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WO2007129195A2 - 4-pyrimidine-5-amino-pyrazole compounds - Google Patents

4-pyrimidine-5-amino-pyrazole compounds Download PDF

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Publication number
WO2007129195A2
WO2007129195A2 PCT/IB2007/001158 IB2007001158W WO2007129195A2 WO 2007129195 A2 WO2007129195 A2 WO 2007129195A2 IB 2007001158 W IB2007001158 W IB 2007001158W WO 2007129195 A2 WO2007129195 A2 WO 2007129195A2
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Prior art keywords
alkyl
membered heterocyclyl
aryl
membered
membered cycloalkyl
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PCT/IB2007/001158
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French (fr)
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WO2007129195A3 (en
Inventor
Peng Chen
Yufeng Hong
Paul Stuart Humphries
Jr. Theodore Otto Johnson
Jennifer Anne Lafontaine
Song Liu
Elizabeht Ann Lunney
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Pfizer Products Inc.
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Publication of WO2007129195A2 publication Critical patent/WO2007129195A2/en
Publication of WO2007129195A3 publication Critical patent/WO2007129195A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered

Definitions

  • the present invention relates to novel substituted 4-pyrir ⁇ iidine-5-amino-pyrazole compounds of Formula (I), to pharmaceutical compositions comprising the compounds, as well as to the use of the compounds in the preparation of a medicament for use in the treatment or prevention of a disease or medical condition mediated through c-Jun N-terminal kinases (JNKs), leading to a decreased glucose threshold for insulin secretion.
  • JNKs c-Jun N-terminal kinases
  • the compounds are predicted to lower blood glucose by increasing hepatic glucose uptake. Such compounds may have utility in the treatment of Type 2 diabetes and obesity.
  • JNKs c-Jun N- terminal kinases
  • SAPK stress activated protein kinase
  • JNK signal transduction system of stress response MAP kinase family system is activated by changes in osmotic pressure, DNA damage, anisomycine, heat shock, ultraviolet radiation, ischemia, inflammatory cytokines and the like and various stress stimulations relating to apoptosis induction, it is considered to constitute a major intracellular information transduction path responsible for stress response (Biochemica et Biophysica Acta, vol. 1333, pp. F85-F104 (1997)). From an experiment using a JNK1 deletion mouse, JNK is reported to be an important mediator involved in obesity and insulin resistance (Nature, vol. 420, pp. 333-336 (2002)). Pyrazole compounds including those described in WO03/049542 have been known in the preparation of a medicament for use in the treatment or prevention of a disease or medical condition mediated through c-Jun N-terminal kinases (JNKs).
  • the present invention relates to a compound of formula (I):
  • -Z- is -C- or -N-;
  • R 1 is H or halo
  • R 2 is H, CF 3 , -CHF 2 , -CH 2 F 1 trifluoromethoxy, (C 1 -C 6 JaIkOXy, (Ci-C 6 )amino(CR 5 R 8 ) vr (d-C ⁇ Jalkyl, -(CR 5 R 6 )v(3-10)-membered cycloalkyl, -(CR 5 R 6 ) v (C 6 -C 10 )aryi, or
  • R 3 is H, (CrC 8 )alkyl, CF 3 , -CHF 2 , -CH 2 F, trifluoromethoxy, (CrC 6 )alkoxy,
  • R 2 together with the -N- to which R 3 and R 7 are attached to form a ring A, which is a (5-8)-membered heterocyclyl;
  • R 7 is a bond, and R 3 may be absent;
  • R 3 together with R 7 and the -C- to which R 3 and R 7 are attached to form a ring B, which is a (3-8)-membered heterocyclyl;
  • R 4 is (d-C ⁇ Jalkyl, -(CR 5 R 6 )v(3-10)-membered cycloalkyl, -(CR 5 R 6 MC 6 -C 1 ,) ⁇ , or -(CR 5 R 6 )v(4- 12)-membered heterocyclyl; each of R 5 and R 6 are independently selected from H, (CrC 6 )alkyl, -(CR 8 R 9 )p(3-10)-membered cycloalkyl, -(CR 8 R 9 )p(C 6 -C 10 )aryl, and -(CR 8 R 9 ) p (4-12)-membered heterocyclyl;
  • R 7 is H or (C,-C 6 )alkyl; any carbon atoms of said ring A, ring B, and the (C r C 6 )alkyl, the (3-10)-membered cycloalkyl, the (C 6 -Cio)aryl and the (4-12)-membered heterocyclyl moieties of the foregoing R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are optionally substituted with 1 to 3 R 10 substituents each independently selected from halo, cyano, -CF 3 , -CHF 2 , -CH 2 F, trifluoromethoxy, hydroxy, (C 1 -C 6 JaIkOXy,
  • any nitrogen atoms of said ring A, ring B, and the (4-12)-membered heterocyclyl moieties of the foregoing R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9a , R 10 , R 11 and R 14 are optionally substituted with R 12 substituents each independently selected from (CrC 6 )alkyl,
  • any carbon atoms of each of the foregoing R 11 and R 12 (Ci-C 6 )alkyl, (3-10)-membered cycloalkyl, (C 6 -C 10 aryl), or (4-12)-membered heterocyclyl moieties are optionally substituted with 1 to 3 R 13 substituents each independently selected from halo, cyano, -CF 3 , -CHF 2 , -CH 2 F, trifluoromethoxy, hydroxy, (Ci-C 6 )alkoxy, (CrC 6 )alkyl, -(CR 8 R 9 ) p (3-10)-membered cycloalkyl, -(CR 8 R 9 )p(C 8 -Ci 0 aryl), -(CR 8 R 9 ) p (4-12)-membere
  • the invention relates to compounds of the formula (I) selected from the group consisting of:
  • the invention relates to compounds of the formula (Ia):
  • R 1 is H or halo
  • R 2 is H 1 CF 3 , -CHF 2 , -CH 2 F, trifluoromethoxy, (C r C 6 )alkoxy, (C 1 -C 8 )amino(CR 5 R 6 )
  • R 1 is H or halo
  • R 2 is H 1 CF 3 , -CHF 2 , -CH 2 F, trifluoromethoxy, (C r C 6 )alkoxy, (C 1 -C 8 )amino(CR 5 R 6 )
  • R 4 is (C r C ⁇ )alkyl, -(CR 5 R ⁇ ) v (3-10)-membered cycloalkyl, -(CR 5 R 8 ) V (C 6 -C 1 o)aryl, or -(CR 5 R 6 ) V (4- 12)-membered heterocyclyl; each of R 5 and R 8 are independently selected from H, (C 1 -C 6 JaIkYl, -(CR 8 R 9 ) p (3-10)-membered cycloalkyl, -(CR 8 R 9 ) p (C 6 -C 10 )aryl, and -(CR 8 R 9 ) p (4-12)-membered heterocyclyl;
  • R 7 is H or (d-C 6 )alkyl; any carbon atoms of the (Ci-C e )alkyl, the (3-10)-membered cycloalkyl, the (C 6 -Ci 0 )aryl and the (4- 12)-membered heterocyclyl moieties of the foregoing R 1 , R 2 , R 3 , R 4 , R 5 , and R 8 are optionally substituted with 1 to 3 R 10 substituents each independently selected from halo, cyano, -CF 3 , -CHF 2 , -CH 2 F, trifluoromethoxy, hydroxy, (d-C 6 )alkoxy,
  • any carbon atoms of each of the foregoing R 10 (d-C 6 )alkyl, (3-10)-membered cycloalkyl, (C ⁇ -C 10 aryl), or (4-12)-membered heterocyclyl moieties are optionally substituted with 1 to 3 R 11 substituents each independently selected from halo, cyano, -CF 3 , -CHF 2 , -CH 2 F, -0-CF 3 , -0-CHF 2 .
  • any nitrogen atoms of the (4-12)-membered heterocyclyl moieties of the foregoing R 1 , R 2 , R 3 , R 4 , R 5 p ⁇ R 9 a R i o R ii and R i4 are opt j ona
  • the invention relates to compounds of the formula (Ia), wherein R 4 is unsubstituted (Ci-C 6 )alkyl, such as isopropyl.
  • any carbon atoms of each of the foregoing R 10 (d-CeJalkyl, (3-10)-membered cycloalkyl, (C ⁇ -C 10 aryl), or (4-12)-membered heterocyclyl moieties are optionally substituted with 1 to 3 R 11 substituents each independently selected from halo, cyano, -CF 3 , -CHF 2 , -CH 2 F, -0-CF 3 , -0-CHF 2 , -0-CH 2 F, hydroxy,
  • R 11 is C 1 -C 6 JaIkOXy.
  • the invention relates to compounds of the formula (Ia), wherein R 4 is unsubstituted -(CR 5 R 6 ) v (3-10)-membered cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, -(CH 3 CH)-cyclohexyl, -(CH 2 )-cyclohexyl, cyclohexyl, or indanyl, preferably cyclohexyl.
  • the invention relates to compounds of the formula (Ia), wherein R 4 is -(CR 5 R 6 ) v (3-10)-membered cycloalkyl substituted with 1 to 3 R 10 substituents each independently selected from halo, cyano, -CF 3 , -CHF 2 , -CH 2 F, trifluoromethoxy, hydroxy,
  • any carbon atoms of each of the foregoing R 10 (d-C 6 )alkyl, (3-10)-membered cycloalkyl, (C 6 -Cioaryl), or (4-12)-membered heterocyclyl moieties are optionally substituted with 1 to 3 R 11 substituents each independently selected from halo, cyano, -CF 3 , -0-CF 3 , -0-CHF 2 , hydroxy, (CrC 6 )alkoxy,
  • the invention relates to compounds of the formula (Ia), wherein R 4 is unsubstituted -(CR 5 R 8 ) v (C 6 -C 1 o)aryl, such as phenyl, naphthyl, -(CH 2 CH 2 )-phenyl, or -(CH 2 )-phenyl.
  • the invention relates to compounds of the formula (Ia), wherein R 4 is -(CR 5 R 6 ) v (C 6 -C 10 )aryl substituted with 1 to 3 R 10 substituents each independently selected from halo, cyano, -CF 3 , -CHF 2 , -CH 2 F, trifluoromethoxy, hydroxy, (Ci-C 6 )alkoxy,
  • R 10 is halo, -CF 3 , hydroxy, (Ci-C ⁇ Jalkoxy, (Ci-C 6 )alkyl, or R 9a .
  • any carbon atoms of each of the foregoing R 10 (C r C 6 )alkyl, (3-10)-membered cycloalkyl, (C 6 -Ci 0 aryl), or (4-12)-membered heterocyclyl moieties are optionally substituted with 1 to 3 R 11 substituents each independently selected from R 14 , and -NR 8 R 9 .
  • the invention relates to compounds of the formula (Ia), wherein R 4 is unsubstituted -(CR 5 R 8 ) « (4-12)-membered heterocyclyl, such as dihydrobenzopyranyl, -(CH 2 )-imidazo[12-a]pyrimidinyl, -(CH 2 )-mo ⁇ holi ⁇ onyl, -(CH 2 CH 2 )-mo ⁇ holinyl, -(CH 2 C(CH 3 ) 2 )-mo ⁇ holinyl
  • any carbon atoms of each of the foregoing R 10 (Ci-C 6 )alkyl, (3-10)-membered cycloalkyl, (C ⁇ -Ci O aryl), or (4-12)-membered heterocyclyl moieties are optionally substituted with 1 to 3 R 11 substituents each independently selected from hydroxy, C 1 -C f OaIkOXy, and (C r C ⁇ )alkyl.
  • R 12 is (C 1 -C 6 )alkyl
  • any carbon atoms of each of the foregoing R 12 (3-10)-membered cycloalkyl, (C 6 -C 10 aryl), or (4-12)-membered heterocyclyl moieties are optionally substituted with 1 to 3 R 13 substituents each independently selected from halo, cyano, -CF 3 , -CHF 2 , -CH 2 F, trifluoromethoxy, hydroxy, (C 1 -C 6 JaIkOXy,
  • R 13 is cyano, (C 1 -C 6 )BIkOXy, (d-C ⁇ Jalkyl, or -(CR 8 R 9 ) p (C 6 -C 10 aryl).
  • the invention relates to compounds of the formula (Ib): wherein ring A is a (5-8)-membered heterocyclyi;
  • -Z- is -C- or -N-;
  • R 1 is H or halo
  • R 3 may be absent
  • R 4 is (C r C 6 )alkyl, -(CR 5 R ⁇ )v(3-10)-membered cycloalkyl, -(CR 5 R 6 ) V (C 6 -C 1 o)aryl, or -(CR 5 R 6 ) V (4- 12)-membered heterocyclyi; each of R 5 and R 6 are independently selected from H, (CrC 6 )alkyl, -(CR 8 R 9 )p(3-10)-membered cycloalkyl, -(CR B R 9 ) p (C 6 -C 10 )aryl, and -(CR 8 R 9 ) p (4-12)-membered heterocyclyi; any carbon atoms of said ring A and the (Ci-C 6 )alkyl, the (3-10)-membered cycloalkyl, the (C 6 - Cio)aryl and the (4-12)-membered heterocyclyi moieties of the fore
  • the invention relates to compounds of the formula (Ib) selected from the group consisting of:
  • the invention relates to compounds of the formula (Ib) selected from the group consisting of: (Ib1), (Ib2), (Ib3), and (Ib7), as described above.
  • the invention relates to compounds of the formula (Ib) 1 wherein R 4 is (C 1 - C 6 )alkyl, such as isopropyl.
  • the invention relates to compounds of the formula (Ib), wherein R 4 is - (CR 5 R 6 ) v (C 6 -Cio)aryl, such as phenyl or naphtyl.
  • the invention relates to compounds of the formula (Ib), wherein R 4 is -(CR 5 R ⁇ )v(4-12)-membered heterocyclyl, such as pyridinyl.
  • the invention relates to compounds of the formula (Ic):
  • ring B is a (3-8)-membered heterocyclyl
  • -Z- is -C- or -N-;
  • R 1 is H or halo
  • R 2 is H, CF 3 , -CHF 2 , -CH 2 F, trifluoromethoxy, (C 1 -C 6 JaIkOXy, (C 1 -C 6 )amino(CR 5 R 6 ) Vi (Ci-C 6 )alkyl, -(CR 5 R 6 ) v (3-10)-membered cycloalkyl, -(CR 5 R 6 )v(C6-Cio)aryl, or
  • R 4 is (CrC 6 )alkyl, -(CR ⁇ R 6 )y(3-10)-membered cycloalkyl, -(CR 5 R ⁇ )v(C 6 -Cio)aryl, or -(CR s R ⁇ ) v (4- 12)-membered heterocyclyl; each of R 5 and R 6 are independently selected from H, (C r C 6 )alkyl, -(CR 8 R 9 )p(3-10)-membered cycloalkyl, -(CR 8 R 9 ) p (C 6 -C 10 )aryl, and -(CR 8 R 9 ) p (4-12)-membered heterocyclyl; any carbon atoms of said ring B, and the (Ci-C 6 )alkyl, the (3-10)-membered cycloalkyl, the (C 6 - Cio)aryl and the (4-12)-membered heterocyclyl moieties
  • any carbon atoms of each of the foregoing R 10 (Ci-C 6 )alkyl, (3-10)-membered cycloalkyl, (C 6 -Ci 0 aryl), or (4-12)-membered heterocyclyl moieties are optionally substituted with 1 to 3 R 11 substituents each independently selected from halo, cyano, -CF 3 , -CHF 2 , -CH 2 F, -0-CF 3 , -0-CHF 2 , -0-CH 2 F, hydroxy, (C r C 6 )alkoxy, (d-C ⁇ Jalkyl, R 14 , -0-R 14 ,
  • any carbon atoms of each of the foregoing R 11 and R 12 (Ci-C ⁇ )alkyi, (3-10)-membered cycloalkyl, (C ⁇ -C 10 aryl), or (4-12)-membered heterocyclyl moieties are optionally substituted with 1 to 3 R 13 substituents each independently selected from halo, cyano, -CF 3 , -CHF 2 , -CH 2 F, trifluoromethoxy, hydroxy, (C 1 -C 6 JaIkOXy, (d-C 6 )alkyl, -(CR 8 R 9 ) p (3-10)-membered cycloalkyl, -(CR 8 R 9 V(C 6 -C 1O a ⁇ I), -(CR 8 R 9 ) p (4-12)-membere
  • the invention relates to compounds of the formula (Ic) 1 wherein Ring B is a (3-8)-membered heterocyclyl selected from the group consisting of morpholinyl, piperidinyl, piperazinyl, and pyrrolidinyl.
  • the invention relates to compounds of the formula (Ic), wherein any carbon atoms of said ring B are optionally substituted with 1 to 3 R 10 substituents each independently selected from -NR 8 R 9 , -S(O) j (C r C 6 )alkyi, and -NR 8 -S(OMd-C 6 )alkyl.
  • R 12 is-(CR 8 R 9 ) q S(O) j (C 1 -C 6 )alkyl. or a pharmaceutically acceptable salt thereof.
  • the invention relates to compounds of the formula (I), wherein -Z- is -N-.
  • the invention relates to compounds of the formula (I), wherein R 1 is H.
  • the invention relates to compounds of the formula (I), wherein R 2 is R 2 is H 1 (C r C 6 )alkyl, -(CR 5 R 6 )v(3-10)-membered cycloalkyl, or -(CR 5 R 6 ) V (4-12)-membered heterocyclyl.
  • the invention relates to compounds of the formula (I), wherein R 3 is H,
  • the invention relates to compounds of the formula (I), wherein R 7 is H or methyl.
  • the invention relates to compounds of the formula (I), selected from the group consisting of: salt thereof.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of compounds of the formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention also relates to a method of treating a condition that is mediated by the modulation of JNK, the method comprising administering to a mammal an effective amount of compounds of the formula (I), or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to a method of treating diabetes, metabolic syndrome, insulin resistance syndrome, obesity, glaucoma, hyperiipidemia, hyperglycemia, hyperinsuli ⁇ emia, osteoporosis, tuberculosis, atherosclerosis, dementia, depression, virus diseases, inflammatory disorders, or diseases in which the liver is a target organ, the method comprising administering to a mammal an effective amount of compounds of the formula (I), or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to a method of treating chronic or acute cardiac failure, cardiac hypertrophy, dilated, hypertrophic or restrictive cardiomyopathy, acute myocardial infarction, post- myocardial infarction, acute or chronic myocarditis, diastolic dysfunction of the left ventricle, systolic dysfunction of the left ventricle, hypertension and nephropathy and nephritis as complications thereof, endothelial dysfunction, arteriosclerosis or post-angioplasty restenosis, which comprises administering an effective amount of compounds of the formula (I), to a mammal in need thereof.
  • the present invention also relates to a method of treating chronic rheumatoid arthritis, osteoarthritis, gout, chronic obstructive pulmonary disease, asthma, bronchitis, cystic fibrosis, inflammatory bowel disease, irritable colon syndrome, mucous colitis, ulcerative colitis, Crohn's disease, gastritis, esophagitis, multiple sclerosis, eczema, dermatitis, hepatitis, glomerulonephritis, diabetes, ophthalmic diseases, diabetic retinopathy, diabetic macular edema, diabetic nephropathy, diabetic neuropathy, obesity, psoriasis or cancer, which comprises administering an effective amount of compounds of the formula (I), to a mammal in need thereof.
  • the present invention also relates to a method of treating Alzheimer's disease, Huntington's chorea, Parkinson's syndrome, epilepsy, amyotrophic lateral sclerosis, peripheral neuropathy, neurodegenerative disease or spinal injury, which comprises administering an effective amount of compounds of the formula (I), to a mammal in need thereof.
  • the present invention also relates to a method of treating cerebral apoplexy, cerebrovascular disorder, an ischemic disorder of an organ selected from the heart, kidney, liver and brain, ischemia- reperfusion injury, organ failure, endotoxin shock or rejection in transplantation, which comprises administering an effective amount of compounds of the formula (I), to a mammal in need thereof.
  • halo as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo.
  • alkyl as used herein, unless otherwise indicated, includes saturated, partially unsaturated, or unsaturated hydrocarbon radicals having straight or branched moieties.
  • alkyl as used herein, includes alkenyl, which includes alkyl moieties having at least one carbon-carbon double bond and including E and Z isomers of said alkenyl moiety.
  • alkyl as used herein, includes alkynyl, which includes alkyl moieties having at least one carbon-carbon triple bond.
  • alkoxy as used herein, unless otherwise indicated, includes O-alkyl groups wherein alkyl is as defined above.
  • Me means methyl
  • Ef means ethyl
  • Ac means acetyl
  • cycloalkyl refers to a non-aromatic, saturated or partially saturated, monocyclic or fused, spiro or unfused bicyclic or tricyclic hydrocarbon referred to herein containing a total of from 3 to 10 carbon atoms, preferably 5-8 ring carbon atoms.
  • exemplary cycloalkyls include monocyclic rings having from 3-10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl.
  • Illustrative examples of cycloalkyl are derived from, but not limited to, the following:
  • aryl as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl.
  • (4-12)-membered heterocyclyl includes aromatic and non-aromatic heterocyclic groups containing one to four heteroatoms each selected from O, S and N, and with the proviso that the ring of said group does not contain two adjacent O or S atoms.
  • Non-aromatic heterocyclic groups include groups having only 3 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system.
  • the heterocyclic groups include benzo-fused ring systems.
  • An example of a 3 membered heterocyclic group is aziridine, an example of a 4 membered heterocyclic group is azetidinyl (derived from azetidine).
  • An example of a 5 membered heterocyclic group is thiazolyl, an example of a 7 membered ring is azepinyl, and an example of a 10 membered heterocyclic group is quinolinyl.
  • non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepi ⁇ yl, 1 ,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3- dioxolanyl, pyrazolinyl,
  • aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, fury), thienyl, isoxazolyt, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazi ⁇ yl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolin
  • a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
  • a group derived from imidazole may be imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached).
  • the 4-12 membered heterocyclic may be optionally substituted on any ring carbon, sulfur, or nitrogen atom(s) by one to two oxo, per ring.
  • heterocyclic group wherein 2 ring carbon atoms are substituted with oxo moieties is 1,1-dioxo-thiomorpholinyl.
  • 4-12 membered heterocyclic are derived from, but not limited to, the following:
  • solvate is intended to mean a pharmaceutically acceptable solvate form of a specified compound that retains the biological effectiveness of such compound.
  • solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, DMSO (dimethylsulfoxide), ethyl acetate, acetic acid, or ethanolamine.
  • phrases "pharmaceutically acceptable salt(s)", as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of formula (I).
  • the compounds of formula (I) that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of formula (I) are those that form non-toxic acid addition salts, Le 1 , salts containing pharmacologically acceptable anions, such as the acetate, benzenesulfonate, benzoate, bicarbonate, bisuifate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edislyate, estolate, esylate, ethylsuccinate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulf
  • liver is a target organ
  • diabetes means diabetes, hepatitis, liver cancer, liver fibrosis, and malaria.
  • Methodabolic syndrome means psoriasis, diabetes mellitus, wound healing, inflammation, neurodegenerative diseases, galactosemia, maple syrup urine disease, phenylketonuria, hypersarcosinemia, thymine uraciluria, sulfinuria, isovaleric acidemia, saccharopinuria, 4-hydroxybutyric aciduria, glucose-6-phosphate dehydrogenase deficiency, and pyruvate dehydrogenase deficiency.
  • R 5 , R 8 , R 8 and R 9 may vary with each iteration of v or p.
  • v or p is 2
  • the terms (CR 5 R 8 Jv or (CR 8 R 9 J p may equal -CH 2 CH 2 -, or -CH(CH 3 )C(CH 2 CH 3 )(CH 2 CH 2 CH 3 )-, or any number of similar moieties falling within the scope of the definitions of R 5 , R 8 , R 8 and R 9 .
  • treating means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating as “treating” is defined immediately above.
  • modulate refers to the ability of a modulator for a member of the steroid/thyroid superfamily to either directly (by binding to the receptor as a ligand) or indirectly (as a precursor for a ligand or an inducer which promotes production of ligand from a precursor) induce expression of gene(s) maintained under hormone expression control, or to repress expression of gene(s) maintained under such control.
  • “obese” is defined, for males, as individuals whose body mass index is greater than 27.8 kg/ m 2 , and for females, as individuals whose body mass index is greater than 27.3 kg/m 2 .
  • the invention method is not limited to those who fall within the above criteria. Indeed, the method of the invention can also be advantageously practiced by individuals who fall outside of these traditional criteria, for example, by those who may be prone to obesity.
  • inflammatory disorders refers to disorders such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, chondrocalcinosis, gout, inflammatory bowel disease, ulcerative colitis, Crohn's disease, fibromyalgia, and cachexia.
  • terapéuticaally effective amount refers to that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other.
  • amount . . . effective to lower blood glucose levels refers to levels of compound sufficient to provide circulating concentrations high enough to accomplish the desired effect. Such a concentration typically falls in the range of about 10 nM up to 2 ⁇ M; with concentrations in the range of about 100 nM up to 500 nM being preferred.
  • concentrations typically falls in the range of about 10 nM up to 2 ⁇ M; with concentrations in the range of about 100 nM up to 500 nM being preferred.
  • the activity of different compounds which fall within the definition of Formula (I) as set forth above may vary considerably, and since individual subjects may present a wide variation in severity of symptoms, it is up to the practitioner to determine a subject's response to treatment and vary the dosages accordingly.
  • insulin resistance refers to the reduced sensitivity to the actions of insulin in the whole body or individual tissues, such as skeletal muscle tissue, myocardial tissue, fat tissue or liver tissue. Insulin resistance occurs in many individuals with or without diabetes mellitus.
  • insulin resistance syndrome refers to the cluster of manifestations that include insulin resistance, hyperinsulinemia, non insulin dependent diabetes mellitus (NIDDM), arterial hypertension, central (visceral) obesity, and dyslipidemia.
  • NIDDM non insulin dependent diabetes mellitus
  • Certain compounds of formula (I) may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of formula (I), and mixtures thereof, are considered to be within the scope of the invention.
  • the invention includes the use of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, or mixtures thereof.
  • the compounds of formula (I) may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.
  • Certain functional groups contained within the compounds of the present invention can be substituted for bioisosteric groups, that is, groups which have similar spatial or electronic requirements to the parent group, but exhibit differing or improved physicochemical or other properties. Suitable examples are well known to those of skill in the art, and include, but are not limited to moieties described in Patini et al., Chem. Rev, 1996, 96, 3147-3176 and references cited therein.
  • the subject invention also includes isotopically-labelled compounds, which are identical to those recited in formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O 1 17 0, 31 P, 32 P, 35 S, 18 F, and 36 CI, respectively.
  • Compounds of the present invention and pharmaceutically acceptable salts s of said compounds which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • Certain isotopically-labelled compounds of the present invention for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • lsotopically labeled compounds of formula (I) of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non- isotopically labelled reagent.
  • the compounds of the present invention may have asymmetric carbon atoms.
  • Diasteromeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixtures into a diastereomric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomeric mixtures and pure enantiomers are considered as part of the invention.
  • the compounds of formulas (I) that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of formula (I) from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt.
  • the acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained.
  • the desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding to the solution an appropriate mineral or organic acid.
  • Those compounds of formula (I) that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • such salts include the alkali metal or alkaline- earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques.
  • the chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of formula (I).
  • Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium calcium and magnesium, etc.
  • salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure.
  • they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before.
  • stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.
  • the compounds of the present invention may also be useful in the treatment of other metabolic disorders associated with impaired glucose utilization and insulin resistance include major late-stage complications of NIDDM, such as diabetic angiopathy, atherosclerosis, diabetic nephropathy, diabetic neuropathy, and diabetic ocular complications such as retinopathy, cataract formation and glaucoma, and many other conditions linked to NIDDM, including dyslipidemia glucocorticoid induced insulin resistance, dyslipidemia, polycystic ovarian syndrome, obesity, hyperglycemia, hyperlipemia, hypercholesteremia, hypertriglyceridemia, hyperinsulinemia, and hypertension. Brief definitions of these conditions are available in any medical dictionary, for instance, Stedman's Medical Dictionary (Xth Ed.).
  • the amino heterocyclyl compounds of formula (I) may be provided in suitable topical, oral and parenteral pharmaceutical formulations for use in the treatment of GK mediated diseases.
  • the compounds of the present invention may be administered orally as tablets or capsules, as oily or aqueous suspensions, lozenges, troches, powders, granules, emulsions, syrups or elixirs.
  • the compositions for oral use may include one or more agents for flavoring, sweetening, coloring and preserving in order to produce pharmaceutically elegant and palatable preparations. Tablets may contain pharmaceutically acceptable excipients as an aid in the manufacture of such tablets.
  • these tablets may be coated with a pharmaceutically acceptable enteric coating, such as glyceryl monostearate or glyceryl distearate, to delay disintegration and absorption in the gastrointestinal tract to provide a sustained action over a longer period.
  • a pharmaceutically acceptable enteric coating such as glyceryl monostearate or glyceryl distearate
  • Formulations for oral use may be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin.
  • the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions normally contain active ingredients in admixture with excipients suitable for the manufacture of an aqueous suspension.
  • excipients may be a suspending agent, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; a dispersing or wetting agent that may be a naturally occurring phosphatide such as lecithin, a condensation product of ethylene oxide and a long chain fatty acid, for example polyoxyethylene stearate, a condensation product of ethylene oxide and a long chain aliphatic alcohol such as heptadecaethylenoxycetanol, a condensation product of ethylene oxide and a partial ester derived from a fatty acid and hexitol such as polyoxyethylene sorbitol monooleate or a fatty acid hexitol anhydrides such as polyoxyethylene sorbitan mono
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension may be formulated according to know methods using those suitable dispersing or wetting agents and suspending agents that have been mentioned above.
  • the sterile injectable preparation may also be formulated as a suspension in a non toxic perenterally-acceptable diluent or solvent, for example as a solution in 1 ,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringers solution and isotonic sodium chloride solution.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the amino heterocyclyl compounds of formula (I) may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at about 25 Celcius but liquid at rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient that is solid at about 25 Celcius but liquid at rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials include cocoa butter and other glycerides.
  • topical use preparations for example, creams, ointments, jellies solutions, or suspensions, containing the compounds of the present invention are employed.
  • the amino heterocyclyl compounds of formula (I) may also be administered in the form of liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles and multimellar vesicles.
  • Liposomes can be formed from a variety of phospholipides, such as cholesterol, stearylamine or phosphatidylcholines.
  • Dosage levels of the compounds of the present invention are of the order of about 0.5 mg/kg body weight to about 100 mg/kg body weight.
  • a preferred dosage rate is between about 30 mg/kg body weight to about 100 mg/kg body weight. It will be understood, however, that the specific dose level for any particular patient will depend upon a number of factors including the activity of the particular compound being administered, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • reaction flasks were fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried. Analytical thin layer chromatography (TLC) was performed using glass-backed silica gel 60 F 254 precoated plates (Merck Art 5719) and eluted with appropriate solvent ratios (v/v). Reactions were assayed by TLC or LCMS and terminated as judged by the consumption of starting material.
  • TLC thin layer chromatography
  • TLC plates Visualization of the TLC plates was done with UV light (254 nM wavelength) or with an appropriate TLC visualizing solvent and activated with heat. Flash column chromatography (Still et al., J. Org. Chem., 1978, 43, 2923) was performed using silica gel 60 (Merck Art 9385) or various MPLC systems, such as Biotage or ISCO purification system.
  • Peak multiplicities are designated as follows: s, singlet; d, doublet; dd, doublet of doublets; t, triplet; dt, doublet of triplets; q, quartet; br, broadened; m, multiplet. Coupling constants are given in Hertz (Hz). Mass spectra (MS) data were obtained using Agilent mass spectrometer with APCI or ESI ionization. Elemental microanalyses were performed by Atlantic Microlab Inc. and gave results for the elements stated within ⁇ 0.4% of the theoretical values.
  • Preferred compounds in accordance with the invention may be prepared in manners analogous to those specifically described below.
  • Et 2 O refers to diethyl ether.
  • DMF refers to ⁇ /,/V-dimethylformamide.
  • DMSO refers to dimethylsulfoxide.
  • MTBE refers to ferf-butylmethyl ether.
  • Pyrimidine 1e (4-methyl-2-(methylthio)pyrimidine) was prepared from 4-methylpyrimidine-2-thiol (1f) according to the procedure described in Org. Lett. 2003, 4 (6), 979.
  • Oxalyl chloride (33 mL, 375 mmol) was added dropwise via addition funnel to an ice-cooled mixture of DMF (30 mL, 393 mmol) in CHCI 3 (218 mL) with vigorous stirring. The mixture was stirred for 5 minutes after the addition was complete, and the solution was then warmed to 45 0 C and allowed to stir for 30 minutes. The mixture then re-cooled to 0 0 C, and 1e (25.0 g, 179 mmol) in CHCI 3 (10 mL) was added dropwise via an addition funnel. The solution was then warmed to 45 °C, and the mixture was allowed to stir vigorously for 12 hour(s).
  • Hydroxylamine hydrochloride (30.0 g, 434 mmol) was dissolved in water (400 mL) at room temperature. Na 2 CO 3 (55.3 g, 521 mmol) was added slowly and the mixture stirred rapidly for 10 minutes. Compound 1d (30.0 g, 119 mmol) was then added portion-wise over 15 minutes, and the resulting mixture was stirred rapidly at room temperature with the aid of a mechanical stirrer. After stirring for an additional 5 hour(s), the solid was filtered off, washed with cold water, and dried under high vacuum. The resulting tan solid (18.7 g) was suspended in CH 3 CN / methanol (60 mL of each), and the mixture cooled to 0 0 C.
  • Isoxazole 1c (2.50 g, 12.9 mmol) was dissolved in acetic acid (50 mL) and cooled in an ice bath to 0 0 C. The mixture was stirred vigorously while methylhydrazine (10.3 mL, 194 mmol) was added dropwise via syringe at a rate such that the internal temperature remained below 35 0 C. After the addition was complete, the mixture was removed from the ice bath, allowed to slowly warm to room temperature over 15 minutes, and then slowly warmed in an oil bath until a temperature of 85 0 C was reached.
  • the reactio ⁇ was stirred vigorously at 85 0 C for 4.5 hour(s), at which time the flask was removed from the oil bath and cooled to 0 0 C.
  • the mixture was basified with NH 4 OH (concentrated ) to a pH of 10.
  • the solid that precipitated out was filtered off, rinsed with a small amount of cold water, and dried under high vacuum.
  • the resultant crude product (7, light tan solid, 2.12 g, 74 %) contained a mixture of regioisomers (6:1 , methyl-5-aminopyrazole: methyl-3-aminopyrazole) and was used without further purification.
  • Isoxazole 1c (1.80 g, 9.32 mmol) was dissolved in ethanol (30 ml_), and 4-methoxybenzylbenzylhydrazine hydrochloride (1.76 g, 9.32 mmol) and sodium methoxide (0.504 g, 9.32 mmol) were added sequentially. The mixture was refluxed under N 2 for 15 hour(s), and then was allowed to cool to room temperature. Analysis of an aliquot by LCMS showed incomplete conversion.
  • Methylthiopyrimidi ⁇ e 1b (2.20 g, 3.40 mmol) was dissolved in methanol/water (10 mL/1.2 mL) and a suspension of oxone (2.93 g, 4.76 mmol) in water (8.5 mL) was added in portions while stirring the methylthiopyrimidine solution at room temperature. An additional 8.5 mL of water was used to complete the addition of oxone. The resulting yellow suspension turned orange in color after stirring 3 hour(s) at room temperature. The suspension was filtered, and the filtrate was extracted several times with 10% methanol in CH 2 CI 2 . The combined organic extracts were dried (MgSO 4 ) and concentrated in vacuo to afford the crude product (900 mg).
  • Compound 2a was prepared analogous to the method of preparing compound 1a.
  • Methylthiopyrimidine 4b (2.00 g, 6.12 mmol) was reacted with oxone as described in the synthesis of compound 1a to yield a mixture of sulfoxide 4a and the corresponding sulfoxide (total of 1.60 g, 70%, 4a:sulfoxide in a 2:1 ratio by 1 H NMR) as a pale yellow solid.
  • Methylsulfonylpyrimidine 1a (315 mg, 0.96 mmol) was suspended in 1,4-dioxane (2 mL) and trans- aminocyclohexanol (553 mg, 4.80 mmol) was added at room temperature. The resulting suspension was stirred at 85 0 C for 2.5 days under an inert atmosphere in a sealed tube. The solution was cooled to room temperature, and the resulting slurry was dissolved in CH 2 CI 2 with the aid of a small amount of methanol. The solution thus obtained was concentrated in vacuo.
  • Compound 122 was prepared as a white solid following the general procedure described above. Aminopyrazole 122a (50 mg, 0.23 mmol), cyclobutanone (81 mg, 1.1 mmol), Na(OAc) 3 BH (98 mg, 0.46 mmol) and glacial acetic acid (0.015 mL) were reacted in dichloroetha ⁇ e (1.5 mL) to afford the title compound 122 (6 mg, 10 %). See Table 5.
  • Methane sulfonyl chloride 25 mg, 0.22 mmol was added drop wise to a mixture of 128a (50 mg, 0.18 mmol) and DIEEA (59 mg, 0.46 mmol) in DMF (1 ml.) at 0 C. The resulting mixture was stirred at room temperature for 15 minutes. DMF and DIE ⁇ A were removed under reduced pressure at 85 0 C. The residue triturated with 10% K 2 CO 3 aqueous solution. The solid product was then filtered and washed with water, ethyl acetate to gain 52 mg colorless solid product 133.
  • Compound 149 was prepared according to the method described for preparation of 148 starting from 3- nicotinaldehyde instead of thiazole-5-carboxaldehyde.
  • Isovaleryl chloride (27 mg, 0.22 mmol) was added to a mixture of 127 (55 mg, 0.20 mmol) and DIE ⁇ A (52 mg, 0.40 mmol) in DMF (1.0 mL) at 0 0 C. The resulting mixture was stirred at room temperature for 15 min. The mixture was diluted with ethyl acetate (15 mL) and washed with 10% NaCO3 aqueous solution (1 mL). The organic layer was separated and concentrated. The crude product was purified by ISCO silica get column chromatography, eluting with CHCI3: MeOH (9:1), to gain 30 mg (42%) of colorless solid product.
  • Trans-N-[4-(5-ami ⁇ o-1 -methyl-1 W-pyrazol-4-yl)pyrimidin-2-yl]cyclohexane-1,4-diamine (107 trans) was prepared above as described in method I. 107 trans (35 mmol) and various isocyanatomethylbe ⁇ zene (1 eq, 0.35 mmol) were dissolved in 5 ml_ of DMF. The reaction was stirred at 75 0 C for 16 hours. The reaction mixture was filtrated and the crude materials were purified by HPLC to give the urea product with yield from 9- 60%. Table 11. Compounds 209-273 were prepared according to the method J as described above.
  • Methylsulfonylpyrimidine 4a (2.0 g, 6.0 mmol) was suspended in a mixed solvent 1,4-dioxane (8 mL) and isopropanol (3 m L).
  • Trans-1 4-diaminocyclohexane (1.6 g, 13.9 mmol) was added at room temperature.
  • the resulting suspension was heated at 130 0 C for 1.5 hours by microwave in a sealed tube.
  • the solution was cooled to room temperature, and the resulting suspension was filtrated to remove remaining diamine.
  • the solution thus obtained was extracted with EtOAc (100 mL x 2), dried over MgSO 4 and concentrated in vacuo.
  • the resulting crude residue was purified by column chromatography (0 - 15% methanol in CH 2 CI 2 ) to yield 1.9 g (81 %) of the title compound.
  • the above compound 281 was prepared according to the general procedure Method N-a as described above.
  • the above compound 288 was prepared according to the general procedure Method N-b.
  • N-(tra ⁇ s-4- ⁇ [4-(5-amino-1-methyl-1H-py ⁇ azol-4-yl)pyrimidin-2-yl]amino ⁇ cyclohexyl) metha ⁇ esulfonamide (296a) was prepared according to method N-b. To a solution of 296a ( 0.175 g, 0.48 mmol) in THF (10 mL) at O 0 C, NaH (0.019 g, 0.48 mmol, 60 % dispersion in oil) was added in one portion. The mixture was stirred at O 0 C for 10 minutes, and methyl iodide (0.05 mL, 0.72 mmol) was added dropwise.
  • the above compound 298 was prepared according to the general procedure Method N-c as described above.
  • the above compound 300 was prepared according to the general procedure Method N-d as described above.
  • N,1-dimethyl-4-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-pyrazol-5-amine (280b)(150mg, 0.56 mmol), 5-amino-2-methylpyridi ⁇ e (182mg, 1.68 mmol) and were dissolved in 5 ml_ of THF and cooled to 0 0 C. The reaction was then treated with NaH (67 mg, 1.68 mmol). The reaction was removed from ice bath and allowed to warm to r.t. The reaction was diluted with 2-methyl THF and washed with water (1 X 2OmL) & sat. NaCI(I X 2OmL).
  • N- ⁇ 1-methyl-4-[2-(methylsulfonyl)pyrimidin-4-yl]-1H-pyrazol-5-yl ⁇ acetamide (0.065 g crude, 0.22 mmol) and trans-4-aminocyclohexanol (0.075 g, 0.66 mmol) in 5 mL of isopropanol was heated in the automated Microwave Reactor for 1.5 h at 15O 0 C . The solution was concentrated under vacuum. The residue was purified by HPLC (20-100% CH 3 CN/H2O gradient) to yield 21 mg (27%) the title compound.
  • NAD+ through the action of of of pyruvate kinase (PK) and lactic dehydrogenase (LDH), was used to determine the potency (percent inhibition at 1 or 10 ⁇ M or K 1 ) of compounds against JNK1 ⁇ 1 (Genbank Accession Number: L26318).
  • PK pyruvate kinase
  • LDH lactic dehydrogenase
  • the final reaction conditions were as follows: 20 mM HEPES pH 7.6, 10 mM MgCI 2 , 1 mM DTT, 200 ⁇ M peptide substrate (KRELVEPLTPSGEAPNQALLR), 300 ⁇ M NADH, 500 ⁇ M PEP (phophoenolpyruvate), 9-10 units/mL LDH, 8-12 units/mL PK, 40 nM JNK1 ⁇ 1_364nHis (catalytic domain containing amino acids 1-364 and N-terminal hexahistidine tag, previously activated by MKK4 and MKK7beta in vitro), 0-100 ⁇ M test compound, 2.5% DMSO, and 50 ⁇ M ATP (2.5X Km).
  • the reaction was monitored by following the decrease in absorbance at 340 nm.
  • the initial reaction rate was determined by the slope of the change in absorbance.
  • percent inhibition the rate of the reaction in the presence of 1 or 10 ⁇ M compound was compared to the rate of the reaction with only DMSO multiplied by 100 percent.
  • the background rate of the above reaction in the presence of 10 ⁇ M PHA-00738186 was subtracted from all rates.
  • the reaction rates (with the background subtracted) were plotted vs. the compound concentration (0-100 ⁇ M) and fit to the tight binding for competitive inhibitors (Morrison) equation (see below).
  • Y is initial reaction velocity
  • X is inhibitor concentration
  • A is [ATP]
  • Ki inhibition constant
  • Vm is Vmax
  • Eo is total (initial) enzyme concentration
  • Km is ATP Km
  • the compounds were prepared in 100% DMSO at a 40X concentration. For percent inhibition experiments this would be 400 or 40 ⁇ M for 10 and 1 ⁇ M final concentration, respectively.
  • 3X serial dilutions were made starting at 4 mM (100 ⁇ M at 1X) in DMSO. A total of 11 concentrations were used for the analysis.
  • the compounds were added to the reaction plate first.
  • a solution containing the HEPES, MgCI 2 , DTT, peptide substrate, NADH, PEP 1 PK/LDH enzyme, and JNK1 ⁇ 1_364nHis enzyme was added to the assay plate. The plate was incubated at room temperature for 15 minutes. Then the plate was warmed to 30 0 C for 5 minutes. The reaction was initiated with the addition of ATP.
  • the reaction was run in a plate reader at 30 0 C for 20 minutes with absorbance readings made about every 10 seconds.
  • IPTG isopropylthiogalactoside
  • the cell pellet can be stored at -8O 0 C for future purification.
  • Cell pellet (1L culture) was resuspended with lysis buffer at 5-10mL/wet cell pellet. The maximum and minimum volumes were 350 mL and 60 mL.
  • the lysis buffer was filtered before use.
  • the cell were lyzed with microfluidizer (three times) and ultracentrifuged at 40,000rpm for 45 minutes at 4 0 C. The supernatant was transferred to a chilled flask. A 2OuI aliquot was saved for gel analysis.
  • Ni-NTA column (23m L) lines were rinsed with lysis buffer.
  • the column (23m L) was washed with 16OmL of lysis buffer at 5mL/min.
  • the protein was eluted with imidazole gradient (from 2OmM to 0.5M).
  • the elution buffer was prepared as follows:
  • the elution buffer was filtered before use
  • the elution settings were as follows.
  • the record speed was set @1.0 mm/min.
  • BP break point
  • %B means % buffer grading
  • FR means flow rate
  • FS fraction size
  • Superdex buffer at 2 mL/min.
  • the Superdex buffer was prepared as follows: Superdex buffer IL
  • Dundee buffer was used for Superdex column.
  • the Dundee buffer was prepared as follows:
  • the concentrated sample was transferred to pre-chilled 1.5mL tubes and spinned at max for 10 minutes in cold room. The supernatant was transferred to 5OmL chilled tube.
  • the sample was injected (total volume equals total sample loop volume plus 0.3mL) to pre- washed loop (4-6mL). A 5ul aliquat was saved of the remaining sample for SDS-PAGE (a detergent).
  • the protein was eluted overnight according to the following settings.
  • the record speed was set at 0.2 mm/min.
  • BP break point
  • FR flow rate
  • FS fraction size
  • I inject
  • L load
  • the peak fractions were pooled and the pool concentration was measured.
  • the protein was concentrated down to 7-8mg/mL in hepes buffer protein. Aliquots of the protein were placed into chilled 0.5m L tubes at 100ul/tube, which were then snapped frozen in liquid nitrogen and stored at
  • Ni-NTA column was washed with 8OmL of dH 2 O at 5mL/min. Next it was washed with 8OmL of 0.1 M
  • the Superdex 200 column was washed with 70OmL of filtered dH 2 O at 2 mL/mi ⁇ .
  • the data obtained from the compounds of the invention according to the above protocol are tabulated below.
  • the column with "#” heading refers to compound number as exemplified in the E ⁇ xamples section.
  • the column with "Ki” heading refers to Ki (in nM).
  • the column with "% Inhibition” heading refers to percent inhibition at 1 ⁇ M (in %).

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Abstract

The present invention relates to compounds with the formula (I), or a pharmaceutically acceptable salt thereof, wherein: -Z- is -C- or -N-; and R<SUP>1</SUP>, R<SUP>2</SUP>, R<SUP>3</SUP>, R<SUP>4</SUP> and R<SUP>7</SUP> are as defined in the specification. The invention also relates to pharmaceutical compositions comprising the compounds of formula (I) and methods of treating a condition that is mediated by the modulation of JNK, the method comprising administering to a mammal an effective amount of a compound of formula (I).

Description

4-PYRIMIDINE-S-AMINO-PYRAZOLE COMPOUNDS
Field of the Invention
The present invention relates to novel substituted 4-pyrirτiidine-5-amino-pyrazole compounds of Formula (I), to pharmaceutical compositions comprising the compounds, as well as to the use of the compounds in the preparation of a medicament for use in the treatment or prevention of a disease or medical condition mediated through c-Jun N-terminal kinases (JNKs), leading to a decreased glucose threshold for insulin secretion. In addition the compounds are predicted to lower blood glucose by increasing hepatic glucose uptake. Such compounds may have utility in the treatment of Type 2 diabetes and obesity.
Background of the Invention
Mammalian cells respond to extracellular stimuli by activating signaling cascades that are mediated by members of the mitogen-activated protein (MAP) kinase family, which include the c-Jun N- terminal kinases (JNKs), also known as stress activated protein kinase (SAPK). Three distinct genes, JNK1, JNK2, JNK3 have been identified and at least ten different splicing isoforms of JNKs exist in mammalian cells [Gupta et al., EMBO J., 15:2760-70 (1996)]. While JNK1 and JNK2 express in many tissues, JNK3 specifically expresses in the brain. Thus, JNK3 has a potential to be particularly involved in nervous function. The JNK signal transduction system of stress response MAP kinase family system is activated by changes in osmotic pressure, DNA damage, anisomycine, heat shock, ultraviolet radiation, ischemia, inflammatory cytokines and the like and various stress stimulations relating to apoptosis induction, it is considered to constitute a major intracellular information transduction path responsible for stress response (Biochemica et Biophysica Acta, vol. 1333, pp. F85-F104 (1997)). From an experiment using a JNK1 deletion mouse, JNK is reported to be an important mediator involved in obesity and insulin resistance (Nature, vol. 420, pp. 333-336 (2002)). Pyrazole compounds including those described in WO03/049542 have been known in the preparation of a medicament for use in the treatment or prevention of a disease or medical condition mediated through c-Jun N-terminal kinases (JNKs).
Summary of the Invention
The present invention relates to a compound of formula (I):
Figure imgf000002_0001
or a pharmaceutically acceptable salt thereof, wherein:
-Z- is -C- or -N-;
R1 is H or halo;
R2 is H, CF3, -CHF2, -CH2F1 trifluoromethoxy, (C1-C6JaIkOXy, (Ci-C6)amino(CR5R8)vr (d-CβJalkyl, -(CR5R6)v(3-10)-membered cycloalkyl, -(CR5R6)v(C6-C10)aryi, or
-(CR5Rβ)v(4-12)-membered heterocyclyl; R3 is H, (CrC8)alkyl, CF3, -CHF2, -CH2F, trifluoromethoxy, (CrC6)alkoxy,
(CrCeJaminoCC^R6^, -(C=O)-O-R5, -(C=O)-NR5R6, -S(O)15NR5R6,
-S(O)j(Ci-C6)alkyl, -(CR5R6)v(3-10)-membered cycloalkyl, -(CR5R6)v(Cβ-C1oaryl)>
-(CR5R6)v(4-12)-membereci heterocyclyl, -(CR5R6)q(C=O)(CrCβ)alkyl, -(CR5R6)q(C=O)(CR5R8)v(3-10)- membered cycloalkyl, -(CR5R6)q(C=0)(CR5Rβ)v(C6-Cio)aryl, -(CR5R6)q(C=O)(CR5R6)v(4-12)-membered heterocyclyl, -(CR5R6)qS(O>J(C1-C6)alkyl, -(CR5R6)qS(O)j(CR5Rβ)v(C6-C10)aryl, or -(CR5R6)qS(O)i(CR5R6)v(4- 12)-membered heterocyclyl;
Or optionally, R2 together with the -N- to which R3 and R7 are attached to form a ring A, which is a (5-8)-membered heterocyclyl;
Provided that when R2 together with the -N- to which R3 and R7 are attached to said ring A (5-8)- membered heterocyclyl, R7 is a bond, and R3 may be absent;
Or optionally, R3 together with R7 and the -C- to which R3 and R7 are attached to form a ring B, which is a (3-8)-membered heterocyclyl;
R4 is (d-CβJalkyl, -(CR5R6)v(3-10)-membered cycloalkyl, -(CR5R6MC6-C1,)^, or -(CR5R6)v(4- 12)-membered heterocyclyl; each of R5 and R6 are independently selected from H, (CrC6)alkyl, -(CR8R9)p(3-10)-membered cycloalkyl, -(CR8R9)p(C6-C10)aryl, and -(CR8R9)p(4-12)-membered heterocyclyl;
R7 is H or (C,-C6)alkyl; any carbon atoms of said ring A, ring B, and the (CrC6)alkyl, the (3-10)-membered cycloalkyl, the (C6-Cio)aryl and the (4-12)-membered heterocyclyl moieties of the foregoing R1, R2, R3, R4, R5, and R6 are optionally substituted with 1 to 3 R10 substituents each independently selected from halo, cyano, -CF3, -CHF2, -CH2F, trifluoromethoxy, hydroxy, (C1-C6JaIkOXy,
(CpCfOalkyl, R9a, -(CR8R9)q-(C=O)-R8, -(CR8R9)q-(C=O)-R9a,
-(CR8R9)q-(C=O)-O-(Ci-C6)alkyl, -(CR8R9)q-(C=O)-O-R9a, -0-(C=O)-R8, -0-(C=0)-R9a,
-NR8-(CR8R9)q(C=O)-R9, -NR8-(CR8R9)q(C=O)R9a, -NR8-(CR8R9)q(C=O)-O(C1-Cβ)alkyl,
-NR8-(CR8R9)q(C=O)-OR9, -NR8-(C=O)NR8R9, -NR8-(C=O)NR8R9a, -NR8-(C=O)-(C=O)-NR8R9, -NR8- (C=O)-(C=O)-NR8R98, -NR8-(CR8R9)q(C=O)OR9a,
-(C=O)-NR8R9, -(C=O)NR8R93, -NR8R9, -NR8R9a, -NR8OR9, -NR8OR9a, -S(O)15NR8R9, -S(O)15 NR l88RR99aa,
Figure imgf000003_0001
-S(O)jR9a,
Figure imgf000003_0002
a nnn^d
Figure imgf000003_0003
wherein any carbon atoms of each of the foregoing R10 (Ci-C6)alkyl, (3-10)-membered cycloalkyl,
Figure imgf000003_0004
or (4-12)-membered heterocyclyl moieties are optionally substituted with 1 to 3 R11 substituents each independently selected from halo, cyano, -CF3, -CHF2, -CH2F, -0-CF3, -0-CHF2, -0-CH2F, hydroxy, (CrCβJalkoxy, (CrCβJalkyl, R14, -0-R14, -(C=O)-R8, -(C=O)-R14, -(C=O)-O-(CrC6)alkyl, -(C=O)-O-R14, -0-(C=O)-R8, -O- (C=O)-R14, -NR8(C=O)-R9, -NR8(C=O)-R14, -(C=O)-NR8R9, -(C=O)-NR8R14, -NR8R9, -NR8R14, -NR8OR9, - NR8OR14, -S(O)15NR8R9, -S(O)15NR8R14, ^(O^d-CsJalkyl,
-S(O)jR14, NR8-S(O)k(C1-C6)alkyl, NR14-S(O)k(C1-C6)alkyl, and -NR8-S(O)kR14; any nitrogen atoms of said ring A, ring B, and the (4-12)-membered heterocyclyl moieties of the foregoing R1, R2, R3, R4, R5, R6, R9a, R10, R11 and R14 are optionally substituted with R12 substituents each independently selected from (CrC6)alkyl,
-(C=O)-R8, -(C=O)-R 14a 8D9 38D14a rVi4β
-(C=O)-O-(Ci-C6)alkyl. -(C=0)-NR"Ra, -(C=O)-NR0R
?14a.
-(CR8R3)q(C=0)R14a, and -(CRBRs)qS(O)jR wherein any carbon atoms of each of the foregoing R11 and R12 (Ci-C6)alkyl, (3-10)-membered cycloalkyl, (C6-C10aryl), or (4-12)-membered heterocyclyl moieties are optionally substituted with 1 to 3 R13 substituents each independently selected from halo, cyano, -CF3, -CHF2, -CH2F, trifluoromethoxy, hydroxy, (Ci-C6)alkoxy, (CrC6)alkyl, -(CR8R9)p(3-10)-membered cycloalkyl, -(CR8R9)p(C8-Ci0aryl), -(CR8R9)p(4-12)-membered heterocyclyl, -(C=O)-R8, -(C=O)-O-(Cr C6)alkyl, -0-(C=O)-R8, -NR8(C=O)-R9, -(C=O)-NR8R9,
-(C=O)-NR8R14, -NR8R9, -NR8OR9, -S(O)kNR8R9, -StO^CrCsJalkyl, and -NR8S(O)k(C1-C6)alkyl; each R8 and R9 are independently H or (CrC6)alkyl; each R", R14, and R14a are independently -(CR8R9)v(3-10)-membered cycloalkyl, -(CR8R9)v(C6-C10)aryl, or -(CR8R9)v(4-12)-membered heterocyclyl; p, q, and v are each independently 0, 1, 2, 3, 4, or 5; n and j are each independently O1 1 , or 2; w is 0, 1 , 2, or 3, and k is 1 or 2.
In another embodiment, the invention relates to compounds of the formula (I) selected from the group consisting of:
Figure imgf000004_0001
or a pharmaceutically acceptable salt thereof, wherein: -Z-; Ring A, Ring B, R1, R2, R3, R4 and R7 are as defined above.
In another embodiment, the invention relates to compounds of the formula (Ia):
Figure imgf000004_0002
or a pharmaceutically acceptable salt thereof, wherein: R1 is H or halo; R2 is H1 CF3, -CHF2, -CH2F, trifluoromethoxy, (CrC6)alkoxy, (C1-C8)amino(CR5R6)Vi
(CrCβ)alkyl, -(CR5R6)v(3-10)-membered cycloalkyl, -(CR5R6)v(Cβ-C10)aryl, or
-(CR5R6)v(4-12)-membered heterocyclyl;
R3 is H1 (CrC6)alkyl, CF3, -CHF2, -CH2F, trifluoromethoxy, (C1-C6JaIkOXy, (C1-Cβ)amlno(CR6Rβy,i -(C=O)-O-R5, -(C=O)-NR5R6, -S(OXNR5R8,
-S(O)j(d-C6)alkyl, -(CR5R8)v(3-10)-membered cycloalkyl, -(CR5R8)v(C6-Cioaryl),
-(CR5R8)v(4-12)-membered heterocyclyl, -(CR5R8)q(C=O)(C1-C6)alkyl, -(CR5R6Jq(C=O)(CR5R6US-IO)- membered cycloalkyl, -(CR5R6)q(C=0)(CR5R6)v(Cff-C1o)aryl, -(CR5R6)q(C=O)(CR5R6)v(4-12)-membered heterocyclyl, -(CR5R6)qS(O)i(C1-C6)alkylI -(CR5R6)qS(0)j(CR5R8)v(C6-C1o)aryl, or -(CR5R8)qS(O)j(CRsR6)v(4- 12)-membered heterocyclyl;
R4 is (CrCβ)alkyl, -(CR5Rβ)v(3-10)-membered cycloalkyl, -(CR5R8)V(C6-C1o)aryl, or -(CR5R6)V(4- 12)-membered heterocyclyl; each of R5 and R8 are independently selected from H, (C1-C6JaIkYl, -(CR8R9)p(3-10)-membered cycloalkyl, -(CR8R9)p(C6-C10)aryl, and -(CR8R9)p(4-12)-membered heterocyclyl;
R7 is H or (d-C6)alkyl; any carbon atoms of the (Ci-Ce)alkyl, the (3-10)-membered cycloalkyl, the (C6-Ci0)aryl and the (4- 12)-membered heterocyclyl moieties of the foregoing R1, R2, R3, R4, R5, and R8 are optionally substituted with 1 to 3 R10 substituents each independently selected from halo, cyano, -CF3, -CHF2, -CH2F, trifluoromethoxy, hydroxy, (d-C6)alkoxy,
(d-C6)alkyl, R9a, -(CR8R9)q-(C=O)-R8, -(CR8R9)q-(C=O)-R9a,
-(CR8R9)q-(C=O)-O-(CrC6)alkyl, -(CR8R9)q-(C=O)-O-R9a, -0-(C=O)-R8, -0-(C=O)-R99,
-NR8-(CR8R9)q(C=O)-R9, -NR8-(CR8R9)q(C=O)R", -NR8-(CR8R9)q(C=O)-O(CrC6)alkyl,
-NR8-(CR8R9)q(C=O)-OR9, -NR8-(C=O)NR8R9, -NR8-(C=O)NR8R9a, -NR8-(C=O)-(C=O)-NR8R9, -NR8- (C=O)-(C=O)-NR8R93, -NR8-(CR8R9)q(C=O)OR9a,
-(C=O)-NR8R9, -(C=O)NR8R98, -NR8R9, -NR8R9a, -NR8OR9, -NR8OR9a, -S(OJkNR8R9, -S(0)k NR8R9a, -SfO^d-CfOalkyl, -S(O)1R99,
-NR8-S(O)k(CrC6)alkyl, -NR8-S(O)kR9a, -NR^S(O)15NR93, and -(CR8R9)qS(O)jR9a; wherein any carbon atoms of each of the foregoing R10 (d-C6)alkyl, (3-10)-membered cycloalkyl, (Cβ-C10aryl), or (4-12)-membered heterocyclyl moieties are optionally substituted with 1 to 3 R11 substituents each independently selected from halo, cyano, -CF3, -CHF2, -CH2F, -0-CF3, -0-CHF2. -0-CH2F, hydroxy, (C1-C6)BIkOXy, (CrC6)alkyl, R14, -0-R14, -(C=O)-R8, -(C=O)-R14, -(C=O)-O-(CrC6)alkyl, -(C=O)-O-R14, -0-(C=O)-R8, -O- (C=O)-R14, -NR8(C=O)-R9, -NR8(C=O)-R14, -(C=O)-NR8R9, -(C=O)-NR8R14, -NR8R9, -NR8R14, -NR8OR9, - NR8OR14, -S(O)kNR8R9, -S(O)15NR8R14, -SP^d-C^alkyl,
-S(OJjR14, NR8-S(O)k(CrC6)alkyl, NR^-SfOMd-CeOalkyl, and -NR8-S(O)kR14; any nitrogen atoms of the (4-12)-membered heterocyclyl moieties of the foregoing R1, R2, R3, R4, R 5 p^ R 9a R io R ii and R i4 are optjona||y substituted with R12 substituents each independently selected from (d-CeJalkyl, -(C=O)-R8, -(C=O)-R143, -(C=O)-O-(d-C6)alkyl,
-(C=O)-NR8R9, -(C=O)-NR8R143, R14a, -(CR8R9)q(C=O)R14a, and -(CR8R9)qS(O)jR14a; wherein any carbon atoms of each of the foregoing R11 and R12 (Ci-Cβ)alkyl,
(3-10)-membered cycloalkyl, (C6-C10aryl), or (4-12)-membered heterocyclyl moieties are optionally substituted with 1 to 3 R13 substituents each independently selected from halo, cyano, -CF3, -CHF2, -CH2F, trifluoromethoxy, hydroxy, (Ci-C6)alkoxy, (Ci-C6)alkyl, -(CR8R9)p(3-10)-membered cycloalkyl, -(CR8R9)p(C6-Ci0aryl), -(CR8R9)p(4-12)-membered heterocyclyl, -(C=O)-R8, -(C=O)-O-(C1- C6)alkyl, -0-(C=O)-R8, -NR8(C=O)-R9, -(C=O)-NR8R9,
-(C=O)-NR8R14, -NR8R9, -NR8OR9, -S(O)kNR8R9, -S(OMCrCβ)alkyl, and -NR8-S(O)k(C1-CB)alkyl; each R8 and R9 are independently H or (Ci-C6)alkyl; each R98, R14, and R14a are independently -(CR8R9)«(3-10)-membered cycloalkyl, -(CR8R9)y(Cβ-Cio)aryl, or -(CR8R9)v(4-12)-membered heterocyclyl; p, q, and v are each independently 0, 1, 2, 3, 4, or 5; n and j are each independently 0, 1, or 2; w is O, 1 , 2, or 3.
In another embodiment, the invention relates to compounds of the formula (Ia), wherein R4 is unsubstituted (Ci-C6)alkyl, such as isopropyl.
In another embodiment, the invention relates to compounds of the formula (Ia), wherein R4 is (Ci-Cβ)alkyl, such as methyl, ethyl, or butyl, substituted with 1 to 3 R10 substituents each independently selected from halo, cyano, -CF3, -CHF2, -CH2F1 trifluoromethoxy, hydroxy, (d-Cβialkoxy, (CrC6)alkyl, R9a, -(CR8RV(C=O)-R8, -(CR8R9)q-(C=O)-R9a,
-(CR8R9)q-(C=O)-O-(C1-C6)alkyl, -(CR8R9)q-(C=O)-O-R9a, -0-(C=O)-R8, -0-(C=O)-R99,
-NR8-(CR8R9)q(C=O)-R9, -NR8-(CR8R9)q(C=O)R9a, -NR8-(CR8R9)q(C=O)-O(CrC6)alkyl,
-NR8-(CR8R9)q(C=O)-OR9, -NR8-(C=O)NR9, -NR8-(C=O)NR9a, -NR8-(CR8R9)q(C=O)OR9a,
-(C=O)-NR8R9, -(C=O)NR8R93, -NR8R9, -NR8R98, -NR8OR9, -NR8OR9a, -S(OXNR8R9, -S(O)k NR8R98, -SfOMCVCβJalkyl, -S(O)jR9a,
-NR8-S(O)k(Ci-C6)alkyl, -NR8-S(O)kR9a, -NR^S(O)11NR99, and -(CR8R9)qS(O)jR9a.
In another sub-embodiment, R10 is independently selected from (Ci-C6)alkoxy, R9a, -NR8-(CR8R9)q(C=O)-O(CrC6)alkyl, -NR8-(CR8R9)q(C=O)-OR9, -NR8-(CR8R9)q(C=O)OR9a, -NR8R9a, -NR8-S(O)k(CrC6)alkyl, -NR8-S(O)kR9a, and -(CR8R9)qS(O)jR9a.
Within the foregoing embodiment and sub-embodiment, any carbon atoms of each of the foregoing R10 (d-CeJalkyl, (3-10)-membered cycloalkyl, (Cβ-C10aryl), or (4-12)-membered heterocyclyl moieties are optionally substituted with 1 to 3 R11 substituents each independently selected from halo, cyano, -CF3, -CHF2, -CH2F, -0-CF3, -0-CHF2, -0-CH2F, hydroxy,
(CrCβ)alkoxy, (d-CβJalkyl, R14, -0-R14, -(C=O)-R8, -(C=O)-R14, -(C=0)-0-(Ci-C6)alkyl, -(C=O)-O-R14, -O- (C=O)-R8, -0-(C=O)-R14, -NR8(C=O)-R9, -NR8(C=O)-R14, -(C=O)-NR8R9, -(C=O)-NR8R14, -NR8R9, -NR8R14, -NR8OR9, -NR8OR14, -S(O)kNR8R9, -S(O^NR8R14, -S(O)j(C1-C6)alkyl, -S(O)jR14,
Figure imgf000006_0001
and -NR8-S(O)kR14.
In another sub-embodiment, R11 is C1-C6JaIkOXy. In another embodiment, the invention relates to compounds of the formula (Ia), wherein R4 is unsubstituted -(CR5R6)v(3-10)-membered cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, -(CH3CH)-cyclohexyl, -(CH2)-cyclohexyl, cyclohexyl, or indanyl, preferably cyclohexyl.
In another embodiment, the invention relates to compounds of the formula (Ia), wherein R4 is -(CR5R6)v(3-10)-membered cycloalkyl substituted with 1 to 3 R10 substituents each independently selected from halo, cyano, -CF3, -CHF2, -CH2F, trifluoromethoxy, hydroxy,
(CrCfOalkoxy, (CrC6)alkyl, R99, -(CR8R9)q-(C=O)-R8, -(CR8R9)q-(C=O)-R9a,
-(CR8R9)q-(C=O)-O-(CrCβ)alkyl, -(CR8R9)q-(C=O)-O-R9a, -0-(C=O)-R8, -0-(C=0)-R9a,
-NR8-(CR8R9)q(C=O)-R9, -NR8-(CR8R9)q(C=O)R9a, -NR8-(CR8R9)q(C=O)-O(C1-C6)alkyl,
-NR8-(CR8R9)q(C=O)-OR9, -NR8-(C=O)NR9, -NR8-(C=O)NR9a, -NR8-(CR8R9)q(C=O)OR9a,
-(C=O)-NR8R9, -(C=O)NR8R98, -NR8R9, -NR8R9a, -NR8OR9, -NR8OR98, -S(O)11NR8R9, -S(O)k NR8R98, -Sp^d-CeJalkyl, -S(O)jR9a,
-NR8-S(O)k(CrC6)alkyl, -NR8-S(O)kR9a, -NR^S(O)1JMR98, and -(CR8R9)qS(O)jR9a.
In another sub-embodiment R10 is hydroxy, (CrC6)alkyl, R98, -NR8-(CR8R9)q(C=O)-R9, -NR8- (CR8R9Jq(C=O)R98, - -NR8-(C=O)NR9a, -NR8R9, -NR8R9a, -NR8-S(O)k(C1-C6)alkyl> and -NR8-S(O)κR98.
Within the foregoing embodiment and sub-embodiment, any carbon atoms of each of the foregoing R10 (d-C6)alkyl, (3-10)-membered cycloalkyl, (C6-Cioaryl), or (4-12)-membered heterocyclyl moieties are optionally substituted with 1 to 3 R11 substituents each independently selected from halo, cyano, -CF3, -0-CF3, -0-CHF2, hydroxy, (CrC6)alkoxy,
(CrC6)alkyl, R14, and -(C=O)-R8.
In another embodiment, the invention relates to compounds of the formula (Ia), wherein R4 is unsubstituted -(CR5R8)v(C6-C1o)aryl, such as phenyl, naphthyl, -(CH2CH2)-phenyl, or -(CH2)-phenyl.
In another embodiment, the invention relates to compounds of the formula (Ia), wherein R4 is -(CR5R6)v(C6-C10)aryl substituted with 1 to 3 R10 substituents each independently selected from halo, cyano, -CF3, -CHF2, -CH2F, trifluoromethoxy, hydroxy, (Ci-C6)alkoxy,
(d-CeJalkyl, R98, -(CR8R9)q-(C=O)-R8, -(CR8R9)q-(C=O)-R9a,
-(CR8R9)q-(C=O)-O-(C1-C6)alkylI -(CR8R9)q-(C=O)-O-R9a, -0-(C=O)-R8, -0-(C=O)-R98,
-NR8-(CR8R9)q(C=O)-R9, -NR8^CR8R9Jq(C=O)R98, -NR8-(CR8R9)q(C=O)-O(CrC6)alkyl,
-NR8-(CR8R9)q(C=O)-OR9, -NR8-(C=O)NR9, -NR8-(C=O)NR9a, -NR8-(CR8R9)q(C=O)OR9a,
-(C=O)-NR8R9, -(C=O)NR8R98, -NR8R9, -NR8R9a, -NR8OR9, -NR8OR98, -S(OJkNR8R9, -S(O)k NR8R98, -S(O)j(CrC6)alkyl, -S(O)JR98,
-NR8-S(O)k(Ci-C6)alkyl, -NR8-S(O)kR9a, -NR^S(O)1JMR98, and -(CR8R9)qS(O)jR9a.
In another sub-embodiment, R10 is halo, -CF3, hydroxy, (Ci-CβJalkoxy, (Ci-C6)alkyl, or R9a.
Within the foregoing embodiment and sub-embodiment, any carbon atoms of each of the foregoing R10 (CrC6)alkyl, (3-10)-membered cycloalkyl, (C6-Ci0aryl), or (4-12)-membered heterocyclyl moieties are optionally substituted with 1 to 3 R11 substituents each independently selected from R14, and -NR8R9.
In another embodiment, the invention relates to compounds of the formula (Ia), wherein R4 is unsubstituted -(CR5R8)«(4-12)-membered heterocyclyl, such as dihydrobenzopyranyl, -(CH2)-imidazo[12-a]pyrimidinyl, -(CH2)-moφholiπonyl, -(CH2CH2)-moφholinyl, -(CH2C(CH3)2)-moφholinyl
-(CH2)-oxa-azaspiro[4.5]decyl, piperidinyl, pyridinyl, -(CH2)-pyridinyl, pyrazolidinyl,
-(CH3CHCH2)-pyrazolyl, pyrroiidinonyl,: -(CH2C(CH3)2)-pyrrolidiπyl, -(CH2CH2CH2)-piperazinyl, quiπolinyl, - (CH2)-quinolinyl, sulfonylcyclopentyl, -(CH2CH2CH2)-triazolyl, tetrahydropyranyl, tetrahydrofuranyl, -(CH2)- tetrahydropyranyl, -(CH2CH2)-tetrahydropyranylI or -(CH2)-tetrahydroisoquinolinyl.
In another embodiment, the invention relates to compounds of the formula (Ia), wherein R4 is -(CR5R8)v(4-12)-membered heterocyclyl substituted on any carbon atoms with 1 to 3 R10 substituents each independently selected from halo, cyano, -CF3, -CHF2, -CH2F, trifluoromethoxy, hydroxy, (C1-CeJaIkOXy, (CrC6)alkyl, R9a, -(CR8R9)q-(C=O)-R8, -(CR8R9)q-(C=O)-R9a,
-(CR8R9)q-(C=O)-O-(C1-C8)alkylI -(CR8R9)q-(C=O)-O-R9a, -0-(C=O)-R8, -0-(C=O)-R93,
-NR8-(CR8R9)q(C=O)-R9,
Figure imgf000008_0001
-NR8-(CR8R9)c(C=O)-O(Ci-C6)alkvl,
-NR8-(CR8R9)q(C=O)-OR9, -NR8-(C=O)NR9, -NR8-(C=O)NR9a, -NR8-(CR8R9)q(C=O)OR9a,
-(C=O)-NR8R9, -(C=O)NR8R98, -NR8R9, -NR8R9a, -NR8OR9, -NR8OR9a, -S(OXNR8R9,
-S(O)15 NR -,8BrR,9saa, -SfOtød-COalkyl, -S(O)1R"8,
-NR8-S(O)k(CrC6)alkyl, -NR8-S(O)kR9a, -NR8-S(O)kNR", and -(CR8R9)qS(O)jR9β.
In another sub-embodiment, R10 is halo, cyano, -CFa, hydroxy, (C1-C6JaIkOXy1 (GpCβJalkyl, R9a, or -(C=O)NR8R98.
Within the foregoing embodiment and sub-embodiment, any carbon atoms of each of the foregoing R10 (Ci-C6)alkyl, (3-10)-membered cycloalkyl, (Cβ-CiOaryl), or (4-12)-membered heterocyclyl moieties are optionally substituted with 1 to 3 R11 substituents each independently selected from hydroxy, C1-CfOaIkOXy, and (CrCβ)alkyl.
In another embodiment, the invention relates to compounds of the formula (Ia), wherein R4 is -(CR5R6)v(4-12)-membered heterocyclyl substituted on any nitrogen atoms with 1 to 3 R12 substituents each independently selected from (d-CβJalkyl, -(C=O)-R8, -(C=O)-R148, -(C=O)-O-(CrC6)alkyl, -(C=O)- NR8R9, -(C=O)-NR8R148, R14a, -(CR8R9)q(C=O)R14β, and -(CR8R9)qS(O)jR14β.
In another sub-embodiment, R12 is (C1-C6)alkyl,
-(C=O)-R8, -(C=O)-O-(CrC6)alkyl, -(C=O)-NR8R9, -(CR8R9)p(C6-C10aryl), -(CR8R9)p(4-12)-membered heterocyclyl, -(CR8R9)qS(O)j(C1-C6)alkylJ -(CR8R9)qS(O)J(CR8R9)p(C6-C10)gryl, and
-(CR8R9)qS(O)j(CR8R9)p(4-12)-membered heterocyclyl.
Within the foregoing embodiment and sub-embodiment, any carbon atoms of each of the foregoing R12 (3-10)-membered cycloalkyl, (C6-C10aryl), or (4-12)-membered heterocyclyl moieties are optionally substituted with 1 to 3 R13 substituents each independently selected from halo, cyano, -CF3, -CHF2, -CH2F, trifluoromethoxy, hydroxy, (C1-C6JaIkOXy,
(d-CβJalkyl, -(CR8R9)p(3-10)-membered cycloalkyl, -(CR8R9)p(C6-C10aryl), -(CR8R9)p(4-12)-membered heterocyclyl, -(C=O)-R8, -(C=O)-O-(CrC6)alkyl, -0-(C=O)-R8, -NR8(C=O)-R9, -(C=O)-NR8R9, -NR8R9, - NR8OR9, -S(O)kNR8R9, -SfO^d-CtOalkyl, and -NR8-S(O)k(C1-C6)alkyl.
In another sub-embodiment, R13 is cyano, (C1-C6)BIkOXy, (d-CβJalkyl, or -(CR8R9)p(C6-C10aryl).
In another embodiment, the invention relates to compounds of the formula (Ib):
Figure imgf000009_0001
wherein ring A is a (5-8)-membered heterocyclyi;
-Z- is -C- or -N-;
R1 is H or halo,
R3 is H, (d-CβJalkyl, CF3, -CHF2, -CH2F, trifluoromethoxy, (C1-C6JaIkOXy, (C1-C6)SmInO(CR5R6),, -(C=O)-O-R5, -(C=O)-NR5R6, -S(OkNR5R6,
Figure imgf000009_0002
-(CR5R8)v(3-10)-membered cycloalkyl, -(CR5R6)v(C6-C10aryl),
-(CR5R8)v(4-12)-membered heterocyclyi, -(CR5R6)q(C=O)(CrC6)alkyl, -(CR5R6)q(C=O)(CR5R6)v(3-10)- membered cycloalkyl, -(CRsR6)q(C=0)(CRsR8)v(C6-C1o)aryl, -(CR5R8)q(C=O)(CR5R6)v(4-12)-membered heterocyclyi, -(CR5R6)qS(O),(C1-C6)alkyl, -(CR5R6)qS(0)j(CR5RB)v(C6-C1o)arylI or -(CR5R6)qS(O)i(CR5R6)v(4- 12)-membered heterocyclyi;
Or R3 may be absent;
R4 is (CrC6)alkyl, -(CR5Rβ)v(3-10)-membered cycloalkyl, -(CR5R6)V(C6-C1o)aryl, or -(CR5R6)V(4- 12)-membered heterocyclyi; each of R5 and R6 are independently selected from H, (CrC6)alkyl, -(CR8R9)p(3-10)-membered cycloalkyl, -(CRBR9)p(C6-C10)aryl, and -(CR8R9)p(4-12)-membered heterocyclyi; any carbon atoms of said ring A and the (Ci-C6)alkyl, the (3-10)-membered cycloalkyl, the (C6- Cio)aryl and the (4-12)-membered heterocyclyi moieties of the foregoing R1, R3, R4, R5, and R8 are optionally substituted with 1 to 3 R10 substituents each independently selected from halo, cyano, -CF3, -CHF2, -CH2F, trifluoromethoxy, hydroxy, (C1-C6JaIkOXy,
(CrC6)alkyl, R9a, -(CR8R9)q-(C=O)-R8, -(CR8R9)q-(C=O)-R9a,
-(CR8R9)q-(C=O)-O-(C1-Cβ)alkyl, -(CR8R9)q-(C=O)-O-R9a, -0-(C=O)-R8, -0-(C=0)-R9a,
-NR8-(CR8R9)q(C=O)-R9,
Figure imgf000009_0003
-NR8-(CR8R9)q(C=O)-O(C1-C6)alkyl,
-NR8-(CR8R9)q(C=O)-OR9, -NR8-(C=O)NR8R9, -NR8-(C=O)NR8R9a, -NR8-(C=O)-(C=O)-NR8R9, -NR8- (C=O)-(C=O)-NR8R98, -NR8-(CR8R9)q(C=O)OR9a,
-(C=O)-NR8R9, -(C=O)NR8R98, -NR8R9, -NR8R9a, -NR8OR9, -NR8OR9a, -S(O)11NR8R9, -S(0)k NR8R9a,
Figure imgf000009_0004
-S(O)jR9a,
-NR8-S(O)k(CrCs)alkyl, -NR8-S(O)kR9a, -NR^S(O)1JMR98, and -(CR8R9)qS(O)jR9a; wherein any carbon atoms of each of the foregoing R10 (CrC^alkyl, (3-10)-membered cycloalkyl, (C6-C10aryl), or (4-12)-membered heterocyclyi moieties are optionally substituted with 1 to 3 R11 substituents each independently selected from halo, cyano, -CF3, -CHF2, -CH2F, -0-CF3, -0-CHF2, -0-CH2F, hydroxy, (C1-C6JaIkOXy, (CrCeOalkyl, R14, -0-R14, -(C=O)-R8, -(C=O)-R14, -(C=O)-O-(CrC6)alkyl, -(C=O)-O-R14, -0-(C=O)-R8, -O- (C=O)-R14, -NR8(C=O)-R9, -NR8(C=O)-R14, -(C=O)-NR8R9, -(C=O)-NR8R14, -NR8R9, -NR8R14, -NR8OR9, - NR8OR14, -S(O)kNR8R9, -S(O)kNR8R14,
Figure imgf000010_0001
-S(0)jR14, NR8-S(O)k(CrC6)alkyl, NR14-S(O)k(Ci-Cβ)alkyl) and -NR8-S(O)kR14; any nitrogen atoms of said ring A and the (4-12)-membered heterocyclyl moieties of the foregoing R1, R3, R4, R5, R6, R98, R10, R11 and R14 are optionally substituted with R12 substituents each independently selected from (d-CeJalkyl, -(C=O)-R8, -(C=O)-R148, -(C=0)-0-(CrC6)alkyl, -(C=O)-NR8R9, -(C=O)-NR8R149, R14a, -(CR8R9)q(C=O)R14a, and -(CR8R9)qS(O)jR14β; wherein any carbon atoms of each of the foregoing R11 and R12 (Ci-Cβ)alkyl, (3-10)-rnembered cycloalkyl, (Cβ-Cioaryl), or (4-12)~membered heterocyclyl moieties are optionally substituted with 1 to 3 R13 substituents each independently selected from halo, cyano, -CF3, -CHF2, -CH2F, trifluoromethoxy, hydroxy, (CrC6)alkoxy, (CrC6)alkyl, -(CR8R9)p(3-10)-membered cycloalkyl, -(CR8R9)P(C6-C1oaryl), -(CR8R9)p(4-12)-membered heterocyclyl, -(C=O)-R8, -(C=O)-O-(C1- C6)alkyl, -0-(C=O)-R8, -NR8(C=O)-R9, -(C=O)-NR8R9,
-(C=O)-NR8R14, -NR8R9, -NR8OR9, -S(O)kNR8R9, -S(O)j(CrC6)alkyl, and -NR8-S(O)k(CrC8)alkyl; each R8 and R9 are independently H or (d-CeJalkyl; each R93, R14, and R14a are independently -(CR8R9)«(3-10)-membered cycloalkyl, -(CR8R9)v(Cβ-C1o)aryl, or -(CR8R9)v(4-12)-membered heterocyclyl; p, q, and v are each independently 0, 1, 2, 3, 4, or 5; n and j are each independently 0, 1 , or 2; w is 0, 1 , 2, or 3, and k is 1 or 2.
In another embodiment, the invention relates to compounds of the formula (Ib) selected from the group consisting of:
Figure imgf000010_0002
(Ib6); and
Figure imgf000011_0001
In another embodiment, the invention relates to compounds of the formula (Ib) selected from the group consisting of: (Ib1), (Ib2), (Ib3), and (Ib7), as described above.
In another embodiment, the invention relates to compounds of the formula (Ib)1 wherein R4 is (C1- C6)alkyl, such as isopropyl.
In another embodiment, the invention relates to compounds of the formula (Ib), wherein R4 is -(CRsRB)v(3-10)-membered cycloalkyl, such as cyclohexyl, optionally substituted on any carbon atoms by R10, such as hydroxy, -NR^SCMCrC^alkyl, or -NR8-(CR8R9)q(C=O)R9a.
In another embodiment, the invention relates to compounds of the formula (Ib), wherein R4 is - (CR5R6)v(C6-Cio)aryl, such as phenyl or naphtyl.
In another embodiment, the invention relates to compounds of the formula (Ib), wherein R4 is -(CR5Rβ)v(4-12)-membered heterocyclyl, such as pyridinyl.
Specific embodiments of compounds of the formula (Ib) are selected from the group consisting of:
Figure imgf000011_0002
Figure imgf000012_0001
-SO2-CH2CH3
Figure imgf000012_0002
Figure imgf000012_0003
Figure imgf000013_0001
-SO2-CH2CH3 -SO2-CH2CH3
Figure imgf000013_0002
Figure imgf000013_0003
Figure imgf000013_0004
a pharmaceutically acceptable salt thereof.
In another embodiment, the invention relates to compounds of the formula (Ic):
Figure imgf000014_0001
wherein ring B is a (3-8)-membered heterocyclyl;
-Z- is -C- or -N-;
R1 is H or halo;
R2 is H, CF3, -CHF2, -CH2F, trifluoromethoxy, (C1-C6JaIkOXy, (C1-C6)amino(CR5R6)Vi (Ci-C6)alkyl, -(CR5R6)v(3-10)-membered cycloalkyl, -(CR5R6)v(C6-Cio)aryl, or
-(CR5Rβ)v(4-12)-membered heterocyclyl;
R4 is (CrC6)alkyl, -(CRεR6)y(3-10)-membered cycloalkyl, -(CR5Rβ)v(C6-Cio)aryl, or -(CRsRβ)v(4- 12)-membered heterocyclyl; each of R5 and R6 are independently selected from H, (CrC6)alkyl, -(CR8R9)p(3-10)-membered cycloalkyl, -(CR8R9)p(C6-C10)aryl, and -(CR8R9)p(4-12)-membered heterocyclyl; any carbon atoms of said ring B, and the (Ci-C6)alkyl, the (3-10)-membered cycloalkyl, the (C6- Cio)aryl and the (4-12)-membered heterocyclyl moieties of the foregoing R1, R2, R4, R5, and R8 are optionally substituted with 1 to 3 R10 substituents each independently selected from halo, cyano, -CF3, -CHF2, -CH2F, trifluoromethoxy, hydroxy, (d-C6)alkoxy,
(CrC6)alkyl, R9a, -(CR8R9V(C=O)-R8, -(CR8R9)q-(C=O)-R99,
-(CR8R9V(C=O)-O-(CrC6)alkyl, -(CR8R9V(C=O)-O-R93, -0-(C=O)-R8, -O-(C=O)-R9a,
-NR8-(CR8R9)q(C=O)-R9, -NR8-(CR8R9)q(C=O)R9a, -NR8-(CR8R9)q(C=O)-O(C1-C6)alkyl,
-NR8-(CR8R9)q(C=O)-OR9, -NR8-(C=O)NR8R9, -NR8-(C=O)NR8R9a, -NR8-(C=O)-(C=O)-NR8R9, -NR8- (C=O)-(C=O)-NR8R93, -NR8-(CR8R9)q(C=O)OR9a,
-(C=O)-NR8R9, -(C=O)NR8R93, -NR8R9, -NR8R93, -NR8OR9, -NR8OR33, -S(O)11NR8R9, -S(0)k NR8R99, -SfOKCrCβialkyl, -S(O)jR9a,
-NR8-S(O)k(CrC6)alkyl, -NR8-S(O)kR9β, -NR8-S(O)kNR9a, and -(CR8R9)qS(O)jR9a; wherein any carbon atoms of each of the foregoing R10 (Ci-C6)alkyl, (3-10)-membered cycloalkyl, (C6-Ci0aryl), or (4-12)-membered heterocyclyl moieties are optionally substituted with 1 to 3 R11 substituents each independently selected from halo, cyano, -CF3, -CHF2, -CH2F, -0-CF3, -0-CHF2, -0-CH2F, hydroxy, (CrC6)alkoxy, (d-CβJalkyl, R14, -0-R14, -(C=O)-R8, -(C=O)-R14, -(C=O)-O-(C1-C6)alkyI, -(C=O)-O-R14, -0-(C=O)-R8, -O- (C=O)-R14, -NR8(C=O)-R9, -NR8(C=O)-R14, -(C=O)-NR8R9, -(C=O)-NR8R14, -NR8R9, -NR8R14, -NR8OR9, - NR8OR14, -S(O)kNR8R9, -S(O)kNR8R14,
Figure imgf000014_0002
-S(O)jR14, NR8-S(O)k(CrC6)alkyl, NR14-S(O)k(C1-C6)alkyl, and -NR8-S(O)kR14; any nitrogen atoms of said ring B, and the (4-12)-membered heterocyclyl moieties of the foregoing R1, R2, R4, R5, R6, R9a, R10, R11 and R14 are optionally substituted with R12 substituents each independently selected from (CrC6)alkyl, -(C=O)-R8, -(C=O)-R149, -(C=O)-O-(C1-C6)alkyl) -(C=O)-NR8R9, -(C=O)-NR8R149, R14a,
-(CR8R9)q(C=O)R14a, and -(CR8R9)qS(O)jR14a; wherein any carbon atoms of each of the foregoing R11 and R12 (Ci-Cβ)alkyi, (3-10)-membered cycloalkyl, (Cβ-C10aryl), or (4-12)-membered heterocyclyl moieties are optionally substituted with 1 to 3 R13 substituents each independently selected from halo, cyano, -CF3, -CHF2, -CH2F, trifluoromethoxy, hydroxy, (C1-C6JaIkOXy, (d-C6)alkyl, -(CR8R9)p(3-10)-membered cycloalkyl, -(CR8R9V(C6-C1Oa^I), -(CR8R9)p(4-12)-membered heterocyclyl, -(C=O)-R8, -(C=O)-O-(C1- C6)alkyl, -0-(C=O)-R8, -NR8(C=O)-R9, -(C=O)-NR8R9,
-(C=O)-NR8R14, -NR8R9, -NR8OR9, -S(O)kNR8R9, -S(O)j(CrC6)alkyl, and -NR8-S(O)k(C1-C6)alkyl; each R8 and R9 are independently H or (CrC6)alkyl; each R98, R14, and R14a are independently -(CR8R9)v(3-10)-membered cycloalkyl, -(CR8R9)v(C6-Cio)aryl, or -(CR8R9)v(4-12)-membered heterocyclyl; p, q, and v are each independently 0, 1 , 2, 3, 4, or 5; n and j are each independently 0, 1 , or 2; w is 0, 1 , 2, or 3, and k is 1 or 2.
In another embodiment, the invention relates to compounds of the formula (Ic)1 wherein Ring B is a (3-8)-membered heterocyclyl selected from the group consisting of morpholinyl, piperidinyl, piperazinyl, and pyrrolidinyl.
In another embodiment, the invention relates to compounds of the formula (Ic), wherein any carbon atoms of said ring B are optionally substituted with 1 to 3 R10 substituents each independently selected from -NR8R9, -S(O)j(CrC6)alkyi, and -NR8-S(OMd-C6)alkyl.
In another embodiment, the invention relates to compounds of the formula (Ic)1 wherein any nitrogen atoms of said ring B are optionally substituted with R12 substituents each independently selected from (C1-COaIkVl, -(C=O)-R8, -(C=O)-R143, -(C=O)-O-(C1-C6)alkyl,
-(C=O)-NR8R9, -(C=O)-NR8R148, R14a, -(CR8R9)q(C=O)R14a, and -(CR8R9)qS(O)jR14a.
In another sub-embodiment, R12 is-(CR8R9)qS(O)j(C1-C6)alkyl. or a pharmaceutically acceptable salt thereof.
In another embodiment, the invention relates to compounds of the formula (I), wherein -Z- is -N-.
In another embodiment, the invention relates to compounds of the formula (I), wherein R1 is H.
In another embodiment, the invention relates to compounds of the formula (I), wherein R2 is R2 is H1 (CrC6)alkyl, -(CR5R6)v(3-10)-membered cycloalkyl,
Figure imgf000015_0001
or -(CR5R6)V(4-12)-membered heterocyclyl.
In another embodiment, the invention relates to compounds of the formula (I), wherein R2 is R2 is H, (C1-C6JaIkVl, benzyl, or phenyl, wherein any carbon atoms of the said benzyl or phenyl are optionally substituted with 1 to 3 R10 substituents each independently selected from halo, cyano, hydroxy, (C1- C6)alkoxy, (d-C6)alkyl, -(C=O)-R8, -(C=O)-O-(CrC6)alkyl, -0-(C=O)-R8, -(C=O)-NR8R9, -S(O)kNR8R9,
Figure imgf000015_0002
and -NR8-S(O)k(d-C8)alkyl. In another embodiment, the invention relates to compounds of the formula (I), wherein R3 is H,
(Ci-Cβ)alkyl, -(CR5R6)v(3-10)-membered cycloalkyl,
Figure imgf000016_0001
-(CR5R6)v(4-12)-membered heterocyclyl, -(CR5R6)q(C=O)(C1-C6)alkyl, -(CR5R6)q(C=O)(CR5R6)v(3-10)- membered cycloalkyl, -(CR5R6)q(C=0)(CR5R6)v(C6-C1o)aryl, -(CR5R6)q(C=O)(CRsR6)v(4-12)-membered heterocyclyl, -(CR6RV(OMCi-Cβ)alkyl, -(CR5R6)qS(O)j(CR5R6)v(C6-C10)aryl, or -(CR5R6)qS(O)j(CR5R8)v(4- 12)-membered heterocyclyl.
In another embodiment, the invention relates to compounds of the formula (I), wherein R3 is H, (CrCfOalkyl, -(CR5R6)v(Cβ-Ci0aryl), -(CR5R8)q(C=O)(C1-Cβ)alkyl, -(CR5R6)q(C=O)(CR5R6)v(3-10)- membered cycloalkyl, -(CR5R6)q(C=0)(CR5Rβ)v(C6-Cio)aryl, -(CRsR8)q(C=O)(CRsR6)v(4-12)-membered heterocyclyl, or -(CR5R6)qS(O)j(Ci-C6)alkyl.
In another embodiment, the invention relates to compounds of the formula (I), wherein any carbon atoms of said R3 (C1-C6JaIkVl, (3-10)-membered cycloalkyl, (Cβ-Cioaryl), or (4-12)-membered heterocyclyl moieties are optionally substituted with 1 to 3 R10 substituents each independently selected from halo, cyano, -CF3, hydroxy, (CrC6)alkoxy, (C1-C6JaIkVl, -(C=O)-R8, -(C=O)-O-(C1-C6)alkyl, -0-(C=O)-R8, -NR8(C=O)-R9, -(C=O)-NR8R9, -NR8R9, -NR8OR9, -S(OXNR8R9, -S(0)j(CrC6)alkyl, -NR8-S(O)k(Ci-C6)alkyl, -(CR8R9)p(3-10)-membered cycloalkyi, -(CR8R9)p(C6-Cioaryl), -(CR8R9)p(4-12)-membered heterocyclyl, -(CR8R9)q(C=O)(CR8R9)p(C6-Ci0)aryl, -(CR8R9)q(C=O)(CR8R9)p(4- 12)-membered heterocyclyl, -(CR8R9)qO(CR8R9)p(CfrC10)aryl, -(CR8R9)qO(CR8R9)p(4-12)-membered heterocyclyl, -(CR8R9)qS(O)j(CR8R9)p(C6-Ci0)aryl, and -(CR8R9)qS(O)j(CR8R9)p(4-12)-membered heterocyclyl.
In another embodiment, the invention relates to compounds the formula (I), wherein R4 is
Figure imgf000016_0002
or -(CR5R6)v(4-12)-membered heterocyclyl; wherein any carbon atoms of said R4 are optionally substituted with 1 to 3 R10 substituents each independently selected from halo, cyano, -CF3, hydroxy, (C1-C6JaIkOXy, (C1-C6JaIkVl, R3a, -(CR8R9)q-(C=O)-R8,
-(CR8R9)q-(C=O)-R9a, -(CR8R9)q-(C=O)-O-(C1-C6)alkyl, -(CR8R9)q-(C=O)-O-R9a, -0-(C=O)-R8, -0-(C=0)-R9a, -NR8-(CR8R9)q(C=O)-R9, -NR8-(CR8R9)q(C=O)R9a,
-NR8-(CR8R9)q(C=O)-O(C1-C6)alkyl, -NR8-(CR8R9)q(C=O)-OR9, -NR8-(C=O)NR9, -NR8-(C=O)NR9a, - NR8-(CR8R9)q(C=O)OR9a, -(C=O)-NR8R9, -(C=O)NR8R33, -NR8R9,
-NR8R93, -NR8OR9, -NR8OR98, -S(O)kNR8R9, -S(O)kNR8R9a,
-NR8-S(O)k(C1-C6)alkyl, -NR8-S(O)kR9a, and -(CR8R9)qS(O)jR9a.
In another embodiment, the invention relates to compounds of the formula (I), wherein R7 is H or methyl.
In another specific embodiment, the invention relates to compounds of the formula (I), selected from the group consisting of:
Figure imgf000017_0001
salt thereof.
The present invention also relates to a pharmaceutical composition comprising an effective amount of compounds of the formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The present invention also relates to a method of treating a condition that is mediated by the modulation of JNK, the method comprising administering to a mammal an effective amount of compounds of the formula (I), or a pharmaceutically acceptable salt thereof.
The present invention also relates to a method of treating diabetes, metabolic syndrome, insulin resistance syndrome, obesity, glaucoma, hyperiipidemia, hyperglycemia, hyperinsuliπemia, osteoporosis, tuberculosis, atherosclerosis, dementia, depression, virus diseases, inflammatory disorders, or diseases in which the liver is a target organ, the method comprising administering to a mammal an effective amount of compounds of the formula (I), or a pharmaceutically acceptable salt thereof.
The present invention also relates to a method of treating chronic or acute cardiac failure, cardiac hypertrophy, dilated, hypertrophic or restrictive cardiomyopathy, acute myocardial infarction, post- myocardial infarction, acute or chronic myocarditis, diastolic dysfunction of the left ventricle, systolic dysfunction of the left ventricle, hypertension and nephropathy and nephritis as complications thereof, endothelial dysfunction, arteriosclerosis or post-angioplasty restenosis, which comprises administering an effective amount of compounds of the formula (I), to a mammal in need thereof.
The present invention also relates to a method of treating chronic rheumatoid arthritis, osteoarthritis, gout, chronic obstructive pulmonary disease, asthma, bronchitis, cystic fibrosis, inflammatory bowel disease, irritable colon syndrome, mucous colitis, ulcerative colitis, Crohn's disease, gastritis, esophagitis, multiple sclerosis, eczema, dermatitis, hepatitis, glomerulonephritis, diabetes, ophthalmic diseases, diabetic retinopathy, diabetic macular edema, diabetic nephropathy, diabetic neuropathy, obesity, psoriasis or cancer, which comprises administering an effective amount of compounds of the formula (I), to a mammal in need thereof.
The present invention also relates to a method of treating Alzheimer's disease, Huntington's chorea, Parkinson's syndrome, epilepsy, amyotrophic lateral sclerosis, peripheral neuropathy, neurodegenerative disease or spinal injury, which comprises administering an effective amount of compounds of the formula (I), to a mammal in need thereof.
The present invention also relates to a method of treating cerebral apoplexy, cerebrovascular disorder, an ischemic disorder of an organ selected from the heart, kidney, liver and brain, ischemia- reperfusion injury, organ failure, endotoxin shock or rejection in transplantation, which comprises administering an effective amount of compounds of the formula (I), to a mammal in need thereof.
Definitions
For purposes of the present invention, as described and claimed herein, the following terms are defined as follows:
As used herein, the terms "comprising" and "including" are used in their open, non-limiting sense.
The term "halo", as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo.
The term "alkyl", as used herein, unless otherwise indicated, includes saturated, partially unsaturated, or unsaturated hydrocarbon radicals having straight or branched moieties. The term "alkyl", as used herein, includes alkenyl, which includes alkyl moieties having at least one carbon-carbon double bond and including E and Z isomers of said alkenyl moiety. The term "alkyl", as used herein, includes alkynyl, which includes alkyl moieties having at least one carbon-carbon triple bond.
The term "alkoxy", as used herein, unless otherwise indicated, includes O-alkyl groups wherein alkyl is as defined above.
The term "Me" means methyl, "Ef means ethyl, and "Ac" means acetyl.
The term "cycloalkyl", as used herein, unless otherwise indicated refers to a non-aromatic, saturated or partially saturated, monocyclic or fused, spiro or unfused bicyclic or tricyclic hydrocarbon referred to herein containing a total of from 3 to 10 carbon atoms, preferably 5-8 ring carbon atoms. Exemplary cycloalkyls include monocyclic rings having from 3-10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl. Illustrative examples of cycloalkyl are derived from, but not limited to, the following:
Figure imgf000018_0001
The term "aryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl.
The term "(4-12)-membered heterocyclyl", "(4-10)-membered heterocyclyl", "(4-7)-membered heterocyclyl", "(5-8)-membered heterocyclyl", or "(3-8)-membered heterocyclyl"as used herein, unless otherwise indicated, includes aromatic and non-aromatic heterocyclic groups containing one to four heteroatoms each selected from O, S and N, and with the proviso that the ring of said group does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups include groups having only 3 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system. The heterocyclic groups include benzo-fused ring systems. An example of a 3 membered heterocyclic group is aziridine, an example of a 4 membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5 membered heterocyclic group is thiazolyl, an example of a 7 membered ring is azepinyl, and an example of a 10 membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepiπyl, 1 ,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3- dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl and quinolizinyl. EExamples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, fury), thienyl, isoxazolyt, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triaziπyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups, as derived from the groups listed above, may be C-attached or reattached where such is possible. For instance, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole may be imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached). The 4-12 membered heterocyclic may be optionally substituted on any ring carbon, sulfur, or nitrogen atom(s) by one to two oxo, per ring. An example of a heterocyclic group wherein 2 ring carbon atoms are substituted with oxo moieties is 1,1-dioxo-thiomorpholinyl. Other Illustrative examples of 4-12 membered heterocyclic are derived from, but not limited to, the following:
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000020_0002
Unless otherwise indicated, the term "oxo" refers to =0.
A "solvate" is intended to mean a pharmaceutically acceptable solvate form of a specified compound that retains the biological effectiveness of such compound. Examples of solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, DMSO (dimethylsulfoxide), ethyl acetate, acetic acid, or ethanolamine.
The phrase "pharmaceutically acceptable salt(s)", as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of formula (I). The compounds of formula (I) that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of formula (I) are those that form non-toxic acid addition salts, Le1, salts containing pharmacologically acceptable anions, such as the acetate, benzenesulfonate, benzoate, bicarbonate, bisuifate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edislyate, estolate, esylate, ethylsuccinate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phospate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodode, and valerate salts.
The term "diseases in which the liver is a target organ", as used herein, unless otherwise indicated means diabetes, hepatitis, liver cancer, liver fibrosis, and malaria.
The term "Metabolic syndrome", as used herein, unless otherwise indicated means psoriasis, diabetes mellitus, wound healing, inflammation, neurodegenerative diseases, galactosemia, maple syrup urine disease, phenylketonuria, hypersarcosinemia, thymine uraciluria, sulfinuria, isovaleric acidemia, saccharopinuria, 4-hydroxybutyric aciduria, glucose-6-phosphate dehydrogenase deficiency, and pyruvate dehydrogenase deficiency.
In the compounds of formula (I), where terms such as (CR5R8Jv or (CR8R9)P are used, R5, R8, R8and R9 may vary with each iteration of v or p. For instance, where v or p is 2 the terms (CR5R8Jv or (CR8R9Jp may equal -CH2CH2-, or -CH(CH3)C(CH2CH3)(CH2CH2CH3)-, or any number of similar moieties falling within the scope of the definitions of R5, R8, R8and R9.
The term "treating", as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment", as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined immediately above.
The term "modulate" or "modulating", as used herein, refers to the ability of a modulator for a member of the steroid/thyroid superfamily to either directly (by binding to the receptor as a ligand) or indirectly (as a precursor for a ligand or an inducer which promotes production of ligand from a precursor) induce expression of gene(s) maintained under hormone expression control, or to repress expression of gene(s) maintained under such control.
The term "obesity" or "obese", as used herein, refers generally to individuals who are at least about 20-30% over the average weight for his/her age, sex and height. Technically, "obese" is defined, for males, as individuals whose body mass index is greater than 27.8 kg/ m2, and for females, as individuals whose body mass index is greater than 27.3 kg/m2. Those of skill in the art readily recognize that the invention method is not limited to those who fall within the above criteria. Indeed, the method of the invention can also be advantageously practiced by individuals who fall outside of these traditional criteria, for example, by those who may be prone to obesity.
The term "inflammatory disorders", as used herein, refers to disorders such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, chondrocalcinosis, gout, inflammatory bowel disease, ulcerative colitis, Crohn's disease, fibromyalgia, and cachexia.
The phrase "therapeutically effective amount" , as used herein, refers to that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other.
The phrase "amount . . . effective to lower blood glucose levels", as used herein, refers to levels of compound sufficient to provide circulating concentrations high enough to accomplish the desired effect. Such a concentration typically falls in the range of about 10 nM up to 2 μM; with concentrations in the range of about 100 nM up to 500 nM being preferred. As noted previously, since the activity of different compounds which fall within the definition of Formula (I) as set forth above may vary considerably, and since individual subjects may present a wide variation in severity of symptoms, it is up to the practitioner to determine a subject's response to treatment and vary the dosages accordingly.
The phrase "insulin resistance", as used herein, refers to the reduced sensitivity to the actions of insulin in the whole body or individual tissues, such as skeletal muscle tissue, myocardial tissue, fat tissue or liver tissue. Insulin resistance occurs in many individuals with or without diabetes mellitus.
The phrase "insulin resistance syndrome", as used herein, refers to the cluster of manifestations that include insulin resistance, hyperinsulinemia, non insulin dependent diabetes mellitus (NIDDM), arterial hypertension, central (visceral) obesity, and dyslipidemia.
Certain compounds of formula (I) may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of formula (I), and mixtures thereof, are considered to be within the scope of the invention. With respect to the compounds of formula (I), the invention includes the use of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, or mixtures thereof. The compounds of formula (I) may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.
Certain functional groups contained within the compounds of the present invention can be substituted for bioisosteric groups, that is, groups which have similar spatial or electronic requirements to the parent group, but exhibit differing or improved physicochemical or other properties. Suitable examples are well known to those of skill in the art, and include, but are not limited to moieties described in Patini et al., Chem. Rev, 1996, 96, 3147-3176 and references cited therein.
The subject invention also includes isotopically-labelled compounds, which are identical to those recited in formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O1 170, 31P, 32P, 35S, 18F, and 36CI, respectively. Compounds of the present invention and pharmaceutically acceptable salts s of said compounds which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances, lsotopically labeled compounds of formula (I) of this invention thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non- isotopically labelled reagent.
Other aspects, advantages, and features of the invention will become apparent from the detailed description below. Detailed Description and Embodiments of the invention
The compounds of the present invention may have asymmetric carbon atoms. Diasteromeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixtures into a diastereomric mixture by reaction with an appropriate optically active compound (e.g., alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomeric mixtures and pure enantiomers are considered as part of the invention.
The compounds of formulas (I) that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of formula (I) from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding to the solution an appropriate mineral or organic acid.
Those compounds of formula (I) that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline- earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of formula (I). Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium calcium and magnesium, etc. These salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.
The compounds of the present invention may also be useful in the treatment of other metabolic disorders associated with impaired glucose utilization and insulin resistance include major late-stage complications of NIDDM, such as diabetic angiopathy, atherosclerosis, diabetic nephropathy, diabetic neuropathy, and diabetic ocular complications such as retinopathy, cataract formation and glaucoma, and many other conditions linked to NIDDM, including dyslipidemia glucocorticoid induced insulin resistance, dyslipidemia, polycystic ovarian syndrome, obesity, hyperglycemia, hyperlipemia, hypercholesteremia, hypertriglyceridemia, hyperinsulinemia, and hypertension. Brief definitions of these conditions are available in any medical dictionary, for instance, Stedman's Medical Dictionary (Xth Ed.).
Pharmaceutical Compositions/Formulations. Dosaginq and Modes of Administration
Methods of preparing various pharmaceutical compositions with a specific amount of active compound are known, or will be apparent, to those skilled in this art. In addition, those of ordinary skill in the art are familiar with formulation and administration techniques. Such topics would be discussed, e.g. in Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, current edition, Pergamon Press; and Remington's Pharmaceutical Sciences, current edition. Mack Publishing, Co., Easton, Pa. These techniques can be employed in appropriate aspects and embodiments of the methods and compositions described herein. The following examples are provided for illustrative purposes only and are not meant to serve as limitations of the present invention.
The amino heterocyclyl compounds of formula (I) may be provided in suitable topical, oral and parenteral pharmaceutical formulations for use in the treatment of GK mediated diseases. The compounds of the present invention may be administered orally as tablets or capsules, as oily or aqueous suspensions, lozenges, troches, powders, granules, emulsions, syrups or elixirs. The compositions for oral use may include one or more agents for flavoring, sweetening, coloring and preserving in order to produce pharmaceutically elegant and palatable preparations. Tablets may contain pharmaceutically acceptable excipients as an aid in the manufacture of such tablets. As is conventional in the art these tablets may be coated with a pharmaceutically acceptable enteric coating, such as glyceryl monostearate or glyceryl distearate, to delay disintegration and absorption in the gastrointestinal tract to provide a sustained action over a longer period.
Formulations for oral use may be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
Aqueous suspensions normally contain active ingredients in admixture with excipients suitable for the manufacture of an aqueous suspension. Such excipients may be a suspending agent, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; a dispersing or wetting agent that may be a naturally occurring phosphatide such as lecithin, a condensation product of ethylene oxide and a long chain fatty acid, for example polyoxyethylene stearate, a condensation product of ethylene oxide and a long chain aliphatic alcohol such as heptadecaethylenoxycetanol, a condensation product of ethylene oxide and a partial ester derived from a fatty acid and hexitol such as polyoxyethylene sorbitol monooleate or a fatty acid hexitol anhydrides such as polyoxyethylene sorbitan monooleate.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to know methods using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation may also be formulated as a suspension in a non toxic perenterally-acceptable diluent or solvent, for example as a solution in 1 ,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringers solution and isotonic sodium chloride solution. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition fatty acids such as oleic acid find use in the preparation of injectables.
The amino heterocyclyl compounds of formula (I) may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at about 25 Celcius but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and other glycerides.
For topical use preparations, for example, creams, ointments, jellies solutions, or suspensions, containing the compounds of the present invention are employed.
The amino heterocyclyl compounds of formula (I) may also be administered in the form of liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles and multimellar vesicles. Liposomes can be formed from a variety of phospholipides, such as cholesterol, stearylamine or phosphatidylcholines.
Dosage levels of the compounds of the present invention are of the order of about 0.5 mg/kg body weight to about 100 mg/kg body weight. A preferred dosage rate is between about 30 mg/kg body weight to about 100 mg/kg body weight. It will be understood, however, that the specific dose level for any particular patient will depend upon a number of factors including the activity of the particular compound being administered, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy. To enhance the therapeutic activity of the present compounds they may be administered concomitantly with other orally active antidiabetic compounds such as the sulfonylureas, for example, tolbutamide and the like.
The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. It is to be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations. In the following examples molecules with a single chiral center, unless otherwise noted, exist as a racemic mixture. Those molecules with two or more chiral centers, unless otherwise noted, exist as a racemic mixture of diastereomers. Single enantiomers/diastereomers may be obtained by methods known to those skilled in the art.
The invention will now be described in reference to the following Examples. These Examples are not to be regarded as limiting the scope of the present invention, but shall only serve in an illustrative manner.
EXAMPLES
In the examples described below, unless otherwise indicated, all temperatures are set forth in degrees Celsius and all parts and percentages are by weight. Reagents may be purchased from commercial suppliers, such as Sigma-Aldrich Chemical Company, Acros Organics, or Lancaster Synthesis Ltd. and may be used without further purification unless otherwise indicated. Tetrahydrofuran (THF), methylene chloride (CH2CI2), and Λ/,Λ/-dimethylformamide (DMF) may be purchased from Aldrich in Sure-Seal bottles and used as received. All solvents may be purified using standard methods known to those skilled in the art, unless otherwise indicated.
The reactions set forth below were done generally under a positive pressure of argon or nitrogen or with a drying tube, at ambient temperature (unless otherwise stated), in anhydrous solvents, and the reaction flasks were fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried. Analytical thin layer chromatography (TLC) was performed using glass-backed silica gel 60 F 254 precoated plates (Merck Art 5719) and eluted with appropriate solvent ratios (v/v). Reactions were assayed by TLC or LCMS and terminated as judged by the consumption of starting material. Visualization of the TLC plates was done with UV light (254 nM wavelength) or with an appropriate TLC visualizing solvent and activated with heat. Flash column chromatography (Still et al., J. Org. Chem., 1978, 43, 2923) was performed using silica gel 60 (Merck Art 9385) or various MPLC systems, such as Biotage or ISCO purification system.
The compound structures in the examples below were confirmed by one or more of the following methods: proton magnetic resonance spectroscopy, mass spectroscopy, and elemental microanalysis. Proton magnetic resonance (1H NMR) spectra were determined using a Bruker spectrometer operating at a field strength of 300 or 400 megahertz (MHz). Chemical shifts are reported in parts per million (PPM, δ) downfield from an internal tetramethylsilane standard. Alternatively, 1H NMR spectra were referenced to signals from residual protons in deuterated solvents as follows: CDCI3 = 7.25 ppm; DMSO-d6 = 2.49 ppm; C6D6 = 7.16 ppm; CD3OD = 3.30 ppm. Peak multiplicities are designated as follows: s, singlet; d, doublet; dd, doublet of doublets; t, triplet; dt, doublet of triplets; q, quartet; br, broadened; m, multiplet. Coupling constants are given in Hertz (Hz). Mass spectra (MS) data were obtained using Agilent mass spectrometer with APCI or ESI ionization. Elemental microanalyses were performed by Atlantic Microlab Inc. and gave results for the elements stated within ±0.4% of the theoretical values.
Preferred compounds in accordance with the invention may be prepared in manners analogous to those specifically described below.
The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. It is to be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations. The skilled artisan will recognize that different acids, amines, alkyl halides, aryl halides, coupling reagents, and heterocycles may be substituted in the following descriptions to suit the preparations of a desired embodiment. The following methods may be scaled upwards or downwards to suit the amount of desired material.
In the examples and specification, "Ef means ethyl, "Ac" means acetyl, "Me" means methyl, ΕTOAC" or ΕtOAc" means ethyl acetate, "THF" means tetrahydrofuran, and "Bu" means butyl. Et2O refers to diethyl ether. DMF refers to Λ/,/V-dimethylformamide. DMSO refers to dimethylsulfoxide. MTBE refers to ferf-butylmethyl ether. Other abbreviations include: CH3OH or MeOH (methanol), EtOH (ethanol), DME (ethylene glycol dimethyl ether), DCM or CH2CI2 (dichloromethane or methylene chloride), CHCI3 (chloroform), 1,2-DCE (1 ,2-dichloroethane), Ph (phenyl), TFA (trifluoroacetic acid), DIEA (N,N- diisopropylethylamine), TEA or Et3N (triethylamine), NMM (4-methylmorpholine), HOBt (1- hydroxybenzotriazole hydrate), HATU [O-(7-azabenzotriazol-1-yl)-Λ/,Λ/,Λ/',W'-tetramethyluronium hexafluorophosphate], EDCI [1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride], DCC (dicyclohexyl carbodiimide), DMAP (4-dimethylaminopyridine), NaOH (sodium hydroxide), KOH (potassium hydroxide), HCI (hydrogen chloride), MgSO4 (magnesium sulfate), Na2SO4 (sodium sulfate), NH4CI (ammonium chloride), and NaHCO3 (sodium bicarbonate).
Method A:
ature
Figure imgf000027_0001
Figure imgf000027_0002
1c
1b R = benzyl (Bn) 1a R = Bn
2b R = phenyl 2a R = Ph
3b R = methyl 3a R = Me
4b R = p-methoxybenzyl (PMB) 4a R = PMB
Figure imgf000027_0003
xanyl
Pyrimidine 1e (4-methyl-2-(methylthio)pyrimidine) was prepared from 4-methylpyrimidine-2-thiol (1f) according to the procedure described in Org. Lett. 2003, 4 (6), 979.
Preparation of (Z)-N-(3-(Dimethylamino)-2-(2-(methylthio)pyrimidin-4-yl)allylidene)-N- methylmethanaminium (1d)
Oxalyl chloride (33 mL, 375 mmol) was added dropwise via addition funnel to an ice-cooled mixture of DMF (30 mL, 393 mmol) in CHCI3 (218 mL) with vigorous stirring. The mixture was stirred for 5 minutes after the addition was complete, and the solution was then warmed to 450C and allowed to stir for 30 minutes. The mixture then re-cooled to 00C, and 1e (25.0 g, 179 mmol) in CHCI3 (10 mL) was added dropwise via an addition funnel. The solution was then warmed to 45 °C, and the mixture was allowed to stir vigorously for 12 hour(s). The mixture was then removed from the heat, and the resulting solid mass was filtered, washed with cold CHCI3, and dried under high vacuum to yield a pale brown solid (44.5 g, 99 %). This crud=e product (1d) was used without further purification. 1H NMR (400 MHz, DMSO-D6) δ ppm 8.53 (d, 1 H), 8.19 (s, 2 H), 7.14 (d, 1 H), 3.42 (s, 6 H), 2.84 (s, 6 H), 2.52 (s, 3 H). LRMS m/z calculated for C12H20N4S ([M+H]+): 252. Found: 252.
Preparation of 4-(lsoxazol-4-yl)-2-(methylthio)pyrimidine (1c)
Hydroxylamine hydrochloride (30.0 g, 434 mmol) was dissolved in water (400 mL) at room temperature. Na2CO3 (55.3 g, 521 mmol) was added slowly and the mixture stirred rapidly for 10 minutes. Compound 1d (30.0 g, 119 mmol) was then added portion-wise over 15 minutes, and the resulting mixture was stirred rapidly at room temperature with the aid of a mechanical stirrer. After stirring for an additional 5 hour(s), the solid was filtered off, washed with cold water, and dried under high vacuum. The resulting tan solid (18.7 g) was suspended in CH3CN / methanol (60 mL of each), and the mixture cooled to 00C. TFA (10 mL) was added as a stream over 5 minutes. The mixture was then allowed to warm to room temperature and stirred for 2 hour(s). After re-cooling to 00C, the mixture was basified with NH4OH (concentrated aq), and the solid was filtered off, rinsed with cold water, and dried under high vacuum. The light tan solid (1c, 15.2 g, 66 %) was used without further purification. 1H NMR (400 MHz, CD2CI2) δ ppm 9.13 (s, 1 H), 8.84 (s, 1 H), 8.60 (d, 1 H), 7.21 (d, 1 H), 2.64 (s, 3 H). LRMS m/z calculated for C8H8N3OS ([M+H]+): 194. Found: 194.
Preparation of 1-benzyl-4-[2-(methylthio)pyrimidin-4-yl]-1H-pyrazol-5-amiπe (1b)
Isoxazole 1c (3.86 g, 20.0 mmol) was dissolved in ethanol (60 mL), and benzylhydrazine dihydrochloride (3.25 g, 16.7 mmol) and sodium methoxide (1.06 g, 33.4 mmol) were added sequentially. The mixture was heated at 850C for 15 hour(s), and then was allowed to cool to room temperature. The precipitate thus formed was filtered, washed thoroughly with ether, and dried in vacuo to yield pure methylthiopyrimidine 1b as a pale yellow solid (2.23 g, 40 %). The filtrate was concentrated in vacuo to give an orange solid which, upon washing with ether followed by filtration, afforded an orange solid (1.40 g) which consisting of the desired product 1b and unreacted isoxazole 1c. 1H NMR (400 MHz, CD2CI2) δ ppm 2.34 (s, 3 H), 5.02 (s, 2 H), 5.39 (s, 2 H), 6.82 (d, 1 H), 7.03 (d, 2 H), 7.12 - 7.21 (m, 3 H), 7.59 (s, 1 H), 8.12 (d, 1 H). LRMS m/z calculated for C15H16N5S [M+Hf 298. Found: 298.
Preparation of 1-Methyl-4-(2-methylthio)pyrimidin-4-yl)-1H-pyrazole-5-amine (3b)
Isoxazole 1c (2.50 g, 12.9 mmol) was dissolved in acetic acid (50 mL) and cooled in an ice bath to 00C. The mixture was stirred vigorously while methylhydrazine (10.3 mL, 194 mmol) was added dropwise via syringe at a rate such that the internal temperature remained below 350C. After the addition was complete, the mixture was removed from the ice bath, allowed to slowly warm to room temperature over 15 minutes, and then slowly warmed in an oil bath until a temperature of 850C was reached. The reactioπ was stirred vigorously at 850C for 4.5 hour(s), at which time the flask was removed from the oil bath and cooled to 00C. The mixture was basified with NH4OH (concentrated ) to a pH of 10. The solid that precipitated out was filtered off, rinsed with a small amount of cold water, and dried under high vacuum. The resultant crude product (7, light tan solid, 2.12 g, 74 %) contained a mixture of regioisomers (6:1 , methyl-5-aminopyrazole: methyl-3-aminopyrazole) and was used without further purification. 1H NMR (400 MHz, DMSO-D6) δ ppm 8.30 (d, 1 H), 7.87 (s, 1 H), 7.22 (d, 1 H), 6.64 (s, 2 H), 3.56 (s, 3 H), 2.52 (s, 3 H). LRMS m/z calculated for C9H12N5S ([M+H]+): 222. Found: 222.
Preparation of 1-(4-methoxybenzyl)-4-[2-(methylthio)pyrinnidin-4-yl]-1H-pyrazol-5-amine (4b)
Isoxazole 1c (1.80 g, 9.32 mmol) was dissolved in ethanol (30 ml_), and 4-methoxybenzylbenzylhydrazine hydrochloride (1.76 g, 9.32 mmol) and sodium methoxide (0.504 g, 9.32 mmol) were added sequentially. The mixture was refluxed under N2 for 15 hour(s), and then was allowed to cool to room temperature. Analysis of an aliquot by LCMS showed incomplete conversion. An additional portion of 4- methoxybenzylbenzylhydrazine hydrochloride (0.352 g, 1.86 mmol) and sodium methoxide (0.100 g, 1.86 mmol) were added, and the mixture was then refluxed for an additional 8 hour(s). The resulting solution was cooled to room temperature and concentrated in vacuo, and the resulting solid was dissolved in CH2CI2, washed with saturated aqueous NaHCO3, dried over MgSO4, and filtered. The filtrate thus obtained was concentrated in vacuo to give reddish paste. Purification by column chromatography (0 -50 % ethyl acetate in hexanes) yielded pyrimidine 4b (1.52 g, 50 %) as an orange solid. 1H NMR (400 MHz, CD2CI2) δ ppm 2.34 (s, 3 H), 5.02 (s, 2 H), 5.39 (s, 2 H), 6.82 (d,1 H), 7.03 (d, 2 H), 7.12 - 7.21 (m, 3 H), 7.59 (s, 1 H), 8.12 (d,1 H). LRMS m/z calculated for C16H18N5O2S [M+Hf 344. Found: 344.
Preparation of 1-benzyl-4-[2-(methylsulfonyl)pyrimidin-4-yl]-1H-pyrazol-5-amine (1a)
Methylthiopyrimidiπe 1b (2.20 g, 3.40 mmol) was dissolved in methanol/water (10 mL/1.2 mL) and a suspension of oxone (2.93 g, 4.76 mmol) in water (8.5 mL) was added in portions while stirring the methylthiopyrimidine solution at room temperature. An additional 8.5 mL of water was used to complete the addition of oxone. The resulting yellow suspension turned orange in color after stirring 3 hour(s) at room temperature. The suspension was filtered, and the filtrate was extracted several times with 10% methanol in CH2CI2. The combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford the crude product (900 mg). Purification by column chromatography (0 - 70 % ethyl acetate in hexanes) yielded the sulfone 1a (319 mg, 15 %) as a pale yellow solid. 1H NMR (400 MHz, CD3OO) δ ppm 3.35 (s, 3 H), 5.26 (s, 2 H), 7.23 (d, 2 H), 7.27 - 7.71 (m, 5H), 8.03 (s, 1 H), 8.62 (d, 1 H). LRMS m/z calculated for C15H15N5O2S [M+H]+ 330. Found: 330.
Compound 2a was prepared analogous to the method of preparing compound 1a.
Preparation of 1-Methyl-4-(2-methylsulfoπyl)pyrimidin-4-yl)-1H-pyrazole-5-amine (3a)
Compound 3b (2.00 g, 9.05 mmol) was dissolved in THF (40 mL), cooled in an ice bath to 0 0C, and m- CPBA (4.81 g, 27.9 mmol, 77 % tech grade) was added in one portion. The mixture was then allowed to warm to room temperature slowly, and stirred for 6 hour(s). The mixture was then cooled to 00C and quenched with saturated aqueous NaHCO3 until a pH of 9 was reached. The aqueous solution was extracted with ethyl acetate (6 x 50 mL), the combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to provide a dark orange oil. The crude product was purified by medium pressure liquid chromatography (CH2CI2 to 100 % ethyl acetate / CH2CI2) to afford pure product (3a) as a white solid (1.85 g, 81 %). 1H NMR (400 MHz, DMSO-D6) δ ppm 8.65 (d, 1 H), 8.01 (s, 1 H), 7.75 (d, 1 H), 6.88 (S, 2 H), 3.59 (s, 3 H), 3.37 (s, 3 H). LRMS m/z calculated for C9H1IN3O2S ([M+H]+): 254. Found: 254.
Preparation of 1-(4-methoxybenzyl)-4-[2-(methylsulfonyl)pyrimidin-4-yl]-1H-pyrazol-5-amine (4a)
Methylthiopyrimidine 4b (2.00 g, 6.12 mmol) was reacted with oxone as described in the synthesis of compound 1a to yield a mixture of sulfoxide 4a and the corresponding sulfoxide (total of 1.60 g, 70%, 4a:sulfoxide in a 2:1 ratio by 1H NMR) as a pale yellow solid. For the mixture of 4a and sulfoxide: 1H NMR (400 MHz, CD2CI2) δ ppm 2.73 - 2.80 (m, 2 H), 3.15 - 3.23 (m, 5 H), 3.67 - 3.76 (m, 8 H), 5.05 (s, 5 H), 5.69 (s, 3 H), 5.92 (s, 1 H), 6.76 - 6.87 (m, 5 H), 7.08 (d, J = 8.6 Hz1 5 H), 7.17 (d, J = 5.6 Hz, 1 H), 7.30 (d, J = 5.6 Hz, 2 H), 7.69 - 7.77 (m, 2 H), 8.46 (d, J = 5.6 Hz, 2 H). Sulfone 4a: LRMS m/z calculated for Ci6H18N5O3S [M+H]+360. Found: 360.; Sulfoxide: LRMS m/z calculated for C16H18N5O2S [M+H]+344. Found: 344.
Preparation of traπs-4-{[4-(5-amino-1-benzyl-1H-pyrazol-4-yl)pyrimidiπ-2-yl]amino}cyclohexanol (1)
Methylsulfonylpyrimidine 1a (315 mg, 0.96 mmol) was suspended in 1,4-dioxane (2 mL) and trans- aminocyclohexanol (553 mg, 4.80 mmol) was added at room temperature. The resulting suspension was stirred at 850C for 2.5 days under an inert atmosphere in a sealed tube. The solution was cooled to room temperature, and the resulting slurry was dissolved in CH2CI2 with the aid of a small amount of methanol. The solution thus obtained was concentrated in vacuo. The resulting crude residue was purified by column chromatography (0 - 7% methanol in CH2CI2) to yield fraπs-pyrimidine 1 (197 mg, 59%) as a pale yellow solid. 1H NMR (400 MHz, CD2CI2) δ ppm 1.29 - 1.42 (m, 5 H), 1.94 - 2.03 (m, 2 H), 2.15 (dd, 2 H), 3.63 - 3.75 (m, 2 H), 5.00 (s, 1 H)1 5.22 (s, 2 H), 5.59 (s, 2 H), 6.64 (d, 1 H), 7.21 - 7.29 (m, 2 H), 7.32 - 7.43 (m, 3 H), 7.74 (s, 1 H), 8.12 (d, 1 H). LRMS m/z calculated for C20H25N6O [M+H]+365. Found: 365.
Preparation of 4-[5-amino-1-(4-methoxybeπzyl)-1H-pyrazol-4-yl]-W-isopropylpyrimidin-2-amine (7)
A mixture of sulfone 4a and the corresponding sulfoxide (1.50 g, 4.23 mmol) were reacted as described for the synthesis of compound 1, except that aminocyclohexanol was replaced with isopropyl amine, to afford compound 7 (1.28 g, 89%) as an off-white solid. See tabulated data.
Preparation of 4-(5-Amino-1-methyl-1 H-pyrazol-4-yl)-N-((1 R,4R)-4-(benzyloxy)cyclohexyl)pyrimidin- 2-amiπe (9)
Compound 3a (0.30 g, 1.18 mmol) was dissolved in dioxane (12 mL) in a sealed tube, and trans-4- benzyloxy-cyclohexylamine (2.40 g, 11.7 mmol) was added in one portion. The mixture was warmed to 1250C and stirred for 24 hour(s). The mixture was then removed from the oil bath and concentrated in vacuo to afford a reddish oil. The crude product was purified by medium pressure liquid chromatography (hexanes to ethyl acetate) to afford pure product (9) as a white solid (0.29 g, 65 %). 1H NMR (400 MHz, CD2CI2) δ ppm 8.07 (d, 1 H), 7.61 (s, 1 H), 7.22 - 7.37 (m, 5 H), 6.57 (d, 1 H), 5.59 (br s, 2 H), 4.84 - 5.02 (m, 1 H), 4.54 (s, 2 H), 3.69 - 3.83 (m, 1 H), 3.62 (s, 3 H), 3.35 - 3.48 (m, 1 H), 2.06 - 2.25 (m, 4 H)1 1.39 - 1.53 (m, 2 H), 1.22 - 1.38 (m, 2 H). LRMS m/z calculated for C2IH27N6O ([M+H]+): 379. Found: 379.
Table 1. Compounds 1-109 were prepared according to the method A as described above.
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
TIB2007/001158
-36-
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
IB2007/001158
-43-
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Method B:
Figure imgf000049_0001
9 HOa 110
Preparation of N-((1 R,4R)-4-(Benzyloxy)cyclohexyl)-4-(1-methyl-5-(methylamino)-1 H-pyrazol-4- yl)pyrimidin-2-amine (110a)
Compound 9 (0.10 g, 0.27 mmol) was suspended in triethylorthoformate (1 ml_) and pTsOH (0.03 g, 0.13 mmoi) was added. The mixture was heated to 1450C while being stirred vigorously. After stirring for 10 minutes, the mixture was removed from the oil bath, cooled to 00C, and basified to pH of 9 using Na2CO3 (saturated aqueous solution). The aqueous mixture was extracted with ethyl acetate (3 x 50 ml_), and the combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to yield an orange oil. This crude product was dissolved in methanol (3 ml_), cooled to 00C, and NaBH4 (0.26 g, 5.30 mmol) was added in one portion. The mixture was allowed to warm to room temperature and stirred for 72 hour(s), after which the reaction was quenched with 0.5 M Rochelle's salt solution. The resulting aqueous solution was diluted with ethyl acetate and stirred for 3 hour(s). The layers were separated, the aqueous phase was further extracted with ethyl acetate (2 x 50 mL), and the combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to afford a brown oil. The crude material was purified by medium pressure liquid chromatography (hexanes to ethyl acetate) to afford pure product (110a) as a colorless oil (0.07 g, 67 %). i H NMR (400 MHz, CD2Cl2) δ ppm 8.01 - 8.11 (d, 1 H), 7.68 (s, 1 H), 7.23 - 7.41 (m, 5 H), 7.12 - 7.22 (m, 1 H), 6.53 - 6.63 (d, 1 H), 4.87 - 5.03 (m, 1 H), 4.55 (s, 2 H), 3.80 (s, 3 H), 3.67 - 3.76 (m, 1 H), 3.37 - 3.46 (m, 1 H), 3.00 (d, 3 H), 2.09 - 2.25 (m, 4 H), 1.39 - 1.51 (m, 2 H)1 1.24 - 1.37 (m, 2 H). LRMS m/z calculated for C22H29N6O ([M+H]+): 393. Found: 393.
Preparation of (1R,4R)-4-(4-(1-iVlethyl-5-(methyla!T!ino)-1H-pyrazol-4-yl)pyrimidin-2- y!amino)cyc!ohexanol (110)
Compound 110a (60 mg, 0.15 mmol) was dissolved in methanol (1 mL) and added slowly via syringe to a flask containing 10% Pd/C (30 mg) under argon. HCl (cone, 0.04 mL, 0.46 mmol) was added, then the reaction flask was evacuated, and H2 gas was introduced via a balloon. The mixture was stirred at room temperature for 4 hour(s), after which time the H2 balloon was removed. Amberlite lRA-410 ion-exchange resin (0.50 g) was then added and the mixture was stirred at room temperature for 10 minutes. The resin was filtered off, and the filtrate was concentrated to an oil. The crude product was purified by medium pressure liquid chromatography (CH2CI2 to 10 % methanol / CH2CI2) to afford pure product 32 as a white solid (0.03 g, 67 %). 1H NMR (400 MHz, CD2CI2) δ ppm 8.06 (d, 1 H), 7.62 (s, 1 H), 7.10 - 7.26 (m, 1 H), δ.57 (d, 1 H), 4,84 - 4.99 (m, 1 H), 3.80 (s, 3 H), 3.57 - 3.77 (m, 2 H), 2.95 (d, 3 H), 2.10 - 2.22 (m, 2 H), 1.95 - 2.10 (m, 2 H)1 1.23 - 1.49 (m, 4 H). LRMS m/z calculated for Ci5H23N6O ([M+H]+): 303. Found:
303.
Figure imgf000050_0001
111 Preparation of 4-(5-Amino-1-benzyl-1H-pyrazol-4-yl)-N-isopropylpyrimidin-2-amine (111)
The above compound was prepared according to the method described for compound 110a, except that compound 3 was used as the starting material. 1H NMR (400 MHz, CD2CI2) δ ppm 1.13 (d, 6 H), 3.92 - 3.98 (m, 1 H), 4.82 (s, 1 H), 5.10 (s, 2 H), 5.45 (s, 2 H), 6.52 (d, 1 H), 7.11 (d, 2 H), 7.20 - 7.31 (m, 3 H)1 7.62 (s, 1 H), 8.01 (d, 1 H). LRMS m/z calculated for Ci8H22N6 ([M+Hf): 323. Found: 323.
Method C:
Figure imgf000050_0002
Preparation of N-((1 R,4R)-4-(benzyloxy)cyclohexy l)-4-(5-ethylamino)-1 -methyl-1 H-pyrazol-4- yl)pyrimidin-2-amine (112a)
Compound 9 (0.10 g, 0.27 mmol) was dissolved in THF (2 mL) and NaH (0.01 g, 0.27 mmol, 60 % dispersion in oil) was added in one portion. The mixture was stirred at room temperature for 10 minutes, followed by cooling to 00C. Ethyl iodide (0.03 mL, 0.38 mmol) was added dropwise, and then the mixture was slowly allowed to warm to room temperature. After stirring for 5 hour(s), the temperature was warmed to 1000C and the mixture was stirred for 24 hour(s). After cooling to room temperature, the mixture was quenched with saturated aqueous NaHCO3 and extracted with ethyl acetate. The combined organics were dried over MgSO4, filtered, and concentrated in vacuo to a yellow oil. The crude material was purified by column chromatography (CH2CI2 to 100 % ethyl acetate) to afford pure product (111a) as a colorless oil (50 mg, 47 %). 1H NMR (400 MHz, CD2CI2) δ ppm 8.07 (d, 1 H)1 7.63 (s, 1 H), 7.23 - 7.38 (m, 5 H), 6.90 - 7.03 (m, 1 H), 6.58 (d, 1 H), 4.83 - 4.96 (m, 1 H), 4.54 (s, 2 H), 3.76 (s, 3 H), 3.37 - 3.46 (m, 2 H), 3.24 - 3.34 (m, 2 H), 2.07 - 2.24 (m, 4 H), 1.38 - 1.50 (m, 2 H), 1.19 - 1.37 (m, 5 H). LRMS m/z calculated for C23H31N6O ([M+H]+): 407. Found: 407. Preparation of (1R,4R)-4-(4-(5-ethylamino)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2- ylamino)cyclohexanol (112)
Compound 112a was prepared from compound 9 as described in Method B. 1H NMR (400 MHz, CD2CI2) δ ppm 8.06 (d, 1 H), 7.62 (s, 1 H), 6.90 - 6.99 (m, 1 H), 6.57 (d, 1 H), 4.82 - 4.93 (m, 1 H), 3.58 - 3.79 (m, 5 H), 3.23 - 3.33 (m, 2 H), 2.06 - 2.20 (m, 4 H), 1.35 - 1.47 (m, 2 H), 0.98 - 1.19 (m, 5 H). LRMS m/z calculated for Ci6H25N6O ([M+Hf): 317. Found: 317.
Table 2. Compounds 112-114 were prepared according to the method C as described above.
Figure imgf000051_0001
Method D:
Figure imgf000052_0001
11Sa R ' Me 116a R ■ Bn
Figure imgf000052_0002
116 117
Alkylation of an aminopyrazole with a primary alkyl bromide
General Procedure:
To a stirred solution of aminopyrazole 7 in DMAC (3 mUmmol) at room temperature was added 60% NaH in mineral oil (2.2 equivalent). The resulting suspension was stirred for 20 minutes before it was cooled to 0-50C, and the alkyl bromide (1.3 equiv.) was added to the yellowish suspension. After stirring the resulting reaction mixture at 0-50C for an additional 1.5 hour(s), cold water was added. The solution was extracted with ethyl acetate, dried over MgSO4, and concentrated in vacuo. The residue thus obtained was purified by column chromatography using 0-50 % ethyl acetate in hexanes as the eluent.
Preparation of W-isopropyl-4-{1 -(4-methoxybenzyl)-5-[(2-methoxyethyl)amino]-1 H-pyrazol-4- yl}pyrimidin-2-amine (115a)
The above compound was prepared according to the general procedure using aminopyrazole 7 (50 mg, 0.15 mmol) and 2-bromoethylmethyl ether to give the product (34 mg, 57%) as a white solid. 1H NMR (400 MHz, CH2CI2-D2) δ ppm 1.14 (t, J = 6.3 Hz, 7 H), 3.14 - 3.20 (m, 2 H), 3.22 (s, 3 H), 3.34 - 3.41 (m, 2 H), 3.69 (S, 3 H), 3.99 - 4.10 (m, 1 H), 4.84 (s, 1 H), 5.15 (s, 2 H)1 6.51 (d, J = 5.3 Hz, 1 H), 6.75 - 6.83 (m, 2 H), 7.03 (d, J = 8.6 Hz, 2 H), 7.31 (s, 1 H), 7.65 (s, 1 H), 8.02 (d, J = 5.3 Hz, 1 H). LRMS m/z calculated for C2IH29N6O2 [M+H]+397. Found: 397. Preparatioπ of 4-[5-{t2-(benzyloxy)ethyl]amino}-1-(4-methoxybeπzyl)-1H-pyrazol-4-yl]-W- isopropylpyrimidin-2-amine (116a)
The above compound was prepared according to the general procedure using aminopyrazole 7 (100 mg, 0.30 mmol) and benzyl-2-bromoethyl ether to give crude material (64 mg) containing the title compound 116a. The crude material was subjected to debenzylation conditions as described below. LRMS m/z calculated for C27H33N6O2 [M+H]+473. Found: 473.
Preparation of W-isopropyl-4-{5-[(2-methoxyethyl)amino]-1H-pyrazol-4-yl}pyrimidin-2-amine (115)
A solution of pyrazole 115a (34 mg, 0.09 mmol) in TFA (0.5 ml_) was heated at 70 0C for 4 hour(s) while stirring under N2. The reaction mixture was cooled, diluted with CH2CI2 and washed with saturated aqueous NaHCO3, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by column chromatography (0-5% methanol in CH2CI2) to afford methoxyethylaminopyrazole 115 (17 mg, 68%) as an off white solid. See Table 3.
Preparation of 2-{[4-[2-(isopropylamino)pyrimidiπ-4-yl]-1-(4-methoxybenzyl)-1H-pyrazol-5- yl]amino}ethanol (116)
The crude material (64 mg) containing compound 116a was dissolved in methanol (3 ml_) and the resulting solution was purged with N2 for 15 minutes. Pd on carbon (10 %, 13 mg, 20 wt.%) followed by concentrated HCI (3 drops) were added to the solution. The suspension was hydrogenated at atmospheric pressure and room temperature for 3 hour(s). The solids were filtered off, and the residue was washed thoroughly with methanol. The filtrate was concentrated in vacuo, and the resulting oil was taken up in CH2CI2, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (0-5% methanol in CH2CI2) to afford alcohol 116 (17 mg, 15 % for the 2 steps from 7) as an off-white solid. See Table 3.
Preparation of 2-({4-[2-(isopropylamino)pyrimidin-4-yl]-1H-pyrazol-5-yi}amino)ethanol (D5)
A solution of pyrazole D4 (10 mg, 0.03 mmol) in TFA (0.5 ml_) was heated at 70 0C for 15 hour(s) while stirring under N2. The reaction mixture was cooled, diluted with CH2CI2 and washed with saturated aqueous NaHCO3, dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude residue was purified by preparative TLC using 3 % 7 N NH3/methanol in CH2CI2 as the eluant to afford aminopyrazole D5 (3 mg, 38 %) as an off white solid. See Table 3. Table 3. Compounds 115-119 were prepared according to the method D as described above.
Figure imgf000054_0001
Method E:
Figure imgf000055_0001
0C , 48 h
120a 120
Preparation of W-isopropyl-4-[1-(4-methoxybenzyl)-5-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazol- 4-yl]pyrimidiπ-2-amine (120a) and /V-isopropyl-4-[5-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazoI-4- yl]pyrimidin-2-amine (120)
To a stirred solution of aminopyrazole 7 (100 mg, 0.30 mmol) in DMAC (2 mL) at room temperature was added NaH in mineral oil (60 %, 79 mg, 2.0 mmol). The resulting suspension was stirred for 20 minutes, and then tetrahydropyran-4-mesyiate (1.2 g, 6.6 mmol) was added to the yellowish suspension at room temperature. The resulting reaction mixture was stirred under N2 at 120 0C for 48 hour(s). Although analysis of an aliquot by LCMS showed only about 50% conversion to the desired product, cold water was added to quench the reaction. The solution was extracted with ethyl acetate, dried over MgSO4, filtered, and concentrated in vacuo. The residue thus obtained containing compound 120a was subjected to PMB deprotection as described for compound 116 above followed by chromatographic purification (0-5% methanol in CH2CI2 ) to afford 4-terahydropyranylaminopyrazole 120 (10 mg, 11 % for the 2 steps from 7) as a off-white solid. LRMS m/z calculated for C23H31N6O2 [M+Hf 423. Found: 423.
Preparation of (4-[(4-{1-methyl-5-[(tetrahydrofuran-3-ylmethyl)amino]-1 H-pyrazol-4-yl}pyrimidin-2- yl)amino]cyclohexanol) (121)
The above compound 121 was prepared in a similar manner, starting from aminopyrazole 8. See Table 4. i
Table 4. Compounds 120-121 were prepared according to the method E as described above.
Figure imgf000055_0002
Figure imgf000056_0002
Method F:
Amino deprotectioπ followed by Reductive amination of an aminopyrazole with cyclic ketones
General Procedure:
A suspension of aminopyrazole, a ketone (5 eq) and Na(OAc)3BH (2 eq) in dichloroethane (0.15 M) was stirred under N2 at room temperature as glacial acetic acid (1.1 eq) was added at once. Stirring was continued for 15 hour(s) at room temperature, and then the reaction mixture was diluted with CH2CI2, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (0-5% methanol in CH2CI2) to afford the desired product.
Figure imgf000056_0001
122a 122 R = c-butyl 123 R = 3-THF
Preparation of 4-(5-amino-1H-pyrazol-4-yl)-W-isopropylpyrimidin-2-amine (122a)
Pyrazole 7 (150 mg, 0.450 mmol) was deprotected according to the procedure described for the preparation of D5, using TFA (2 ml_) at 70 0C for 48 hour(s). Purification by column chromatography (0- 5% methanol in CH2CI2) afforded aminopyrazole 122a (69 mg, 70 %) as a pale yellow solid. 1H NMR (400 MHz, CD3OD) δ ppm 1.11 - 1.20 (m, 6 H), 3.88 - 3.98 (m, 1 H)1 4.72 (s, 1 H), 6.61 (d, J = 5.6 Hz, 1 H), 7.76 (s, 1 H), 7.86 - 7.94 (m, 1 H). LRMS m/z calculated for C10H115N6 [M+H]+219. Found: 219.
Preparation of (4-(5-amino-1H-pyrazol-4-yl)-N-cyclohexylpyrimidin-2-amine) (124)
The above compound was prepared in a similar manner, starting from compound 6. See Table 5. Preparation of 4-[5-(cyclobutylamino)-1H-pyrazol-4-yl]-W-isopropylpyrimidin-2-amiπe (122)
Compound 122 was prepared as a white solid following the general procedure described above. Aminopyrazole 122a (50 mg, 0.23 mmol), cyclobutanone (81 mg, 1.1 mmol), Na(OAc)3BH (98 mg, 0.46 mmol) and glacial acetic acid (0.015 mL) were reacted in dichloroethaπe (1.5 mL) to afford the title compound 122 (6 mg, 10 %). See Table 5.
Preparation of ΛMsopropyl-4-[5-(tetrahydrof uran-3-ylamino)-1 H-pyrazol-4-yl]pyrimidin-2-amine
(123)
Compound 123 was prepared as an off-white solid following the general procedure described above.
Aminopyrazole 122a (50 mg, 0.23 mmol), tetrahydrofuran-3-one (97 mg, 1.1 mmol), Na(OAc)3BH (98 mg,
0.46 mmol), and glacial acetic acid (0.015 mL) were reacted in dichloroethane (1.5 mL) to afford the title compound 123 (12 mg, 18 %). See Table 5.
Table 5. Compounds 122-127 were prepared according to the method F as described above.
Figure imgf000057_0001
Figure imgf000058_0001
mCPBA
THF1 rt, 4h
Figure imgf000058_0002
Preparation of (1R.4R)-4-(4,5,6,7-tetrahydropyrazolo [I.S-alpyrimidin-Z-ylaminoJcyclohexanol (125)
A solution of compound 3-(2-(methylsulfonyl)pyrimidine-4-yl)-4,5,6,7-tetrahydropyazolo [1,5-a]pyrimidine 125a (287mg, crude), (1R,2R)-4-aminocyclohexanol (500 mg, 4.35 mmol) in isopropanol (6 ml.) was heated to 140°C for 1.5h by microwave. The reaction mixture was cooled to room temperature, extracted with ethyl acetate (2 X 50 mL), dried over MgSO4 filtered, and concentrated in vacuo. The resulting crude residue was purified HPLC to yield frans-cyclohexanol pyrimidine 125 (20 mg) as a pale yellow solid. 1 H NMR (400 MHz, CD3CN) δ ppm 1.12 - 1.41 (m, 6 H) 1.99 - 2.18 (m, 4 H) 2.69 - 2.75 (m, 1 H) 3.35 - 3.46 (m, 2 H) 3.48 - 3.59 (m, 1 H) 3.66 (dd, J = 7.1 , 3.3 Hz, 1 H) 4.01 (t, J = 6.1 Hz, 2 H) 5.70 (s, 1 H) 6.55 (d, J = 5.6 Hz, 1 H) 6.91 (s, 1 H) 7.59 (s, 1 H) 7.88 - 8.02 (m, 1 H). LRMS m/z calcd. for Ci6H23N6O [M+Hf 315. Found: 315.
Preparation of 3-(2-(methylsulfonyl)pyrimidiπe-4-yl)-4,5,6,7-tetrahydropyazolo [1,5-a]pyrimidine (125a)
The crude product 3-(2-(methylthio)pyrimidine-4-yl)-4,5,6,7-tetrahydropyazolo [1 ,5-a]pyιimidine 125b (310mg) was dissolved in THF (8 mL). To the solution was added 3-chloroperoxybenzoic acide (mCPBA) (810 mg, 3.63 mmol, 77 % tech grade) at O0C. The mixture was then allowed to warm to room temperature slowly, and stirred for 4 hours. The mixture was then quenched with NaHCO3 (saturated, aqueous) until a pH of 9 was reached. The aqueous solution was extracted with ethyl acetate (3 x 50 mL), the combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to provide a orange oil (287mg, crude).
Preparation of 3-(2-(methylthio)pyrimidine-4-yl)-4,5,6,7-tetrahydropyrazolo [1,5-a]pyrimidine (125b) 4-(2-(methylthio)pyrimidine-4-yl)-1H-pyrazole-5-amine (B) (300mg, 1.45 mmol) was dissolved in THF (5 mL). To the solution was added 60%NaH (182mg, 4.35 mmol) slowly. The suspension was stirred at room temperature for 5 minutes followed by addition of 1-chloro-3-iodopropane (295mg, 1.45 mmol). The solution was heated to 1000C by microwave for 20 minutes, cooled to room temperature, extracted with ethyl acetate (3 X 5OmL)1 the combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to provide 312 mg of orange solid crude product. Preparation of 4-(2-(methylthio)pyrimidine-4-yl)-1H-pyrazole-5-amine (125c):
To a suspension of 4-(isoxazol-4-yl)-2-(methylthio)pyrimidine 12Sd (3.9 g, 20.2 mmol) in acetic acid (5OmL) was added hydrazine (3.0 ml_, 61.8 mmol) dropwise over 5 min at 00C. After the reaction mixture was stirred for 10 min the ice bath was removed. The suspension was stirred at room temperature for 1hour and slowly heated to 850C for δhours. The crude mixture was cooled to room temperature, basified with NH4OH to pH ~9, filtered, and dried in vacuo. The resulting crude residue was purified by column chromatography (0 - 10% MeOH in CH2CI2) to yield pure methylthiopyrimidine 125c as a pale yellow solid (3.12 g, 75 %). 1 H NMR (400 MHz, CDCI3) δ ppm 2.55 (s, 3 H), 5.35 (m, 2H), 6.91 (d, J = 5.3 Hz, 1 H), 7.77 (s, 1 H), 8.29 (d, J = 5.3 Hz, 1 H). LRMS m/z calcd. for C8H10N5S [M+H]+208. Found: 208.
Figure imgf000059_0001
125d 126c 126b mCPBA THF1 rt, 4h
Figure imgf000059_0002
Preparation 7-[2-(4-Hydroxy-cyclohexylamino)-pyrimidin-4-yl]-1 H-imidazo[1 ,2-ϋ]pyrazol-2-one (126)
Compound 126 was prepared in a similar manner described for preparation of 125 starting from compound 126a. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.22 (s, 1 H) 8.17 (d, J = 5.3 Hz, 1 H) 7.96 (s, 1 H) 6.74 (d, J = 5.3 Hz, 1 H) 6.74 (d, J = 5.3 Hz, 1 H) 6.64 (d, J = 6.6 Hz, 1 H) 6.64 (d, J = 6.6 Hz, 1 H) 4.77 (s, 2 H) 4.55 (d, J = 4.3 Hz, 1 H) 3.55 - 3.76 (m, 1 H) 3.37 - 3.49 (m, 1 H) 1.90 - 2.03 (m, 2 H) 1.79 - 1.88 (m, 2 H) 1.18 - 1.30 (m, 4 H). LRMS m/z calcd. for C15H19N6O2 [M+H]+ 315. Found: 315. Preparation of 7-(2-Methanesulfonyl-pyrimidin-4-yl)-1H-imidazo[1,2-ή]pyrazol-2-one
(126a)
Compound 126a was prepared in a similar manner described for preparation of 12Sa. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.01 (s, 1 H) 8.89 (d, J = 5.3 Hz, 1 H) 8.23 (s, 1 H) 7.89 (d, J = 5.5 Hz, 1 H) 4.83 (s, 2 H) 3.50 (s, 3 H). LRMS m/z calcd. for C10H10N5O3S [M+Hf 280. Found: 280. Preparation of 7-(2-Methylsulfanyl-pyrimidin-4-yl)-1tt-imidazo[1,2-b]pyrazol-2-one (126b): HATU (6.56 g, 17.2 mmol) was added to a stirring mixture of 1 (3.52 g, 13.3 mmol), DIEΞA (3.00 ml_, 17.2 mmol) in DMF (78 mL) at 450C. The resulting mixture was stirred at 600C for 2 hours. DMF was evaporated under reduced pressure; the residue was washed with water (250 mL). The yellow solid crude product was collected by filtration and then stirred in ethyl acetate (50 mL) for 16 hours. The yellow solid product was filtered off and air dried to gain 2.05 g, 62 % yield. 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.81 (s, 1 H), 8.48 (d, J = 5.3 Hz, 1 H), 8.08 (s, 1 H), 7.33 (d, J = 5.5 Hz, 1 H), 4.79 (s, 2 H), 2.53 (s, 3 H). LRMS m/z calcd. for C10H10N5OS [M+H]+248. Found: 248. Preparation of [5-Amino-4-(2-methylsulfanyl-pyrimidin-4-yl)-pyrazol-1-yl]-acetic acid
(126c):
Ethyl hydrazinoacetate HCI (Aldrich) (2.10 g, 13.6 mmol) was added to a mixture of 12Sd (2.5 g, 12.9 mmol) in Ethanol (20 mL). The reaction was completed after the above mixture was stirred at 950C for 3 hours. The pyrazole ethyl ester product was detected by LCMS [M=H] = 294. The reaction mixture was diluted with ethanol (60 mL) and treated with a mixture of NaOH (1.29 g, 32.3 mmol) in H2O (6 mL) at 5O0C while stirring. The acid product was precipitated immediately after the addition was completed. The pH of the mixture was adjusted to 7- 6 with 1 N HCI aq. solution, and the resulting mixture was concentrated down to the volume of 30 m L. The light yellow solid crude product (3.9 g) was collected by filtration and dried under reduced pressure. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.29 (d, J = 5.5 Hz, 1 H) 7.81 (s, 1 H) 7.21 (d, J = 5.5 Hz, 1 H) 6.61 (s, 2 H) 4.34 (s, 2 H) 3.16 (s, 3 H). LRMS m/z calcd. for C10H12N5O2S [M+Hf 266. Found: 266.
Figure imgf000061_0001
125d 127b 127a
lsopropanol microwave, 14O0C, 1.5h
H2N-^)- 'OH
Figure imgf000061_0002
127
Preparation ^[^(IH-lmidazoϊi^-blpyrazol-T-yO-pyrimidin^-ylaminol-cyclohexanol (127)
Compound 127 was prepared in a similar manner described for preparation of 125 starting from compound 127a instead of 125a. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.45 (s, 1 H) 8.12 (s, 1 H), 8.08 (d, J = 5.0 Hz, 1 H)1 7.69 (s, 1 H), 7.38 (s, 1 H), 6.72 (d, J = 5.3 Hz, 1 H), 6.33 (s, 1 H), 3.57 - 3.79 (m, 1 H), 3.39 - 3.55 (m, 2 H)1 1.91 - 2.05 (m, 2 H), 1.78 - 1.90 (m, 2 H), 1.21 - 1.34 (m, 2 H). LRMS m/z calcd. for C15H19N6O [MtHf 299. Found: 299.
Preparation of 7-(2-Methanesulfonyl-pyrimidiπ-4-yl)-1H-imidazo[1,2-ύ]pyrazole (127a) Compound 127a was prepared in a similar manner described for preparation of 125a starting from compound 127b instead of 125b. 1H NMR (400 MHz1 CDCI3) δ ppm 10.13 (s, 1 H) 8.53 (d, J=5.5 Hz, 1 H) 8.14 (d, J=1.0 Hz, 1 H) 7.41 - 7.46 (m, 2 H) 7.07 - 7.11 (m, 1 H) 3.36 (s, 3 H). LRMS m/z calcd. for C10H10N5O2S [M+H]+264. Found: 264.
Preparation of 7-(2-Methylsulfanyl-pyrimidin-4-yl)-1H-imidazo[1,2-6]pyrazole(127b): 1-(2-2-dimethoxyethyl) hydrazine (0.93 g, 7.7 mmol) (see US 005334595A) was added to a suspension of compound 125d (1.5 g, 7.7 mmol) in absolute ethanol (15 mL) at room temperature. The red solution resulting mixture was stirred at 600C for 16 hours. After cooling to room temperature, 20% v/v H2SO4 aqueous solution (15 mL) was added and the resulting mixture was stirred at 950C further 1hour. After cooling to room temperature the mixture was poured into crushed ice and the pH was brought to 8 by adding solid NaHCO3. The mixture was extracted into DCM (2x70 mL), washed with brine, dried over MgSO4, and concentrated to gain 1.5 g of dark semi solid crude product. The crude product was triturated with ethyl acetate. The tan color solid desired product (800 mg) was filtrated and air dried, the dark red filtrate was concentrated down to the volume of 15 mL and diluted with Hexanes. The resulting dark red solution was stirred at room temperature 16 hours. The red solid product was filtered to gain 250 mg product 127b. The total amount of isolated product was 1.05 g (58%). 1H NMR (400 MHz, CDCI3) δ ppm 8.93 (s, 1 H), 8.34 (d, J = 5.3 Hz, 1 H)1 8.09 (s, 1 H), 7.42 (d, J = 2.3 Hz, 1 H), 7.06 (dd, J=2.3, 1.3 Hz, 1 H), 7.03 (d, J=5.3 Hz, 1 H) 2.62 (s, 3 H). LRMS m/z calcd. for C10H10N5S [M+Hf 232. Found: 232.
Method G
Figure imgf000062_0001
128
Preparation of 4-[4-(5-Amino-1-methyl-1 H-pyrazol-4-yl)-pyrimidin-2-ylamino]-piperidine-1- carboxylic acid isobutyl ester (128)
Iso-butyl chloroformate (36 mg, 0.26 mmol) was added to a mixture of 128a (65 mg, 0.24 mmol) and DIEΞA (34 mg, 0.26 mmol) in DMF (1.5 mL) at room temperature. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The mixture was diluted with ethyl acetate (25 mL) and washed with water, dried MgSO4, concentrated to dryness. The crude product was purified by ISCO silica gel column chromatography, eluting with CHCI3: MeOH (9:1) to gain 52 mg (58%) of off white solid product G3. 1H NMR (400 MHz, CDCI3) δ ppm 8.10 (d, J = 5.5 Hz, 1 H), 7.67 (s, 1 H), 6.6 (d, J = 5.5 Hz, 1 H), 5.58 (s, 2 H), 5.20 (s, 1 H), 4.05 - 4.25 (m, 2 H)1 3.88 (d, J = 6.6 Hz, 2 H) 3.67 (s, 3 H) 3.02 (t, J = 11.6 Hz, 2 H), 2.09 (dd, J = 12.8, 3.0 Hz, 2 H), 1.76 - 2.02 (m, 2 H) 1.47 (q, J = 9.8 Hz, 2 H), 0.94 (d, J = 6.8 Hz, 6 H).. LRMS m/z calcd. for C18H28N7O2 [M+Hf 374. Found: 374.
Preparation of t4-(5-Amino-1-methyl-1 W-pyrazol-4-yl)-pyrimidin-2-yl]-piperidin-4-yl-amine (128a) A mixture of 128b (0.9 g, 2.4 mmol) in 4 mL of DCM: TFA (1 :1) was stirred at room temperature for 10 min. Solvent and TFA were removed under reduced pressure. The residue was taken to CHCI3: IPA (4:1) (50 mL) and treated with 10% KOH aqueous solution (5 mL). The organic layer was separated, concentrated to dryness to gain a light yellow solid. The crude product was washed with ethyl acetate to gain 0.63 g colorless solid product 128a. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.69 (d, J = 4.3 Hz, 1 H), 8.58 (s, 1 H), 8.05 (d, J = 6.3 Hz, 1 H), 7.94 (s, 1 H), 7.04 (s, 1 H), 6.92 (s, 2 H)1 3.84 - 4.04 (m, 1 H), 3.59
(s, 3 H)1 3.37 (d, J = 12.1 Hz, 2 H), 2.88 - 3.06 (m, 2 H), 2.10 (d, J = 13.4 Hz, 2 H), 1.63 - 1.75 (m, 2 H).
LRMS m/z calcd. for Ci3H20N7S [M+H]+ 274. Found: 274.
Preparation of 4-[4-(5-Amino-1-methyl-1 H-pyrazol-4-yl)-pyrimidin-2-ylamino]-piperidine-1- carboxylic acid tert-butyl ester (128b)
Compound (128b) was prepared according to method A, starting with compound 3a and 4-amino-1-boc- piperidine 1H NMR (400 MHz, CDCI3) δ ppm 8.12 (d, J = 5.3 Hz, 1 H), 7.67 (s, 1 H), 6.62 (d, J = 5.5 Hz, 1
H), 5.55 (s, 2 H), 5.05 (s, 1 H)1 3.97 - 4.10 (m, 2 H), 3.93 (s, 1 H), 3.67 (s, 3 H), 2.96 (t, J = 12.0 Hz, 2 H),
2.06 - 2.12 (m, 2 H), 1.48 (s, 9 H), 1.40 - 1.47 (m, 2 H). LRMS m/z calcd. for C18H28N7O2 [M+H]+374.
Found: 374.
Table 6. Compounds 128-132 were prepared according to the method G as described above.
δ ppm 7.67 (s, 1 5.58 (s, 4.25 (m, 2 2 H), 3.67 (s, 3 H), 2.09 1.76 - Hz, 2 H).
δ ppm (s, 1 H), - 7.41 Hz, 2 H), (s, 2 (m, 2 (m, 2
δ ppm 7.75 (s, 1 (d, J = Hz, 1 H), 5.25 (s, 1 2 H), 3.54 (q, J = 5.9
Figure imgf000063_0001
δ ppm 7.74 (s, 1 7.21 (d, J = 5.3 Hz, (s, 2 H), (m, 2 H), - 3.44 (m,
δ ppm 7.67 (s, 1 6.63 (d, H), 5.15 Hz, 1 H), 2 H), 3.81 H), 3.05 (t, J = 12.8
Figure imgf000064_0001
2 H)
Method H
Figure imgf000064_0002
133
Preparation of [4-(5-Amino-1-methyl-1 H-pyτazol-4-yl)-pyrimidiπ-2-yl]-(1-methanesulfonyl-piperidin- 4-yl)-amine (133)
Methane sulfonyl chloride (25 mg, 0.22 mmol) was added drop wise to a mixture of 128a (50 mg, 0.18 mmol) and DIEEA (59 mg, 0.46 mmol) in DMF (1 ml.) at 0 C. The resulting mixture was stirred at room temperature for 15 minutes. DMF and DIEΞA were removed under reduced pressure at 850C. The residue triturated with 10% K2CO3 aqueous solution. The solid product was then filtered and washed with water, ethyl acetate to gain 52 mg colorless solid product 133. 1 H NMR (400 MHz, CDCI3) δ ppm 8.13 (d, J = 5.0 Hz1 1 H), 7.67 (s, 1 H), 6.65 (d, J = 5.3 Hz, 1 H), 5.53 (s, 2 H), 4.90 (d, J = 3.5 Hz1 1 H), 3.90 - 4.13 (m, 1 H), 3.76 (d, J = 12.1 Hz, 2 H)1 3.68 (s, 3 H)1 2.94 (t, J = 10.7 Hz, 2 H)1 2.82 (s, 3 H)1 2.21 (d, J = 11.3 Hz1 2 H)1 1.66 - 1.79 (m, 2 H). LRMS m/z calcd. for CuH22N7O2S [M+H]+352. Found: 352. Table 7. Compounds 134-140 were prepared according to the method H as described above.
Figure imgf000065_0001
Figure imgf000066_0002
Figure imgf000066_0001
Preparation of [4-(5-Amino-1-benzyl-1 H-pyrazol-4-yl)-pyrimidin-2-yl]-(1-methanesulfonyl-piperidin- 4-yl)-amine (141)
Compound 141 was prepared according to the method described for preparation of 133 starting from compound 141a . 1H NMR (400 MHz, DMSO-d6) δ ppm 8.05 (d, J = 5.3 Hz1 1 H), 7.80 (s, 1 H), 7.32 (t, J = 7.3 Hz, 2 H), 7.25 (t, J = 7.3 Hz, 1 H), 7.15 (d, J = 7.3 Hz, 2 H), 7.08 (d, J = 7.6 Hz, 1 H), 6.87 (s, 2 H),
6.68 (d, J = 5.3 Hz, 1 H), 5.20 (s, 2 H), 3.67 - 3.92 (m, 1 H), 3.55 (d, J = 12.1 Hz, 2 H), 2.87 (s, 3 H), 2.80 - 2.91 (m, 2 H), 1.90 - 2.09 (m, 2 H), 1.39 - 1.61 (m, 2 H). LRMS m/z calcd. for C20H26N7O2S [M+H]+428. Found: 428.
Preparation of [4-(5-Amino-1-benzyl-1H-pyrazol"4-yl)-pyrimidin-2-yl]-piperidin-4-y!-amine (141a) Compound 141a was prepared according to the method described for preparation of 128a starting from compound 141b. 1H NMR (400 MHz, CDCI3) δ ppm 7.75 (s, 1 H) 7.29 - 7.40 (m, 3 H) 7.21 (d, J = 6.8 Hz, 2 H), 6.63 (d, J = 5.3 Hz, 1 H), 5.47 (s, 2 H), 5.22 (s, 2 H), 4.93 (d, J = 5.0 Hz, 1 H), 3.69 - 3.95 (m, 1 H), 2.99 - 3.16 (m, 2 H), 2.59 - 2.81 (m, 2 H), 2.06 (dd, J = 12.2, 3.2 Hz, 2 H), 1.94 (s, 2 H), 1.30 - 1.46 (m, 2 H). LRMS m/z calcd. for C19H24N7 [M+H]+ 350. Found: 350.
Preparation of 4-[4-(5-Amino-1-benzyl-1H-pyrazol-4-yl)-pyrimidin-2-ylamino]-piperidlne-1- carboxylic acid tert-butyl ester (141b)
Compound 141b was prepared according to the method described for preparation of 128b starting from compound 1a instead of 3a. 1H NMR (400 MHz, CDCI3) δ ppm 8.13 (d, J = 5.5 Hz, 1 H), 7.75 (s, 1 H)1 7.36 (d, J = 7.8 Hz, 2 H), 7.30 - 7.40 (m, 1 H), 7.21 (d, J = 7.6 Hz, 2 H), 6.65 (d, J = 5.5 Hz, 1 H), 5.43 (s, 2 H), 5.22 (s, 2 H), 4.87 (d, J = 2.3 Hz, 1 H), 4.03 (d, J = 12.3 Hz, 2 H), 3.90 (dd, J = 7.3, 3.8 Hz, 1 H), 2.93 (t, J = 12.3 Hz, 2 H), 2.03 (dd, J = 12.3, 2.0 Hz, 2 H), 1.46 (s, 9 H) 1.32 - 1.45 (m, 2 H). LRMS m/z calcd. for C24H32N7O2 [M+Hf 450. Found: 450.
Table 8. Compounds 141-143 were prepared according to the method of preparation of compound 141 as described above. Compound 142 was prepared according to the method described for preparation of 141 with the substitution of benzenesulfonyl chloride instead of methanesuifonyl chloride.
Figure imgf000067_0001
Figure imgf000068_0002
Figure imgf000068_0001
Preparation of [4-(5-Amino-1-methyl-1 H-pyrazol-4-yl)-pyrimidin-2-yl]-(1-benzenesulfonyl-azetidin-3- yl)-amine (143)
Compound 143 was prepared according to the method described for preparation of 142 starting from compound 143a. 1H NMR (400 MHz, CDCI3) δ ppm 8.06 (d, J = 4.0 Hz, 1 H), 7.88 (d, J = 7.1 Hz, 2 H), 7.66 - 7.74 (m, 1 H)1 7.65 (s, 1 H), 7.62 (d, J = 7.6 Hz, 2 H), 6.67 (d, J = 4.3 Hz, 1 H), 5.49 (s, 2 H), 5.12 (d, J = 5.8 Hz, 1 H), 4.46 - 4.69 (m, 1 H), 4.18 (t, J = 7.4 Hz1 2 H), 3.68 - 3.73 (m, 2 H)1 3.67 (s, 3 H). LRMS m/z calcd. for C17H20N7O2S [M+H]+386. Found: 386.
Preparation of [4-(5-Amino-1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-azetidin-3-yl-amine (143a) Compound 143a was prepared according to the method described for preparation of 128a starting from compound 143b. 1H NMR (400 MHz1 DMSO-d6) δ ppm 8.20 (d, J=7.3 Hz, 1 H), 8.03 (s, 1 H)1 7.69 - 7.85 (m, 1 H)1 7.32 (s, 2 H)1 7.03 (d, J = 7.1 Hz, 1 H)1 6.68 (d, J = 7.3 Hz1 1 H)1 4.38 - 4.57 (m, 1 H)1 4.17 - 4.28 (m, 2 H), 4.09 - 4.17 (m, 1 H)1 3.85 - 4.01 (m, 1 H)1 3.59 (s, 3 H). LRMS m/z calcd. for C11H16N7 [M+Hf 246. Found: 246. Preparation of 4-[4-(5-Amino-1-methyl-1 H-pyrazol-4-yl)-pyrimidin-2-ylamino]-azitidine-1-carboxylic acid tert-butyl ester (143b)
Compound (143b) was prepared according to method A starting with 3a and 3-amino-1-boc-azetidine 1H NMR (400 MHz, CDCI3) δ ppm 8.13 (d, J = 4.8 Hz, 1 H), 7.67 (s, 1 H), 6.68 (d, J=5.0 Hz, 1 H), 5.54 (s, 2 H), 5.39 (d, J = 4.3 Hz, 1 H), 4.50 - 4.80 (m, 1 H), 4.31 (t, J = 8.1 Hz, 2 H), 3.76 - 3.95 (m, 2 H), 3.67 (s, 3 H), 1.46 (s, 9 H). LRMS m/z calcd. for C16H24N7O2 [M+Hf 346. Found: 346.
Table 9. Compounds 144-147 were prepared according to the method described for preparation of 143 as described above.
Figure imgf000069_0001
Figure imgf000070_0001
145 ,
Preparation of 3-{[4-(5-Amino-1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-ylamino]-methyl}-azetidiπe-1- carboxylic acid tert-butyl ester (145b)
Compound (145b) was prepared according to method A as described above starting with 3a and displacing the sulfonyl with 3-aminomethyl-i-boc-azitidine. 1H NMR (400 MHz, CDCI3) δ ppm 8.12 (d, J =
5.5 Hz, 1 H), 7.67 (s, 1 H), 6.65 (d, J = 5.5 Hz, 1 H), 5.56 (s, 2 H)1 5.22 (d, J = 4.3 Hz, 1 H), 4.05 (t, J = 8.4
Hz, 2 H), 3.69 - 3.72 (m, 2 H)1 3.67 (s, 3 H), 3.63 - 3.66 (m, 2 H), 2.83 - 2.90 (m, 1 H), 1.44 (s, 9 H). LRMS m/z calcd. for C17H26N7O2 [M+H]+360. Found: 360.
Preparation of [4-(5-Amino-1 -methyl-1 W-pyrazol-4-yl)-pyrimidin-2-yl]-azetidin-3-ylmethyl-amine
(145a)
Compound 145a was prepared according to the method described for preparation of 128a starting from compound 145b. LRMS m/z calcd. for C12H18N7 [M+H]+260. Found: 260.
Preparation of [4-(5-Amino-1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-(1-benzenesulfonyl-azetidin-3- ylmethyl)-amine (145)
Compound 145 was prepared according to the method described for preparation of 143 starting from compound 145a. 1H NMR (400 MHz, CDCI3) δ ppm 8.07 (d, J = 5.5 Hz, 1 H) 7.77 - 7.87 (m, 2 H) 7.67 (s,
1 H) 7.61 - 7.66 (m, 1 H) 7.54 - 7.60 (m, 2 H) 6.64 (d, J = 5.3 Hz, 1 H) 5. Hz, 2 H) 3.68 (s, 3 H) 3.66 (d, J =
5.0 Hz, 1 H) 3.64 (d, J=5.0 Hz, 1 H) 3.56 (t, J = 6.6 Hz, 2 H) 2.63 - 2.74 (m, 1 H). LRMS m/z calcd. for
C18H22N7O2S [M+Hf 400. Found: 400.
Figure imgf000071_0001
Preparation of W-{2-[4-(5-Amino-1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-ylamino]-ethyl}- benzenesulfonamide (146)
Compound 146 was prepared according to the method described for preparation of 143 starting from compound 146a. 1H NMR (400 MHz, CDCI3) δ ppm 8.10 (d, J=5.5 Hz, 1 H), 7.82 (d, J = 7.6 Hz, 2 H), 7.67 (s, 1 H), 7.51 - 7.59 (m, 1 H), 7.48 (d, J = 7.6 Hz1 2 H), 6.66 (d, J = 5.3 Hz, 1 H), 5.77 (s, 1 H), 5.51 (s, 2 H), 5.03 - 5.18 (m, 1 H), 3.68 (s, 3 H), 3.58 (q, J = 6.0 Hz, 2 H), 3.23 (q, J = 5.7 Hz, 2 H). LRMS m/z calcd. for Ci6H20N7O2S [M+H]+374. Found: 374.
Preparation of W1-[4-(5-Amino-1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-ethane-1, 2-diamine. (146a) Compound (146a) was prepared according to method A as described above starting with 3a and displacing the sulfone with 1 , 2-diaminoethane. LRMS m/z calcd. for C10H15N7 [M+H]+ 234. Found: 234.
Figure imgf000071_0002
Preparation of W-{2-[4-(5-Amino-1 -benzyl-1 H-pyrazol-4-yl)-pyrimidin-2-ylamino]-ethyl}- methanesulfonamide (147)
Compound 147 was prepared according to the method described for preparation of 146 starting from compound 147a. 1 H NMR (400 MHz1 CDCI3) δ ppm 8.01 (d, J = 5.5 Hz, 1 H), 7.70 (s, 1 H), 7.30 (d, J = 7.3 Hz, 2 H), 7.25 - 7.36 (m, 1 H), 7.16 (d, J = 7.1 Hz, 2 H), 6.62 (d, J = 5.3 Hz, 1 H), 5.53 - 5.82 (m, 2 H), 5.27 (s, 2 H), 5.16 (s, 2 H), 3.50 (t, J = 5.9 Hz, 2 H), 3.38 (s, 3 H), 3.25 (t, J = 5.8 Hz, 2 H). LRMS m/z calcd. for C17H22N7O2S [M+H]+388. Found: 388.
Preparation of Λ/1-[4-(5-Amino-1 -benzyl-1 H-pyrazol-4-yl)-pyrimidin-2-yl]-ethane-1, 2-diamine. (147a)
Compound (147a) was prepared according to method A as described above starting with 1a and displacing the sulfone with 1, 2-diaminoethane. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.03 (d, J = 5.3 Hz, 1 H), 7.79 (s, 1 H), 7.32 (t, J = 7.3 Hz, 2 H)1 7.21 - 7.28 (m, 1 H), 7.16 (d, J = 7.1 Hz, 2 H)1 7.02 (s, 1 H),
6.87 (s, 2 H), 6.66 (d, J = 5.3 Hz, 1 H), 5.20 (s, 2 H), 3.25 (q, J = 6.1 Hz, 2 H), 2.97 - 3.50 (m, 2 H), 2.69 (t, J = 6.3 Hz, 2 H). LRMS m/z calcd. for Ci6H20N7 [M+Hf 310. Found: 310.
Figure imgf000072_0001
Preparation of [4-(5-Amino-1-methyl-1 H-pyrazol-4-yl)-pyrimidin-2-yl]-(1-thiazol-5-ylmethyl- piperidin-4-yl)-amine (148)
Sodium triacetoxyhydroborate (97 mg, 0.45 mmol) was added to a mixture of 127 (50 mg, 0.18 mmol), thiazole-5-carboxaldehyde (52 mg, 0.46 mmol) and acetic acid (22 mg, 0.37 mmol) in dichloroethaπe ( 1.5 mL) at room temperature. The resulting was stirred at 450C for 45 minutes. After cooling to room temperature, the mixture was diluted with CHCI3 (55 mL) and washed with 10% aqueous Na2CO3 solution. The organic layer was separated, dried over MgSO4, then concentrated. The crude product was purified by ISCO silica gel column chromatography, eluting with CHCI3: MeOH (9:1) to gain 45 mg (66%) of colorless solid 148. 1H NMR (400 MHz, CDCI3) δ ppm 8.77 (s, 1 H) 8.11 (d, J = 5.3 Hz, 1 H), 7.72 (s, 1 H), 7.66 (s, 1 H), 6.61 (d, J = 5.3 Hz, 1 H), 5.56 (s, 2 H), 4.80 - 5.14 (m, 1 H), 3.81 - 3.99 (m, 1 H), 3.79 (s, 2 H), 3.67 (s, 3 H), 2.89 (d, J = 11.6 Hz, 2 H), 2.16 - 2.36 (m, 2 H), 2.02 - 2.13 (m, 2 H), 1.43 - 1.68 (m, 2 H). LRMS m/z calcd. for C17H23N8S [M+H]+371. Found: 371.
Figure imgf000072_0002
149
Preparation of [4-(5-Amino-1-methyl-1H-pyrazol-4-yl)-N-(1-(pyridiπ-3-ylmethyl)piperidin-4- yl)pyrimidin-2-amine (149)
Compound 149 was prepared according to the method described for preparation of 148 starting from 3- nicotinaldehyde instead of thiazole-5-carboxaldehyde. 1H NMR (400 MHz, CDCI3) δ ppm 8.55 (d, J = 1.8 Hz, 1 H), 8.52 (dd, J = 4.8, 1.5 Hz, 1 H), 8.11 (d, J = 5.3 Hz, 1 H), 7.68 (d, J = 7.8 Hz, 1 H), 7.66 (s, 1 H), 7.26 - 7.30 (m, 1 H), 6.60 (d, J = 5.5 Hz, 1 H), 5.57 (s, 2 H), 4.98 (s, 1 H), 3.75 - 3.87 (m, 1 H), 3.67 (s, 3 H), 3.54 (s, 2 H), 2.85 (d, J = 11.6 Hz, 2 H), 2.21 (t, J = 11.2 Hz, 2 H), 2.03 - 2.12 (m, 2 H), 1.52 - 1.66 (m, 2 H). LRMS m/z calcd. for C19H25N8 [M+H]+365. Found: 365.
Figure imgf000073_0001
Preparation of 4-[4-(5-Amino-1-methyl-1 /*-pyrazol-4-yl)-pyrimidin-2-ylamino]-piperidine-1- carboxylic acid ethylamide (150)
Ethyl isocyanate (13 mg, 0.18 mmol) was added to a mixture of 127 (45 mg, 0.17 mmol) and DIE=A (32 mg, 0.25 mmol) in DMF (1mL) at 00C. The resulting mixture was stirred at room temperature for 15 min. DMF was evaporated under reduced pressure. The residue was diluted with CHCI3 (15 mL) and washed with 10% NaCO3 aq. solution. The organic layer was separated and concentrated to dryness. The crude product was washed with diethyl ether to gain 36 mg (63%) of colorless solid product. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.02 (d, J = 5.5 Hz1 1 H), 7.71 (s, 1 H), 7.00 (d, J = 7.6 Hz, 1 H), 6.67 (s, 2 H), 6.63 (d, J = 5.3 Hz, 1 H), 6.47 (t, J = 5.0 Hz, 1 H), 3.91 (d, J = 13.4 Hz, 2 H), 3.83 (s, 1 H), 3.56 (s, 3 H), 2.91 - 3.13 (m, 2 H), 2.77 (t, J = 11.8 Hz, 2 H), 1.85 (d, J = 10.3 Hz, 2 H), 1.30 (q, J = 11.1 Hz, 2 H), 1.01 (t, J = 7.2 Hz, 3 H). LRMS m/z calcd. for C16H25N8O [M+H]+ 345. Found: 345.
Figure imgf000073_0002
Preparation of 1-{4-[4-(5-Amino-1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-ylamino]-piperidin-1-yl}-3- methyl-butan-1-one (151)
Isovaleryl chloride (27 mg, 0.22 mmol) was added to a mixture of 127 (55 mg, 0.20 mmol) and DIEΞA (52 mg, 0.40 mmol) in DMF (1.0 mL) at 00C. The resulting mixture was stirred at room temperature for 15 min. The mixture was diluted with ethyl acetate (15 mL) and washed with 10% NaCO3 aqueous solution (1 mL). The organic layer was separated and concentrated. The crude product was purified by ISCO silica get column chromatography, eluting with CHCI3: MeOH (9:1), to gain 30 mg (42%) of colorless solid product. 1H NMR (400 MHz, CDCI3) δ ppm 8.11 (d, J = 5.5 Hz, 1 H), 7.66 (s, 1 H), 6.62 (d, J = 5.5 Hz, 1 H), 5.59 (s, 2 H), 5.04 (s, 1 H), 4.52 (d, J = 13.3 Hz, 1 H), 4.01 (d, J = 7.3 Hz, 1 H), 3.87 (d, J = 13.6 Hz, 1 H), 3.66 (s, 3 H), 3.20 (t, J = 11.5 Hz, 1 H), 2.87 (t, J = 11.7 Hz, 1 H), 2.23 (d, J = 7.1 Hz, 2 H), 2.06 - 2.21 (m, 3 H), 1.32 - 1.55 (m, 2 H), 0.98 (d, J = 6.6 Hz, 6 H). LRMS m/z calcd. for Ci8H28N7O [M+H]+358.
Found: 358.
General method I:
Figure imgf000074_0001
107 (trans)
Trans-N-[4-(5-amino-1-methyl-1W-pyrazol-4-yl)pyrimidin-2-yl]cyclohexane-1,4-diamine (107 trans) (100 mg, 0.35 mmol), sulfonyl chloride (1 eq, 0.35 mmol) and triethylamine (35 mg, 0.35 mmol) were mixed in 7 mL of dichloroethane:dimethoxyethane (1:2) and the solution was stirred at room temperature for 16 h. The reaction mixture was filtered and the crude materials were purified by HPLC to give the sulfonamide product with yield 30-65% varying with different sulfonyl chlorides used.
rrans-W-[4-(5-amino-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl]cyclohexane-1,4-diamine (107 trans)
Figure imgf000074_0002
107 (trans)
4-(1,5-dimethyl~1H-pyrazol-4-yl)-2-(methylsulfoπyl)pyrimidine (10.0 g, 39.5 mmol) and frans-cyclohexane- 1 ,4-diamine (9.0 g, 79.0 mmol) were dissolved in 40 mL isopropanol. This mixture was transferred into a microwave-reaction tube, and was heated to 140 0C under microwave radiation for 1.5 hrs. After cooling down to room temperature, the solvent was evaporated and the crude product was precipitated from EA. Collected the solid material and washed with ether many times to remove the excess diamino- cyclohexane. The product was place under vacuum to dry and yielded 4.02 g of solid. The mother liquid was further purified by a silica gel column with 10 % MeOH in ethyl acetate to give additional 2.1 g of the product (total 6.12 g, 56%). 1H NMR (400 MHz, D2O) ppm 50.99 - 1.21 (m, 4 H), 1.64 - 1.93 (m, 4 H), 2.49 - 2.79 (m, 1 H), 3.07 - 3.22 (m, 1 H), 3.41 (s, 3 H), 6.20 (d, J = 5.5 Hz, 1 H), 7.35 (s, 1 H), 7.64 (d, J = 5.5 Hz, 1 H). LRMS : 287. [(M + H)+. Table 10. Compounds 152-207 were prepared according to the method I as described above.
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
δ ppm 1.64 (m, 1 (s, 1 H) 3.58 (m, 1 (d, Hz, 1
1.33 - (m, 4 H) 3.23 (m, 1 (m, 1 H) (s, 1 H)
2.00 - (m, 2 H) 3.71 (m, 1 Hz, 1 H) 7.22 - 8.01 (d,
Figure imgf000082_0001
Figure imgf000083_0002
General method J:
Figure imgf000083_0001
107 (trans)
Trans-N-[4-(5-amiπo-1 -methyl-1 W-pyrazol-4-yl)pyrimidin-2-yl]cyclohexane-1,4-diamine (107 trans) was prepared above as described in method I. 107 trans (35 mmol) and various isocyanatomethylbeπzene (1 eq, 0.35 mmol) were dissolved in 5 ml_ of DMF. The reaction was stirred at 75 0C for 16 hours. The reaction mixture was filtrated and the crude materials were purified by HPLC to give the urea product with yield from 9- 60%. Table 11. Compounds 209-273 were prepared according to the method J as described above.
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Method K
Figure imgf000095_0001
4a (prepared according to K1 method A)
Figure imgf000095_0002
AcOH, 1100C, 2h
Figure imgf000095_0003
Figure imgf000095_0004
General method K is described below using the preparation of 274 as an example of KS: Preparation of W-(fraπsJ-4-{[4-(4,5,6,7-tetrahydropyrazolo[1 ,5-a]pyrimidin-3-yl)pyrimidin-2- yl]amiπo}cyclohexyl) ethanesulfonamide (274)
Figure imgf000095_0005
274
Preparation of (fraπs)-N1-(4-(1-(4-methoxybenzyl)-5-amino-1 H-pyrazol-4-yl)pyrimidin-2- yl)cyclohexane-1 ,4-diamine(K1 )
Methylsulfonylpyrimidine 4a (2.0 g, 6.0 mmol) was suspended in a mixed solvent 1,4-dioxane (8 mL) and isopropanol (3 m L). Trans-1 , 4-diaminocyclohexane (1.6 g, 13.9 mmol) was added at room temperature. The resulting suspension was heated at 130 0C for 1.5 hours by microwave in a sealed tube. The solution was cooled to room temperature, and the resulting suspension was filtrated to remove remaining diamine. The solution thus obtained was extracted with EtOAc (100 mL x 2), dried over MgSO4 and concentrated in vacuo. The resulting crude residue was purified by column chromatography (0 - 15% methanol in CH2CI2) to yield 1.9 g (81 %) of the title compound.
1H NMR (400 MHz1 CDCI3) δ ppm 1.15 - 1.32 (m, 4 H), 1.61 (br s, 2 H), 1.92 (br s, 2 H), 2.13 (br s, 2 H), 2.75 (br s, 1 H), 3.67 (br s, 1 H), 3.80 (s, 3 H), 4.80 (br s, 1 H), 5.15 (s, 2 H), 5.45 (brs, 2 H), 6.57 - 6.66 (m, 1 H), 6.89 (d, J= 8.6 Hz, 2 H), 7.18 (d, J= 8.3 Hz, 2 H), 7.73 (s, 1 H), 8.11 (d, J = 4.3 Hz, 1 H).
Preparation of N-((*raπs)-4-(4-(1-(4-methoxybenzyl)-5-amino-1 H-pyrazol-4-yl)pyrimidin-2- ylamino)cyclohexyl)ethanesulfonamide(274c)
To a solution of (fra/Js)-N1-(4-(1-(4-methoxybenzyl)-5-amino-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane- 1,4-diamine (1.00 g, 2.54 mmol)) and triethylamine (5.08 mmol, 0.71 mL) in dichloromethane (8.5 mL) was added ethane sulfonyl chloride (3.05 mmol, 0.29 mL) at 00C. The solution was stirred for 30 mins, poured into water (15 ml_)and extracted with EtOAc (25 mL X 2). The organic layer was dried over MgSO4 and concentrated under vacuum to give (1.1g) the title compound as brown oil, which was carried on crude.
1H NMR (400 MHz, DMSO-c/6) δ ppm 1.14 - 1.25 (m, 3 H)1 1.51 - 1.98 (m, 8 H), 2.94 - 3.04 (m, 2 H), 3.24 - 3.41 (m, 2 H), 3.64 - 3.73 (m, 3 H), 5.07 - 5.14 (m, 2 H), 6.82 - 6.94 (m, 4 H), 7.10 - 7.19 (m, 2 H)1 7.72 - 7.80 (m, 1 H), 7.98 - 8.08 (m, 1 H). LRMS m/z calcd. for C23H32N7O3S [M+Hf 486. Found: 486.
Preparation of W-(fraπsJ-4-{[4-(5-amino-1 H-pyrazol-4-yl)pyrimidin-2-yl]amino}cyclohexyl) ethanesulfonamide(274b)
Crude N-((frans)-4-(4-(1 -(4-methoxybenzyl)-5-amino-1 H-pyrazol-4-yl)pyrimidin-2- ylamiπo)cyclohexyl)ethanesulfonamide (1.1 g, -80% pure ) was dissolved in 10 mL of neat TFA. The dark brown solution was heated to reflux for 3 hours. TFA was removed by evaporation under vacuum to give crude product as dark oil (0.83g). 150 mg of the crude material was purified by HPLC (10-40% CH3CN in water) to yield 30 mg of the title compound as a white powder.
1H NMR (400 MHz, CD3OD) δ ppm 1.32 - 1.41 (m, 3 H), 1.52 - 1.64 (m, 1 H), 1.78 - 1.96 (m, 6 H), 2.15 (s, 1 H), 2.99 - 3.19 (m, 2 H), 3.47 - 3.58 (m, 1 H), 3.62 - 3.80 (m, 1 H), 7.20 (d, J = 6.1 Hz, 1 H), 8.06 (t, J = 6.6 Hz1 1 H)1 8.52 - 8.71 (m, 1 H). LRMS m/z calcd. for C15H24N7O2S [M+H]+366. Found: 366
Preparation of N-(fraπs)-4-(4-(pyrazolo[1 ,5-a]pyrimidin-3-yl)pyrimidin-2- ylamino)cyclohexyl)ethanesulfonamide(274a)
A solution of Λ/-(/raπsj-4-{[4-(5-amino-1H-pyrazol-4-yl)pyrimidin-2-yl]amino}cyclohexyl) ethanesulfonamide (600 mg, 1.64 mmol) and 1 , 1, 3, 3-tetramethoxy propane (540 mg, 3.29 mmol) in acetic acid was heated to reflux for 2 hours. Evaporation yielded 0.59 g (90%) the title compound. Preparatioπ of W-(fra/7s)-4-{[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)pyrimidin-2- yl]amino}cyclohexyl) ethanesulfonamide(274)
A solution of N-(frans)-4-(4-(pyrazolo[1,5-a]pyrimidin-3-yl)pyrimidin-2- ylamino)cyclohexyl)ethanesulfonamide (250mg, 0.62 mmol) and 10% Pd/C (10 mg) in MeOH (20 mL) was hydrogenated at room temperature under 50 psi pressure of hydrogen. The reaction was held at room temperature for 24 hours. The solution was filtrated and evaporated. The residue was purified by HPLC (10-40% CH3CN) to give 89 mg (35%)of the title compound.
1H NMR (400 MHz, CD3OD) δ ppm 1.11 - 1.29 (m, 3 H), 1.37 - 1.51 (m, 1 H), 1.66 - 1.85 (m, 5 H), 1.87 - 2.07 (m, 2 H), 2.07 - 2.21 (m, 2 H), 2.87 - 3.07 (m, 2 H), 3.36 - 3.67 (m, 4 H), 3.98 - 4.19 (m, 2 H), 6.89 - 7.07 (m, 1 H), 7.79 - 7.95 (m, 1 H), 8.31 (s, 1 H). LRMS m/z calcd. for C15H28N7O2S [M+H]+406. Found: 406.
Table 12. Compounds 274-277 were prepared according to the method K as described above.
δ ppm 1.51 (m, 1 - 2.07 H) 2.87 - 4 H) 7.07 (m, 1 (s, 1 H).
δ 1.85 (br. s., - 3.47 (m, H) 3.71 J=5.31 7.14 (d, 8.02 (d,
δ ppm 2.18 (m, 4 - 3.46 H) 3.66 4.01 (t, 6.55 (d, 7.59 (s,
δ 1.91 - 2.01 (s, 3 H) 3.41 (m, 2 (t, Hz, 1 (d, (m, 1 H)
Figure imgf000097_0001
Method L
following method K
Figure imgf000098_0001
278
Preparation of N-((trans)-4-((4-(5-amiπo-1-(4-methoxybenzyl) -1H-pyrazol-4-yl)pyrimidin-2- yl)methyl)cyclohexyl)cyclopropanecarboxamide (278a)
To a solution of N-((trans)-4-(1-(4-methoxyben-.yl)-5-amino-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane- 1,4-diamiπe (2g, 5.08 mmol) and triethylamine (10.16 mmol, 1.42 mL) in dichloromethane (32 mL) was added HATU (6.10 mmol, 2.33 g). The reaction was held at room temperature for 5 minutes, then treated with cyclopropane carboxylic acid (6.10 mmol, 0.49 mL). The solution was stirred for 1h at room temperature, then washed with brine (2x30 mL) and extracted with CH2CI2 (75 mL), then and concentrated. Purification by silica gel chromatography (0-30% MeOH-EtOAc) yielded 1.8g (77%) of N- ((trans)-4-(4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)pyrimidin-2-ylamino) cyclohexyl)cyclopropanecarboxamide.
Figure imgf000098_0002
Method M
Figure imgf000099_0001
Prepared by method L
Figure imgf000099_0002
280
Prepared by method K
Preparation of N-(<rans-4-{[4-(5,6,7,8-tetrahydro-4H-pyrazolo[1 ,5-a][1 ,3]diazepin-3-yl)pyτimidin-2- yl]amino}cyclohexyl) cyclopropanecarboxamide (280)
A solution of containing N-(trans-4-(4-(5-amino-1H-pyrazol-4-yl)pyrimidin-2- ylamiπo)cyclohexyl)cyclopropanecarboxamidθ (280a) (0.73 mmol, 250 mg), 1 ,4-dibromobutane (471 mg, 2.20 mmol) and K2CO3 ( 507 mg, 3.67 mmol) in CH3CN (5 ml_) was heated to reflux overnight. The solution was extracted with EtOAc (5O mL x 2). The combined oil layer was concentrated to dry under vacuum. The residue was purified by HPLC (10-50% CH3CN in water) to yield 52 mg (18%) of product. C21 H30N7O [M+H]+396. Found: 396.
Table 13. Compounds 279-280 were prepared according to the method M as described above.
Figure imgf000099_0003
# Structure Compound Name M+1 NMR Data
N-N ) N-(trans-4-{[4-(5,6,7,8-
1 H NMR (400 MHz, DMSO-d6) δ ppm 1.27 tβtrahydro-4H- pyrazolo[1 ,5- - 1.39 (m, 4 H) 1.78 (s, 4 H) 1.90 - 2.04 (m,
280 T H H O a][1,3]diazθpin-3- 406 4 H) 2.92 (S, 3 H) 3.16 (s, 4 H) 3.99 - 4.10 yl)pyrimidin-2- (m, 2 H) 6.67 (d, J=3.79 Hz, 1 H) 7.05 (d, yljamino}cyclohexyl)met J=7.07 Hz, 2 H) 7.76 (s, 2 H) 8.06 (d, hanesulfonamide J=5.31 Hz, 1 H)
H
Method N
Figure imgf000100_0001
Preparation of N-[trans-4-({4-[1-methyl-5-(methylamino)-1H-pyrazol-4-yl]pyrimidin-2- yl}amino)cyclohexyl]cyclopropanecarboxamide (281)
Figure imgf000101_0001
The above compound 281 was prepared according to the general procedure Method N-a as described above.
Preparation of N,1-dimethyl-4-[2-(methylthio)pyrimidin-4-yl]-1H-pyrazol-5-amine (281c)
1-methyl-4-[2-(methylthio)pyrimidin-4-yl]-1 H-pyrazol-5-amiπe (1.0 g, 3.2 mmol) was dissolved in THF (10 mL) and NaH (0.39 g, 9.6 mmol, 60 % dispersion in oil) was added in one portion. The mixture was stirred at room temperature for 10 minutes, Methyl iodide (0.4 mL, 6.4 mmol) was added dropwise. The mixture was stirred for 24 hour(s). The mixture was quenched with NaHCO3 (saturated aq.) and extracted with ethyl acetate. The combined organics were dried over MgSO4, filtered, and concentrated in vacuo .This crude was used without further purification.
Preparation of N,1-dimethyl-4-[2-(methylsulfonyl)pyrimidin-4-yl]-1H-pyrazol-5-amine (281b)
A solution of N,1-dimethyl-4-[2-(methylthio)pyrimidin-4-yl]-1H-pyrazol-5-amine (0.5g, 2.1 mmol) in THF (10 mL) was cooled to O0C. To the solution was added 3-chloroperoxy benzoic acid (mCPBA) (0.86g, 5.25 mmol, 77 % tech grade). After being stirred for 30 minutes the ice bath was removed and the reaction was allowed to be stirred at RT for 6 hours. The solution was basified with NaHCO3, saturated with NaCI and extracted with THF. The organic layer was concentrated to give N,1-dimethyl-4-[2- (methylsulfoπyl)pyrimidin-4-yl]-1 H-pyrazol-5-amine and the corresponding sulfoxide . The mixture was used in next step without purification.
Preparation of trans-N-{4-[1 -methyl-5-(methylamino)-1 H-pyrazol-4-yl]pyrimidin-2-yl}cyclohexane- 1,4-diamine (281a)
N, 1-dimethyl-4-[2-(methylsulfonyl)pyrimidin-4-yl]-1 H-pyrazol-5-amine (0.5 g crude, 1.78 mmol) and traπs- cyc!ohexane-1,4-diamiπe (0.406 g, 3.55 mmol) were dissolved in 10 mL of isopropanol The solution was heated in the automated Microwave Reactor at 14O0C for 1.5h. The resulting suspension was filtrated to remove remaining diamine. The solution thus obtained was extracted with EtOAc (50 mL X 2), dried over MgSO4 and concentrated in vacuo. The mixture was used in next step without purification. Preparation of N-[traπs-4-({4-[1-methyl-5-(methylamino)-1 H-pyrazol-4-yl]pyrimidin-2- yl}amino)cyclohexyl]cyclopropanecarboxamide (281)
To a solution of cyclopropane carboxylic acid ( 62 mg, 0.72 mmol) and triethylamine (0.13 mL, 0.9 mmol) in 10 mL of dichloromethane was added HATU (0.34 g, 0.9 mmol). After being stirred for 5 minutes, to the solution was added trans-N-{4-[1-methyl-5-(methylamino)-1H-pyrazol-4-yl]pyrimidin-2-yl}cyclohexane-1,4- diamine (0.18 g, 0.6 mmol). The solution was stirred for 1h, extracted with CH2CI2, dried over MgSO4 and concentrated in vacuo. The residue was purified by HPLC (20-100% CH3CN/H2O gradient) to afford 32 mg (21%) of the desired product.
1H NMR (400 MHz, CD3OD) δ ppm 0.52 - 0.66 (m, 2 H), 0.68 - 0.80 (m, 2 H), 1.32 (t, J = 9.7 Hz, 4 H), 1.41 - 1.52 (m, 1 H), 1.85 - 2.13 (m, 4 H), 2.88 - 3.01 (m, 3 H), 3.49 - 3.64 (m, 1 H), 3.74 (s, 3 H), 6.61 (d, J = 5.6 Hz, 1 H), 7.68 (s, 1 H)1 7.87 - 7.95 (m, 1 H). LRMS m/z calcd. for Ci9H28N7O [M+Hf 370. Found: 370.
Table 14. Compounds 281-287 were prepared according to the method N-a as described above.
Figure imgf000102_0001
Figure imgf000103_0001
Preparation of N-[trans-4-({4-[1-methyl-5-(methylamiπo)-1 H-pyrazol-4-yl]pyrimidin-2- yl}amino)cyclohexyl]cyclopropaπesulfonamide (288)
The above compound 288 was prepared according to the general procedure Method N-b.
To a solution of trans-N-{4-[1-methyl-5-(methylamino)-1H-pyrazol-4-yl]pyrimidin-2-yl}cyclohexane-1,4- diamine (0.25 g crude containing -50% of the compound 288a, 0.42 mmol) and triethylamine (0.115 mL, 0.84 mmol) in 5 mL of dichloromethane was added cyclopropanesuifonyl chloride (0.085 mL , 0.84 mmol) at 00C. The solution was stirred for 30 mins, poured into water and extracted with EtOAc (10O mL X 2). The organic layer was dried over MgSO4 and concentrated under vacuum. The residue was purified by HPLC (20-100% CH3CN/H2O gradient) to afford the title compound 288.
1H NMR (400 MHz, CD3OD) δ ppm 0.87 - 0.97 (m, 4 H),1.26 - 1.47 (m, 4 H), 1.91 - 2.11 (m, 4 H), 2.13 - 2.22 (m, 1 H), 2.93 - 3.05 (m, 3 H), 3.06 - 3.11 (m, 1 H), 3.49 - 3.56 (m, 1 H), 3.71 - 3.79 (m, 3 H), 6.63 - 6.72 (m, 1 H), 7.72 (s, 1 H), 7.86 (d, J = 6.1 Hz, 1 H). LRMS m/z calcd. for C18H28N7O2S [M+H]+406. Found: 406. Table 15. Compounds 288-295 were prepared according to the method N-b as described above.
Figure imgf000104_0001
δ ppm 2.06 (m, 4 - 2.99 (m, 3.68 - 3.77 1 H) 7.62 Hz, 1
δ ppm 1.96 (m, 4 H) 3.03 - (m, 1 H) Hz, 1 H) (t, 1 H) (d, 1
δ ppm 2.17 (m, 4 3.22 - (m, 1 H) Hz, 1 H) - 7.31 (d, J=6.57
Figure imgf000105_0001
Further modification of compounds produced by Method N-b:
Preparation of N-(trans-4-{[4-(5-amino-1-methyl-1 H-pyrazol-4-yl)pyrimidin-2-yl]amino}cyclohexyl)-
N-methylmethaπesulfonamide (296) and
N-methyl-N-[trans-4-({4-[1-methyl-5-(methylamino)-1H-pyrazol-4-yi]pyrimidin-2- yl}amino)cyclohexyl]methanesulfonamide (297)
N-(traπs-4-{[4-(5-amino-1-methyl-1H-pyτazol-4-yl)pyrimidin-2-yl]amino}cyclohexyl) methaπesulfonamide (296a) was prepared according to method N-b. To a solution of 296a ( 0.175 g, 0.48 mmol) in THF (10 mL) at O0C, NaH (0.019 g, 0.48 mmol, 60 % dispersion in oil) was added in one portion. The mixture was stirred at O0C for 10 minutes, and methyl iodide (0.05 mL, 0.72 mmol) was added dropwise. The mixture was allowed to warm up gradually to room temperature and was stirred for 16 hour(s). The mixture was quenched with NaHCO3 (saturated aq.) and extracted with ethyl acetate. The combined organics were dried over MgSO4, and concentrated in vacuo This residue was purified by HPLC (20-100% CH3CN/H2O gradient) to yield N-(trans-4-{[4-(5-amino-1-methyl-1H-pyrazol-4- yl)pyrimidin-2-yl]amino}cyclohexyl)-N-methylmethanesulfonamide (296) and N-methyl-N-[trans-4-({4-[1- methyl-5-(methylamino)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)cyclohexyl]methanesulfonamide (297).
296:. LRMS m/z calcd. for C16H26N7O2S [M+H]+380. Found: 380. 297: LRMS m/z calcd. for C17H28N7O2S [M+H]+394. Found: 394.
Table 16. Compounds 296-297 were prepared according to the modified method N-b as described above.
Figure imgf000106_0001
Preparation of N-[trans-4-({4-[1 -methyl-5-(methylamino)-1 H-pyrazol-4-yl]pyrimidin-2- yl}amino)cyclohexyl]moφholine-4-sulfonamide (298)
The above compound 298 was prepared according to the general procedure Method N-c as described above.
To a solution of trans-N-{4-[1-methyl-5-(methylamino)-1H-pyrazol-4-yl]pyrimidin-2-yl}cyclohexane-1,4- diamine ( 0.25 g crude containing -50% of the compound, 0.42 mmol) in 5 mL of DMF was added triethylamine (0.115 mL, 0.84 mmol) and 4-Morpholinesulfonyl chloride (0.154 g, 0.84 mmol). The mixture was heated in the automated Microwave Reactor to 8O0C for 30 minutes. The solution was extracted with EtOAc, dried over MgSO4 and concentrated under vacuum. The residue was purified by HPLC (20-100%
CH3CN/H2O gradient) to yield 76 mg (37%) of the title compound 298.
1H NMR (400 MHz, CD3OD) δ ppm 1.26 - 1.58 (m, 2 H), 4.00 (d, J = 11.1 Hz, 2 H), 3.07 (s, 3 H) 3.12 - 3.18 (m, 4 H), 3.20 - 3.29 (m, 9 H), 3.21 - 3.28 (m, 4 H), 3.58 - 3.68 (m, 1 H), 3.81 - 3.90 (m, 3 H), 6.71 (d, J = 5.6 Hz, 1 H), 7.79 (s, 1 H)1 8.04 (d, J = 5.3 Hz, 1 H). LRMS m/z calcd. for C19H31N8O3S [M+H]+451. Found: 451.
Table 17. Compounds 298-299 were prepared according to the method N-c as described above.
Figure imgf000107_0002
Preparation of N-[traπs-4-({4-[1-methyl-5-(methylamino)-1 H-pyrazol-4-yl]pyrimidin-2- yl}amino)cyclohexyl]morpholine-4-carboxamide (300)
Figure imgf000107_0001
300
The above compound 300 was prepared according to the general procedure Method N-d as described above.
To a solution of trans-N-{4-[1-methyl-5-(methylamino)-1H-pyrazol-4-yl]pyrimidin-2-yl}cyclohexane-1,4- diamine (0.25 g crude containing -50% of compound 300a, 0.42 mmol) in 5 mL of DMF was added triethylamiπe (0.115 mL, 0.84 mmol) and 4-Morpholine-carbonyl chloride ( 0.1 ml_, 0.84 mmol). The mixture was stirred at rtfor 15 minutes. The solution was extracted with 2-methyl tetrahydrofuran, dried over MgSO4 and concentrated under vacuum. The residue was purified by HPLC (20-100% CH3CIM/H2O gradient) to yield 19 mg (6%) of the title compound 300. LRMS m/z calcd. for C20H31N8O2 [M+H]+415. Found: 415.
Table 18. Compounds 300-301 were prepared according to the method N-d as described above.
Figure imgf000108_0002
Method N-e
Figure imgf000108_0001
Table 19. Compounds 302-312 were prepared according to the method N-e as described above.
Figure imgf000108_0003
δ ppm 1.56 (m, 8.46 2 H) 3.57 - 3 H) (s, 1 H)
δ ppm (m, 4 (m, 2 H) - 4.57 (m, 2 - 7.00 7.71 -
δ ppm (m, 4 - 3.70 (d, J=6.06 7.06 - 1 H) Hz, 1 H)
δ ppm 1.69 (m, 3 - 2.17 3.74 - Hz, 1 (s, 1 H)
δ ppm J=6.57 - 2.09 (m, - 3.64 Hz, 1 6.58 (d, (m, 5 H)
Figure imgf000109_0001
δ ppm J=6.82 - 2.11 (m, 3.64 - 3.73 (d, J=5.56 7.61 (s, H).
δ ppm 2.04 (m, 2 - 3.72 - 4.04 (m, H) 5.31 6.10 (m, 1 7.81 (s, 1
δ ppm (m, 2 (s, 6 H) (m, 1 (d, J=5.31 Hz, 1 7.27 (t, 1 8.13 (d,
δ ppm - 2.02 (m, 2 (s, 3 H) (s, 2 H) Hz, 2 H) 1 H)
Figure imgf000110_0001
Figure imgf000111_0002
Method 0
Figure imgf000111_0001
313
Preparation of (fraπs)-4-(4-(1-methyl-5-(piperidin-1-yl)-1 H-pyrazol-4-yl)pyrimidin-2- ylamino)cyclohexanol (313):
Preparation of 4-(5-bromo-1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimϊdine (313b)
To a suspension of 1-methyl-4-(2-(methylsulfonyl)pyrimidiπ-4-yl)-1H-pyrazol-5-amine (3a) (0.95 g, 3.75 mmol), which was prepared as described in Method A above, and CuBr2 (1.0 g) in acetonitrile at O 0C, t- Butyl nitrite (90%, 0.65 mL) was added dropwise. The solution was allowed to warm to room temperature overnight, then diluted with ethyl acetate (50 mL) and washed with 1N HCI (3X 2OmL), water (1X 2OmL)1 and brine (1 X 2OmL). The organic layer was dried over MgSO4 and concentrated to yield 4-(5-bromo-1- methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidine (0.68g, 58% yield).
Preparation of trans-4-(4-(5-bromo-1-methyl-1 H-pyrazol-4-yl)pyrimidin-2-ylamino)cyclohexanol (313a)
In a 2OmL microwave tube, 4-(5-bromo-1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidine (0.9Og, 2.84 mmol) and fraπs-4-aminocyclohexanol was dissolved in isopropanol (15 mL), sealed and heated to 1600C in the Biotage microwave for 1 hour. The solvent was concentrated and residue purified on Biotage column eluting with 5% CH3OH in CH2CI2 to yield fraπs-4-(4-(5-bromo-1 -methyl- 1 H-pyrazol-4- yl)pyrimidin-2-ylamino)cyclohexanol (0.97g, 96.8% yield)
1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 - 1.35 (m, 4 H)1 1.78 - 1.87 (m, 2 H), 1.90 (d, J = 10.1 Hz, 2 H), 3.37 (br s, 1 H), 3.66 - 3.81 (m, 1 H), 3.89 (s, 3 H), 4.55 (br s, 1 H), 6.93 (br s, 2 H), 8.10 (br s, 1 H), 8.24 (br s, 1 H).
Preparation of (fra/?s)-4-(4-(1-methyl-5-(piperidin-1-yl)-1 H-pyrazol-4-yl)pyrimidin-2- ylamino)cyclohexaπol (313):
In a 1OmL microwave tube, fraπs-4-(4-(5-bromo-1-methyl-1H-pyrazol-4-yl)pyrimidin-2- ylamino)cyclohexanol (0.3g, 0.85mmol) and piperidine (0.75m L, 5.06mmol) was dissolve in 1-butanol. The reaction mixture was heated in the Biotage microwave to 2000C for 4 h. Solvent was evaporated and the residue was purified by HPLC (20-100% MeOH-CH3CN) to yield 59 mg (20%) ((frans)-4-(4-(1-methyl- 5-(piperidin-1-yl)-1H-pyrazol-4-yl)pyrimidin-2-ylamino)cyclohexanol 1H NMR (400 MHz, CD3OD) δ ppm 1.28 - 1.48 (m, 5 H), 1.71 (d, J = 3.8 Hz, 6 H), 1.99 (s, 2 H), 2.08 (br s, 3 H), 3.13 (br s, 4 H), 3.51 - 3.64 (m, 1 H), 3.76 (s, 3 H)1 3.99 (br s, 1 H)1 6.80 (d, J = 5.3 Hz, 1 H), 7.75 (s, 1 H), 8.11 (d, J = 5.1 Hz, 1 H). LRMS m/z calcd. for C19H29N6O [M+H]+357. Found: 357.
Table 20. Compounds 313-322 were prepared according to the method O as described above.
Figure imgf000112_0001
δ ppm 3H) 1.97- (br.s., (m,1H) Hz, 1H) J= 5.31
δ - 1.87 Hz, 2 H) (m, 1 H) H) 6.93 8.24 (br.
δ 1.61 (d, s., 2 H) s., 4 H) H) 6.76 s., 1 H) Hz, 1 H)
δ - 1.73 3.88 (s, (d, J=5.05 1 H) Hz,
δ 1.84 (d, s., 4 H) s., 2 H) H) 4.57 Hz, 1 H) Hz, 1 H)
1.81 (br. s., (br. s., (d, J=4.29 (br. s., 1 J=5.05 7.80 (s, 1
Figure imgf000113_0001
Figure imgf000114_0002
Method P
Figure imgf000114_0001
P reparation of (1s,4s)-4-(4-(7-isopropyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)pyrimidin-2- ylamino)cyclohexanol (323, which is an example of compound P):
Figure imgf000115_0001
Preparation of 4-(2-(methylthio)pyrimidin-4-vO-1H-pyrazol-5-amine (P5)
4-(lsoxazol-4-yl)-2-(methylthio)pyrimidiπe 1c, which was prepared via method A, (6.3g, 32.6 mmol) was dissolved in AcOH (50 mL). The solution was cooled to O0C in an ice bath. To the solution was added hydrazinemonohydrate (5.0 mL, 94.9 mmol) dropwise over 10 minutes. The solution was warmed up to room temperature in 2 hours. The solution was warmed to 5O0C for 30 minutes, and then to 850C for 3 hours. The reaction mixture was allowed to cool to room temperature, basified with NH4OH to pH 9. The precipitate thus formed was filtered, washed thoroughly with water, and dried in vacuo to yield 4-(2- (methylthio)pyrimidin-4-yl)-1H-pyrazol-5-amine as an orange solid (4.85 g, 67 %). The filtrate was saturated with NaCI and extracted with THF, concentrated to give an orange which consisting of the desired product and unreacted isoxazole 1c.
1H NMR (400 MHz, DMSO-Cf6) δ ppm 2.58 (s, 3 H), 7.32 - 7.42 (m, 1 H), 8.28 (s, 1 H), 8.49 (d, J = 5.3 Hz, 1 H).
Preparation of 3-(2-(methylthiotoyrimidin-4-vπpyrazolori.5-aipyrimidiπe (P4)
To a suspension of 4-(2-(methylthio)pyrimidin-4-yl)-1H-pyrazol-5-amine (P5) (1.Og, 4.8 mmol) in AcOH (20 mL) was added 1 ,1 ,3,3-tetramethoxypropane (1.0 mL, 6.0 mmol). The solution was heated to 11O0C overnight. The solution was cooled to RT, poured into water, basified with NH4OH and extracted with EtOAc, dried over MgSO4 and concentrated under vacuum to give 1.33 g (99%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.59 (s, 3 H), 7.29 (dd, J = 7.0, 4.2 Hz, 1 H), 8.10 (d, J= 5.3 Hz, 1 H), 8.61 (d, J = 5.3 Hz, 1 H), 8.84 (dd, J = 4.0, 1.8 Hz, 1 H), 8.92 (s, 1 H), 9.32 (dd, J = 7.1, 1.8 Hz, 1 H).
Preparation of 3-(2-(methylsulfonvπpyrimidin-4-vflpyrazoloH,5-aipyrimidine IP3)
A solution of 3-(2-(methylthio)pyrimidin-4-yl)pyrazolo[1,5-a]pyrimidine (P4) (1.Og, 4.1 mmol) in THF (20 mL) was cooled to O0C. To the solution was added 3-chloroperoxybenzoic acide (mCPBA) (3.Og, 13.3 mmol, 77 % tech grade). After being stirred for 30 minutes the ice bath was removed and the reaction was allowed to be stirred at RT for 6 hours. The solution was basified with NaHCO3, saturated with NaCI and extracted with THF. The organic layer was concentrated to give 3-(2-(methylsulfonyl)pyrimidin-4- yl)pyrazolo[1 ,5-a]pyrimidine and the corresponding sulfoxide (980 mg). The mixture was used in next step without purification. Preparation of frans-4-r(4-pyrazolori.5-aipyrimidin-3-ylpyrimidin-2-yl)amino1cvclohexanol (P2)
Cπjde 3-(2-(methylsulfonyl)pyrimidin-4-yl)pyrazolo[1,5-a]pyrimidine (P3) (500 mg) and (trans)-4- aminocyclohexanol were dissolved in 20 m L of dioxane. The solution was heated to reflux for 4 hours, cooled to RT and extracted with EtOAc1 dried over MgSO4 and concentrated. The residue was purified by a silica gel chromatography (0-5% MeOH in CH2CI2) to give fraπs-4-[(4-pyrazolo[1,5-a]pyrimidin-3- ylpyrim idin-2-yl)am ino]cyclohexanol (310mg).
1 H NMR (400 MHz, DMSO-Cf6) δ ppm 1.26 - 1.54 (m, 4 H) 1.82 - 2.07 (m, 4 H) 3.48 (s, 1 H) 3.75 - 4.19 (m, 1 H) 7.42 (dd, J = 6.8, 4.3 Hz, 1 H) 7.93 (d, J = 6.6 Hz, 1 H) 8.39 (d, J = 5.3 Hz, 1 H) 8.95 (dd, J = 4.3,
1.8 Hz, 1 H) 9.10 (d, 1 H) 9.43 (d, J = 6.1 Hz, 1 H).
Preparation of (fraπs)-4-(4-(7-isopropyl-6,7-dihvdropyrazolo|i .5-aipyrimidin-3-yl)pyrimidin-2- ylamino)cvclohexanol (323a)
A solution of frans^-^-pyrazoloti.S-aJpyrimidin-S-ylpyrimidin^-ylJaminolcyclohexanol (321b) (600 mg,
1.9 mmol) in THF (20 mL) was cooled to -780C under N2. To the solution was added CH3MgCI ( 3.5 ml_, 2M in THF, 7 mmol) dropwise. The reaction was warmed up to room temperature slowly and stirred for 18 hours. The reaction was quenched by NH4CI and extracted with EtOAc The organic layer was dried over MgSO4 and concentrated to give 800 mg of crude product (trans)-4-(4-(7-isopropyl-6,7- dihydropyrazolo[1,5-a]pyrimidin-3-yl)pyrimidin-2-ylamino)cyclohexanol. 100mg of crude material was purified by HPLC (10-40% CH3CN in water).
1 H NMR (400 MHz, CD3OD) δ ppm 0.75 (d, J = 6.6 Hz, 3 H), 0.95 (d, J = 7.1 Hz, 3 H), 1.26 - 1.54 (m, 4 H), 1.94 - 2.05 (m, 2 H), 2.05 - 2.17 (m, 2 H), 2.38 - 2.52 (m, 1 H), 3.55 - 3.78 (m, 2 H), 4.57 - 4.66 (m, 2 H), 4.68 - 4.77 (m, 1 H), 6.51 (d, J = 8.1 Hz, 1 H), 6.72 (d, J = 5.6 Hz1 1 H), 7.87 (s, 1 H), 8.04 (d, J = 5.6 Hz, 1 H).
Preparation of (frans)-4-(4-(7-isopropyl-4,5.6.7-tetrahvdropyrazolori.5-aipyrimidin-3-vπpyrimidin-2- ylamino)cvclohexanol (323)
The hydrogenation of crude material (700 mg) containing (trans)-4-(4-(7-isopropyl-6,7- dihydropyrazolo[1 ,5-a] pyrimidin -3-yl) pyrimidin-2-ylamino)cyclohexanol and 10% Pd/C in MeOH (10 mL) was curried out by a balloon filled with H2 for 66 hours. LCMC indicated 70% starting material was converted. The solution was filtrated and concentrated. The residue was purified by HPLC (10-40% CH3CN in water) to give 17 mg (3%) of the title compound.
1 H NMR (400 MHz, CD3OD) δ ppm 0.88 (d, J = 6.8 Hz, 3 H), 1.05 (d, J = 7.1 Hz1 2 H), 1.28 - 1.50 (m, 4 H)1 1.93 - 2.04 (m, 2 H), 2.04 - 2.18 (m, 4 H), 2.39 - 2.51 (m, 1 H), 3.39 - 3.53 (m, 2 H), 3.53 - 3.69 (m, 2 H), 3.95 - 4.06 (m, 1 H), 6.65 (d, J = 5.6 Hz, 1 H), 7.73 (s, 1 H), 7.95 (br s, 1 H). LRMS m/z calcd. for C19H29N6O [M+Hf 357. Found: 357. Tablθ 21. Compounds 323-325 were prepared according to the method P as described above.
δ ppm (d, (m, 4 H) 2.18 (m, 4 - 3.53 3.95 - Hz, 1 1
δ ppm (d, (m, 4 H) 2.18 (m, 4 - 3.53 3.95 - Hz, 1 1
δ ppm (d, (m, 4 H) 2.17 (m, 2 - 3.78 4.68 - Hz, 1 7.87
Figure imgf000117_0001
Method Q
Figure imgf000117_0002
Prepared by method N Preparation of 4-[1-methyl-5-(methylamino)-1 H-pyrazol-4-yl]-N-(6-methylpyridin-3-yl)pyrimidin-2- amine (326):
In a scintillation vial, N,1-dimethyl-4-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-pyrazol-5-amine (280b)(150mg, 0.56 mmol), 5-amino-2-methylpyridiπe (182mg, 1.68 mmol) and were dissolved in 5 ml_ of THF and cooled to 00C. The reaction was then treated with NaH (67 mg, 1.68 mmol). The reaction was removed from ice bath and allowed to warm to r.t. The reaction was diluted with 2-methyl THF and washed with water (1 X 2OmL) & sat. NaCI(I X 2OmL). The organic layer was dried over MgSO4, filtered and cone. The residue was taken up in DMSO and purified by HPLC (20-100% CH3CN/H2O gradient) yielding 4-[1- methyl-5-(methylamino)-1H-pyrazol-4-yl]-N-(6-methylpyridin-3-yl)pyrimidin-2-amine (9.5 mg, 5%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.43 (s, 3 H), 3.00 (d, J = 5.6 Hz, 3 H), 3.79 (s, 3 H), 6.96 (d, J = 5.6 Hz, 1 H), 7.22 (d, J = 8.3 Hz, 2 H)1 7.87 (s, 1 H), 8.03 (dd, J = 8.7, 1.4 Hz, 1 H), 8.24 (d, J= 5.6 Hz1 1 H), 8.65 (d, J = 2.0 Hz, 1 H), 9.49 (s, 1 H). LRMS m/z calcd. for C15H18N7 [M+Hf 296. Found: 296.
Table 22. Compounds 326-338 were prepared according to the method Q as described above.
S Hz, Hz, H) 7.87 (s, Hz, 1 H) (d,
S ppm 2.39 (m, 3 - 3.68 1 H) - 7.63 8.21 (d,
δ (m, 2 (m, 1 H) Hz, 1 H) (dd, (s, 1 H)
Figure imgf000118_0001
δ H) 6.80 2 H) 6.95 J=7.96 (d, J=8.34 1 H)
δ 3 H) 6.70 1 H) 6.93 (m, 2 H) (d,
δ H) 3.57 2 H) (s, 1
δ Hz, Hz, (d, 7.91 (s, 8.35 (d,
δ H) 3.78 (s, 7.22 (d, (m, 1 H) J=5.56 1 H) 9.35
δ 3.79 (s, 7.17 (s, 1 8.45 (s, 1
Figure imgf000119_0001
δ (m, Hz, 1 J=3.03 Hz, 1 8.34 (s, 1 8.93 (s, 1
δ H) 7.06 2 H) (s, 1
+D2O) δ (s, 3 3 H) (d, 7.96 (d, Hz, 1
δ 3.81 (s, 7.25 (d, Hz, 1 Hz, 1 1 H) (s, 1
Figure imgf000120_0001
Method R
Figure imgf000120_0002
108 trans 339 Preparation of 1-((fraπs)-4-(4-(5-amino-1-methyl-1 H-pyrazol-4-yl)pyrimidin-2-ylamino) cyclohexyl)pyrrolidin-2-oπe (339)
In a 1OmL microwave tube, (fraπs)-N1-(4-(5-amino-1-methyl-1H-pyrazol-4-yl)pyrimidiπ-2-yl)cyclohexaπe- 1,4-diamine (108 trans) (150mg, 0.52 mmol), methyl 4-chlorobutaπoate (85mg, 0.62 mmol) and K2CO3 (216mg, 1.56 mmol) were suspended in acetonitrile (5 mL), sealed and heated to 12O0C in the Biotage microwave for 30 minutes. The solution was filtrated and concentrated. The residue was purified by HPLC (10-50% acetonitrile-water) to give 15mg (8%) of the title compound 339. 1H NMR (400 MHz, CD3OD) δ ppm 1.57 - 1.72 (m, 2 H), 1.81 - 2.07 (m, 4 H), 2.17 - 2.29 (m, 2 H), 2.37 (d, J = 11.1 Hz, 2 H), 2.58 (t, J = 8.1 Hz, 2 H), 3.63 - 3.72 (m, 2 H)1 3.81 (s, 3 H), 3.84 - 3.90 (m, 1 H), 4.02 - 4.19 (m, 1 H), 4.73 - 4.90 (m, 1 H), 6.87 (d, J = 5.6 Hz, 1 H), 7.92 (s, 1 H) 8.19 (d, J = 5.6 Hz, 1 H). LRMS m/z calcd. for C18H26N7O [M+H]+ 356. Found: 356
Preparation of [(trans-4-{[4-(5-amino-1-methyl-1 H-pyrazol-4-yl)pyrimidin-2- yl]amino}cyclohexyl)amino]acetonitrile (340)
Figure imgf000121_0001
108 trans 340
To a solution of (fraπs)-N1-(4-(5-amino-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)cyclohexane-1 ,4-diamine (0.045 g, 0.16 mmol) in 5 mL of DMF was added K2CO3 ( 0.054 g, 0.39 mmol) and lodoacetonitrile ( 0.039 g, 0.23 mmol) . The mixture was stirred at room temperature for 16 hr. The mixture was extracted with 2- methyl tetrahydrofuran (25 mL X 2), the combined organics were dried over MgSO4 and concentrated under vacuum. The residue was purified by HPLC (20-100% CH3CN/H2O gradient) to yield 10 mg (13%) the title compound 340.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 - 1.46 (m, 4 H), 1.95 - 2.22 (m, 4 H), 2.88 - 3.15 (m, 1 H), 3.35 - 3.52 (m, 2 H), 3.44 - 3.56 (m, 1 H), 3.59 (s, 3 H), 6.92 (d, 1 H), 7.17 (s, 1 H), 7.98 (d, J = 6.3 Hz, 1 H). LRMS m/z calcd. for Ci6H23N8 [M+Hf 327. Found: 327 LCMS [M+H]+ = 327.2 Table 23. Compounds 339-341 were prepared according to the method R as described above.
Figure imgf000122_0001
Method S
Figure imgf000123_0001
Prepared according to Method A
Figure imgf000123_0002
Preparation of N-(4-{2-[(trans-4-hydroxycyclohexyl)amino]pyrimidin-4-yl}-1-methyl-1 H-pyrazol-5- yl)acetamide (342):
Preparation of N-{1-methyl-4-[2-(methylsulfonyl)pyrimidin-4-yl]-1H-pyrazol-5-yl}acetamide 342a)
To a solution of 1-methyl-4-[2-(methylsulfonyl)pyrimidin-4-yl]-1H-pyrazol-5-amine (0.06 g, 0.23 mmol) in 5 mL of dichlorom ethane was added triethylamine (0.06 ml_, 0.46 mmol) and acetyl chloride ( 0.05 mL , 0.46 mmol). The mixture was stirred at rt for 15 minutes. The solution was concentrated under vacuum. The residue was used in next step without purification.
Preparation of N-(4-{2-[(trans-4-hydroxycyclohexyl)amino]pyrimidin-4-yl}-1 -methyl-1 H-pyrazol-5- yl)acetamide (342)
N-{1-methyl-4-[2-(methylsulfonyl)pyrimidin-4-yl]-1H-pyrazol-5-yl}acetamide (0.065 g crude, 0.22 mmol) and trans-4-aminocyclohexanol (0.075 g, 0.66 mmol) in 5 mL of isopropanol was heated in the automated Microwave Reactor for 1.5 h at 15O0C . The solution was concentrated under vacuum. The residue was purified by HPLC (20-100% CH3CN/H2O gradient) to yield 21 mg (27%) the title compound. 1H NMR (400 MHz, CD3OD) δ ppm 1.29 - 1.51 (m, 4 H), 1.94 - 2.02 (m, 2 H), 2.02 - 2.11 (m, 2 H)1 2.27 (s, 3 H), 3.53 - 3.65 (m, 1 H), 3.69 - 3.76 (s, 3 H), 3.75 - 3.88 (m, 1 H), 6.77 (d, J = 5.3 Hz, 1 H), 7.99 (s, 1 H), 8.15 (d, J = 5.3 Hz1 1 H). LRMS m/z calcd. for C16H23N6O2 [M+H]+ 331. Found: 331.
Table 24. Compounds 342-349 were prepared according to the method S as described above. δ ppm 2.02 (m, 2 (s, 3 H) 3.76 (s, 3 (d, 8.15 (d,
δ ppm 2.05 (m, 2 (s, 3 H) 3.88 (m, 1 8.00 (s, 1 H)
δ ppm 1.52 (m, 4 - 2.22 H) 3.70 - Hz, 1 Hz, 1
δ ppm - 1.48 H) 1.92 - Hz, 2 H) (s, 3 H) J=5.31 J=5.30
δ ppm 2.12 (m, 4 (m, 1 H) 1 H) Hz, 1 H) Hz, 1 H)
Figure imgf000124_0001
δ ppm 1.96 (m, 2 - 3.62 3.86 (s, H) 7.70 (t, 1 H) 8.13 J=7.83
δ ppm 2.09 (m, 4 - 3.70 (d, J=5.31 (t, 1 H) Hz, 2 H)
δ ppm - 1.57 (m, 4 - 2.15 3.70 (s, (d, 8.13 (d,
Figure imgf000125_0001
OTHER COMPOUNDS OF THE INVENTION:
Method T
Figure imgf000125_0002
107 (trans)
To a solution of equal stoichiometry of the 107 (trans) (0.2M) and acids (0.2M) and triethylamine (0.5M) all in DMF stirred at room temperature, was added 1 eq. of O-(7-azabenzotriazol-1-yl)-N, N1 N', N'-tetra- methyluronium hexafluorophosphate (HATU) (0.5M) in DMF. The reaction was stirred at room temperature for 16 h. The crude was purified by preHPLC to afford the amide product (with yield 30-95% depending on the acid used). Table 25. Compounds 349-458 were prepared according to the methods T as described above.
451
432
447
428
Figure imgf000126_0001
442
494
490
Figure imgf000127_0001
489
462
473
428
433
Figure imgf000128_0001
478
435
425
439
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
413
433
477
491
Figure imgf000133_0001
449
415
445
Figure imgf000134_0001
400
464
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
394
Figure imgf000138_0001
428
447
Figure imgf000139_0001
- 447
497
Figure imgf000140_0001
Figure imgf000141_0001
460
430
H-pyrazole- 459
428
Figure imgf000142_0001
Figure imgf000143_0001
444
477
455
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
476
400
Figure imgf000147_0001
415
488
Figure imgf000148_0001
Figure imgf000149_0002
Method U
Figure imgf000149_0001
107 (trans)
To a 0.4M solution of aldehyde or ketone (0.08 mmole) and 107 (trans) (0.08 mmole) in a mixed solvent of anhydrous THF and anhydrous DMSO (1 :1 ), was added a solution of 330 μL (0.2 mmole, or 2.5 equiv) of the sodium triacetoxyborohydride in THF/DMSO (1:1) and then 10 uL of glacial acetic acid. The mixture was stirred at room temperature for 24 h. The reaction was quenched with (3M) Na2COa aqueous and EtOH. Insoluble substance was filtered off and the filtrate was evaporated to give a crude product. The crude was dissolved in DMSO and purified using prepHPLC to afford the pure product (yield range from
30 to 70% depending on the aldehyde or ketone used).
Table 26. Compounds 459-571 were prepared according to the method U as described above.
461
,4- 419
,4- 436
457
Figure imgf000150_0001
447
421
489
409
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
idin-2-
480
489
409
386
Figure imgf000154_0001
402
423
439
429
360
Figure imgf000155_0001
,4-diaminβ 419
411
420
Figure imgf000156_0001
394
,4- 419
,4-diamine 427
419
idiπ-2- ,4-diamine 447
439
Figure imgf000157_0001
Figure imgf000158_0001
456
395
,4- 397
Figure imgf000159_0001
Figure imgf000160_0001
422
465
,4- 371
396
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
459
423
43Θ
Figure imgf000165_0001
477
463
,4- 446
496
Figure imgf000166_0001
Figure imgf000167_0001
430
412
458
Figure imgf000168_0001
437
491
480
476
Figure imgf000169_0001
Figure imgf000170_0001
Biological activity
The percentage of inhibition (at 1 and 10 μM unless otherwise stated) and/or the Ki (in nM unless otherwise stated) for the compounds exemplified in the present application were obtained according to the protocol below:
% Inhibition and K1 Determination A coupled spectrophotometry assay, coupling JNK1α1 activity to to the oxidation of β-NADH to
NAD+ through the action of of pyruvate kinase (PK) and lactic dehydrogenase (LDH), was used to determine the potency (percent inhibition at 1 or 10 μM or K1) of compounds against JNK1α1 (Genbank Accession Number: L26318). The final reaction conditions were as follows: 20 mM HEPES pH 7.6, 10 mM MgCI2, 1 mM DTT, 200 μM peptide substrate (KRELVEPLTPSGEAPNQALLR), 300 μM NADH, 500 μM PEP (phophoenolpyruvate), 9-10 units/mL LDH, 8-12 units/mL PK, 40 nM JNK1α1_364nHis (catalytic domain containing amino acids 1-364 and N-terminal hexahistidine tag, previously activated by MKK4 and MKK7beta in vitro), 0-100 μM test compound, 2.5% DMSO, and 50 μM ATP (2.5X Km). The reaction was monitored by following the decrease in absorbance at 340 nm. The initial reaction rate was determined by the slope of the change in absorbance. To calculate percent inhibition the rate of the reaction in the presence of 1 or 10 μM compound was compared to the rate of the reaction with only DMSO multiplied by 100 percent. Note, the background rate of the above reaction in the presence of 10 μM PHA-00738186 was subtracted from all rates. To calculate the Kj, the reaction rates (with the background subtracted) were plotted vs. the compound concentration (0-100 μM) and fit to the tight binding for competitive inhibitors (Morrison) equation (see below).
Formula: Y=(-X+Eo-(Ki*(1+A/Km))+((X-
Eo+(Ki*(1 +A/Km)))Λ2+4*Eo*(Ki*(1 +A/Km)))Λ0.5)*(Vm*A/(Km+A)/(2*Eo))
Parameters: Eo1 Ki, A, Km, Vo
Y is initial reaction velocity;
X is inhibitor concentration;
A is [ATP];
Ki is inhibition constant;
Vm is Vmax;
Eo is total (initial) enzyme concentration;
Km is ATP Km;
The compounds were prepared in 100% DMSO at a 40X concentration. For percent inhibition experiments this would be 400 or 40 μM for 10 and 1 μM final concentration, respectively. For the Ki determination 3X serial dilutions were made starting at 4 mM (100 μM at 1X) in DMSO. A total of 11 concentrations were used for the analysis. The compounds were added to the reaction plate first. Next, a solution containing the HEPES, MgCI2, DTT, peptide substrate, NADH, PEP1 PK/LDH enzyme, and JNK1α1_364nHis enzyme was added to the assay plate. The plate was incubated at room temperature for 15 minutes. Then the plate was warmed to 30 0C for 5 minutes. The reaction was initiated with the addition of ATP. The reaction was run in a plate reader at 30 0C for 20 minutes with absorbance readings made about every 10 seconds. JNK1a1 364nHis purification procedure
Growth and induction conditions
BL21 (DE3) cells containing JNK1a1_364nHis vector were grown at 370C until optical density
(OD6Oo) was between 0.6 to 0.8. Expression was induced by addition of isopropylthiogalactoside (IPTG) to a final concentration of 0.1 -0.2m M and incubated at 230C overnight. The cells were harvested at 5000 rpm for
15 minutes at 40C. The cell pellet can be stored at -8O0C for future purification.
Purification procedure
1. Cell pellet (1L culture) was resuspended with lysis buffer at 5-10mL/wet cell pellet. The maximum and minimum volumes were 350 mL and 60 mL.
Lvsis Buffer IL
25mM Tris-HCI, pH8.0 25ml_ of 1 M
30OmM NaCI 60mL of 5M
14m M β-ME (add fresh) 1mL of 14M stock 2OmM Imidazole 5m L of 4M dH2O 909m L
The lysis buffer was filtered before use.
2. The cell were lyzed with microfluidizer (three times) and ultracentrifuged at 40,000rpm for 45 minutes at 40C. The supernatant was transferred to a chilled flask. A 2OuI aliquot was saved for gel analysis.
3. Ni-NTA column (23m L) lines were rinsed with lysis buffer. The column (23m L) was washed with 16OmL of lysis buffer at 5mL/min.
4. The supernatant was loaded onto Ni-NTA column at 4ml_/min.
5. The unbound was washed with 16OmL of lysis buffer at 5ml_/min.
6. The protein was eluted with imidazole gradient (from 2OmM to 0.5M). The elution buffer was prepared as follows:
Elution Buffer 25OmL
25mM Tris-HCI, pH7.5 6.25mL of 1 M
30OmM NaCI 15mL of 5M
14mM β-ME (add fresh) 0.25mL of 14M stock
0.5M Imidazole 31.25m L of 4M dH2O 197.25mL
The elution buffer was filtered before use
7. The elution settings were as follows. The record speed was set @1.0 mm/min.
BP %B FR FS
0 0 3 8
200 100 3 8
250 100 3 8
At the end of the elution the record speed was returned to 0.1 mm/min. Referring to the template above, BP means break point, %B means % buffer grading, FR means flow rate, and FS means fraction size.
8. The peak fractions were pooled. A 4OuI aliquot was saved for gel analysis.
9. The sample was concentrated down to 4-6mL with ultrafiltration cell under nitrogen. 10. While sample was being concentrated, the Superdex 200 column was washed with 45OmL
Superdex buffer at 2 mL/min. The Superdex buffer was prepared as follows: Superdex buffer IL
25mM Hepes pH 7.5, 25mL
5% Glycerol 10OmL
1OmM DTT 1.54g
5OmM NaCI 1OmL dH2O 865m L
To prepare the protein that was used for the assay, Dundee buffer was used for Superdex column. The Dundee buffer was prepared as follows:
Dundee Buffer IL
5OmM Tris Cl pH 7.5, 5OmL
27OmM Sucrose 92.4g
15OmM NaCI 3OmL
0.1mM EGTA 1mL
0.1% bMe 1mL
0.03% Brij-35 1mL
1mM Benzamidine 1mL
0.2mM PMSF 1mL dH2O to 1L
11. The concentrated sample was transferred to pre-chilled 1.5mL tubes and spinned at max for 10 minutes in cold room. The supernatant was transferred to 5OmL chilled tube.
12. The sample was injected (total volume equals total sample loop volume plus 0.3mL) to pre- washed loop (4-6mL). A 5ul aliquat was saved of the remaining sample for SDS-PAGE (a detergent).
13. The protein was eluted overnight according to the following settings. The record speed was set at 0.2 mm/min.
BP FR FS Injection valve
0 0.5 5 I
20 0.5 5 I
20.1 0.5 5 L
400 0.5 5 L
At the completion of the elution, the record speed was returned to 0.1 mm/min. Referring to the template above, BP means break point, FR means flow rate, FS means fraction size, I means inject, and L means load.
14. The peak fractions were pooled and the pool concentration was measured. The protein was concentrated down to 7-8mg/mL in hepes buffer protein. Aliquots of the protein were placed into chilled 0.5m L tubes at 100ul/tube, which were then snapped frozen in liquid nitrogen and stored at
-8O0C. The following procedure to regenerate the Ni-NTA and the Superdex 200 columns was used:
Ni-NTA Column
The Ni-NTA column was washed with 8OmL of dH2O at 5mL/min. Next it was washed with 8OmL of 0.1 M
EDTA, pH8.0 at 5mL/miπ. The flow was collected through in flask for proper disposal. The column was further washed with 15OmL of dH2O at 5mL/min. and charged with 6OmL of 10OmM NiCI2 at 5mL/min.
The flow was collected through in the same waste flask. The column was then washed with 6OmL of dH2O at 5mL/miπ and the flow was again collected through in the same waste flask. The column was then washed with 16OmL of dH2O at 5ml_/min.
Superdex 200 Column
The Superdex 200 column was washed with 70OmL of filtered dH2O at 2 mL/miπ.
The data obtained from the compounds of the invention according to the above protocol are tabulated below. The column with "#" heading refers to compound number as exemplified in the EΞxamples section. The column with "Ki" heading refers to Ki (in nM). The column with "% Inhibition" heading refers to percent inhibition at 1 μM (in %).
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Various embodiments of the present invention have been described above but a person skilled in the art realizes further minor alterations that would fall into the scope of the present invention. The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.

Claims

We Claim:
1. A compound of formula (I):
Figure imgf000187_0001
or a pharmaceutically acceptable salt thereof, wherein:
-Z- is -C- or -N-;
R1 is H or halo;
R2 is H, CF3, -CHF2, -CH2F1 trifluoromethoxy, (Ci-C6)alkoxy, (Ci-C6)amino(CRsR6)v, (CrC6)alkyl, -(CR5R6)v(3-10)-membered cycloalkyl, -(CR5R6)V(C8-C1o)aryl, or
-(CR5R6)V(4-12)-membered heterocyclyl;
R3 is H, (Ci-Cβ)alkyl, CF3, -CHF2, -CH2F, trifluoromethoxy, (Ci-C6)alkoxy, (CrC6)amino(CR5R6)v, -(C=O)-O-R5, -(C=O)-NR5R6, -S(O)RNR5R6,
-StO^d-CeJalkyl, -(CR5R6)v(3-10)-membered cycloalkyl, -(CR5R6)v(C6-C10aryl),
-(CR5R6)v(4-12)-membered heterocyclyl, -(CR5R6)q(C=O)(CrC6)alkyl, -(CR5R6)q(C=O)(CR5R8)v(3-10)- membered cycloalkyl, -(CR5R6)q(C=O)(CR5R6)v(C6-C10)aryll -(CR5R6)q(C=O)(CR5R6)v(4-12)-membered heterocyclyl, -(CR5R6)qS(O)j(CrC6)alkyl, -(CR5R6)qS(0)j(CR5R6)v(C6-C1o)aryl, or -(CR5R6)qS(O)j(CR5R6)v(4- 12)-membered heterocyclyl;
Or optionally, R2 together with the -N- to which R3 and R7 are attached to form a ring A, which is a (5-8)-membered heterocyclyl;
Provided that when R2 together with the -N- to which R3 and R7 are attached to said ring A (5-8)- membered heterocyclyl, R7 is a bond, and R3 may be absent;
Or optionally, R3 together with R7 and the -C- to which R3 and R7 are attached to form a ring B1 which is a (3-8)-membered heterocyclyl;
R4 is (CrC6)alkyl, -(CR5R6M3-10)-membered cycloalkyl, -(CR5R6MC6-C10)aryl, or -(CRδR6)v(4- 12)-membered heterocyclyl; each of R5 and R6 are independently selected from H, (Ci-Cβ)alkyl, -(CR8R9)p(3-10)-membered cycloalkyl, -(CR8R9Jp(C6-C10)aryl, and -(CR8R9)p(4-12)-membered heterocyclyl;
R7 is H or (d-CsJalkyl; any carbon atoms of said ring A, ring B, and the (CrC6)alkyl, the (3-10)-membered cycloalkyl, the (C6-Cio)aryl and the (4-12)-membered heterocyclyl moieties of the foregoing R1, R2, R3, R4, R5, and R6 are optionally substituted with 1 to 3 R10 substituents each independently selected from halo, cyaπo, -CF3, -CHF2, -CH2F, trifluoromethoxy, hydroxy, (d-CβJalkoxy,
(d-CfOalkyl, R9a, -(CR8R9)q-(C=O)-R8,
-(CR8R9)q-(C=O)-O-(C1-C6)alkyl, -(CR8R9)q-(C=O)-O-R9a, -0-(C=O)-R8, -0-(C=0)-R9a,
-NR8-(CR8R9)q(C=O)-R9, -NR8-(CR8R9)q(C=O)R9a, -NR8-(CR8R9)q(C=O)-O(C1-C6)alkyl, -NRβ-(CR8R9)q(C=O)-OR9, -NR8-(C=O)NR8R9, -NR8-(C=O)NR8R9a, -NR8-(C=O)-(C=O)-NR8R9, -NR8-
(C=O)-(C=O)-NR8R98, -NR^(CR8R9Jq(C=O)OR93,
-(C=O)-NR8R9, -(C=O)NR8R93, -NR8R9, -NR8R93, -NR8OR9, -NR8OR98, -S(O)RNR8R9, -S(OJk NR8R93, -SfOMCrQOalkyl, -S(O)jR9a,
-NR8-S(O)k(CrC6)alkyl, -NR8-S(O)kR9a, -NR^S(OJkNR93, and -(CR8R9)qS(O)jR9a; wherein any carbon atoms of each of the foregoing R10 (Ci-C6)alkyl, (3-10)-membered cycloalkyl, (C6-C10aryl), or (4-12)-membered heterocyclyl moieties are optionally substituted with 1 to 3 R11 substituents each independently selected from halo, cyano, -CF3, -CHF2, -CH2F, -0-CF3, -0-CHF2, -0-CH2F, hydroxy, (Ci-C6)alkoxy, (CrC6)alkyl, R14, -0-R14, -(C=O)-R8, -(C=O)-R14, -(C=O)-O-(Ci-C6)alkyl, -(C=O)-O-R14, -0-(C=O)-R8, -O- (C=O)-R14, -NR8(C=O)-R9, -NR8(C=O)-R14, -(C=O)-NR8R9, -(C=O)-NR8R14, -NR8R9, -NR8R14, -NR8OR9, - NR8OR14, -S(O)11NR8R9, -S(O)kNR8R14,
Figure imgf000188_0001
-S(O)1R14, NR8-S(O)k(CrC6)alkyl, NR14-S(O)k(C1-C6)alkyl, and -NR8-S(O)kR14; any nitrogen atoms of said ring A, ring B, and the (4-12)-membered heterocyclyl moieties of the foregoing R1, R2, R3, R4, R5, R6, R9a, R10, R11 and R14 are optionally substituted with R12 substituents each independently selected from (Ci-C6)alkyl,
-(C=O)-R8, -(C=O)-R148, -(C=O)-O-(Ci-C6)alkyl, -(C=O)-NR8R9, -(C=O)-NR8R143, R14a, -(CR8R9)q(C=O)R143, and -(CR8R9JqS(OJjR148; wherein any carbon atoms of each of the foregoing R11 and R12 (Ci-Cejalkyl, (3-10)-membered cycloalkyl, (C6-C10aryl), or (4-12)-membered heterocyclyl moieties are optionally substituted with 1 to 3 R13 substituents each independently selected from halo, cyano, -CF3, -CHF2, -CH2F, trifluoromethoxy, hydroxy, (C1-C6JaIkOXy, (C^CeJalkyl, -(CR8R9)p(3-10)-membered cycloalkyl, -(CR8R9Jp(C6-C1 oaryl), -(CR8R9)p(4-12)-membered heterocyclyl, -(C=O)-R8, -(C=O)-O-(C1- C6)alkyl, _O-(C=O)-R8, -NR8(C=O)-R9, -(C=OJ-NR8R9,
-(C=O)-NR8R14, -NR8R9, -NR8OR9, -S(O)kNR8R9,
Figure imgf000188_0002
and -NR8-S(O)k(Ci-Cβ)alkyl; each R8 and R9 are independently H or (CrC6)alkyl; each R93, R14, and R14a are independently -(CR8R9)v(3-10)-membered cycloalkyl, -(CR8R9)v(C6-C10)aryl, or -(CR8R9)v(4-12)-membered heterocyclyl; p, q, and v are each independently 0, 1, 2, 3, 4, or 5; n and j are each independently 0, 1 , or 2; w is O, 1 , 2, or 3, and k is 1 or 2.
2. A compound of formula (Ia):
Figure imgf000188_0003
or a pharmaceutically acceptable salt thereof, wherein:
R1 is H or halo;
R2 is H1 CF3, -CHF2, -CH2F, trifluoromethoxy, (C1-C6JaIkOXy, (Ci-Ce)amino(CR5R6)v, (CrC6)alkyl, -(CR5R6)v(3-10)-membered cycloalkyl,
Figure imgf000189_0001
or
-(CR5R6)V(4-12)-membered heterocyclyl;
R3 is H, (C1-C6JaIlCyI1 CF3, -CHF2, -CH2F, trifluoromethoxy, (C1-C6JaIkOXy, (CrCeOaminofCR^X,, -(C=O)-O-R6, -(C=O)-NR5R6, -S(OJkNR5R6,
-S(O)j(C1-C6)alkyl, -(CR5R6)v(3-10)-membered cycloalkyl, -(CR5R6)v(CfrC10aryl),
-(CR5R6)v(4-12)-membered heterocyclyl, -(CR5R6)q(C=O)(CrC6)alkyl, -(CR5R6)q(C=O)(CR5R6)v(3-10)- membered cycloalkyl, -(CR5R6)q(C=O)(CR5R6)v(C6-C10)aryl, -(CR5R6)q(C=O)(CR5R8)v(4-12)-membered heterocyclyl, -(CR5R6)qS(O)J(C1-C6)alkylI -(CR5R6)qS(O)j(CR5R6)v(C6-C10)aryl, or -(CR5R6)qS(O)i(CR5R6)v(4- 12)-membered heterocyclyl;
R4 is (d-CβJalkyl, -(CRsR6M3-10)-membered cycloalkyl, -(CR5R8)v(C6-C10)aryl, or -(CR5R6)V(4- 12)-membered heterocyclyl; each of R5 and R6 are independently selected from H, (CrC6)alkyi, -(CR8R9)p(3-10)-membered cycloalkyl, -(CR8R9)p(C6-C10)aryl, and -(CR8R9)p(4-12)-membered heterocyclyl;
R7 is H or (d-CβJalkyl; any carbon atoms of the (d-CβJalkyl, the (3-10)-membered cycloalkyl, the (C6-C10)aryl and the (4- 12)-membered heterocyclyl moieties of the foregoing R1, R2, R3, R4, R5, and R6 are optionally substituted with 1 to 3 R10 substituents each independently selected from halo, cyano, -CF3, -CHF2, -CH2F, trifluoromethoxy, hydroxy, (C1-C6JaIkOXy,
(CrCe)alkyl, R9a, -(CR8R9)q-(C=O)-R8, -(CR8R9)q-(C=O)-R9a,
-(CR8R9)q-(C=O)-O-(C1-C6)alkyl, -(CR8R9)q-(C=O)-O-R9a, -0-(C=O)-R8, -0-(C=O)-R98,
-NR8-(CR8R9)q(C=O)-R9,
Figure imgf000189_0002
-NR8-(CR8R9)q(C=O)-O(CrC6)alkyl,
-NR8-(CR8R9)q(C=O)-OR9, -NR8-(C=O)NR8R9, -NR8-(C=O)NR8R9a, -NR8-(C=O)-(C=O)-NR8R9, -NR8- (C=O)-(C=O)-NR8R93, -NR^(CR8R9Jq(C=O)OR93,
-(C=O)-NR8R9, -(C=O)NR8R93, -NR8R9, -NR8R9a, -NR8OR9, -NR8OR93, -S(OXNR8R9, -S(0)k NR8R93, -S(OJj(C1-C6)alkyl, -S(O)jR9a,
-NR8-S(O)k(CrC6)alkyl, -NR8-S(O)kR9a, -NR^S(OJkNR93, and -(CR8R9)qS(O)jR9a; wherein any carbon atoms of each of the foregoing R10 (d-CβJalkyl, (3-10)-membered cycloalkyl, (C6-C10aryl), or (4-12)-membered heterocyclyl moieties are optionally substituted with 1 to 3 R11 substituents each independently selected from halo, cyano, -CF3, -CHF2, -CH2F, -0-CF3, -0-CHF2, -0-CH2F, hydroxy, (C1-C6JaIkOXy1 (CrCfOalkyl, R14, -0-R14, -(C=O)-R8, -(C=O)-R14, -(C=O)-O-(CrC6)alkyl, -(C=O)-O-R14, -0-(C=O)-R8, -O- (C=O)-R14, -NR8(C=O)-R9, -NR8(C=O)-R14, -(C=O)-NR8R9, -(C=O)-NR8R14, -NR8R9, -NR8R14, -NR8OR9, - NR8OR14, -S(O)11NR8R9, -S(O)kNR8R14, -SfOtøCrQOalkyl,
-S(OJjR14, NR8-S(O)k(C1-C6)alkyl,
Figure imgf000189_0003
and -NR8-S(O)kR14; any nitrogen atoms of the (4-12)-membered heterocyclyl moieties of the foregoing R1, R2, R3, R4, R5, R6, R9a, R10, R11 and R14 are optionally substituted with R12 substituents each independently selected from (CrCfsJalkyl, -(C=O)-R8, -(C=O)-R143, -(C=O)-O-(Ci-C6)alkyl,
-(C=O)-NR8R9, -(C=O)-NR8R148, R14a, -(CR8R9)q(C=O)R14a, and -(CR8R9)qS(O)jR14a; wherein any carbon atoms of each of the foregoing R11 and R12 (Ci-C6)alkyl, (3-10)-membered cycloalkyl, (C6-Ci oaryl), or (4-12)-membered heterocyclyl moieties are optionally substituted with 1 to 3 R13 substituents each independently selected from halo, cyano, -CF3, -CHF2, -CH2F, trifluoromethoxy, hydroxy, (C1-C6JaIkOXy, (CrC6)alkyl, -(CR8R9)p(3-10)-membered cycloalkyl, -(CR8R9Jp(C6-C1 oaryl), -(CR8R9)p(4-12)-membered heterocyclyl, -(C=O)-R8, -(C=O)-O-(C1- C6)alkyl, -0-(C=O)-R8, -NR8(C=O)-R9, -(C=O)-NR8R9,
-(C=O)-NR8R14, -NR8R9, -NR8OR9, -S(O)kNR8R9, -S(O)i(C1-C6)alkyl, and -NR8-S(O)k(CrC6)alkyl; each R8 and R9 are independently H or (Ci-Cβ)alkyl; each R99, R14, and R14a are independently -(CR8R9)«(3-10)-membered cycloalkyl, -(CR8R9Jv(C6-C10)aryl, or -(CR8R9)v(4-12)-membered heterocyclyl; p, q, and v are each independently O1 1, 2, 3, 4, or 5; n and j are each independently 0, 1 , or 2; w is O, 1 , 2, or 3, and k is 1 or 2.
3. A compound of formula (Ib):
Figure imgf000190_0001
(Ib); wherein ring A is a (5-8)-membered heterocyclyl;
-Z- is -C- or -N-;
R1 is H or halo,
R3 is H, (CrC6)alkyl. CF3, -CHF2, -CH2F, trifluoromethoxy, (C1-C6JaIkOXy, -(C=O)-O-R5, -(C=O)-NR5R6, -S(OJkNR5R6,
Figure imgf000190_0002
-(CR5R6)V(3-10)-membered cycloalkyl, -(CR5R6)v(C6-C10aryl),
-(CR5R6)v(4-12)-membered heterocyclyl, -(CR5R6)q(C=O)(C1-C6)alkyl, -(CR5R6)q(C=O)(CR5R6)v(3-10J- membered cycloalkyl, -(CR5R6)q(C=O)(CR5R6)v(CtrC10)aryl, -(CR5R6)q(C=O)(CRsR6)v(4-12)-membered heterocyclyl, -(CR5R6)qS(O)i(C1-C6)alkyl, -(CR5R6)qS(O)j(CR5R6)v(C6-C10)aryl, or -(CR5R6)qS(O)j(CR5R6)v(4- 12)-membered heterocyclyl;
Or R3 may be absent;
R4 is (CrC6)alkyl, -(CR5R6M3-10)-membered cycloalkyl, -(CR5R6X(C6-C10)aryl, or -(CR5R6)V(4- 12)-membered heterocyclyl; each of R5 and R6 are independently selected from H, (C1-C6JaIk^,
:>8O9\
-(CRBRs)p(3-10)-membered cycloalkyl, -(CR D8oRD9a)p(C6-C10)aryl, and -(CR8R9)p(4-12)-membered heterocyclyl; any carbon atoms of said ring A and the (Ci-C6)alkyl, the (3-10)-membered cycloalkyl, the (C6-
C10)aryl and the (4-12)-membered heterocyclyl moieties of the foregoing R1, R3, R4, R5, and R6 are optionally substituted with 1 to 3 R10 substituents each independently selected from halo, cyano, -CF3, -CHF2, -CH2F, trifluoromethoxy, hydroxy, (d-C6)alkoxy,
(CrCjOalkyl, R9a, -(CR8R9)q-(C=O)-R8, -(CR8R9)q-(C=O)-R9a,
-(CR8R9)q-(C=O)-O-(CrC6)alkyl, -(CR8R9)q-(C=O)-O-R9a, -0-(C=O)-R8, -0-(C=O)-R93,
-NR8-(CR8R9)q(C=O)-R9, -NR8-(CR8R9)q(C=O)R9a, -NR8-(CR8R9)q(C=O)-O(CrC6)alkyl,
-NR8-(CR8R9)q(C=O)-OR9, -NR8-(C=O)NR8R9, -NR8-(C=O)NR8R9a, -NR8-(C=O)-(C=O)-NR8R9, -NR8- (C=O)-(C=O)-NR8R98, -NR8-(CR8R9)q(C=O)OR9a,
-(C=O)-NR8R9, -(C=O)NR8R98, -NR8R9, -NR8R93, -NR8OR9, -NR8OR98, -S(OJkNR8R9, -S(O)k NR8R98, -SfOKd-CβJalkyl, -S(O)JR98,
-NR8-S(O)k(CrC6)alkyl, -NR8-S(O)kR9a,
Figure imgf000191_0001
and -(CR8R9)qS(O)jR9a; wherein any carbon atoms of each of the foregoing R10 (C1-C6)alkyl, (3-10)-membered cycloalkyl, (C6-C10aryl), or (4-12)-membered heterocyclyl moieties are optionally substituted with 1 to 3 R11 substituents each independently selected from halo, cyano, -CF3, -CHF2, -CH2F, -0-CF3, -0-CHF2, -0-CH2F, hydroxy, (C1-C6JaIkOXy, (Ci-C6)alkyl, R14, -0-R14, -(C=O)-R8, -(C=O)-R14, -(C=O)-O-(CrC6)alkyl, -(C=O)-O-R14, -0-(C=O)-R8, -O- (C=O)-R14, -NR8(C=O)-R9, -NR8(C=O)-R14, -(C=O)-NR8R9, -(C=O)-NR8R14, -NR8R9, -NR8R14, -NR8OR9, - NR8OR14, -S(O)15NR8R9, -S(O)kNR8R14, -S(O)j(CrC6)alkyl,
-S(O)jR14, NR8-S(O)k(CrC6)alkyl, NR14-S(O)k(C1-C6)alkyl, and -NR8-S(O)kR14; any nitrogen atoms of said ring A and the (4-12)-membered heterocyclyl moieties of the foregoing R1, R3, R4, R5, R6, R", R10, R11 and R14 are optionally substituted with R12 substituents each independently selected from (CrC6)alkyl,
-(C=O)-R8, -(C=O)-R143, -(C=O)-O-(C1-C6)alkyl, -(C=O)-NR8R9, -(C=O)-NR8R148, R14a, -(CR8R9)q(C=O)R14a, and -(CR8R9)qS(O)jR14a; wherein any carbon atoms of each of the foregoing R11 and R12 (Ci-C6)alkyl, (3-10)-membered cycloalkyl, (C6-C10aryl), or (4-12)-membered heterocyclyl moieties are optionally substituted with 1 to 3 R13 substituents each independently selected from halo, cyano, -CF3, -CHF2, -CH2F, trifluoromethoxy, hydroxy, (CrC6)alkoxy, (Ci-C6)alkyl, -(CR8R9)p(3-10)-membered cycloalkyl, -(CR8R9Jp(C6-C1 oaryl), -(CR8R9)p(4-12)-membered heterocyclyl, -(C=O)-R8, -(C=O)-O-(C1- C6)alkyl, -0-(C=O)-R8, -NR8(C=O)-R9, -(C=O)-NR8R9,
-(C=O)-NR8R14, -NR8R9, -NR8OR9, -S(O)kNR8R9, -S(O)j(CrC6)alkyl, and -NR8-S(O)k(CrC6)alkyl; each R8 and R9 are independently H or (CrCeJalkyl; each R93, R14, and R14a are independently -(CR8R9)v(3-10)-membered cycloalkyl, -(CR8R9)v(C6-C10)aryl, or -(CR8R9)v(4-12)-membered heterocyclyl; p, q, and v are each independently 0, 1 , 2, 3, 4, or 5; n and j are each independently 0, 1 , or 2; w is O, 1 , 2, or 3, and k is 1 or 2.
4. The compound according to claim 3 selected from the group consisting of:
Figure imgf000192_0001
Figure imgf000192_0002
of formula (Ic):
Figure imgf000192_0003
wherein ring B is a (3-8)-membered heterocyclyl; -Z- is -C- or -N-;
R1 is H or halo;
R^ is H1 CF3, -CHF2, -CH2F1 trifluoromethoxy, (CrC6)alkoxy, (d-CeJaminotCR^6^,
(CrC6)alkyl, -(CR ,5b OR6H)v(3-10)-membered cycloalkyl, τSf->6'
-(CR3R°)v(C6-C10)aryl, or
Figure imgf000192_0004
heterocyclyl;
R4 is (CrCfOalkyl, -(CR5R6)«(3-10)-membered cycloalkyl,
Figure imgf000192_0005
or -(CR5R6)V(4- 12)-membered heterocyclyl; each of R5 and R6 are independently selected from H, (Ci-C6)alkyl, -(CR8R9)p(3-10)-membered cycloalkyl, -(CR8R9)p(C6-C10)aryl, and -(CR8R9)p(4-12)-membered heterocyclyl; any carbon atoms of said ring B, and the (CrC^alkyl, the (3-10)-membered cycloalkyl, the (C6- C10)aryl and the (4-12)-membered heterocyclyl moieties of the foregoing R1, R2, R4, R5, and R6 are optionally substituted with 1 to 3 R10 substituents each independently selected from halo, cyano, -CF3, -CHF2, -CH2F, trifluoromethoxy, hydroxy, (CrC6)alkoxy,
(CrC6)alkyl, R9a, -(CR8R9)q-(C=O)-R8, -(CR8R9)q-(C=O)-R9a,
-(CR8R9)q-(C=O)-O-(CrC6)alkyl, -(CR8R9)q-(C=O)-O-R9a, -0-(C=O)-R8, -0-(C=0)-R9a,
-NR8-(CR8R9)q(C=O)-R9, -NR8-(CR8R9)q(C=O)R9a, -NR8-(CR8R9)q(C=O)-O(CrC6)alkyl,
-NR8-(CR8R9)q(C=O)-OR9, -NR8-(C=O)NR8R9, -NR8-(C=O)NR8R9a, -NR8-(C=O)-(C=O)-NR8R9, -NR8- (C=O)-(C=O)-NR8R93, -NR8-(CR8R9)q(C=O)OR9a,
-(C=O)-NR8R9, -(C=O)NR8R93, -NR8R9, -NR8R9a, -NR8OR9, -NR8OR93, -S(O^NR8R9, -S(OX NR8R93, -SfOMd-QOalkyl, -S(O)1R93,
-NR8-S(O)k(CrC6)alkyl, -NR8-S(O)kR9a, -NR^S(O)RNR93, and -(CR8R9)qS(O)jR9a; wherein any carbon atoms of each of the foregoing R10 (Ci-C6)alkyl, (3-10)-membered cycloalkyl, (C6-Cioaryl), or (4-12)-membered heterocyclyl moieties are optionally substituted with 1 to 3 R11 substituents each independently selected from halo, cyano, -CF3, -CHF2, -CH2F, -0-CF3, -0-CHF2, -0-CH2F, hydroxy, (CrC6)alkoxy, (d-CsJalkyl, R14, -0-R14, -(C=O)-R8, -(C=O)-R14, -(C=O)-O-(C1-C6)alkyl, -(C=O)-O-R14, -0-(C=O)-R8, -O- (C=O)-R14, -NR8(C=O)-R9, -NR8(C=O)-R14, -(C=O)-NR8R9, -(C=O)-NR8R14, -NR8R9, -NR8R14, -NR8OR9, - NR8OR14, -S(O)15NR8R9, -S(O)kNR8R14, -S(O)j(Ci-C6)alkyl,
-S(O)jR14, NR8-S(O)k(CrC6)alkyl, NR14-S(O)κ(CrC6)alkyl, and -NR8-S(O)kR14; any nitrogen atoms of said ring B, and the (4-12)-membered heterocyclyl moieties of the foregoing R1, R2, R4, R5, R6, R9a, R10, R11 and R14 are optionally substituted with R12 substituents each independently selected from (d-CeJalkyl, -(C=O)-R8, -(C=O)-R143, -(C=O)-O-(C1-C6)alkyl, -(C=O)-NR8R9, -(C=O)-NR8R143, R143, -(CR8R9)q(C=O)R14a, and -(CR8R9)qS(O)jR14a; wherein any carbon atoms of each of the foregoing R11 and R12 (Ci-C6)alkyl, (3-10)-membered cycloalkyl, (C6-C1 oaryl), or (4-12)-membered heterocyclyl moieties are optionally substituted with 1 to 3 R13 substituents each independently selected from halo, cyano, -CF3, -CHF2, -CH2F, trifluoromethoxy, hydroxy, (C1-C6JaIkOXy1 (d-CβJalkyl, -(CR8R9)p(3-10)-membered cycloalkyl,
Figure imgf000193_0001
-(CR8R9)p(4-12)-membered heterocyclyl, -(C=O)-R8, -(C=O)-O-(C1- C6)alkyl, -0-(C=O)-R8, -NR8(C=O)-R9, -(C=O)-NR8R9,
-(C=O)-NR8R14, -NR8R9, -NR8OR9, -S(O)kNR8R9, -S(O)j(CrC6)alkyl, and -NR8-S(O)k(C.,-C6)alkyl; each R8 and R9 are independently H or (Ci-Cβ)alkyl; each R93, R14, and R14a are independently -(CR8R9)v(3-10)-membered cycloalkyl, -(CR8R9)v(C6-C10)aryl, or -(CR8R9)v(4-12)-membered heterocyclyl; p, q, and v are each independently 0, 1 , 2, 3, 4, or 5; n and j are each independently 0, 1, or 2; w is 0, 1, 2, or 3, and k is 1 or 2.
5. The compound according to any one of claims 1 , 2, 3, or 4, wherein -Z- is -N-.
6. The compound according to any one of claims 1, 2, 3, or 4, wherein R1 is H or F.
7. The compound according to any one of claims 1, 2, or 4, wherein R2 is H, (Gt-CβJalkyl, benzyl, phenyl, or (4-12)-membered heterocyclyl, wherein any carbon' atoms of the said (C1- C6)alkyl, benzyl, phenyl, or (4-12)-membered heterocyclyl are optionally substituted with 1 to 3 R10 substituents each independently selected from halo, cyano, hydroxy, (CrC6)alkoxy, (Ci-C6)alkyl, -(C=O)-R8, -(C=O)-R98, -(C=O)-O-(C1 -Cgjalkyl, -0-(C=O)-R8, -(C=O)-NR8R9, -NR8R9, -NR8R9a,,-S(O)kNR8R9, -SfO^d-QOalkyl, and -NR8-S(O)k(Ci-Cβ)alkyl.
8. The compound according to any one of claims 1, 2, or 3, wherein R3 is H, (CrC6)alkyl, -(CRsR6)v(3-10)-membered cycloalkyl, -(CR5R6Jv(C6-C1OaITl), -(CR5R6)v(4-7)-membered heterocyclyl, -(CR5R6)q(C=O)(C1-C6)alkyl, -(CR5R6)q(C=O)(CR5R6)v(3-10)- membered cycloalkyl, -(CR5R6)q(C=O)(CR5R6)v(C6-C10)aryl, -(CR5R6)q(C=O)(CR5R6)v(4-12)-membered heterocyclyl, -(CR5R6JqS(O)2(C1 -QOalkyl, -(CRsR6)qS(O)2(CR5R6)v(C6-C10)aryl, or -(CR5R6)qS(O)2(CR5R6)v(4-7)-membered heterocyclyl; wherein any carbon atoms of said R3 (CrC6)alkyl, (3-10)-membered cycloalkyl, (Ce-C^aryl), or (4- 7)-membered heterocyclyl moieties are optionally substituted with 1 to 3 R10 substituents each independently selected from halo, cyano, hydroxy, (C1-C6)alkoxy, [C-\-C6)a\ky\, R93, -(CR8RV(C=O)-R8, -(CR8R9)q-(C=O)-R9a, -(CR8R9)q-(C=O)-O-(CrC6)alkyl,
-(CR8R9)q-(C=O)-O-R9a, -0-(C=O)-R8, -0-(C=0)-R9a, -NR8-(CR8R9)q(C=O)-R9,
-NR8-(CR8R9)q(C=O)R9a, -NR8-(CR8R9)q(C=O)-O(Ci-C6)alkyl,
-NR8-(CR8R9)q(C=O)-OR9, -NR8-(C=O)NR9, -NR8-(C=O)NR9a, -NR8-(CR8R9)q(C=O)OR9a,
-(C=O)-NR8R9, -(C=O)NR8R98, -NR8R9, -NR8R98, -NR8OR9, -NR8OR98, -S(O)11NR8R9, -S(O)Ic NR8R98, -S(Oi(Ci-Cβ)alkyl, -S(O)jR9a, -NR^S(O)11(C1 -QOalkyl, -N R^S(OJkR98, -NR8-S(O)kNR9a, and -(CR8R9JqS(O)JR98.
9. The compound according to any one of claims 1, 2, 3, or 4, wherein R4 is (C1-C6JaIkYl; wherein any carbon atoms of said R4 are optionally substituted with with 1 to 3 R10 substituents each independently selected from halo, cyano, - CF3, -CHF2, -CH2F, trifluoromethoxy, hydroxy, (Ci-C6)alkoxy, (d-CeJalkyl, R9a, -(CR8R9)q-(C=O)-R8, -(CR8R9)q-(C=O)-R9a, -(CR8R9)q-(C=O)-O-(C1-C6)alkyl, -(CR8R9)q-(C=O)-O-R9a, -0-(C=O)-R8, -0-(C=O)-R98, -NR8-(CR8R9)q(C=O)-R9, -NR8-(CR8R9)q(C=O)R9a, -NR8-(CR8R9)q(C=O)-O(CrC6)alkyl, -NR8-(CR8R9)q(C=O)-OR9, -NR8-(C=O)NR9, -NR^(C=O)NR98, -NR8-(CR8R9)q(C=O)OR9a, -(C=O)-NR8R9, -(C=O)NR8R98, -NR8R9, -NR8R98, -NR8OR9, -NR8OR93, -S(O)15NR8R9, -S(0)k NR8R98, -S(O)i(C1-C6Jalkyl, -S(OJjR98, -NR8-S(O)k(CrC6)alkyl, -NR8-S(O)kR9a, -NR^S(OJkNR98, and -(CR8R9)qS(O)jR9a.
10. The compound according to any one of claims 1, 2, 3, or 4, wherein R4 is -(CR5R6)v(3-10)-membered cycloalkyl, -(CR5R6Jv(C6-C10)aryl, or -(CR5R6)v(4-12)-membered heterocyclyl; wherein any carbon atoms of said R4 (3-10)-membered cycloalkyl, (C6-C10aryl), or (4-12)-membered heterocyclyl moieties are optionally substituted with with 1 to 3 R10 substituents each independently selected from halo, cyano, -CF3, -CHF2, - CH2F, trifluoromethoxy, hydroxy, (C1-C6JaIkOXy, (CrC6)alkyl, R9a, -(CR8R9)q-(C=O)-R8, -(CR8R9)q-(C=O)-R9a, -(CR8R9)q-(C=O)-O-(CrC6)alkyl, -(CR8R9Jq-(C=O)-O-R98, -0-(C=O)-R8, -0-(C=O)-R98, -NR8-(CR8R9)q(C=O)-R9, --NNRR88--((CCRR88RR99))qq((CC==OO))RR99aa,, -NR8-(CR8R9)q(C=O)-O(C1-C6)alkyl,
-NR8-(CR8R9)q(C=O)-OR9, -NR8-(C=O)NR9, -NR8-(C=O)NR9a, -NR8-(CR8R9)q(C=O)OR9a,
-(C=O)-NR8R9, -(C=O)NR8R98, -NR8R9, -NR8R98, -NR8OR9, -NR8OR98, -S(OJkNR8R9,
9a
-S(0)k NRBRsa, -S(0)i(CrC6)alkyl, -S(0)jRs
-NR8-S(O)k(CrC6)alkyl, -NR8-S(O)kR9a, -NR^SfO^NR98, and -(CR8R9)qS(O)jR9a; wherein any nitrogen atoms of said R4 (4-12)-membered heterocyclyl moeieties are optionally substituted with R 312 substituents each independently selected from (C1-C3)alkyl,
-,14a ,8o14a R14a
-(C=O)-R", -(C=O)-R1"8, -(C=O)-O-(C1-C6)alkyl. -(C=O)-NR8R9, -(C=O)-NR-R148, -(CR8R9)q(C=O)R14a, and -(CR8R9)qS(O)jR14; wherein any carbon atoms of each of the foregoing R11 and R12 (Ci-C6)alkyl, (3-10)-membered cycloalkyl, (C6-Cioaryl), or (4-12)-membered heterocyclyl moieties are optionally substituted with 1 to 3 R13 substituents each independently selected from halo, cyano, -CF3, -CHF2, -CH2F, trifluoromethoxy, hydroxy, (C1-C6JaIkOXy, (CrC6)alkyl, -(CR8R9)p(3-10)-membered cycloalkyl, -(CR8R9Jp(C6-C1 oaryl), -(CR8R9)p(4-12)-membered heterocyclyl, -(C=O)-R8, -(C=O)-O-(C1- C6)alkyl, -0-(C=O)-R8, -NR8(C=O)-R9, -(C=O)-NR8R9,
-(C=O)-NR8R14, -NR8R9, -NR8OR9, -S(O)kNR8R9, -SfO^CrCeJalkyl, and -NR8-S(O)k(CrC6)alkyl;
11. The compound according to claim 1, selected from the group consisting of:
Figure imgf000195_0001
pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
13. A method of treating a condition that is mediated by the modulation of JNK, the method comprising administering to a mammal an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
14. A method of treating diabetes, metabolic syndrome, insulin resistance syndrome, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, osteoporosis, tuberculosis, atherosclerosis, dementia, depression, virus diseases, inflammatory disorders, or diseases in which the liver is a target organ, the method comprising administering to a mammal an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
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