cyclohexyl)-5-
(trifluoromethyl)pyridin-2-amine
Figure imgf000035_0002
Step 1: To a solution of tert- butyl (/ran.s'-4-((4-biOmophcnyl)thio)cyclohcxyl)carbamatc (4.90 g, 12.68 mmol) in EA (10 mL) was added HC1/EA (4M, 25.0 mL). The mixture was stirred at 25 °C for an hour and concentrated in vacuo to give trans - 4 - ( ( 4 - b ro m o p h c n y 1 ) t h i o ) c y c 1 o h c x a n - 1-amine (3.60 g, 99% yield, HC1 salt) as a white solid. LC-MS (ESI) [(M+H)+]: 285.8.
Step 2: To a solution of trans-4-((4-bromophenyl)thio)cyclohexan-l -amine (HC1 salt, 3.60 g, 11.16 mmol) and A, A- d i i s o p ro p y 1 c t h y 1 a m i n c (4.33 g, 33.47 mmol, 5.83 mL) in DMF (40 mL) was added 2-fluoro-5-(trifluoromethyl)pyridine (2.21 g, 13.39 mmol). The mixture was stirred at 100 °C for 3 hours, cooled to room temperature, diluted with water (120 mL) and extracted with EA (200 mL x 2). The organic layers were washed with brine (150 mL x 2), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate in petroleum ether from 0 to 50%) to give trans-N-(4-((4-bromophenyl)thio)cyclohexyl)-5- (trifluoromethyl)pyridin-2-amine (3.4 g, 71% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 431.1.
Step 3: To a suspension of trans-N-(4-((4-bromophenyl)thio)cyclohexyl)-5-
(trifluoromethyl)pyridin-2-amine (2.66 g, 6.17 mmol) and potassium acetate (1.21 g, 12.33 mmol) in dioxane (35 mL) were added Pd(dppf)Cl2 (225.6 mg, 308.36 μmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.72 g, 6.78 mmol). The mixture was degassed with N2 and stirred at 100 °C for 5 hours, cooled to room temperature and filtered through a Celite pad. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate in petroleum ether from 0 to 80%) give trans-N-(4-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)thio)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine (2.90 g, 98% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 478.8.
Int. 2
Figure imgf000036_0001
Trans -/V-(4-((4-bromophenyl)sulfonyl)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine
Int. 3
Figure imgf000036_0002
Trans-N-(4-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)cyclohexyl)-
5-(trifluoromethyl)pyridin-2-amine
Figure imgf000037_0001
Step 1: To solution of tert-butyl cw-A/-(4-hydroxycyclohexyl)carbamate (23.00 g, 106.83 mmol), methanesulfonic anhydride (26.05 g, 149.57 mmol) and DMAP (1.31 g, 10.68 mmol) in THF (460 mL) was added dropwise TEA (30.27 g, 299.13 mmol, 41.69 mL) at 0 °C. The mixture was stirred at this temperature for 30 minutes, allowed to warm to room temperature slowly and stirred overnight until the starting material was totally consumed. The mixture was quenched with H2O (300 mL) and extracted with ethyl acetate (200 mL x 2). The organic layers were washed with brine (200 mL x 2), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with methanol in dichloromethane from 0 to 2%) to give cis-A-{{tert- butoxycarbonyl)amino)cyclohexyl methanesulfonate (28.30 g, 94% yield) as a white solid. 'H NMR (400 MHz, CDC13) δ 4.88-4.81 (m, 1H), 4.46 (s, 1H), 3.49 (s, 1H), 2.98 (s, 3H), 2.08- 1.96 (m, 2H), 1.85-1.76 (m, 2H), 1.75-1.66 (m, 2H), 1.53 (td, J = 13.1 Hz, 3.4 Hz, 2H), 1.41 (s, 9H).
Step 2: To a solution of cA-4-((tert-butoxycarbonyl)amino)cyclohexyl methanesulfonate (27.50 g, 93.74 mmol) and 4-bromobenzenethiol (17.72 g, 93.74 mmol) in DMF (400 mL) was added cesium carbonate (91.62 g, 281.21 mmol). The mixture was stirred at 100 °C for 3 hours, cooled to room temperature, diluted with water (800 mL) and extracted with ethyl acetate (500 mL x 3). The organic layers were washed with brine (300 mL x 2), dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate in petroleum ether from 0 to 50%) to give tert-butyl (trans-4-((4-bromophcnyl)thio)cyclohcxyl (carbamate (17.50 g, 48% yield) as a white solid.
Step 3: To a solution of tert-butyl (trans-4-((4-bromophcnyl)thio)cyclohcxyl (carbamate (19.20 g, 49.70 mmol) in CH2CI2 (300 mL) was added 3-chlorobenzenecarboperoxoic acid (25.73 g, 149.09 mmol). The mixture was stirred at 25 °C for 2 hours until the starting material was totally consumed. The mixture was quenched with Na2S03 aqueous solution (200 mL, 1M) and extracted with CH2CI2 (150 mL x 3). The organic layers were washed with brine (100 mL x 2), dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate in petroleum ether from 0 to 60%) to give tert-butyl (trans-4-((4- bromophenyl)sulfonyl)cyclohexyl)carbamate (22 g, crude) as a white solid. LC-MS (ESI) [(M+Na)+]: 418.1.
Step 4: To a solution of crude tert-butyl (trans- 4-((4- bromophenyl)sulfonyl)cyclohexyl)carbamate (14.0 g, 33.47 mmol) in EA (20 mL) was added HC1/EA (4M, 60 mL). The mixture was stirred at 25 °C for an hour and concentrated in vacuo to give / ran .s-4-((4-b ro m o p h c n y 1 ) s u l fo n y 1 ) c y c 1 o h c x a n - 1 - a m i n c (12.80 g, crude, HC1 salt) as a white solid. LC-MS (ESI) [(M+H)+]: 318.1.
Step 5: To a solution of trans-4-((4-bromophenyl)sulfonyl)cyclohexan- 1-amine (HC1 salt, 12.80 g, 40.22 mmol) and A,A-diisopropylcthylaminc (15.60 g, 120.67 mmol, 21.02 mL) in DMF (60 mL) was added 2-fluoro-5-(trifluoromethyl)pyridine (7.97 g, 48.27 mmol). The mixture was stirred at 100 °C for 6 hours, cooled to room temperature, diluted with water (120 mL) and extracted with EA (200 mL x 2). The organic layers were washed with brine (150 mL x 2), dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate in petroleum ether from 0 to 50%) to give t ran .y - N (4- - ((4 - b ro m o p h c n y 1 ) s u 1 fo n y 1 ) c y c 1 o h c x y 1 ) - 5-(trifluoromethyl)pyridin-2-amine (8.50 g, 46% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 463.1.
Step 6: To a suspension of trans-4- (4 - ((4 - b ro m o p h c n y 1 ) s u 1 fo n y 1 ) c y c 1 o h c x y 1 ) - 5 - (trifluoromethyl)pyridin-2-amine (6.30 g, 13.60 mmol) and potassium acetate (2.80 g, 28.56 mmol) in dioxane (65 mL) were added Pd(dppf)Cl2 (497.5 mg, 679.89 μmol ) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (3.63 g, 14.28 mmol). The mixture was degassed with N2 and stirred at 100 °C for 2.5 hours, cooled to room temperature and filtered through a Celite pad. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate in petroleum ether from 0 to 80%) give iran,y-/V-(4-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)sulfonyl)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine (6.60 g, 95% yield) as a white solid, which contained a little boric acid product. LC-MS (ESI) [(M+H)+]: 510.8. Section 3. Synthetic Procedure for Preparing Exemplified Compounds
Example 1
Figure imgf000039_0001
pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)picolinamide
Figure imgf000039_0002
Step 1: To a stirred solution of tert- butyl {trans- 4-((4- bromophenyl)sulfonyl)cyclohexyl)carbamate (2.0 g, 4.78 mmol) and 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.46 g, 5.74 mmol) in 1,4-dioxane (40 mL) were added potassium acetate (1.41 g, 14.34 mmol) and Pd(dppf)Cl2 (349.8 mg, 478.07 μmol). The reaction mixture was stirred at 100 °C under N2 atmosphere for 16 hours, cooled to room temperature, diluted with EA (150 mL) and washed with brine (50 mL x 3). The organic phase was dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with MeOH/DCM: 1/15) to give tert-butyl (trans-4-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)sulfonyl)cyclohexyl)carbamate (2.2 g, 99% yield) as a white solid. LC-MS (ESI) [(M+H)+] : 466.1.
Step 2: To a stirred solution of tert-butyl (trans-4-((4-(4,4,5,5-tctramcthyl- 1 ,3,2-dioxaborolan- 2-yl)phenyl)sulfonyl)cyclohexyl)carbamate (2.2 g, 4.73 mmol) and 4-chloropicolinamide (888.1 mg, 5.67 mmol) in mixed solvent of 1,4-dioxane (40 mL) and H2O (10 mL) were added potassium phosphate (3.01 g, 14.18 mmol) and Pd(dppf)Cl2 (345.9 mg, 472.70 μmol). The reaction mixture was stirred at 100 °C under N2 atmosphere for 16 hours, cooled to room temperature, diluted with EA (150 mL) and washed with brine (50 mL x 3). The organic phase was dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with MeOH/DCM: 1/15) to give tert- butyl (trans-4-((4-(2-carbamoylpyndin-4- yl)phenyl)sulfonyl)cyclohexyl)carbamate (2.0 g, 92% yield) as a white solid. LC-MS (ESI) [(M+H)+] : 460.1.
Step 3: To a stirred solution of tert- butyl (trans-4-((4-(2-carbamoylpyndin-4- yl)phenyl)sulfonyl)cyclohexyl)carbamate (2.0 g, 4.35 mmol) in DCM (40 mL) was added HC1/EA (4M, 20 mL). The mixture was stirred at 25 °C for 1 hour, and concentrated in vacuo to give 4-(4-((trans-4-aminocyclohcxyl)suironyl)phcnyl)picolinamidc (1.6 g, quantitative) as a white solid. LC-MS (ESI) [(M+H)+]: 360.1.
Step 4: To a stirred solution of 4-(4-((trans-4-aminocyclohcxyl)suironyl)phcnyl)picolinamidc (200 mg, 556.42 μmol) and 2,3-difluoro-5-(trifluoromethyl)pyridine (112.1 mg, 612.06 μmol, 76.2 μL) in DMF (4.0 mL) was added DIPEA (287.7 mg, 2.23 mmol, 387.7 μL). The mixture was stirred at 100 °C for 4 hours, diluted with water (10 mL) and extracted with EA (30 mL x 3). The organic layer was washed with brine (10 mL x 4), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with MeOH in DCM from 0 to 10%) to give 4-{4-{{trans- 4-((3-fluoro-5-(trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)sulfonyl)phenyl)picolinamide (48.1 mg, 17% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 523.1.
Figure imgf000040_0001
NMR (400 MHz, DMSO-de) d 8.78 (d, J= 5.1 Hz, 1H), 8.39 (d, J= 1.1 Hz, 1H), 8.23 (s, 1H), 8.20-8.14 (m, 3H), 8.02 (dd, / = 5.3 Hz, 3.1 Hz, 3H), 7.82-7.68 (m, 2H), 7.33 (d, J = 7.1 Hz, 1H), 3.67 (s, 1H), 3.43 (s, 1H), 2.02 (d, J = 8.7 Hz, 4H), 1.53-1.32 (m, 4H).
Example 2
Figure imgf000040_0002
4-(4-((7>ans-4-((3-cyano-5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)picolinamide
Synthesized according to Example 1, using 2-chloro-5-(trifluoromethyl)pyridine-3-carbonitrile replacing 2,3-difluoro-5-(trifluoromethyl)pyridine in Step 4. As a white solid. LC-MS (ESI) [(M+H)+] : 530.1.
Figure imgf000040_0003
NMR (400 MHz, DMSO -d6) d 8.78 (d, J = 5.1 Hz, 1H), 8.59 (d, J = 1.7 Hz, 1H), 8.37 (dd, / = 10.8 Hz, 1.7 Hz, 2H), 8.23 (s, 1H), 8.17 (d, J = 8.4 Hz, 2H), 8.02 (dd, / = 5.3 Hz, 3.1 Hz, 3H), 7.77 (s, 1H), 7.65 (d, J = 7.7 Hz, 1H), 3.67 (s, 1H), 3.43 (s, 1H), 2.06- 1.92 (m, 4H), 1.59-1.39 (m, 4H). Example 3
Figure imgf000041_0001
Methyl 2-((frans-4-((4-(2-carbamoylpyridin-4-yl)phenyl)sulfonyl)cyclohexyl)amino)-5-
(trifluoromethyl)isonicotinate Synthesized according to Example 1, using methyl 2-chloro-5-(trifluoromethyl)pyridine-4- carboxylate replacing 2,3-difluoro-5-(trifluoromethyl)pyridine in Step 4. As a white solid. LC- MS (ESI) [(M+H)+] : 563.1.
Figure imgf000041_0002
8.78 (d, J = 5.1 Hz, 1H), 8.38 (s, 1H), 8.23 (s, 1H), 8.16 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 8.4 Hz, 3H), 7.78 (s, 1H), 7.70 (d, J = 9.1 Hz, 1H), 7.60 (d, J = 7.5 Hz, 1H), 6.67 (d, J= 8.4 Hz, 1H), 3.83 (s, 3H),3.67 (s, 1H), 3.43 (s, 1H),2.01 (s, 4H), 1.56-1.32 (m, 4H).
Example 4
Figure imgf000041_0003
4-(4-((7Vans-4-((6-(trifluoromethyl)pyridazin-3- yl)amino)cyclohexyl)sulfonyl)phenyl)picolinamide
Figure imgf000041_0004
Step 1: To a solution of 3-chloro-6-(trifluoromethyl)pyridazine (182.5 mg, 1.0 mmol) and l ra n ,v - 4 - ((4 - h ro in o p h c n y 1 ) s u 1 fo n y 1 ) c y c 1 o h c x a n - 1 - a m i n c (349.8 mg, 986.1 , HC1 salt) in μmol NMP (4 mL) was added DIPEA (318.6 mg, 2.5 mmol, 429.4 μL). The mixture was stirred at 210 °C for 3 hours, cooled to room temperature, poured into water (20 mL) and extracted with EA (40 mL x 3). The organic layer was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with EA in PE from 0 to 70%) to give trans- A-(4-((4-bromophenyl)sulfonyl)cyclohexyl)-6-(trifluoromethyl)pyridazin-3-amine (350 mg, crude) as brown oil. LC-MS (ESI) [(M+H)+]: 463.9.
Step 2: To a solution of / ran s - A- (4 - ((4 - h ro m o p h c n y 1 ) s u 1 fo n y 1 ) c y c 1 o h c x y 1 ) - 6 -
(trifluoromethyl)pyridazin-3-amine (300 mg, 646.1 μmol) and 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(l,3,2-dioxaborolane) (164.1 mg, 646.1 μmol) in dioxane (8 mL) were added Pd(dppf)Cl2 (94.6 mg, 129.2 μmo)l and potassium acetate (190.2 mg, 1.9 mmol) under the atmosphere of N2. The mixture was stirred at 110 °C under the atmosphere of N2 for 4 hours, cooled to room temperature and filtered. The filtrate was concentrated in vacuo to afford trans- A-(4-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)cyclohexyl)-6- (trifluoromethyl)pyridazin-3-amine (crude), which was used in the next step without further purifications. LC-MS (ESI) [(M+H)+]: 512.2.
Step 3: To a solution of 4-bromopyridine-2-carboxamide (86.5 mg, 430.2 μmo)l and trans-N- (4-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)cyclohexyl)-6- (trifluoromethyl)pyridazin-3-amine (330 mg, 645.3 μmo)l in dioxane/water (9 mL, 8/1) were added Pd(dppf)Cl2 (63.0 mg, 86.0 μmo)l and K2CO3 (178.4 mg, 1.3 mmol). The mixture was stirred at 110 °C under N2 atmosphere for 6 hours, cooled to room temperature and filtered through a Celite pad. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with methanol in dichloromethane from 0 to 10%) and further by prep-HPLC to give 4-(4-((trans-4-((6-(trifluoromethyl)pyridazin-3- yl)amino)cyclohexyl)sulfonyl)phenyl)picolinamide (5.5 mg, 3% yield) as a white solid. LC- MS (ESI) [(M+H)+] : 506.0.
Figure imgf000042_0001
8.78 (d, J = 5.2 Hz, 1H), 8.38 (s, 1H), 8.24 (s, 1H), 8.17 (d, J= 8.4 Hz, 2H), 8.08-7.95 (m, 3H), 7.78 (s, 1H), 7.63 (d, J= 9.2 Hz, 1H), 7.56 (d, J = 6.0 Hz, 1H), 6.92 (d, J = 9.2 Hz, 1H), 3.85-3.75 (m, 1H), 3.48-3.44 (m, 1H), 2.17-2.07 (m, 2H), 2.05-1.97 (m, 2H), 1.59-1.45 (m, 2H), 1.37-1.22 (m, 2H).
Example 5
Figure imgf000042_0002
4-(4-((7r«H.s-4-((5-(trifluoromethyl)pyrazin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)picolinamide
Synthesized according to Example 4, with the alternative procedure in Step 1 : To a solution of l ra n .y - 4 - ((4 - b ro m o p h c n y 1 ) s u 1 fo n y 1 ) c y c 1 o h c x a n - 1 - a m i n c (250 mg, 704.8 , HC1 salt) in μmol DMF (8 mL) were added potassium carbonate (487.1 mg, 3.5 mmol) and 2-chloro-5- (trifluoromethyl)pyrazine (167.3 mg, 916.3 μmo)l. The mixture was stirred at 90 °C for 4 hours and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with EA in PE from 0 to 70%) to give trans-N-( 4-((4- bromophenyl)sulfonyl)cyclohexyl)-5-(trifluoromethyl)pyrazin-2-amine (190 mg, 58% yield) as a yellow solid. LC-MS (ESI) [(M+H)+]: 463.9.
As a white solid. LC-MS (ESI) [(M+H)+]: 506.0.
Figure imgf000043_0001
NMR (400 MHz, DMSO -d6) d 8.78 (d, J = 5.2 Hz, 1H), 8.38 (d, J = 1.2 Hz, 1H), 8.35 (s, 1H), 8.24 (d, 7 = 2.0 Hz, 1H), 8.17 (d, J = 8.4 Hz, 2H), 8.05-7.98 (m, 3H), 7.95 (s, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.78 (d, J = 2.0 Hz, 1H), 3.73-3.62 (m, 1H), 3.47-3.39 (m, 1H), 2.10-1.97 (m, 4H), 1.55-1.42 (m, 2H), 1.36-1.24 (m, 2H).
Example 6
Figure imgf000043_0002
4- (4-( (Trans -4- ((5- (dimethylphosphoryl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)picolinamide
Synthesized according to Example 4, with the alternative procedure in Step 1 : To a solution of l ra /7.V - 4 - ((4 - b ro m o p h c n y 1 ) s u 1 fo n y 1 ) c y c 1 o h c x a n - 1 - a m i n c (0.2 g, 628.5 ) in DMF (5 mL) μmol were added DIPEA (162.4 mg, 1.3 mmol, 218.9 μL) and 5-dimethylphosphoryl-2-fluoro- pyridine (130.5 mg, 754.1 μmo)l. The mixture was stirred at 100 °C for 5 hours, cooled to room temperature, diluted with water (30 mL) and extracted with EtOAc (20 mL x 2). The combined organic layer was dried over anhydrous NaiSCE and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with DCM/MeOH: 5/1) to afford (6-((trans-4-((4- bromophenyl)sulfonyl)cyclohexyl)amino)pyridin-3-yl)dimethylphosphine oxide (130.0 mg, 43% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 471.2. As a white solid. LC-MS (ESI) [(M+H)+]: 513.1. NMR (400 MHz, DMSO -d6) d 8.78 (d, J = 4.0 Hz, 1H), 8.38 (d, J = 2.0 Hz, 1H), 8.26-8.19 (m, 2H), 8.17 (d, J = 12.0 Hz, 2H), 8.06- 7.91 (m, 3H), 7.78 (d, J = 2.0 Hz, 1H), 7.63-7.54 (m, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.49 (d, J = 8.0 Hz, 1H), 3.70-3.62 (m, 1H), 3.44-3.38 (m, 1H), 1.90-2.11 (m, 4H), 1.62-1.48 (m, 6H), 1.45-1.42 (m, 2H), 1.30-1.22 (m, 2H). 31P NMR (162 MHz, DMSO -d6) d 30.77.
5-Dimethylphosphoryl-2-fluoro-pyridine was synthesized as below: To a solution of 5-bromo- 2-fluoro-pyridine (2.0 g, 11.3 mmol, 1.2 mL), dimethylphosphine oxide (975.7 mg, 12.5 mmol) in dioxane (20 mL) were added palladium (II) acetate (510.2 mg, 2.2 mmol), XantPhos (2.0 g, 3.4 mmol) and potassium phosphate (4.8 g, 22.7 mmol). The mixture was stirred at 110 °C under N2 atmosphere for 16 hours, cooled to room temperature and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with hexanes/ethyl acetate: 10/1) to afford 5-dimethylphosphoryl-2-fluoro- pyridine (1.3 g, 66% yield) as a gray solid. LC-MS (ESI) [(M+H)+]: 174.1.
Example 7
Figure imgf000044_0001
4-(4-(7>ans-4-((5-(trifluoromethyl)pyridin-2-yl)amino)cyclohexane-l- sulfonimidoyl)phenyl)picolinamide
Figure imgf000044_0002
Step 1: To a solution of 4-bromopyridine-2-carboxamide (252.1 mg, 1.2 mmol) and int. 1 (400 mg, 836.1 μmol) in mixed solvent of dioxane (5 mL), ethanol (3 mL) and water (1 mL) were added Pd(dppf)Cl2 (91.8 mg, 125.4 μmo)l and potassium carbonate (346.7 mg, 2.5 mmol). The mixture was stirred at 110 °C under N2 atmosphere for 16 hours, cooled to room temperature and filtered through a Celite pad. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate in dichloromethane from 0 to 100%) to give 4-(4-((irans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)thio)phenyl)picolinamide (170 mg, crude) as yellow oil. LC-MS (ESI) [(M+H)+] : 473.1.
Step 2: To a mixture of 4-(4-((irans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)thio)phenyl)picolinamide (170 mg, 359.7 μmol ) and ammonium carbamate (70.2 mg, 899.4 μmo)l in methanol (10 mL) was added iodobenzene diacetate (231.7 mg, 719.5 μmo)l. The mixture was stirred at 25 °C for 15 minutes and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with methanol in dichloromethane from 0 to 10%) to give 4-(4-(trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexane-l-sulfonimidoyl)phenyl)picolinamide (3.2 mg, 0.8% yield of 2 steps) as a white solid. LC-MS (ESI) [(M+H)+]: 504.1.
Figure imgf000045_0001
NMR (400 MHz, DMSO -d6) d 8.76 (d, J = 5.2 Hz, 1H), 8.37 (d, J = 1.2 Hz, 1H), 8.23 (d, J= 8.4 Hz, 2H), 8.11 (d, J = 8.4 Hz, 2H), 8.04- 7.97 (m, 3H), 7.77 (s, 1H), 7.57 (dd, /= 8.8 Hz, 2.4 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 6.53 (d, / = 8.8 Hz, 1H), 4.36 (s, 1H), 3.62 (s, 1H), 3.13 (t, /= 12.0 Hz, 1H), 2.08-1.92 (m, 4H), 1.51- 1.34 (m, 2H), 1.32-1.08 (m, 2H). 19F NMR (400 MHz, DMSO -d6) d -59.22.
Example 7A & 7B
SFC chiral separation of Example 7 provided enantiomers of 4-(4-(trans-4-((5- (trifluoromethyl)pyridin-2-yl)amino)cyclohexane-l-sulfonimidoyl)phenyl)picolinamide. The stereochemistry was not confirmed, and two products were arbitrarily assigned.
Example 7A: LC-MS (ESI) [(M+H)+] : 504.1. Chiral-HPLC retention time: 2.428 min; ee value: > 99%.
Example 7B: LC-MS (ESI) [(M+H)+] : 504.1. Chiral-HPLC retention time: 3.362 min; ee value: > 99%.
Example 8
Figure imgf000045_0002
4- (4- (Trans - A- methyl-4- ((5- (trifluoromethyl)pyridin-2-yl)amino)cy clohexane- 1 - sulfonimidoyl)phenyl)picolinamide
Figure imgf000046_0001
Step i: To a mixture of /<? /7-butyl (7f<ms'-4-((4-bromophcnyl)thio)cyclohcxyl (carbamate (1.5 g, 3.9 mmol) and ammonium carbamate (909.3 mg, 11.7 mmol) in methanol (15 mL) was added iodobenzene diacetate (3.8 g, 11.7 mmol). The mixture was stirred at 25 °C for 30 minutes and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with EtOAc/DCM from 0 to 30%) to give tert-butyl (trans-4-(4- bromophenylsulfonimidoyl)cyclohexyl)carbamate (1.4 g, 84% yield) as a white solid. LC-MS (ESI) [(M+H)+] : 417.1.
Step 2: To a solution of tert-butyl (/ran.s'-4-(4- bromophenylsulfonimidoyl)cyclohexyl)carbamate (1.3 g, 3.1 mmol) in DML (10 mL) was added NaH (60% dispersion in mineral oil, 211.8 mg, 5.3 mmol) at 0 °C. The mixture was stirred at 0 °C for 10 minutes, followed by the addition of iodomethane (455.4 mg, 3.2 mmol, 199.7 μL). The mixture was stirred at 20 °C for 3 hours., quenched with water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layer was washed with brine (60 mL), dried over anhydrousNa2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with EtOAc/PE from 0 to 70%) to afford tert-butyl ( l ra / / .v - 4 - (4 - b ro m o - A- methylphenylsulfonimidoyl)cyclohexyl)carbamate (1.3 g, 94% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 431.1.
Step 3: To a solution of tert- butyl ( / ran.s' - 4 - ( 4 - b ro m o - N- methylphenylsulfonimidoyl)cyclohexyl)carbamate (700 mg, 1.6 mmol) in DCM (5 mL) was added HC1/EA (4M, 15 mL). The reaction mixture was stirred at room temperature for 4 hours and concentrated in vacuo to afford ilrans -A- a m i n o c y c 1 o h c x y 1 ) (4 - b ro m o p h c n y 1 ) (in c t h y 1 i in i n o ) - l6 - s u 1 fa n o n c (560 mg, crude, HC1 salt) as a white solid. LC-MS (ESI) [(M+H)+] : 331.1. Step 4\ To a solution of (iran5-4-aminocyclohexyl)(4-bromophenyl)(methylimino)-X6- sulfanone (560 mg, 1.5 mmol, HC1 salt) in DMF (8 mL) were added DIPEA (984.1 mg, 7.6 mmol, 1.3 mL) and 2-fluoro-5-(trifluoromethyl)pyridine (326.8 mg, 2.0 mmol). The mixture was stirred at 90 °C for 8 hours and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc/PE from 0 to 60%) to afford (4- hiOmophcnyl)(mcthyli mi no)(/ra77.s,-4-((5-(trifluoiO methyl )pyridin-2-yl)amino)cyclohcxyl)- X6-sulfanone (480 mg, 66% yield) as yellow oil. LC-MS (ESI) [(M+H)+]: 476.1.
Step 5: To a solution of (4-bromophcnyl)(mcthylimino)(trans-4-((5-(tnfhioromcthyl)pyndin- 2-yl)amino)cyclohexyl)- X6-sulfanone (250 mg, 524.8 μmo)l and 4,4,4',4',5,5,5',5'-octamethyl- 2,2'-bi(l,3,2-dioxaborolane) (199.9 mg, 787.2 μmol ) in dioxane (10 mL) were added Pd(dppf)Cl2 (76.8 mg, 105.0 μmo)l and potassium acetate (206.0 mg, 2.1 mmol) under the atmosphere of N2. The mixture was stirred at 110 °C under the atmosphere of N2 for 3 hours, cooled to room temperature and filtered. The filtrate was concentrated in vacuo to afford (methylimino)(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)(/ra775-4-((5- (trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)- X6-sulfanone (280 mg, crude) as a black oil which was used in the next step without further purifications. LC-MS (ESI) [(M+H)+]: 524.1.
Step 6: To a solution of 4-bromopyridine-2-carboxamide (107.5 mg, 535.0 μmol) and (methylimino)(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)(/ra775-4-((5- (trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)- X6-sulfanone (280 mg, 535.0 μmol ) in mixed solvent of dioxane (10 mL), ethanol (10 mL) and water (0.6 mL) were added Pd(dppf)Cl2 (78.3 mg, 107. μmo)l and Na2C03 (170.1 mg, 1.6 mmol). The mixture was stirred at 110 °C under N2 atmosphere for 5 hours, cooled to room temperature and filtered through a Celite pad. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate in dichloromethane from 0 to 100%) and further by prep-HPLC to give 4-(4-(/ra/7.s'-A/-mcthyl-4-((5-(tnfhioromcthyl)pyndin-2- yl)amino)cyclohexane-l-sulfonimidoyl)phenyl)picolinamide (90 mg, 33% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 518.1.
Figure imgf000047_0001
8.76 (d, J = 5.2 Hz, 1H), 8.37 (d, J = 1.2 Hz, 1H), 8.26-8.20 (m, 2H), 8.13 (d, J= 8.4 Hz, 2H), 8.02 (dd, /= 5.2 Hz, 2.0 Hz, 1H), 7.89 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 2.0 Hz, 1H), 7.57 (dd, / = 8.8 Hz, 2.4 Hz, 1H), 7.23 (d, 7 = 7.6 Hz, 1H), 6.53 (d, J = 8.8 Hz, 1H), 3.67-3.57 (m, 1H), 3.28-3.22 (m, 1H), 2.54 (s, 3H), 2.28-2.15 (m, 1H), 2.09-1.95 (m, 2H), 1.94-1.81 (m, 1H), 1.53-1.35 (m, 2H), 1.31- 1.14 (m, 2H). 19F NMR (376 MHz, DMSO -d6) d -59.21. Example 9
Figure imgf000048_0001
7-(4-((7>ans-4-((5-(trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)sulfonyl)phenyl)-3,4- dihydroisoquinolin- 1 (2//)-one
Figure imgf000048_0002
Step 1: To a solution of 6-bromoisoindolin-l-one (56.1 mg, 264.5 μmo)l and int. 3 (135 mg, 264.5 m mol) in mixed solvent of dioxane (6 mL), ethanol (6 mL) and water (0.5 mL) were added Pd(dppf)Cl2 (38.7 mg, 52.9 μmo)l and sodium carbonate (84.1 mg, 793.5 μmol). The mixture was stirred at 110 °C under N2 atmosphere for 5 hours, cooled to room temperature and filtered through a Celite pad. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with EA/PE from 0 to 100%) to give 7-(4-((trans-4-((5-(trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)sulfonyl)phenyl)- 3,4-dihydroisoquinolin- 1 (2/7)-onc (89 mg, 65% yield) as an off-white solid. LC-MS (ESI) [(M+H)+] : 530.1. 'HNMR (400 MHZ, DMSO -d6) S 8.29-8.15 (m, 2H), 8.10-8.03 (m, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 8.4 Hz, 2H), 7.89 (dd, / = 7.6 Hz, 2.0 Hz, 1H), 7.58 (dd, / =
8.8 Hz, 2.4 Hz, 1H), 7.48 (d, J= 8.0 Hz, 1H), 7.25 (d, J= 7.6 Hz, 1H), 6.54 (d, J= 8.8 Hz, 1H), 3.75-3.57 (m, 1H), 3.48-3.39 (m, 2H), 3.39-3.34 (m, 1H), 2.97 (t, / = 6.4 Hz, 2H), 2.09-1.94 (m, 4H), 1.56-1.37 (m, 2H), 1.32-1.19 (m, 2H). 19F NMR (376 MHz, DMSO -d6) d -59.21.
Example 10
Figure imgf000048_0003
7-(4-(7raH.s-4-((5-(trifluoromethyl)pyridin-2-yl)amino)cyclohexane-l- sulfonimidoyl)phenyl)-3,4-dihydroisoquinolin-l(2//)-one
Figure imgf000049_0001
Step 1: A mixture of 6-bromoisoindolin-l-one (100 mg, 442.34 mihoΐ), tetrakis(triphenylphosphine) palladium (153.4 mg, 132.70 μmo)l, int. 1 (253.9 mg, 530.81 pmol) and sodium carbonate (117.2 mg, 1.11 mmol) in dioxane/water (2 mL, 4/1) was stirred at 100 °C for 1 hour under N2 atmosphere, cooled to room temperature, and diluted with ethyl acetate (20 mL). The resulting mixture was washed with H2O (10 mL x 3). The organic layer was dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate/hexanes from 0 to 100%) and further by prep-HPLC to give Ί -{A-{{trans-A-{{5- (trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)thio)phenyl)-3,4-dihydroisoquinolin-l(27 )- one (120 mg, 55% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 497.8.
Step 2: To a mixture of 7-(4-((irans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)thio)phenyl)-3,4-dihydroisoquinolin-l(27/)-one (120 mg, 241.17 μmo)l and ammonium carbamate (37.7 mg, 482.34 μmo)l in methanol (4 mL) was added iodobenzene diacetate (156.3 mg, 482.34 μmol). The mixture was stirred at 25 °C for 30 minutes and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with MeOH/DCM from 0 to 10%) and further by prep-HPLC to give Ί -{A-{trans-A- ((5-(trifluoromethyl)pyridin-2-yl)amino)cyclohexane-l-sulfonimidoyl)phenyl)-3,4- dihydroisoquinolin- 1 (2//)-onc (85 mg, 67% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 528.8. NMR (400 MHz, DMSO -d6) d 8.25 (s, 1H), 8.19 (d, J = 1.8 Hz, 1H), 8.06 (s, 1H), 7.99-7.91 (m, 4H), 7.89 (dd, / = 7.9 Hz, 2.0 Hz, 1H), 7.58 (dd, / = 8.9 Hz, 2.3 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 7.4 Hz, 1H), 6.53 (d, J = 8.9 Hz, 1H), 4.26 (s, 1H), 3.63 (s, 1H), 3.46-3.38 (m, 2H), 3.10 (t, / = 12.1 Hz, 1H), 2.97 (t, /= 6.4 Hz, 2H), 2.02 (d, J= 8.2 Hz, 4H), 1.43 (td, /= 23.1, 12.2 Hz, 2H), 1.29-1.16 (m, 2H).
Example 11
Figure imgf000049_0002
3-(4-((7>ans-4-((5-(trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)sulfonyl)phenyl)-7,8- dihydro-1, 6-naphthyridin-5(6iT)-one
Figure imgf000050_0001
Step 1: To a solution of 3 - b ro m o - 7 , 8 - d i h yd ro - 6 /7- L 6 - n a p h t h y ri d i n - 5 - o n c (88.1 mg, 388.0 pmol) and int. 3 (198 mg, 388.0 p mol) in mixed solvent of dioxane (15 mL), ethanol (15 mL) and water (3 mL) were added Pd(dppf)Cl2 (56.8 mg, 77.6 μmol) and sodium carbonate (82.2 mg, 775.9 μmo)l. The mixture was stirred at 110 °C under N2 atmosphere for 8 hours, cooled to room temperature and filtered through a Celite pad. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with MeOH/DCM from 0 to 10%), and the impure product was triturated in DCM (5 mL). The off- white solid was collected by filtration and dried in vacuo to give 3-(4-((/ran.s'-4-((5- (trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)sulfonyl)phenyl)-7, 8-dihydro- 1,6- n ap h t h yridi n -5 (6H)-o nc (60 mg, 29% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 531.1.
NMR (400 MHz, DMSO -d6) S 9.05 (d, J = 2.4 Hz, 1H), 8.46 (d, J = 2.4 Hz, 1H), 8.25 (s, 2H), 8.09 (d, J = 8.5 Hz, 2H), 7.97 (d, J = 8.4 Hz, 2H), 7.58 (dd, / = 8.8 Hz, 2.4 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 6.54 (d, J = 8.8 Hz, 1H), 3.72-3.63 (m, 1H), 3.56-3.48 (m, 2H), 3.43-3.35 (m, 1H), 3.13 (t, /= 6.8 Hz, 2H), 2.02 (t, / = 12.0 Hz, 4H), 1.54-1.42 (m, 2H), 1.32-1.20 (m, 2H). 19F NMR (376.5 MHz, DMSO-d6) d 59.21.
Example 12
Figure imgf000050_0002
3-(4-(7>ans-4-((5-(trifluoromethyl)pyridin-2-yl)amino)cyclohexane-l- sulfonimidoyl)phenyl)-7,8-dihydro-l,6-naphthyridin-5(6//)-one
Figure imgf000050_0003
Step 1: To a solution of 3 - b ro m o - 7 , 8 - d i h yd ro - 6 //- 1 , 6 - n a p h t h y ri d i n - 5 - o n c (91.1 mg, 401.4 p mol) and int. 1 (160.0 mg, 334.5 p mol) in mixed solvent of dioxane (5 mL), ethanol (2 mL) and water (1 mL) were added Pd(dppf)Cl2 (36.7 mg, 50.2 μmol) and potassium carbonate (138.7 mg, 1.0 mmol). The mixture was stirred at 110 °C under N2 atmosphere for 3 hours, cooled to room temperature and filtered through a Celite pad. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with MeOH/DCM from 0 to 10%), to give 3-(4-((irans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)thio )phenyl)-7, 8-dihydro- l,6-naphthyridin-5(67/)-one (140 mg, 84% yield) as a yellow solid. LC-MS (ESI) [(M+H)+]: 499.1.
Step 2: To a mixture of 3-(4-((irans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohcxyl)thio)phcnyl)-7,8-di hydro- 1 ,6-naphthyridin-5(6//)-onc (120.0 mg, 240.7 pmol) and ammonium carbamate (37.6 mg, 481.4 μmo)l in methanol/DCM (4 mL, 3/1) was added iodobenzene diacetate (155.1 mg, 481.4 μmo)l. The mixture was stirred at 25 °C for 30 minutes and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with MeOH/DCM from 0 to 6%) and further by prep-HPLC to give 3-(4- (/ran.s'-4-((5-(trifluoiOmcthyl)pyridin-2-yl)amino)cyclohcxanc-l -sulfonimidoyl)phcnyl)-7,8- dihydro- l,6-naphthyridin-5(67/)-one (40 mg, 32% yield) as a white solid. LC-MS (ESI) [(M+H)+] : 530.1.
Figure imgf000051_0001
NMR (400 MHz, DMSO -d6) S 9.01 (d, J = 2.4 Hz, 1H), 8.42 (d, J = 2.4
Hz, 1H), 8.22 (s, 2H), 8.00 (d, J= 8.4 Hz, 2H), 7.93 (s, 1H), 7.55 (dd, /= 8.8 Hz, 2.4 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 6.50 (d, J= 8.8 Hz, 1H), 4.28 (s, 1H), 3.60 (s, 1H), 3.50-3.38 (m, 2H), 3.12-3.06 (m, 3H), 2.05-1.95 (m, 4H), 1.44-1.38 (m, 2H), 1.24-1.18 (m, 2H). 19L NMR (376 MHz, DMSO-ife) d -59.23.
Example 13
Figure imgf000051_0002
3-(4-((7>ans-4-((5-(trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)sulfonyl)phenyl)-l,6- naphthyridine-5,7(6//,8//)-dione
Figure imgf000051_0003
Step 1: To a solution of 7-hromo-4/7-isoquinolinc- 1 ,3-dionc (22.4 mg, 93.5 p mol) and int. 3 (45 mg, 88.2 p mol) in mixed solvent of dioxane (5 mL), ethanol (5 mL) and water (0.3 mL) were added Pd(dppf)Cl2 (12.9 mg, 17.6 μmo)l and sodium carbonate (28.0 mg, 264.5 μmo)l. The mixture was stirred at 110 °C under N2 atmosphere for 5 hours, cooled to room temperature and filtered through a Celite pad. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with MeOH/EA from 0 to 10%) and further by prep-HPLC to give 3-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)-l,6-naphthyridine-5, 7(677, 8T7)-dione (9 mg, 19% yield) as a green solid. LC-MS (ESI) [(M+H)+]: 544.1.
Figure imgf000052_0001
NMR (400 MHz, OMSO-dc) d 12.07 (s, 0.1H), 11.43 (s, 0.7H), 8.46-8.42 (m, 0.15H), 8.37-8.32 (m, 0.72H), 8.32-8.25 (m, 1H), 8.21- 7.81 (m, 5H), 7.68-7.48 (m, 2H), 7.25 (d, J = 7.6 Hz, 1H), 6.54 (d, J = 8.8 Hz, 1H), 4.11 (s, 1.5H), 3.73-3.60 (m, 1H), 3.44-3.36 (m, 1H), 2.14-1.93 (m, 4H), 1.55-1.39 (m, 2H), 1.32-1.18 (m, 2H). 19F NMR (376 MHz, OMSO-dc) d -59.25.
Example 14
Figure imgf000052_0002
7- (4- ((Trans -4- ((5- (trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)isoquinolin-l(27/)-one
Figure imgf000052_0003
110 °C
Step 7: To a solution of 7-bromo-2T7-isoquinolin-l-one (35.1 mg, 156.7 μmo)l and int. 3 (80 mg, 156.7 μmol) in mixed solvent of dioxane (2.5 mL), ethanol (1 mL) and water (0.5 mL) were added Pd(dppf)Cl2 (17.2 mg, 23.5 μmo) l and potassium carbonate (65.0 mg, 470.2 μmo)l. The mixture was stirred at 110 °C under N2 atmosphere for 3 hours, cooled to room temperature and filtered through a Celite pad. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with MeOH/DCM from 0 to 10%) and further by prep-HPLC to give 7-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)isoquinolin-l(277)-one (46 mg, 56% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 528.1. NMR (400 MHz, OMSO-dc) <5 11.39 (d, J = 5.6 Hz, 1H), 8.53 (s, 1H), 8.25 (s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 8.4 Hz, 2H), 7.82 (d, J= 8.4 Hz, 1H), 7.58 (d, J= 8.8 Hz, 1H), 7.28-7.22 (m, 2H), 6.63 (d, J = 7.2 Hz, 1H), 6.54 (d, J= 8.8 Hz, 1H), 3.68 (s, 1H), 3.39-3.36 (m, 1H), 2.07-1.99 (m, 4H), 1.50- 1.45 (m, 2H), 1.29-1.24 (m, 2H). 19F NMR (376 MHz, DMSO -d6) S -59.21 (s, 1H).
Example 15
Figure imgf000053_0001
2-Methyl-7-(4-((/raH.s-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)-3,4-dihydroisoquinolin-l(2//)-one
Figure imgf000053_0002
Step 1: To a solution of 7-bromo-3,4-dihydro-2//-isoquinolin-l-one (120 mg, 530.8 μmo)l in anhydrous DMF (5 mL) was added NaH (60% dispersion in mineral oil, 106.2 mg, 2.7 mmol) at 0 °C. The mixture was stirred at 0 °C for 10 minutes, and iodomethane (226.0 mg, 1.6 mmol, 99.1 μL) was added thereto. The mixture was stirred at 20 °C for 3 hours, quenched with water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layer was washed with brine (60 mL), dried over anhydrousNa2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (EtO Ac/PE from 0 to 50%) to afford 7 - b ro m o - 2 - m c t h y 1 - 3 , 4 - d i h yd ro i s o q u i n o 1 i n - 1 (2 // ) - o n c (116 mg, 91% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 240.1.
Step 2: To a solution of 7-bromo-2-mcthyl-3,4-dihydroisoquinolin- 1 (2/7)-onc (45 mg, 187.4 pmol) and int. 3 (90 mg, 176.3 μmo)l in mixed solvent of dioxane (65 mL), ethanol (6mL) and water (0.3 mL) were added Pd(dppf)Cl2 (25.8 mg, 35.3 μmo)l and sodium carbonate (56.1 mg, 529.0 μmol). The mixture was stirred at 110 °C under N2 atmosphere for 5 hours, cooled to room temperature and filtered through a Celite pad. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with EtO Ac/PE from 0 to 100%) to give 2-methyl-7-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)-3,4-dihydroisoquinolin-l(27/)-one (68 mg, 71% yield) as a yellow solid. LC-MS (ESI) [(M+H)+]: 544.1. NMR (400 MHz, DMSO -d6) S 8.25-8.21 (m, 2H), 7.98-7.94 (m, 4H), 7.89 (d, J = 7.2 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.24 (d, J = 7.2 Hz, 1H), 6.54 (d, J = 8.8 Hz, 1H), 3.73-3.63 (m, 1H), 3.60 (t, / = 6.4 Hz, 2H), 3.39-3.33 (m, 1H), 3.16-2.98 (m, 5H), 2.11-1.94 (m, 4H), 1.54-1.40 (m, 2H), 1.32- 1.20 (m, 2H). 19F NMR (376 MHz, DMSO -d6) S -59.21.
Example 16
Figure imgf000054_0001
6-(4-((7>ans-4-((5-(trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)sulfonyl)phenyl)-3,4- dihydroisoquinolin- 1 (2//)-one
Figure imgf000054_0002
Step 1: To a solution of 6-bromo-3 ,4-di hydro-2/7-i soqui nol i n- 1 -one (35.4 mg, 156.7 m mol) and int. 3 (80 mg, 156.7 m mol) in mixed solvent of dioxane (2.5 mL), ethanol (2 mL) and water (1 mL) were added Pd(dppf)Cl2 (17.2 mg, 23.5 μmo)l and potassium carbonate (66.0 mg, 470.2 pmol). The mixture was stirred at 110 °C under N2 atmosphere for 3 hours, cooled to room temperature and filtered through a Celite pad. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with MeOH/DCM from 0 to 10%) and further by prep-HPLC to give 6-(4-((irans-4-((5-(trifluoromethyl)pyridin- 2-y l)amino)cyclohcxyl)sul I'ony l)phcnyl)-3,4-dihydroi soqui nol i n- 1 (2/7)-onc (60 mg, 73% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 530.1.
Figure imgf000054_0003
NMR (400 MHz, DMSO -d6) S 8.25 (s, 1H), 8.04-8.01 (m, 3H), 7.99-7.93 (m, 3H), 7.77-7.73 (m, 2H), 7.58 (dd, /= 8.8 Hz, 2.4 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H), 6.54 (d, J = 8.8 Hz, 1H), 3.67 (s, 1H), 3.45-3.40 (m, 2H), 3.36- 3.34 (m, 1H), 3.00 (t, / = 6.4 Hz, 2H), 2.06-2.02 (m, 4H), 1.49-1.45 (m, 2H), 1.27-1.24 (m, 2H). 19F NMR (376 MHz, DMSO -d6) S -59.24.
Example 17
Figure imgf000054_0004
Trans -/V-(4-((4-(l, 2,3,· 4-tetrahydroisoquinolin-7-yl)phenyl)sulfonyl)cyclohexyl)-5-
(trifluoromethyl)pyridin-2-amine
Figure imgf000055_0001
Step 1: To a solution of 7-bromo-l,2,3,4-tetrahydroisoquinoline hydrochloride (54 mg, 220 mihoΐ) and int. 3 (112 mg, 0.2 mmol) in mixed solvent of dioxane (10 mL), ethanol (10 mL) and water (1 mL) were added Pd(dppf)Cl2 (32 mg, 44 μmo)l and sodium carbonate (140 mg, 1.3 mmol). The mixture was stirred at 110 °C under N2 atmosphere for 5 hours, cooled to room temperature and filtered through a Celite pad. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with MeOH/DCM from 40 to 50%) and further by prep-HPLC to give trans-N-(4-((4-(l,2,3,4- tetrahydroisoquinolin-7-yl)phenyl)sulfonyl)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine (23 mg, 20% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 516.1.
Figure imgf000055_0002
NMR (400 MHz,
DMSO-ife) d 8.25 (s, 1H), 8.03-7.80 (m, 4H), 7.59 (d, 7= 8.0 Hz, 1H), 7.51 (d, 7= 8.0 Hz, 1H), 7.44 (s, 1H), 7.32-7.09 (m, 2H), 6.55 (d, 7= 8.0 Hz, 1H), 3.93 (s, 2H), 3.74-3.59 (m, 1H), 3.31- 3.27 (m, 1H), 3.04-2.89 (m, 2H), 2.80-2.67 (m, 2H), 2.13-1.90 (m, 4H), 1.55-1.36 (m, 2H), 1.31-1.19 (m, 2H). 19F NMR (376 MHz, DMSO -d6) S -59.22. Example 18
Figure imgf000055_0003
Trans -/V-(4-((4-(l, 2,3,· 4-tetrahydroisoquinolin-6-yl)phenyl)sulfonyl)cyclohexyl)-5-
(trifluoromethyl)pyridin-2-amine
Figure imgf000055_0004
Step 1: To a solution of /<? /7-butyl 6-bromo-3,4-dihydiO-l /7-isoqui noli nc-2-carboxy late (137.6 mg, 440.9 μmol) and int. 3 (225 mg, 440.9 μmo)l in mixed solvent of dioxane (10 mL) and water (0.5 mL) were added Pd(dppf)Cl2 (64.5 mg, 88.2 μmo)l and potassium carbonate (182.9 mg, 1.3 mmol). The mixture was stirred at 110 °C under N2 atmosphere for 5 hours, cooled to room temperature and filtered through a Celite pad. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with EA/PE from 0 to 50%) to give /<? /7-butyl 6-(4-((irans-4-((5-(trifluoromethyl)pyridin-2- y l)amino)cyclohcxyl)sul I'ony l)phcnyl)-3,4-dihydroisoqui nol i nc-2( l /7)-carboxy late (115 mg,
42% yield) as a yellow gum. LC-MS (ESI) [(M+H)+]: 616.1.
Step 2: To a solution of tert-butyl 6-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- y l)amino)cyclohcxyl)sul I'ony l)phcnyl)-3,4-dihydroisoqui nol i nc-2( l /7)-carboxy late (115 mg, 186.8 μmol) in DCM (5 mL) was added HC1/EA (4M, 3 mL). The reaction mixture was stirred at room temperature for 12 hours and concentrated in vacuo. The residue was purified by prep- HPLC to afford trans-N-(4-((4-( 1,2,3, 4-tetrahydroisoquinolin-6- yl)phenyl)sulfonyl)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine (43 mg, 45% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 516.1.
Figure imgf000056_0001
NMR (400 MHz, DMSO -d6) d 8.25 (s, 1H), 8.02-7.86 (m, 4H), 7.64-7.51 (m, 3H), 7.26 (t, /= 6.8 Hz, 2H), 6.54 (d, J = 8.8 Hz, 1H), 4.21- 3.96 (m, 2H), 3.73-3.58 (m, 1H), 3.39-3.28 (m, 1H), 3.26-3.04 (m, 2H), 2.99-2.82 (m, 2H),
2.11-1.92 (m, 4H), 1.55-1.36 (m, 2H), 1.32-1.16 (m, 2H). 19F NMR (376 MHz, DMSO -d6) d - 59.20.
Example 19
Figure imgf000056_0002
8-(4-((trans-4- ((5-(trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)sulfonyl)phenyl)-3,4- dihydro-2//-pyrido[l ,2-«]pyrazine- 1 ,6-dione
Figure imgf000057_0001
Step 1: To a solution of methyl 4-bromopyridine-2-carboxylate (5 g, 23.1 mmol) in DCM (100 mL) was added 3-chlorobenzenecarboperoxoic acid (12.0 g, 69.4 mmol) at 0 °C. The mixture was stirred at 25 °C for 36 hours and quenched with NaHC03 aqueous solution (2M, 100 mL). The two phases were separated, and the organic phase was washed with Na2S203 aqueous solution (2M, 100 mL) and brine (40 mL x 2), dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate in petroleum ether from 0 to 100%) to give methyl 4-bromo-2-(methoxycarbonyl)pyridine 1-oxide (4.4 g, 81% yield) as a white solid. LC-MS (ESI) [(M+H)+] : 232.1.
Figure imgf000057_0002
8.25 (d, J = 7.2 Hz, 1H), 8.05 (d, J = 2.8 Hz, 1H), 7.79 (dd, / = 7.2 Hz, 2.8 Hz, 1H), 3.87 (s, 3H).
Step 2: To a solution of methyl 4-bromo-2-(methoxycarbonyl)pyridine 1-oxide (3.4 g, 14.6 mmol) in THF (40 mL) were added triethylamine (7.3 g, 71.8 mmol, 10.0 mL) and TFAA (3.7 g, 17.6 mmol, 2.5 mF) at 0 °C. The mixture was stirred at 25 °C for 3 hours and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate in petroleum ether from 0 to 60%) to give methyl 4-bromo-6-oxo-l,6- dihydropyridine-2-carboxylate (1.4 g, 42% yield) as a white solid. FC-MS (ESI) [(M+H)+]: 232. NMR (400 MHz, DMSO -d6) d 12.04 (s, 1H), 7.27 (s, 1H), 7.07 (s, 1H), 3.85 (s, 3H).
Step 3: To a solution of methyl 4-bromo-6-oxo-l,6-dihydropyridine-2-carboxylate (1.3 g, 5.6 mmol) in methanol (20 mF) was added 2-(benzylamino)ethanol (931.8 mg, 6.2 mmol, 879.1 pF) at 25 °C. The mixture was stirred under reflux for 36 hours and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with methanol in dichloromethane from 0 to 10%) to give N-benzyl-4-bromo- V-(2-hydroxyethyl)-6-oxo-l,6- dihydropyridine-2-carboxamide (4.0 g, crude) as yellow oil. FC-MS (ESI) [(M+H)+]: 351.1. Step 4: To a solution of N-benzyl-4-bromo-/V-(2-hydroxyethyl)-6-oxo-l,6-dihydropyridine-2- carboxamide (3.5 g, 10.0 mmol) in DCM (50 mL) were added DIPEA (3.9 g, 29.9 mmol, 5.2 mL) and HATU (4.6 g, 12.0 mmol). The mixture was stirred at 25 °C for 40 hours, diluted with water (50 mL) and extracted with DCM (100 mL x 3). The combined organic layer was washed with brine (20 mL x 3), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with EA/DCM from 0 to 10%) to give 2-bcnzyl-8-bromo-3,4-dihydro-2/7-pyndo[ 1 ,2- ajpyrazinc- 1 ,6-dionc (2.8 g, impure) as a white solid. LC-MS (ESI) [(M+H)+]: 333.1.
Step 5: To a solution of 2-bcnzyl-8-biOmo-3,4-dihydro-2/7-pyndo[ 1 ,2-aJpyrazinc- 1 ,6-dionc (2.3 g, 6.9 mmol) in toluene (50 mL) was added trifluoromethanesulfonic acid (5.2 g, 34.5 mmol, 3.0 mL). The mixture was stirred at 110 °C for 26 hours, cooled to room temperature and concentrated in vacuo. The residue was diluted with DCM (50 mL), washed with saturated NaHCCL aqueous solution (100 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with CH3OH in DCM from 0 to 50%) to give 8-bromo- 3,4-dihydro-2//-pyrido[ 1 ,2-aJpyrazine-l ,6-dionc (400 mg, impure) as a light-yellow solid. 1 H NMR (400 MHz, DMSO -d6) S 8.79 (s, 1H), 6.97-6.91 (m, 2H), 4.01-3.97 (m, 2H), 3.47-3.43 (m, 2H).
Step 6: To a stirred solution of int. 3 (100.0 mg, 195.93 μmo)l and 8 - b ro m o - 3 , 4 - d i h y d ro - 277- pyrido[l,2-(3]pyrazine-l,6-dione (57.2 mg, 235.12 μmo)l in mixed solvent of 1,4-dioxane (4.0 mL) and water (1 mL) was added potassium phosphate (124.8 mg, 587.80 μmo)l, RuPhos Pd G2 (15.2 mg, 19.59 μmo)l. The reaction mixture was stirred at 100 °C under N2 atmosphere for 2 hours, cooled to room temperature, diluted with EA (100 mL) and washed with brine (30 mL x 3). The organic phase was dried over anhydrousNa2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with MeOH/DCM: 1/12) to give 8-(4-((irans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)-3 ,4-dihydro-2//-pyrido[ 1 ,2-aJpyrazine- 1 ,6-dione (20.0 mg, 19% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 547.1.
Figure imgf000058_0001
NMR (400 MHz, DMSO- de) d 8.79 (s, 1H), 8.25 (s, 1H), 8.06 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 8.4 Hz, 2H), 7.59 (dd, J = 8.9 Hz, 2.3 Hz, 1H), 7.29 (d, J = 2.0 Hz, 2H), 7.07 (d, J = 2.0 Hz, 1H), 6.55 (d, J = 8.9 Hz, 1H), 4.15-4.07 (m, 2H), 3.53 (s, 2H), 2.02 (t, /= 14.7 Hz, 4H), 1.47 (dd, / = 24.0 Hz, 11.7 Hz, 2H), 1.27-1.23 (m, 2H). Example 20
Figure imgf000059_0001
8-(4-(7>ans-4-((5-(trifluoromethyl)pyridin-2-yl)amino)cyclohexane-l- sulfonimidoyl)phenyl)-3,4-dihydro-2//-pyrido[l,2-«]pyrazine-l,6-dione
Figure imgf000059_0002
Step 1: To a stirred solution of int. 1 (187.5 mg, 391.87 p mol) and 8 - b ro m o - 3 , 4 - d i h y d ro - 2 /7- pyrido[l,2-(3]pyrazine-l,6-dione (142.9 mg, 587.80 μmo)l in mixed solvent of 1,4-dioxane (8 mL) and water (2 mL) was added potassium phosphate (249.6 mg, 1.18 mmol), RuPhos Pd G2 (30.5 mg, 39.19 μmo)l. The reaction mixture was stirred at 100 °C under N2 atmosphere for 2 hours, cooled to room temperature, diluted with EA (40 mL) and washed with brine (10 mL x 3). The organic phase was dried over anhydrousNa2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with MeOH/DCM: 1/15) to give 8-(4-((irans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)thio)phenyl)-3 ,4-dihydro-2H-pyrido[ 1 ,2-aJpyrazinc- 1 ,6-dione (100 mg, 47% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 515.1.
Step 2: To a solution of 8-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)thio)phenyl)-3 ,4-dihydro-2H-pyrido[ 1 ,2-aJpyrazinc- 1 ,6-dione (100 mg, 194.34 μmol) and ammonium carbamate (30.3 mg, 388.68 μmo)l in MeOH (3 mL) was added iodobenzene diacetate (125.2 mg, 388.68 μmo)l. The mixture was stirred at 25 °C for 0.5 hour and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with MeOH/DCM: 1/12) to give 8-(4-(irans-4-((5-(trifluoromethyl)pyridin-2- yljaminojcyclohexane- 1 -sulfonimidoyl)phcnyl)-3,4-dihydro-2H-pyndo[ 1 ,2-aJpyrazine-l ,6- dione (30 mg, 14% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 546.1.
Figure imgf000060_0001
NMR (400 MHz, DMSO -de) d 8.77 (s, 1H), 8.24 (s, 1H), 7.98 (dd, / = 20.7 Hz, 8.5 Hz, 3H), 7.57 (dd, / = 8.9 Hz, 2.3 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H), 7.22 (d, J = 7.3 Hz, 1H), 7.06 (d, J = 2.0 Hz, 1H), 6.53 (d, J = 8.9 Hz, 1H), 4.34 (s, 1H), 4.16-4.06 (m, 2H), 3.63 (s, 1H), 3.52 (s, 2H), 3.12 (t, J
= 12.1 Hz, 1H), 2.02 (s, 3H), 1.54-1.33 (m, 2H), 1.23 (t, /= 9.1 Hz, 2H).
Example 21
Figure imgf000060_0002
4,4-Difluoro-7-(4-((/raH.s-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)-3,4-dihydroisoquinolin-l(2//)-one
Figure imgf000060_0003
Step 1: To a stirred solution of 7-bromo-2//-isoquinolin- 1 -one (2.00 g, 8.93 mmol) in MeCN/Water (22 mL, 10/1) was added selectfluor (3.48 g, 9.82 mmol). The reaction mixture was stirred at 30 °C overnight, diluted with 20 mL of water, and extracted with DCM (20 mL x 3). The combined organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with EtOAc:petroleum ether from 0 to 80%) to give 7-bromo-4-fluoro-3- hydroxyisoquinolin- 1 (2//)-onc (1.50 g, 65% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 260.1. Step 2: To a stirred solution of 7-bromo-4-fluoro-3-hydroxyisoquinolin-l(2//)-one (1.50 g, 5.77 mmol) in DCM (15 mL) was added methanesulfonic acid (2.77 g, 28.84 mmol, 1.87 mL). The reaction mixture was stirred at room temperature overnight, diluted with DCM (20 mL) and washed with water (20 mL) and brine (20 mL). The organic phase was dried over anhydrousNa2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate/petroleum ether from 0 to 80%) to give 7-bromo-4- IΊ uoroi soqui nol i n- 1 (2/7)-onc (1.20 g, 86% yield) as a light yellow solid. LC-MS (ESI) [(M+H)+]: 242.1.
Step 3: To a stirred solution of 7-bromo-4- IΊ uoroi soqui nol i n- 1 (2/7)-onc (500.0 mg, 2.07 mmol) in MeCN/Water (22 mL, 10/1) was added selectfluor (804.4 mg, 2.27 mmol). The reaction mixture was stirred at 30 °C overnight, diluted with 20 mL of water, and extracted with DCM (20 mL x 3). The combined organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with EtOAc:petroleum ether from 0 to 90%) to give 7- bromo-4, 4-difluoro-3 -hydroxy-3, 4-dihydroisoquinolin-l(27/)-one 300.0 mg, 1.08 mmol, 52.23% yield) as a light yellow solid. LC-MS (ESI) [(M+H)+]: 278.1.
Step 4\ To a stirred solution of 7-bromo-4,4-difluoro-3-hydroxy-3,4-dihydroisoquinolin- l(27/)-one (300.0 mg, 1.08 mmol) in DCM (10 mL) were added methanesulfonic acid (414.8 mg, 4.32 mmol, 280.3 μL) and triethyl silane (627.3 mg, 5.39 mmol, 861.7 μL). The reaction mixture was stirred at room temperature overnight, quenched with saturated sodium bicarbonate aqueous solution (15 mL), and extracted with DCM (30 mL x 3). The organic phases were washed with water (20 mL) and brine (20 mL), dried over anhydrous NaiSCC and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate/petroleum ether from 0 to 80%) to give 7-bromo-4,4-di fl uoro-3 ,4-di hydroi soqui nol i n- 1 (2//)-onc (100.0 mg, 35% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 262.1.
Step 5: A mixture of 7-bromo-4,4-difluoro-3,4-dihydroisoquinolin-l(27/)-one (50.0 mg, 190.80 μmol), int. 3 (97.4 mg, 190.80 μmo)l, Pd(PPh3)2Cl2 (25.0 mg, 35.66 μmo) l and K2CO3 (88.0 mg, 637.68 μmol) in dioxane/water (10 mL, 3/1) was stirred at 100 °C under N2 atmosphere for 4 hours, cooled to room temperature, diluted with ethyl acetate (20 mL) and washed with water (10 mL x 3). The organic layer was dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate/petroleum ether from 0 to 100%) and further by prep-HPLC to give 4,4-difluoro-7-(4-((/ra«5-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)-3,4-dihydroisoquinolin-l(2//)-one (35.0 mg, 32% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 566.1. NMR (400 MHz, DMSO -d6) d 8.60 (s, 1H), 8.31 (s, 1H), 8.26 (s, 1H), 8.19 (dd, J= 8.0, 1.6 Hz, 1H), 8.07 (d, 7= 8.4 Hz, 2H), 7.99 (d, 7 = 8.4 Hz, 2H), 7.91 (d, 7 = 8.0 Hz, 1H), 7.59 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.26 (d, 7 = 7.2
Hz, 1H), 6.55 (d, 7 = 8.8 Hz, 1H), 4.04-3.94 (m, 2H), 3.67 (s, 1H), 3.40 (d, 7 = 12.0 Hz, 1H), 2.10-1.97 (m, 4H), 1.48 (dd, J= 22.8 Hz, 12.4 Hz, 2H), 1.26 (dd, J = 23.2 Hz, 11.2 Hz, 2H).
Example 22
Figure imgf000062_0001
4,4-Difluoro-7-(4-(frans-4-((5-(trifluoromethyl)pyridin-2-yl)amino)cyclohexane-l- sulfonimidoyl)phenyl)-3,4-dihydroisoquinolin-l(2//)-one
Figure imgf000062_0002
Step 1: A mixture of 7-bromo-4,4-di IΊ uoro-3 ,4-di hydroi soqui nol i n- 1 (2/7)-onc (50 mg, 190.80 pmol), int. 1 (91.3 mg, 190.80 μmo)l, Pd(PPh3)2Cl2 (27 mg, 38.52 μmo)l and K2CO3 (79 mg, 572.46 μmol) in dioxane/water (6 mL, 2/1) was stirred at 100 °C under N2 atmosphere for 4 hours, cooled to room temperature, diluted with ethyl acetate (20 mL) and washed with water (10 mL x 3). The organic layer was dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate/petroleum ether from 0 to 100%) to give 4,4-difluoro-7-(4- ((trans-4-((5-(tnfLioromcthyl)pyndin-2-yl)amino)cyclohcxyl)thio)phcnyl)-3,4- dihydroisoquinolin- 1 (2//)-onc (60 mg, 59% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 534.1. Step 2: To a mixture of 4,4-difluoro-7-(4-((/rarz5-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)thio)phenyl)-3,4-dihydroisoquinolin-l(2//)-one (30 mg, 56.23 μmo)l and ammonium carbamate (8.8 mg, 112.45 μmo)l in methanol (5 mL) was added iodobenzene diacetate (36.5 mg, 112.45 μmol). The mixture was stirred at 25 °C for 5 hours and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with methanol in dichloromethane from 0 to 10%) and further by prep-HPLC to give 4,4-difhioro-7-(4-(trans-4-((5-(tnfhioromcthyl)pyndin-2-yl)amino)cyclohcxanc- 1 - sulfonimidoyl)phenyl)-3,4-dihydroisoquinolin-l(27/)-one (14.2 mg, 45% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 565.1.
Figure imgf000063_0001
NMR (400 MHz, DMSO -d6) d 8.58 (s, 1H), 8.30 (s, 1H), 8.24 (s, 1H), 8.17 (dd, / = 8.0 Hz, 1.7 Hz, 1H), 8.05-7.95 (m, 4H), 7.90 (d, J = 8.0 Hz, 1H), 7.58 (dd, / = 8.8 Hz, 2.4 Hz, 1H), 7.22 (d, J= 7.2 Hz, 1H), 6.53 (d, J= 8.8 Hz, 1H), 4.32 (s, 1H), 4.04-3.93 (m, 2H), 3.65 (s, 1H), 3.12 (t, /= 12.0 Hz, 1H), 2.13-1.97 (m, 4H), 1.44 (td, /= 22.8 Hz, 12.0 Hz, 2H), 1.24 (dd, /= 14.0 Hz, 10.4 Hz, 2H).
Example 23
Figure imgf000063_0002
6- (4-( (Trans -4- ((5- (trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)isoindolin-l-one
Figure imgf000063_0003
Step 1: To a solution of 6-bromoisoindolin-l-one (56.1 mg, 264.5 μmo)l and int. 3 (135 mg, 264.5 μmol) in mixed solvent of dioxane (6 mL), ethanol (6 mL) and water (0.5 mL) were added Pd(dppf)Cl2 (38.7 mg, 52.9 μmo)l and sodium carbonate (84.1 mg, 793.5 μmol). The mixture was stirred at 110 °C under N2 atmosphere for 5 hours, cooled to room temperature and filtered through a Celite pad. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with EA/PE from 40 to 100%) to give 6-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)isoindolin-l-one (89 mg, 65% yield) as an off-white solid. LC-MS (ESI) [(M+H)+]: 516.1. NMR (400 MHz, DMSO -d6) S 8.69 (s, 1H), 8.25 (s, 1H), 8.13-7.97 (m, 4H), 7.95 (d, J= 8.4 Hz, 2H), 7.77-7.69 (m, 1H), 7.59 (dd, /= 8.8 Hz, 2.4 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H), 6.54 (d, J = 8.8 Hz, 1H), 4.46 (s, 2H), 3.76-3.58 (m, 1H), 3.42-3.35 (m, 1H), 2.08-1.98 (m, 4H), 1.57-1.39 (m, 2H), 1.34-1.16 (m, 2H). 19F NMR (376 MHz, DMSO-<fe) <5 -59.21.
Example 24
Figure imgf000064_0001
6-(4-(7r«H.s-4-((5-(trifluoromethyl)pyridin-2-yl)amino)cyclohexane-l- sulfonimidoyl)phenyl)isoindolin-l-one
Figure imgf000064_0002
Step 1: To a solution of 6-bromoisoindolin-l-one (178.2 mg, 840.3 μmo)l and int. 1 (335 mg, 700.3 p mol) in mixed solvent of dioxane (10 mL), ethanol (10 mL) and water (0.5 mL) were added Pd(dppf)Cl2 (102.5 mg, 140.06 μmo)l and sodium carbonate (222.7 mg, 2.1 mmol). The mixture was stirred at 110 °C under N2 atmosphere for 7 hours, cooled to room temperature and filtered through a Celite pad. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with EA/PE from 0 to 100%) to give 6-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)thio)phenyl)isoindolin-l-one (270 mg, 80% yield) as a yellow solid. LC- MS (ESI) [(M+H)+] : 484.1.
Step 2: To a solution of 6-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)thio)phenyl)isoindolin-l-one (130 mg, 268.9 μmol) and ammonium carbamate (63.0 mg, 806.5 μmo)l in methanol (15 mL) was added PhI(OAc)2 (259.8 mg, 806.5 pmol). The reaction mixture was stirred at room temperature for 50 minutes and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc/PE from 0 to 100%) and further by prep-HPLC to afford 6-(4-(trans-4-((5- (trifluoromethyl)pyridin-2-yl)amino)cyclohexane-l-sulfonimidoyl)phenyl)isoindolin-l-one (53 mg, 38% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 515.1.
Figure imgf000064_0003
NMR (400 MHz, DMSO -d6) d 8.68 (s, 1H), 8.24 (s, 1H), 8.08-7.89 (m, 6H), 7.72 (d, J = 8.4 Hz, 1H), 7.57 (dd, / = 8.8 Hz, 2.4 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 6.53 (d, J = 8.8 Hz, 1H), 4.45 (s, 2H), 4.28 (s, 1H), 3.69-3.57 (m, 1H), 3.15-3.05 (m, 1H), 2.12-1.93 (m, 4H), 1.51-1.34 (m, 2H), 1.30-1.16 (m, 2H). 19F NMR (376 MHz, DMSO -d6) d -59.19.
Example 25
Figure imgf000065_0001
3-(4-((trans-4- ((5-(trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)sulfonyl)phenyl)-6,7- dihydro-5//-pyrrolo[3,4-/:>]pyridin-5-one
Figure imgf000065_0002
Step 1: A solution of 5-bromopyridine-2,3-dicarboxylic acid (2.5 g, 10.2 mmol) in acetic anhydride (4 mL) was stirred at 120 °C for 3 hours. To the above mixture was added ammonia acetate (1.7 g, 22.4 mmol) at 25 °C. The resulting mixture was stirred at 100 °C for another 2 hours and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate in petroleum ether from 0 to 20%) to give 3-bromo-5/7- pyrrolo[3,4-h]pyridine-5,7(67/)-dione (1.4 g, 61% yield) as a white solid. LC-MS (ESI) [(M+H)+] : 227.2.
Step 2: To a solution of 3-bromo-57/-pyrrolo[3,4-h]pyridine-5,7(67/)-dione (1.4 g, 6.2 mmol) in methanol (100 mL) and DCM (100 mL) was added NaBH4 (186.6 mg, 4.9 mmol) at -40 °C. The mixture was stirred at -40 °C for 1 hour, quenched with HC1 aqueous solution (2M, 10 mL) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with methanol in dichloromethane from 0 to 50%) to give 3-bromo-7-hydroxy-6,7- di hydro-5 /7-pyrrolo[ 3 A-b\ pyricli n-5-one (350 mg, impure) as a white solid. LC-MS (ESI) [(M+H)+] : 229.1.
Step 3: To a solution of 3-bromo-7-hydroxy-6,7-dihydro-5//-pyrrolo[3,4-h]pyridin-5-one (350.0 mg, 1.5 mmol) in DCM (1 mL) were added 2,2,2-trifluoroacetic acid (7.4 g, 64.9 mmol, 5 mL) and triethyl silane (3.6 g, 31.3 mmol, 5 mL). The mixture was stirred at 25 °C for 16 hours and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with EA/DCM from 0 to 50%) to give 3 - b ro m o -6,7-di h yd ro -5/7- pyrrolo[3,4-h]pyridin-5-one (160.0 mg, 49% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 213.1. NMR (400 MHz, DMSO -d6) S 9.00-8.82 (m, 2H), 8.31 (d, J = 1.6 Hz, 1H), 4.41 (s, 2H).
Step 4\ To a solution of 3-bromo-6,7-dihydro-57/-pyrrolo[3,4-h]pyridin-5-one (40.0 mg, 187.7 pmol) and int. 3 (80.4 mg, 187.7 μmo)l in mixed solvent of dioxane (5 mL) and water (0.5 mL) were added Pd(dppf)Cl2 (20.6 mg, 28.2 μmo)l and sodium carbonate (59.7 mg, 563.3 μmo)l. The mixture was stirred at 110 °C under N2 atmosphere for 8 hours, cooled to room temperature and filtered through a Celite pad. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with MeOH/DCM from 0 to 5%) to give 3-(4-((irans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)-6,7-dihydro-57/-pyrrolo[3,4-h]pyridin-5-one (53 mg, 55% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 517.0.
Figure imgf000066_0001
NMR (400 MHz, DMSO -d6) S 9.16 (d, J = 2.4 Hz, 1H), 8.91 (s, 1H), 8.42 (d, J = 2.4 Hz, 1H), 8.23 (s, 1H), 8.13 (d, J = 8.4 Hz, 2H), 7.95 (d, J = 8.4 Hz, 2H), 7.56 (dd, /= 8.8 Hz, 2.4 Hz, 1H), 7.24 (d, J = 7.2 Hz, 1H), 6.52 (d, J= 8.8 Hz, 1H), 4.50 (s, 2H), 3.75-3.62 (m, 1H), 3.54-3.33 (m, 1H), 2.08-1.96 (m, 4H), 1.52-1.38 (m, 2H), 1.28-1.95 (m, 2H). 19L NMR (376 MHz, DMSO -d6) d -59.22.
Example 26
Figure imgf000066_0002
Trans -/V-(4-((4-(8-methoxy-3,4-dihydroisoquinolin-2(l.ir)- yl)phenyl)sulfonyl)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine
Figure imgf000067_0001
Step 1: Under microwave conditions, a mixture of int. 2 (50.0 mg, 107.92 m mol), 8-methoxy- 1,2,3,4-tetrahydroisoquinoline (17.6 mg, 107.92 μmol), Pd2(dba)3 (14.8 mg, 16.2 μmol), RuPhos (10.1 mg, 21.6 μmo)l and CS2CO3 (105.3 mg, 324 μm)o iln dioxane (5 mL) was stirred at 100 °C under the atmosphere of N2 for 2 hours, cooled to room temperature, and filtered through a pad of Celite. The solid cake was washed with ethyl acetate (20 mL), and the combined filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with MeOH/DCM from 0 to 20%) and further by prep- HPLC to give /ran.s'-/V-(4-((4-(8-mcthoxy-3,4-dihydiOisoquinolin-2(l //)- yl)phenyl)sulfonyl)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine (21.7 mg, 37% yield) as oil. LC-MS (ESI) [(M+H)+]: 546.0.
Figure imgf000067_0002
8.24 (s, 1H), 7.63 (d, J = 9.2 Hz, 2H), 7.57 (dd, /= 8.8 Hz, 2.4 Hz, 1H), 7.20 (dd, / = 15.2 Hz, 7.2 Hz, 2H), 7.10 (d, J = 9.2 Hz, 2H), 6.87 (d, J= 8.4 Hz, 1H), 6.82 (d, J= 7.6 Hz, 1H), 6.53 (d, J= 8.8 Hz, 1H), 4.41 (s, 2H), 3.84 (s, 3H), 3.66 (t, /= 5.6 Hz, 2H), 3.61 (d, J = 10.4 Hz, 1H), 3.08 (t, / = 12.0 Hz, 1H), 2.91 (t, / = 5.6 Hz, 2H), 1.99 (t, / = 12.8 Hz, 4H), 1.37 (dd, / = 24.0 Hz, 11.6 Hz, 2H),
1.23 (t, /= 11.6 Hz, 2H).
Example 27
Figure imgf000067_0003
7r«H.s-Ai-(4-((4-(8-methoxy-3,4-dihydro-2,7-naphthyridin-2(l//)- yl)phenyl)sulfonyl)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine
Figure imgf000067_0004
Step 1: To a solution of 4-iodo-2-methoxy-pyridine-3-carbaldehyde (410.0 mg, 1.6 mmol) and ethynyl(trimethyl) silane (306.2 mg, 3.1 mmol, 440.6 μL) in THF (5 mL) were added TEA (473.2 mg, 4.7 mmol, 651.8 μL), Cul (29.7 mg, 155.8 μmol ) and bis(triphenylphosphine)palladium(II) chloride (109.4 mg, 155.8 μmol). The mixture was degassed with N2 and stirred in a sealed tube at 60 °C for 2 hours and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate in petroleum ether from 0 to 20%) to give 2-methoxy-4-(2-trimethylsilylethynyl) pyridine-3-carbaldehyde (230.0 mg, 64% yield) as yellow oil. LC-MS (ESI) [(M+H)+]: 234.1.
Step 2: To a solution of 2-methoxy-4-(2-trimethylsilylethynyl) pyridine-3-carbaldehyde (200 mg, 857.1 μmol) in methanol (5 mL) was added NEL/MeOH (2M, 5 mL). The mixture was stirred at 50 °C for 3 hours and concentrated in vacuo to give l-methoxy-2,7-naphthyridine (130 mg, crude) as black oil. LC-MS (ESI) [(M+H)+]: 161.2.
Step 3: To a solution of l-methoxy-2,7-naphthyridine (220 mg, 1.4 mmol) in mixed solvent of methanol (2.5 mL) and acetic acid (1 mL) was added 10% Pd/C (100 mg). The mixture was degassed with Eb and stirred at 25 °C for 16 hours and filtered through a Celite pad. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with methanol in dichloromethane from 0 to 20%) to give 8-methoxy-l,2,3,4- tetrahydro-2,7-naphthyridine (200 mg, impure) as a red solid. LC-MS (ESI) [(M+H)+]: 165.1.
Step 4\ A mixture of int. 2 (176.4 mg, 380.6 μmol), 8-methoxy-l,2,3,4-tetrahydro-2,7- naphthyridine (100.0 mg, 609.0 μmo)l, Pd2(dba)3 (34.8 mg, 38.1 μmo),l RuPhos (35.5 mg, 76.1 pmol) and CS2CO3 (372.0 mg, 1.1 mmol) in dioxane (5 mL) was stirred at 110 °C under the atmosphere of N2 for 3 hours, cooled to room temperature, and filtered through a pad of Celite. The solid cake was washed with ethyl acetate (20 mL), and the combined filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether from 0 to 80%) to give iran5-A-(4-((4-(8-methoxy-3,4- dihydro-2,7-naphthyridin-2(l//)-yl)phenyl)sulfonyl)cyclohexyl)-5-(trifluoromethyl)pyridin- 2-amine (50 mg, 24% yield) as a pale yellow solid. LC-MS (ESI) [(M+H)+]: 547.0.
Figure imgf000068_0001
NMR (400 MHz, DMSO -d6) d 8.15 (s, 1H), 7.92 (d, J = 5.2 Hz, 1H), 7.71 (d, J = 9.2 Hz, 2H), 7.53 (dd, /= 8.8 Hz, 2.4 Hz, 1H), 7.15 (d, J= 9.2 Hz, 2H), 6.82 (d, J= 5.6 Hz, 1H), 6.51 (d, J= 8.8 Hz, 1H), 4.40 (s, 2H), 3.99 (s, 3H), 3.74 (t, / = 5.6 Hz, 2H), 3.66 (s, 1H), 3.03-2.99 (m, 1H), 2.98-2.94 (m, 2H), 2.17-2.10 (m, 4H), 1.57-1.53 (m, 2H), 1.26-1.22 (m, 2H). 19F NMR (376 MHz, CD3OD) d -62.77. Example 28
Figure imgf000069_0001
7-(4-((7>ans-4-((5-(trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)sulfonyl)phenyl)- 5,6,7,8-tetrahydro-2,7-naphthyridin-l (2//)-one
Figure imgf000069_0002
Step 1: To a solution of iran,s'-/V-(4-((4-(8-methoxy-3,4-dihydro-2,7-naphthyridin-2(l//)- yl)phenyl)sulfonyl)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine (30.0 mg, 54.9 μmol) in DMF (5 mL) were added 4-methylbenzenesulfonic acid (9.5 mg, 54.9 μmol) and lithium chloride (2.3 mg, 54.9 μmo)l. The mixture was stirred at 120 °C for 1 hour and concentrated in vacuo. The residue was purified by prep-HPLC to give l-{A-{{lrans-A-{{5- (trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)sulfonyl)phenyl)-5,6,7,8-tetrahydro-2,7- naphthyridin- 1(27/) -one (14.0 mg, 48% yield) as a yellow solid. LC-MS (ESI) [(M+H)+]: 533.1.
Figure imgf000069_0003
11.53 (s, 1H), 8.22 (s, 1H), 7.61 (d, J = 9.2 Hz, 2H), 7.56- 7.49 (m, 1H), 7.23-7.19 (m, 2H), 7.11 (d, J = 9.2 Hz, 2H), 6.51 (d, J = 8.8 Hz, 1H), 6.08 (d, J = 6.8 Hz, 1H), 4.12 (s, 2H), 3.64-3.59 (m, 3H), 3.10-3.06 (m, 1H), 2.74-2.70 (m, 2H), 2.03- 1.96 (m, 4H), 1.37-1.33 (m, 2H), 1.24-1.18 (m, 2H). 19F NMR (376 MHz, DMSO-ife) S -59.23.
Example 29
Figure imgf000069_0004
Trans -A/-(4-((3-fluoro-4-(8-methoxy-3,4-dihydro-2,7-naphthyridin-2(lFT)- yl)phenyl)sulfonyl)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine
Figure imgf000069_0005
Step 1: A mixture of ira«s-A-(4-((4-bromo-3-fluorophenyl)sulfonyl)cyclohexyl)-5- (trifluoromethyl)pyridin-2-amine (36.5 mg, 76.1 μmol ), 8-methoxy-l,2,3,4-tetrahydro-2,7- naphthyridine (20.0 mg, 122.0 μmo)l, Pd2(dba)3 (17.5 mg, 19.1 μmo),l RuPhos (18.0 mg, 38.0 pmol) and CS2CO3 (74.4 mg, 0.22 mmol) in dioxane (3 mL) was stirred at 110 °C under the atmosphere of N2 for 3 hours, cooled to room temperature, and filtered through a pad of Celite. The solid cake was washed with ethyl acetate (20 mL), and the combined filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether from 0 to 100%) to give iran,s'- V-(4-((3-fluoro-4-(8-methoxy- 3,4-dihydro-2,7-naphthyridin-2(17/)-yl)phenyl)sulfonyl)cyclohexyl)-5- (trifluoromethyl)pyridin-2-amine (3.5 mg, 5% yield) as a pale yellow solid. LC-MS (ESI) [(M+H)+] : 565.2.
Figure imgf000070_0001
NMR (400 MHz, DMSO -d6) d 8.25 (s, 1H), 7.97 (d, J= 5.2 Hz, 1H), 7.58
(dd, / = 6.4 Hz, 5.2 Hz, 3H), 7.31 (t, / = 8.8 Hz, 1H), 7.24 (d, J = 7.2 Hz, 1H), 6.85 (d, J = 5.2 Hz, 1H), 6.54 (d, J = 8.8 Hz, 1H), 4.28 (s, 2H), 3.91 (s, 3H), 3.64 (s, 1H), 3.56 (t, / = 5.6 Hz, 2H), 3.26 (s, 1H), 2.92 (t, /= 5.2 Hz, 2H), 2.00 (dd, /= 22.0 Hz, 12.0 Hz, 4H), 1.40 (t, /= 12.0 Hz, 2H), 1.23 (d, J= 12.4 Hz, 2H).
7ran,s'- V-(4-((4-bromo-3-fluorophenyl)sulfonyl)cyclohexyl)-5-(trifluoromethyl)pyridin-2- amine was synthesized according to int. 2, using 4-bromo-3-fluorobenzenethiol replacing 4- bromobenzenethiol in Step 2. LC-MS (ESI) [(M+H)+]: 482.7.
4-Bromo-3-fluorobenzenethiol was synthesized as below: To a stirred solution 4-bromo-3- fluoro-benzenesulfonyl chloride (2.0 g, 7.31 mmol, 1.08 mL) in toluene was added triphenylphosphine (7.67 g, 29.25 mmol). The reaction mixture was stirred at room temperature for 15 minutes, diluted with water (10 mL) and stirred for 10 minutes. The two phases were separated, and the organic phase was washed with 10% NaOH aqueous solution (25 mL x 2). The combined NaOH aqueous phase was washed with toluene (50 mL), acidified with dilute HC1 to pH 4~5, and extracted with CH2CI2 (40 mL x 2). The organic phases were dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate in petroleum ether from 0 to 3%) to afford 4-bromo-3-fluoro-benzenethiol (1.2 g, 79% yield) as colorless oil. LC-MS (ESI) [(M+H)+]: 206.7. Example 30
Figure imgf000071_0001
7-(4-(7>ans-4-((5-(trifluoromethyl)pyridin-2-yl)amino)cyclohexane-l- sulfonimidoyl)phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-l(2//)-one
Figure imgf000071_0002
Step 1: Under microwave conditions, a mixture of trans-N-{4-{{4- bromophenyl)thio)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine (131.3 mg, 304.50 μmo)l, 8-methoxy-l,2,3,4-tetrahydro-2,7-naphthyridine (50 mg, 304.50 μmol), Pd2(dba)3 (55.7 mg, 60.90 μmol), RuPhos (42.6 mg, 91.35 μmo)l and CS2CO3 (296.9 mg, 913.50 μm)o iln dioxane (10 mL) was stirred at 110 °C under the atmosphere of N2 for 2 hours, cooled to room temperature, and filtered through a pad of Celite. The solid cake was washed with ethyl acetate (20 mL), and the combined filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (methanol/DCM from 0 to 5%) to give trans-N-(4- ((4-(8-methoxy-3,4-dihydro-2,7-naphthyridin-2(17/)-yl)phenyl)thio)cyclohexyl)-5- (trifluoromethyl)pyridin-2-amine (80 mg, 51% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 515.1.
Step 2: A mixture of irans-A-(4-((4-(8-rnethoxy-3,4-dihydro-2,7-naphthyridin-2(l//)- yl)phenyl)thio)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine (40 mg, 77.73 μmol), TsOH (20.2 mg, 388.65 μmo)l and LiCl (16.5 mg, 388.65 μmo)l in DMF (3 mL) was stirred at 120 °C for 2 hours and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with methanol/DCM from 0 to 10%) to give l-{A-{{trans- 4-((5-(trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)thio)phenyl)-5,6,7,8-tetrahydro-2,7- naphthyridin- 1(27/) -one (25 mg, 64% yield) as oil.. LC-MS (ESI) [(M+H)+]: 501.0.
Step 3: To a mixture of 7-(4-((irans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)thio)phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-l(2//)-one (25 mg,
49.94 μmol) and ammonium carbamate (7.8 mg, 0.1 mmol) in methanol (5 mL) was added iodobenzene diacetate (36.5 mg, 112.45 μmo)l. The mixture was stirred at 25 °C for 5 hours and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with methanol in dichloromethane from 0 to 10%) and further by prep-HPLC to give 7-(4-(trans-4-((5-(tnfhioromcthyl)pyndin-2-yl)amino)cyclohcxanc-l- sulfonimidoyl)phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-l(2//)-one (2.4 mg, 9% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 532.1.
Figure imgf000072_0001
NMR (400 MHz, DMSO -d6) d 11.53 (s, 1H), 8.23 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.57 (d, J = 8.8 Hz, 1H), 7.26-7.17 (m, 2H), 7.10 (d, J = 9.2 Hz, 2H), 6.51 (d, J= 8.4 Hz, 1H), 6.09 (d, J= 6.8 Hz, 1H), 4.11 (s, 2H), 3.82 (s, 1H), 3.61 (t, 7= 5.6 Hz, 2H), 2.90 (s, 1H), 2.73 (s, 2H), 1.99 (s, 4H), 1.24 (dd, / = 41.2 Hz, 29.2 Hz, 4H).
Example 31
Figure imgf000072_0002
7-(4-((7>ans-4-((5-(trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)sulfonyl)phenyl)-
5,6,7,8-tetrahydro-2,7-naphthyridin-l-amine
Figure imgf000072_0003
Step 1: To a solution of 4-methylpyridine-3-carbonitrile (2.00 g, 16.93 mmol) in DMF (10 mL) was added DMF-DMA (6.04 g, 50.79 mmol). The reaction mixture was stirred at 110 °C in a sealed tube overnight and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with EA/PE from 0 to 100%) to give (£)-4-(2- (dimethylamino)vinyl)nicotinonitrile (1.80 g, 61% yield) as colorless oil. LC-MS (ESI) [(M+H)+] : 174.2.
Step 2: To a solution of (E)-4-(2-(di methyl ami no) vinyl)nicotinonitrilc (1.80 g, 10.39 mmol) in acetic acid (10 mL) was added ammonium formate (5.24 g, 83.13 mmol). The mixture was stirred at 115 °C for 4 hours, cooled to room temperature, and diluted with ¾0 (10 mL), which was basified with ammonia hydroxide aqueous solution (20 mL) and then extracted with DCM (30 mL x 3). The organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with EtOAc/petroleum ether from 0 to 100 %) to give 2,7-naphthyridin-l -amine (800 mg, 53% yield) as light yellow oil. LC-MS (ESI) [(M+H)+]: 146.1.
Step 3: To a solution of 2,7-naphthyridin-l -amine (800.0 mg, 5.51 mmol) in acetic acid (10 mL) was added small portions of NaBPL (416.6 mg, 11.02 mmol). The resulting mixture was stirred at room temperature until completed, poured into ice, basified with ammonia hydroxide aqueous solution (20 mL) and then extracted with DCM (30 mL x 3). The organic layers were washed with water (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with MeOH/DCM from 0 to 100%) to give 5,6,7,8-tetrahydro-2,7-naphthyridin-l- amine (600.0 mg, 73% yield) as yellow oil. LC-MS (ESI) [(M+H)+]: 150.0.
Step 4\ Under microwave conditions, a mixture of int. 2 (93.0 mg, 200.73 μmol), 5, 6,7,8- tetrahydro-2,7-naphthyridin-l -amine (30.0 mg, 201.08 μmol), Pd2(dba)3 (28.0 mg, 30.60 pmol), RuPhos (20.0 mg, 42.92 μmo)l and CS2CO3 (196.0 mg, 603.08 μm)o iln dioxane (5 mL) was stirred at 100 °C under the atmosphere of N2 for 2 hours, cooled to room temperature, and filtered through a pad of Celite. The solid cake was washed with ethyl acetate (20 mL), and the combined filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with MeOH/DCM from 0 to 100%) and further by prep- HPLC to give 7-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin- 1-amine (8.3 mg, 8% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 532.1.
Figure imgf000073_0001
NMR (400 MHz, DMSO -d6) d 8.27 (d, J = 12.4 Hz, 2H), 7.97 (d, J = 5.2 Hz, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 8.8 Hz, 2H), 7.58 (dd, / = 8.8 Hz, 2.0 Hz, 1H), 7.24 (d, J = 7.2 Hz, 1H), 6.72 (d, J = 5.2 Hz, 1H), 6.53 (d, J = 8.8 Hz, 1H), 3.81 (s, 2H), 3.64 (s, 1H), 3.14 (t, / = 11.6 Hz, 1H), 2.91 (t, / = 5.6 Hz, 2H), 2.66 (d, J = 5.2 Hz, 2H), 2.01 (t, / = 14.0 Hz, 4H), 1.40 (dd, / = 24.0 Hz, 12.0 Hz, 2H), 1.24 (d, J = 6.0 Hz, 2H).
Example 32
Figure imgf000074_0001
7-(4-((7>ans-4-((5-(trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)sulfonyl)phenyl)- 5,6,7,8-tetrahydro-2,7-naphthyridine-l-carboxylic acid
Figure imgf000074_0002
Step 1: To a stirred solution of 7-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridin-l-amine (30 mg, 56.43 μmol) in acetic acid (3 mL) were added sodium nitrite (3.9 mg, 56.43 μmo)l and copper(I) cyanide (5.1 mg, 56.43 μmo)l. The resulting mixture was stirred at room temperature for 1 hour, basified with NaOH aqueous solution (10M, 9 mL) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with methanol/DCM from 0 to 20%) and prep-HPLC to give T-(4-((trans-4-((5-
(trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)sulfonyl)phenyl)-5,6,7,8-tetrahydro-2,7- naphthyridine- 1 -carboxylic acid (1.8 mg, 6% yield) as a yellow solid. LC-MS (ESI) [(M+H)+]: 561.2. NMR (400 MHz, DMSO -d6) d 8.64 (s, 1H), 8.26 (s, 1H), 8.06 (d, J = 4.8 Hz, 1H), 7.85 (t, /= 10.0 Hz, 2H), 7.74-7.65 (m, 2H), 7.59 (d, J= 6.8 Hz, 1H), 7.25 (d, J= 6.8 Hz, 2H), 6.82 (d, J = 5.2 Hz, 1H), 6.54 (d, J = 8.4 Hz, 2H), 4.65-4.56 (m, 2H), 3.68 (d, J = 4.4 Hz, 2H),
3.16 (s, 1H), 2.86 (s, 1H), 2.00 (d, J= 13.2 Hz, 4H), 1.42 (d, J= 13.6 Hz, 2H), 1.24 (s, 4H).
Example 33
Figure imgf000074_0003
5- (4- ((Trans -4- ((5- (trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)isoquinolin-l-amine
Figure imgf000075_0001
Step 1: To a solution of 5-bromoisoquinolin-l-amine (49 mg, 220 μmol) and int. 3 (112 mg, 200 μmol) in mixed solvent of dioxane (10 mL), ethanol (10 mL) and water (1 mL) were added Pd(dppf)Cl2 (32 mg, 44 μmo)l and sodium carbonate (70 mg, 660 μmol). The mixture was stirred at 110 °C under N2 atmosphere for 5 hours, cooled to room temperature and filtered through a Celite pad. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with MeOH in dichloromethane from 50 to 55%) and further by prep-HPLC to give 5-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)isoquinolin-l -amine (51 mg, 44% yield) as a white solid. LC-MS (ESI) [(M+H)+] : 527.1.
Figure imgf000075_0002
8.24 (m, 2H), 8.04- 7.91 (m, 2H), 7.86-7.69 (m, 3H), 7.66-7.48 (m, 3H), 7.28 (d, J= 8.0 Hz, 1H), 6.95 (s, 2H), 6.74 (d, J = 6.0 Hz, 1H), 6.56 (d, J = 8.8 Hz, 1H), 3.73-3.67 (m, 1H), 3.30-3.28 (m, 1H), 2.20-1.85 (m, 4H), 1.60-1.43 (m, 2H), 1.37-1.19 (m, 2H). 19F NMR (376 MHz, DMSO -d6) S -59.19.
Example 34
Figure imgf000075_0003
Trans -N-( 4-((3 ' -(3-aminooxetan-3-yl)- [1,1 ' -biphenyl] -4-yl)sulfonyl)cyclohexyl)-5-
(trilluoromethyl)pyridin-2-amine
Figure imgf000075_0004
Step 1: To a mixture of int. 3 (100 mg, 195.93 p mol) and 3-(3-bromophenyl)oxetan-3-amine hydrochloride (51.8 mg, 195.93 p mol) in mixed solvent of dioxane and H2O (4/1, 3.0 mL) were added potassium carbonate (81.2 mg, 587.80 μmo)l and Pd(dppf)Cl2 (14.3 mg, 19.59 μmo)l. The mixture was degassed with N2, and stirred at 100 °C under microwave conditions for an hour, until the starting material was totally consumed. The reaction mixture was filtered through a pad of silica gel, and washed with ethyl acetate (10 mL x 2). The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with EtOAc/petroleum ether, 0/1— 100%, v/v) and prep-HPLC to afford trans-N- (4-((3'-(3-aminooxetan-3-yl)-[l,r-biphenyl]-4-yl)sulfonyl)cyclohexyl)-5- (trifluoromethyl)pyridin-2-amine (18 mg, 19% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 531.8. NMR (400 MHz, DMSO -d6) d 8.26 (s, 1H), 8.00 (d, 7 = 8.5 Hz, 2H), 7.95 (s, 1H), 7.93 (d, 7 = 1.6 Hz, 2H), 7.69 (d, 7 = 7.7 Hz, 2H), 7.57 (dt, 7 = 15.7 Hz, 5.0 Hz, 2H), 7.25 (d, 7 = 7.4 Hz, 1H), 6.55 (d, 7 = 8.9 Hz, 1H), 4.80 (d, 7 = 6.1 Hz, 2H), 4.69 (d, 7 = 6.1 Hz, 2H), 3.66 (s, 1H), 3.37 (d, 7 = 12.3 Hz, 1H), 2.67 (s, 2H), 2.01 (dd, J = 29.9 Hz, 16.7 Hz, 4H), 1.47 (dd, J = 23.7 Hz, 11.7 Hz, 2H), 1.33-1.20 (m, 2H).
Example 35
Figure imgf000076_0001
Trans -A/-(4-((4-(2-(3-aminooxetan-3-yl)pyridin-4-yl)phenyl)sulfonyl)cyclohexyl)-5-
(trifluoromethyl)pyridin-2-amine
Figure imgf000076_0002
Step 1: To a solution of 2,4-dibromopyridine (1.0 g, 4.22 mmol) in anhydrous toluene (15 mL) was added dropwise n-butyl lithium hexane solution (2.5M, 5.00 mmol, 2 mL) at -78 °C. The reaction mixture was stirred for 20 minutes at this temperature, followed by the dropwise addition of the solution of 2-methyl- V-(oxetan-3-ylidene)propane-2-sulfinamide (739.8 mg, 4.22 mmol) in 1 mL of anhydrous toluene. The resulting mixture was stirred at -78 °C for 50 minutes until the reaction was completed, quenched with saturated NH4CI aqueous solution (10 mL) and extracted with EA (30 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate in petroleum ether from 0 to 60%) to give N-(3-(4-bromopyridin-2-yl)oxetan-3- yl)-2-methylpropane-2-sulfinamide (0.44 g, 31% yield). LC-MS (ESI) [(M+H)+]: 332.8. Step 2: To a solution of N- (3-(4-bromopyridin-2-yl)oxetan-3-yl)-2-methylpropane-2- sulfinamide (440 mg, 1.32 mmol) in MeOH (2 mL) was added 4 M HCl/dioxane (5 mL). The mixture was stirred at 25 °C for an hour until the reaction was completed, and concentrated in vacuo to give 3-(4-bromopyridin-2-yl)oxetan-3-amine (0.31 g, 88% yield, HC1 salt) as a white solid. LC-MS (ESI) [(M+H)+]: 228.8.
Step 3: To a mixture of int. 3 (100 mg, 195.93 μmol) and 3-(4-bromo-2-pyridyl)oxetan-3- amine (44.9 mg, 169.09 μmo,l HC1 salt) in mixed solvent of dioxane and H2O (4/1, 3.0 mL) were added potassium carbonate (81.2 mg, 587.80 μmo)l and Pd(dppf)Cl2 (14.3 mg, 19.59 pmol). The mixture was degassed with N2, and stirred at 100 °C under microwave conditions for an hour, until the starting material was totally consumed. The reaction mixture was filtered through a pad of silica gel, and washed with ethyl acetate (10 mL x 2). The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with methanol in dichloromethane from 0 to 20%) to afford trans-N-(4-((4-(2-(3- aminooxetan-3-yl)pyridin-4-yl)phenyl)sulfonyl)cyclohexyl)-5-(trifluoromethyl)pyridin-2- amine (23 mg, 22% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 532.8. Ή NMR (400 MHz, DMSO-de) d 8.74 (d, J= 5.1 Hz, 1H), 8.25 (s, 1H), 8.12 (s, 1H), 8.10 (s, 1H), 8.01 (s, 2H), 7.99 (s, 1H), 7.72 (dd, J = 5.1 Hz, 1.4 Hz, 1H), 7.58 (dd, / = 8.9, 2.3 Hz, 1H), 7.25 (d, J = 7.4 Hz, 1H), 6.54 (d, J = 8.9 Hz, 1H), 4.98 (d, J = 5.6 Hz, 2H), 4.60 (d, J = 5.6 Hz, 2H), 3.66 (s, 1H), 3.38 (t, / = 12.1 Hz, 1H), 2.84 (s, 2H), 2.02 (t, / = 13.6 Hz, 4H), 1.47 (dd, / = 23.6 Hz, 11.8 Hz, 2H), 1.26 (dd, /= 15.0 Hz, 8.8 Hz, 2H).
Example 36
Figure imgf000077_0001
(4-(2-(3-Aminooxetan-3-yl)pyridin-4-yl)phenyl)(imino)(trans-4-((5-
(trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)-λ6-sulfanone
Figure imgf000077_0002
Step 1: To a mixture of int. 1 (100 mg, 209.04 mihoΐ) and 3-(4-bromo-2-pyridyl)oxetan-3- amine (58.3 mg, 219.49 p mol, HC1 salt) in mixed solvent of dioxane and thO (4/1, 3.0 mL) were added potassium carbonate (86.7 mg, 627.12 μmo)l and Pd(dppf)Cl2 (15.3 mg, 20.90 pmol). The mixture was degassed with N2, and stirred at 110 °C under microwave conditions for an hour, until the starting material was totally consumed. The reaction mixture was filtered through a pad of silica gel, and washed with ethyl acetate (10 mL x 2). The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with methanol in dichloromethane from 0 to 20%) to afford trans-N-(4-((4-(2-(3- aminooxetan-3-yl)pyridin-4-yl)phenyl)thio)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine (70 mg, 67% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 501.0.
Step 2: To a mixture of /ran.s-/V-(4-((4-(2-(3-aminooxctan-3-yl)pyridin-4- yl)phenyl)thio)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine (70 mg, 139.84 μmol) and ammonium carbamate (21.8 mg, 279.68 μmol ) in MeOH (3 mL) was added (diacetoxyiodo)benzene (90.1 mg, 279.68 μmol). The mixture was stirred at 25 °C for 15 minutes until the reaction was completed, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with methanol in dichloromethane from 0 to 10%) and prep-HPLC to give (4-(2-(3-aminooxetan-3-yl)pyridin-4- yl)phenyl)(imino)(trans-4-((5-(trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)- 6-sulfanone (8 mg, 11% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 532.1.
Figure imgf000078_0001
NMR (400 MHz, DMSO-ί/ό) d 8.72 (d, 7 = 5.0 Hz, 1H), 8.24 (s, 1H), 8.06 (s, 1H), 8.04 (s, 1H), 8.00 (s, 2H), 7.98 (s, 1H), 7.71 (t, 7= 4.8 Hz, 1H), 7.57 (d, 7= 8.8 Hz, 1H), 7.22 (d, 7 = 7.3 Hz, 1H), 6.53 (d, 7 = 9.0 Hz, 1H), 4.97 (t, 7 = 5.8 Hz, 2H), 4.64-4.57 (m, 2H), 4.33 (s, 1H), 3.63 (s, 1H), 3.12 (s, 1H), 2.02 (s, 4H), 1.43 (dd, J = 24.1 Hz, 12.1 Hz, 2H), 1.22 (d, 7= 12.4 Hz, 3H).
Example 37
Figure imgf000078_0002
Trans -/V-(4-((4-(2-(3-(dimethylamino)oxetan-3-yl)pyridin-4- yl)phenyl)sulfonyl)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine
Figure imgf000079_0001
Step 1: A mixture of 3-(4-bromo-2-pyridyl)oxetan-3-amine (100 mg, 376.60 p mol, HC1 salt) and 37% aqueous solution of formaldehyde (611.2 mg, 7.53 mmol) in mixed solvent of THF (3 mL) and DCM (2 mL) was stirred at 0 °C for 30 minutes, followed by the addition of sodium triacetoxyborohydride (119.7 mg, 564.90 p mol). The resulting mixture was stirred for an hour until the reaction was complete, diluted with thO (5 mL) and extracted with EA (10 mL x 2). The organic layers were washed with brine (10 mL x 2), dried over anhydrousNa2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by prep-HPLC to afford 3-(4-bromopyridin-2-yl)-A,A-dimethyloxetan-3-amine (20 mg, 21% yield). LC-MS (ESI) [(M+H)+]: 257.2.
Step 2: To a mixture of int. 3 (40 mg, 78.37 μmol) and 3-(4-bromopyridin-2-yl)-A,A- dimethyloxetan-3-amine (20.2 mg, 78.37 μmo)l in mixed solvent of dioxane and EbO (4/1, 2.0 mL) were added potassium carbonate (32.5 mg, 235.12 μmo)l and Pd(dppf)Cl2 (5.73 mg, 7.84 pmol). The mixture was degassed with N2, and stirred at 110 °C under microwave conditions for 2 hours, until the starting material was totally consumed. The reaction mixture was filtered through a Celite pad, and the pad was washed with ethyl acetate (10 mL x 2). The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with methanol in dichloromethane from 0 to 20%) to afford trans-N-{ 4-((4-(2-(3- (dimethylamino)oxetan-3-yl)pyridin-4-yl)phenyl)sulfonyl)cyclohexyl)-5- (trifluoromethyl)pyridin-2-amine (16 mg, 36% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 561.1. 'H NMR (400 MHZ, DMSO-rfc) d 8.75 (d, 7 = 5.1 Hz, 1H), 8.25 (s, 1H), 8.14 (d, 7= 8.4 Hz, 2H), 8.00 (d, 7= 8.4 Hz, 2H), 7.81-7.74 (m, 1H), 7.71 (s, 1H), 7.59 (dd, J= 8.9 Hz, 2.2 Hz, 1H), 7.26 (d, 7 = 7.5 Hz, 1H), 6.54 (d, 7 = 8.9 Hz, 1H), 4.94 (d, 7 = 6.3 Hz, 2H), 4.72 (d, 7 = 6.3 Hz, 2H), 3.66 (s, 1H), 3.40 (d, 7 = 12.3 Hz, 1H), 2.04 (s, 6H), 1.99 (s, 2H), 1.48 (dd, J = 23.7 Hz, 11.6 Hz, 2H), 1.25 (dd, J= 23.1 Hz, 11.6 Hz, 2H).
Figure imgf000080_0001
N- (3-(4-(4-((/raH.s-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)oxetan-3-yl)acetamide
Figure imgf000080_0002
Step 1: To a solution of DIPEA (43.7 mg, 337.98 p mol, 58.9 μL) and acetyl chloride (9.7 mg, 123.93 p mol, 7.5 μL) in dichloromethane (10 mL) was added the solution of 3-(4- bromopyridin-2-yl)oxetan-3-amine (30 mg, 112.66 μmo)l in dichloromethane (2 mL) at 0 °C. The mixture was stirred at room temperature for an hour and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with methanol/dichloromethane from 0 to 10%) and further by prep-HPLC to give N-{ 3-(4- bromopyridin-2-yl)oxetan-3-yl)acetamide (24 mg, 79% yield) as a yellow solid. LC-MS (ESI) [(M+H)+] : 271.0.
Step 2: A mixture of int. 3 (229.7 mg, 450.12 μmol), N-(3-(4-bromopyridin-2-yl)oxetan-3- yl)acetamide (122 mg, 450.12 μmol), Pd(dppf)Cl2 (65.9 mg, 90.02 μmo)l and K2CO3 (186.4 mg, 1.35 mmol) in dioxane/water (10 mL, 4/1) was stirred at 100 °C under N2 atmosphere for 4 hours, cooled to room temperature, diluted with ethyl acetate (30 mL) and washed with water (10 mL x 2). The organic phase was dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with methanol in dichloromethane from 0 to 10%) and further by prep-HPLC to afford A-(3-(4-(4-((iran5-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)oxetan-3-yl)acetamide (24 mg, 9% yield) as a yellow solid. LC-MS (ESI) [(M+H)+]: 575.1. NMR (400 MHz, DMSO -d6) d 9.15 (s, 1H), 8.77 (d, J = 5.2 Hz, 1H), 8.25 (s, 1H), 8.07-7.98 (m, 4H), 7.72 (d, J = 5.2 Hz, 1H), 7.69 (s, 1H), 7.60-7.56 (m, 1H), 7.25 (d, J = 7.6 Hz, 1H), 6.54 (d, J = 8.8 Hz, 1H), 5.02 (d, J = 6.4 Hz, 2H), 4.77 (d, J = 6.4 Hz, 2H), 3.66 (s, 1H), 3.39 (s, 1H), 2.09-1.94 (m, 7H), 1.51-1.43 (m, 2H), 1.25 (d, J = 11.6 Hz, 2H).
Example 39
Figure imgf000081_0001
Trans -/V-(4-((4-(2-(3-(methylamino)oxetan-3-yl)pyridin-4- yl)phenyl)sulfonyl)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine
Figure imgf000081_0002
Step 1: To a stirred mixture of N-(3-(4-bromopyridin-2-yl)oxetan-3-yl)-2-methylpropane-2- sulfinamide (80 mg, 240.06 μmo)l in anhydrous THF (3 mL) was added sodium hydride (60% dispersion in mineral oil) (14.4 mg, 360.10 μmo)l at 0 °C. The mixture was stirred at 0 °C for 15 minutes, followed by the addition of iodomethane (51.1 mg, 360.10 μmol, 22.4 μL). The reaction mixture was stirred at room temperature for 18 hours until the reaction was completed, quenched with H2O (5 mL), and extracted with EA (10 mL x 2). The organic layers were washed with brine (10 mL x 2), dried over anhydrousNa2SO4 and filtered. The filtrate was concentrated in vacuo to give N-(3-(4-bromopyridin-2-yl)oxetan-3-yl)- V,2-dimethylpropane-
2-sulfinamide (120 mg, crude) as oil. LC-MS (ESI) [(M+H)+]: 347.2.
Step 2: To a mixture of int. 3 (110 mg, 215.53 μmo)l and N-(3-(4-bromopyridin-2-yl)oxetan-
3-yl)-A,2-dimethylpropane-2-sulfinamide (74.9 mg, 215.53 μmo)l in mixed solvent of dioxane and H2O (4/1, 3.8 mL) were added potassium carbonate (89.4 mg, 646.58 μmol) and Pd(dppf)Cl2 (15.8 mg, 21.55 μmo)l. The mixture was degassed with N2, and stirred at 110 °C under microwave conditions for an hour, until the starting material was totally consumed. The reaction mixture was filtered through a Celite pad, and the pad was washed with ethyl acetate (10 mL x 2). The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with methanol in dichloromethane from 0 to 20%) to afford /V,2-di methyl -/ran.s-/V-(3-(4-(4-((4-((5-(frifluoiOmcthyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)oxetan-3-yl)propane-2-sulfinamide (70 mg, 50% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 651.1.
Step 3: To A/,2-dimethyl-iran,s'- V-(3-(4-(4-((4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)oxetan-3-yl)propane-2-sulfinamide (70 mg, 107.56 μmol) was added HCl/dioxane (3 mL) at 0 °C, and the mixture was stirred at this temperature for 30 minutes and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with methanol/dichloromethane from 0 to 10%) and prep-HPLC to give iran,s'- V-(4-((4-(2-(3-(methylamino)oxetan-3-yl)pyridin-4- yl)phenyl)sulfonyl)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine (8 mg, 14% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 547.0.
Figure imgf000082_0001
NMR (400 MHz, DMSO -d6) d 8.74 (d, 7= 5.2 Hz, 1H), 8.25 (s, 1H), 8.13 (d, 7= 8.5 Hz, 1H), 8.10 (s, 1H), 8.01 (s, 1H), 7.99 (s, 1H), 7.89 (s, 1H), 7.74 (dd, J= 5.2 Hz, 1.6 Hz, 1H), 7.59 (dd, J= 8.9 Hz, 2.3 Hz, 1H), 7.25 (d, 7 = 7.4 Hz, 1H), 6.54 (d, 7= 8.9 Hz, 1H), 4.97 (d, 7= 5.9 Hz, 2H), 4.65 (d, 7= 6.0 Hz, 2H), 3.68 (s, 1H), 2.12 (s, 3H), 2.03 (t, 7 = 13.8 Hz, 4H), 1.47 (dd, J = 23.7 Hz, 12.0 Hz, 2H), 1.25 (q, 7 = 11.4 Hz, 2H).
Example 40
Figure imgf000082_0002
Trans -A/-(4-((4-(2-(3-(ethylamino)oxetan-3-yl)pyridin-4-yl)phenyl)sulfonyl)cyclohexyl)-
5-(trifluoromethyl)pyridin-2-amine
Synthesized according to Example 39, using iodoethane replacing iodomethane in Step 1. As a white solid. LC-MS (ESI) [(M+H)+]: 561.1.
Figure imgf000082_0003
NMR (400 MHz, DMSO -d6) d 8.71 (d, 7= 5.2 Hz, 1H), 8.24 (s, 1H), 8.10 (d, 7 = 8.4 Hz, 2H), 7.99 (d, 7 = 8.4 Hz, 2H), 7.89 (s, 1H), 7.72 (dd, 7 = 5.2 Hz, 1.5 Hz, 1H), 7.58 (dd, J= 8.9 Hz, 2.3 Hz, 1H), 7.24 (d, 7 = 7.4 Hz, 1H), 6.53 (d, 7 = 8.9 Hz, 1H), 4.97 (d, 7= 5.9 Hz, 2H), 4.65 (d, 7 = 5.9 Hz, 2H), 3.65 (s, 1H), 3.39 (d, 7= 12.2 Hz, 1H), 2.99 (s, 1H), 2.29 (q, 7 = 7.0 Hz, 2H), 2.03 (dd, J = 24.4 Hz, 11.0 Hz, 4H), 1.47 (dd, 7= 23.6 Hz, 11.7 Hz, 2H), 1.25 (dd, J= 23.5 Hz, 11.1 Hz, 2H), 0.99 (t, 7= 7.1 Hz, 3H). Example 41
Figure imgf000083_0001
Trans -/V-(4-((4-(2-(3-methoxyazetidin-3-yl)pyridin-4-yl)phenyl)sulfonyl)cyclohexyl)-5-
(trifluoromethyl)pyridin-2-amine
Figure imgf000083_0002
Step 1: To a solution of 2,4-dibromopyridine (1.5 g, 6.33 mmol) in anhydrous DCM (30 mL) was added dropwise n-butyl lithium ( 2.5M in THF, 2.8 mL) at -60 °C under N2 atmosphere. The reaction mixture was stirred for 15 minutes at this temperature, followed by the dropwise addition of /<? /7-butyl 3-oxoazetidine-l-carboxylate (1.08 g, 6.33 mmol). The resulting mixture was stirred at -60 °C for an hour and poured into saturated NH4CI aqueous solution (30 mL). The two phases were separated, and the organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate in petroleum ether from 0 to 50%) to give tert-butyl 3-(4-bromopyridin-2-yl)-3- hydroxyazetidine-l-carboxylate (1.3 g, 62% yield). LC-MS (ESI) [(M+H)+]: 329.2.
Step 2: To a stirred mixture of tert-butyl 3-(4-bromopyridin-2-yl)-3-hydroxyazetidine-l- carboxylate (0.5 g, 1.52 mmol) in anhydrous THF (8 mL) was added sodium hydride (60% dispersion in mineral oil) (72.9 mg, 1.82 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 minutes, followed by the addition of iodomethane (258.7 mg, 1.82 mmol, 113.5 μL). The reaction mixture was stirred at room temperature for 18 hours until the reaction was completed, quenched with H2O (8 mL), and extracted with EA (20 mL x 2). The organic layers were washed with brine (20 mL x 2), dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo to give tert-butyl 3-(4-bromopyridin-2-yl)-3-methoxyazetidine-l- carboxylate (480 mg, 92% yield) as oil. LC-MS (ESI) [(M+H)+]: 343.1.
Step 3: To a mixture of int. 3 (100 mg, 195.93 μmo)l and tert-butyl 3-(4-bromopyridin-2-yl)- 3-methoxyazetidine-l-carboxylate (74.0 mg, 215.53 μmo)l in mixed solvent of dioxane and H2O (4/1, 3.8 mL) were added potassium carbonate (81.2 mg, 587.80 m mol) and Pd(dppf)Cl2 (14.3 mg, 19.59 μmol). The mixture was degassed with N2, and stirred at 110 °C under microwave conditions for 2 hours, until the starting material was totally consumed. The reaction mixture was filtered through a Celite pad, and the pad was washed with ethyl acetate (10 mL x 2). The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with methanol in dichloromethane from 0 to 20%) to afford /<? /7-butyl 3-mcthoxy-3-(4-(4-((trans-4-((5-(tnfhioromcthyl)pyndin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)azetidine-l-carboxylate (75 mg, 59% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 647.0. Step 4\ To tert-butyl 3-mcthoxy-3-(4-(4-((trans-4-((5-(tnfhioromcthyl)pyndin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)azetidine-l-carboxylate (75 mg, 115.97 pmol) was added HCl/dioxane (3 mL) at 0 °C, and the mixture was stirred at this temperature for 30 minutes and concentrated in vacuo. The residue was purified by prep-HPLC to give /ra/7.s'-A/-(4-((4-(2-(3-mcthoxyazctidin-3-yl)pyndin-4-yl)phcnyl)suironyl)cyclohcxyl)-5- (trifluoromethyl)pyridin-2-amine (10 mg, 16% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 547.1. NMR (400 MHz, DMSO -d6) d 8.78 (d, J = 5.0 Hz, 1H), 8.42 (d, J = 8.4 Hz, 2H), 8.25 (s, 1H), 8.15 (s, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7.59 (dd, / = 8.3 Hz, 2.9 Hz, 2H), 7.26 (d, / = 7.4 Hz, 1H), 6.54 (d, J = 8.9 Hz, 1H), 3.87 (d, J = 8.9 Hz, 2H), 3.66 (d, J = 8.8 Hz, 3H), 3.08 (s, 3H), 2.03 (t, /= 12.7 Hz, 4H), 1.47 (dd, J = 22.9 Hz, 12.5 Hz, 2H), 1.31-1.20 (m, 2H).
Example 42
Figure imgf000084_0001
Trans -/V-(4-((4-(2-(3-methoxy-l-methylazetidin-3-yl)pyridin-4- yl)phenyl)sulfonyl)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine
Figure imgf000085_0001
Step 1: The mixture of tert- butyl 3-(4-bromo-2-pyridyl)-3-methoxy-azetidine-l-carboxylate (180 mg, 524.45 p mol) in HCl/ethyl acetate (4M, 5 mL) was stirred at room temperature for 30 minutes and diluted with saturated sodium bicarbonate aqueous solution (5 mL). The resulting mixture was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with methanol/dichloromethane from 0 to 10%) and further by prep-HPLC to give 4-bromo-2-(3-methoxyazetidin-3-yl)pyridine (100 mg, quantitative) as oil. LC-MS (ESI) [(M+H)+]: 243.2.
Step 2: To a mixture of 4-bromo-2-(3-methoxyazetidin-3-yl)pyridine (100 mg, 411.35 μmo)l, sodium acetate (67.5 mg, 822.71 μmo)l and acetic acid (49.4 mg, 822.71 μmol, 47.1 μL) in dichloromethane (10 mL) was added formaldehyde (37% aqueous solution, 822.71 μmo,l 0.2 mL) at 25 °C. The mixture was stirred at 25 °C for 45 minutes, followed by the addition of sodium triacetoxyborohydride (261.6 mg, 1.23 mmol) in one portion at 0-5 °C, and 10 minutes after the addition was stirred at 25 °C for another hour. The reaction mixture was quenched with NaOH aqueous solution (0.5M, 2 mL), and two layers were separated. The aqueous layer was extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrousNa2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate/PE from 0 to 100%) to give 4-bromo-2-(3-methoxy-l-methyl-azetidin-3- yl)pyridine (80 mg, 76% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 257.1.
Step 3: A mixture of int. 3 (138.9 mg, 272.24 μmol), 4-bromo-2-(3-methoxy- 1 -methyl - azetidin-3-yl)pyridine (70 mg, 272.24 μmo)l Pd(dppf)Cl2 (39.8 mg, 54.45 μmo)l and K2CO3 (150.6 mg, 1.09 mmol) in dioxane/water (10 mL, 4/1) was stirred at 100 °C under N2 atmosphere for 4 hours, cooled to room temperature, diluted with ethyl acetate (30 mL) and washed with water (10 mL x 2). The organic layer was dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with methanol in dichloromethane from 0 to 10%) and further by prep-HPLC to afford iran5-A/-(4-((4-(2-(3-methoxy-l-methylazetidin-3-yl)pyridin- 4-yl)phenyl)sulfonyl)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine (75 mg, 49% yield) as a yellow solid. LC-MS (ESI) [(M+H)+]: 561.0.
Figure imgf000086_0001
NMR (400 MHz, DMSO -d6) d 8.74 (d, J = 5.1 Hz, 1H), 8.25 (s, 1H), 8.12 (d, J = 8.3 Hz, 2H), 7.99 (d, J = 8.3 Hz, 2H), 7.85 (s,lH), 7.77 (d, J = 3.9 Hz, 1H), 7.59 (d, J = 7.0 Hz, 1H), 7.25 (d, J = 7.4 Hz, 1H), 6.54 (d, J = 8.9 Hz, 1H), 3.79 (d, J = 7.9 Hz, 2H), 3.66 (s, 1H), 3.39 (s, 1H), 3.36 (s, 2H), 3.06 (s, 3H), 2.33 (s, 3H), 2.03 (t, /= 13.6 Hz, 4H), 1.51-1.42 (m, 2H), 1.25 (d, J = 11.9 Hz, 2H).
Example 43
Figure imgf000086_0002
3-(4-(4-((7r«H.s-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)azetidin-3-ol
Figure imgf000086_0003
Step 1: To a solution /<? /7-butyl 3-(4-bromo-2-pyridyl)-3-hydroxy-azetidine-l-carboxylate (500 mg, 1.52 mmol) in DCM (10 mL) was added HCl/dioxane (4M, 5 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 minutes and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with methanol/dichloromethane from 0 to 20%) to give 3-(4-bromo-2-pyridyl)azetidin-3-ol (300 mg, 86% yield) as a white solid. LC- MS (ESI) [(M+H)+] : 229.1.
Step 2: A mixture of int. 3 (222.8 mg, 436.54 μmo)l, 3-(4-bromo-2-pyridyl)azetidin-3-ol (100 mg, 436.54 μmol) Pd(dppf)Cl2 (63.9 mg, 87.31 μmo)l and K2CO3 (150.6 mg, 1.09 mmol) in dioxane/water (10 mL, 4/1) was stirred at 100 °C under N2 atmosphere for 4 hours, cooled to room temperature, diluted with ethyl acetate (30 mL) and washed with water (10 mL x 2). The organic layer was dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with methanol in dichloromethane from 0 to 10%) and further by prep-HPLC to afford 3-(4-(4- ((irafts-4-((5-(trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2- yl)azetidin-3-ol (11.5 mg, 5% yield) as a yellow solid. LC-MS (ESI) [(M+H)+]: 533.2. Ή NMR (400 MHz, DMSO -d6) d 8.80 (d, 7 = 5.1 Hz, 1H), 8.24 (s, 1H), 8.10 (d, 7 = 8.4 Hz, 2H), 8.02 (d, 7 = 8.4 Hz, 2H), 7.97 (s, 1H), 7.83 (dd, J = 5.1 Hz, 1.5 Hz, 1H), 7.58 (dd, J = 8.9 Hz, 2.2 Hz, 1H), 7.26 (d, 7= 7.3 Hz, 1H), 7.14 (s, 1H), 6.54 (d, 7= 8.9 Hz, 1H), 4.45 (d, 7 = 10.8 Hz, 2H), 4.13 (d, 7= 10.7 Hz, 2H), 3.65 (s, 1H), 3.38 (s, 1H), 2.00 (d, 7= 13.6 Hz, 4H), 1.24 (d, 7 = 7.6 Hz, 4H).
Example 44
Figure imgf000087_0001
l-Methyl-3-(4-(4-((/raH.s-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)azetidin-3-ol
Figure imgf000087_0002
Step 1 : To a mixture of 3-(4-bromopyridin-2-yl)azetidin-3-ol (80 mg, 349.23 μmo)l, sodium acetate (57.3 mg, 698.47 μmol) and acetic acid (41.9 mg, 698.47 μmol, 40.0 μL) in dichloromethane (10 mL) was added formaldehyde (37% aqueous solution, 822.71 μmo,l 0.2 mL) at 25 °C. The mixture was stirred at 25 °C for 45 minutes, followed by the addition of sodium triacetoxyborohydride (222.1 mg, 1.05 mmol) in one portion at 0-5 °C, and 10 minutes after the addition was stirred at 25 °C for another hour. The reaction mixture was quenched with NaOH aqueous solution (0.5M, 2 mL), and two layers were separated. The aqueous layer was extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrousNa2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with methanol/dichloromethane from 0 to 20%) to give 3-(4-bromo-2-pyridyl)-l-methyl-azetidin- 3-ol (60 mg, 71% yield) as white solid. LC-MS (ESI) [(M+H)+]: 243.0. Step 2: A mixture of int. 3 (125.9 mg, 246.81 μmo)l, 3-(4-bromo-2-pyridyl)-l-methyl-azetidin- 3-ol (60 mg, 246.81 μmo)l Pd(dppf)Cl2 (36.1 mg, 49.36 μmo)l and K2CO3 (85.1 mg, 617.03 pmol) in dioxane/water (10 mL, 4/1) was stirred at 100 °C under N2 atmosphere for 4 hours, cooled to room temperature, diluted with ethyl acetate (30 mL) and washed with water (10 mL x 2). The organic layer was dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with methanol in dichloromethane from 0 to 10%) and further by prep-HPLC to afford l-methyl-3-(4-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)azetidin-3-ol (30 mg, 22% yield) as a yellow solid. LC-MS (ESI) [(M+H)+]: 547.1.
Figure imgf000088_0001
NMR (400 MHz, DMSO -d6) d 8.81 (d, J = 5.1 Hz, 1H), 8.25 (s, 1H), 8.10 (d, J = 8.3 Hz, 2H), 8.02 (d, J= 8.4 Hz, 2H), 7.97 (s, 1H), 7.83 (d, J = 3.7 Hz, 1H), 7.61-7.57 (m, 1H), 7.24 (d, J=7.3 Hz, 1H), 7.09 (s, 1H), 6.55 (d, J = 8.9 Hz, 1H), 4.53 (s, 2H), 4.21 (d, J= 9.3 Hz, 2H), 3.67 (s, 1H), 3.40 (s, 1H), 2.95 (s, 3H), 2.03 (t, /= 13.4 Hz, 4H), 1.47 (d, J= 11.5 Hz, 2H), 1.35-1.28 (m, 2H).
Example 45
Figure imgf000088_0002
3-(4-(4-((trans-4- ((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)oxetan-3-ol
Figure imgf000088_0003
Step 1: To a solution of 2,4-dibromopyridine (1.0 g, 4.22 mmol) in anhydrous dichloromethane (20 mL) was added n-butyl lithium (4.65 mmol, 1.86 mL, 2.5 mol/L in THF) at -60 °C under the atmosphere of N2. 15 minutes after completion of addition, oxetan-3-one (304.2 mg, 4.22 mmol, 271.6 μL) was added into the solution at -60 °C. The reaction mixture was stirred at - 60 °C for one hour and poured into saturated ammonium chloride aqueous solution (30 mL). The organic layer was separated, washed with brine (20 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate/PE from 0 to 50%) to give 3- (4-bromo-2-pyridyl)oxetan-3-ol (630.0 mg, 65% yield). LC-MS (ESI) [(M+H)+]: 229.8.
Step 2: A mixture of 3-(4-bromo-2-pyridyl)oxetan-3-ol (60.0 mg, 260.80 μmol), int. 3 (133.0 mg, 260.59 μmo)l, Pd(PPh3)2Cl2 (36.6 mg, 52.21 μmo) l and K2CO3 (108.0 mg, 782.61 μmo)l in dioxane/water (10 mL, 4/1) was stirred at 110 °C under N2 atmosphere for 4 hours, cooled to room temperature, diluted with ethyl acetate (30 mL) and washed with water (10 mL x 3). The organic layer was dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate/petroleum ether from 0 to 100%) to give 3-(4-(4-((iran,s-4-((5- (trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)oxetan-3-ol (25 mg, 18% yield) as a yellow solid. LC-MS (ESI) [(M+H)+]: 534.0.
Figure imgf000089_0001
NMR (400 MHz, DMSO- de) d 8.78 (d, J = 5.2 Hz, 1H), 8.25 (s, 1H), 8.09 (d, J = 8.4 Hz, 2H), 8.00 (d, J = 8.4 Hz, 2H), 7.94 (s, 1H), 7.76 (d, J= 3.6 Hz, 1H), 7.60-7.57 (m, 1H), 7.26 (d, J = 7.2 Hz, 1H), 6.68 (s, 1H), 6.54 (d, J = 8.8 Hz, 1H), 4.99 (d, J = 6.0 Hz, 2H), 4.71 (d, J = 6.0 Hz, 2H), 3.66 (s, 1H), 3.42 (s, 1H), 2.03 (t, / = 13.6 Hz, 4H), 1.48 (d, J= 12.0 Hz, 2H), 1.25 (d, J= 10.0 Hz, 2H).
Example 46
Figure imgf000089_0002
(4-(2-(3-Hydroxyoxetan-3-yl)pyridin-4-yl)phenyl)(imino)(trans-4-((5-
(trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)-λ6-sulfanone
Figure imgf000089_0003
Step 1: A mixture of 3-(4-bromo-2-pyridyl)oxetan-3-ol (60.0 mg, 260.80 μmol), int. 1 (124.8 mg, 260.80 μmo)l, Pd(PPh3)2Cl2 (36.6 mg, 52.21 μmo) l and K2CO3 (108.0 mg, 782.61 μmo)l in dioxane/water (10 mL, 4/1) was stirred at 110 °C under N2 atmosphere for 4 hours, cooled to room temperature, diluted with ethyl acetate (30 mL) and washed with water (10 mL x 2). The organic layer was dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate/petroleum ether from 0 to 100%) to give 3-(4-(4-((trans-4-((5- (trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)thio)phenyl)pyridin-2-yl)oxetan-3-ol (60.0 mg, 46% yield) as a yellow solid. LC-MS (ESI) [(M+H)+]: 502.0.
Step 2: To a mixture of 3-(4-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)thio)phenyl)pyridin-2-yl)oxetan-3-ol (50.0 mg, 99.69 μmol ) and ammonium carbamate (23.5 mg, 301.01 μmol) in methanol (10 mL) was added iodobenzene diacetate (64.8 mg, 199.93 μmol). The mixture was stirred at 25 °C for 3 hours and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with methanol in dichloromethane from 0 to 10%) and further by prep-HPLC to give (4-(2-(3-hydroxyoxctan-3-yl)pyridin-4-yl)phcnyl)(imino)(trans-4-((5- (trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)-X6-sulfanone (10.0 mg, 19% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 533.1. NMR (400 MHz, DMSO -d6) d 8.76 (d, J = 5.2 Hz, 1H), 8.24 (s, 1H), 8.00 (q, J= 8.8 Hz, 4H), 7.91 (s, 1H), 7.73 (dd, J= 5.2 Hz, 1.6 Hz, 1H), 7.57 (dd, / = 8.8 Hz, 2.4 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 6.66 (s, 1H), 6.52 (d, J = 9.2 Hz, 1H), 4.98 (d, J = 6.0 Hz, 2H), 4.70 (d, J = 6.1 Hz, 2H), 4.34 (s, 1H), 3.61 (s, 1H), 3.10 (d, J = 11.6 Hz, 1H), 2.01 (s, 4H), 1.42 (d, J= 13.6 Hz, 2H), 1.21 (d, J= 12.4 Hz, 2H).
Example 47
Figure imgf000090_0001
Trans-N- (4-((4-(2-(3-methoxyoxetan-3-yl)pyridin-4-yl)phenyl)sulfonyl)cyclohexyl)-5- -
(trifluoromethyl)pyridin-2-amine
Figure imgf000090_0002
Step 1: To a solution of 3-(4-bromo-2-pyridyl)oxetan-3-ol (100 mg, 434.67 μmo)l in anhydrous THF (4 mL) was added NaH (60% dispersion in mineral oil, 15.0 mg, 652.01 μmol) at 0 °C under the atmosphere of N2. 30 minutes after completion of addition, iodomethane (67.9 mg, 478.14 μmol, 29.8 μL) was added thereto at 25 °C. The resulting mixture was stirred at 25 °C for 2 hours and poured into saturated NH4CI aqueous solution (10 mL). The organic layer was separated, and the aqueous phase was extracted with DCM (10 mL x 3). The combine organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate/PE from 0 to 50%) to give 4-bromo-2-(3-methoxyoxetan- 3-yl)pyridine (90 mg, 85% yield) as colorless oil. LC-MS (ESI) [(M+H)+]: 243.8.
Step 2: A mixture of 4-bromo-2-(3-methoxyoxetan-3-yl)pyridine (90 mg, 368.72 μmol), tetrakis(triphenylphosphine) palladium (85.2 mg, 73.74 μmo)l, int. 3 (207.0 mg, 405.60 μmo)l and sodium carbonate (97.7 mg, 921.81 μmo)l in dioxane/water (2 mL, 4/1) was stirred at 100 °C for 1 hour under N2 atmosphere, cooled to room temperature, and diluted with ethyl acetate (20 mL). The resulting mixture was washed with H2O (10 mL x 3). The organic layer was dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate/hexanes from 0 to 100%) and further by prep-HPLC to give trans-N-(4-((4-(2-(3- methoxyoxetan-3-yl)pyridin-4-yl)phenyl)sulfonyl)cyclohexyl)-5-(trifluoromethyl)pyridin-2- amine (55 mg, 27% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 547.8. Ή NMR (400 MHz, DMSO-ί/ό) d 11.90 (s, 1H), 8.84 (s, 1H), 8.44 (s, 1H), 7.95 (d, J = 1.9 Hz, 1H), 7.75 (s, 1H), 7.63 (d, J = 3.3 Hz, 1H), 7.17 (d, J = 1.8 Hz, 1H), 6.71 (d, J = 3.1 Hz, 1H), 4.16 (s, 4H), 2.89 (s, 1H), 1.94 (s, 1H), 1.80-1.69 (m, 1H), 1.54-1.33 (m, 2H).
Example 48
Figure imgf000091_0001
Oxetan-3-yl(4-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)methanol
Figure imgf000091_0002
Step 1: To a solution of 2,4-dibromopyridine (100 mg, 422.13 μmo)l in anhydrous THE (2 mL) was added n-BuLi (2.5M in THE, 0.2 mL) at -78 °C under the atmosphere of N2. 15 minutes after completion of addition, oxetane-3-carbaldehyde (40.0 mg, 464.35 p mol) was added thereto at -60 °C. The resulting mixture was stirred at -60 °C for one hour, and poured into saturated NH4CI aqueous solution (30 mL). The organic layer was separated, and the aqueous phase was extracted with DCM (20 mL x 3). The combine organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate/PE from 0 to 50%) to give (4-bromopyridin-2-yl)(oxetan-3-yl)methanol (50 mg, 49% yield) as colorless oil. LC-MS (ESI) [(M+H)+]: 243.8.
Step 2: A mixture of (4-bromopyridin-2-yl)(oxetan-3-yl)methanol (100 mg, 409.69 μmol), tetrakis(triphenylphosphine) palladium (94.7 mg, 81.94 μmo)l, int. 3 (209.1 mg, 409.69 μmo)l and sodium carbonate (108.6 mg, 1.02 mmol) in dioxane/water (2 mL, 4/1) was stirred at 100 °C for 1 hour under N2 atmosphere, cooled to room temperature, and diluted with ethyl acetate (20 mL). The resulting mixture was washed with H2O (10 mL x 3). The organic layer was dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate/hexanes from 0 to 100%) and further by prep-HPLC to give o x c t a n - 3 - y 1 (4 - (4 ( ( t ran s - 4-((5-(trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)methanol (33 mg, 15% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 612.8.
Figure imgf000092_0001
NMR (400 MHz, DMSO -de) d 8.67-8.06 (m, 6H), 7.97 (d, J = 8.3 Hz, 2H), 7.59 (dd, / = 8.9 Hz, 2.6 Hz, 1H), 7.43 (dd, / = 8.0 Hz, 4.7 Hz, 1H), 7.25 (d, J = 7.4 Hz, 1H), 6.54 (d, J = 8.9 Hz, 1H), 5.89 (d, J = 4.8 Hz, 1H), 4.93 (dd, / = 7.8 Hz, 4.6 Hz, 1H), 4.58-4.47 (m, 4H) , 3.68 (s, 1H), 2.03 (t, / = 16.8 Hz, 4H), 1.48-1.42 (m, 2H), 1.30-1.20 (m, 2H).
Example 49
Figure imgf000092_0002
l-(4-(4-((Trans-4- ((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)cyclobutan-l-ol
Figure imgf000093_0001
Step 1: To a solution of 2,4-dibromopyridine (1.19 g, 5.04 mmol) in anhydrous DCM (10 mL) was added nBuLi (2.2 M hexane solution, 2.52 mL) dropwise at -78 °C over 20 minutes. The resulting solution was stirred at the same temperature for 30 minutes, followed by the dropwise addition of cyclobutanone (353.3 mg, 5.04 mmol, 376.6 μL) over 5 minutes. The reaction mixture was stirred at -78 °C for 1 hour, allowed to warm to room temperature spontaneously, and quenched with saturated NH4CI aqueous solution (10 mL). The two phases were separated, and the aqueous phase was extracted with DCM (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with PE/EA: 10/1 to 4/1) to afford l-(4-bromo-2-pyridyl)cyclobutanol (400 mg, 35% yield) as yellow oil. LC-MS (ESI) [(M+H)+]: 228.0.
Step 2: To a stirred solution of l-(4-bromo-2-pyridyl)cyclobutanol (107.3 mg, 470.24 μmo)l and int. 3 (200 mg, 391.87 μmo)l in mixed solvent of dioxane (4 mL) and H2O (0.5 mL) were added RuPhos Pd G2 (30.5 mg, 39.19 μmo)l and K3PO4 (249.5 mg, 1.18 mmol). The mixture was stirred at 100 °C for 2 hours under N2 atmosphere, cooled to room temperature, diluted with EA (50 mL) and washed with brine (20 mL x 2). The organic phase was dried over anhydrous Na2S04 and filtered. The filtration was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with MeOH/DCM: 1/12) to give l-(4-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)cyclobutan-l-ol (40 mg, 19% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 532.1.
Figure imgf000093_0002
NMR (400 MHz, DMSO -d6) d 8.69 (d, 7= 5.1 Hz, 1H), 8.25 (s, 1H), 8.06 (d, 7 = 8.5 Hz, 2H), 7.99 (d, 7 = 8.5 Hz, 2H), 7.90 (d, 7 = 0.9 Hz, 1H), 7.66 (dd, J = 5.1 Hz, 1.7 Hz, 1H), 7.59 (dd, J = 8.9 Hz, 2.3 Hz, 1H), 7.25 (d, 7 = 7.4 Hz, 1H), 6.54 (d, J = 8.9 Hz, 1H), 5.87 (s, 1H), 3.66 (s, 1H), 3.39 (d, 7 = 10.4 Hz, 1H), 2.67-2.56 (m, 2H), 2.33-2.21 (m, 2H), 2.04 (dd, J = 24.3 Hz, 10.9 Hz, 4H), 1.97-1.78 (m, 2H), 1.47 (dd, 7 = 23.8 Hz, 11.6 Hz, 2H), 1.25 (dd, J = 23.3 Hz, 11.0 Hz, 2H). Example 50
Figure imgf000094_0002
Trans -/V-(4-((4-(2-(3-aminoazetidin-l-yl)pyridin-4-yl)phenyl)sulfonyl)cyclohexyl)-5-
(trifluoromethyl)pyridin-2-amine
Figure imgf000094_0001
Step 1: To a solution of 4-bromo-2-fluoro-pyridine (200 mg, 1.14 mmol, 117.0 μL) and azetidin-3-amine (90.1 mg, 1.25 mmol) in n-butanol (4 mL) was added TEA (345.0 mg, 3.41 mmol, 475.2 μL). The mixture was stirred at 100 °C for 3 hours, cooled to room temperature, diluted with water (10 mL) and extracted with DCM (30 mL x 3). The organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate in petroleum ether from 0 to 50%) to give l-(4-bromo-2- pyridyl)azetidin-3-amine (180 mg, 69% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 229.0.
Step 2: To a stirred solution of l-(4-bromo-2-pyridyl)azetidin-3-amine (107.3 mg, 470.24 μmo)l and int. 3 (200 mg, 391.87 μmo)l in mixed solvent of dioxane (4 mL) and H2O (0.5 mL) were added RuPhos Pd G2 (30.5 mg, 39.19 μmo)l and K3PO4 (249.5 mg, 1.18 mmol). The mixture was stirred at 100 °C for 2 hours under N2 atmosphere, cooled to room temperature, diluted with EA (50 mL) and washed with brine (20 mL x 2). The organic phase was dried over anhydrous Na2S04 and filtered. The filtration was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with MeOH/DCM: 1/10) to give iran5-A-(4-((4-(2-(3-aminoazetidin-l-yl)pyridin-4-yl)phenyl)sulfonyl)cyclohexyl)-5- (trifluoromethyl)pyridin-2-amine (85 mg, 41% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 532.2. NMR (400 MHz, DMSO -d6) d 8.25 (s, 1H), 8.17 (d, J = 5.3 Hz, 1H), 8.01 (d, J= 8.5 Hz, 2H), 7.95 (d, J = 8.4 Hz, 2H), 7.58 (dd, J = 8.9 Hz, 2.2 Hz, 1H), 7.24 (d, J = 7.4 Hz, 1H), 6.98 (dd, J = 5.3 Hz, 1.3 Hz, 1H), 6.68 (s, 1H), 6.54 (d, J = 8.9 Hz, 1H), 4.18 (t, J = 7.7 Hz, 2H), 3.89-3.80 (m, 1H), 3.65 (s, 1H), 3.61 (dd, J = 8.0 Hz, 5.9 Hz, 2H), 3.39 (s, 1H), 2.67 (s, 2H), 2.02 (t, J= 14.6 Hz, 4H), 1.46 (d, J= 12.3 Hz, 2H), 1.26 (dd, J = 13.2 Hz, 9.3 Hz, 2H).
Example 51
Figure imgf000095_0001
N- (azetidin-3-yl)-4-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-amine
Figure imgf000095_0002
Step 1: To a solution of 4-bromo-2-fluoro-pyridine (500 mg, 2.84 mmol, 292.4 μL) and tert- butyl 3-aminoazetidine-l-carboxylate (587.2 mg, 3.41 mmol) in DMF (10 mL) was added cesium carbonate (2.78 g, 8.52 mmol). The mixture was stirred at 100 °C for 16 hours, cooled to room temperature, diluted with H2O (10 mL) and EA (100 mL) and washed with and brine (20 mL x 4). The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate in petroleum ether from 0 to 50%) to give tert-butyl 3-((4- bromopyridin-2-yl)amino)azetidine-l-carboxylate (600 mg, 64% yield) as red oil. LC-MS (ESI) [(M+H)+]: 329.2.
Step 2: To a stirred solution of tert-butyl 3-((4-bromopyridin-2-yl)amino)azetidine-l- carboxylate (308.7 mg, 940.48 μmol) and int. 3 (400 mg, 783.74 μmo)l in mixed solvent of dioxane (8 mL) and H2O (1 mL) were added RuPhos Pd G2 (61.0 mg, 78.37 μmo)l and K3PO4 (499.1 mg, 2.35 mmol). The mixture was stirred at 100 °C for 2 hours under N2 atmosphere, cooled to room temperature, diluted with EA (100 mL) and washed with brine (20 mL x 3). The organic phase was dried over anhydrous Na2SO4 and filtered. The filtration was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with MeOH/DCM: 1/15) to give tert-butyl 3-((4-(4-((trans-4-((5- (trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2- yl)amino)azetidine-l-carboxylate (200 mg, 40% yield) as a white solid. LC-MS (ESI) [(M+H)+] : 632.1.
Step 3: A solution of tert- butyl 3-((4-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)amino)azetidine- 1-carboxylate (200 mg, 316.60 μmol) in HCl/dioxane (4M, 6 mL) was stirred at 25 °C for 16 hours and concentrated in vacuo. The residue was basified to pH to 8 with saturated NaHCO3 aqueous solution, and extracted with EA (20 mL x 3). The organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with MeOH/DCM: 1/10) to give A-(azctidin-3-yl)-4-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-amine (24 mg, 14% yield) as a white solid. LC-MS (ESI) [(M+H)+] : 532.0. NMR (400 MHz, DMSO -d6) d 8.19 (d, J = 44.6 Hz, 2H), 8.05 (dd, J = 17.1 Hz, 8.5 Hz, 2H), 7.95 (q, J = 8.7 Hz, 2H), 7.58 (d, J = 8.9 Hz, 1H), 7.24 (s, 2H), 6.82 (s, 1H), 6.54 (d, J= 8.8 Hz, 1H), 4.82-4.64 (m, 1H), 4.47 (s, 1H), 4.31 (d, J = 4.5 Hz, 1H), 4.19-4.11 (m, 1H), 3.93-3.85 (m, 1H), 3.68 (s, 1H), 3.41 (s, 1H), 2.02 (t, J= 14.1 Hz, 4H), 1.55-1.38 (m, 2H), 1.25 (dd, J = 8.2 Hz, 4.4 Hz, 2H).
Example 52
Figure imgf000096_0001
N-(tetrahydrofuran-3-yl)-4-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-amine
Figure imgf000096_0002
Step 1: To a solution of 4-bromo-2-fluoro-pyridine (500 mg, 2.84 mmol, 292.4 μL) and tetrahydrofuran-3-amine (297.02 mg, 3.41 mmol) in DMF (10 mL) was added cesium carbonate (2.78 g, 8.52 mmol). The mixture was stirred at 100 °C for 16 hours, cooled to room temperature, diluted with H2O (10 mL) and EA (100 mL) and washed with brine (20 mL x 4). The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate in petroleum ether from 0 to 50%) to give 4 - b ro m o - A- (t c t r a h y d ro fu r a n - 3 - yl)pyridin-2-amine (500 mg, 72% yield) as red oil. LC-MS (ESI) [(M+H)+]: 244.1.
Step 2: To a stirred solution of 4-bromo-N-(tetrahydrofuran-3-yl)pyridin-2-amine (114.3 mg, 470.24 μmol) and int. 3 (200 mg, 391.87 μmo)l in mixed solvent of dioxane (4 mL) and H2O (0.5 mL) were added RuPhos Pd G2 (30.5 mg, 39.19 μmo)l and K3PO4 (249.5 mg, 1.18 mmol). The mixture was stirred at 100 °C for 2 hours under N2 atmosphere, cooled to room temperature, diluted with EA (100 mL) and washed with brine (20 mL x 3). The organic phase was dried over anhydrous Na2S04 and filtered. The filtration was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with MeOH/DCM: 1/15) to give A-(tetrahydrofuran-3-yl)-4-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-amine (60 mg, 28% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 547.2. NMR (400 MHz, DMSO -d6) d 8.25 (s, 1H), 8.10 (d, 7= 5.3 Hz, 1H), 7.94 (q, 7 = 8.6 Hz, 4H), 7.58 (dd, J = 8.9 Hz, 2.3 Hz, 1H), 7.25 (d, 7 = 7.4 Hz, 1H), 6.98 (s, 1H), 6.86 (dd, J = 10.6 Hz, 9.3 Hz, 2H), 6.55 (d, 7 = 8.9 Hz, 1H), 4.48-4.38 (m, 1H), 3.87 (ddd, J = 15.0 Hz, 10.4 Hz, 6.6 Hz, 2H), 3.76-3.62 (m, 2H), 3.55 (dd, J= 8.8 Hz, 3.9 Hz, 1H), 3.35 (s, 2H), 2.25-2.12 (m, 1H), 2.02 (t, J = 14.2 Hz, 4H), 1.82 (d, 7 = 4.8 Hz, 1H), 1.47 (d, 7 = 11.9 Hz, 2H), 1.26 (dd, J= 16.8 Hz, 8.6 Hz, 2H).
Example 53
Figure imgf000097_0001
N-(tetrahydro-2H-pyran-4-yl)-4-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-amine J
Figure imgf000098_0001
Step 1: To a solution of 4-bromo-2-fluoro-pyridine (500 mg, 2.84 mmol, 292.4 μL) and tetrahydropyran-4-amine (344.8 mg, 3.41 mmol) in DMF (10 mL) was added cesium carbonate (2.78 g, 8.52 mmol). The mixture was stirred at 100 °C for 16 hours, cooled to room temperature, diluted with H2O (10 mL) and EA (100 mL) and washed with brine (20 mL x 4). The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate in petroleum ether from 0 to 50%) to give 4 - b ro m o - N- ( t e t r a h y d ro - 2 H- p y r a n - 4-yl)pyridin-2-amine (550 mg, 75% yield) as red oil. LC-MS (ESI) [(M+H)+]: 258.2.
Step 2: To a stirred solution of 4-Bromo-N-(tctrahydro-2H-pyran-4-yl)pyridin-2-aminc (120.9 mg, 470.24 μmol) and int. 3 (200 mg, 391.87 μmo)l in mixed solvent of dioxane (4 mL) and H2O (0.5 mL) were added RuPhos Pd G2 (30.5 mg, 39.19 μmo)l and K3PO4 (249.5 mg, 1.18 mmol). The mixture was stirred at 100 °C for 2 hours under N2 atmosphere, cooled to room temperature, diluted with EA (100 mL) and washed with brine (20 mL x 3). The organic phase was dried over anhydrous Na2S04 and filtered. The filtration was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with MeOH/DCM: 1/15) to give A-(tetrahydro-2H-pyran-4-yl)-4-(4-((trans-4-((5-
(trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-amine (70 mg, 32% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 561.2. NMR (400 MHz, DMSO -d6) d 8.25 (s, 1H), 8.08 (d, J = 5.4 Hz, 1H), 7.94 (q, J = 8.5 Hz, 3H), 7.58 (dd, J = 8.9 Hz, 2.3 Hz, 1H), 7.26 (d, J = 7.4 Hz, 1H), 6.89-6.78 (m, 2H), 6.69 (s, 1H), 6.54 (d, J = 8.9 Hz, 1H), 4.04-3.92 (m, 1H), 3.87 (d, J = 11.4 Hz, 2H), 3.68 (s, 1H), 3.42 (dd, J = 11.4 Hz, 9.7 Hz, 2H), 3.36 (s, 1H), 2.02 (t, J = 14.5 Hz, 4H), 1.90 (d, J= 10.5 Hz, 2H), 1.55-1.38 (m, 4H), 1.31-1.19 (m, 3H).
Example 54
Figure imgf000098_0002
N- (oxetan-3-yl)-4-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-amine
Figure imgf000099_0001
Step 1: To a solution of 4-bromo-2-fluoro-pyridine (200 mg, 1.14 mmol, 117.0 μL) and oxetan- 3-amine (99.7 mg, 1.36 mmol) in DMF (5 mL) was added cesium carbonate (1.11 g, 3.41 mmol). The mixture was stirred at 100 °C for 3 hours, cooled to room temperature, diluted with H2O (10 mL) and EA (100 mL) and washed with brine (20 mL x 4). The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with EA/PE: 1/10) to give 4-bromo-N-(oxetan-3-yl)pyridin-2-amine (180 mg, 69% yield) as a white solid. LC-MS (ESI) [(M+H)+] : 229.2.
Step 2: To a stirred solution of 4-bromo-/V-(oxetan-3-yl)pyridin-2-amine (116.7 mg, 509.43 μmol) and int. 3 (200 mg, 391.87 μmo)l in mixed solvent of dioxane (4 mL) and H2O (0.5 mL) were added RuPhos Pd G2 (30.5 mg, 39.19 μmol) and K3PO4 (249.5 mg, 1.18 mmol). The mixture was stirred at 100 °C for 2 hours under N2 atmosphere, cooled to room temperature, diluted with EA (100 mL) and washed with brine (20 mL x 3). The organic phase was dried over anhydrous Na2S04 and filtered. The filtration was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with MeOH/DCM: 1/15) to give A-(oxctan-3-yl)-4-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-amine (50 mg, 24% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 533.1.
Figure imgf000099_0002
8.25 (s, 1H), 8.13-8.07 (m, 1H), 8.06-7.88 (m, 4H), 7.58 (dd, J = 8.9 Hz, 2.2 Hz, 1H), 7.45 (d, J = 6.1 Hz, 1H), 7.24 (d, J = 7.4 Hz, 1H), 6.93-6.82 (m, 1H), 6.77 (d, J = 19.6 Hz, 1H), 6.54 (d, J = 8.8 Hz, 1H), 4.87 (dt, J = 13.2 Hz, 6.7 Hz, 2H), 4.46 (dd, J = 16.1 Hz, 10.0 Hz, 2H), 3.66 (s, 1H), 3.35 (s, 1H), 2.83 (d, J = 4.8 Hz, 1H), 2.02 (t, J = 14.1 Hz, 4H), 1.47 (dd, J = 24.2 Hz, 11.8 Hz, 2H), 1.27-1.22 (m, 2H). Example 55
Figure imgf000100_0001
N-methyl-N-(oxetan-3-yl)-4-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- - yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-amine
Figure imgf000100_0002
Step 1: To a stirred mixture of 4-bromo-N-(oxetan-3-yl)pyridin-2-amine (180 mg, 785.77 m mol) in anhydrous DMF (10 mL) was added sodium hydride (60% dispersion in mineral oil, 47.1 mg, 1.18 mmol) at 0 °C. 20 min later, iodomethane (167.3 mg, 1.18 mmol, 73.4 μL) was added into the solution. The reaction mixture was stirred at 0 °C for an hour, quenched with 2 mL of water and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with methanol/dichloromethane from 0 to 100%) to give 4-bromo-/V- methyl-/V-(oxetan-3-yl)pyridin-2-amine (100 mg, 52% yield, impure) as oil, which was used in the next step without further purifications. LC-MS (ESI) [(M+H)+]: 243.1.
Step 2: A mixture of 4-bromo-N-methyl-N-(oxetan-3-yl)pyridin-2-amine (100 mg, 411.35 pmol), int. 3 (209.9 mg, 411.35 μmo)l, Pd(dppf)Cl2 (60.2 mg, 82.27 μmo)l and K2CO3 (141.9 mg, 1.03 mmol) in dioxane/water (10 mL, 4/1) was stirred at 100 °C for 4 hours, cooled to room temperature, diluted with ethyl acetate (30 mL) and washed with water (10 mL x 2). The organic layer was dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with methanol/dichloromethane from 0 to 20%) and further by prep-HPLC to give A-mcthyl-A- (oxctan-3-yl)-4-(4-((trans-4-((5-(trifhioromcthyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-amine (30 mg, 13% yield) as a yellow solid. LC-MS (ESI) [(M+H)+]: 547.1.
Figure imgf000100_0003
8.43 (s,lH), 8.31 (s, 1H), 8.24 (d, 7= 8.0 Hz, 1H), 8.11 (d, J = 7.9 Hz, 2H), 7.65 (d, 7 = 4.9 Hz, 2H), 7.39 (s, 1H), 7.30 (d, 7 = 6.8 Hz, 1H), 6.61 (d, 7= 8.8 Hz, 1H), 5.31 (s, 1H), 4.85 (s, 1H), 4.60 (s, 1H), 4.36 (s, 1H), 3.91 (d, J = 10.2 Hz, 1H), 3.72 (s, 1H), 3.66-3.62 (m, 1H), 3.26 (s, 3H), 2.12-2.04 (m, 4H), 1.53 (d, J = 11.0 Hz, 2H), 1.36 (s, 2H).
Example 56
Figure imgf000101_0001
Trans -A-(4-((4'-fluoro-3'-(oxetan-3-ylamino)-[l,l'-biphenyl]-4-yl)sulfonyl)cyclohexyl)-5-
(trifluoromethyl)pyridin-2-amine
Figure imgf000101_0002
Step 1: To a mixture of 5-bromo-2-fluoro-aniline (500 mg, 2.63 mmol), oxetan-3-one (189.6 mg, 2.63 mmol, 169.3 μL) and sodium triacetoxyborohydride (1.12 g, 5.26 mmol) in dichloromethane (10 mL) was added molecular sieves (4 A, 1 g). The mixture was stirred at room temperature overnight and filtered through a pad of Celite. The solid cake was washed with DCM (20 mL) and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate/PE from 0 to 50%) to give A- (5 - b ro m o - 2 - fl u o ro - p h c n y 1 ) o x c t a n - 3 - a m i n c (100 mg, 15% yield) as oil. LC-MS (ESI) [(M+H)+]: 246.1.
Step 2: A mixture of A- (5 - b ro m o - 2 - fl u o ro - p h c n y 1 ) o x c t a n - 3 - a m i n c (70 mg, 284.47 ), int. μmol 3(145.2 mg, 284.47 μmo)l, Pd(dppf)Cl2 (41.6 mg, 56.89 μmo)l and K2CO3 (98.1 mg, 711.16 pmol) in dioxane/water (10 mL, 4/1) was stirred at 100 °C for 4 hours, cooled to room temperature, diluted with ethyl acetate (30 mL) and washed with water (10 mL x 2). The organic layer was dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with methanol/dichloromethane from 0 to 20%) and further by prep-HPLC to give trans-N-(A-((A'- fluoro-3 '-(oxetan-3 -ylamino)-[ 1 , 1 '-biphenyl] -4-yl)sulfonyl)cyclohexyl)-5 - (trifluoromethyl)pyridin-2-amine (23 mg, 15% yield) as a yellow solid. LC-MS (ESI) [(M+H)+] : 550.1. NMR (400 MHz, DMSO -d6) δ 8.25 (s, 1H), 7.93-7.86 (m, 4H), 7.59 (dd, J = 8.9 Hz, 2.2 Hz, 1H), 7.27-7.17 (m, 2H), 7.02-6.96 (m, 1H), 6.80 (d (d, J= 8.4 Hz, 1.8 Hz, 1H), 6.54 (d, J = 8.9 Hz, 1H), 6.40 (d, J = 5.6 Hz, 1H), 4.87 (t, J = 6.4 Hz, 2H), 4.76 (dd, J = 13.0 Hz, 6.5 Hz, 1H), 4.57 (t, J = 6.0 Hz, 2H), 3.66 (s, 1H), 3.38 (s, 1H), 2.03 (t, J = 13.2 Hz, 4H), 1.51-1.40 (m, 2H), 1.25 (d, J= 9.5 Hz, 2H).
Example 57
Figure imgf000102_0001
Trans -N-(4-((4-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-4- yl)phenyl)sulfonyl)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine
Figure imgf000102_0002
Step 1: To a solution of 4-bromo-2-fluoro-pyridine (100 mg, 568.23 p mol, 58.5 μL) in acetonitrile (10 mL) were added 2-oxa-6-azaspiro[3.3]heptane (56.3 mg, 568.23 μmol) and K2CO3 (196.0 mg, 1.42 mmol). The reaction mixture was stirred at 75 °C overnight, cooled to room temperature, diluted with water (10 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate/PE from 0 to 60%) to give 6-(4-bromo-2-pyridyl)-2-oxa-6- azaspiro[3.3]heptane (70 mg, 48% yield) as oil. LC-MS (ESI) [(M+H)+]: 255.0.
Step 2: A mixture of 6-(4-bromo-2-pyridyl)-2-oxa-6-azaspiro[3.3]heptane (70 mg, 274.39 pmol), int. 3 (140.0 mg, 274.39 μmo)l, Pd(dppf)Cl2 (40.1 mg, 54.88 μmo)l and K2CO3 (94.7 mg, 685.98 μmol) in dioxane/water (10 mL, 4/1) was stirred at 100 °C for 4 hours, cooled to room temperature, diluted with ethyl acetate (30 mL) and washed with water (10 mL x 2). The organic layer was dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with methanol/dichloromethane from 0 to 10%) and further by prep-HPLC to give trans-N-{ 4-((4- (2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-4-yl)phenyl)sulfonyl)cyclohexyl)-5- (trifluoromethyl)pyridin-2-amine (30 mg, 20% yield) as a yellow solid. LC-MS (ESI) [(M+H)+] : 559.0.
Figure imgf000103_0001
NMR (400 MHz, DMSO -d6) d 8.25 (s, 1H), 8.19 (d, J= 5.3 Hz, 1H), 8.02 (d, J = 8.5 Hz, 2H), 7.96 (d, 7= 8.5 Hz, 2H), 7.59 (dd, / = 8.9 Hz, 2.3 Hz, 1H), 7.23 (d, J = 7.4 Hz, 1H), 7.02 (dd, /= 5.3 Hz, 1.2 Hz, 1H), 6.72 (s, 1H), 6.55 (d, J= 8.9 Hz, 1H), 4.74 (s, 4H), 4.18 (s, 4H), 3.66 (s, 1H), 3.36 (s, 1H), 2.01 (d, J = 15.0 Hz, 4H), 1.47 (dd, /= 24.1 Hz, 11.6 Hz, 2H), 1.24 (t, / = 11.5 Hz, 2H)
Example 58
Figure imgf000103_0002
Trans -/V-(4-((4-(2-(3-(aminomethyl)oxetan-3-yl)pyridin-4- yl)phenyl)sulfonyl)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine
Figure imgf000103_0003
Step 1: To a solution of oxetan-3-one (900 mg, 12.49 mmol, 803.6 μL) in nitromethane (10 mL) was added a catalytic amount of triethylamine (126.38 mg, 1.25 mmol, 174.1 μL) at room temperature. The reaction mixture was stirred for 2 hours and concentrated in vacuo to give crude 3-(nitromethyl)oxetan-3-ol (1.2 g, 72% yield) without further purifications. LC-MS (ESI) [(M+H)+] : 134.2.
Step 2: To a stirred solution of 3-(nitromethyl)oxetan-3-ol (1.2 g, 9.02 mmol) in dichloromethane (10 mL) was added DAST (2.18 g, 13.53 mmol, 1.79 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour and quenched with saturated potassium bicarbonate aqueous solution (10 mL). The resulting mixture was exacted with DCM (30 mL x 3), and the organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with EA/PE from 0 to 50%) to give 3-(nitromethylene)oxetane (800 mg, 77% yield) as yellow oil. LC-MS (ESI) [(M+H)+]: 116.2.
Step 3: To a stirred solution of 2,4-dibromopyridine (824 mg, 3.48 mmol) in anhydrous DCM (20 mL) was added n-butyl lithium (1.4 mL, 2.5 mol/L in THF) at -60 °C under the atmosphere of N2. 15 minutes after completion of addition 15 minutes, 3-(nitromethylene)oxetane (400 mg, 3.48 mmol) was added into the solution at -60 °C. The reaction mixture was stirred at -60 °C for one hour and poured into saturated ammonium chloride aqueous solution (30 mL). The organic layer was separated, washed with brine (20 mL), dried over anhydrous NaiSCE and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate/PE from 0 to 90%) to give 4-bromo- 2-[3-(nitromethyl)oxetan-3-yl]pyridine (140 mg, 15% yield). LC-MS (ESI) [(M+H)+]: 273.1.
Step 4\ A mixture of 4-bromo-2-[3-(nitromethyl)oxetan-3-yl]pyridine (140 mg, 512.66 μmo)l, int. 3 (261.6 mg, 512.66 μmo)l, Pd(dppf)Cl2 (75.0 mg, 102.53 μmo)l and K2CO3 (212.2 mg, 1.54 mmol) in dioxane/water (10 mL, 4/1) was stirred at 100 °C under N2 atmosphere for 4 hours, cooled to room temperature, diluted with ethyl acetate (30 mL) and washed with water (10 mL x 2). The organic layer was dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with methanol/dichloromethane from 0 to 10%) and further by prep-HPLC to give iran5-A-(4-((4-(2-(3-(nitromethyl)oxetan-3-yl)pyridin-4-yl)phenyl)sulfonyl)cyclohexyl)-5- (trifluoromethyl)pyridin-2-amine (160 mg, 54% yield) as a yellow solid. LC-MS (ESI) [(M+H)+]: 577.1.
Step 5: To a mixture of trans-A-(4-((4-(2-(3-(nitromethyl)oxetan-3-yl)pyridin-4- yl)phenyl)sulfonyl)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine (100 mg, 173.43 μmol) and zinc powder (2 g, 1.73 mmol) in methanol (10 mL) was added HO Ac (3 drops). The reaction mixture was stirred under the atmosphere of N2 at 80 °C for 4 hours and filtered through a pad of Celite. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with MeOH/CH2Cl2 from 0 to 100%) and further by prep-HPLC to afford trans-A-(4-((4-(2-(3-(aminomethyl)oxetan-3-yl)pyridin-4- yl)phenyl)sulfonyl)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine (7 mg, 7% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 547.2.
Figure imgf000104_0001
NMR (400 MHz, DMSO -d6) d 8.68 (d, J= 5.1 Hz, 1H), 8.25 (s, 1H), 8.12 (d, J = 8.4 Hz, 2H), 7.99 (d, J = 8.4 Hz, 2H), 7.70-7.65 (m, 2H), 7.59 (dd, / = 8.9 Hz, 2.2 Hz, 1H), 7.25 (d, J = 7.4 Hz, 1H), 6.54 (d, J = 8.9 Hz, 1H), 4.90 (d, J = 6.0 Hz, 2H), 4.69 (d, J= 5.9 Hz, 2H), 3.66 (s, 1H), 3.39 (s, 1H), 3.13 (s, 2H), 2.02 (t, /= 14.2 Hz, 4H), 1.25 (q, / = 11.7 Hz, 4H).
Example 59
Figure imgf000105_0001
3-(5-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridazin-3-yl)oxetan-3-ol
Figure imgf000105_0002
Step 1 : A mixture of 5-chloropyridazin-3-ol (500. 0 mg, 3.83 mmol) and phosphorus oxybromide (1.10 g, 3.83 mmol) in acetonitrile (5 mL) was stirred in a sealed tube at 80 °C for 4 hours, cooled to room temperature, quenched with saturated NaHC03 aqueous solution to adjust pH 9~10, and extracted with EtOAc (150 mL x 3). The combined organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with EA/PE = 80%) to give 3,5-dibromopyridazine (700.0 mg, 77% yield) as yellow oil. LC-MS (ESI) [(M+H)+]: 237.1.
Step 2: To a solution of 3,5-dibromopyridazine (500.0 mg, 2.10 mmol) in anhydrous dichloromethane (20 mL) was added n-butyl lithium (2.52 mmol, 1 mL, 2.5 mol/L in THF) at -60 °C under the atmosphere of N2. 15 minutes after completion of addition, oxetan-3-one (15E5 mg, 2.10 mmol, 135.3 μL) was added into the solution at -60 °C. The reaction mixture was stirred at -60 °C for one hour and poured into saturated ammonium chloride aqueous solution (30 mL). The organic layer was separated, washed with brine (20 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate/PE from 0 to 100%) to give 3-(5-bromopyridazin-3-yl)oxetan-3-ol (300.0 mg, 62% yield) as yellow oil. LC- MS (ESI) [(M+H)+]: 231.1.
Step 3: A mixture of 3-(5-bromopyridazin-3-yl)oxetan-3-ol (50.0 mg, 216.41 μmol), int. 3 (110.0 mg, 215.53 μmo),l l,r-bis(triphenylphosphine)ferrocenepalladium(II) dichloride (31.7 mg, 43.31 μmo)l and K2CO3 (90.0 mg, 651.18 μmo)l in dioxane/water (10 mL, 4/1) was stirred at 110 °C under N2 atmosphere for 4 hours, cooled to room temperature, diluted with ethyl acetate (30 mL) and washed with water (10 mL x 2). The organic layer was dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with methanol/dichloromethane from 0 to 10%) to give 3-(5-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridazin-3-yl)oxetan-3-ol (25.3 mg, 22% yield) as a yellow solid. LC-MS (ESI) [(M+H)+]: 535.2.
Figure imgf000106_0001
NMR (400 MHz, DMSO -d6) d 9.70 (d, 7 = 2.2 Hz, 1H), 8.26-8.20 (m, 3H), 8.16 (d, 7 = 2.2 Hz, 1H), 8.04 (d, 7 = 8.4 Hz, 2H), 7.59 (dd, J = 8.9 Hz, 2.3 Hz, 1H), 7.26 (d, 7 = 7.3 Hz, 1H), 6.92 (s, 1H), 6.54 (d, 7= 8.9 Hz, 1H), 5.11 (d, 7 = 6.5 Hz, 2H), 4.80 (d, 7= 6.5 Hz, 2H), 3.66 (s, 1H), 3.42 (s, 1H), 2.03 (t, 7 = 14.5 Hz, 4H), 1.48 (d, 7= 12.7 Hz, 2H), 1.25 (d, 7 = 11.5 Hz, 2H).
Example 60
Figure imgf000106_0002
Trans-A/-(4-((4-(2-(2H-l,2,3-triazol-2-yl)pyridin-4-yl)phenyl)sulfonyl)cyclohexyl)-5-
(trifluoromethyl)pyridin-2-amine
Figure imgf000106_0003
Step 1: To a mixture of 4-bromo-2-fluoro-pyridine (200 mg, 1.14 mmol) and 2/7-triazole (117.7 mg, 1.70 mmol) in DMF (2 mL) was added TEA (230.0 mg, 2.27 mmol). The reaction mixture was stirred at 110 °C for 1 hour, cooled to room temperature, and diluted with ethyl acetate (100 mL). The resulting mixture was washed with H2O (20 mL x 3). The organic layer was dried over anhydrous NaiSCE and filtered. The filtrate was concentrated in vacuo , and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate/hexanes from 0 to 100%) to give 4-bromo-2-(triazol-2-yl)pyridine (180 mg, 70% yield) as a yellow solid. LC-MS (ESI) [(M+H)+]: 181.8. The structure was arbitrarily assigned.
Step 2: A mixture of 4-bromo-2-(triazol-2-yl)pyridine (60 mg, 266.61 μmol ), tetrakis(triphenylphosphine) palladium (92.4 mg, 79.98 μmo)l, int. 3 (136.1 mg, 266.61 μmo)l and sodium carbonate (70.7 mg, 666.53 μmo)l in dioxane/water (2 mL, 4/1) was stirred at 100 °C for 1 hour under N2 atmosphere, cooled to room temperature, and diluted with ethyl acetate (20 mL). The resulting mixture was washed with H2O (10 mL x 3). The organic layer was dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate/hexanes from 0 to 100%) and further by prep-HPLC to give trans-N-(4-((4-(2-(2H- l,2,3-triazol-2-yl)pyridin-4-yl)phenyl)sulfonyl)cyclohexyl)-5-(trifluoromethyl)pyridin-2- amine (33 mg, 23% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 528.8.
Figure imgf000107_0001
(400 MHz, DMSO -d6) d 8.95 (s, 1H), 8.75 (d, J= 5.2 Hz, 1H), 8.47 (d, J = 1.6 Hz, 1H), 8.28-8.20 (m, 3H), 8.08-8.01 (m, 3H), 8.01-7.95 (m, 1H), 7.59 (dd, J = 9.0 Hz, 2.6 Hz, 1H), 7.26 (d, J = 7.4 Hz, 1H), 6.55 (d, J = 8.9 Hz, 1H), 3.68 (d, J = 10.7 Hz, 1H), 3.43 (dt, J = 12.0 Hz, 3.2 Hz, 1H), 2.04 (td, J = 14.7 Hz, 3.9 Hz, 4H), 1.49 (ddt, J = = 15.9 Hz, 12.3 Hz, 6.6 Hz, 2H), 1.26 (qd, J = 14.1 Hz, 3.7 Hz, 2H).
Example 61
Figure imgf000107_0002
(4-(2-(2H-l,2,3-triazol-2-yl)pyridin-4-yl)phenyl)(imino)(trans-4-((5- -
(trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)-λ6-sulfanone Example 62
Figure imgf000108_0001
(4-(2-(1H-l,2,3-triazol-l-yl)pyridin-4-yl)phenyl)(imino)(trans-4-((5-
(trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)-X6-sulfanone
Figure imgf000108_0002
Step 1: A mixture of 4-bromo-2-fluoro-pyridine (600 mg, 3.41 mmol, 350.9 μL), 1 H-triazolc (235.5 mg, 3.41 mmol) and K2CO3 (1.18 g, 8.52 mmol) in acetonitrile (10 mL) was stirred at 100 °C for 4 hours and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate/PE from 0 to 30%) to give 4-bromo- 2-(triazol-2-yl)pyridine (140 mg, 18% yield) as a white solid and 4-bromo-2-(triazol-l- yl)pyridine (140 mg, 18% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 225.0 (both). The structure was arbitrarily assigned.
Step 2: A mixture of 4-bromo-2-(triazol-2-yl)pyridine (70 mg, 311.05 μmo)l, int. 1 (148.8 mg, 311.05 μmol), Pd(PPh3)2Cl2 (44 mg, 62.77 μmo)l and K2CO3 (129 mg, 934.78 μmol) in dioxane/water (6 mL, 2/1) was stirred at 100 °C under N2 atmosphere for 4 hours, cooled to room temperature, diluted with ethyl acetate (20 mL) and washed with water (10 mL x 3). The organic layer was dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate/petroleum ether from 0 to 100%) to give lrans-N-(4-((4-(2-(2H- 1 ,2,3-triazol-2- yl)pyridin-4-yl)phenyl)thio)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine (70 mg, 45% yield) as a yellow solid. LC-MS (ESI) [(M+H)+]: 497.1. Step 3: To a mixture of trans-N-(4-((4-(2-(2H-1 ,2,3-triazol-2-yl)pyridin-4- yl)phenyl)thio)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine (50 mg, 100.69 μmol) and ammonium carbamate (15.7 mg, 201.10 μmo)l in methanol (5 mL) was added iodobenzene diacetate (65.3 mg, 201.47 μmol). The mixture was stirred at 25 °C for 5 hours and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with methanol in dichloromethane from 0 to 10%) and further by prep-HPLC to give (4-(2-(2H- 1 ,2,3-triazol-2-yl)pyridin-4-yl)phcnyl)(imino)(trans-4-((5-
(trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)-X6-sulfanone (18.6 mg, 35% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 528.1. NMR (400 MHz, DMSO -d6) d 8.95 (d, 7 = 1.2 Hz, 1H), 8.74 (d, 7 = 5.2 Hz, 1H), 8.47 (s, 1H), 8.25 (s, 1H), 8.19 (d, 7 = 8.4 Hz, 2H), 8.04 (d, 7 = 8.4 Hz, 3H), 7.98 (dd, J = 5.2 Hz, 1.5 Hz, 1H), 7.58 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.23 (d, 7 = 7.2 Hz, 1H), 6.53 (d, J= 8.8 Hz, 1H), 4.40 (s, 1H), 3.64 (s, 1H), 3.16 (t, 7 = 12.0 Hz, 1H), 2.04 (s, 4H), 1.45 (dd, J = 24.4 Hz, 10.5 Hz, 2H), 1.24 (t, 7= 8.4 Hz, 2H).
(4-(2-(1H-l,2,3-triazol-l-yl)pyridin-4-yl)phenyl)(imino)(trans-4-((5- (trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)-λ6-sulfanone was synthesized according to Example 62 of (4-(2-(2N-l,2,3-triazol-2-yl)pyridin-4-yl)phenyl)(imino)(trans-4-((5- (trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)-λ6-sulfanon, using 4-bromo-2-(triazol- 1- yl)pyridine replacing 4-bromo-2-(triazol-2-yl)pyridine in Step 2. A white solid. LC-MS (ESI) [(M+H)+] : 528.1.
Figure imgf000109_0001
NMR (400 MHz, DMSO -d6) d 8.72 (d, 7= 5.2 Hz, 1H), 8.35 (s, 1H), 8.25 (s, 3H), 8.16 (d, 7 = 8.4 Hz, 2H), 8.03 (d, 7 = 8.4 Hz, 2H), 7.94 (dd, J = 5.2 Hz, 1.5 Hz, 1H), 7.58 (dd, J = 8.8 Hz, 2.3 Hz, 1H), 7.23 (d, 7 = 7.6 Hz, 1H), 6.53 (d, 7 = 8.8 Hz, 1H), 4.39 (s, 1H), 3.63 (s, 1H), 3.15 (t, 7 = 12.0 Hz, 1H), 2.04 (s, 4H), 1.45 (dd, J = 24.8 Hz, 10.4 Hz, 2H), 1.24 (t, 7= 8.8 Hz, 2H).
Example 63
Figure imgf000109_0002
7r«77.s-/V-(4-((4-(2-(4H-l,2,4-triazol-3-yl)pyridin-4-yl)phenyl)sulfonyl)cyclohexyl)-5-
(trifluoromethyl)pyridin-2-amine
Figure imgf000110_0001
Step 1: A mixture of sodium methoxide (147.6 mg, 2.73 mmol) and 4-bromopyridine-2- carbonitrile (500.0 mg, 2.73 mmol) in MeOH (10 mL) was stirred at room temperature for 2 hours. NH4CI (579.2 mg, 10.93 mmol) was added thereto. The reaction mixture was stirred at 25 °C overnight and concentrated in vacuo to give 4-bromopicolinimidamide (500 mg, 91% yield), which was used in the next step without further purifications. LC-MS (ESI) [(M+H)+]: 199.8.
Step 2: A mixture of 4-bromopicolinimidamide (500.0 mg, 2.50 mmol) and formylhydrazide (180.13 mg, 3.00 mmol) in ethanol (10 mL) was stirred at 90 °C overnight and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate / PE from 0 to 50%) to give 4-bromo-2-(4H-l,2,4-triazol-3-yl)pyridine (250.0 mg, 44% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 224.8.
Step 3: A mixture of 4-bromo-2-(4H-l,2,4-triazol-3-yl)pyridine (60 mg, 266.61 μmol), tetrakis(triphenylphosphine) palladium (30 mg, 25.96 μmo)l, int. 3 (163.29 mg, 319.94 μmo)l and sodium carbonate (70 mg, 660.44 μmo)l in dioxane/water (2 mL, 4/1) was stirred at 130 °C for 8 hours under N2 atmosphere, cooled to room temperature, and diluted with ethyl acetate (20 mL). The resulting mixture was washed with H2O (10 mL x 3). The organic layer was dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate/hexanes from 0 to 100%) and further by prep-HPLC to give trans -N-(4-((4-(2-(4H- 1,2,· 4-triazol-3- yl)pyridin-4-yl)phenyl)sulfonyl)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine (6 mg, 4% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 528.8.
Figure imgf000110_0002
NMR (400 MHz, DMSO -d6) d 8.84 (s, 1H), 8.42 (d, J = 7.4 Hz, 1H), 8.25 (s, 1H), 8.16 (d, J = 14.1 Hz, 2H), 8.07-7.92 (m, 2H), 7.58 (dd, / = 9.0 Hz, 2.2 Hz, 1H), 7.25 (d, J = 7.5 Hz, 1H), 6.54 (d, J = 9.1 Hz, 1H), 3.67 (s, 1H), 3.39 (d, J = 12.0 Hz, 1H), 2.03 (t, J= 12.4 Hz, 4H), 1.48 (dd, J= 23.3 Hz, 12.1 Hz, 2H), 1.33-1.21 (m, 2H). Example 64
Figure imgf000111_0001
(4-(2-(4H-l,2,4-triazol-3-yl)pyridin-4-yl)phenyl)(imino)(trans-4-((5-
(trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)-λ6-sulfanone
Figure imgf000111_0002
Step 1 : To a solution of 4-bromo-2-(4H-l,2,4-triazol-3-yl)pyridine (110 mg, 488.79 μmo)l and DMAP (59.7 mg, 488.79 p mol) in THF (10 mL) was added BociO. The reaction mixture was stirred at room temperature for 10 minutes and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with methanol/dichloromethane from 0 to 5%) to give tert-butyl 3-(4-bromopyridin-2-yl)-4H-l,2,4-triazole-4-carboxylate (90 mg, 57% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 325.2.
Step 2: A mixture of tert-butyl 3-(4-bromopyridin-2-yl)-4H-l,2,4-triazole-4-carboxylate (140.0 mg, 430.56 μmo)l, l,l'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (63.0 mg, 86.10 μmo)l, int. 1 (206.0 mg, 430.62 μmo)l and sodium carbonate (45.6 mg, 430.23 μmo)l in dioxane/water (10 mL, 4/1) was stirred at 100 °C for 4 hours under N2 atmosphere, cooled to room temperature, and diluted with ethyl acetate (30 mL). The resulting mixture was washed with H2O (10 mL x 2). The organic layer was dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate/ petroleum ether from 0 to 100%) to give /ran.s'-/V-(4-((4-(2-(4//-l ,2,4-triazol-3-yl)pyridin-4-yl)phcnyl)thio)cyclohcxyl)-5-
(trifluoromethyl)pyridin-2-amine (70 mg, 33% yield) as a yellow solid. LC-MS (ESI) [(M+H)+] : 497.0. Step 3: To a mixture of trans-N--(4-((4-(2-(4H-l,2,4-triazol-3-yl)pyridin-4- yl)phenyl)thio)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine (20.0 mg, 40.32 μmol) and ammonium carbamate (7.8 mg, 99.91 μmol) in methanol (5 mL) was added iodobenzene diacetate (21.7 mg, 66.95 μmo)l. The mixture was stirred at 25 °C for 3 hours and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with methanol in dichloromethane from 0 to 10%) and further by prep-HPLC to give (4-(2-(4 H- l,2,4-triazol-3-yl)pyridin-4-yl)phenyl)(imino)(trans-4-((5-(trifluoromethyl)pyridin-2- y 1 ) a m i n o ) c y c 1 o h c x y 1 ) - l6 - s u 1 fa n o n c (2.5 mg, 12% yield) as a white solid. LC-MS (ESI) [(M+H)+] : 528.1. 'HNMR (400 MHz, DMSO -d6) d 8.82 (d, 7= 5.1 Hz, 1H), 8.40 (s, 1H), 8.24 (s, 1H), 8.12 (d, 7 = 8.3 Hz, 2H), 8.02 (d, 7 = 8.4 Hz, 2H), 7.92 (s, 1H), 7.57 (dd, J = 8.9 Hz,
2.2 Hz, 1H), 7.22 (d, 7 = 7.4 Hz, 1H), 6.53 (d, 7 = 8.8 Hz, 1H), 4.36 (s, 1H), 3.62 (s, 2H), 2.02 (d, 7 = 7.5 Hz, 4H), 1.23 (s, 4H).
Figure imgf000112_0001
Trans- N- (4-((4-(2-(3-aminopyrrolidin-l-yl)pyridin-4-yl)phenyl)sulfonyl)cyclohexyl)-5-
(trifluoromethyl)pyridin-2-amine
Figure imgf000112_0002
Step 1 : A mixture of 2,4-dibromopyridine (200 mg, 844.27 μmo)l, tert-butyl N-pyrrolidin-3- ylcarbamate (173.0 mg, 928.69 μmo)l, (lS,2S)-Nl,N2-dimethylcyclohexane- 1,2-diamine (60.0 mg, 422.13 μmo,l 66.6 μL), K3PO4 (179.2 mg, 844.27 μmo)l and Cul (48.2 mg, 253.28 μmo)l in dioxane (4 mL) was stirred at 105 °C for 1 hour under N2 atmosphere, cooled to room temperature, and diluted with ethyl acetate (20 mL). The resulting mixture was washed with H2O (10 mL x 3). The organic layer was dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate/hexanes from 0 to 100%) to give tert- butyl (l-(4- bromopyridin-2-yl)pyrrolidin-3-yl)carbamate (120 mg, 42% yield) as a yellow solid. LC-MS (ESI) [(M+H)+] : 341.8.
Step 2: A mixture of tert- butyl (l-(4-bromopyridin-2-yl)pyrrolidin-3-yl)carbamate (120 mg, 350.64 μmol), tetrakis(triphenylphosphine) palladium (60.8 mg, 52.60 μmo)l, int. 3 (196.9 mg, 385.70 μmol) and sodium carbonate (92.9 mg, 876.60 μmo)l in dioxane/water (2 ruL, 4/1) was stirred at 100 °C for 1 hour under N2 atmosphere, cooled to room temperature, and diluted with ethyl acetate (20 ruL). The resulting mixture was washed with H2O (10 ruL x 3). The organic layer was dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate/hexanes from 0 to 100%) to give tert- butyl (l-(4-(4-((trans-4-((5-
(trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)pyrrolidin-3- yl)carbamate (100 mg, 44% yield) as a yellow solid. LC-MS (ESI) [(M+H)+]: 645.8.
Step 3: To a solution of tert- butyl (l-(4-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate (100 mg, 154.86 pmol) in DCM (2 ruL) was added HCl/dioxane (4M, 2 ruL). The reaction mixture was stirred at room temperature for 30 minutes and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with MeOH/DCM = 1/4) and further by prep-HPLC to give trans-N-(4-((4-(2-(3-aminopyrrolidin-l-yl)pyridin-4- yl)phenyl)sulfonyl)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine (41 mg, 49% yield) as a yellow solid. LC-MS (ESI) [(M+H)+]: 545.8.
Figure imgf000113_0001
NMR (400 MHz, DMSO -d6) d 8.35 (s, 1H), 8.25 (d, J = 2.5 Hz, 1H), 8.19 (d, J = 5.2 Hz, 1H), 8.03 (d, J = 8.2 Hz, 2H), 7.96 (d, J = 8.3 Hz, 2H), 7.59 (dd, /= 8.9 Hz, 2.6 Hz, 1H), 7.27 (d, J = 7.4 Hz, 1H), 6.93 (dd, / = 5.2 Hz, 1.4 Hz, 1H), 6.74 (s, 1H), 6.55 (d, J = 8.9 Hz, 1H), 3.73 (s, 1H), 3.66 (dd, / = 7.3 Hz, 3.9 Hz, 2H), 3.64-3.57 (m, 2H), 3.50 (ddd, /= 10.8 Hz, 8.2 Hz, 5.2 Hz, 2H), 3.35 (dd, / = 11.3 Hz, 3.8 Hz, 2H), 2.19 (dq, /= 13.4 Hz, 6.9 Hz, 1H), 2.09-1.97 (m, 4H), 1.91 (dt, /= 12.3 Hz, 6.5 Hz, 1H), 1.47 (qd, / = 12.5 Hz, 6.3 Hz, 2H), 1.25 (qd, /= 14.3 Hz, 3.7 Hz, 2H). Example 66
Figure imgf000114_0001
l-(4-(4-((trans-4- ((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)pyrrolidin-2-one
Figure imgf000114_0002
Step 1: To a stirred mixture of 2-bromo-4-chloro-pyridine (200 mg, 1.04 mmol), pyrrolidin-2- one (88.5 mg, 1.04 mmol) and K3PO4 (441.2 mg, 2.08 mmol) in 1,4-dioxane (4 mL) were added palladium acetate (7.0 mg, 31.18 μmo)l, l,l'-bis(diphenylphosphino)ferrocene (51.9 mg, 93.54 pmol). The mixture was stirred at 100 °C for 2 hours under N2 atmosphere, cooled to room temperature, diluted with EA (50 mL) and washed with brine (20 mL x 2). The organic phase was dried over anhydrous Na2SO4 and filtered. The filtration was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with EA/PE: 1/15) to give l-(4-chloropyridin-2-yl)pyrrolidin-2-one (150 mg, 73% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 197. 1. Step 2: To a stirred solution of l-(4-chloropyridin-2-yl)pyrrolidin-2-one (92.5 mg, 470.24 μmo)l and int. 3 (200 mg, 391.87 μmo)l in mixed solvent of dioxane (4 mL) and H2O (0.5 mL) were added RuPhos Pd G2 (30.5 mg, 39.19 μmo)l and K3PO4 (249.6 mg, 1.18 mmol). The mixture was stirred at 100 °C for 2 hours under N2 atmosphere, cooled to room temperature, diluted with EA (20 mL) and washed with brine (10 mL x 2). The organic phase was dried over anhydrous Na2S04 and filtered. The filtration was concentrated in vacuo, and the residue was purified by prep-HPLC to give l-(4-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)pyrrolidin-2-one (32.5 mg, 15% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 545.1. NMR (400 MHz, DMSO -de) d 8.67 (s, 1H), 8.52 (d, J= 5.2 Hz, 1H), 8.25 (s, 1H), 8.01 (s, 4H), 7.62-7.50 (m, 2H), 7.25 (d, J = 7.4 Hz, 1H), 6.54 (d, J = 8.9 Hz, 1H), 4.05 (t, J = 7.1 Hz, 2H), 3.66 (s, 1H), 3.38 (d, J = 12.1 Hz, 1H), 2.62 (t, /= 8.0 Hz, 2H), 2.06 (ddd, J = 28.8 Hz, 18.1 Hz, 10.5 Hz, 6H), 1.47 (dd, / = 23.1 Hz, 12.2 Hz, 2H), 1.25 (dd, J = 23.5 Hz, 11.2 Hz, 2H).
Example 67
Figure imgf000115_0001
4-Amino-l-(4-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)pyrrolidin-2-one
Figure imgf000115_0002
Step 1: To a stirred mixture of 2-bromo-4-chloro-pyridine (300 mg, 1.56 mmol), /<? /7-butyl N- (5-oxopyrrolidin-3-yl)carbamate (312.2 mg, 1.56 mmol) and K3PO4 (661.8 mg, 3.12 mmol) in 1,4-dioxane (6 mL) were added palladium acetate (10.5 mg, 46.77 μmol ), 1,1'- bis(diphenylphosphino)ferrocene (77.8 mg, 140.30 μmo)l. The mixture was stirred at 100 °C for 2 hours under N2 atmosphere, cooled to room temperature, diluted with EA (50 mL) and washed with brine (20 mL x 2). The organic phase was dried over anhydrous Na2SO4 and filtered. The filtration was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with EA/PE: 1/15) to give tert-butyl (l-(4-chloropyridin- 2-yl)-5-oxopyrrolidin-3-yl)carbamate (220 mg, 45% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 312.E
Step 2: To a stirred solution of tert-butyl (l-(4-chloropyridin-2-yl)-5-oxopyrrolidin-3- yl)carbamate (219.9 mg, 705.36 μmo)l and int. 3 (300 mg, 587.80 μmo)l in mixed solvent of dioxane (8 mL) and H2O (1 mL) were added RuPhos Pd G2 (45.7 mg, 58.78 mihoΐ) and K3PO4 (374.3 mg, 1.76 mmol). The mixture was stirred at 100 °C for 2 hours under N2 atmosphere, cooled to room temperature, diluted with EA (50 mL) and washed with brine (20 mL x 2). The organic phase was dried over anhydrous Na2S04 and filtered. The filtration was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with MeOH/DCM: 1/20) to give tert- butyl (5-oxo-l-(4-(4-((trans-4-((5-
(trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)pyrrolidin-3- yl)carbamate (150 mg, 39% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 660.1.
Step 3: To a stirred solution of tert- butyl (5-oxo-l-(4-(4-((trans-4-((5-(trifluoromethyl)pyridin- 2-yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate (150 mg, 227.37 μmol) in DCM (3 mL) was added TLA (518.5 mg, 4.55 mmol, 350.3 μL). The mixture was stirred at 25 °C for an hour and concentrated in vacuo. The residue was basified to pH 8- 9 with saturated sodium carbonate aqueous solution, and extracted with EA (20 mL x 3). The organic phases were washed with brine (30 mL), dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by prep-HPLC to give 4- amino-l-(4-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)pyrrolidin-2-one (50 mg, 39% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 560.1.
Figure imgf000116_0001
NMR (400 MHz, DMSO -d6) d 8.68 (s, 1H), 8.51 (d, 7 = 5.2 Hz, 1H), 8.25 (s, 1H), 8.00 (d, 7 = 9.1 Hz, 4H), 7.58 (dd, J = 8.9 Hz, 2.2 Hz, 1H), 7.53 (dd, J = 5.2 Hz, 1.5 Hz, 1H), 7.24 (d, 7 = 7.4 Hz, 1H), 6.54 (d, 7= 8.9 Hz, 1H), 4.10 (dd, J = 11.2 Hz, 6.0 Hz, 1H), 3.80 (dd, J = 11.2 Hz, 2.9 Hz, 1H), 3.68 (dd, J = 6.2 Hz, 3.1 Hz, 2H), 3.38 (d, 7 = 12.2 Hz, 1H), 2.87 (dd, J = 16.9 Hz, 6.9 Hz, 1H), 2.32 (dd, J = 16.8 Hz, 3.6 Hz, 1H), 2.02 (t, 7 = 12.9 Hz, 4H), 1.48 (dd, J = 23.8 Hz, 11.5 Hz, 2H), 1.25 (dd, J = 23.4 Hz, 11.4 Hz, 2H).
Example 68
Figure imgf000116_0002
3-(4-(4-((trans-4- ((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)pyrrolidin-2-one
Figure imgf000117_0001
Step 1: To a solution of 4-bromo-2-methyl-pyridine (5.1 g, 29.65 mmol, 3.52 mL) and dimethyl carbonate (4.01 g, 44.47 mmol, 3.74 mL) in anhydrous THF (30 mL) was added LDA (2 M, 23.72 mL) at -78 °C over 30 minutes. The reaction mixture was allowed to warm to room temperature slowly and stirred overnight. The reaction mixture was quenched with saturated NH4CI aqueous solution (50 mL) at 0 °C and diluted with H2O (40 mL). The resulting mixture was extracted with DCM (100 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with EA/PE from 0/1 to 1/4) to afford methyl 2-(4-bromo-2-pyridyl)acetate (4.8 g, 70% yield) as brown oil. LC-MS (ESI) [(M+H)+]: 230.1.
Step 2: To a solution of methyl 2-(4-bromo-2-pyridyl)acetate (1 g, 4.35 mmol) in anhydrous THF (10 mL) was added sodium hydride (60% dispersion in mineral oil, 249.8 mg, 6.52 mmol) in portions. The resulting mixture was stirred at 0 °C for 30 minutes, followed by the addition of the solution of tert-butyl A- (2 - b ro m o c t h y 1 ) c a r b a m a t c (1.17 g, 5.22 mmol) in anhydrous THF (10 mL) slowly. The reaction mixture was allowed to warm to room temperature slowly, stirred overnight, quenched with saturated NH4CI aqueous solution (5 mL) at 0 °C and diluted with H2O (10 mL). The resulting mixture was extracted with DCM (30 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with EA/PE from 0/1 to 1/4) to afford methyl 2-(4-bromo-2-pyridyl)-4-(tert- butoxycarbonylamino)butanoate (200 mg, 12% yield) as light brown oil. LC-MS (ESI) [(M+H)+] : 373.0.
Step 3: To methyl 2-(4-bromo-2-pyridyl)-4-(tert-butoxycarbonylamino)butanoate (200 mg, 535.85 μmol) was added HCl/dioxane (4M, 1 mL). The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was triturated in EA (5 mL) and PE (10 mL) and filtered to afford 3-(4-bromo-2-pyridyl)pyrrolidin-2-one (90 mg, 70% yield) as an off-white solid. LC-MS (ESI) [(M+H)+]: 241.1.
Step 4\ A mixture of 3-(4-bromo-2-pyridyl)pyrrolidin-2-one (133.3 mg, 555.6 μmol), int. 3 (283.5 mg, 555.6 μmo)l, Pd(dppf)Cl2 (123.6 mg, 168.8 μmo)l and K2CO3 (229.9 mg, 1665.9 pmol) in dioxane/water (20 mL, 4/1) was stirred at 100 °C for 4 hours, cooled to room temperature, diluted with ethyl acetate (100 mL) and washed with water (30 mL x 3). The organic layer was dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with methanol/dichloromethane from 0 to 10%) and further by prep-HPLC to give 3-(4-(4-((/ran.s'- 4-((5-(trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2- yl)pyrrolidin-2-one (230 mg, 76% yield) as a yellow solid. LC-MS (ESI) [(M+H)+]: 544.7. XH NMR (400 MHz, DMSO -d6) d 8.66 (d, J= 5.2 Hz, 1H), 8.25 (s, 1H), 8.08 (d, J = 8.5 Hz, 2H), 8.00 (d, J = 8.3 Hz, 2H), 7.85 (s, 1H), 7.74 (s, 1H), 7.69 (d, J = 5.0 Hz, 1H), 7.59 (d, J = 9.1 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H), 6.54 (d, J = 8.8 Hz, 1H), 3.82 (t, / = 8.8 Hz, 1H), 3.66 (s, 2H), 2.68 (s, 1H), 2.07-1.98 (m, 4H), 1.48 (d, J= 11.5 Hz, 3H), 1.24 (s, 4H).
Example 69
Figure imgf000118_0001
2,2-Difluoro-2-(4-(4-(trans-4- ((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)ethan-l-ol
Figure imgf000118_0002
Step 1: To a suspension of Cu (2.64 g, 41.57 mmol) in DMSO (30 mL) was added ethyl 2- bromo-2,2-difluoro-acetate (4.22 g, 20.79 mmol, 2.67 mL). After the mixture was stirred at room temperature for 1 hour, 2-bromo-4-chloro-pyridine (2 g, 10.39 mmol) was added thereto. The resulting mixture was stirred at room temperature for 15 hours, diluted with saturated NH4CI aqueous solution (15 mL) and extracted with CH2CI2 (50 mL x 3). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with MeOH/DCM: 1/12) to give ethyl 2- (4-chloropyridin-2-yl)-2,2-difluoroacetate (1.3 g, 53% yield) as yellow oil. LC-MS (ESI) [(M+H)+]: 236.1.
Step 2: To a stirred solution of int. 3 (400 mg, 783.74 μmo)l and ethyl 2-(4-chloropyridin-2- yl)-2,2-difluoroacetate (221.6 mg, 940.48 μmo)l in mixed solvent of 1,4-dioxane (10 mL) and water (2 mL) was added potassium phosphate (499.1 mg, 2.35 mmol), RuPhos Pd G2 (61.0 mg, 78.37 μmo)l. The reaction mixture was stirred at 100 °C under N2 atmosphere for 2 hours, cooled to room temperature, diluted with EA (50 mL) and washed with brine (10 mL x 3). The organic phase was dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with MeOH/DCM: 1/20) to give ethyl 2,2-difluoro-2-(4-(4-((trans-4-((5-(trifluoromethyl)pyridin- 2-yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)acetate (210 mg, 46% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 584.2.
Step 3: To a stirred solution of ethyl 2,2-difluoro-2-(4-(4-((trans-4-((5- (trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)acetate (50 mg, 85.68 μmol) in EtOH (2 mL) was added NaBH4 (6.5 mg, 171.36 μmo)l at 0 °C. The mixture was stirred at 0 °C for 2 hours, diluted with ice water (100 mL), and extracted with EA (50 mL x 3). The organic phase was dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with MeOH/DCM: 1/10) to give 2,2-difluoro-2-(4-(4-((trans-4-((5- (trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)ethan-l-ol (7 mg, 15% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 542.0.
Figure imgf000119_0001
NMR (400 MHz, DMSO- de) d 8.82 (d, J = 5.1 Hz, 1H), 8.25 (s, 1H), 8.16 (d, J = 8.4 Hz, 2H), 8.02 (s, 2H), 8.00 (s, 1H), 7.97 (d, J = 5.0 Hz, 1H), 7.59 (dd, / = 8.9 Hz, 2.3 Hz, 1H), 7.26 (d, J = 7.4 Hz, 1H), 6.54 (d, J = 8.9 Hz, 1H), 5.62 (t, / = 6.3 Hz, 1H), 4.07 (td, / = 14.1 Hz, 6.3 Hz, 2H), 3.66 (s, 1H), 3.41 (d, J = 12.1 Hz, 1H), 2.02 (t, / = 13.6 Hz, 4H), 1.48 (dd, J = 23.8 Hz, 11.6 Hz, 2H), 1.34-1.24 (m, 2H). Example 70
Figure imgf000120_0001
2,2-Difluoro-2-(4-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)acetic acid
Figure imgf000120_0002
Step 1: To a stirred solution of ethyl 2,2-difluoro-2-(4-(4-((trans-4-((5- (trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)ethan-l-ol (160 mg, 274.17 μmol) in THF (3 mL) was added LiOH aqueous solution (1.0M, 2.0 mL). The mixture was stirred at room temperature for 2 hours, acidified to pH 5 ~ 6 with 3M hydrochloric acid aqueous solution, and extracted with EA (30 mL x 3). The organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with MeOH/DCM: 1/10) to give 2,2-difluoro-2-(4-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)acetic acid (150 mg, 98% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 556.1.
Figure imgf000120_0003
8.69 (d, J = 5.0 Hz, 1H), 8.25 (s, 1H), 8.08 (d, J = 8.4 Hz, 2H), 8.00 (d, J = 8.4 Hz, 2H), 7.87 (s, 1H), 7.82 (d, J = 5.0 Hz, 1H), 7.58 (d, J = 8.6 Hz, 1H), 7.26 (d, J = 7.5 Hz, 1H), 6.54 (d, J = 8.8 Hz, 1H), 3.68 (s, 1H), 3.38 (s, 1H), 2.02 (t, J= 13.1 Hz, 4H), 1.52-1.43 (m, 2H), 1.24 (d, J= 5.5 Hz, 2H).
Example 71
Figure imgf000120_0004
2,2-Difluoro-2-(4-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)acetamide
Figure imgf000121_0001
Step 1: To a solution of 2,2-difluoro-2-(4-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)acetic acid (300 mg, 540.04 μmol) and HATU (410.7 mg, 1.08 mmol) in DMF (3.0 mL) were added DIPEA (209.4 mg, 1.62 mmol, 282.2 μL) and NH4CI (86.7 mg, 1.62 mmol). The mixture was stirred at 25 °C for 16 hours, diluted with water (10 mL) and extracted with EA (30 mL x 2). The organic layer was washed with brine (10 mL x 3), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with MeOH/DCM from 0 to 1/10) to give 2,2-difluoro-2-(4-(4-((trans-4-((5- (trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)acetamide (210 mg, 70% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 555.1.
Figure imgf000121_0002
NMR (400 MHz, DMSO- d6) d 8.81 (d, J = 5.1 Hz, 1H), 8.37 (s, 1H), 8.25 (s, 1H), 8.18 (s, 1H), 8.10 (s, 2H), 8.06-8.00 (m, 2H), 7.59 (dd, J = 8.9 Hz, 2.3 Hz, 1H), 7.26 (d, J = 7.4 Hz, 1H), 6.54 (d, J = 8.9 Hz, 1H),
3.66 (s, 1H), 3.42 (d, J = 12.0 Hz, 1H), 2.02 (t, J = 13.7 Hz, 4H), 1.48 (dd, J = 23.0 Hz, 11.6 Hz, 2H), 1.32-1.24 (m, 2H).
Example 72
Figure imgf000121_0003
Trans -A/-(4-((4-(2-(2-amino-l,l-difluoroethyl)pyridin-4-yl)phenyl)sulfonyl)cyclohexyl)-
5-(trifluoromethyl)pyridin-2-amine
Figure imgf000122_0001
Step 1 : To a stirred solution of ethyl 2-(4-chloropyridin-2-yl)-2,2-difluoroacetate (500 mg, 2.12 mmol) in EtOH (5 mL) was added NaBH4 (160.6 mg, 4.24 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 hours, diluted with ice water (100 mL), and extracted with EA (50 mL x 3). The organic phase was dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo to give 2-(4-chloropyridin-2-yl)-2,2-difluoroethan-l-ol (400 mg, 97% yield) as white oil. LC-MS (ESI) [(M+H)+]: 194.1.
Step 2: To a stirred solution of 2-(4-chloropyridin-2-yl)-2,2-difluoroethan-l-ol (400 mg, 2.07 mmol) and pyridine (261.5 mg, 3.31 mmol, 267.4 μL) in acetonitrile (4 mL) was added Tf2O (641.3 mg, 2.27 mmol, 381.7 μL) at 0 °C. The mixture was stirred at 0 °C for 1 hour, and ammonium hydroxide aqueous solution (1 mL) was added thereto. The reaction mixture was stirred at room temperature overnight, diluted with water (10 mL), and extracted with EA (20 mL x 3). The organic phase was washed with brine (20 mL), dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with MeOH/DCM: 1/30) to give 2-(4-chloropyridin-2- yl)-2,2-difluoroethan-l -amine (140 mg, 35% yield) as white oil. LC-MS (ESI) [(M+H)+]: 193.2.
Step 3: To a stirred solution of int. 3 (150 mg, 293.90 μmo)l and 2-(4-chloropyridin-2-yl)-2,2- difluoroethan-1 -amine (140 mg, 729.17 μmo)l in mixed solvent of 1,4-dioxane (4 mL) and water (0.5 mL) was added potassium phosphate (187.2 mg, 881.70 μmo)l, RuPhos Pd G2 (22.9 mg, 29.39 μmo)l. The reaction mixture was stirred at 100 °C under N2 atmosphere for 2 hours, cooled to room temperature, diluted with EA (50 mL) and washed with brine (10 mL x 3). The organic phase was dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by prep-HPLC to give trans-N-(4-((4-(2-(2-amino-l,l- difluoroethyl)pyridin-4-yl)phenyl)sulfonyl)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine
(33 mg, 21% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 541.2.
Figure imgf000122_0002
NMR (400 MHz, DMSO-d6) d 8.81 (d, J= 5.1 Hz, 1H), 8.25 (s, 1H), 8.17 (s, 1H), 8.01 (d, J= 8.6 Hz, 3H), 7.96 (d, J = 4.9 Hz, 1H), 7.58 (dd, J = 8.9 Hz, 2.2 Hz, 1H), 7.25 (d, J = 7.4 Hz, 1H), 6.54 (d, J = 8.9 Hz, 1H), 3.66 (s, 1H), 3.43-3.37 (m, 1H), 2.02 (t, J= 13.9 Hz, 4H), 1.70 (s, 2H), 1.47 (dd, J = 24.0 Hz, 11.6 Hz, 2H), 1.25 (dd, J = 23.2 Hz, 11.4 Hz, 2H).
Example 73
Figure imgf000123_0001
Trans -/V-(4-((4-(2-(l,l-difluoro-2-(methylamino)ethyl)pyridin-4- yl)phenyl)sulfonyl)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine
Figure imgf000123_0002
Step 1: To a stirred solution of 2-(4-chloropyridin-2-yl)-2,2-difluoroethan-l-ol (120 mg, 619.90 p mol) and pyridine (78.5 mg, 0.99 mmol, 80.2 μL) in acetonitrile (3 mL) was added Tf20 (209.9 mg, 743.89 μmo,l 124.9 μL) at 0 °C. The mixture was stirred at 0 °C for 1 hour, and methylamine (21.2 mg, 681.89 μmol, 23.6 μL) was added thereto. The reaction mixture was stirred at room temperature overnight, diluted with water (10 mL), and extracted with EA (20 mL x 3). The organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with MeOH/DCM: 1/30) to give 2-(4- chloropyridin-2-yl)-2,2-difluoro-/V-methylethan-l -amine (60 mg, 47% yield) as white oil. LC- MS (ESI) [(M+H)+]: 206.8.
Step 2: A mixture of 2-(4-chloropyridin-2-yl)-2,2-difluoro-/V-methylethan-l -amine (60 mg, 290.39 μmol), tetrakis(triphenylphosphine) palladium (100.7 mg, 87.12 μmo)l, int. 3 (177.5 mg, 348.47 μmo)l and sodium carbonate (77.0 mg, 725.97 μmo)l in dioxane/water (2 mL, 4/1) was stirred at 100 °C for 1 hour under N2 atmosphere, cooled to room temperature, and diluted with ethyl acetate (20 mL). The resulting mixture was washed with H20 (10 mL x 3). The organic layer was dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate/hexanes from 0 to 100%) and further by prep-HPLC to give trans-N-(4-((4-(2- (l,l-difluoro-2-(methylamino)ethyl)pyridin-4-yl)phenyl)sulfonyl)cyclohexyl)-5- (trifluoromethyl)pyridin-2-amine (12 mg, 7% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 554.8. NMR (400 MHz, DMSO -d6) d 8.81 (d, J = 5.1 Hz, 1H), 8.25 (d, J = 2.6 Hz, 1H),
8.16 (d, J = 8.3 Hz, 2H), 8.05-7.98 (m, 3H), 7.96 (dd, J = 5.1 Hz, 1.8 Hz, 1H), 7.59 (dd, J = 8.9 Hz, 2.6 Hz, 1H), 7.25 (d, J = 7.4 Hz, 1H), 6.54 (d, J = 8.9 Hz, 1H), 3.67 (s, 1H), 3.38 (s, 3H), 2.29 (s, 3H), 2.09-1.97 (m, 4H), 1.47 (tt, J= 12.6 Hz, 7.0 Hz, 2H), 1.26 (q, J= 10.9 Hz, 2H). Example 74
Figure imgf000124_0001
Trans-N-(4-((4-(2-(l -amino-2, 2, 2-trifluoroethyl)pyridin-4- yl)phenyl)sulfonyl)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine
Figure imgf000124_0002
Step 1 : A mixture of 4-chloropyridine-2-carbaldehyde (0.8 g, 5.65 mmol), 2-methylpropane-2- sulfinamide (685.0 mg, 5.65 mmol) and cesium carbonate (2.76 g, 8.48 mmol) in CH2CI2 (20 mL) was stirred at room temperature for 3 hours and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate in petroleum ether from 0 to 30%) to yield (E)-A/-((4-chloropyridin-2- yl)methylene)-2-methylpropane-2-sulfinamide (1.2 g, 87% yield) as a white solid. LC-MS (ESI) [(M+H)+] : 244.8. Step 2: To a solution of (£')-A/-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2- sulfinamide (0.8 g, 3.27 mmol) and tetrabutylammonium difluorotriphenylsilicate (1.94 g, 3.60 mmol) in THF (20 mL) was added (trifluoromethyl) trimethylsilane (1.16 g, 8.17 mmol, 1.30 mL) at -78 °C under N2 atmosphere. The reaction mixture was stirred at -20 °C for 1.5 hours, quenched with saturated ammonium chloride aqueous solution (15 mL), and diluted with ethyl acetate (15 mL) and water (15 mL). The two phases were separated, and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate in petroleum ether from 0 to 50%) to yield N-(l-(4-chloropyridin-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2- sulfinamide (0.71 g, 69% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 314.8.
Step 3: To a solution of N-(l-(4-chloropyridin-2-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2- sulfinamide (710 mg, 2.26 mmol) in MeOH (2.0 mL) was added HCl/dioxane (4M, 3.5 mL). The mixture was stirred at 25 °C for 1 hour and concentrated in vacuo to give l-(4- chloropyridin-2-yl)-2,2,2-trifluoroethan-l -amine (650 mg, crude, HC1 salt) as a white solid. LC-MS (ESI) [(M+H)+]: 210.8.
Step 4\ To a stirred solution of l-(4-chloropyridin-2-yl)-2, 2, 2-trifluoroethan- 1-amine (650 mg, crude, HC1 salt), pyridine (624.4 mg, 7.89 mmol, 638.4 μL) and DMAP (32.1 mg, 263.11 μmo)l in dioxane (20 mL) was added B0C2O (1.15 g, 5.26 mmol, 1.21 mL) over 10 minutes at 5 °C. The reaction mixture was stirred at room temperature overnight and diluted with EtOAc (50 mL) and water (30 mL). The two layers were separated, and the aqueous layer was extracted with EtOAc (40 mL x 2). The combined organic phase was washed with brine (80 mL), dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate in petroleum ether from 0 to 25%) and further by prep-HPLC to afford tert-butyl (l-(4- chloropyridin-2-yl)-2,2,2-trifluoroethyl)carbamate (200 mg, 24% yield) as a white solid. LC- MS (ESI) [(M+H)+] : 310.8.
Step 5: Under microwave condition, the mixture of int. 3 (150 mg, 293.90 μmo)l, tert-butyl (1- (4-chloropyridin-2-yl)-2,2,2-trifluoroethyl)carbamate (91.3 mg, 293.90 μmol), Pd(dppf)Cl2 (21.5 mg, 29.39 μmo)l and potassium carbonate (81.2 mg, 587.80 μmo)l in dioxane/H2O (4/1, 3.0 mL) was stirred at 110 °C under N2 atmosphere for 2 hours, cooled to room temperature and filtered through a pad of silica gel. The solid cake was washed with ethyl acetate (10 mL x 2), and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with McOH/CH2C12 from 0 to 20%) to afford tert-butyl (2,2,2-trifluoro-l-(4-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)ethyl)carbamate (30 mg, 16% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 658.7. Step 6: To a stirred solution of tert-butyl (2,2,2-trifluoro-l-(4-(4-((trans-4-((5- (trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2- yl)ethyl)carbamate (30 mg, 45.55 μmo)l in MeOH (0.5 mL) was added HCl/dioxane (4M, 2 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 hour and concentrated in vacuo. The residue was purified by prep-HPLC to give trans-N-(A-((A-(2-(l -amino-2,2,2- trifluoroethyl)pyridin-4-yl)phenyl)sulfonyl)cyclohexyl)-5-(trifluoromethyl)pyridin-2-amine (20 mg, 79% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 558.8.
Figure imgf000126_0001
NMR (400 MHz, DMSO-d6) d 8.73 (d, J= 5.2 Hz, 1H), 8.25 (s, 1H), 8.12 (s, 1H), 8.10 (s, 1H), 8.03 (s,2H), 8.01 (s, 1H), 7.83 (dd, J = 5.2 Hz, 1.4 Hz, 1H), 7.59 (dd, J = 8.8 Hz, 2.2 Hz, 1H), 7.26 (d, J = 7.4 Hz, 1H), 6.54 (d, J = 8.8 Hz, 1H), 4.68 (d, J = 7.6 Hz, 1H), 3.66 (s, 1H), 3.41 (d, J = 12.0 Hz, 1H), 2.72 (s, 2H), 2.03 (t, J = 14.0 Hz, 4H), 1.48 (dd, J = 23.8 Hz, 11.8 Hz, 2H), 1.24 (t, J =
11.4 Hz, 2H).
Example 75
Figure imgf000126_0002
(4-(2-(l- Amino-2, 2, 2-trifluoroethyl)pyridin-4-yl)phenyl)(imino)(trans-4-(tra(5n-s-4- (trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)-λ6-sulfanone
Figure imgf000126_0003
Step 1 : Under microwave condition, the mixture of int. 1 (200 mg, 418.08 μmo)l, tert-butyl (1- (4-chloropyridin-2-yl)-2,2,2-trifluoroethyl)carbamate (129.9 mg, 418.08 μmol), Pd(dppf)Cl2 (30.6 mg, 41.81 μmo)l and potassium carbonate (115.6 mg, 836.16 μmo)l in dioxane/HiO (4/1, 3.0 mL) was stirred at 110 °C under N2 atmosphere for 2 hours, cooled to room temperature and filtered through a pad of silica gel. The solid cake was washed with ethyl acetate (10 mL x 2), and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with McOH/CH2C12 from 0 to 20%) to afford tert-butyl (2,2,2-trifluoro-l-(4-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)thio)phenyl)pyridin-2-yl)ethyl)carbamate (240 mg, 92% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 626.8.
Step 2: To a mixture of tert-butyl (2,2,2-trifluoro-l-(4-(4-((trans-4-((5- (trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)thio)phenyl)pyridin-2-yl)ethyl)carbamate (240 mg, 382.99 μmo)l and ammonium carbamate (74.8 mg, 957.46 μmo)l in MeOH (5 mL) was added iodobenzene diacetate (246.7 mg, 765.97 μmo)l. The mixture was stirred at 25 °C for 15 minutes and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with methanol in dichloromethane from 0 to 20%) and further by prep-HPLC to give tert-butyl (2,2,2-tnfluoiO- 1 -(4-(4-(trans-4-((5- (trifluoromethyl)pyridin-2-yl)amino)cyclohexane-l-sulfonimidoyl)phenyl)pyridin-2- yl)ethyl)carbamate (200 mg, 79% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 657.7.
Step 3: To a stirred solution of tert-butyl (2,2,2-tnfluoiO- 1 -(4-(4-(/ran.s'-4-((5- (trifluoromethyl)pyridin-2-yl)amino)cyclohexane-l-sulfonimidoyl)phenyl)pyridin-2- yl)ethyl)carbamate (200 mg, 304.10 μmo)l in MeOH (6 mL) was added HCl/dioxane (4M, 6 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 hour and concentrated in vacuo. The residue was purified by prep-HPLC to give (4-(2-(l -amino-2, 2, 2-trifluoroethyl)pyridin-4- yl)phenyl)(imino)(trans-4-((5-(trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)-λ6-sulfanone
(100 mg, 59% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 557.8.
Figure imgf000127_0001
NMR (400 MHz, DMSO-d6) d 8.66 (d, 7 = 5.2 Hz, 1H), 8.17 (s, 1H), 7.99 (s, 1H), 7.97 (s, 2H), 7.95 (s, 1H), 7.93 (s, 1H), 7.77 (d, 7 = 4.0 Hz, 1H), 7.50 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.17 (d, 7 = 7.4 Hz, 1H), 6.46 (d, 7 = 8.8 Hz, 1H), 4.74 (d, J= 7.4 Hz, 1H), 3.58 (s, 1H), 3.06 (t, 7 = 12.0 Hz, 1H), 1.95 (s, 4H), 1.43-1.26 (m, 2H), 1.16 (s, 2H).
Example 76
Figure imgf000127_0002
2,2,2-Trifluoro-l-(4-(4-(trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2-yl)ethan-l-ol
Figure imgf000128_0001
Step 1: To a mixture of 4-chloropyridine-2-carbaldehyde (2.0 g, 14.13 mmol) and potassium carbonate (195.3 mg, 1.41 mmol) in DMF (10 mL) was added trimethyl(trifluoromethyl)silane (2.41 g, 16.95 mmol, 2.69 mL) dropwise. The mixture was stirred at 25 °C for 15 hours, diluted with water (20 mL) and extracted with EA (20 mL x 2). The organic layer was washed with brine (30 mL x 2) and concentrated in vacuo. The residue was stirred at 25 °C for 2 hours in HC1 aqueous solution (2M, 10 mL), adjusted to pH 8~9 with NaOH aqueous solution (2M), and extracted with EA (40 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate in petroleum ether from 0 to 25%) to give l-(4-chloropyridin-2-yl)-2,2,2-trifluoroethan-l-ol (2.6 g, 87% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 211.8.
Step 2: Under microwave condition, the mixture of int. 3 (100 mg, 195.93 μmol), l-(4- chloropyridin-2-yl)-2,2,2-trifluoroethan-l-ol (43.5 mg, 205.73 μmo)l, Pd(dppf)Cl2 (14.3 mg, 19.59 μmol) and potassium carbonate (54.2 mg, 391.87 μmo)l in dioxane/HiO (4/1, 2.5 mL) was stirred at 110 °C under N2 atmosphere for 3 hours, cooled to room temperature and filtered through a pad of silica gel. The solid cake was washed with ethyl acetate (10 mL x 2), and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with MeOH/CH2Cl2 from 0 to 20%) to afford 2,2,2-trifluoro-l-(4-(4- (iran5-4-((5-(trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)sulfonyl)phenyl)pyridin-2- yl)ethan-l-ol (45 mg, 41% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 559.8.
Figure imgf000128_0002
NMR (400 MHz, DMSO -d6) d 8.74 (d, J= 5.2 Hz, 1H), 8.25 (s, 1H), 8.11 (s, 1H), 8.09 (s, 1H), 8.03 (s, 1H), 8.01 (s, 1H), 7.97 (s, 1H), 7.87 (dd, / = 5.2 Hz, 1.6 Hz, 1H), 7.59 (dd, / = 8.8 Hz, 2.4 Hz, 1H), 7.26 (d, J= 7.4 Hz, 1H), 7.15 (d, J= 6.4 Hz, 1H), 6.54 (d, J= 8.8 Hz, 1H), 5.29-5.19 (m, 1H), 3.67 (s, 1H), 3.40 (d, J = 12.2 Hz, 1H), 2.03 (t, / = 13.4 Hz, 4H), 1.48 (dd, / = 23.6, 11.6 Hz, 2H), 1.31-1.22 (m, 2H). Example 77
Figure imgf000129_0003
Imino(4-(2-(2,2,2-trifluoro-l-hydroxyethyl)pyridin-4-yl)phenyl)(trans-4-((5-
(trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)-λ6-sulfanone
Figure imgf000129_0001
Step 1: Under microwave condition, the mixture of int. 1 (100 mg, 209.04 m mol), l-(4- chloropyridin-2-yl)-2,2,2-trifluoroethan-l-ol (46.4 mg, 219.49 m mol), Pd(dppf)Cl2 (15.3 mg, 20.90 μmol) and potassium carbonate (57.8 mg, 418.08 μmo)l in dioxane/HiO (4/1, 3.0 mL) was stirred at 110 °C under N2 atmosphere for 2.5 hours, cooled to room temperature and filtered through a pad of silica gel. The solid cake was washed with ethyl acetate (10 mL x 2), and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with MeOH/CH2Cl2 from 0 to 20%) to afford 2,2,2- trifluoro-l-(4-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)thio)phenyl)pyridin-2-yl)ethan-l-ol (50 mg, 45% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 527.7.
Step 2: To a mixture of 2,2,2-trifluoro-l-(4-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)thio)phenyl)pyridin-2-yl)ethan-l-ol (50 mg, 94.78 μmo)l and ammonium carbamate (18.5 mg, 236.96 μmo)l in MeOH (3 mL) was added iodobenzene diacetate (61.1 mg, 189.56 umol). The mixture was stirred at 25 °C for 15 minutes and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with methanol in dichloromethane from 0 to 20%) and further by prep-HPLC to give imino(4-(2-(2,2,2- trifluoro-l-hydroxyethyl)pyridin-4-yl)phenyl)(trans-4-((5-(trifluoromethyl)pyridin-2- y 1 ) a m i n o ) c y c 1 o h e x y 1 ) - l6 - s u 1 fa n o n c (31 mg, 59% yield) as a white solid. LC-MS (ESI) [(M+H)+] : 558.8.
Figure imgf000129_0002
d 8.78 (d, J = 5.2 Hz, 1H), 8.26 (s, 1H), 8.24 (s, 2H), 8.21 (s, 1H), 8.18 (d, J = 6.6 Hz, 1H), 8.04 (s, 1H), 7.94 (dd, J = 5.2 Hz, 1.6 Hz, 1H), 7.90 (d, J= 9.0 Hz, 1H), 6.99 (d, J= 9.0 Hz, 1H), 5.29 (dd, J = 14.6 Hz, 7.2 Hz, 2H), 4.22 (t, J = 11.8 Hz, 1H), 3.80 (s, 1H), 2.38 (d, J= 11.8 Hz, 1H), 2.22-1.97 (m, 3H), 1.62 (ddd, J = 28.8 Hz, 17.2 Hz, 7.8 Hz, 2H), 1.42 (dt, J= 21.4, 11.4 Hz, 2H).
Example 78
Figure imgf000130_0001
4-Methyl-5-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)sulfonyl)phenyl)thiophene-2-carboxamide
Figure imgf000130_0002
Step 1: To a mixture of 4-methylthiophene-2-carboxylic acid (1.5 g, 10.55 mmol) in acetic acid (15 mL) was added BR2 (1.85 g, 11.61 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes and concentrated in vacuo. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with H2O (10 mL x 3). The combined organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate/hexanes from 0 to 100%) to give 5-bromo-4-methylthiophene-2-carboxylic acid (1.9 g, 81% yield) as a yellow solid. LC-MS (ESI) [(M+H)+]: 220.8.
Step 2: A mixture of 5-bromo-4-methyl-thiophene-2-carboxylic acid (800 mg, 3.62 mmol) in SOCI2 (5 mL) was stirred at 80 °C for 60 minutes and concentrated in vacuo. To the residue was added NH3Ή2O (6 mL) at 0 °C, and the resulting mixture was stirred for 30 minutes at this temperature and filtered to give 5-bromo-4-methylthiophene-2-carboxamide (670 mg, 84% yield) as a yellow solid. LC-MS (ESI) [(M+H)+]: 219.8. Step 3: A mixture of 5-bromo-4-methylthiophene-2-carboxamide (80 mg, 363.49 p mol), tetrakis(triphenylphosphine) palladium (126.0 mg, 109.05 μmo)l, int. 3 (222.6 mg, 436.19 pmol) and sodium carbonate (96.3 mg, 908.73 μmo)l in dioxane/water (2 mL, 4/1) was stirred at 100 °C for 1 hour under N2 atmosphere, cooled to room temperature, and diluted with ethyl acetate (20 mL). The resulting mixture was washed with H2O (10 mL x 3). The organic layer was dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate/hexanes from 0 to 100%) and further by prep-HPLC to give 4-mcthyl-5-(4-((/ran.s'-4- ((5-(trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)sulfonyl)phenyl)thiophene-2- carboxamide (43 mg, 23% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 523.8. XH NMR (400 MHz, DMSO -d6) d 8.29-8.23 (m, 1H), 8.02 (s, 1H), 7.94 (d, J= 8.2 Hz, 2H), 7.81 (d, J = 8.1 Hz, 2H), 7.67 (s, 1H), 7.59 (dd, /= 8.9 Hz, 2.6 Hz, 1H), 7.49 (s, 1H), 7.26 (d, J = 7.4 Hz, 1H), 6.55 (d, J= 8.9 Hz, 1H), 3.68 (s, 1H), 2.34 (s, 3H), 2.08-1.97 (m, 4H), 1.54-1.42 (m, 2H), 1.26 (q, /= 12.0 Hz, 2H).
Example 79
Figure imgf000131_0001
4-Methyl-5-(4-(trans-4-((5-(trifluoromethyl)pyridin-2-yl)amino)cyclohexane-l- sulfonimidoyl)phenyl)thiophene-2-carboxamide
Figure imgf000131_0002
Step 1: A mixture of 5-bromo-4-methylthiophene-2-carboxamide (80 mg, 363.49 μmol), tetrakis(triphenylphosphine) palladium (126.0 mg, 109.05 μmo)l, int. 1 (208.7 mg, 436.19 pmol) and sodium carbonate (96.3 mg, 908.73 μmo)l in dioxane/water (2 mL, 4/1) was stirred at 100 °C for 1 hour under N2 atmosphere, cooled to room temperature, and diluted with ethyl acetate (20 mL). The resulting mixture was washed with ¾0 (10 mL x 3). The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate/hexanes from 0 to 100%) and further by prep-HPLC to give 4-methyl-5-(4-((trans-4- ((5-(trifluoromethyl)pyridin-2-yl)amino)cyclohexyl)thio)phenyl)thiophene-2-carboxamide (50 mg, 28% yield) as a white solid. LC-MS (ESI) [(M+H)+]: 491.8.
Step 2: To a mixture of 4-methyl-5-(4-((trans-4-((5-(trifluoromethyl)pyridin-2- yl)amino)cyclohexyl)thio)phenyl)thiophene-2-carboxamide (50 mg, 101.92 μmol ) and ammonium carbamate (19.9 mg, 254.79 μmo)l in mixed solvent of MeOH (0.5 mL) and DCM (1 mL) was added iodobenzene diacetate (66.1 mg, 203.83 μmo)l. The mixture was stirred at room temperature for 1 hour and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with MeOH/DCM: 1/9) and further by prep- HPLC to give 4- mcthyl-5 -(4-(trans-4-((5-(trifluoiO methyl )pyridi n-2-yl )ami no)cyclohcxanc- 1 - sulfonimidoyl)phenyl)thiophene-2-carboxamide (27 mg, 51% yield) as a white solid. LC-MS (ESI) [(M+H)+] : 522.8.
Figure imgf000132_0001
8.23 (m, 1H), 8.04-7.97 (m, 1H), 7.96-7.91 (m, 2H), 7.78-7.72 (m, 2H), 7.66 (s, 1H), 7.58 (dd, J = 8.9 Hz, 2.6 Hz, 1H), 7.50-7.42 (m, 1H), 7.23 (d, J = 7.4 Hz, 1H), 6.54 (d, J= 8.9 Hz, 1H), 4.30 (s, 1H), 3.65 (s, 1H), 3.11 (t, J= 12.2 Hz, 1H), 2.33 (s, 3H), 2.09-1.98 (m, 4H), 1.52-1.36 (m, 2H), 1.23 (q, J= 12.8 Hz, 2H).
Section 4. Biological assays a. FLIPR assay for CCL20-induced intracellular Ca2+ influx Assay
1. Materials/Reagents
Figure imgf000132_0002
Figure imgf000133_0001
2. Procedures for Compound Preparation i. CCL20: dissolved with DMSO to make 100 mM stock solution, aliquoted and stored at -20°C. ii. Test compounds are dissolved with DMSO to make 30 mM stock solution, aliquoted and stored at -20°C. iii. A serial of compounds concentration is diluted in DMSO to obtain working solution (top concentration 10 mM, 3-fold dilution, 11-dose). iv. Preparation 9X compound to 384 well plate (Cat#6008590) in HBSS+20 mM HEPES buffer by Bravo. v. Add 5 mΐ 9X compound to 384 well black plate (Cat#3712) with Bravo.
3. FLIPR assay procedures i. Culture CHO/CCR6 cells with cell culture medium (10% FBS). ii. When cells reach 80% confluence, dissociate cells with 0.25% Trypsin. iii. Measure the cell density and dilute the cells to 5x105 cells/ml with F12 (10% FBS). iv. Dispense 30 mΐ cells into each well of 384 well black plate with multidrop and culture at 37°C with 5% C02 for 20-24 hrs. v. On the day of assay, add dye-loading solution into wells (40 mΐ per well for 384 well black plates Cat# 3712). Incubate the assay plate at 37°C with 5% C02 in dark for lh. vi. Immediately add 5 μl 9X working concentration of compounds into wells by Bravo. vii. Incubate the plate at 25°C in dark for 30 min before calcium signal readout. viii. Prepare compound plates prior to the assay. Prepare at least 30 mΐ work concentration (5.5X) of agonist (CCL20 =110 nM) in IX HBSS+20mM HEPES+0.1% BSA. The concentration of CCL20 used in the assay was determined by CCL20 dose performed before EC50 assay. 20 nM was used in the assay as final agonist concentration. ix. Read with FLIPR at room temperature using the specified settings and save data. Collect data for 2 min.
4. Data analysis The percent (%) inhibition at each concentration of compound is calculated based on and relative to the signal in the High and Low control wells contained within each assay plate.
The High control wells as 0% inhibition, and the low control wells contain reference compound at IOmM as 100% inhibition. The concentrations and % inhibition values for tested compounds are plotted and the concentration of compound required for 50% inhibition
(IC50) is determined with a Three-parameter logistic dose response equation. The endpoint value (IC50) for the reference peptide/compound is evaluated in each experiment as a quality control measure. If the endpoint value is within 3-fold of the expected value, then the experiment is deemed acceptable.
The FLIPR assay data obtained from exemplary compounds are listed in the Tables 1 below.
Table 1
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0003
In Tables 1, the IC50 values are indicated as "++++", for values less than or equal to 100 nM; "+++", for higher values than “++++” but less than or equal to 1
Figure imgf000143_0001
for higher values than “+++” but less than or equal to 10 pM; and
Figure imgf000143_0002
for greater than 10 pM, respectively.
Section 5. ADME Comparison
Assay procedures for ADME solubility study in PBS (pH = 7.4)
1. Preheat 0.1 M NaP04 buffer, pH 7.4:
Add 11 g of Na2HP04 (FW: 141.96) and 3.5 g of NaH2P042H20 (FW: 156.03) to 1 F of Mili-Q water. Adjust pH to 7.4 with phosphoric acid or NaOH.
2. Aliquots of 8 pF of reference and test compound stock solutions (10 mM) are added into 792 pF of 100 mM phosphate buffer (pH 7.4). (Final DMSO cone.: 1%).
3. Sample tubes are shaken for 1 hour (1000 rpm) at room temperature.
4. Calibration curve preparation: 4.1 Prepare 300 pM spiking solution (SS) in MeOH/ACN (4:1):
- add 6 pF 10 mM compound in 194 pF MeOH/ACN (4:1).
4.2 Prepare standard curve in MeOH/ACN (4:1):
Figure imgf000144_0001
5. Samples are centrifuged (10 min - 12000 rpm) to precipitate un-dissolved particles. And transfer the supernatants to a new tube or plate.
6. Supernatants are diluted 10 times and 100 times with 100 mM buffer - add 10 μL of Supernatants (1:1) into 90 μL of 100 mM buffer to make 10 times dilution
- add 10 μL of Supernatants (1:1) into 990 μL of buffer to make 100 times dilution
7. Sample preparation for LC-MS/MS
Add 5 μL of samples (no diluted, 10 times diluted and 100 times diluted) and standard curve samples to 95 μL of ACN (containing IS).
Assay procedures for ADME PPB study
1. Spiking Solutions of Test and Reference Compounds
1.1 Solution A (0.5 mM): Add 10 μL of lOmM stock solution into 190 μL of DMSO.
1.2 Solution B (0.02 mM): Add 8 μL of Solution A into 192 μL of 0.05 M sodium phosphate buffer. The final DMSO concentration in Solution B is 4%.
2. Preparation of Test and Reference Compounds in plasma
2.1 Preload a 96-well plate with 380 μL aliquots of plasma in the wells designated for plasma and buffer, respectively.
2.2 Spike 20 μL of Solution B (0.02 mM of test and reference compounds) into the pre- loaded plasma in the 96-well plate. The final test concentration is 1 pM containing 0.2%
DMSO.
3. Dialysis Sample Loading
3.1 Preparing plasma against buffer system (duplicate): Apply aliquots of 100 μL of blank dialysis buffer to the receiver side of dialysis chambers. Then apply aliquots of 100 μL of the plasma spiked with test and reference compounds to the donor side of the dialysis chambers (always add the blank buffer to the receiver first, clearly mark the buffer and plasma chamber holes to avoid cross contamination).
3.2 Preparing TO plasma samples for initial concentrations (duplicate):
3.2.1 Aliquot 25 μL of the plasma spiked with test and reference compounds into a 96-well sample preparation plate as TO plasma samples
3.2.2 Mix the aliquots with same volume of blank buffer (50:50, v/v).
3.2.3 Quench the samples with 200 μL of acetonitrile containing internal standard (IS).
3.3 Cover the dialysis block with a plastic lid and place the entire apparatus in a shaker (60 rpm) for 5 hours at 37°C.
3.4 Preparing dialyzed samples after 5-hour incubation:
3.4.1 Aliquot 25 μL from both the donor sides and receiver sides of the dialysis apparatus into new sample preparation plates and mix the aliquots with same volume of opposite matrixes (blank buffer to plasma and vice versa).
3.4.2 Quench the samples with 200 μL acetonitrile containing internal standard (IS). Vortex all the samples (from Oh and 5h) at 600 rpm for 10 min followed by centrifugation at 5594 g for 15 minutes (Thermo Multifuge x 3R).
3.4.3 Transfer 50 μL of the supernatants to a new 96-well plate and mix the samples with 50 μL of Milli-Q water. Cover the sample plate and store it in a freezer (-20 °C) until LC/MS/MS analysis.
Data Analysis
Figure imgf000145_0001
As shown in Table 2 below, Compound A has a poor solubility in phosphate-buffered saline (PBS) and a high plasma protein binding (PPB) across all three species. Surprisingly, the compounds in the present disclosure significantly improved solubility in PPB (3~24 fold compared with Compound A). Moreover, a good number of compounds of the present disclosure also demonstrate that these compounds have lower PPB values, which means more free drugs in the plasma. This is criticaly important for the drug development because the less bound a drug is, the more efficiently it can traverse cell membranes and diffuse. Table 2
Figure imgf000146_0001
*No Data

Claims

CLAIMS What is claimed is:
1. A compound of formula (I):
Figure imgf000147_0001
a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein:
Y is O or NR7; wherein R7 is hydrogen, Ci-6 alkyl, or C3-6cycloalkyl; wherein said Ci-6 alkyl or C3-6cycloalkyl is optionally substituted by one or more halogen or OH;
R1 is hydrogen, halogen, -CN, -NO2, -C(0)0Ra, -C(0)NRaRb, -S02Ra, -S02NRaRb, -P(0)RaRb, -C(0)Ra, -C1-4alkyl, or C2-4alkynyl; wherein said C1-4 alkyl represented by R1 is optionally substituted by one or more halogen, ORa, or NRaRb;
X1 is N or CR2;
X2 is N or CR3;
X3 is N or CR4; wherein R2, R3, and R4 are each independently hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -ORa, -NRaRb, -C(0)Ra, -C(0)0Ra, -C(0)NRaRb, -S02Ra, -S02NRaRb, -P(0)RaRb, -NRaC(0)Rb, -NRaS02Rb, 3-12 membered carbocyclyl, or 3-12 membered heterocyclyl; wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl,
3-12 membered carbocyclyl, or 3-12 membered heterocyclyl represented by R2, R3, or R4 is optionally substituted by one to four Rd; wherein
Ra and Rb are each independently selected from the group consisting of hydrogen, C1-6alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl,
6-10 membered aryl, and 5-10 membered heteroaryl; or Ra and Rb together with the N or P atom to which they are attached, form 4-12 membered heterocyclyl or 5-10 membered heteroaryl; each Rd is independently hydrogen, halogen, oxo (as appropriate), -CN, C1-6alkyl, -ORa, -NRaRb, -C(0)Ra, -C(0)0Ra, -C(0)NRaRb, -S02Ra, -S02NRaRb, -P(0)RaRb, -NRaC(0)Rb, -or NRaS02Rb;
R5 is hydrogen, halogen, -CN, or C1-6alkyl; R6 is halogen, -CN, -ORa, -NRaRb, or C1-6alkyl; R8 is halogen, -CN, -ORa, -NRaRb, or C1-6alkyl; R9 is selected from the group consisting of a) a moiety represented by formula (IA):
Figure imgf000148_0001
wherein Ring A is phenyl or 5-6 membered heteroaryl optionally substituted by one or more R10;
Figure imgf000148_0002
wherein Ring B is phenyl or 5-6 membered heteroaryl optionally substituted by one or more R10; c) a moiety represented by formula (IC):
Figure imgf000148_0003
wherein Ring C is phenyl or 5-6 membered heteroaryl optionally substituted by one or more R10; and d) 7-11 membered bicyclic nitrogen containing heterocyclyl or 8-11 membered bicyclic nitrogen containing heteroaryl, wherein said heterocyclyl or heteroaryl represented by R9 is optionally substituted with one to four Rf; wherein R10 is hydrogen, halogen, -CN, -ORa, -P(0)RaRb, -NRaC(0)Rb, -NRaS02Rb,
-NRaRb, -C(0)0Ra, -C(0)NRaRb, -S02Ra, -S02NRaRb, C1-6alkyl, 3-12 membered carbocyclyl, or 3-12 membered heterocyclyl;
L is a bond, -0-, -N(R11)-, or -C(R12)(R13)-; wherein R11 is hydrogen, C1-6alkyl, 3-6 membered cycloalkyl, or 4-6 membered heterocyclyl; wherein said C1-6alkyl represented by R11 is optionally substituted by halogen, -ORa, -NRaRb, -C(0)0Ra, or -C(0)NRaRb;
R12 and R13 are independently hydrogen, -ORa, -NRaRb, -C(0)0Ra, -C(0)NRaRb, or C1-6alkyl; wherein said C1-6alkyl represented by R12 or R13 is optionally substituted by halogen, -ORa, -NRaRb, -C(0)0Ra, or -C(0)NRaRb;
Z is -CONH2, 4-11 membered carbocyclyl, 4-11 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; wherein said 4-11 membered carbocyclyl,
4-11 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl represented by Z is optionally substituted by one to four Re; provided that when Z is -CONH2, Y is NR7; wherein Re, in each occurrence, is C1-6alkyl, C1-6alkyleneOR', C1-6alkyleneN(R)(R ), oxo (as appropriate), -OR, -N(R')(R"), -NR'C(0)R", C(0)OR', C(0)NR'R", or 3-6 membered cycloalkyl, wherein said C1-6alkyl is optionally substituted by C(0)OR', C(0)NR'R", or NR'C(0)R";
R14 is Ci-ealkyl, C1-6alkyleneOR', Ci-6alkyleneN(R')(R"), -COOR', or -CON(R')(R") , wherein said C1-6alkyl is optionally substituted by -C(0)OR , -C(0)NR R , or -NR C(0)R ;
R15 is -OR, -N(R)(R ), Ci-ealkyl, C1-6alkyleneOR', Ci-6alkyleneN(R')(R"), -COOR', -CON(R)(R ), or -NRC(0)R , wherein said C1-6alkyl is optionally substituted by -C(0)OR , -C(0)NRR , or -NR'C(0)R";
Rf is halogen, -CN, Ci-ealkyl, oxo, -N(R')(R"), OR, -COOR', -NRC(0)R , or -CON(R)(R );
R and R , in each occurrence, are independently hydrogen or C1-6alkyl; or R and R together with the N atom to which they are attached form 4-12 membered heterocyclyl or 5-10 membered heteroaryl; m is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and n is 0, 1, 2, 3, or 4.
2. The compound of claim 1, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein Y is O.
3. The compound of claim 1, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein Y is NR7; wherein R7 is hydrogen or -CH3.
4. The compound of any one of claims 1-3, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R9 is a moiety represented by formula (A):
Figure imgf000150_0001
wherein
U is CH or N; and
V is N or CR10; wherein R10 is hydrogen, halogen, -CN, -C(0)NRaRb, or C1-6alkyl; wherein Ra or Rb are each independently selected from the group consisting of hydrogen, C1-6alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl.
5. The compound of any one of claims 1-3, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R9 is a moiety represented by formula (B):
Figure imgf000150_0002
wherein
U is CH or N; and
V is N or CR10; wherein R10 is hydrogen, halogen, -CN, -C(0)NRaRb, or C1-6alkyl; wherein Ra or Rb are each independently selected from the group consisting of hydrogen, C1-6alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl.
6. The compound of any one of claims 1-3, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R9 is a moiety represented by formula (C):
Figure imgf000150_0003
wherein
U is CH or N; and V is N or CR10; wherein R10 is hydrogen, halogen, -CN, -C(0)NRaRb, or C1-6alkyl; wherein Ra or Rb are each independently selected from the group consisting of hydrogen, C1-6alkyl, 3-12 membered carbocyclyl, 3-12 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl.
7. The compound of any one of claims 1-3, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R9 is 7-11 membered bicyclic nitrogen containing heterocyclyl or 8-11 membered bicyclic nitrogen containing heteroaryl, wherein said heterocyclyl or heteroaryl represented by R9 is optionally substituted with one to four Rf.
8. The compound of any one of claims 1-3, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
R1 is halogen, -CN, -CF , or -P(0)(CH3)2;
X1 is N or CR2; and R2 is hydrogen;
X2 is N;
X3 is N or CR4; and R4is hydrogen or -C(0)OCH3;
R5 is hydrogen, fluorine, or -CN; m is 0; and n is 0.
9. The compound of any one of claims 1-4 and 8, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
R9 is a moiety represented by formula (A);
Figure imgf000151_0001
U is CH or N;
V is N or CR10; wherein R10 is hydrogen, halogen, -CN, -C(0)NRaRb; wherein Ra or Rb are each independently selected from the group consisting of hydrogen, Ci-4alkyl, 3-8 membered carbocyclyl, 4-8 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl;
L is a bond, O, -N(R11)-, or -C(R12)(R13)-; wherein R11 is hydrogen, Ci-4alkyl, 3-6 membered cycloalkyl, or 4-6 membered heterocyclyl;
R12 and R13 are independently hydrogen, -OR, -NRR , or Ci^alkyl;
Z is 4-6 membered carbocyclyl, 4-9 membered heterocyclyl, or 5-6 membered heteroaryl; wherein said 4-6 membered carbocyclyl, 4-9 membered heterocyclyl, or 5-6 membered heteroaryl represented by Z is optionally substituted by one to two Re;
Re, in each occurrence, is C1-6alkyl, -C1-6alkyleneOR', -C1-6alkyleneN(R)(R ), oxo (as appropriate), -OR, -N(R')(R"), -NR'C(0)R", -C(0)OR', -C(0)NR'R", or 3-6 membered cycloalkyl, wherein said C1-6alkyl is optionally substituted by -C(0)OR , -C(0)NRR", or -NRC(0)R ;
R and R , in each occurrence, are independently hydrogen or Ci-4alkyl; or R and R together with the N atom to which they are attached form 5-8 membered heterocyclyl or 5-6 membered heteroaryl.
10. The compound of any one of claims 1-4, 8, and 9, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
R9 is a moiety represented by formula (A):
Figure imgf000152_0001
U is CH or N;
V is N or CR10; wherein R10 is hydrogen or halogen;
L is a bond, -N(R11)-, or -C(R12)(R13)-; wherein R11 is hydrogen or Ci-4alkyl;
R12 and R13 are independently hydrogen, -OH, or Ci-4alkyl;
Z is 4-6 membered carbocyclyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl; wherein said 4-6 membered carbocyclyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl represented by Z is optionally substituted by one to two Re;
Re, in each occurrence, is independently Ci-4alkyl, -NR'C(0)R", -Ci-4alkyleneOR', -OR, Ci-4alkyleneN(R)(R ), -N(R)(R ), or oxo (as appropriate); R and R , in each occurrence, are independently hydrogen or Ci-4alkyl.
11. The compound of any one of claims 1-4 and 8-10, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R9 is a moiety represented by formula (Al), (A2), or (A3):
Figure imgf000153_0001
wherein
R10 is hydrogen or halogen;
L is a bond, -N(R11)-, or -C(R12)(R13)-; wherein R11 is hydrogen or Ci-4alkyl;
R12 and R13 are independently hydrogen, -OH, or Ci-3alkyl;
Z is 4-6 membered cycloalkyl, 4-6 membered saturated monocyclic heterocyclyl,
7 membered saturated bicyclic heterocyclyl, or 5 membered heteroaryl; wherein said 4-6 membered cycloalkyl, 4-6 membered saturated monocyclic heterocyclyl, 7 membered saturated bicyclic heterocyclyl, or 5 membered heteroaryl represented by Z is optionally substituted by one to two Re; and
Re, in each occurrence, is independently Ci-2alkyl, -NR'C(0)R", Ci-2alkyleneOR', -OR, -N(R)(R ), or oxo (as appropriate);
R and R , in each occurrence, are independently hydrogen or Ci-2alkyl.
12. The compound of claim 1-4 and 8-11, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
R10 is hydrogen or fluoro;
L is a bond, -NH-, -N(CH3)-, or -CH(OH)-;
Z is cyclobutyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, azaspiro[3.3]heptanyl, or triazolyl; wherein said cyclobutyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, azaspiro[3.3]heptanyl, or triazolyl is optionally substituted by one to two Re; and
Re, in each occurrence, is -CH3, -OH, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, oxo (as appropriate), -NHC(0)CH3, -OCH3, or -CH2NH2.
13. The compound of claims 1, 4, and 8, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein Y is NR7; wherein R7 is hydrogen or -CH3; R9 is a moiety represented by formula (A);
Figure imgf000154_0001
L is a bond; and Z is -CONH2.
14. The compound of any one of claims 1-4 and 8-12, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R9 is selected from the group consisting of
Figure imgf000154_0002
Figure imgf000155_0001
15. The compound of any one of claims 1-3, 5, and 8, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
R9 is a moiety represented by formula (B);
Figure imgf000155_0002
U is CH;
V is N;
R14 is Ci-4alkyleneOR', Ci-6alkyleneN(R')(R"), -COOR', or -CON(R')(R"); and R and R , in each occurrence, are independently hydrogen or Ci-2alkyl.
16. The compound of any one of claims 1-3, 5, 8, and 15, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R9 is selected from the group consisting of
Figure imgf000155_0003
17. The compound of any one of claims 1-3, 6, and 8, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
R9 is a moiety represented by formula (C);
Figure imgf000155_0004
U is CH; V is N; and
R15 is -OR' or -N(R')(R "); and
R and R , in each occurrence, are independently hydrogen or Ci-4alkyl.
18. The compound of any one of claims 1-3, 6, 8, and 17, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
R9 is a moiety represented by formula (C);
Figure imgf000156_0001
U is CH;
V is N; and R15 is OH or NH2.
19. The compound of any one of claims 1-3, 7, and 8, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
R9 is 8-10 membered bicyclic nitrogen containing heterocyclyl or 8-10 membered bicyclic nitrogen containing heteroaryl, wherein said heterocyclyl or heteroaryl represented by R9 is optionally substituted with one to three Rf; and
Rf is halogen, Ci-4alkyl, oxo (as appropriate), -NH2, C1-4alkoxy, or-COOH.
20. The compound of any one of claims 1-3, 7, 8, and 19, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R9 is selected from the group consisting of
Figure imgf000157_0001
21. The compound of any one of claims 1-20, a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R1 is -CF3;
X1 is CH;
X2 is N;
X3 is CH;
R5 is hydrogen; m is 0; and n is 0.
22. A compound of Table 1, a pharmaceutically acceptable salt, or a stereoisomer thereof.
23. A pharmaceutical composition comprising the compound of any one of claims 1-22, or a pharmaceutically acceptable salt or a stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.
24. A method of treating a disease or condition modulated at least in part by CCR6, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of any of claims 1 to 22, or a pharmaceutically acceptable salt, or a stereoisomer thereof.
25. The method in accordance with claim 24, wherein said disease or condition is an autoimmune disease or condition.
26. The method of claim 24 or claim 25, wherein said disease or condition is rheumatoid arthritis, juvenile arthritis, juvenile rheumatoid arthritis, systemic onset rheumatoid arthritis, pauciarticular rheumatoid arthritis, pauciarticular juvenile rheumatoid arthritis, polyarticular rheumatoid arthritis, enteropathic arthritis, juvenile Reiter's Syndrome, ankylosing spondylitis, juvenile ankylosing spondylitis, SEA Syndrome, reactive arthritis (reactive arthropathy), psoriatic arthropathy, juvenile enteropathic arthritis, polymyalgia rheumatica, enteropathic spondylitis, juvenile idiopathic arthritis (JIA), juvenile psoriatic arthritis, juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, giant cell arteritis, or secondary osteoarthritis from inflammatory diseases in a human.
27. The method of any one of claims 24-26, wherein said disease or condition is inflammatory bowel disease, Crohn's disease, or ulcerative colitis in a human.
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