WO2007023382A2 - Pyrimidine amino pyrazole compounds, potent kinase inhibitors - Google Patents

Pyrimidine amino pyrazole compounds, potent kinase inhibitors Download PDF

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WO2007023382A2
WO2007023382A2 PCT/IB2006/002344 IB2006002344W WO2007023382A2 WO 2007023382 A2 WO2007023382 A2 WO 2007023382A2 IB 2006002344 W IB2006002344 W IB 2006002344W WO 2007023382 A2 WO2007023382 A2 WO 2007023382A2
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alkylene
cycloalkyl
alkyl
ring
compound
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PCT/IB2006/002344
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French (fr)
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WO2007023382A3 (en
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Chuangxing Guo
Mary Catherine Johnson
Haitao Li
Joseph Timothy Marakovits
Indrawan James Mcalpine
Liming Dong
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Pfizer Inc.
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Publication of WO2007023382A3 publication Critical patent/WO2007023382A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D403/14—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
    • 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
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged 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
    • C07D491/08—Bridged systems

Definitions

  • the present invention relates generally to novel chemical compounds and methods. More particularly, the invention provides novel pyrimidine amino pyrazole compounds and their analogs, having protein kinase activity, and methods of synthesizing and using such compounds.
  • Protein kinases are a family of enzymes that catalyze phosphorylation of the hydroxyl groups of specific tyrosine, serine, or threonine residues in proteins. Typically, such phosphorylation dramatically change the function of the protein and thus protein kinases are pivotal in the regulation of a wide variety of cellular process, including metabolism, cell proliferation, cell differentiation, and cell survival. The mechanism of these cellular process provide basis for targeting protein kinases to treat disease conditions resulting from or involving disorder of these cellular process. Examples of such diseases are, but are not limited to, cancer and diabetes.
  • Protein kinases can be broken into two types, the protein tyrosine kinases (PTKs) and the serine-threonine kinases (STKs). Both PTKs and STKs can be receptor protein kinases or non-receptor protein kinases.
  • PAK is a family of non-receptor STKs.
  • the p21 -activated protein kinase (PAK) family of serine/threonine protein kinases plays important roles in cytoskeletal organization and cellular morphogenesis (Daniels et al., Trends Biochem. ScL 24: 350-355 (1999); Sells et al., Trends Cell. Biol. 7: 162-167 (1997)).
  • PAK proteins were initially identified by their interaction with the active small GTPases, Cdc42, and Rac, and their homology to yeast kinase Ste20 (Manser et al., Nature 367: 40-46 (1994)). In addition to mediating the regulation of actin cytoskeleton and cell adhesion by Cdc42 and Rac (Daniels et al., Trends Biochem. ScL 24: 350-355 (1999)), it was determined that some PAK proteins protect cells from apoptosis (Gnesutta et al., J. Biol. Chem.
  • PAK proteins regulate cell proliferation and migration.
  • the full-length PAK4 nucleic acid and amino acid sequences are disclosed in U.S. Patent No.
  • PAK4 Modulation of human PAK4 activity is reported to result in alterations in cellular processes affecting cell growth and adhesion. For example, overexpression of PAK4 in fibroblasts leads to morphological changes that are characteristic of oncogenic transformation through induction of anchorage-independent growth and inhibition of apoptosis (Gnesutta et al., J. Biol. Chem. 276:14414-14419 (2001); Qu et al., MoI. Cell. Biol. 21 : 3523-2533 (2001)).
  • PAK4 is an attractive target for developing therapeutic agents effective for use in processes and disorders involving cytoskeletal alterations, such as, for example, cancer.
  • the invention provides compounds of formula I,
  • Z 1 , Z 2 , Z 3 and Z 4 are independently CH or N, provided that at least one of Z 1 , Z 2 , Z 3 and Z 4 is CH and at least one of Z 1 , Z 2 , Z 3 and Z 4 is N, and the ring formed by Z 1 , Z 2 , Z 3 , Z 4 and the two intervening carbons is optionally further substituted by 1 to 3 R 4 groups;
  • R 1 represents 1 or 2 optional substituents
  • Ring A is 3-4 member cycloalkyl, 3-4 member heterocyclyl, 5-7 member bicyclic heterocyclyl or 5-7 member bicyclic nonaromatic carbocyclyl, and Ring A is optionally further substituted by 1-6 groups selected from R 7 and oxo; each R 1 , R 4 , and R 7 is independently R, and each R 1 , R 4 and R 7 is optionally independently further substituted by 1-6 groups selected from R x and oxo, provided that when R x is a substitutent of R 7 , R x is optionally further substituted by 1-6 groups selected from R y and oxo;
  • R is selected from the group consisting of C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, -(C 1 -C 3 alkylene) m -(C 3 -C 12 cycloalkyl), -(C 1 -C 3 alkylene) m -phenyl, -(C 1 -C 3 alkylene) m -(5-10 member heteroaryl), -(C 1 -C 3 alkylene) m -(3-10 member heterocyclyl), - (C 1 -C 3 alkylene) m -(3-12 member unsaturated non-aromatic carbocyclyl), -(C 1 -C 6 perfluoroaklyl), -(C 1 -C 3 alkylene) m -halide, -(C 1 -C 3 alkylene) m -CN, -(C 1 -C 3 alkylene) m - C
  • the ring formed by Z 1 , Z 2 , Z 3 , Z 4 and the two intervening carbons is selected from wherein the said ring is optionally further substituted by 1-3 R 4 , and wherein 1 indicates the point of attachment to the aminopyrazole in formula I, and 2 indicates the point of attachment to Ring A in formula I.
  • the invention provides compounds of formula II,
  • each R 2 , R 3 , R 5 and R 6 is independently H or R;
  • Ring A is 3-4 member cycloalkyl, 3-4 member heterocyclyl, 5-7 member bicyclic heterocyclyl or 5-7 member bicyclic nonaromatic carbocyclyl, and Ring A is optionally further substituted by 1-6 groups selected from R 7 and oxo;
  • R 7 is R
  • R is selected from the group consisting of C 1 -C 8 alky], C 2 -C 8 alkenyl, C 2 -C 8 aikynyl, -(CrC 3 alkylene) m -(C 3 -C 12 cycloalkyl), -(C 1 -C 3 alkylene) m -phenyl, -(C 1 -C 3 alkylene) m -(5-10 member heteroaryl), -(C 1 -C 3 alkylene) m -(3-10 member heterocyclyl), - (C 1 -C 3 alkylene) m -(3-12 member unsaturated non-aromatic carbocyclyl), -(C 1 -C 6 perfluoroaklyl), -(C 1 -C 3 alkylene) m -halide, -(C 1 -C 3 alkylene) m -CN, -(C 1 -C 3 alkylene) m - C(
  • R 2 and R 3 are independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, -(C 1 -C 3 alkylene) m -(C 3 -C 6 cycloalkyl), -(C 1 -C 3 alkylene) m -(C 3 -C 6 cycloalkenyl), C 2 -C 6 alkynyl and -(C 1 -C 6 perfluoroalkyl), R 2 and R 3 are optionally independently further substituted by 1-6 groups selected from oxo, -(C 1 -C 3 alkylene) m -halide, -(C 1 -C 3 alkylene) m -CN, -(C 1 -C 3 alkylene) m -C(O)R a , -(C 1 -C 3 alkylene) m - C
  • R 2 is H, C 1 -C 6 alkyl or -(C 1 -C 3 alkylene) m -(C 3 -C 6 cycloalkyl)
  • R 3 is H, C 1 -C 6 alkyl, or -(C 1 -C 3 alkylene) m -(C 3 -C 6 cycloalkyl)
  • each R 2 and R 3 is indepdently optionally further substituted by 1-6 groups selected from halide, oxo, -CN, -0R a and -NR 3 R b , wherein each R a and R b is independently H, C 1 -C 6 alkyl or -(C 1 -C 3 alkylene) m -(C 3 -C 6 cycloalkyl), and when connecting to the same atom, R a and R b may optionally form a ring selected from the list of -(5-7 member hetero
  • R 2 is unsubstituted C 1 -C 6 alkyl or unsubstituted - (C 1 -C 3 alkylene) m -(C 3 -C 6 cycloalkyl), and R 3 is H.
  • R 5 is selected from the group consisting of H, C 1 -C 6 alkyl and -(C 1 -C 3 alkylene) m -(C 3 -C 6 cycloalkyl), and R 5 is optionally further substituted by 1-6 groups selected from R x and oxo.
  • R 5 is H, unsubstituted C 1 -C 6 alkyl or unsubstituted - (C 1 -C 3 alkylene)m-(C 3 -C 6 cycloalkyl), halide.
  • R 6 is selected from the group consisting of (C 1 - C 3 alkylene) m -phenyl, (C 1 -C 3 alkylene) m -(5-10 member heteroaryl), (C 1 -C 3 alkylene) m (3- 8 member heterocyclyl), (C 1 -C 3 alkylene) m -(5-12 member bicyclic non-aromatic carbocyclyl) and -(C 1 -C 6 perfluoroaklyl), and R 6 is optionally further substituted by 1-6 groups selected from R x and oxo wherein R x is R.
  • Ring A is selected from the group consisting of
  • Ring A is optonally further substituted by 1-6 groups selected from R 7 and oxo.
  • R 7 is selected from halide, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, -(C 1 -C 3 alkylene) m -(C 3 -C 6 cycloalkyl), C 1 -C 6 perfluroalkyl, -(C 1 -C 3 alkylene) m - C(O)NR a R b , -(C 1 -C 3 alkylene) m -C(O)OR a , -(C 1 -C 3 alkylene) m -C(O)R a , -(C 1 -C 3 alkylene) m - NR a R b , -(C 1 -C 3 alkylene) m -NR c -C(O)R a , -(C 1 -C 3 alkylene) m -NR c -C-C-C-C(O)R a , -(C
  • R 2 and R 3 are independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, -(C 1 -C 3 alkylene) m -(C 3 -C 6 cycloalkyl), -(C 1 -C 3 alkylene) m -(C 3 -C 6 cycloalkenyl), C 2 -C 6 alkynyl and -(C 1 -C 6 perfluoroalkyl), each R 2 and R 3 is optionally independently further substituted by 1-6 groups selected from oxo, -(C 1 -C 3 alkylene) m -halide, -(C 1 -C 3 alkylene) m -CN, -(C 1 -C 3 alkylene) m -C(O)R a , -(C 1 -C 3 alkylene) m -C(O)OR a , -(C
  • R 2 is H, C 1 -C 6 alkyl or -(C 1 -C 3 alkylene) m - (C 3 -C 6 cycloalkyl),
  • R 3 is H, C 1 -C 6 alkyl or C 1 -C 3 alkylene) m -(C 3 -C 6 cycloalkyl), and each R 2 and R 3 is optionally further substituted by 1-6 groups selected from halide, oxo, -CN, -OR a and - NR a R b , wherein each R a and R b is independently H, C 1 -C 6 alkyl or -(C 1 -C 3 alkylene) m - (C 3 -C 6 cycloalkyl), and when connected to the same atom, R a and R b may optionally form a ring selected from-(5-7 member heteroaryl) and -(3-8 member heterocyclyl); R 5 is H, unsubstituted C 1 -C 6 alkyl, unsubstituted -(C 1 -C 3 alkylene) m -(C 3 -C 6 cycloalkyl) or hal
  • R 2 is unsubstituted C 1 -C 6 alkyl or unsubstituted -(C 1 -C 3 alkylene) m -(C 3 -C 6 cycloalkyl);
  • R 3 is H,
  • R 5 is H, unsubstituted C 1 -C 6 alkyl, unsubstituted -(C 1 -C 3 alkylene) m -(C 3 -C 6 cycloalkyl) or halide;
  • R 6 is selected from the group consisting of (C 1 -C 3 alkylene) m -phenyl, (C 1 -C 3 alkylene) m -(5-10 member heteroaryl), (C 1 -C 3 alkylene) m (3-8 member heterocyclyl), (C 1 -C 3 alkylene) m -(5-12 member bicyclic non-aromatic carbocyclyl) and -(C 1 -C 6 perfluoroalkyl);
  • Ring A is optionally further substituted by 1-6 groups selected from R 7 and oxo.
  • the invention provides compounds of formula III,
  • R 2 is unsubstituted C 1 -C 6 alkyl or unsubstituted -(C 1 -C 3 alky!ene) m -(C 3 -C 6 cycloalkyl)
  • R 8 represents 1-3 optional substituents, and each R 8 is independently R.
  • the compound is of formula III, wherein R 2 is unsubstituted C 1 -C 6 alkyl or unsubstituted -(C 1 -C 3 alkylene) m -(C 3 -C 6 cycloalkyl); R 8 represents 1-3 optional substituents, and each R 8 is independently R; Ring A is selected from the group consisting of
  • Ring A is optonally further substituted by 1-6 groups selected from R 7 and oxo; and R 7 is selected from halide, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, -(C 1 -C 3 alkylene) m -(C 3 -C 6 cycloalkyl), C 1 -C 6 perfluroalkyl, -(C 1 -C 3 alkylene) m -C(O)NR a R b , -(C 1 -C 3 alkylene) m -C(O)OR a , -(C 1 -C 3 alkylene) m -C(O)R a , -(C 1 -C 3 alkylene) m -NR a R b , -(C 1 -C 3 alkylene) m -NR c -C(O)R
  • the invention provides compounds of formula IV,
  • Ring A is 3-4 member cycloalkyl, 3-4 member heterocyclyl, 5-7 member bicyclic heterocyclyl or 5-7 member bicyclic nonaromatic carbocyclyl, and Ring A is optionally further substituted by 1-6 groups selected from R 7 and oxo;
  • each R 2 and R 3 is independently H or R;
  • R 7 is R; each R 2 , R 3 , R 7 and B is independently optionally further substituted by 1-6 groups selected from R x and oxo, provided that when R x is an substituent of R 7 , R x is optionally further substituted by 1-6 groups selected from R y and oxo;
  • R is selected from the group consisting of C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, -(C 1 -C 3 alkylene) m -(C 3 -Ci 2 cycloalkyl), -(C 1 -C 3 alkylene) m -phenyl, -(C 1 -C 3 , alkylene) m -(5-10 member heteroaryl), -(C 1 -C 3 alkylene) m -(3-10 member heterocyclyl); - (C 1 -C 3 alkylene) m -(3-12 member unsaturated non-aromatic carbocyclyl), -(C 1 -C 6 perfluoroaklyl), -(C 1 -C 3 alkylene) m -halide, -(C 1 -C 3 alkylene) m -CN, -(C 1 -C 3 alkylene) m
  • R 2 is H, C 1 -C 6 alkyl or -(C 1 -C 3 alkylene) m -(C 3 -C 6 cycloalkyl)
  • R 3 is H, C 1 -C 6 alkyl or -(C 1 -C 3 alkylene) m -(C 3 -C 6 cycloalkyl)
  • each R 2 and R 3 is independently optionally further substituted by 1-6 groups selected from halide, oxo, -CN, -OR a and -NR a R b , wherein each R a and R b is independently H 1 C 1 -C 6 alkyl Or -(C 1 -C 3 alkylene) m -(C 3 -C 6 cycloalkyl).
  • the invention provides comounds of formula V,
  • R 9 represents 1-2 optional substituents and R 9 is R.
  • Ring A is selected from the group consisting of
  • Ring A is optionally further substituted by 1-6 groups selected from oxo and R 7 .
  • R 7 is selected from halide, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, -(C 1 -C 3 alkylene) m -(C 3 -C 6 cycloalkyl), C 1 -C 6 perfluroalkyl, -(C 1 -C 3 alkylene) m - C(O)NR a R b , -(C 1 -C 3 alkylene) m -C(O)OR a , -(C 1 -C 3 alkylene) m -C(O)R a , -(C 1 -C 3 alkylene) m - NR a R b , -(C 1 -C 3 alkylene) m -NR c -C(O)R a , -(C 1 -C 3 alkylene) m -NR c -C-C-C-C(O)R a , -(C
  • B represents a ring selected from 5-6 member heteroaryl containing 1-2 atoms selected from O, N and S, 5-6 member heterocyclyl containing 1-2 atoms selected from O, N and S, phenyl and 5-6 member nonaromatic carbocyclyl, and that the said ring is fused to the pyrimidine ring in formula IV.
  • B represents a ring selected from thiophenyl, pyrrolyl, furanyl and phenyl, and that the said ring is fused to the pyrimidine ring in formula IV.
  • R 2 is H, C 1 -C 6 alkyl, or -(C 1 -C 3 alkylene) m -(C 3 -C 6 cycloalkyl);
  • R 3 is H, C 1 -C 6 alkyl, Or-(C 1 -C 3 alkylene) m -(C 3 -C 6 cycloalkyl); each R 2 and R 3 is independently optionally further substituted by 1-6 groups selected from halide, oxo, -CN, -0R a , and -NR a R b , wherein each R a and R b is independently H, C 1 - C 6 alkyl or -(C 1 -C 3 alkylene) m -(C 3 -C 6 cycloalkyl);
  • B represents a ring selected from 5-6 member heteroaryl containing 1-2 atoms selected from O, N and S, 5-6 member heterocyclyl containing 1-2 atoms selected from O, N
  • — indicates the point of attachment to the pyrimidine ring 2 position, and Ring A is optionally further substituted by 1-6 groups selected from oxo and R 7 .
  • R 2 is H, C 1 -C 6 alkyl, or -(C 1 -C 3 alkylene) m -(C 3 -C 6 cycloalkyl);
  • R 3 is H, C 1 -C 6 alkyl, Or-(C 1 -C 3 alkylene) m -(C 3 -C 6 cycloalkyl); each R 2 and R 3 is independently optionally further substituted by 1-6 groups selected from halide, oxo, -CN, -0R a , and -NR a R b , wherein each R a and R b is independently H, C 1 - C 6 alkyl or -(C 1 -C 3 alkylene) m -(C 3 -C 6 cycloalkyl);
  • B represents a ring selected from 5-6 member heteroaryl containing 1-2 atoms selected from O, N and S, 5-6 member heterocyclyl containing 1-2 atoms selected from O, N
  • R 7 is selected from halide, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, -(Ci-C 3 alkylene) m -(C 3 -C 6 cycloalkyl), C 1 -C 6 perfluroalkyl, -(C 1 -C 3 alkylene) m -C(O)NR a R b , -(C 1 -C 3 alkylene) m -C(O)OR a , -(C 1 -C 3 alkylene) m -C(O)R a , -(C 1 -C 3 alkylene) m -NR a R b , -(C 1 -C 3 alkylene) m -NR c -C
  • R 2 is H, C 1 -C 6 alkyl, or -(C 1 -C 3 alkylene) m -(C 3 -C 6 cycloalkyl);
  • R 3 is H, C 1 -C 6 alkyl, Or -(C 1 -C 3 alkylene) m -(C 3 -C 6 cycloalkyl); each R 2 and R 3 is independently optionally further substituted by 1-6 groups selected from halide, oxo, -CN, -OR a , and -NR a R b , wherein each R a and R b is independently H, C 1 - C 6 alkyl or -(C 1 -C 3 alkylene) m -(C 3 -C 6 cycloalkyl);
  • B represents a ring selected from thiophenyl, pyrrolyl, furanyl, phenyl, the said ring is fused to the pyrimidine ring in formula IV
  • Ring A is optionally further substituted by 1-6 groups selected from oxo and R 7 ; and R 7 is selected from halide, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, -(C 1 -C 3 alkylene) m -(C 3 -C 6 cycloalkyl), C 1 -C 6 perfluroalkyl, -(C 1 -C 3 , alkylene) m -C(O)NR a R b , -(C 1 -C 3 alkylene) m -C(O)OR a , -(C 1 -C 3 alkylene) m -C(O)R a , -(C 1 -C 3 alkylene) m -NR a R b , -(C 1 -C 3 alkylene) m -
  • the invention provides a compound selected from the group consisting of
  • the invention provides a method of modulating the activity of PAK4 protein kinase, comprising contacting the protein kinase with an effective amount of a compound of formula I to V, pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt, solvate or hydrate of the compounds of of formula I to IV.
  • the invention provides a method of treating abnormal cell growth in a mammal, comprising administering to a mammal a therapeutically acceptable amount of a compound, salt, hydrate or solvate of any of the compounds of this invention.
  • the abnormal cell growth is cancer.
  • the invention provides a method for the treatment of abnormal cell growth in a mammal, including a human, comprising administering to said mammal an amount of a compound of Formula I, as defined above, or a pharmaceutically acceptable salt, hydrate or solvate thereof, that is effective in treating abnormal cell growth.
  • the abnormal cell growth is cancer, including, but not limited to, mesothelioma, hepatobiliary (hepatic and billiary duct), a primary or secondary CNS tumor, a primary or secondary brain tumor, lung cancer (NSCLC and SCLC), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue,
  • the cancer is selected from lung cancer (NSCLC and SCLC), cancer of the head or neck, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, breast cancer, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, non hodgkins's lymphoma, spinal axis tumors, or a combination of one or more of the foregoing cancers.
  • lung cancer NSCLC and SCLC
  • SCLC central nervous system
  • CNS central nervous system
  • primary CNS lymphoma non hodgkins's lymphoma
  • spinal axis tumors or a combination of one or more of the foregoing cancers.
  • the cancer is selected from lung cancer (NSCLC and SCLC), ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, or a combination of one or more of the foregoing cancers.
  • the cancer is selected from lung cancer (NSCLC and SCLC), ovarian cancer, colon cancer, rectal cancer-. or a combination of one or more of the foregoing cancers.
  • said abnormal cell growth is a benign proliferative disease, including, but not limited to, psoriasis, benign prostatic hypertrophy or restinosis.
  • This invention also relates to a method for the treatment of abnormal cell growth in a mammal which comprises administering to said mammal an amount of a compound of Formula I-V, or a pharmaceutically acceptable salt, hydrate or solvate thereof, that is effective in treating abnormal cell growth in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti- hormones, and anti-androgens.
  • an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti- hormones, and anti-androgens.
  • This invention also relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal, including a human, comprising an amount of a compound of the Formula I-V, as defined above, or a pharmaceutically acceptable salt, hydrate or solvate thereof, that is effective in treating abnormal cell growth, and a pharmaceutically acceptable carrier.
  • said abnormal cell growth is cancer, including, but not limited to, mesothelioma, hepatobiliary (hepatic and billiary duct), a primary or secondary CNS tumor, a primary or secondary brain tumor, lung cancer (NSCLC and SCLC), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of
  • the invention also relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal, including a human, which comprises an amount of a compound of Formula I-V, as defined above, or a pharmaceutically acceptable salt or solvate thereof, that is effective in treating abnormal cell growth in combination with a pharmaceutically acceptable carrier and an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, and anti-androgens.
  • an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, and anti-androgens.
  • the invention also relates to a method for the treatment of a hyperproliferative disorder in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of Formula I-V, or a pharmaceutically acceptable salt or hydrate thereof, in combination with an anti-tumor agent selected from the group consisting antiproliferative agents, kinase inhibitors, angiogenesis inhibitors, growth factor inhibitors, cox-l inhibitors, cox-ll inhibitors, mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti- hormones, statins, and anti-androgens.
  • an anti-tumor agent selected from the group consisting antiproliferative agents, kinase inhibitors, angiogenesis inhibitors, growth factor inhibitors, cox-l inhibitors, cox-ll inhibitors, mitotic inhibitors,
  • the anti-tumor agent used in conjunction with a compound of Formula I and pharmaceutical compositions described herein is an anti-angiogenesis agent, kinase inhibitor, pan kinase inhibitor or growth factor inhibitor.
  • Preferred pan kinase inhibitors include SU-11248, described in U.S. Patent No. 6,573,293 (Pfizer, Inc, NY, USA).
  • Anti-angiogenesis agents include but are not limited to the following agents, such as EGF inhibitor, EGFR inhibitors, VEGF inhibitors, VEGFR inhibitors, TIE2 inhibitors, IGF1 R inhibitors, COX-II (cyclooxygenase II) inhibitors, MMP-2 (matrix- metalloprotienase 2) inhibitors, and MMP-9 (matrix-metalloprotienase 9) inhibitors.
  • VEGF inhibitors include for example, Avastin (bevacizumab), an anti- VEGF monoclonal antibody of Genentech, Inc. of South San Francisco, California. Additional VEGF inhibitors include CP-547,632 (Pfizer Inc., NY, USA), AG13736 (Pfizer Inc.), ZD-6474 (AstraZeneca), AEE788 (Novartis), AZD-2171), VEGF Trap (Regeneron/Aventis), Vatalanib (also known as PTK-787, ZK-222584: Novartis & Schering AG), Macugen (pegaptanib octasodium, NX-1838, EYE-001, Pfizer Inc./Gilead/Eyetech), IM862 (Cytran Inc.
  • Avastin bevacizumab
  • Additional VEGF inhibitors include CP-547,632 (Pfizer Inc., NY, USA), AG13736 (Pfizer
  • VEGF inhibitors useful in the practice of the present invention are disclosed in US Patent No. 6,534,524 and 6,235,764, both of which are incorporated in their entirety for all purposed.
  • VEGF inhibitors include CP-547,632, AG13736, Vatalanib, Macugen and combinations thereof.
  • VEGF inhibitors are described in, for example in WO 99/24440 (published May 20, 1999), PCT International Application PCT/IB99/00797 (filed May 3, 1999), in WO 95/21613 (published August 17, 1995), WO 99/61422 (published December 2, 1999), United States Patent 6, 534,524 (discloses AG13736), United States Patent 5,834,504 (issued November 10, 1998), WO 98/50356 (published November 12, 1998), United States Patent 5,883,113 (issued March 16, 1999), United States Patent 5,886,020 (issued March 23, 1999), United States Patent 5,792,783 (issued August 11, 1998), U.S. Patent No.
  • antiproliferative agents that may be used with the compounds of the present invention include inhibitors of the enzyme farnesyl protein transferase and inhibitors of the receptor tyrosine kinase PDGFr, including the compounds disclosed and claimed in the following United States patent applications: 09/221946 (filed December 28, 1998); 09/454058 (filed December 2, 1999); 09/501163 (filed February 9, 2000); 09/539930 (filed March 31 , 2000); 09/202796 (filed May 22, 1997); 09/384339 (filed August 26, 1999); and 09/383755 (filed August 26, 1999); and the compounds disclosed and claimed in the following United States provisional patent applications: 60/168207 (filed November 30, 1999); 60/170119 (filed December 10, 1999); 60/177718 (filed January 21, 2000); 60/168217 (filed November 30, 1999), and 60/200834 (filed May 1 , 2000).
  • Each of the foregoing patent applications and provisional patent applications is herein incorporated by reference in their entirety.
  • PDGRr inhibitors include but not limited to those disclosed international patent application publication number WO01/40217, published July 7, 2001 and international patent application publication number WO2004/020431 , published March 11, 2004, the contents of which are incorporated in their entirety for all purposes.
  • Preferred PDGFr inhibitors include Pfizer's CP-673,451 and CP-868,596 and its pharmaceutically acceptable salts.
  • Preferred GARF inhibitors include Pfizer's AG-2037 (pelitrexol and its pharmaceutically acceptable salts.
  • GARF inhibitors useful in the practice of the present invention are disclosed in US Patent No. 5,608,082 which is incorporated in its entirety for all purposed.
  • COX-II inhibitors which can be used in conjunction with a compound of Formula I and pharmaceutical compositions described herein include CELEBREXTM (celecoxib), parecoxib, deracoxib, ABT-963, MK-663 (etoricoxib), COX- 189 (Lumiracoxib), BMS 347070, RS 57067, NS-398, Bextra (valdecoxib), paracoxib, Vioxx (rofecoxib), SD-8381 , 4-Methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoyl-phenyl)-1 H- pyrrole, 2-(4-Ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-1 H-pyrrole, T-614, JTE-522, S-2474, SVT-2016, CT-3, SC-58125 and Arcoxia (etoricoxib).
  • COX-I CELEBREXTM
  • the anti-tumor agent is celecoxib as disclosed in U.S. Patent No. 5,466,823, the contents of which are incorporated by reference in its entirety for all purposes.
  • the structure for Celecoxib is shown below:
  • the anti-tumor agent is valecoxib as disclosed in U.S. Patent No. 5,633,272, the contents of which are incorporated by reference in its entirety for all purposes.
  • the structure for valdecoxib is shown below:
  • the anti-tumor agent is parecoxib as disclosed in U.S. Patent No. 5,932,598, the contents of which are incorporated by reference in its entirety for all purposes.
  • the structure for paracoxib is shown below:
  • the anti-tumor agent is deracoxib as disclosed in U.S. Patent No. 5,521,207, the contents of which are incorporated by reference in its entirety for all purposes.
  • deracoxib The structure for deracoxib is shown below:
  • the anti-tumor agent is SD-8381 as disclosed in U.S. Patent No. 6,034,256, the contents of which are incorporated by reference in its entirety for all purposes.
  • the structure for SD-8381 is shown below:
  • the anti-tumor agent is ABT-963 as disclosed in International Publication Number WO 2002/24719, the contents of which are incorporated by reference in its entirety for all purposes.
  • the structure for ABT-963 is shown below:
  • the anti-tumor agent is MK-663 (etoricoxib) as disclosed in International Publication Number WO 1998/03484, the contents of which are incorporated by reference in its entirety for all purposes.
  • the structure for etoricoxib is shown below:
  • the anti-tumor agent is COX-189 (Lumiracoxib) as disclosed in International Publication Number WO 1999/11605, the contents of which are incorporated by reference in its entirety for all purposes.
  • the structure for Lumiracoxib is shown below:
  • the anti-tumor agent is BMS-347070 as disclosed in United States Patent No. 6,180,651 , the contents of which are incorporated by reference in its entirety for all purposes.
  • the structure for BMS-347070 is shown below:
  • the anti-tumor agent is NS-398 (CAS 123653-11-2).
  • the structure for NS-398 is shown below:
  • the anti-tumor agent is RS 57067 (CAS 17932-91- 3).
  • the structure for RS-57067 (CAS 17932-91-3) is shown below:
  • the anti-tumor agent is 4-Methyl-2-(3,4- dimethylphenyl)-1-(4-sulfamoyl-phenyl)-1H-pyrrole.
  • the structure for 4-Methyl-2-(3,4- dimethylphenyl)-1-(4-sulfamoyl-phenyl)-1 H-pyrrole is shown below:
  • the anti-tumor agent is 2-(4-Ethoxyphenyl)-4- methyl-1-(4-sulfamoylphenyl)-1H-pyrrole.
  • the structure for 2-(4-Ethoxyphenyl)-4-methyl- 1-(4-sulfamoylphenyl)-1 H-pyrrole is shown below:
  • the anti-tumor agent is meloxicam.
  • the structure for meloxicam is shown below:
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • Preferred COX-I inhibitors include ibuprofen (Motrin), nuprin, naproxen (Aleve), indomethacin (Indocin), nabumetone (Relafen) and combinations thereof.
  • Targeted agents used in conjunction with a compound of Formula I and pharmaceutical compositions described herein include EGFr inhibitors such as Iressa (gefitinib, AstraZeneca), Tarceva (erlotinib or OSI-774, OSI Pharmaceuticals Inc.), Erbitux (cetuximab, lmclone Pharmaceuticals, Inc.), EMD-7200 (Merck AG), ABX-EGF (Amgen Inc.
  • Preferred EGFr inhibitors include Iressa, Erbitux, Tarceva and combinations thereof.
  • the present invention also relates to anti-tumor agents selected from pan erb receptor inhibitors or ErbB2 receptor inhibitors, such as CP-724,714 (Pfizer, Inc.), Cl- 1033 (canertinib, Pfizer, Inc.), Herceptin (trastuzumab, Genentech Inc.), Omitarg (2C4, pertuzumab, Genentech Inc.), TAK-165 (Takeda), GW-572016 (lonafarnib, GlaxoSmithKline), GW-282974 (GlaxoSmithKline), EKB-569 (Wyeth), PKI-166 (Novartis), dHER2 (HER2 Vaccine, Corixa and GlaxoSmithKline), APC8024 (HER2 Vaccine, Dendreon), anti-HER2/neu bispecific antibody (Decof Cancer Center), B7.her2.lgG3 (Agensys), AS HER2 (Research Institute for Rad Biology & Medicine), trifun
  • Preferred pan erbb receptor inhibitors include GW572016, CI-1033, EKB-569, and Omitarg and combinations thereof.
  • Additional erbB2 inhibitors include those described in WO 98/02434 (published January 22, 1998), WO 99/35146 (published July 15, 1999), WO 99/35132 (published July 15, 1999), WO 98/02437 (published January 22, 1998), WO 97/13760 (published April 17, 1997), WO 95/19970 (published July 27, 1995), United States Patent 5,587,458 (issued December 24, 1996), and United States Patent 5,877,305 (issued March 2, 1999), each of which is herein incorporated by reference in its entirety.
  • ErbB2 receptor inhibitors useful in the present invention are also described in United States Patent Nos. 6,465,449, and 6,284,764, and International Application No. WO 2001/98277 each of which are herein incorporated by reference in their entirety.
  • anti-tumor agents may be selected from the following agents, BAY-43-9006 (Onyx Pharmaceuticals Inc.), Genasense (augmerosen, Genta), Panitumumab (Abgenix/Amgen), Zevalin (Schering), Bexxar (Corixa/GlaxoSmithKline), Abarelix, Alimta, EPO 906 (Novartis), discodermolide (XAA-296), ABT-510 (Abbott), Neovastat (Aeterna), enzastaurin (EIi Lilly), Combrestatin A4P (Oxigene), ZD-6126 (AstraZeneca), flavopiridol (Aventis), CYC-202 (Cyclacel), AVE-8062 (Aventis), DMXAA (Roche/Antisoma), Thymitaq (Eximias), Temodar (temozolomide, Schering Plough) and Revilimd (Celegene) and combinations thereof.
  • anti-tumor agents may be selected from the following agents, CyPat (cyproterone acetate), Histerelin (histrelin acetate), Plenaixis (abarelix depot), Atrasentan (ABT-627), Satraplatin (JM-216), thalomid (Thalidomide), Theratope, Temilifene (DPPE), ABI-007 (paclitaxel), Evista (raloxifene), Atamestane (Biomed-777), Xyotax (polyglutamate paclitaxel), Targetin (bexarotine) and combinations thereof.
  • CyPat cyproterone acetate
  • Histerelin histrelin acetate
  • Plenaixis abarelix depot
  • ABT-627 Atrasentan
  • JM-216 thalomid (Thalidomide)
  • Theratope Temilifene (DPPE), ABI-007 (paclitaxel), Evista (raloxi
  • anti-tumor agents may be selected from the following agents, Trizaone (tirapazamine), Aposyn (exisulind), Nevastat (AE-941), Ceplene (histamine dihydrochloride), Orathecin (rubitecan), Virulizin, Gastrimmune (G17DT), DX-8951f (exatecan mesylate), Onconase (ranpimase), BEC2 (mitumoab), Xcytrin (motexafin gadolinium) and combinations thereof.
  • anti-tumor agents may selected from the following agents, CeaVac (CEA), NeuTrexin (trimetresate glucuronate) and combinations thereof.
  • Additional anti-tumor agents may selected from the following agents, OvaRex (oregovomab), Osidem (IDM-1), and combinations thereof. Additional anti-tumor agents may selected from the following agents, Advexin (ING 201), Tirazone (tirapazamine), and combinations thereof.
  • Additional anti-tumor agents may selected from the following agents, RSR13 (efaproxiral), Cotara (1311 chTNT 1/b), NBI-3001 (IL-4) and combinations thereof.
  • Additional anti-tumor agents may selected from the following agents, Canvaxin, GMK vaccine, PEG lnteron A, Taxoprexin (DHA/paciltaxel) and combinations thereof.
  • Pfizer's MEK1/2 inhibitor PD325901 Array Biopharm's MEK inhibitor ARRY-142886, Bristol Myers' CDK2 inhibitor BMS- 387,032, Pfizer's CDK inhibitor PD0332991 and AstraZeneca's AXD-5438 and combinations thereof.
  • mTOR inhibitors may also be utilized such as CCI-779 (Wyeth) and rapamycin derivatives RAD001 (Novartis) and AP-23573 (Ariad), HDAC inhibitors SAHA (Merck Inc./Aton Pharmaceuticals) and combinations thereof.
  • Additional anti-tumor agents include aurora 2 inhibitor VX-680 (Vertex), Chk1/2 inhibitor XL844 (Exilixis).
  • cytotoxic agents e.g., one or more selected from the group consisting of epirubicin (Ellence), docetaxel (Taxotere), paclitaxel, Zinecard (dexrazoxane), rituximab (Rituxan) imatinib mesylate (Gleevec), and combinations thereof, may be used in conjunction with a compound of Formula I and pharmaceutical compositions described herein.
  • the invention also contemplates the use of the compounds of the present invention together with hormonal therapy, including but not limited to, exemestane (Aromasin, Pfizer Inc.), leuprorelin (Lupron or Leuplin, TAP/Abbott/Takeda), anastrozole (Arimidex, Astrazeneca), gosrelin (Zoladex, AstraZeneca), doxercalciferol, fadrozole, formestane, tamoxifen citrate (tamoxifen, Nolvadex, AstraZeneca), Casodex (AstraZeneca), Abarelix (Praecis), Trelstar, and combinations thereof.
  • exemestane Amasin, Pfizer Inc.
  • leuprorelin Louprorelin
  • anastrozole Arimidex, Astrazeneca
  • gosrelin Zoladex, AstraZeneca
  • doxercalciferol
  • the invention also relates to hormonal therapy agents such as anti-estrogens including, but not limited to fulvestrant, toremifene, raloxifene, lasofoxifene, letrozole (Femara, Novartis), anti-androgens such as bicalutamide, flutamide, mifepristone, nilutamide, Casodex®(4'-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3'-
  • the invention provides a compound of the present invention alone or in combination with one or more supportive care products, e.g., a product selected from the group consisting of Filgrastim (Neupogen), ondansetron (Zofran), Fragmin, Procrit, Aloxi, Emend, or combinations thereof.
  • supportive care products e.g., a product selected from the group consisting of Filgrastim (Neupogen), ondansetron (Zofran), Fragmin, Procrit, Aloxi, Emend, or combinations thereof.
  • Particularly preferred cytotoxic agents include Camptosar, Erbitux, Iressa, Gleevec, Taxotere and combinations thereof.
  • topoisomerase I inhibitors may be utilized as anti-tumor agents camptothecin, irinotecan HCI (Camptosar), edotecarin, orathecin (Supergen), exatecan (Daiichi), BN-80915 (Roche) and combinations thereof.
  • Particularly preferred toposimerase Il inhibitors include epirubicin (Ellence).
  • the compounds of the invention may be used with antitumor agents, alkylating agents, antimetabolites, antibiotics, plant-derived antitumor agents, camptothecin derivatives, tyrosine kinase inhibitors, antibodies, interferons, and/or biological response modifiers.
  • Alkylating agents include, but are not limited to, nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, mitobronitol, carboquone, thiotepa, ranimustine, nimustine, temozolomide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, carmustine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, mafosfamide, and mitolactol; platinum-coordinated alkylating compounds include but are not limited to, cisplatin, Paraplatin (carboplatin), eptaplatin, lobaplatin, nedaplatin, Eloxatin (oxaliplatin, Sanofi) or satrplatin and combinations thereof.
  • alkylating agents include Eloxatin (oxaliplatin).
  • Antimetabolites include but are not limited to, methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil (5-FU) alone or in combination with leucovorin, tegafur, UFT, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-1, Alimta (premetrexed disodium, LY231514, MTA), Gemzar (gemcitabine, EIi Lilly), fludarabin, 5-azacitidine, capecitabine, cladribine, clofarabine, decitabine, eflornithine, ethynylcytidine, cytosine arabinoside, hydroxyurea, TS-1, melphalan, nelarabine, nolatrexed, ocfosfate, disodium premetrexed, pentostat
  • Antibiotics include intercalating antibiotics but are not limited to: aclarubicin, actinomycin D, amrubicin, annamycin, adriamycin, bleomycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, galarubicin, idarubicin, mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin, valrubicin, zinostatin and combinations thereof.
  • Plant derived anti-tumor substances include for example those selected from mitotic inhibitors, for example vinblastine, docetaxel (Taxotere), paclitaxel and combinations thereof.
  • Cytotoxic topoisomerase inhibiting agents include one or more agents selected from the group consisting of aclarubicn, amonafide, belotecan, camptothecin, 10- hydroxycamptothecin, 9-aminocamptothecin, diflomotecan, irinotecan HCI (Camptosar), edotecarin, epirubicin (Ellence), etoposide, exatecan, gimatecan, lurtotecan, mitoxantrone, pirarubicin, pixantrone, rubitecan, ⁇ sobuzoxane, SN-38, tafluposide, topotecan, and combinations thereof.
  • Preferred cytotoxic topoisomerase inhibiting agents include one or more agents selected from the group consisting of camptothecin, 10-hydroxycamptothecin, 9- aminocamptothecin, irinotecan HCI (Camptosar), edotecarin, epirubicin (Ellence), etoposide, SN-38, topotecan, and combinations thereof.
  • Interferons include interferon alpha, interferon alpha-2a, interferon, alpha-2b, interferon beta, interferon gamma-1a, interferon gamma-1b (Actimmune), or interferon gamma-n1 and combinations thereof.
  • agents include filgrastim, lentinan, sizofilan, TheraCys, ubenimex, WF-10, aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab, denileukin, gemtuzumab ozogamicin, ibritumomab, imiquimod, lenograstim, lentinan, melanoma vaccine (Corixa), molgramostim, OncoVAX-CL, sargramostim, tasonermin, tecleukin, thymalasin, tositumomab, Virulizin, Z-100, epratuzumab, mitumomab, oregovomab, pemtumomab (Y-muHMFG1), Provenge (Dendreon) and combinations thereof.
  • Biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth, or differentiation of tissue cells to direct them to have anti-tumor activity.
  • agents include krestin, lentinan, sizofiran, picibanil, ubenimex and combinations thereof.
  • anticancer agents include alitretinoin, ampligen, atrasentan bexarotene, bortezomib. Bosentan, calcitriol, exisulind, finasteride.fotemustine, ibandronic acid, miltefosine, mitoxantrone, l-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pegaspargase, pentostatin, tazarotne, Telcyta (TLK-286, Telik Inc.), Velcade (bortemazib, Millenium), tretinoin, and combinations thereof.
  • anti-angiogenic compounds include acitretin, fenretinide, thalidomide, zoledronic acid, angiostatin, aplidine, cilengtide, combretastatin A-4, endostatin, halofuginone, rebimastat, removab, Revlimid, squalamine, ukrain, Vitaxin and combinations thereof.
  • Platinum-coordinated compounds include but are not limited to, cisplatin, carboplatin, nedaplatin, oxaliplatin, and combinations thereof.
  • Camptothecin derivatives include but are not limited to camptothecin, 10- hydroxycamptothecin, 9-aminocamptothecin, irinotecan, SN-38, edotecarin, topotecan and combinations thereof.
  • antitumor agents include mitoxantrone, l-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pentostatin, tretinoin and combinations thereof.
  • Anti-tumor agents capable of enhancing antitumor immune responses such as CTLA4 (cytotoxic lymphocyte antigen 4) antibodies, and other agents capable of blocking CTLA4 may also be utilized, such as MDX-010 (Medarex) and CTLA4 compounds disclosed in United States Patent No. 6,682,736; and anti-proliferative agents such as other famesyl protein transferase inhibitors, for example the famesyl protein transferase inhibitors.
  • CTLA4 antibodies that can be used in the present invention include those described in United States Provisional Application 60/113,647 (filed December 23, 1998), United States Patent No. 6, 682,736 both of which are herein incorporated by reference in their entirety.
  • Gene therapy agents may also be employed as anti-tumor agents such as TNFerade (GeneVec), which express TNFalpha in response to radiotherapy.
  • statins may be used in conjunction with a compound of Formula I and pharmaceutical compositions.
  • HMG-CoA reducatase inhibitors may be selected from the group consisting of Atorvastatin (Lipitor, Pfizer Inc.), Pravastatin (Pravachol, Bristol-Myers Squibb), Lovastatin (Mevacor, Merck Inc.), Simvastatin (Zocor, Merck Inc.), Fluvastatin (Lescol, Novartis), Cerivastatin (Baycol, Bayer), Rosuvastatin (Crestor, AstraZeneca), Lovostatin and Niacin (Advicor, Kos Pharmaceuticals), derivatives and combinations thereof.
  • statin is selected from the group consisting of Atovorstatin and Lovastatin, derivatives and combinations thereof.
  • Alkyl refers to a saturated aliphatic hydrocarbon radical including straight chain and branched chain groups of 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
  • “Lower alkyl” refers specifically to an alkyl group with 1 to 4 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, 2-propyl, cyclopropyl, n-butyl, /so-butyl, tert- butyl, pentyl and the like. Alkyl may be substituted or unsubstituted.
  • Typical substituent groups include nonaromatic carbocyclyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N- carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, nitro, silyl, amino and -NR x R y , where R x and R y are independently selected from the group consisting of hydrogen, alkyl, nonaromatic carbocyclyl, aryl, carbonyl, acetyl, sulfonyl, trifluoromethanesulfonyl and, combined, a five- or six-member heterocyclyl ring.
  • Cycloalkyl refers to a cyclic saturated hydrocarbon radical having from 3 to 20 carbon atoms.
  • a cycloalkyl group may be monocyclic and where permissible may be bicyclic or polycyclic.
  • a cycloalkyl group may be optionally substituted by at least one substituent. Suitable substituents on a cycloalkyl group are the same as those described for an alkyl group.
  • cycloalkyl groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, nobornyl, adamantyl, and the like, including substitutued forms thereof.
  • Nonaromatic carbocyclyl refers to a 3 to 8 member all-carbon monocyclic ring group, all-carbon bicyclic or multicyclic ring system group wherein one or more of the rings may contain one or more double bonds but none of the rings has a completely conjugated pi-electron system.
  • Examples, without limitation, of nonaromatic carbocyclyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexadienyl, adamantanyl, cycloheptyl, cycloheptatrienyl, and the like.
  • a nonaromatic carbocyclyl may be substituted or unsubstituted.
  • Typical substituent groups include alkyl, aryl, heteroaryl, heteroalycyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, O-carbamyl, N-carbamyl, C-amido, N- amido, nitro, amino and -NR x R y , with R x and R y as defined above.
  • Illustrative examples of nonaromatic carbocyclyl are derived from, but not limited to, the following:
  • Unsaturated nonaromatic carbocyclyl refers to a nonaromatic carbocyclyl, as defined herein, that contains at least one carbon carbon double bond, one carbon carbon trible bond or a benzene ring.
  • Alkenyl refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon double bond, but contains no benzene ring. Representative examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, cyclopentenyl and the like.
  • Cycloalkenyl refers to a cycloalkyl group, as defined herein, consisting of at least one carbon-carbon double bond. Representative examples include, but are not limited to, 1-cyclopentyl, cyclohexenyl.
  • Alkynyl refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon triple bond. Representative examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like.
  • Aryl refers to an all-carbon monocyclic or fused-ring polycyclic groups of 6 to 12 carbon atoms having a completely conjugated pi-electron system. Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. The aryl group may be substituted or unsubstituted.
  • Typical substituents include halo, trihalomethyl, alkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C- amido, N-amido, sulfinyl, sulfonyl, amino and -NR x R y , with R x and R y as defined above.
  • Heteroaryl refers to a monocyclic or fused ring group of 5 to 12 ring atoms containing one, two, three or four ring heteroatoms selected from N, O, and S, the remaining ring atoms being C, and, in addition, having a completely conjugated pi- electron system.
  • unsubstituted heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, purine, tetrazole, triazine, and carbazole.
  • the heteroaryl group may be substituted or unsubstituted.
  • Typical substituents include alkyl, nonaromatic carbocyclyl, halo, trihalomethyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, sulfonamido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, amino and -NR x R y with R x and R y as defined above.
  • a pharmaceutically acceptable heteroaryl is one that is sufficiently stable to be attached to a compound of the invention, formulated into a pharmaceutical composition and subsequently administered to a patient in need thereof.
  • Examples of typical monocyclic heteroaryl groups include, but are not limited to:
  • bicyclic heteroaryl groups examples include, but are not limited to:
  • pyrido[2,3-d]pyrimidine pyrido[2,3-b]pyrazine pyrido[3,4-b]pyrazine (pyrido[2,3-d]pyrimidinyl) (pyrido[2,3-b]pyrazinyl) (pyrido[3,4-b]pyrazinyl) pyrimido[5,4-d]pyrimidine pyrazino[2,3-b]pyrazine pyrimido[4,5-d]pyrimidine (pyrimido[5,4-d]pyrimidinyl) (pyrazino[2,3-b]pyrazinyl) (pyrimido ⁇ .S-dlpyrimidinyl)
  • Heterocyclyl refers to a monocyclic or bicyclic ring group having in the ring(s) of 3 to 12 ring atoms, in which one or two ring atoms are heteroatoms selected from N, O, and S(O) n (where n is O, 1 or 2), the remaining ring atoms being C.
  • the rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system.
  • suitable saturated heterocyclyl groups include, but are not limited to:
  • piperazine 1 ,4-azathiane oxepane thiepane azepane piperazinyl (1 ,4-azathianyl) (oxepanyl) (thiepanyl) (azepanyl)
  • Suitable partially unsaturated heterocyclyl groups include, but are not limited to:
  • the heterocyclyl group is optionally substituted with one or two substituents independently selected from halo, lower alkyl, lower alkyl substituted with carboxy, ester hydroxy, or mono or dialkylamino.
  • the new term refers to a diradical formed by removing one hydrogen atom from the original term of which the new term derived from.
  • an alkylene refers to a diradical group formed by removing one hydrogen atom from an alkyl group and that a "methylene” refers to a divalent radical -CH2- derived from removing one hydrogen atom from methyl.
  • diradicals include, but are not limited to: alkenylene, alkynylene, cycloalkylene, phenylene, heterocyclylene, heteroarylene and (nonaromatic unsaturated carbocyclylene), which are derived from alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclyl, heteroaryl and (nonaromatic unsaturated carbocyclyl), respectively.
  • Hydrophilicity refers to an -OH group.
  • Alkoxy refers to both an -O-(alkyl) or an -O-(nonaromatic carbocyclyl) group. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • Haloalkoxy refers to an -O-(haloalkyl) group. Representative examples include, but are not limited to, trifluoromethoxy, tribromomethoxy, and the like.
  • Aryloxy refers to an -O-aryl or an -O-heteroaryl group, as defined herein. Representative examples include, but are not limited to, phenoxy, pyridinyloxy, furanyloxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, and the like, and derivatives thereof.
  • Alkylthio refers to an -S-(alkyl) or an -S-(nonaromatic carbocyclyl) group. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like.
  • Arylthio refers to an -S-aryl or an -S-heteroaryl group, as defined herein. Representative examples include, but are not limited to, phenylthio, pyridinylthio, furanylthio, thienylthio, pyrimidinylthio, and the like and derivatives thereof.
  • Acyl or “carbonyl” refers to a -C(O)R" group, where R" is selected from the group consisting of hydrogen, lower alkyl, trihalomethyl, nonaromatic carbocyclyl, aryl optionally substituted with one or more, preferably one, two, or three substituents selected from the group consisting of lower alkyl, trihalomethyl, lower alkoxy, halo and - NR x R y groups, heteroaryl (bonded through a ring carbon) optionally substituted with one or more, preferably one, two, or three substitutents selected from the group consisting of lower alkyl, trihaloalkyl, lower alkoxy, halo and -NR x R y groups and heterocyclic (bonded through a ring carbon) optionally substituted with one or more, preferably one, two, or three substituents selected from the group consisting of lower alkyl, trihaloalkyl, lower alkoxy, halo and -NR x
  • Aldehyde refers to an acyl group in which R" is hydrogen.
  • Thioacyl or “thiocarbonyl” refers to a -C(S)R" group, with R" as defined above.
  • a “thiocarbonyl” group refers to a -C(S)R" group, with R" as defined above.
  • C-carboxy refers to a -C(O)OR” group, with R" as defined above.
  • O-carboxy refers to a -OC(O)R" group, with R" as defined above.
  • Ester refers to a -C(O)OR” group with R" as defined herein except that R" cannot be hydrogen.
  • Alcohol refers to a -C(O)CH 3 group.
  • Halo group refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
  • Trihalomethyl refers to a methyl group having three halo substituents, such as a trifluoromethyl group.
  • Cyano refers to a -C ⁇ N group.
  • a “sulfinyl” group refers to a -S(O)R" group wherein, in addition to being as defined above, R" may also be a hydroxy group.
  • a “sulfonyl” group refers to a -S(O) 2 R" group wherein, in addition to being as defined above, R" may also be a hydroxy group.
  • S-sulfonamido refers to a -S(O) 2 NR x R y group, with R x and R y as defined above.
  • N-sulfonamido refers to a -NR x S(O) 2 R y group, with R x and R y as defined above.
  • O-carbamyl refers to a -OC(O)NR x R y group with R x and R y as defined above.
  • N-carbamyl refers to an R y OC(O)NR x - group, with R x and R y as defined above.
  • O-thiocarbamyl refers to a -OC(S)NR x R y group with R x and R y as defined above.
  • N-thiocarbamyl refers to a R y OC(S)NR x - group, with R y and R x as defined above.
  • Amino refers to an -NR x R y group, wherein R x and R y are both hydrogen.
  • C-amido refers to a -C(O)NR x R y group with R x and R y as defined above.
  • N-amido refers to a R x C(O)NR y - group, with R x and R y as defined above.
  • Niro refers to a -NO 2 group.
  • Haloalkyl means an alkyl, preferably lower alkyl, that is substituted with one or more same or different halo atoms, e.g., -CH 2 CI, -CF 3 , -CH 2 CF 3 , -CH 2 CCI 3 , and the like.
  • Hydroxyalkyl means an alkyl, preferably lower alkyl, that is substituted with one, two, or three hydroxy groups; e.g., hydroxymethyl, 1 or 2-hydroxyethyl, 1 ,2-, 1 ,3-, or 2,3- dihydroxypropyl, and the like.
  • Alkyl means alkyl, preferably lower alkyl, that is substituted with an aryl group as defined above; e.g., -CH 2 phenyl, -(CH 2 ) 2 phenyl, -(CH 2 ) 3 phenyl, CH 3 CH(CH 3 )CH 2 phenyl,and the like and derivatives thereof.
  • Heteroaralkyl means alkyl, preferably lower alkyl, that is substituted with a heteroaryl group; e.g., -CH 2 pyridinyl, -(CH 2 ) 2 pyrimidinyl, -(CH 2 ) 3 imidazolyl, and the like, and derivatives thereof.
  • “Monoalkylamino” means a radical -NHR where R is an alkyl or unsubstituted nonaromatic carbocyclyl group; e.g., methylamino, (i-methylethyl)amino, cyclohexylamino, and the like.
  • Dialkylamino means a radical -NRR where each R is independently an alkyl or unsubstituted nonaromatic carbocyclyl group; dimethylamino, diethylamino, (i-methylethyl)-ethylamino, cyclohexylmethylamino, cyclopentylmethylamino, and the like.
  • heterocyclyl group optionally substituted with an alkyl group means that the alkyl may but need not be present, and the description includes situations where the heterocyclyl group is substituted with an alkyl group and situations where the heterocyclyl group is not substituted with the alkyl group.
  • Perfluoroalkyl refers to an alkyl group in which all of its hydrogen atoms are replaced by fluorine atoms.
  • a “pharmaceutical composition” refers to a mixture of one or more of the compounds described herein, or physiologically/pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof, with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
  • a “physiologically/pharmaceutically acceptable carrier” refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • a "pharmaceutically acceptable excipient” refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • salts As used herein, the term “pharmaceutically acceptable salt” refers to those salts which retain the biological effectiveness and properties of the parent compound. Such salts include:
  • acid addition salts which can be obtained by reaction of the free base of the parent compound with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, and perchloric acid and the like, or with organic acids such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid or malonic acid and the like; or
  • a metal ion e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion
  • coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
  • PK refers to receptor protein tyrosine kinase (RTKs), non-receptor or “cellular” tyrosine kinase (CTKs) and serine-threonine kinases (STKs).
  • RTKs receptor protein tyrosine kinase
  • CTKs non-receptor or “cellular” tyrosine kinase
  • STKs serine-threonine kinases
  • Modulation refers to the alteration of the catalytic activity of RTKs, CTKs and STKs.
  • modulating refers to the activation of the catalytic activity of RTKs, CTKs and STKs, preferably the activation or inhibition of the catalytic activity of RTKs, CTKs and STKs, depending on the concentration of the compound or salt to which the RTK, CTK or STK is exposed or, more preferably, the inhibition of the catalytic activity of RTKs, CTKs and STKs.
  • Catalytic activity refers to the rate of phosphorylation of tyrosine under the influence, direct or indirect, of RTKs and/or CTKs or the phosphorylation of serine and threonine under the influence, direct or indirect, of STKs.
  • Contacting refers to bringing a compound of this invention and a target PK together in such a manner that the compound can affect the catalytic activity of the PK, either directly, i.e., by interacting with the kinase itself, or indirectly, i.e., by interacting with another molecule on which the catalytic activity of the kinase is dependent.
  • Such "contacting” can be accomplished “in vitro,” i.e., in a test tube, a petri dish or the like. In a test tube, contacting may involve only a compound and a PK of interest or it may involve whole cells. Cells may also be maintained or grown in cell culture dishes and contacted with a compound in that environment.
  • the ability of a particular compound to affect a PK related disorder i.e., the IC 50 of the compound, defined below, can be determined before use of the compounds in vivo with more complex living organisms is attempted.
  • IC 50 of the compound defined below
  • multiple methods exist, and are well-known to those skilled in the art, to get the PKs in contact with the compounds including, but not limited to, direct cell microinjection and numerous transmembrane carrier techniques.
  • In vitro refers to procedures performed in an artificial environment such as, e.g., without limitation, in a test tube or culture medium.
  • In vivo refers to procedures performed within a living organism such as, without limitation, a mouse, rat or rabbit.
  • PK related disorder refers to a condition characterized by inappropriate, i.e., under or, more commonly, over, PK catalytic activity, where the particular PK can be an RTK, a CTK or an STK.
  • Inappropriate catalytic activity can arise as the result of either: (1) PK expression in cells which normally do not express PKs, (2) increased PK expression leading to unwanted cell proliferation, differentiation and/or growth, or, (3) decreased PK expression leading to unwanted reductions in cell proliferation, differentiation and/or growth.
  • Over-activity of a PK refers to either amplification of the gene encoding a particular PK or production of a level of PK activity which can correlate with a cell proliferation, differentiation and/or growth disorder (that is, as the level of the PK increases, the severity of one or more of the symptoms of the cellular disorder increases). Under-activity is, of course, the converse, wherein the severity of one or more symptoms of a cellular disorder increase as the level of the PK activity decreases.
  • Treating refers to a method of alleviating or abrogating a PK mediated cellular disorder and/or its attendant symptoms. With regard particularly to cancer, these terms simply mean that the life expectancy of an individual affected with a cancer will be increased or that one or more of the symptoms of the disease will be reduced.
  • Organism refers to any living entity comprised of at least one cell.
  • a living organism can be as simple as, for example, a single eukariotic cell or as complex as a mammal, including a human being.
  • “Therapeutically effective amount” refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated. In reference to the treatment of cancer, a therapeutically effective amount refers to that amount which has at least one of the following effects:
  • Monitoring means observing or detecting the effect of contacting a compound with a cell expressing a particular PK.
  • the observed or detected effect can be a change in cell phenotype, in the catalytic activity of a PK or a change in the interaction of a PK with a natural binding partner.
  • Techniques for observing or detecting such effects are well-known in the art. The effect is selected from a change or an absence of change in a cell phenotype, a change or absence of change in the catalytic activity of said protein kinase or a change or absence of change in the interaction of said protein kinase with a natural binding partner in a final aspect of this invention.
  • Cell phenotype refers to the outward appearance of a cell or tissue or the biological function of the cell or tissue. Examples, without limitation, of a cell phenotype are cell size, cell growth, cell proliferation, cell differentiation, cell survival, apoptosis, and nutrient uptake and use. Such phenotypic characteristics are measurable by techniques well-known in the art.
  • Natural binding partner refers to a polypeptide that binds to a particular PK in a cell. Natural binding partners can play a role in propagating a signal in a PK-mediated signal transduction process. A change in the interaction of the natural binding partner with the PK can manifest itself as an increased or decreased concentration of the PK/natural binding partner complex and, as a result, in an observable change in the ability of the PK to mediate signal transduction.
  • Scheme 1 illustrates the synthesis of the compound of formula I.
  • the dicholo heteroaryl compound A reacts with a first nucleophilic moiety, the amino pyrazole compound B, to give the mono chloro heteroaryl amino pyrazole compound C.
  • This transformation can be carried out through an alkylation reaction in the presence of a base.
  • a typical reaction condition is to disolve A and B in DMA, followed by addition of 2 equivalents of TEA and subsequent heating the reaction mixture to 120 "C overnight. Subsequent aqueous workup and purification affords compound C.
  • the mono chloro heteroaryl amino pyrazole compound C then reacts with a second nucleophilic moiety, compound D, to give compound of formula I.
  • M is typically hydrogen, connected to a ring nitrogen atom of compound D.
  • M can be a metal, such as Li, Cu, Pd, Mg, and any other metal that is used in the art to form organo metallic nucleophilic reagent, and M is connected to one of the ring atoms of compound D.
  • the transformation from C and D to compound of formula 1 can be carried out through a nucleophilic attack of compound D on the heteroaryl chloride compound C, in the presence of a base, and quite frequently, in a dipolar aprotic solvent such as NMP, DMF, DMSO.
  • a typical reaction condition of this transformation wherein M is hydrogen and the hydrogen is connected to a nitrogen ring atom of compound D, is to dissolve compound C and D in NMP in the presence of 1.5 equivalent of TEA in a microwave reaction vessel followed by microwaving the reaction mixed in a Biotage Smith Synthesizer microwave reactor for 60 minutes at 200°C. Subsequent aqueous workup and purification affords compound of formula I.
  • Scheme 2 illustrates several methods to prepare compound A and some of its specific embodiments when compound A is not commercially available.
  • Compound A can be prepared by treating compound A1 first with a hydroxyl activating agent in the presence of a base, and second with a chlorination agent.
  • a typical reaction condition for this transformation is to reflux a mixture of compound A1 with large excess of POCI 3 in the presence of DMA for 14 hours, removing excess POCI 3 , followed by treating the residue with large excess of chloroform. Subsequent aqueous workup and purification affords compound A.
  • Compound A2 includes two tautermers, which can be transformed in to compound A3, a specific embodiment of compound A, following the same method used in transforming compound A1 into compound A.
  • Compound A5, also a specific embodiment of compound A can be prepared by mono alkylation of the trichloride compound A4.
  • a typical reaction condition to carry out the transformation from A4 to A5 is to mix the trichloride compound A4 with catalytic amount of Pd(PPh 3 ) 4 in anhydrous THF, flush the mixture with N 2 under vacuum, followed by addition of a R 6 zinc bromide THF solution, and the reaction mixture is allowed to stir at 50 ° C for 2 hours. Subsequent aqueous workup and purification affords compound A5.
  • the dichloro pyrimidine compound A8, a specific embodiment of compound A, can be prepared from the amine ester compound A6 by an annulations between compound A6 and urea to form the pyrimidine compound A7. Subsequent chlorination of compound A7 gives compound A8.
  • a typical reaction condition of transformation from A6 to A7 is to mix compound A6 with urea and heat the neat mixture in oil bath to 200 " C for 3 hours, cooling the mixture to room temperature, then adding 2N aqueous NaOH to the mixture and allowing complete dissolution. Subsequent purification and neutralization of the solution affords compound A7.
  • Compound A7 can be transformed to compound A8 following the same method indicated above of transforming compound A1 to compound A.
  • Scheme 3 illustrates one of the commonly used routes to make compound B.
  • Substitued ester B1 reacts with substituted methyl cyanide B2 in the presence of a strong base and gives a 1-carbonyl-3-cyano moiety B3.
  • a typical reaction condition of this transformation is to to use NaNH 2 as the base and carry out the reaction in liquid ammonia under inert atmosphere at -78°C followed by warming up the reaction mixture to room temperature overnight. Reaction mixture is then quenched with water and acidified. Subsequent workup and purification gives compound B3.
  • B3 is then reacted with hydrazine to give compound B.
  • Typical reaction condition for this transformation is to reflux compound B3 and hydrazine in EtOH for 24 hours. Subsequent purification gives compound B.
  • references herein to the inventive compounds include references to salts, solvates, hydrates and complexes thereof, and to solvates, hydrates and complexes of salts thereof, including polymorphs, stereoisomers, and isotopically labeled versions thereof.
  • Pharmaceutically acceptable salts include acid addition and base salts (including disalts).
  • Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and tri
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • a pharmaceutically acceptable salt of the inventive compounds can be readily prepared by mixing together solutions of the compound and the desired acid or base, as appropriate.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionization in the salt may vary from completely ionized to almost non-ionized.
  • the compounds of the invention may exist in both unsolvated and solvated forms.
  • the term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • the term 'hydrate' is employed when the solvent is water.
  • Pharmaceutically acceptable solvates in accordance with the invention include hydrates and solvates wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, d 6 -acetone, d 6 -DMSO.
  • complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts.
  • complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts.
  • the resulting complexes may be ionized, partially ionized, or non-ionized.
  • polymorphs, prodrugs, and isomers including optical, geometric and tautomeric isomers of the inventive compounds
  • Derivatives of compounds of the invention which may have little or no pharmacological activity themselves but can, when administered to a patient, be converted into the inventive compounds, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may be found in 'Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and 'Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association), the disclosures of which are incorporated herein by reference in their entireties.
  • Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the inventive compounds with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in "Design of Prodrugs” by H Bundgaard (Elsevier, 1985), the disclosure of which is incorporated herein by reference in its entirety.
  • prodrugs in accordance with the invention include:
  • inventive compounds may themselves act as prodrugs of other of the inventive compounds.
  • Compounds of the invention containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of the invention contains an alkenyl or alkenylene group, geometric cisltrans (or Z/E) isomers are possible. Where the compound contains, for example, a keto or oxime group or an aromatic moiety, tautomeric isomerism ('tautomerism') can occur. A single compound may exhibit more than one type of isomerism.
  • stereoisomers include compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof.
  • acid addition or base salts wherein the counterion is optically active for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine.
  • Cisltrans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1- phenylethylamine.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1- phenylethylamine.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art.
  • Chiral compounds of the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.
  • Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art; see, for example, “Stereochemistry of Organic Compounds” by E L Eliel (Wiley, New York, 1994), the disclosure of which is incorporated herein by reference in its entirety.
  • the invention also includes isotopically-labeled compounds of the invention, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulfur, such as 35 S.
  • Certain isotopically-labeled compounds of the invention are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, 3 H, and carbon-14, 14 C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with heavier isotopes such as deuterium, 2 H may 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.
  • Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
  • solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, de- acetone, de-DMSO.
  • Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products, or mixtures thereof. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
  • the compounds can be administered alone or in combination with one or more other compounds of the invention, or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients.
  • excipient is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • compositions suitable for the delivery of compounds of the invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in 'Remington's Pharmaceutical Sciences', 19th Edition (Mack Publishing Company, 1995), the disclosure of which is incorporated herein by reference in its entirety. Oral Administration
  • the compounds of the invention may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid- filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films (including muco-adhesive), ovules, sprays and liquid formulations.
  • Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be used as fillers in soft or hard capsules and typically include a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • a carrier for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil
  • emulsifying agents and/or suspending agents may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • the compounds of the invention may also be used in fast-dissolving, fast- disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, H (6), 981-986 by Liang and Chen (2001), the disclosure of which is incorporated herein by reference in its entirety.
  • the drug may make up from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% of the dosage form.
  • tablets generally contain a disintegrant.
  • disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate.
  • the disintegrant will comprise from 1 wt% to 25 wt%, preferably from 5 wt% to 20 wt% of the dosage form.
  • Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
  • lactose monohydrate, spray-dried monohydrate, anhydrous and the like
  • mannitol xylitol
  • dextrose sucrose
  • sorbitol microcrystalline cellulose
  • starch dibasic calcium phosphate dihydrate
  • Tablets may also optionally include surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.
  • surface active agents such as sodium lauryl sulfate and polysorbate 80
  • glidants such as silicon dioxide and talc.
  • surface active agents are typically in amounts of from 0.2 wt% to 5 wt% of the tablet, and glidants typically from 0.2 wt% to 1 wt% of the tablet.
  • Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
  • Lubricants generally are present in amounts from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet.
  • Other conventional ingredients include anti-oxidants, colorants, flavoring agents, preservatives and taste-masking agents.
  • Exemplary tablets contain up to about 80 wt% drug, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% lubricant.
  • Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting.
  • the final formulation may include one or more layers and may be coated or uncoated; or encapsulated.
  • Solid formulations for oral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained:-, pulsed-, controlled-, targeted and programmed release.
  • Suitable modified release formulations are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles can be found in Verma et a/, Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298. The disclosures of these references are incorporated herein by reference in their entireties. Parenteral Administration
  • the compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrastemal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile nonaqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • a suitable vehicle such as sterile, pyrogen-free water.
  • the preparation of parenteral formulations under sterile conditions for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • solubility of compounds of the invention used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA microspheres.
  • the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated; see, for example, J Pharm Sci, 88 (10), 955- 958 by Finnin and Morgan (October 1999).
  • topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. PowderjectTM, BiojectTM, ete.) injection.
  • electroporation iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free injection.
  • iontophoresis iontophoresis
  • phonophoresis phonophoresis
  • sonophoresis e.g. PowderjectTM, BiojectTM, ete.
  • microneedle or needle-free injection e.g. PowderjectTM, BiojectTM, ete.
  • Formulations for topical administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1 ,1,1,2-tetrafluoroethane or 1 ,1,1 ,2,3,3,3-heptafluoropropane.
  • the powder may include a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • the drug product Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • comminuting method such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • Capsules made, for example, from gelatin or HPMC
  • blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and. a performance modifier such as /-leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
  • Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
  • a suitable solution formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from 1 ⁇ g to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1 ⁇ L to 100 ⁇ L.
  • a typical formulation includes a compound of the invention, propylene glycol, sterile water, ethanol and sodium chloride.
  • Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
  • Suitable flavors such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
  • Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, poly(DL-lactic-coglycolic acid (PGLA).
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the dosage unit is determined by means of a valve which delivers a metered amount.
  • Units in accordance with the invention are typically arranged to administer a metered dose or "puff' containing a desired mount of the compound of the invention.
  • the overall daily dose may be administered in a single dose or, more usually, as divided doses throughout the day. Rectal/1 ntravaqinal Administration
  • Compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema.
  • Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • Compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH- adjusted, sterile saline.
  • Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and nonbiodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
  • a polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride.
  • a preservative such as benzalkonium chloride.
  • Such formulations may also be delivered by iontophoresis.
  • Formulations for ocular/aural administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release.
  • Compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol- containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
  • soluble macromolecular entities such as cyclodextrin and suitable derivatives thereof or polyethylene glycol- containing polymers
  • Drug-cyclodextrin complexes are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used.
  • the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubilizer. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in PCT Publication Nos. WO 91/11172, WO 94/02518 and WO 98/55148, the disclosures of which are incorporated herein by reference in their entireties.
  • an effective dosage is typically in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 0.01 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.07 to about 7000 mg/day, preferably about 0.7 to about 2500 mg/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be used without causing any harmful side effect, with such larger doses typically divided into several smaller doses for administration throughout the day. Kit-of-Parts
  • kits suitable for coadministration of the compositions may conveniently be combined in the form of a kit suitable for coadministration of the compositions.
  • the kit of the invention includes two or more separate pharmaceutical compositions, at least one of which contains a compound of the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
  • the kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit typically includes directions for administration and may be provided with a memory aid. Examples
  • BOC means H-tert- butoxycarbonyl
  • DCM means CH 2 CI 2
  • DIPEA means diisopropyl ethyl amine
  • DMA means dimethyl amine
  • DMF means dimethyl formamide
  • DMSO means dimethylsulfoxide
  • DPPP means 1 ,3-bis(diphenylphosphino)propane
  • MTBE means methyl t-butyl ether
  • NMP means 1 -methyl 2-pyrrolidinone
  • TEA means triethyl amine
  • TFA means trifluoro acetic acid.
  • Example 1 fert-Butyl ((1R,5S)-3- ⁇ 4-[(5-cyclopropyl-1t ⁇ -pyrazoI-3- yl)amino]thieno[3,2-d]pyrimidin-2-yl ⁇ -3-azabicyclo[3.1.0]hex-6-yl)carbamate.
  • This oil (493.80 g) was mixed with methyl thioglycolate (422.77 g, 3.98 mol) and the resulting solution was added slowly (1.5 h) to a slurry of K 2 CO 3 (1651 g, 11.95 mol) in methanol (2.2 L) at 10 0 C. The final slurry was allowed to warm up to room temperature and was stirred at ambient temperature for 5 h. Salts were filtered out and washed with methanol (2 L). The organic solutions were combined and evaporated. The residue was redissolved in ethyl acetate (3 L) and passed through a silica gel plug. The plug was washed with extra ethyl acetate (2 L).
  • Cis-racemic methyl 3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride compound 4h (1.50 g, 8.26 mmol) was dissolved in MeOH (20 mL) and cooled to O 0 C. Anhydrous methylamine gas was bubbled through the solution for 30 minutes. The flask was then fitted with a Suba-seal stopper secured with copper wire and warmed gradually to room temperature where it was allowed to stand for 5 days. The solvent was removed in vacuo, and the residue partitioned between CHCI 3 and water. The organic phase was separated, washed with water and dried (MgSO 4 ). The cis-racemic product compound 6a was obtained as a white solid (0.37 g).
  • Boc-L-2-azetidine carboxylic acid compound 8a (2.01 g, 10.0 mmol) was dissolved in CH 2 CI 2 (50.0 mL) and cooled to 0 0 C. To this was added in succession HOBt (1.62 g, 11.99 mmol), methylamine hydrochloride (2.02 g, 30.0 mmol), N-methylmorpholine (4.39 mL, 40.0 mmol), and EDC (2.10 g, 10.99 mmol). The reaction was stirred at O 0 C for one hour, then warmed to room temperature and stirred overnight. The reaction was diluted' with EtOAc. The organic layer was separated, washed successively with 1 N HCI, saturated NaHCO 3 , and brine.
  • Boc-L-2-azetidinecarboxylic acid compound 8a (2.91 g, 14.45 mmol) and Et 3 N (2.01 mL, 14.45 mmol) were dissolved in THF (33 mL) and cooled to -1O 0 C. Ice-cooled ethyl chloroformate was added dropwise followed by continued stirring for twenty minutes at the same temperature. A solution of 28% NH 4 OH (3.21 mL) was added, and the reaction gradually warmed to ambient temperature. The THF solvent was removed under reduced pressure, and the residue partitioned between EtOAc and water. The organic phase was separated, dried (MgSO 4 ), and the solvent removed to give compound 9a as a white crystalline solid (2.36 g, 82%).
  • a microwave reaction vessel was charged with 3-((2-Chloro-6-(5-ethyl-1H-pyrazol-3- ylamino)pyrimidin-4-yl)methyl)benzonitrile 10e (140 mg, 0.414 mmol), AXL012352 (86 mg, 0.435 mmol) compound 1f, TEA (0.12 mL, 0.83 mmol) and amyl alcohol (3 mL). It was sealed and then heated in a Biotage Smith Synthesizer microwave at 200 0 C for 20 minutes. Purification by Biotage (0 to 80% ethyl acetate in hexane) gave compound 10 as a light yellow solid (78 mg, 38%).
  • Example 12 2-((1S,4S)-5-Oxa-2-aza-bicyclo[2.2.1]heptan-2-yl)-6-benzyl-N-(5- cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine
  • 2,4,6-Trichloropyrimidine 10b (97%, 23.0 mL, 200 mmol) was dissolved in THF and cooled to -78 0 C.
  • Benzylmagnesium chloride 12a (2M in THF, 100 mL, 200 mmol) was added to the reaction which was then warmed to room temperature overnight. The solvent was removed under reduced pressure, and the residue partitioned between CH 2 CI 2 and water. The organic layer was separated, washed with brine, dried (MgSO 4 ), and evaporated.
  • PAK4 KD PAK4 Kinase domain
  • PAK4 KD was then subcloned into expression plasmid pET28a(+), pET24a(+), or pGST4.5.
  • the recombinant plasmids containing PAK4 KD was transformed into BL21(DE3) cells for recombinant protein expression.
  • the production of PAK4 KD was induced at 37 ° C by the addition of IPTG into the cells.
  • the cells were then harvested and lyzed for protein purification.
  • Ni-NTA column (pET28a(+), pET24a(+)) and glutathione column (pGST4.5) were used for the purification.
  • the purified protein was then subjected to thrombin to cleave the N-terminal tags that were inherited from the expression plasmids, and thus gave the PAK4 KD that were used for the Ki assay of this invention.
  • PAK4 kinase domain enzymatic assay conditions the enzymatic activity of PAK4 KD was measured by its ability to catalyze the transfer of a phosphate residue from a nucleoside triphosphate to an amino acid side chain of a commercially available peptide (amino acid sequence EVPRRKSLVGTPYWM). The conversion of ATP to ADP accompanies the catalytic reaction. The PAK4 KD catalyzed production of ADP from ATP was coupled to the oxidation of NADH through the activities of pyruvate kinase (PK) and lactate dehydrogenase (LDH).
  • PK pyruvate kinase
  • LDH lactate dehydrogenase
  • Typical reaction solutions contain 2 mM phosphoenolpyruvate, 0.35 mM NADH, 10 mM MgCI 2 , 1 mM DTT 1 0.4mM peptide (EVPRRKSLVGTPYWM) 0.4 mM ATP, 1 units/mL PK, 1 units/mL LDH, 0.01 % Tween 20 in 50 mM HEPES, pH 7.5. Assays are initiated with the addition of 25nM PAK4 KD.
  • PAK KD Ki of each compound of the invention was calculated based on multiple of Percent Inhibition numbers of the inhibitor at different inhibitor concentrations.
  • the peptide (amino sequence EVPRRKSLVGTPYWM) was purchased from American Peptide Company. NADH, MgCI 2 , HEPES, DTT, ATP and PK/LDH were purchased from Sigma. Tween 20 was purchased from Calbiochem.

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Abstract

Pyrrole pyrazole compounds of formula I, compositions including these compounds, and methods of their use are provided. Ring A is optionally substituted. The ring formed by Z1, Z2, Z3, Z4 and the two intervening carbons is also optionally substituted. Preferred compounds of formula I have activity as protein kinase inhibitors, including as inhibitors of PAK4.

Description

PYRIMIDINE AMINO PYRAZOLE COMPOUNDS, POTENT KINASE
INHIBITORS Field of the Invention
The present invention relates generally to novel chemical compounds and methods. More particularly, the invention provides novel pyrimidine amino pyrazole compounds and their analogs, having protein kinase activity, and methods of synthesizing and using such compounds.
Background
Protein kinases are a family of enzymes that catalyze phosphorylation of the hydroxyl groups of specific tyrosine, serine, or threonine residues in proteins. Typically, such phosphorylation dramatically change the function of the protein and thus protein kinases are pivotal in the regulation of a wide variety of cellular process, including metabolism, cell proliferation, cell differentiation, and cell survival. The mechanism of these cellular process provide basis for targeting protein kinases to treat disease conditions resulting from or involving disorder of these cellular process. Examples of such diseases are, but are not limited to, cancer and diabetes.
Protein kinases can be broken into two types, the protein tyrosine kinases (PTKs) and the serine-threonine kinases (STKs). Both PTKs and STKs can be receptor protein kinases or non-receptor protein kinases. PAK is a family of non-receptor STKs. The p21 -activated protein kinase (PAK) family of serine/threonine protein kinases plays important roles in cytoskeletal organization and cellular morphogenesis (Daniels et al., Trends Biochem. ScL 24: 350-355 (1999); Sells et al., Trends Cell. Biol. 7: 162-167 (1997)). PAK proteins were initially identified by their interaction with the active small GTPases, Cdc42, and Rac, and their homology to yeast kinase Ste20 (Manser et al., Nature 367: 40-46 (1994)). In addition to mediating the regulation of actin cytoskeleton and cell adhesion by Cdc42 and Rac (Daniels et al., Trends Biochem. ScL 24: 350-355 (1999)), it was determined that some PAK proteins protect cells from apoptosis (Gnesutta et al., J. Biol. Chem. 276: 14414-14419 (2001); Rudel et al., Science 276: 1571-1574 (1997); Schurmann et al., MoI. Cell. Biol. 20: 453-461 (2000)); modulate mitogen activated protein (MAP) kinase pathways (Bagrodia et al., J. Biol. Chem. 270: 27995- 27998 (1995); Brown et al., Curr. Biol. 6: 598-605 (1996); Chaudhary et al., Curr. Biol. 10: 551-554 (2000); Frost et al., EMBO J. 16: 6426-6438 (1997); King et al., Nature 396: 180- 183 (1998); Sun et al., Curr. Biol. 10: 281-284 (2000)); mediate T-cell antigen receptor (TCR) signaling (Yablonski et al., EMBO J. 17: 5647-5657 (1998)); and respond to DNA damage (Roig et al., J. Biol. Chem. 274: 31119-31122 (1999)). Through these diverse functions, PAK proteins regulate cell proliferation and migration. The full-length PAK4 nucleic acid and amino acid sequences are disclosed in U.S. Patent No. 6,013,500 and have been deposited in GenBank under accession numbers AF005046 (mRNA) and AAD01210 (amino acid). Modulation of human PAK4 activity is reported to result in alterations in cellular processes affecting cell growth and adhesion. For example, overexpression of PAK4 in fibroblasts leads to morphological changes that are characteristic of oncogenic transformation through induction of anchorage-independent growth and inhibition of apoptosis (Gnesutta et al., J. Biol. Chem. 276:14414-14419 (2001); Qu et al., MoI. Cell. Biol. 21 : 3523-2533 (2001)).
PAK4 is an attractive target for developing therapeutic agents effective for use in processes and disorders involving cytoskeletal alterations, such as, for example, cancer.
For other background references, see US Patent Application Publication No.2003/0171357 and PCT Publication WO02/12242.
Summary
In one embodiment, the invention provides compounds of formula I,
Figure imgf000003_0001
I wherein:
Z1, Z2, Z3 and Z4 are independently CH or N, provided that at least one of Z1, Z2, Z3 and Z4 is CH and at least one of Z1, Z2, Z3 and Z4 is N, and the ring formed by Z1, Z2, Z3, Z4 and the two intervening carbons is optionally further substituted by 1 to 3 R4 groups;
R1 represents 1 or 2 optional substituents;
Ring A is 3-4 member cycloalkyl, 3-4 member heterocyclyl, 5-7 member bicyclic heterocyclyl or 5-7 member bicyclic nonaromatic carbocyclyl, and Ring A is optionally further substituted by 1-6 groups selected from R7 and oxo; each R1, R4, and R7 is independently R, and each R1, R4 and R7 is optionally independently further substituted by 1-6 groups selected from Rx and oxo, provided that when Rx is a substitutent of R7, Rx is optionally further substituted by 1-6 groups selected from Ry and oxo;
R is selected from the group consisting of C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, -(C1-C3 alkylene)m-(C3-C12 cycloalkyl), -(C1-C3 alkylene)m-phenyl, -(C1-C3 alkylene)m-(5-10 member heteroaryl), -(C1-C3 alkylene)m-(3-10 member heterocyclyl), - (C1-C3 alkylene)m-(3-12 member unsaturated non-aromatic carbocyclyl), -(C1-C6 perfluoroaklyl), -(C1-C3 alkylene)m-halide, -(C1-C3 alkylene)m-CN, -(C1-C3 alkylene)m- C(O)R3, -(C1-C3 alkylene)m-C(O)ORa, -(C1-C3 alkylene)m-C(O)NRaRb, -(C1-C3 alkylene)m- ORa, -(C1-C3 alkylene)m-OC(O)Ra, -(C1-C3 alkylene)m-OC(O)NRaRb, -(C1-C3 alkylene)m-O- S(O)R3, -(C1-C3 alkylene)m-OS(O)2Ra, -(C1-C3 alkylene)m-OS(O)2NR3Rb, -(C1-C3 alkylene)m-0S(0)NR3Rb, -(C1-C3 alkylene)m-NO2, -(C1-C3 alkylene)m-NRaRb , -(C1-C3 alkylene)m-N(Ra)C(O)Rb, -(C1-C3 alkylene)m-N(Ra)C(O)ORb, -(C1-C3 alkylene)m- N(Rc)C(O)NRaRb, -(C1-C3 alkylene)m-N(R3)S(O)2Rb, -(C1-C3 alkylene)m-N(R3)S(O)Rb, -(C1- C3 alkylene)m-SRa, -(C1-C3 alkylene)m-S(O)Ra, -(C1-C3 alkylene)m-S(O)2Ra, -(C1-C3 alkylene)m-S(O)NRaRb and -(C1-C3 alkylene)m-S(O)2NR3Rb, wherein each R3, Rb and R° is independently H, C1-C8 alkyl, C2-C8 alkenyl, -(C1-C3 alkylene)m-(C3-C8 cycloalkyl), -(C1-C3 alkylene)m-(C3-C8 cycloalkenyl), C2-C8 alkynyl, -(C1-C3 alkylene)m-phenyl, -(C1-C3 alkylene)m-(5-7 member heteroaryl) or -(C1-C3 alkylene)m-(3-8 member heterocyclyl), and when connected to the same atom, Ra and Rb may optionally form a ring selected from- (5-7 member heteroaryl) and -(3-8 member heterocyclyl); each Rx and Ryis independently R; two R4 on adjacent atoms may optionally form a ring selected from phenyl, 4-7 member nonaromatic carbocyclyl, 5-7 member heteroaryl containing 1-4 atoms selected from O, N, and S, and 4-7 member heterocyclyl containing 1-4 atoms selected from O, N and S, wherein the said ring is optionally further substituted by 1-6 groups selected from Rx and oxo; and each m is independently O or 1 , or a pharmaceutically acceptable salt, solvate or hydrate thereof.
In a particular aspect of this embodiment, the ring formed by Z1, Z2, Z3, Z4 and the two intervening carbons is selected from
Figure imgf000005_0001
wherein the said ring is optionally further substituted by 1-3 R4, and wherein 1 indicates the point of attachment to the aminopyrazole in formula I, and 2 indicates the point of attachment to Ring A in formula I.
In another embodiment, the invention provides compounds of formula II,
Figure imgf000005_0002
Il wherein: each R2, R3, R5 and R6 is independently H or R;
Ring A is 3-4 member cycloalkyl, 3-4 member heterocyclyl, 5-7 member bicyclic heterocyclyl or 5-7 member bicyclic nonaromatic carbocyclyl, and Ring A is optionally further substituted by 1-6 groups selected from R7 and oxo;
R7 is R;
R is selected from the group consisting of C1-C8 alky], C2-C8 alkenyl, C2-C8 aikynyl, -(CrC3 alkylene)m-(C3-C12 cycloalkyl), -(C1-C3 alkylene)m-phenyl, -(C1-C3 alkylene)m-(5-10 member heteroaryl), -(C1-C3 alkylene)m-(3-10 member heterocyclyl), - (C1-C3 alkylene)m-(3-12 member unsaturated non-aromatic carbocyclyl), -(C1-C6 perfluoroaklyl), -(C1-C3 alkylene)m-halide, -(C1-C3 alkylene)m-CN, -(C1-C3 alkylene)m- C(O)Ra, -(C1-C3 alkylene)m-C(O)ORa, -(C1-C3 alkylene)m-C(O)NRaRb, -(C1-C3 alkylene)m- ORa, -(C1-C3 alkylene)m-OC(O)Ra, -(C1-C3 alkylene)m-OC(O)NRaRb, -(C1-C3 alkylene)m-O- S(O)Ra, -(C1-C3 alkylene)m-OS(O)2Ra, -(C1-C3 alkylene)m-OS(O)2NRaRb, -(C1-C3 alkylene)m-OS(O)NRaRb, -(C1-C3 alkylene)m-NO2, -(C1-C3 alkylene)m-NRaRb, -(C1-C3 alkylene)m-N(Ra)C(O)Rb, -(C1-C3 alkylene)m-N(Ra)C(O)ORb, -(C1-C3 alkylene)m- N(Rc)C(O)NRaRb, -(C1-C3 alkylene)m-N(Ra)S(O)2Rb, -(C1-C3 alkylene)m-N(Ra)S(O)Rb, -(C1- C3 alkylene)m-SRa, -(C1-C3 alkylene)m-S(O)Ra, -(C1-C3 alkylene)m-S(O)2Ra, -(C1-C3 alkylene)m-S(O)NRaRb and -(C1-C3 alkylene)m-S(O)2NRaRb, wherein each Ra, Rb and Rc is independently H, C1-C8 alkyl, C2-C8 alkenyl, -(C1-C3 alkylene)m-(C3-C8 cycloalkyl), -(C1-C3 alkylene)m-(C3-C8 cycloalkenyl), C2-C8 alkynyl, -(C1-C3 alkylene)m-phenyl, -(C1-C3 alkylene)m-(5-7 member heteroaryl) or -(C1-C3 alkylene)m-(3-8 member heterocyclyl), and when connected to the same atom, Ra and Rb may optionally form a ring selected from- (5-7 member heteroaryl) and -(3-8 member heterocyclyl); each R2, R3, R5, R6 and R7 is independently optionally further substituted by 1-6 groups selected from Rx and oxo, provided that when Rx is an substituent of R7, Rx is optionally further substituted by 1-6 groups selected from Ry and oxo; each Rx and Ry is independently R; and each m is independently 0 or 1 , or a pharmaceutically acceptable salt, solvate or hydrate thereof.
In a particular aspect of this embodiment, and in combination with any other particular aspects not inconsistent, R2 and R3 are independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, -(C1-C3 alkylene)m-(C3-C6 cycloalkyl), -(C1-C3 alkylene)m-(C3-C6 cycloalkenyl), C2-C6 alkynyl and -(C1-C6 perfluoroalkyl), R2 and R3 are optionally independently further substituted by 1-6 groups selected from oxo, -(C1-C3 alkylene)m-halide, -(C1-C3 alkylene)m-CN, -(C1-C3 alkylene)m-C(O)Ra, -(C1-C3 alkylene)m- C(O)OR3, -(C1-C3 alkylene)m-C(O)NRaRb, -(C1-C3 alkylene)m-ORa, -(C1-C3 alkylene)m- OC(O)R3 and -(C1-C3 alkylene)m-OC(O)NRaRb, wherein each Ra and Rb is independently H, C1-C5 alkyl or -(C1-C3 alkylene)m-(C3-C6 cycloalkyl), and when connecting to the same atom, Ra and Rb may optionally form a ring selected from -(5-7 member heteroaryl) and - (3-8 member heterocyclyl), and wherein each m is independently O or 1.
In another particular aspect of this embodiment, and in combination with any other particular aspects not inconsistent, R2 is H, C1-C6 alkyl or -(C1-C3 alkylene)m-(C3-C6 cycloalkyl), R3 is H, C1-C6 alkyl, or -(C1-C3 alkylene)m-(C3-C6 cycloalkyl), each R2 and R3 is indepdently optionally further substituted by 1-6 groups selected from halide, oxo, -CN, -0Ra and -NR3Rb, wherein each Ra and Rb is independently H, C1-C6 alkyl or -(C1-C3 alkylene)m-(C3-C6 cycloalkyl), and when connecting to the same atom, Ra and Rb may optionally form a ring selected from the list of -(5-7 member heteroaryl) and -(3-8 member heterocyclyl). In another particular aspect of this embodiment, and in combination with any other particular aspects not inconsistent, R2 is unsubstituted C1-C6 alkyl or unsubstituted - (C1-C3 alkylene)m-(C3-C6 cycloalkyl), and R3 is H.
In another particular aspect of this embodiment, and in combination with any other particular aspects not inconsistent, R5 is selected from the group consisting of H, C1-C6 alkyl and -(C1-C3 alkylene)m-(C3-C6 cycloalkyl), and R5 is optionally further substituted by 1-6 groups selected from Rxand oxo.
In another particular aspect of this embodiment, in combination with any other particular aspects not inconsistent, R5 is H, unsubstituted C1-C6 alkyl or unsubstituted - (C1-C3 alkylene)m-(C3-C6 cycloalkyl), halide.
In another particular aspect of this embodiment, and in combination with any other particular aspects not inconsistent, R6 is selected from the group consisting of (C1- C3 alkylene)m-phenyl, (C1-C3 alkylene)m -(5-10 member heteroaryl), (C1-C3 alkylene)m (3- 8 member heterocyclyl), (C1-C3 alkylene)m-(5-12 member bicyclic non-aromatic carbocyclyl) and -(C1-C6 perfluoroaklyl), and R6 is optionally further substituted by 1-6 groups selected from Rx and oxo wherein Rx is R.
In another particular aspect of this embodiment, and in combination with any other particular aspects not inconsistent, Ring A is selected from the group consisting of
Figure imgf000007_0001
wherein — indicates the point of attachment to the pyrimidine ring 2 position, and Ring A is optonally further substituted by 1-6 groups selected from R7 and oxo.
In another particular aspect of this embodiment, and in combination with any other particular aspects not inconsistent, R7 is selected from halide, C1-C6 alkyl, C2-C6 alkenyl, -(C1-C3 alkylene)m-(C3-C6 cycloalkyl), C1-C6 perfluroalkyl, -(C1-C3 alkylene)m- C(O)NRaRb, -(C1-C3 alkylene)m-C(O)ORa, -(C1-C3 alkylene)m-C(O)Ra, -(C1-C3 alkylene)m- NRaRb, -(C1-C3 alkylene)m-NRc-C(O)Ra, -(C1-C3 alkylene)m-NRc-C(O)NRaRb, -(C1-C3 alkylene)m -ORa, wherein each Ra Rb and RG is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, and that R7 is unsubstituted.
In another aspect of this embodiment, R2 and R3 are independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, -(C1-C3 alkylene)m-(C3-C6 cycloalkyl), -(C1-C3 alkylene)m-(C3-C6 cycloalkenyl), C2-C6 alkynyl and -(C1-C6 perfluoroalkyl), each R2 and R3 is optionally independently further substituted by 1-6 groups selected from oxo, -(C1-C3 alkylene)m-halide, -(C1-C3 alkylene)m-CN, -(C1-C3 alkylene)m-C(O)Ra, -(C1-C3 alkylene)m-C(O)ORa, -(C1-C3 alkylene)m-C(O)NRaRb, -(C1-C3 alkylene)m-ORa, -(C1-C3 alkylene)m-OC(O)Ra and -(C1-C3 alkylene)m-OC(O)NRaRb, wherein each Ra and Rb is independently H, C1-C6 alky or -(C1-C3 alkylene)m-(C3-C6 cycloalkyl), and when connected to the same atom, Ra and Rb, may optionally form a ring selected from -(5-7 member heteroaryl) and -(3-8 member heterocyclyl), R5 is selected from the group consisting of H, C1-C6 alkyl and -(C1-C3 alkylene)m-(C3-C6 cycloalkyl), and R5 is independently optionally further substituted by 1-6 groups selected from Rxand oxo.
In another aspect of this embodiment, R2 is H, C1-C6 alkyl or -(C1-C3 alkylene)m- (C3-C6 cycloalkyl),
R3 is H, C1-C6 alkyl or C1-C3 alkylene)m-(C3-C6 cycloalkyl), and each R2 and R3 is optionally further substituted by 1-6 groups selected from halide, oxo, -CN, -ORa and - NRaRb, wherein each Ra and Rb is independently H, C1-C6 alkyl or -(C1-C3 alkylene)m- (C3-C6 cycloalkyl), and when connected to the same atom, Ra and Rb may optionally form a ring selected from-(5-7 member heteroaryl) and -(3-8 member heterocyclyl); R5 is H, unsubstituted C1-C6 alkyl, unsubstituted -(C1-C3 alkylene)m-(C3-C6 cycloalkyl) or halide; R6 is selected from the group consisting of (C1-C3 alkylene)m-phenyl, (C1-C3 alkylene)m -(5- 10 member heteroaryl), (C1-C3 alkylene)m (3-8 member heterocyclyl), (C1-C3 alkylene)m- (5-12 member bicyclic non-aromatic carbocyclyl) and -(C1-C6 perfluoroaklyl), and R6 is optionally further substituted by 1-6 groups selected from Rx and oxo wherein Rx is R.
In another aspect of this embodiment, R2 is unsubstituted C1-C6 alkyl or unsubstituted -(C1-C3 alkylene)m-(C3-C6 cycloalkyl); R3 is H, R5 is H, unsubstituted C1-C6 alkyl, unsubstituted -(C1-C3 alkylene)m-(C3-C6 cycloalkyl) or halide; R6 is selected from the group consisting of (C1-C3 alkylene)m-phenyl, (C1-C3 alkylene)m -(5-10 member heteroaryl), (C1-C3 alkylene)m (3-8 member heterocyclyl), (C1-C3 alkylene)m-(5-12 member bicyclic non-aromatic carbocyclyl) and -(C1-C6 perfluoroalkyl); and R6 is optionally further substituted by 1-6 groups selected from Rx and oxo wherein Rx is R, and Ring A is selected from the group consisting of
Figure imgf000008_0001
wherein — indicates the point of attachment to the pyrimidine ring 2 position, and Ring A is optionally further substituted by 1-6 groups selected from R7 and oxo.
In another aspect of this embodiment, the invention provides compounds of formula III,
Figure imgf000009_0001
III wherein R2 is unsubstituted C1-C6 alkyl or unsubstituted -(C1-C3 alky!ene)m-(C3-C6 cycloalkyl), R8 represents 1-3 optional substituents, and each R8 is independently R.
In another particular aspect of this embodiment, the compound is of formula III, wherein R2 is unsubstituted C1-C6 alkyl or unsubstituted -(C1-C3 alkylene)m-(C3-C6 cycloalkyl); R8 represents 1-3 optional substituents, and each R8 is independently R; Ring A is selected from the group consisting of
Figure imgf000009_0002
, wherein — indicates the point of attachment to the pyrimidine ring 2 position, and Ring A is optonally further substituted by 1-6 groups selected from R7 and oxo; and R7 is selected from halide, C1-C6 alkyl, C2-C6 alkenyl, -(C1-C3 alkylene)m-(C3-C6 cycloalkyl), C1-C6 perfluroalkyl, -(C1-C3 alkylene)m-C(O)NRaRb, -(C1-C3 alkylene)m-C(O)ORa, -(C1-C3 alkylene)m-C(O)Ra, -(C1-C3 alkylene)m-NRaRb, -(C1-C3 alkylene)m-NRc-C(O)Ra, -(C1-C3 alkylene)m-NRc-C(O)NRaRb, - (C1-C3 alkylene)m -ORa, wherein each Ra Rb and Rc is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, and that R7 is unsubstituted.
In another embodiment, the invention provides compounds of formula IV,
Figure imgf000009_0003
IV wherein:
Ring A is 3-4 member cycloalkyl, 3-4 member heterocyclyl, 5-7 member bicyclic heterocyclyl or 5-7 member bicyclic nonaromatic carbocyclyl, and Ring A is optionally further substituted by 1-6 groups selected from R7 and oxo;
B represents a fused phenyl group, a fused 4-7 member nonaromatic carbocyclyl group, a fused 5-7 member heteroaryl group containing 1-4 atoms selected from O, N, and S or a fused 4-7 member heterocyclyl group containing 1-4 atoms selected from O, N and S; each R2 and R3 is independently H or R;
R7 is R; each R2, R3, R7 and B is independently optionally further substituted by 1-6 groups selected from Rx and oxo, provided that when Rx is an substituent of R7, Rx is optionally further substituted by 1-6 groups selected from Ry and oxo;
R is selected from the group consisting of C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, -(C1-C3 alkylene)m-(C3-Ci2 cycloalkyl), -(C1-C3 alkylene)m-phenyl, -(C1-C3 , alkylene)m-(5-10 member heteroaryl), -(C1-C3 alkylene)m-(3-10 member heterocyclyl); - (C1-C3 alkylene)m-(3-12 member unsaturated non-aromatic carbocyclyl), -(C1-C6 perfluoroaklyl), -(C1-C3 alkylene)m-halide, -(C1-C3 alkylene)m-CN, -(C1-C3 alkylene)m- C(O)Ra, -(C1-C3 alkylene)m-C(O)ORa, -(C1-C3 alkylene)m-C(O)NRaRb, -(C1-C3 alkyiene)m- ORa, -(C1-C3 alkylene)m-OC(O)Ra, -(C1-C3 alkylene)m-OC(O)NRaRb, -(C1-C3 alkylene)m-O- S(O)Ra, -(C1-C3 alkyiene)m-OS(O)2Ra, -(C1-C3 alkylene)m-OS(O)2NRaRb, -(C1-C3 alkylene)m-OS(O)NRaRb, -(C1-C3 alkylene)m-NO2, -(C1-C3 alkylene)m-NRaRb -(C1-C3 alkylene)m-N(Ra)C(O)Rb, -(C1-C3 alkylene)m-N(Ra)C(O)ORb, -(C1-C3 alkylene)m- N(Rc)C(O)NRaRb, -(C1-C3 alkylene)m-N(Ra)S(O)2Rb, -(C1-C3 alkylene)m-N(Ra)S(O)Rb, -(C1- C3 alkylene)m-SRa, -(C1-C3 alkylene)m-S(O)Ra, -(C1-C3 alkylene)m-S(O)2Ra, -(C1-C3 alkylene)m-S(O)NRaRb and -(C1-C3 alkylene)m-S(O)2NRaRb, wherein each Ra, Rb and Rc is independently H, C1-C8 alkyl, C2-C8 alkenyl, -(C1-C3 alkylene)m-(C3-C8 cycloalkyl), -(C1-C3 alkylene)m-(C3-C8 cycloalkenyl), C2-C8 alkynyl, -(C1-C3 alkylene)m-phenyl, -(C1-C3 alkylene)m-(5-7 member heteroaryl) or -(C1-C3 alkylene)m-(3-8 member heterocyclyl), and when connected to the same atom, Ra and Rb may optionally form a ring selected from- (5-7 member heteroaryl) and -(3-8 member heterocyclyl); each Rx and Ryis independently R; and each m is independently 0 or 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
In a particular aspect of this embodiment, and in combination with any other particular aspects not inconsistent, R2 is H, C1-C6 alkyl or -(C1-C3 alkylene)m-(C3-C6 cycloalkyl), R3 is H, C1-C6 alkyl or -(C1-C3 alkylene)m-(C3-C6 cycloalkyl), and each R2 and R3 is independently optionally further substituted by 1-6 groups selected from halide, oxo, -CN, -ORa and -NRaRb, wherein each Ra and Rb is independently H1 C1-C6 alkyl Or -(C1-C3 alkylene)m-(C3-C6 cycloalkyl).
In another particular aspect of this embodiment, and in combination with any other particular aspects not inconsistent, the invention provides comounds of formula V,
Figure imgf000011_0001
V wherein R9 represents 1-2 optional substituents and R9 is R.
In another particular aspect of this embodiment, and in combination with any other particular aspects not inconsistent, Ring A is selected from the group consisting of
N n-
Figure imgf000011_0002
wherein — indicates the point of attachment to the pyrimidine ring 2 position, and Ring A is optionally further substituted by 1-6 groups selected from oxo and R7.
In another particular aspect of this embodiment, and in combination with any other particular aspects not inconsistent, R7 is selected from halide, C1-C6 alkyl, C2-C6 alkenyl, -(C1-C3 alkylene)m-(C3-C6 cycloalkyl), C1-C6 perfluroalkyl, -(C1-C3 alkylene)m- C(O)NRaRb, -(C1-C3 alkylene)m-C(O)ORa, -(C1-C3 alkylene)m-C(O)Ra, -(C1-C3 alkylene)m- NRaRb, -(C1-C3 alkylene)m-NRc-C(O)Ra, -(C1-C3 alkylene)m-NRc-C(O)NRaRb, -(C1-C3 alkylene)m -ORa, wherein each Ra Rb and Rc is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, and that R7 is unsubstituted.
In another particular aspect of this embodiment, and in combination with any other particular aspects not inconsistent, B represents a ring selected from 5-6 member heteroaryl containing 1-2 atoms selected from O, N and S, 5-6 member heterocyclyl containing 1-2 atoms selected from O, N and S, phenyl and 5-6 member nonaromatic carbocyclyl, and that the said ring is fused to the pyrimidine ring in formula IV. In another particular aspect of this embodiment, and in combination with any other particular aspects not inconsistent, B represents a ring selected from thiophenyl, pyrrolyl, furanyl and phenyl, and that the said ring is fused to the pyrimidine ring in formula IV.
In another particular aspect of this embodiment, R2 is H, C1-C6 alkyl, or -(C1-C3 alkylene)m-(C3-C6 cycloalkyl); R3 is H, C1-C6 alkyl, Or-(C1-C3 alkylene)m-(C3-C6 cycloalkyl); each R2 and R3 is independently optionally further substituted by 1-6 groups selected from halide, oxo, -CN, -0Ra, and -NRaRb, wherein each Ra and Rb is independently H, C1- C6 alkyl or -(C1-C3 alkylene)m-(C3-C6 cycloalkyl); B represents a ring selected from 5-6 member heteroaryl containing 1-2 atoms selected from O, N and S, 5-6 member heterocyclyl containing 1-2 atoms selected from O, N and S, phenyl and 5-6 member nonaromatic carbocyclyl, the said ring is fused to the pyrimidine ring in formula IV; and Ring A is selected from the group consisting of
*n VA, %z
Figure imgf000012_0001
, wherein — indicates the point of attachment to the pyrimidine ring 2 position, and Ring A is optionally further substituted by 1-6 groups selected from oxo and R7.
In another particular aspect of this embodiment, R2 is H, C1-C6 alkyl, or -(C1-C3 alkylene)m-(C3-C6 cycloalkyl); R3 is H, C1-C6 alkyl, Or-(C1-C3 alkylene)m-(C3-C6 cycloalkyl); each R2 and R3 is independently optionally further substituted by 1-6 groups selected from halide, oxo, -CN, -0Ra, and -NRaRb, wherein each Ra and Rb is independently H, C1- C6 alkyl or -(C1-C3 alkylene)m-(C3-C6 cycloalkyl); B represents a ring selected from 5-6 member heteroaryl containing 1-2 atoms selected from O, N and S, 5-6 member heterocyclyl containing 1-2 atoms selected from O, N and S, phenyl and 5-6 member nonaromatic carbocyclyl, the said ring is fused to the pyrimidine ring in formula IV; Ring A is selected from the group consisting of
I — 11
Figure imgf000012_0002
, wherein — indicates the point of attachment to the pyrimidine ring 2 position, and Ring A is optionally further substituted by 1-6 groups selected from oxo and R7; and R7 is selected from halide, C1-C6 alkyl, C2-C6 alkenyl, -(Ci-C3 alkylene)m-(C3-C6 cycloalkyl), C1-C6 perfluroalkyl, -(C1-C3 alkylene)m-C(O)NRaRb, -(C1-C3 alkylene)m-C(O)ORa, -(C1-C3 alkylene)m-C(O)Ra, -(C1-C3 alkylene)m-NRaRb, -(C1-C3 alkylene)m-NRc-C(O)Ra, -(C1-C3 alkylene)m-NRc-C(O)NRaRb, - (Ci-C3 alkylene)m -ORa, wherein each Ra Rb and Rc is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, and that R7 is unsubstituted.
In another particular aspect of this embodiment, R2 is H, C1-C6 alkyl, or -(C1-C3 alkylene)m-(C3-C6 cycloalkyl); R3 is H, C1-C6 alkyl, Or -(C1-C3 alkylene)m-(C3-C6 cycloalkyl); each R2 and R3 is independently optionally further substituted by 1-6 groups selected from halide, oxo, -CN, -ORa, and -NRaRb, wherein each Ra and Rb is independently H, C1- C6 alkyl or -(C1-C3 alkylene)m-(C3-C6 cycloalkyl); B represents a ring selected from thiophenyl, pyrrolyl, furanyl, phenyl, the said ring is fused to the pyrimidine ring in formula IV; Ring A is selected from the group consisting of
' — ' ,
Figure imgf000013_0001
, wherein — indicates the point of attachment to the pyrimidine ring 2 position, and Ring A is optionally further substituted by 1-6 groups selected from oxo and R7; and R7 is selected from halide, C1-C6 alkyl, C2-C6 alkenyl, -(C1-C3 alkylene)m-(C3-C6 cycloalkyl), C1-C6 perfluroalkyl, -(C1-C3 , alkylene)m-C(O)NRaRb, -(C1-C3 alkylene)m-C(O)ORa, -(C1-C3 alkylene)m-C(O)Ra, -(C1-C3 alkylene)m-NRaRb, -(C1-C3 alkylene)m-NRc-C(O)Ra, -(C1-C3 alkylene)m-NRc-C(O)NRaRb, - (C1-C3 alkylene)m -0Ra, wherein each Ra Rb and Rc is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, and that R7 is unsubstituted.
In another embodiment, the invention provides a compound selected from the group consisting of
Figure imgf000013_0002
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000017_0002
Figure imgf000018_0001
Figure imgf000019_0001
and or a pharmaceutically acceptable salt, solvate and hydrate thereof.
In another embodiment, the invention provides a method of modulating the activity of PAK4 protein kinase, comprising contacting the protein kinase with an effective amount of a compound of formula I to V, pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt, solvate or hydrate of the compounds of of formula I to IV.
In another embodiment, the invention provides a method of treating abnormal cell growth in a mammal, comprising administering to a mammal a therapeutically acceptable amount of a compound, salt, hydrate or solvate of any of the compounds of this invention.
In a particular aspect of this embodiment, the abnormal cell growth is cancer.
In another embodiment, the invention provides a method for the treatment of abnormal cell growth in a mammal, including a human, comprising administering to said mammal an amount of a compound of Formula I, as defined above, or a pharmaceutically acceptable salt, hydrate or solvate thereof, that is effective in treating abnormal cell growth.
In one embodiment of any of these methods, the abnormal cell growth is cancer, including, but not limited to, mesothelioma, hepatobiliary (hepatic and billiary duct), a primary or secondary CNS tumor, a primary or secondary brain tumor, lung cancer (NSCLC and SCLC), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, non hodgkins's lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocortical cancer, gall bladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the foregoing cancers.
In a preferred embodiment of the present invention the cancer is selected from lung cancer (NSCLC and SCLC), cancer of the head or neck, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, breast cancer, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, non hodgkins's lymphoma, spinal axis tumors, or a combination of one or more of the foregoing cancers.
In another preferred embodiment of the present invention the cancer is selected from lung cancer (NSCLC and SCLC), ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, or a combination of one or more of the foregoing cancers.
In a more preferred embodiment of the present invention the cancer is selected from lung cancer (NSCLC and SCLC), ovarian cancer, colon cancer, rectal cancer-. or a combination of one or more of the foregoing cancers.
In another embodiment of said method, said abnormal cell growth is a benign proliferative disease, including, but not limited to, psoriasis, benign prostatic hypertrophy or restinosis.
This invention also relates to a method for the treatment of abnormal cell growth in a mammal which comprises administering to said mammal an amount of a compound of Formula I-V, or a pharmaceutically acceptable salt, hydrate or solvate thereof, that is effective in treating abnormal cell growth in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti- hormones, and anti-androgens.
This invention also relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal, including a human, comprising an amount of a compound of the Formula I-V, as defined above, or a pharmaceutically acceptable salt, hydrate or solvate thereof, that is effective in treating abnormal cell growth, and a pharmaceutically acceptable carrier. In one embodiment of said composition, said abnormal cell growth is cancer, including, but not limited to, mesothelioma, hepatobiliary (hepatic and billiary duct), a primary or secondary CNS tumor, a primary or secondary brain tumor, lung cancer (NSCLC and SCLC), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, non hodgkins's lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocortical cancer, gall bladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the foregoing cancers. In another embodiment of said pharmaceutical composition, said abnormal cell growth is a benign proliferative disease, including, but not limited to, psoriasis, benign prostatic hypertrophy or restinosis.
The invention also relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal, including a human, which comprises an amount of a compound of Formula I-V, as defined above, or a pharmaceutically acceptable salt or solvate thereof, that is effective in treating abnormal cell growth in combination with a pharmaceutically acceptable carrier and an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, and anti-androgens.
The invention also relates to a method for the treatment of a hyperproliferative disorder in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of Formula I-V, or a pharmaceutically acceptable salt or hydrate thereof, in combination with an anti-tumor agent selected from the group consisting antiproliferative agents, kinase inhibitors, angiogenesis inhibitors, growth factor inhibitors, cox-l inhibitors, cox-ll inhibitors, mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti- hormones, statins, and anti-androgens.
In one embodiment of the present invention the anti-tumor agent used in conjunction with a compound of Formula I and pharmaceutical compositions described herein is an anti-angiogenesis agent, kinase inhibitor, pan kinase inhibitor or growth factor inhibitor. Preferred pan kinase inhibitors include SU-11248, described in U.S. Patent No. 6,573,293 (Pfizer, Inc, NY, USA).
Anti-angiogenesis agents, include but are not limited to the following agents, such as EGF inhibitor, EGFR inhibitors, VEGF inhibitors, VEGFR inhibitors, TIE2 inhibitors, IGF1 R inhibitors, COX-II (cyclooxygenase II) inhibitors, MMP-2 (matrix- metalloprotienase 2) inhibitors, and MMP-9 (matrix-metalloprotienase 9) inhibitors.
Preferred VEGF inhibitors, include for example, Avastin (bevacizumab), an anti- VEGF monoclonal antibody of Genentech, Inc. of South San Francisco, California. Additional VEGF inhibitors include CP-547,632 (Pfizer Inc., NY, USA), AG13736 (Pfizer Inc.), ZD-6474 (AstraZeneca), AEE788 (Novartis), AZD-2171), VEGF Trap (Regeneron/Aventis), Vatalanib (also known as PTK-787, ZK-222584: Novartis & Schering AG), Macugen (pegaptanib octasodium, NX-1838, EYE-001, Pfizer Inc./Gilead/Eyetech), IM862 (Cytran Inc. of Kirkland, Washington, USA); and angiozyme, a synthetic ribozyme from Ribozyme (Boulder, Colorado) and Chiron (Emeryville, California) and combinations thereof. VEGF inhibitors useful in the practice of the present invention are disclosed in US Patent No. 6,534,524 and 6,235,764, both of which are incorporated in their entirety for all purposed.
Particularly preferred VEGF inhibitors include CP-547,632, AG13736, Vatalanib, Macugen and combinations thereof.
Additional VEGF inhibitors are described in, for example in WO 99/24440 (published May 20, 1999), PCT International Application PCT/IB99/00797 (filed May 3, 1999), in WO 95/21613 (published August 17, 1995), WO 99/61422 (published December 2, 1999), United States Patent 6, 534,524 (discloses AG13736), United States Patent 5,834,504 (issued November 10, 1998), WO 98/50356 (published November 12, 1998), United States Patent 5,883,113 (issued March 16, 1999), United States Patent 5,886,020 (issued March 23, 1999), United States Patent 5,792,783 (issued August 11, 1998), U.S. Patent No. US 6,653,308 (issued November 25, 2003), WO 99/10349 (published March 4, 1999), WO 97/32856 (published September 12, 1997), WO 97/22596 (published June 26, 1997), WO 98/54093 (published December 3, 1998), WO 98/02438 (published January 22, 1998), WO 99/16755 (published April 8, 1999), and WO 98/02437 (published January 22, 1998), all of which are herein incorporated by reference in their entirety.
Other antiproliferative agents that may be used with the compounds of the present invention include inhibitors of the enzyme farnesyl protein transferase and inhibitors of the receptor tyrosine kinase PDGFr, including the compounds disclosed and claimed in the following United States patent applications: 09/221946 (filed December 28, 1998); 09/454058 (filed December 2, 1999); 09/501163 (filed February 9, 2000); 09/539930 (filed March 31 , 2000); 09/202796 (filed May 22, 1997); 09/384339 (filed August 26, 1999); and 09/383755 (filed August 26, 1999); and the compounds disclosed and claimed in the following United States provisional patent applications: 60/168207 (filed November 30, 1999); 60/170119 (filed December 10, 1999); 60/177718 (filed January 21, 2000); 60/168217 (filed November 30, 1999), and 60/200834 (filed May 1 , 2000). Each of the foregoing patent applications and provisional patent applications is herein incorporated by reference in their entirety.
PDGRr inhibitors include but not limited to those disclosed international patent application publication number WO01/40217, published July 7, 2001 and international patent application publication number WO2004/020431 , published March 11, 2004, the contents of which are incorporated in their entirety for all purposes.
Preferred PDGFr inhibitors include Pfizer's CP-673,451 and CP-868,596 and its pharmaceutically acceptable salts.
Preferred GARF inhibitors include Pfizer's AG-2037 (pelitrexol and its pharmaceutically acceptable salts. GARF inhibitors useful in the practice of the present invention are disclosed in US Patent No. 5,608,082 which is incorporated in its entirety for all purposed.
Examples of useful COX-II inhibitors which can be used in conjunction with a compound of Formula I and pharmaceutical compositions described herein include CELEBREX™ (celecoxib), parecoxib, deracoxib, ABT-963, MK-663 (etoricoxib), COX- 189 (Lumiracoxib), BMS 347070, RS 57067, NS-398, Bextra (valdecoxib), paracoxib, Vioxx (rofecoxib), SD-8381 , 4-Methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoyl-phenyl)-1 H- pyrrole, 2-(4-Ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-1 H-pyrrole, T-614, JTE-522, S-2474, SVT-2016, CT-3, SC-58125 and Arcoxia (etoricoxib). Additonally, COX-II inhibitors are disclosed in U.S. Patent Application Nos. 10/801 ,446 and 10/801,429, the contents of which are incorporated in their entirety for all purposes.
In one preferred embodiment the anti-tumor agent is celecoxib as disclosed in U.S. Patent No. 5,466,823, the contents of which are incorporated by reference in its entirety for all purposes. The structure for Celecoxib is shown below:
Figure imgf000024_0001
In one preferred embodiment the anti-tumor agent is valecoxib as disclosed in U.S. Patent No. 5,633,272, the contents of which are incorporated by reference in its entirety for all purposes. The structure for valdecoxib is shown below:
Figure imgf000024_0002
In one preferred embodiment the anti-tumor agent is parecoxib as disclosed in U.S. Patent No. 5,932,598, the contents of which are incorporated by reference in its entirety for all purposes. The structure for paracoxib is shown below:
4-7
Figure imgf000024_0003
In one preferred embodiment the anti-tumor agent is deracoxib as disclosed in U.S. Patent No. 5,521,207, the contents of which are incorporated by reference in its entirety for all purposes. The structure for deracoxib is shown below:
Figure imgf000025_0001
In one preferred embodiment the anti-tumor agent is SD-8381 as disclosed in U.S. Patent No. 6,034,256, the contents of which are incorporated by reference in its entirety for all purposes. The structure for SD-8381 is shown below:
Figure imgf000025_0002
In one preferred embodiment the anti-tumor agent is ABT-963 as disclosed in International Publication Number WO 2002/24719, the contents of which are incorporated by reference in its entirety for all purposes. The structure for ABT-963 is shown below:
Figure imgf000025_0003
In one preferred embodiment the anti-tumor agent is rofecoxib as shown below:
Figure imgf000025_0004
In one preferred embodiment the anti-tumor agent is MK-663 (etoricoxib) as disclosed in International Publication Number WO 1998/03484, the contents of which are incorporated by reference in its entirety for all purposes. The structure for etoricoxib is shown below:
Figure imgf000026_0001
In one preferred embodiment the anti-tumor agent is COX-189 (Lumiracoxib) as disclosed in International Publication Number WO 1999/11605, the contents of which are incorporated by reference in its entirety for all purposes. The structure for Lumiracoxib is shown below:
Figure imgf000026_0002
Lumiracoxib
CAS No. 220991-20-8
Novartis
WO 99/11605
In one preferred embodiment the anti-tumor agent is BMS-347070 as disclosed in United States Patent No. 6,180,651 , the contents of which are incorporated by reference in its entirety for all purposes. The structure for BMS-347070 is shown below:
Figure imgf000026_0003
BMS 347070
CAS No . 197438-48-5
6, 180, 651
In one preferred embodiment the anti-tumor agent is NS-398 (CAS 123653-11-2). The structure for NS-398 (CAS 123653-11-2) is shown below:
Figure imgf000027_0001
NS-398
CAS No . 123653-11-2
In one preferred embodiment the anti-tumor agent is RS 57067 (CAS 17932-91- 3). The structure for RS-57067 (CAS 17932-91-3) is shown below:
Figure imgf000027_0002
RS 57067
CAS No . 17932-91-3
In one preferred embodiment the anti-tumor agent is 4-Methyl-2-(3,4- dimethylphenyl)-1-(4-sulfamoyl-phenyl)-1H-pyrrole. The structure for 4-Methyl-2-(3,4- dimethylphenyl)-1-(4-sulfamoyl-phenyl)-1 H-pyrrole is shown below:
Figure imgf000027_0003
In one preferred embodiment the anti-tumor agent is 2-(4-Ethoxyphenyl)-4- methyl-1-(4-sulfamoylphenyl)-1H-pyrrole. The structure for 2-(4-Ethoxyphenyl)-4-methyl- 1-(4-sulfamoylphenyl)-1 H-pyrrole is shown below:
Figure imgf000027_0004
In one preferred embodiment the anti-tumor agent is meloxicam. The structure for meloxicam is shown below:
Figure imgf000028_0001
Other useful inhibitors as anti-tumor agents used in conjunction with a compound of Formula I and pharmaceutical compositions described herein include aspirin, and nonsteroidal anti-inflammatory drugs (NSAIDs) which inhibit the enzyme that makes prostaglandins (cyclooxygenase I and II), resulting in lower levels of prostaglandins, include but are not limited to the following, Salsalate (Amigesic), Diflunisal (Dolobid), lbuprofen (Motrin), Ketoprofen (Orudis), Nabumetone (Relafen), Piroxicam (Feldene), Naproxen (Aleve, Naprosyn), Diclofenac (Voltaren), lndomethacin (Indocin), Sulindac , (Clinoril), Tolmetin (Tolectin), Etodolac (Lodine), Ketorolac (Toradol), Oxaprozin (Daypro) and combinations thereof.
Preferred COX-I inhibitors include ibuprofen (Motrin), nuprin, naproxen (Aleve), indomethacin (Indocin), nabumetone (Relafen) and combinations thereof. Targeted agents used in conjunction with a compound of Formula I and pharmaceutical compositions described herein include EGFr inhibitors such as Iressa (gefitinib, AstraZeneca), Tarceva (erlotinib or OSI-774, OSI Pharmaceuticals Inc.), Erbitux (cetuximab, lmclone Pharmaceuticals, Inc.), EMD-7200 (Merck AG), ABX-EGF (Amgen Inc. and Abgenix Inc.), HR3 (Cuban Government), IgA antibodies (University of Erlangen- Nuremberg), TP-38 (IVAX), EGFR fusion protein, EGF-vaccine, anti-EGFr immunoliposomes (Hermes Biosciences Inc.) and combinations thereof
Preferred EGFr inhibitors include Iressa, Erbitux, Tarceva and combinations thereof.
The present invention also relates to anti-tumor agents selected from pan erb receptor inhibitors or ErbB2 receptor inhibitors, such as CP-724,714 (Pfizer, Inc.), Cl- 1033 (canertinib, Pfizer, Inc.), Herceptin (trastuzumab, Genentech Inc.), Omitarg (2C4, pertuzumab, Genentech Inc.), TAK-165 (Takeda), GW-572016 (lonafarnib, GlaxoSmithKline), GW-282974 (GlaxoSmithKline), EKB-569 (Wyeth), PKI-166 (Novartis), dHER2 (HER2 Vaccine, Corixa and GlaxoSmithKline), APC8024 (HER2 Vaccine, Dendreon), anti-HER2/neu bispecific antibody (Decof Cancer Center), B7.her2.lgG3 (Agensys), AS HER2 (Research Institute for Rad Biology & Medicine), trifuntional bispecific antibodies (University of Munich) and mAB AR-209 (Aronex Pharmaceuticals Inc) and mAB 2B-1 (Chiron) and combinations thereof. Preferred erb selective anti-tumor agents include Herceptin, TAK-165, CP-724,714, ABX- EGF, HER3 and combinations thereof.
Preferred pan erbb receptor inhibitors include GW572016, CI-1033, EKB-569, and Omitarg and combinations thereof.
Additional erbB2 inhibitors include those described in WO 98/02434 (published January 22, 1998), WO 99/35146 (published July 15, 1999), WO 99/35132 (published July 15, 1999), WO 98/02437 (published January 22, 1998), WO 97/13760 (published April 17, 1997), WO 95/19970 (published July 27, 1995), United States Patent 5,587,458 (issued December 24, 1996), and United States Patent 5,877,305 (issued March 2, 1999), each of which is herein incorporated by reference in its entirety. ErbB2 receptor inhibitors useful in the present invention are also described in United States Patent Nos. 6,465,449, and 6,284,764, and International Application No. WO 2001/98277 each of which are herein incorporated by reference in their entirety.
Additionally, other anti-tumor agents may be selected from the following agents, BAY-43-9006 (Onyx Pharmaceuticals Inc.), Genasense (augmerosen, Genta), Panitumumab (Abgenix/Amgen), Zevalin (Schering), Bexxar (Corixa/GlaxoSmithKline), Abarelix, Alimta, EPO 906 (Novartis), discodermolide (XAA-296), ABT-510 (Abbott), Neovastat (Aeterna), enzastaurin (EIi Lilly), Combrestatin A4P (Oxigene), ZD-6126 (AstraZeneca), flavopiridol (Aventis), CYC-202 (Cyclacel), AVE-8062 (Aventis), DMXAA (Roche/Antisoma), Thymitaq (Eximias), Temodar (temozolomide, Schering Plough) and Revilimd (Celegene) and combinations thereof.
Other anti-tumor agents may be selected from the following agents, CyPat (cyproterone acetate), Histerelin (histrelin acetate), Plenaixis (abarelix depot), Atrasentan (ABT-627), Satraplatin (JM-216), thalomid (Thalidomide), Theratope, Temilifene (DPPE), ABI-007 (paclitaxel), Evista (raloxifene), Atamestane (Biomed-777), Xyotax (polyglutamate paclitaxel), Targetin (bexarotine) and combinations thereof.
Additionally, other anti-tumor agents may be selected from the following agents, Trizaone (tirapazamine), Aposyn (exisulind), Nevastat (AE-941), Ceplene (histamine dihydrochloride), Orathecin (rubitecan), Virulizin, Gastrimmune (G17DT), DX-8951f (exatecan mesylate), Onconase (ranpimase), BEC2 (mitumoab), Xcytrin (motexafin gadolinium) and combinations thereof.
Further anti-tumor agents may selected from the following agents, CeaVac (CEA), NeuTrexin (trimetresate glucuronate) and combinations thereof.
Additional anti-tumor agents may selected from the following agents, OvaRex (oregovomab), Osidem (IDM-1), and combinations thereof. Additional anti-tumor agents may selected from the following agents, Advexin (ING 201), Tirazone (tirapazamine), and combinations thereof.
Additional anti-tumor agents may selected from the following agents, RSR13 (efaproxiral), Cotara (1311 chTNT 1/b), NBI-3001 (IL-4) and combinations thereof.
Additional anti-tumor agents may selected from the following agents, Canvaxin, GMK vaccine, PEG lnteron A, Taxoprexin (DHA/paciltaxel) and combinations thereof.
Other preferred anti-tumor agents include Pfizer's MEK1/2 inhibitor PD325901, Array Biopharm's MEK inhibitor ARRY-142886, Bristol Myers' CDK2 inhibitor BMS- 387,032, Pfizer's CDK inhibitor PD0332991 and AstraZeneca's AXD-5438 and combinations thereof.
Additionally, mTOR inhibitors may also be utilized such as CCI-779 (Wyeth) and rapamycin derivatives RAD001 (Novartis) and AP-23573 (Ariad), HDAC inhibitors SAHA (Merck Inc./Aton Pharmaceuticals) and combinations thereof.
Additional anti-tumor agents include aurora 2 inhibitor VX-680 (Vertex), Chk1/2 inhibitor XL844 (Exilixis).
The following cytotoxic agents, , e.g., one or more selected from the group consisting of epirubicin (Ellence), docetaxel (Taxotere), paclitaxel, Zinecard (dexrazoxane), rituximab (Rituxan) imatinib mesylate (Gleevec), and combinations thereof, may be used in conjunction with a compound of Formula I and pharmaceutical compositions described herein.
The invention also contemplates the use of the compounds of the present invention together with hormonal therapy, including but not limited to, exemestane (Aromasin, Pfizer Inc.), leuprorelin (Lupron or Leuplin, TAP/Abbott/Takeda), anastrozole (Arimidex, Astrazeneca), gosrelin (Zoladex, AstraZeneca), doxercalciferol, fadrozole, formestane, tamoxifen citrate (tamoxifen, Nolvadex, AstraZeneca), Casodex (AstraZeneca), Abarelix (Praecis), Trelstar, and combinations thereof.
The invention also relates to hormonal therapy agents such as anti-estrogens including, but not limited to fulvestrant, toremifene, raloxifene, lasofoxifene, letrozole (Femara, Novartis), anti-androgens such as bicalutamide, flutamide, mifepristone, nilutamide, Casodex®(4'-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3'-
(trifluoromethyl) propionanilide, bicalutamide) and combinations thereof.
Further, the invention provides a compound of the present invention alone or in combination with one or more supportive care products, e.g., a product selected from the group consisting of Filgrastim (Neupogen), ondansetron (Zofran), Fragmin, Procrit, Aloxi, Emend, or combinations thereof. Particularly preferred cytotoxic agents include Camptosar, Erbitux, Iressa, Gleevec, Taxotere and combinations thereof.
The following topoisomerase I inhibitors may be utilized as anti-tumor agents camptothecin, irinotecan HCI (Camptosar), edotecarin, orathecin (Supergen), exatecan (Daiichi), BN-80915 (Roche) and combinations thereof. Particularly preferred toposimerase Il inhibitors include epirubicin (Ellence).
The compounds of the invention may be used with antitumor agents, alkylating agents, antimetabolites, antibiotics, plant-derived antitumor agents, camptothecin derivatives, tyrosine kinase inhibitors, antibodies, interferons, and/or biological response modifiers.
Alkylating agents include, but are not limited to, nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, mitobronitol, carboquone, thiotepa, ranimustine, nimustine, temozolomide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, carmustine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, mafosfamide, and mitolactol; platinum-coordinated alkylating compounds include but are not limited to, cisplatin, Paraplatin (carboplatin), eptaplatin, lobaplatin, nedaplatin, Eloxatin (oxaliplatin, Sanofi) or satrplatin and combinations thereof.
Particularly preferred alkylating agents include Eloxatin (oxaliplatin).
Antimetabolites include but are not limited to, methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil (5-FU) alone or in combination with leucovorin, tegafur, UFT, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-1, Alimta (premetrexed disodium, LY231514, MTA), Gemzar (gemcitabine, EIi Lilly), fludarabin, 5-azacitidine, capecitabine, cladribine, clofarabine, decitabine, eflornithine, ethynylcytidine, cytosine arabinoside, hydroxyurea, TS-1, melphalan, nelarabine, nolatrexed, ocfosfate, disodium premetrexed, pentostatin, pelitrexol, raltitrexed, triapine, trimetrexate, vidarabine, vincristine, vinorelbine; or for example, one of the preferred antimetabolites disclosed in European Patent Application No. 239362 such as N-(5-[N-(3,4- dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamic acid and combinations thereof.
Antibiotics include intercalating antibiotics but are not limited to: aclarubicin, actinomycin D, amrubicin, annamycin, adriamycin, bleomycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, galarubicin, idarubicin, mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin, valrubicin, zinostatin and combinations thereof. Plant derived anti-tumor substances include for example those selected from mitotic inhibitors, for example vinblastine, docetaxel (Taxotere), paclitaxel and combinations thereof.
Cytotoxic topoisomerase inhibiting agents include one or more agents selected from the group consisting of aclarubicn, amonafide, belotecan, camptothecin, 10- hydroxycamptothecin, 9-aminocamptothecin, diflomotecan, irinotecan HCI (Camptosar), edotecarin, epirubicin (Ellence), etoposide, exatecan, gimatecan, lurtotecan, mitoxantrone, pirarubicin, pixantrone, rubitecan, < sobuzoxane, SN-38, tafluposide, topotecan, and combinations thereof.
Preferred cytotoxic topoisomerase inhibiting agents include one or more agents selected from the group consisting of camptothecin, 10-hydroxycamptothecin, 9- aminocamptothecin, irinotecan HCI (Camptosar), edotecarin, epirubicin (Ellence), etoposide, SN-38, topotecan, and combinations thereof.
Immunologicals include interferons and numerous other immune enhancing agents. Interferons include interferon alpha, interferon alpha-2a, interferon, alpha-2b, interferon beta, interferon gamma-1a, interferon gamma-1b (Actimmune), or interferon gamma-n1 and combinations thereof. Other agents include filgrastim, lentinan, sizofilan, TheraCys, ubenimex, WF-10, aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab, denileukin, gemtuzumab ozogamicin, ibritumomab, imiquimod, lenograstim, lentinan, melanoma vaccine (Corixa), molgramostim, OncoVAX-CL, sargramostim, tasonermin, tecleukin, thymalasin, tositumomab, Virulizin, Z-100, epratuzumab, mitumomab, oregovomab, pemtumomab (Y-muHMFG1), Provenge (Dendreon) and combinations thereof.
Biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth, or differentiation of tissue cells to direct them to have anti-tumor activity. Such agents include krestin, lentinan, sizofiran, picibanil, ubenimex and combinations thereof.
Other anticancer agents include alitretinoin, ampligen, atrasentan bexarotene, bortezomib. Bosentan, calcitriol, exisulind, finasteride.fotemustine, ibandronic acid, miltefosine, mitoxantrone, l-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pegaspargase, pentostatin, tazarotne, Telcyta (TLK-286, Telik Inc.), Velcade (bortemazib, Millenium), tretinoin, and combinations thereof.
Other anti-angiogenic compounds include acitretin, fenretinide, thalidomide, zoledronic acid, angiostatin, aplidine, cilengtide, combretastatin A-4, endostatin, halofuginone, rebimastat, removab, Revlimid, squalamine, ukrain, Vitaxin and combinations thereof. Platinum-coordinated compounds include but are not limited to, cisplatin, carboplatin, nedaplatin, oxaliplatin, and combinations thereof.
Camptothecin derivatives include but are not limited to camptothecin, 10- hydroxycamptothecin, 9-aminocamptothecin, irinotecan, SN-38, edotecarin, topotecan and combinations thereof.
Other antitumor agents include mitoxantrone, l-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pentostatin, tretinoin and combinations thereof. Anti-tumor agents capable of enhancing antitumor immune responses, such as CTLA4 (cytotoxic lymphocyte antigen 4) antibodies, and other agents capable of blocking CTLA4 may also be utilized, such as MDX-010 (Medarex) and CTLA4 compounds disclosed in United States Patent No. 6,682,736; and anti-proliferative agents such as other famesyl protein transferase inhibitors, for example the famesyl protein transferase inhibitors. Additional, specific CTLA4 antibodies that can be used in the present invention include those described in United States Provisional Application 60/113,647 (filed December 23, 1998), United States Patent No. 6, 682,736 both of which are herein incorporated by reference in their entirety.
Specific IGF1 R antibodies that can be used in the present invention include those described in International Patent Application No. WO 2002/053596, which is herein incorporated by reference in its entirety.
Specific CD40 antibodies that can be used in the present invention include those described in International Patent Application No. WO 2003/040170 which is herein incorporated by reference in its entirety.
Gene therapy agents may also be employed as anti-tumor agents such as TNFerade (GeneVec), which express TNFalpha in response to radiotherapy. In one embodiment of the present invention statins may be used in conjunction with a compound of Formula I and pharmaceutical compositions. Statins (HMG-CoA reducatase inhibitors) may be selected from the group consisting of Atorvastatin (Lipitor, Pfizer Inc.), Pravastatin (Pravachol, Bristol-Myers Squibb), Lovastatin (Mevacor, Merck Inc.), Simvastatin (Zocor, Merck Inc.), Fluvastatin (Lescol, Novartis), Cerivastatin (Baycol, Bayer), Rosuvastatin (Crestor, AstraZeneca), Lovostatin and Niacin (Advicor, Kos Pharmaceuticals), derivatives and combinations thereof.
In a preferred embodiment the statin is selected from the group consisting of Atovorstatin and Lovastatin, derivatives and combinations thereof.
Other agents useful as anti-tumor agents include Caduet. Definitions
Unless otherwise stated, the following terms used in the specification and claims have the meanings discussed below. Variables defined in this section, such as R, X, n and the like, are for reference within this section only, and are not meant to have the save meaning as may be used outside of this definitions section. Further, many of the groups defined herein can be optionally substituted. The listing in this definitions section of typical substituents is exemplary and is not intended to limit the substituents defined elsewhere within this specification and claims.
"Alkyl" refers to a saturated aliphatic hydrocarbon radical including straight chain and branched chain groups of 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms. "Lower alkyl" refers specifically to an alkyl group with 1 to 4 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, 2-propyl, cyclopropyl, n-butyl, /so-butyl, tert- butyl, pentyl and the like. Alkyl may be substituted or unsubstituted. Typical substituent groups include nonaromatic carbocyclyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N- carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, nitro, silyl, amino and -NRxRy, where Rx and Ry are independently selected from the group consisting of hydrogen, alkyl, nonaromatic carbocyclyl, aryl, carbonyl, acetyl, sulfonyl, trifluoromethanesulfonyl and, combined, a five- or six-member heterocyclyl ring.
"Cycloalkyl" refers to a cyclic saturated hydrocarbon radical having from 3 to 20 carbon atoms. A cycloalkyl group may be monocyclic and where permissible may be bicyclic or polycyclic. A cycloalkyl group may be optionally substituted by at least one substituent. Suitable substituents on a cycloalkyl group are the same as those described for an alkyl group. Examples of cycloalkyl groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, nobornyl, adamantyl, and the like, including substitutued forms thereof.
"Nonaromatic carbocyclyl" refers to a 3 to 8 member all-carbon monocyclic ring group, all-carbon bicyclic or multicyclic ring system group wherein one or more of the rings may contain one or more double bonds but none of the rings has a completely conjugated pi-electron system. Examples, without limitation, of nonaromatic carbocyclyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexadienyl, adamantanyl, cycloheptyl, cycloheptatrienyl, and the like. A nonaromatic carbocyclyl may be substituted or unsubstituted. Typical substituent groups include alkyl, aryl, heteroaryl, heteroalycyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, O-carbamyl, N-carbamyl, C-amido, N- amido, nitro, amino and -NRxRy, with Rx and Ry as defined above. Illustrative examples of nonaromatic carbocyclyl are derived from, but not limited to, the following:
Figure imgf000035_0001
"Unsaturated nonaromatic carbocyclyl" refers to a nonaromatic carbocyclyl, as defined herein, that contains at least one carbon carbon double bond, one carbon carbon trible bond or a benzene ring.
"Alkenyl" refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon double bond, but contains no benzene ring. Representative examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, cyclopentenyl and the like.
"Cycloalkenyl" refers to a cycloalkyl group, as defined herein, consisting of at least one carbon-carbon double bond. Representative examples include, but are not limited to, 1-cyclopentyl, cyclohexenyl.
"Alkynyl" refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon triple bond. Representative examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like.
"Aryl" refers to an all-carbon monocyclic or fused-ring polycyclic groups of 6 to 12 carbon atoms having a completely conjugated pi-electron system. Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. The aryl group may be substituted or unsubstituted. Typical substituents include halo, trihalomethyl, alkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C- amido, N-amido, sulfinyl, sulfonyl, amino and -NRxRy, with Rx and Ry as defined above.
"Heteroaryl" refers to a monocyclic or fused ring group of 5 to 12 ring atoms containing one, two, three or four ring heteroatoms selected from N, O, and S, the remaining ring atoms being C, and, in addition, having a completely conjugated pi- electron system. Examples, without limitation, of unsubstituted heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, purine, tetrazole, triazine, and carbazole. The heteroaryl group may be substituted or unsubstituted. Typical substituents include alkyl, nonaromatic carbocyclyl, halo, trihalomethyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, sulfonamido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, amino and -NRxRy with Rx and Ry as defined above.
A pharmaceutically acceptable heteroaryl is one that is sufficiently stable to be attached to a compound of the invention, formulated into a pharmaceutical composition and subsequently administered to a patient in need thereof.
Examples of typical monocyclic heteroaryl groups include, but are not limited to:
H H H ,N.
O (!) ^-N pyrrole furan th Oiophene pyrazole imidazole (pyrrolyl) (furanyl) (thiophenyl) (pyrazolyl) (imidazolyl)
Figure imgf000036_0001
iso Cxazrole oxazole iso Othiaz1ole th Oiazolyl 1 ,2,3-triazole (isoxazolyl) (oxazolyl) (isothiazolyl) (thiazolyl) (1 ,2,3-triazolyl)
H
ON ON
\\ ff < NAN N-N i: N
N
1 ,3,4-triazole 1-oxa-2,3-diazole 1-oxa-2,4-diazole 1-0X3-2, 5-diazole (1 ,3,4-triazolyl) (1-oxa-2,3-diazolyl) (1-oxa-2,4-diazolyl) (1-oxa-2,5-diazolyl)
N'%
N-N
1-oxa-3,4-diazole hia C-2y \\ //
N
1 -t ,3-diazole 1 -thia-2,4-diazole 1-thia-2,5-diazole (1-oxa-3,4-diazolyl) ( 1 -thia-2, 3-diazolyl) ( 1 -thia-2,4-diazolyl) (1-thia-2,5-diazolyl)
Figure imgf000037_0001
ι
1-th -3,4-diazole tetrazole py U ι ridine py UΛN pyrimidine
(1-thia-3,4-diazolyl) (tetrazolyl) (pyridinyl) (pyridazinyl) (pyrimidinyl)
Figure imgf000037_0002
pyrazine 1 ,3,5-triazine (pyrazinyl) triazinyl
Examples of suitable bicyclic heteroaryl groups include, but are not limited to:
Figure imgf000037_0003
Figure imgf000037_0004
benzofuran benzothiophene
Figure imgf000037_0005
benzimidazole indazole (benzofuranyl) (benzothiophenyl) (indolyl) (benzimidazolyl) (indazolyl)
Figure imgf000037_0006
benzotriazole pyrrolo[2,3-b]pyridine pyrrolo[2,3-c]pyridine pyrrolo[3,2-c]pyridine (benzotriazolyl) (pyrrolo[2,3-b]pyridinyl) (pyrrolo[2,3-c]pyridinyl) (pyrrolo[3,2-c]pyridinyl)
Figure imgf000037_0007
pyrrolo[3,2-b]pyridine imidazo[4,5-b]pyridine imidazo[4,5-c]pyridine pyrazolo[4,3-d]pyridine (pyrrolo[3,2-b]pyridinyl) (imidazo[4,5-b]pyridinyl) (imidazo[4,5-c]pyridinyl) (pyrazolo[4,3-d]pyidinyl)
Figure imgf000037_0008
pyrazolo[4,3-c]pyridine pyrazolo[3,4-c]pyridine pyrazolo[3,4-b]pyridine isoindole (pyrazolo[4,3-c]pyidinyl) (pyrazolo[3,4-c]pyidinyl) (pyrazolo[3,4-b]pyidinyl) (isoindolyl)
Figure imgf000038_0001
indazole purine indolizine imidazo[1 ,2-a]pyridine imidazo[1 ,5-a]pyridine (indazolyl) (purinyl) (indolininyl) (imidazo[1 ,2-a]pyridinyl) (imidazo[1 ,5-a]pyridinyl)
Figure imgf000038_0002
pyrazolo[1 ,5-a]pyridine pyrrolo[1 ,2-b]pyridazine imidazo[1 ,2-c]pyrimidine (pyrazolo[1 ,5-a]pyridinyl) (pyrrolo[1-2,b]pyridazinyl) (imidazoti ,2-c]pyrimidinyl)
Figure imgf000038_0003
quinoline isoquinoline cinnoline quinazoline (quinolinyl) (isoquinolinyl) (cinnolinyl) (azaquinazoline)
Figure imgf000038_0004
quinoxaline phthalazine 1 ,6-naphthyridine 1 ,7-naphthyridine (quinoxalinyl) (phthalazinyl) (1 ,6-naphthyridinyl) (1 ,7-naphthyridinyl)
Figure imgf000038_0005
1 ,8-naphthyridine 1 ,5-naphthyridine 2,6 C-naphthyridine 2, -naphthyridine (1 ,8-naphthyridinyl) (1 ,5-naphthyridinyl) (2,6-naphthyridinyl) (2,7-naphthyridinyl)
Figure imgf000038_0006
pyrido[3,2-d]pyrimidine pyrido[4,3-d]pyrimidine pyrido[3,4-d]pyrimidine (pyrido[3,2-d]pyrimidinyl) (pyrido[4,3-d]pyrimidinyl) (pyrido[3,4-d]pyrimidiny!)
Figure imgf000038_0007
pyrido[2,3-d]pyrimidine pyrido[2,3-b]pyrazine pyrido[3,4-b]pyrazine (pyrido[2,3-d]pyrimidinyl) (pyrido[2,3-b]pyrazinyl) (pyrido[3,4-b]pyrazinyl)
Figure imgf000039_0001
pyrimido[5,4-d]pyrimidine pyrazino[2,3-b]pyrazine pyrimido[4,5-d]pyrimidine (pyrimido[5,4-d]pyrimidinyl) (pyrazino[2,3-b]pyrazinyl) (pyrimido^.S-dlpyrimidinyl)
"Heterocyclyl" refers to a monocyclic or bicyclic ring group having in the ring(s) of 3 to 12 ring atoms, in which one or two ring atoms are heteroatoms selected from N, O, and S(O)n (where n is O, 1 or 2), the remaining ring atoms being C. The rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system. Examples of suitable saturated heterocyclyl groups include, but are not limited to:
Figure imgf000039_0002
oxirane thiarane aziridine oxetane thiatane azetidine tetrahydrofuran
(oxiranyl) (thiaranyl) (aziridinyl) (oxetanyl) (thiatanyl) (azetidinyl) (tetrahydrofuranyl)
(!) tetrahydrothiophene pyr όrolidine tetrahy Odropyran tetra Ohydrothiopyran (tetrahydrothiophenyl) (pyrrolidinyl) (tetrahydropyranyl) (tetrahydrothiopyranyl)
Figure imgf000039_0003
piperidine 1 ,4-dioxane 1 ,4-oxathiane morpholine 1 ,4-dithiane (piperidinyl) (1 ,4-dioxanyl) (1 ,4-oxathianyl) (morpholinyl) (1 ,4-dithianyl)
Figure imgf000039_0004
piperazine 1 ,4-azathiane oxepane thiepane azepane (piperazinyl) (1 ,4-azathianyl) (oxepanyl) (thiepanyl) (azepanyl)
Figure imgf000039_0005
1 ,4-dioxepane 1 ,4-oxathiepane 1 ,4-oxaazepane 1 ,4-dithiepane (1 ,4-dioxepanyl) (1 ,4-oxathiepanyl) (1 ,4-oxaazepanyl) (1 ,4-dithiepanyl)
Figure imgf000040_0001
1 ,4-thieazepane 1 ,4-diazepaπe tropane
(1 ,4-thieazepanyl) (1 ,4-diazepanyl) (tropanyl)
Examples of suitable partially unsaturated heterocyclyl groups include, but are not limited to:
Figure imgf000040_0002
3,4-dihydro-2H-pyran 5,6-dihydro-2H-pyran 2H-pyran
(3,4-dihydro-2H-pyranyl) (5,6-dihydro-2H-pyranyl) (2H-pyranyl)
Figure imgf000040_0003
1 ,2,3,4-tetrahydropyridine 1 ,2,5,6-tetrahydropyridine
(1 ,2,3,4-tetrahydropyridinyl) (1 ,2,5,6-tetrahydropyridinyl)
The heterocyclyl group is optionally substituted with one or two substituents independently selected from halo, lower alkyl, lower alkyl substituted with carboxy, ester hydroxy, or mono or dialkylamino.
When "ene" is added after "yl" at the end a term to form a new term, the new term refers to a diradical formed by removing one hydrogen atom from the original term of which the new term derived from. For example, an alkylene refers to a diradical group formed by removing one hydrogen atom from an alkyl group and that a "methylene" refers to a divalent radical -CH2- derived from removing one hydrogen atom from methyl. More examples of such diradicals include, but are not limited to: alkenylene, alkynylene, cycloalkylene, phenylene, heterocyclylene, heteroarylene and (nonaromatic unsaturated carbocyclylene), which are derived from alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclyl, heteroaryl and (nonaromatic unsaturated carbocyclyl), respectively.
"Hydroxy" refers to an -OH group.
"Alkoxy" refers to both an -O-(alkyl) or an -O-(nonaromatic carbocyclyl) group. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
"Haloalkoxy" refers to an -O-(haloalkyl) group. Representative examples include, but are not limited to, trifluoromethoxy, tribromomethoxy, and the like. "Aryloxy" refers to an -O-aryl or an -O-heteroaryl group, as defined herein. Representative examples include, but are not limited to, phenoxy, pyridinyloxy, furanyloxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, and the like, and derivatives thereof.
"Mercapto" refers to an -SH group.
"Alkylthio" refers to an -S-(alkyl) or an -S-(nonaromatic carbocyclyl) group. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like.
"Arylthio" refers to an -S-aryl or an -S-heteroaryl group, as defined herein. Representative examples include, but are not limited to, phenylthio, pyridinylthio, furanylthio, thienylthio, pyrimidinylthio, and the like and derivatives thereof.
"Acyl" or "carbonyl" refers to a -C(O)R" group, where R" is selected from the group consisting of hydrogen, lower alkyl, trihalomethyl, nonaromatic carbocyclyl, aryl optionally substituted with one or more, preferably one, two, or three substituents selected from the group consisting of lower alkyl, trihalomethyl, lower alkoxy, halo and - NRxRy groups, heteroaryl (bonded through a ring carbon) optionally substituted with one or more, preferably one, two, or three substitutents selected from the group consisting of lower alkyl, trihaloalkyl, lower alkoxy, halo and -NRxRy groups and heterocyclic (bonded through a ring carbon) optionally substituted with one or more, preferably one, two, or three substituents selected from the group consisting of lower alkyl, trihaloalkyl, lower alkoxy, halo and -NRxRy groups. Representative acyl groups include, but are not limited to, acetyl, trifluoroacetyl, benzoyl, and the like.
"Aldehyde" refers to an acyl group in which R" is hydrogen.
"Thioacyl" or "thiocarbonyl" refers to a -C(S)R" group, with R" as defined above.
A "thiocarbonyl" group refers to a -C(S)R" group, with R" as defined above.
A "C-carboxy" group refers to a -C(O)OR" group, with R" as defined above.
An "O-carboxy" group refers to a -OC(O)R" group, with R" as defined above.
"Ester" refers to a -C(O)OR" group with R" as defined herein except that R" cannot be hydrogen.
"Acetyl" group refers to a -C(O)CH3 group.
"Halo" group refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
"Trihalomethyl" group refers to a methyl group having three halo substituents, such as a trifluoromethyl group.
"Cyano" refers to a -C≡N group.
A "sulfinyl" group refers to a -S(O)R" group wherein, in addition to being as defined above, R" may also be a hydroxy group. A "sulfonyl" group refers to a -S(O)2R" group wherein, in addition to being as defined above, R" may also be a hydroxy group.
"S-sulfonamido" refers to a -S(O)2NRxRy group, with Rx and Ry as defined above.
"N-sulfonamido" refers to a -NRxS(O)2Ry group, with Rx and Ry as defined above.
"O-carbamyl" group refers to a -OC(O)NRxRy group with Rx and Ry as defined above.
"N-carbamyl" refers to an RyOC(O)NRx- group, with Rx and Ry as defined above.
"O-thiocarbamyl" refers to a -OC(S)NRxRy group with Rx and Ry as defined above.
"N-thiocarbamyl" refers to a RyOC(S)NRx- group, with Ry and Rx as defined above.
"Amino" refers to an -NRxRy group, wherein Rx and Ry are both hydrogen.
"C-amido" refers to a -C(O)NRxRy group with Rx and Ry as defined above.
"N-amido" refers to a RxC(O)NRy- group, with Rx and Ry as defined above.
"Nitro" refers to a -NO2 group.
"Haloalkyl" means an alkyl, preferably lower alkyl, that is substituted with one or more same or different halo atoms, e.g., -CH2CI, -CF3, -CH2CF3, -CH2CCI3, and the like.
"Hydroxyalkyl" means an alkyl, preferably lower alkyl, that is substituted with one, two, or three hydroxy groups; e.g., hydroxymethyl, 1 or 2-hydroxyethyl, 1 ,2-, 1 ,3-, or 2,3- dihydroxypropyl, and the like.
"Aralkyl" means alkyl, preferably lower alkyl, that is substituted with an aryl group as defined above; e.g., -CH2phenyl, -(CH2)2phenyl, -(CH2)3phenyl, CH3CH(CH3)CH2phenyl,and the like and derivatives thereof.
"Heteroaralkyl" group means alkyl, preferably lower alkyl, that is substituted with a heteroaryl group; e.g., -CH2pyridinyl, -(CH2)2pyrimidinyl, -(CH2)3imidazolyl, and the like, and derivatives thereof.
"Monoalkylamino" means a radical -NHR where R is an alkyl or unsubstituted nonaromatic carbocyclyl group; e.g., methylamino, (i-methylethyl)amino, cyclohexylamino, and the like.
"Dialkylamino" means a radical -NRR where each R is independently an alkyl or unsubstituted nonaromatic carbocyclyl group; dimethylamino, diethylamino, (i-methylethyl)-ethylamino, cyclohexylmethylamino, cyclopentylmethylamino, and the like.
"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "heterocyclyl group optionally substituted with an alkyl group" means that the alkyl may but need not be present, and the description includes situations where the heterocyclyl group is substituted with an alkyl group and situations where the heterocyclyl group is not substituted with the alkyl group.
"Perfluoroalkyl" refers to an alkyl group in which all of its hydrogen atoms are replaced by fluorine atoms.
A "pharmaceutical composition" refers to a mixture of one or more of the compounds described herein, or physiologically/pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof, with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
As used herein, a "physiologically/pharmaceutically acceptable carrier" refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
A "pharmaceutically acceptable excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
As used herein, the term "pharmaceutically acceptable salt" refers to those salts which retain the biological effectiveness and properties of the parent compound. Such salts include:
(1) acid addition salts, which can be obtained by reaction of the free base of the parent compound with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, and perchloric acid and the like, or with organic acids such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid or malonic acid and the like; or
(2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
"PK" refers to receptor protein tyrosine kinase (RTKs), non-receptor or "cellular" tyrosine kinase (CTKs) and serine-threonine kinases (STKs).
"Modulation" or "modulating" refers to the alteration of the catalytic activity of RTKs, CTKs and STKs. In particular, modulating refers to the activation of the catalytic activity of RTKs, CTKs and STKs, preferably the activation or inhibition of the catalytic activity of RTKs, CTKs and STKs, depending on the concentration of the compound or salt to which the RTK, CTK or STK is exposed or, more preferably, the inhibition of the catalytic activity of RTKs, CTKs and STKs.
"Catalytic activity" refers to the rate of phosphorylation of tyrosine under the influence, direct or indirect, of RTKs and/or CTKs or the phosphorylation of serine and threonine under the influence, direct or indirect, of STKs.
"Contacting" refers to bringing a compound of this invention and a target PK together in such a manner that the compound can affect the catalytic activity of the PK, either directly, i.e., by interacting with the kinase itself, or indirectly, i.e., by interacting with another molecule on which the catalytic activity of the kinase is dependent. Such "contacting" can be accomplished "in vitro," i.e., in a test tube, a petri dish or the like. In a test tube, contacting may involve only a compound and a PK of interest or it may involve whole cells. Cells may also be maintained or grown in cell culture dishes and contacted with a compound in that environment. In this context, the ability of a particular compound to affect a PK related disorder, i.e., the IC50 of the compound, defined below, can be determined before use of the compounds in vivo with more complex living organisms is attempted. For cells outside the organism, multiple methods exist, and are well-known to those skilled in the art, to get the PKs in contact with the compounds including, but not limited to, direct cell microinjection and numerous transmembrane carrier techniques.
"In vitro" refers to procedures performed in an artificial environment such as, e.g., without limitation, in a test tube or culture medium.
"In vivo" refers to procedures performed within a living organism such as, without limitation, a mouse, rat or rabbit.
"PK related disorder," "PK driven disorder," and "abnormal PK activity" al! refer to a condition characterized by inappropriate, i.e., under or, more commonly, over, PK catalytic activity, where the particular PK can be an RTK, a CTK or an STK. Inappropriate catalytic activity can arise as the result of either: (1) PK expression in cells which normally do not express PKs, (2) increased PK expression leading to unwanted cell proliferation, differentiation and/or growth, or, (3) decreased PK expression leading to unwanted reductions in cell proliferation, differentiation and/or growth. Over-activity of a PK refers to either amplification of the gene encoding a particular PK or production of a level of PK activity which can correlate with a cell proliferation, differentiation and/or growth disorder (that is, as the level of the PK increases, the severity of one or more of the symptoms of the cellular disorder increases). Under-activity is, of course, the converse, wherein the severity of one or more symptoms of a cellular disorder increase as the level of the PK activity decreases.
"Treat", "treating" and "treatment" refer to a method of alleviating or abrogating a PK mediated cellular disorder and/or its attendant symptoms. With regard particularly to cancer, these terms simply mean that the life expectancy of an individual affected with a cancer will be increased or that one or more of the symptoms of the disease will be reduced.
"Organism" refers to any living entity comprised of at least one cell. A living organism can be as simple as, for example, a single eukariotic cell or as complex as a mammal, including a human being.
"Therapeutically effective amount" refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated. In reference to the treatment of cancer, a therapeutically effective amount refers to that amount which has at least one of the following effects:
(1 ) reducing the size of the tumor;
(2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis;
(3) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth, and
(4) relieving to some extent (or, preferably, eliminating) one or more symptoms associated with the cancer.
"Monitoring" means observing or detecting the effect of contacting a compound with a cell expressing a particular PK. The observed or detected effect can be a change in cell phenotype, in the catalytic activity of a PK or a change in the interaction of a PK with a natural binding partner. Techniques for observing or detecting such effects are well-known in the art. The effect is selected from a change or an absence of change in a cell phenotype, a change or absence of change in the catalytic activity of said protein kinase or a change or absence of change in the interaction of said protein kinase with a natural binding partner in a final aspect of this invention.
"Cell phenotype" refers to the outward appearance of a cell or tissue or the biological function of the cell or tissue. Examples, without limitation, of a cell phenotype are cell size, cell growth, cell proliferation, cell differentiation, cell survival, apoptosis, and nutrient uptake and use. Such phenotypic characteristics are measurable by techniques well-known in the art.
"Natural binding partner" refers to a polypeptide that binds to a particular PK in a cell. Natural binding partners can play a role in propagating a signal in a PK-mediated signal transduction process. A change in the interaction of the natural binding partner with the PK can manifest itself as an increased or decreased concentration of the PK/natural binding partner complex and, as a result, in an observable change in the ability of the PK to mediate signal transduction.
Detailed Description
The compounds of formula I-V can be made following the synthetic routes in Scheme 1 and Scheme 2. In Scheme 1 and Scheme 2 and the descriptions following, "BOC" , "Boc" or "boc" means N-ferf-butoxycarbonyl, DCM means CH2CI2, DIPEA means diisopropyl ethyl amine, DMA means dimethyl amine, "DMF" means dimethyl formamide, "DMSO" means dimethylsulfoxide, Et means -CH2CH3, Me means -CH3, "MTBE" means methyl t-butyl ether, NMP means 1 -methyl 2-pyrrolidinone, TEA means triethyl amine, TFA means trifluoro acetic acid, THF means tetrahydro furan.
Scheme 1
Figure imgf000046_0002
Figure imgf000046_0001
Figure imgf000046_0003
Scheme 1 illustrates the synthesis of the compound of formula I. The dicholo heteroaryl compound A reacts with a first nucleophilic moiety, the amino pyrazole compound B, to give the mono chloro heteroaryl amino pyrazole compound C. This transformation can be carried out through an alkylation reaction in the presence of a base. A typical reaction condition is to disolve A and B in DMA, followed by addition of 2 equivalents of TEA and subsequent heating the reaction mixture to 120 "C overnight. Subsequent aqueous workup and purification affords compound C. The mono chloro heteroaryl amino pyrazole compound C then reacts with a second nucleophilic moiety, compound D, to give compound of formula I. M is typically hydrogen, connected to a ring nitrogen atom of compound D. Alternatively, M can be a metal, such as Li, Cu, Pd, Mg, and any other metal that is used in the art to form organo metallic nucleophilic reagent, and M is connected to one of the ring atoms of compound D. The transformation from C and D to compound of formula 1 can be carried out through a nucleophilic attack of compound D on the heteroaryl chloride compound C, in the presence of a base, and quite frequently, in a dipolar aprotic solvent such as NMP, DMF, DMSO. A typical reaction condition of this transformation, wherein M is hydrogen and the hydrogen is connected to a nitrogen ring atom of compound D, is to dissolve compound C and D in NMP in the presence of 1.5 equivalent of TEA in a microwave reaction vessel followed by microwaving the reaction mixed in a Biotage Smith Synthesizer microwave reactor for 60 minutes at 200°C. Subsequent aqueous workup and purification affords compound of formula I.
Figure imgf000047_0001
A1
Figure imgf000047_0002
A2
Figure imgf000048_0001
A4 A5
Figure imgf000048_0002
While many compounds A are commercially available, some of them are not. Scheme 2 illustrates several methods to prepare compound A and some of its specific embodiments when compound A is not commercially available. Compound A can be prepared by treating compound A1 first with a hydroxyl activating agent in the presence of a base, and second with a chlorination agent. A typical reaction condition for this transformation is to reflux a mixture of compound A1 with large excess of POCI3 in the presence of DMA for 14 hours, removing excess POCI3, followed by treating the residue with large excess of chloroform. Subsequent aqueous workup and purification affords compound A. Compound A2 includes two tautermers, which can be transformed in to compound A3, a specific embodiment of compound A, following the same method used in transforming compound A1 into compound A. Compound A5, also a specific embodiment of compound A, can be prepared by mono alkylation of the trichloride compound A4. A typical reaction condition to carry out the transformation from A4 to A5 is to mix the trichloride compound A4 with catalytic amount of Pd(PPh3)4 in anhydrous THF, flush the mixture with N2 under vacuum, followed by addition of a R6 zinc bromide THF solution, and the reaction mixture is allowed to stir at 50°C for 2 hours. Subsequent aqueous workup and purification affords compound A5. The dichloro pyrimidine compound A8, a specific embodiment of compound A, can be prepared from the amine ester compound A6 by an annulations between compound A6 and urea to form the pyrimidine compound A7. Subsequent chlorination of compound A7 gives compound A8. A typical reaction condition of transformation from A6 to A7 is to mix compound A6 with urea and heat the neat mixture in oil bath to 200 "C for 3 hours, cooling the mixture to room temperature, then adding 2N aqueous NaOH to the mixture and allowing complete dissolution. Subsequent purification and neutralization of the solution affords compound A7. Compound A7 can be transformed to compound A8 following the same method indicated above of transforming compound A1 to compound A.
Scheme 3
Etc
Figure imgf000049_0001
Some substituted amino pyrazoles of compound B are commercially available. There are also commonly used synthetic routes to make commercially unavailable substituted aminopyrazoles. Scheme 3 illustrates one of the commonly used routes to make compound B. Substitued ester B1 reacts with substituted methyl cyanide B2 in the presence of a strong base and gives a 1-carbonyl-3-cyano moiety B3. A typical reaction condition of this transformation is to to use NaNH2 as the base and carry out the reaction in liquid ammonia under inert atmosphere at -78°C followed by warming up the reaction mixture to room temperature overnight. Reaction mixture is then quenched with water and acidified. Subsequent workup and purification gives compound B3. B3 is then reacted with hydrazine to give compound B. Typical reaction condition for this transformation is to reflux compound B3 and hydrazine in EtOH for 24 hours. Subsequent purification gives compound B.
Unless indicated otherwise, all references herein to the inventive compounds include references to salts, solvates, hydrates and complexes thereof, and to solvates, hydrates and complexes of salts thereof, including polymorphs, stereoisomers, and isotopically labeled versions thereof.
Pharmaceutically acceptable salts include acid addition and base salts (including disalts).
Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts.
Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
For a review on suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002), the disclosure of which is incorporated herein by reference in its entirety.
A pharmaceutically acceptable salt of the inventive compounds can be readily prepared by mixing together solutions of the compound and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized.
The compounds of the invention may exist in both unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when the solvent is water. Pharmaceutically acceptable solvates in accordance with the invention include hydrates and solvates wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, d6-acetone, d6-DMSO.
Also included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or non-ionized. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975), the disclosure of which is incorporated herein by reference in its entirety.
Also within the scope of the invention are polymorphs, prodrugs, and isomers (including optical, geometric and tautomeric isomers) of the inventive compounds
Derivatives of compounds of the invention which may have little or no pharmacological activity themselves but can, when administered to a patient, be converted into the inventive compounds, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may be found in 'Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and 'Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association), the disclosures of which are incorporated herein by reference in their entireties.
Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the inventive compounds with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in "Design of Prodrugs" by H Bundgaard (Elsevier, 1985), the disclosure of which is incorporated herein by reference in its entirety.
Some examples of prodrugs in accordance with the invention include:
(i) where the compound contains a carboxylic acid functionality (-COOH), an ester thereof, for example, replacement of the hydrogen with (CrC8)alkyl;
(ii) where the compound contains an alcohol functionality (-OH), an ether thereof, for example, replacement of the hydrogen with (CrC6)alkanoyloxymethyl; and
(iii) where the compound contains a primary or secondary amino functionality (- NH2 or -NHR where R ≠ H), an amide thereof, for example, replacement of one or both hydrogens with (CrC10)alkanoyl.
Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references.
Finally, certain inventive compounds may themselves act as prodrugs of other of the inventive compounds.
Compounds of the invention containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of the invention contains an alkenyl or alkenylene group, geometric cisltrans (or Z/E) isomers are possible. Where the compound contains, for example, a keto or oxime group or an aromatic moiety, tautomeric isomerism ('tautomerism') can occur. A single compound may exhibit more than one type of isomerism.
Included within the scope of the invention are all stereoisomers, geometric isomers and tautomeric forms of the inventive compounds, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counterion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine. Cisltrans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.
Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1- phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art.
Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.
Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art; see, for example, "Stereochemistry of Organic Compounds" by E L Eliel (Wiley, New York, 1994), the disclosure of which is incorporated herein by reference in its entirety.
The invention also includes isotopically-labeled compounds of the invention, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such as 123I and 125I, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32P, and sulfur, such as 35S. Certain isotopically-labeled compounds of the invention, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, 3H, and carbon-14, 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, 2H, may 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. Substitution with positron emitting isotopes, such as 11C, 18F, 15O and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. i Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, de- acetone, de-DMSO.
Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products, or mixtures thereof. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
The compounds can be administered alone or in combination with one or more other compounds of the invention, or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
Pharmaceutical compositions suitable for the delivery of compounds of the invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in 'Remington's Pharmaceutical Sciences', 19th Edition (Mack Publishing Company, 1995), the disclosure of which is incorporated herein by reference in its entirety. Oral Administration
The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid- filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films (including muco-adhesive), ovules, sprays and liquid formulations.
Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be used as fillers in soft or hard capsules and typically include a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
The compounds of the invention may also be used in fast-dissolving, fast- disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, H (6), 981-986 by Liang and Chen (2001), the disclosure of which is incorporated herein by reference in its entirety.
For tablet dosage forms, depending on dose, the drug may make up from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate. Generally, the disintegrant will comprise from 1 wt% to 25 wt%, preferably from 5 wt% to 20 wt% of the dosage form.
Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
Tablets may also optionally include surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents are typically in amounts of from 0.2 wt% to 5 wt% of the tablet, and glidants typically from 0.2 wt% to 1 wt% of the tablet.
Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally are present in amounts from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet. Other conventional ingredients include anti-oxidants, colorants, flavoring agents, preservatives and taste-masking agents.
Exemplary tablets contain up to about 80 wt% drug, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% lubricant.
Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting. The final formulation may include one or more layers and may be coated or uncoated; or encapsulated.
The formulation of tablets is discussed in detail in "Pharmaceutical Dosage Forms: Tablets, Vol. 1", by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0-8247-6918-X), the disclosure of which is incorporated herein by reference in its entirety.
Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained:-, pulsed-, controlled-, targeted and programmed release.
Suitable modified release formulations are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles can be found in Verma et a/, Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298. The disclosures of these references are incorporated herein by reference in their entireties. Parenteral Administration
The compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrastemal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile nonaqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water. The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
The solubility of compounds of the invention used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA microspheres. Topical Administration
The compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated; see, for example, J Pharm Sci, 88 (10), 955- 958 by Finnin and Morgan (October 1999). Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. Powderject™, Bioject™, ete.) injection. The disclosures of these references are incorporated herein by reference in their entireties.
Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Inhaled/lntranasal Administration
The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1 ,1,1,2-tetrafluoroethane or 1 ,1,1 ,2,3,3,3-heptafluoropropane. For intranasal use, the powder may include a bioadhesive agent, for example, chitosan or cyclodextrin.
The pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
Capsules (made, for example, from gelatin or HPMC), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and. a performance modifier such as /-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
A suitable solution formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from 1μg to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1μL to 100μL. A typical formulation includes a compound of the invention, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
Suitable flavors, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, poly(DL-lactic-coglycolic acid (PGLA). Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or "puff' containing a desired mount of the compound of the invention. The overall daily dose may be administered in a single dose or, more usually, as divided doses throughout the day. Rectal/1 ntravaqinal Administration
Compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Ocular Administration
Compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH- adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and nonbiodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.
Formulations for ocular/aural administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release. Other Technologies
Compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol- containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubilizer. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in PCT Publication Nos. WO 91/11172, WO 94/02518 and WO 98/55148, the disclosures of which are incorporated herein by reference in their entireties.
Dosage
The amount of the active compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is typically in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 0.01 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.07 to about 7000 mg/day, preferably about 0.7 to about 2500 mg/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be used without causing any harmful side effect, with such larger doses typically divided into several smaller doses for administration throughout the day. Kit-of-Parts
Inasmuch as it may desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound in accordance with the invention, may conveniently be combined in the form of a kit suitable for coadministration of the compositions. Thus the kit of the invention includes two or more separate pharmaceutical compositions, at least one of which contains a compound of the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
The kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically includes directions for administration and may be provided with a memory aid. Examples
In the following examples and preparations, "BOC", "Boc" or "boc" means H-tert- butoxycarbonyl, DCM means CH2CI2, DIPEA means diisopropyl ethyl amine, DMA means dimethyl amine, "DMF" means dimethyl formamide, "DMSO" means dimethylsulfoxide, "DPPP" means 1 ,3-bis(diphenylphosphino)propane, "MTBE" means methyl t-butyl ether, NMP means 1 -methyl 2-pyrrolidinone, TEA means triethyl amine, TFA means trifluoro acetic acid. Specific examples:
Example 1: fert-Butyl ((1R,5S)-3-{4-[(5-cyclopropyl-1tø-pyrazoI-3- yl)amino]thieno[3,2-d]pyrimidin-2-yl}-3-azabicyclo[3.1.0]hex-6-yl)carbamate.
Figure imgf000060_0001
1d
1e
Figure imgf000060_0002
Preparation of Compound 1b: thieno[3,2-ϋ]-pyrimidine-2,4-diol.
A mixture of methyl 3-amino-2-thiophenecarboxylate 1a (50 g, 318 mmol) and urea (57.3 g, 954 mmol) was ground and heated on an oil-bath at 200 °C for 3 h. The dark solid residue was allowed to cool to room temperature and then water (500 ml_) and 2N of aqueous sodium hydroxide solution (1.5 L) were added. After complete dissolution, 1O g of activated charcoal was added. The mixture was stirred for 1 h and filtered over Celite. The filtrate was neutralized with 2N aqueous hydrochloride solution. The precipitate was collected, dried in a high vacuum oven to give thieno[3,2-c/]-pyrimidine-2,4-diol 1b as a yellow solid (38.6 g, 72.3%). APCI MS: m/z 169; H-NMR (300 MHz, DMSO-c/6): δ 11.6 (s, 1 H), 11.2 (s, 1 H), 8.05 (d, J = 5.22 Hz, 1 H), 6.91 (d, J = 5.22 Hz, 1 H). Preparation of Compound 1c: 2,4-Dichloro-thieno[3,2-e/jpyrimidine. To a suspension of thieno[3,2-d]-pyrimidine-2,4-diol 1b (38.2 g, 227 mmol) in POCI3 (300 mL) was added dimethylaniline (8 mL). The mixture was refluxed for 14 h to give a homogenous solution. Excess of POCI3 was evaporated under vacuum. Chloroform (500 mL) was added to the oily residue and concentrated again. This process was repeated once. More chloroform (50 mL) was added and the suspension was slowly poured into ice-water (1.5 L) with vigorously stirring. After warming up to room temperature, the phases were separated. The precipitate in the aqueous phase was collected and dried to give a crude solid. The solid was dissolved in chloroform (500 mL) and insoluble impurities were removed by filtration. The filtrate was concentrated to give the title compound 1c as a yellow solid (34.7 g, 74.4%). Rf: 0.32 (9:1 hexanes/ethyl acetate); Mp: 130-132 0C; APCI MS: m/z 206; H-NMR (300 MHz, DMSO-cfe): δ 8.12 (d, J = 5.46 Hz, 1 H), 7.55 (d, J = 5.46 Hz, 1H).
Preparation of Compound 1e: a-Chloro-W-fS-cyclopropyl-IH-pyrazol-S-yOthienop^- c/]pyrimidin-4-amine.
3-Cyclopropylpyrazol-5-amine 1d (6.89 g, 55.95 mmol) was dissolved in DMA (56 mL). 2,4-Dichlorothieno[3,2-d]pyrimidine 1c (11.47g, 55.95 mmol) was added, followed by the addition of Et3N (11.70 mL, 83.93 mmol). The reaction was heated to 12O0C overnight, and the solvent removed under reduced pressure. The residue was taken up in water, and the resulting solids filtered and washed with water. The product was slurried' with Et2O overnight, filtered, and dried to give an off-white solid (13.15g, 81%) compound 1e. 1H NMR (400MHz, DMSOd6): δ 0.69-0.73 (m, 2H), 0.92-0.97 (m, 2H), 1.89-1.96 (m, 1 H), 6.23 (s, 1H), 7.34 (d, J = 5.3 Hz, 1 H), 8.20 (d, J = 5.3 Hz, 1 H), 10.48 (br, 1 H), 12.41 (br, 1H). LCMS 292 (M+H). Anal. Calcd. FOr C12H10N5SCI: C, 49.40; H, 3.45; N, 24.00. Found: C, 49.62; H, 3.55; N, 23.93.
2-Chloro-Λ/-(5-cyclopropyl-1 H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine compound 1e (0.42 g, 1.45 mmol) was dissolved in NMP (7.0 mL) in a microwave reaction vessel. After addition of AXL 012352 terf-Butyl (IR.δS.δsJ-S-azabicycloβ.i.OJhex-δ-ylcarbamate compound 1f (0.34 g, 1.74 mmol) and Et3N (0.30 mL, 2.17 mmol), the reaction was sealed and placed in a Biotage Smith Synthesizer microwave reactor at 2000C for 60 minutes. The solvent was removed under reduced pressure, and the residue dissolved in 4:1 CHCI3/iPrOH and water. The organic phase was separated, washed with brine, and dried (MgSO4). The product was purified by flash column chromatography eluting with 0- 2% methanolic NH3/CHCI3 to give a white solid as title compound 1 (0.153 g, 23%). Rf = 0.18 (7% methanolic NH3/CHCI3). 1H NMR (400MHz, DMSO-d6): δ 0.68-0.67 (m, 2H), 0.93-0.94 (m, 2H), 1.37 (s, 9H), 1.73-1.91 (m, 3H), 3.50-3.51 (m, 2H), 3.76-3.77 (m, 2H), 6.42 (s, 1 H), 7.07-7.08 (m, 2H), 7.90 (d, J = 4.8 Hz, 1 H), 9.75 (s, 1H), 12.08 (s, 1 H). LCMS 454 (M+H). Anal. Calcd. For C22H27N7O2S: C, 58.26; H, 6.00; N, 21.62. Found: C, 58.01; H, 6.02; N, 21.33. Preparation of intermediate 1h: 2-chIoro-N-(5-methyl-1H-pyrazol-3-yl) thieno [3,2-d] pyrimidin -4-amine
Figure imgf000062_0001
1j
Compound 1h is an analog of compound 1e and will be used as an intermediate in later, examples. To 5-methyl-1 H-pyrazol-3-amine compound 1g (6.35g, 6.35mmol) and 2,4- dichlorothieno[3,2-d]pyrimidine compound 1c (12.5g, 62.84mmol) in 50 ml. NMP was added TEA (6.98g, 69.12 mmol). Microwave at 700C for 30 min. Water (375 mL) was added to the reaction mixture. The crude product precipitated was collect by filtration. It was then recrystalized in EtOAc. Compound 1h was obtained as a white powder (68%). LCMS (APCI, M+H+): 266. 1H NMR (400MHz, DMSO): δ 2.28 (s, 3H), 6.33 (s, 1H), 7.34(d, J=6 Hz, 1 H), 8.19 (d, J=Z Hz, 1 H), 10.51 (s, 1 H), 12.33 (s, 1H). Compound 1j was prepared following the same method compound 1h was prepared. Example 2: 2-[(1 R,5S)-6-Amino-3-azabicyclo[3.1.0]hex-3-yl]-yV-(5-cyclopropyl-1 H- pyrazol-3-yl)thieno[3,2-c/]pyrimidin-4-amine.
Figure imgf000062_0002
2 terf-Butyl ((1R,5S)-3-{4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]thieno[3,2-d]pyrimidin-2-yl}- 3-azabicyclo[3.1.0]hex-6-yl)carbamate 1e (0.13g, 0.29 mmol) was suspended in CH2CI2 (2.0 ml_). A solution of 4 M HCI/dioxane (2.0 mL) was added, and the reaction was stirred at ambient temperature overnight. The solvent was removed under reduced pressure, and the residue dissolved in 4:1 CHCI3/iPrOH and water. The organic phase was separated, washed successively with saturated NaHCO3 solution, water and brine. After drying (MgSO4) the product was purified by flash silica gel chromatography eluting with 0-3% methanolic NH3/CHCI3 to give a white solid (0.03 g, 29%) title compound 2. Rf = 0.11 (7% methanolic NH3/CHCI3). 1H NMR (400MHz, DMSO-d6): δ 0.66-0.69 (m, 2H), 0.93-0.94 (m, 2H), 1.52 (s, 2H), 1.86-1.93 (m, 1 H), 1.97 (s, 1 H), 3.48 (d, J = 10.4 Hz, 2H), 3.70 (d, J = 10.4 Hz, 2H), 6.41 (s, 1 H), 7.06 (d, J = 5.3 Hz, 1 H), 7.89 (d, J = 5.3 Hz, 1 H), 9.72 (br, 1 H), 12.08 (br, 1 H). LCMS 354 (M+H). Anal. Calcd. For C17H19N7S.0.05 hexane.0.30 H2O: C, 57.21 ; H, 5.63; N, 27.00. Found: C, 57.49; H, 5.62; N, 26.80. Example 3: 2-{4-[(5-Cyclopropyl-1 H-pyrazol-3-yl)amino]thieno[3,2-e/]pyrimidin-2-yl}- 2-azabicyclo[2.2.1]heptan-6-exo-ol
Figure imgf000063_0001
Preparation of 3b: 2-Benzyl-2-aza-bicyclo[2.2.1]heptan-6-exo-ol
At O0C, 2-Benzyl-2-aza-bicyclo[2.2.1]hept-5-ene 3a (2.5g, 13.5mmol) was dissolved in dry THF (27ml_). The solution was added BH3 THF (1 M, 27mL). The mixture was stirred for 1 h at 0-50C. Water (0.5mL) was added slowly to quench BH3. Aqueous NaOH solution (10%, 2.5mL) and 30% H2O2 (3ml_) were added. The solution was stirred at 35-390C for 1h. After cooling down to 250C, Potassium carbonate (2g) was added. After concentration in vacuo, the aqueous solution was extracted with CH2CI2 (3x20ml_). The combined organic layers were washed with water (1x50mL), dried (MgSO4) and concentrated. The residue was purified with flash column chromatography (5-7% MeOH in CH2CI2 with 1% NH3), affording 0.77g (28% yield) 3b. LCMS (APCI, M+H+): 204. Preparation of 3c: 2-Aza-bicyclo[2.2.1]heptan-6-exo-ol: At 250C, to a MeOH solution of 2-Benzyl-2-aza-bicyclo[2.2.1]heptan-6-exo-ol 3b (0.77g, 3.79mmol) was added Pd-C (10% 0.24g) and ammonium formate (1.3g, 20.6mmol). The mixture was heated at reflux for 1h. The suspension was cooled down and filtered through celite. The filtrate was concentrated to dryness, affording 3c as a yellow oil (0.47g, quantitative). LCMS (APCI, M+H+): 114. 1H NMR (400MHz, CDCI3): δ 1.43 (m, 1 H), 1.53 (d, J=10.1 Hz, 1 H), 1.80 (d, J=10.6 Hz, 1 H), 1.85 (m, 1H), 2.53 (br s, 1 H), 2.55 (dd, J=9.6, 1 Hz), 1H), 3.48 (s, 1H), 3.49 (br s, 1H), 4.01 (d, J=6.8 Hz, 1H). 2-Chloro-Λ/-(5-cyclopropyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine compound 1e (0.14 g, 0.47 mmol) was dissolved in NMP (2.0 mL) in a microwave reaction vessel. After addition of 2- (6f?)-2-azabicyclo[2.2.1]heptan-6-ol compound 3c (0.063 g, 0.56 mmol) and Et3N (0.098 mL, 0.70 mmol), the reaction was sealed and placed in a Biotage Smith Synthesizer microwave reactor at 2000C for 60 minutes. The solvent was removed under reduced pressure, and the residue dissolved in EtOAc and water. The organic phase was separated, washed with brine, and dried (MgSO^. The product was purified by preparative HPLC to give a white solid as title compound 3 (0.020 g, 9%). 1H NMR (400MHz, DMSO-d6): δ 0.67-0.77 (m, 2H), 0.91-0.93 (m, 2H), 1.40-1.41 (m, 1H), 1.62- 1.63 (m, 1 H), 1.86-1.93 (m, 3H), 2.65-2.66 (m, 1H), 3.03-3.04 (m, 1 H), 3.83-3.84 (m, 1H), 4.38-4.39 (m, 1H), 5.08-5.09 (m, 1 H), 6.41 (s, 1 H), 7.16 (s, 1 H)1 8.10-8.12 (m, 1 H), 12.39 (br, 1H). LCMS 369 (M+H). Anal. Calcd. For C18H2oN6OS.0.80 TFA.1.70 H2O: C, 48.01 ; H, 4.97; N, 17.14. Found: C, 48.15; H, 5.07; N, 17.11. Example 4: 3-{4-[(5-Cyclopropyl-1 W-pyrazol-3-yl)amino]-6-methylthieno[3,2- cflpyrimidin-2-yI}-3-azabicyclo[3.1.0]hexane-2-carboxamide
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000065_0002
Preparation of 4b: Methyl S-amino-S-methylthiophene^-carboxylate
A mixture of cis- and frans-crotononitrile 4a (298.00 g, 4.44 mol) was mixed with pyridine (61.49 g, 0.78 mol) and the resulting mixture was cooled to 00C. Chlorine (314.92 g, 4.44 mol) was passed through the mixture at a rate of 60-65 g/h to maintain the internal temperature at 10-13 0C. When the addition was complete the reaction mixture was allowed to warm up to room temperature and mixed overnight. The resulting oil was dissolved in CH2CI2 (1.5 L) and the solution was passed through a silica gel plug. The filtrate was concentrated in vacuo to give a complex reaction mixture (508.61 g) as brownish oil. This oil (493.80 g) was mixed with methyl thioglycolate (422.77 g, 3.98 mol) and the resulting solution was added slowly (1.5 h) to a slurry of K2CO3 (1651 g, 11.95 mol) in methanol (2.2 L) at 100C. The final slurry was allowed to warm up to room temperature and was stirred at ambient temperature for 5 h. Salts were filtered out and washed with methanol (2 L). The organic solutions were combined and evaporated. The residue was redissolved in ethyl acetate (3 L) and passed through a silica gel plug. The plug was washed with extra ethyl acetate (2 L). The solutions were combined and the solvent was evaporated in vacuo to give brown oil (627 g). The mixture was vacuum distilled at 6 mmHg. An oil that distilled at 138 0C crystallized in the receiving flask (303.07 g). Recrystallizion from methanol yielded 4b (179.00 g, 26%) as white crystals. 1H NMR (CDCI3, 400 MHz) δ 6.25 (s, 1H), 5.30 (bs, 2H), 3.81 (s, 3H), 2.37 (s, 3H). 13C NMR (CDCI3, 100 MHz) 5 165.2, 154.5, 147.2, 119.0, 99.3, 51.4, 16.5. Preparation of 4c: 2,4-Dihydroxy-6-methyl-thieno[3,2-d]pyrimidine Methyl S-amino-δ-methylthiophene^-carboxylate 4b (78.86 g, 0.46 mol) and urea (138.31 g, 2.30 mol) were mixed then heated for 2 h at 2000C. A clear brown molten mass was formed which solidified upon cooling to room temperature. The solid was dissolved in a warm 1 N sodium hydroxide solution and then acidified with 2N hydrochloric acid. The precipitate formed was collected by filtration and recrystallized from water to afford 4c (45.14 g, 54%) as gray solid. 1H NMR (DMSO-Cf6, 400 MHz) δ 11.45 (bs, 1 H), 11.10 (bs, 1 H), 6.68 (s, 1 H), 2.48 (s, 3H).
Preparation of 4d: 2,4-DichIoro-6-methyl-thieno[3,2-d]pyrimidine A mixture of 2,4-dihydroxy-6-methyl-thieno[3,2-d]pyrimidine 4c (45.14 g, 0.25 mol) and phosphorus oxychloride (500 ml) was refluxed for 10 h, whereby a clear brown solution was formed. The reaction mixture was cooled to room temperature and the excess of phosphorus oxychloride was evaporated in vacuo. The residue was poured into ice water and the aqueous mixture was extracted with chloroform. The organic phase was separated, washed with water until neutral and dried over magnesium sulfate. The final solution was passed through a silica gel plug. The solvent was evaporated in vacuo to yield 25.37 g of white solid. Recrystallizion from ethanol afforded 4d (22.5 g, 41%) as white needles. 1H NMR (CDCI3, 400 MHz) δ 7.13 (s, 1 H), 2.66 (s, 3H). 13C NMR (CDCI3, 100 MHz) δ 164.55, 156.48, 156.27, 154.62, 129.44, 122.70, 17.74. Preparation of 4e: 2-Chloro-yV-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methylthieno[3,2- c/]pyrimidin-4-amine
Compound 4e was made from compound 4d (10.11 g, 46.13 mmol) and compound 1d (5.68 g, 46.13 mmol) using the same procedure of making compound 1e, 2-chloro-Λ/-(5- cyclopropyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine, from compound 1c and compound 1d. The title compound 4e was obtained as an off-white solid. (11.55g, 82%). 1H NMR (400MHz, DMSOd6): δ 0.68-0.72 (m, 2H), 0.92-0.96 (m, 2H), 1.88-1.95 (m, 1 H), 2.55 (s, 3H), 6.18 (S, 1H), 7.07 (s, 1 H), 10.29 (s, 1 H), 12.38 (s, 1 H). LCMS 306 (M+H). Anal. Calcd. For C13H12N5SCI.0.05 H2O.0.1 Et2O C, 51.24; H, 4.20; N, 22.30. Found: C, 51.20; H, 4.27; N, 22.05.
Preparation of 4f: 3-AzabicycIo[3.1.0]hexane-2-carboxamide Acetyl chloride (3.75 mL) was added to MeOH (75 ml_) at O0C. After ten minutes racemic 3-azabicyclo[3.1.0]hexane-2-carboxylic acid compound 4g, (2.10 g, 16.52 mmol) was added. The reaction was warmed to room temperature overnight. The solvent was removed to give the cis-racemic product methyl 3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride compound 4h as a tan solid (3.16 g, quant). 1H NMR (400MHz, DMSO- d6): δ 0.58-0.61 (m, 1 H), 0.65-0.70 (m, 1 H), 1.76-1.80 (m, 1 H), 1.96-2.02 (m, 1H), 3.29- 3.30 (m, 2H), 3.78 (s, 3H), 4.55-4.60 (m, 1H), 8.94 (s, 1 H), 10.68 (s, 1H). Cis-racemic Methyl 3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride compound 4h (1.54 g, 8.26 mmol) was dissolved in MeOH (20 mL) and cooled to O0C. Anhydrous ammonia gas was bubbled through the solution for 30 minutes. The flask was then fitted with a Suba- seal stopper secured with copper wire and warmed gradually to room temperature where it was allowed to stand for 5 days. The solvent was removed in vacuo, and the product was purified by flash silica gel chromatography eluting with 0-5% methanolic NH3/CHCI3. The cis-racemic product compound 4f was obtained as a white solid (0.70 g, 67%). Rf = 0.11 (7% methanolic NH3/CHCI3). 1H NMR (400MHz, DMSO-d6): δ 0.22-0.31 (m, 2H), 1.29-1.35 (m, 1 H), 1.52-1.58 (m, 1H), 2.31 (br, 1 H), 2.75 (dd, J = 10.9, 3.5 Hz, 1 H), 2.88 (d, J = 10.9 Hz, 1 H), 3.44 (d, J = 3.5 Hz, 1H), 6.98 (s, 1 H), 7.37 (s, 1 H). IR 1643 cm"1. MS (ES) 127 (M+H).
2-Chloro-Λ/-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methylthieno[3,2-d]pyrimidin-4-amine compound 4e (0.19 g, 0.63 mmol), was dissolved in NMP (3.0 mL) in a microwave reaction vessel. After addition of cis-racemic 3-azabicyclo[3.1.0]hexane-2-carboxamide compound 4f (0.095 g, 0.75 mmol) and Et3N (0.13 mL, 0.93 mmol), the reaction was sealed and placed in a Biotage Smith Synthesizer microwave reactor at 2000C for 90 minutes. The solvent was removed under reduced pressure. LCMS indicated that the crude contained two products of the identical desired mass. The product purified by preparative HPLC to give the faster-eluting cis-racemic product compound 4 as a white solid (0.030 g, 8%). 1H NMR (400MHz, MeOD): S 0.67-0.69 (m, 1 H), 0.71-0.74 (m, 1 H)1 0.84-0.91 (m, 2H), 1.00-1.02 (m, 2H), 1.93-2.02 (m, 2H), 2.24-2.29 (m, 1 H), 2.63 (s, 3H), 3.80-3.89 (m, 2H), 4.79 (d, J = 5.6 Hz, 1 H), 6.30 (br, 1 H), 7.02 (s, 1 H). LCMS 396 (M+H). Anal. Calcd. For C19H2iN7OS.1.60 TFA.0.75 H2O C, 45.08; H, 4.11 ; N, 16.58. Found: C, 45.01; H, 3.99; N, 16.56.
Example 5: 3-{4-[(5-Cyclopropyl-1/V-pyrazol-3-yl)amino]-6-methylthieno[3,2- c/]pyrimidin-2-yl}-3-azabicyclo[3.1.0]hexane-2-carboxamide
Figure imgf000067_0001
Preparative HPLC used in the preparation of compound 4 also affords the trans-racemic compound 5 (0.02Og, 5.6%) as a white solid: 1H NMR (400MHz, MeOD): δ 0.36-0.40 (m, 1 H), 0.78-0.82 (m, 2H), 0.95-0.96 (m, 1H), 1.00-1.03 (m, 2H), 1.92-1.93 (m, 2H), 1.95-
1.99 (m, 1 H), 2.63 (S1 3H), 3.80-3.86 (m, 2H), 4.81-4.82 (m, 1H), 6.27 (s, 1 H), 7.03 (s,
1 H). LCMS 396 (M+H). Anal. Calcd. For C1βH2iN7OS.1.40 TFA.0.70 H2O C, 46.12; H,
4.23; N, 17.27. Found: C, 46.11 ; H, 3.95; N1 17.27.
Example 6: 3-{4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]-6-methyIthieno[3,2- cflpyrimidin-2-yl}-Λ/-methyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
Figure imgf000068_0001
Preparation of 6a: N-Methyl-S-azabicyclofS.I.Olhexane^-carboxamide
Cis-racemic methyl 3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride compound 4h (1.50 g, 8.26 mmol) was dissolved in MeOH (20 mL) and cooled to O0C. Anhydrous methylamine gas was bubbled through the solution for 30 minutes. The flask was then fitted with a Suba-seal stopper secured with copper wire and warmed gradually to room temperature where it was allowed to stand for 5 days. The solvent was removed in vacuo, and the residue partitioned between CHCI3 and water. The organic phase was separated, washed with water and dried (MgSO4). The cis-racemic product compound 6a was obtained as a white solid (0.37 g). A second crop was obtained by salting out the aqueous layers with NaCI and extracting exhaustively with EtOAc, then with CHCI3 to give an additional 0.23 g (total 0.60 g, 52%). Rf = 0.21 (7% methanolic NH3/CHCI3). 1H NMR (400MHz, DMSO-d6): δ 0.21-0.26 (m, 1 H), 0.34 (dd, J = 8.4, 4.3 Hz, 1H), 1.31-1.36 (m, 1H), 1.49-1.55 (m, 1H), 2.59 (d, J = 4.6 Hz, 3H), 2.78 (dd, J = 10.6, 3.5 Hz, 1H), 2.89 (d, J = 10.6 Hz1 1 H), 3.47 (d, J = 3.8 Hz, 1 H), 7.82 (s, 1 H). IR 1710, 1651 , 1567 1412, 1345, 1263 cπf1. MS (ES) 141 (M+H).
Using the procedure described to make 3-{4-[(5-cyclopropyl-1/-/-pyrazol-3-yl)amino]-6- methylthieno[3,2-cf]pyrimidin-2-yl}-3-azabicyclo[3.1.0]hexane-2-carboxamide compound 4, the product was made from 2-chloro-Λ/-(5-cyclopropyl-1H-pyrazol-3-yl)-6- methylthieno[3,2-d]pyrimidin-4-amine 4e (0.19 g, 0.62 mmol) and N-methyl-3- azabicyclo[3.1.0]hexane-2-carboxamide 6a (0.10 g, 0.75 mmol), giving two products of the identical desired mass. Preparative HPLC gave the faster-eluting cis-racemic product compound 6 as a white solid (0.079g, 20%). 1H NMR (400MHz, MeOD): δ 0.65-0.66 (m,
1 H), 0.83-0.88 (m, 2H), 1.01-1.06 (m, 2H), 1.95-2.02 (m, 2H), 2.15-2.19 (m, 1H), 2.64 (s,
3H), 2.68 (s, 3H), 3.80-3.88 (m, 2H), 4.76 (d, J = 5.8 Hz, 1 H), 6.16 (br, 1 H), 7.03 (s, 1 H) .
LCMS 410 (M+H). Anal. Calcd. For C20H23N7OS.1.75 TFA.0.80 H2O C, 45.27; H, 4.26;
N, 15.73. Found: C, 45.22; H, 4.20; N, 15.98.
Example 7: 3-{4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]-6-methylthieno[3,2- c/|pyrimidin-2-yl}-N-methyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
Figure imgf000069_0001
7
Preparative HPLC in the experimental above to make compound 6 also affords as the trans-racemic compound 7 (0.04Og, 9%) as a white solid: 1H NMR (400MHz, MeOD): δ 0.35-0.38 (m, 1H), 0.75-0.81 (m, 2H), 0.90-0.98 (m, 1H), 1.02-1.06 (m, 2H), 1.80-1.90 (m, 1H), 1.93-2.01 (m, 1 H), 2.64 (s, 3H), 2.75 (s, 3H), 3.82-3.85 (m, 2H), 4.82 (s, 1 H), 6.12 (br, 1H), 7.03 (s, 1 H). LCMS 410 (M+H). Anal. Calcd. For C20H23N7OS.2.55 TFA.1.15 H2O C, 41.88; H, 3.89; N, 13.60. Found: C, 41.62; H, 3.52; N, 13.94. Example 8: (2S)-1-{4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]-6-methylthieno[3,2- c/]pyrimidin-2-yl}-Λ/-methylazetidine-2-carboxamide
4M HCI /Dioxane
Figure imgf000069_0002
"" Sb
Figure imgf000070_0001
Preparation of 8b: tert-Butyl (2S)-2-[(methylamino)carbonyl]azetidine-1-carboxylate
Boc-L-2-azetidine carboxylic acid compound 8a (2.01 g, 10.0 mmol) was dissolved in CH2CI2 (50.0 mL) and cooled to 00C. To this was added in succession HOBt (1.62 g, 11.99 mmol), methylamine hydrochloride (2.02 g, 30.0 mmol), N-methylmorpholine (4.39 mL, 40.0 mmol), and EDC (2.10 g, 10.99 mmol). The reaction was stirred at O0C for one hour, then warmed to room temperature and stirred overnight. The reaction was diluted' with EtOAc. The organic layer was separated, washed successively with 1 N HCI, saturated NaHCO3, and brine. After drying (MgSO4) the solvent was removed to give 1.84 g (86%) compound 8b as oil which solidified upon standing. 1H NMR (400MHz, DMSO-d6): δ 1.34 (s, 9H), 1.90-1.98 (m, 1H), 2.29-2.38 (m, 1 H), 2.61 (d, J = 4.5 Hz, 3H)1, 3.75-3.80 (m, 2H), 4.37 (dd, J = 9.1 , 5.6 Hz), 7.87 (br, 1H). Preparation of 8c: (2S)-Λ/-Methylazetidine-2-carboxamide hydrochloride ferf-Butyl (2S)-2-[(methylamino)carbonyl]azetidine-1-carboxylate 8b (1.71 g, 7.97 mmol) was dissolved in dioxane (106 mL). 4M HCI/dioxane (53 mL) was added, and the reaction stirred at ambient temperature for six hours. The solvent was removed by reduced pressure, and the resulting white solids were triturated with diethyl ether and filtered to give compound 8c as a white crystalline solid (1.11 g, 93%). 1H NMR (400MHz, MeOD): δ 2.48-2.57 (m, 1H), 2.75-2.84 (m, 1H), 2.81 (s, 3H), 3.90-3.97 (m, 1H), 4.08-4.15 (m, 1 H), 4.94-4.98 (m, 1 H). IR 1711, 1672, 1571, 1361 , 1222 cπrf1. MS (ES) 115 (M+H).
2-Chloro-Λ/-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methylthieno[3,2-d]pyrimidin-4-amine compound 4e (0.22 g, 0.71 mmol), was dissolved in NMP (3.50 mL) in a microwave reaction vessel. After addition of (2S)-Λ/-methylazetidine-2-carboxamide hydrochloride compound 8c (0.13 g, 0.85 mmol) and AgBF4 (0.69 g, 3.56 mmol), the reaction was sealed and placed in a Biotage Smith Synthesizer microwave reactor at 15O0C for 45 minutes. Another 0.065 g of the azetidine was added, and the reaction heated for an additional 45 minutes at 15O0C. The solvent was removed under reduced pressure, and the product purified by preparative HPLC to give compound 8 as a tan solid (0.075 g, 17%). 1H NMR (400MHz, DMSOd6): δ 0.70-0.73 (m, 2H), 0.92-0.94 (m, 2H), 1.87-1.90 (m, 1 H), 2.25-2.27 (m, 1 H), 2.63 (s, 3H), 2.65 (s, 3H), 2.68-2.69 (m, 1 H), 4.15-4.19 (m, 2H)1 4.90-4.93 (m, 1 H), 6.16 (br, 1H), 7.03 (s, 1 H), 8.14 (d, J = 4.5 Hz, 1 H), 11.41 (br, 1 H), 12.20-13.23 (br, 1H). LCMS 384 (M+H). Anal. Calcd. For C18H21 N7OS.2.10 TFA.0.10 H2O C, 42.68; H, 3.76; N, 15.69. Found: C, 42.63; H, 3.84; N, 15.54. Example 9: (2S)-1-{4-[(5-Cyclopropyl-1W-pyrazol-3-yl)amino]-6-methylthieno[3,2- cf]pyrimidin-2~yl}azetidine-2-carboxamide
Figure imgf000071_0001
8a 9a
Figure imgf000071_0002
Preparation of 9a: tert-Butyl (2S)-2-(aminocarbonyl)azetidine-1-carboxylate
Boc-L-2-azetidinecarboxylic acid compound 8a (2.91 g, 14.45 mmol) and Et3N (2.01 mL, 14.45 mmol) were dissolved in THF (33 mL) and cooled to -1O0C. Ice-cooled ethyl chloroformate was added dropwise followed by continued stirring for twenty minutes at the same temperature. A solution of 28% NH4OH (3.21 mL) was added, and the reaction gradually warmed to ambient temperature. The THF solvent was removed under reduced pressure, and the residue partitioned between EtOAc and water. The organic phase was separated, dried (MgSO4), and the solvent removed to give compound 9a as a white crystalline solid (2.36 g, 82%). 1H NMR (400MHz, DMSO-d6): δ 1.34 (s, 9H), 1.96-1.98 (m, 1 H), 2.30-2.39 (m, 1H), 3.75-3.80 (m, 2H), 4.37 (dd, J = 9.1 , 5.5 Hz), 7.11 (s, 1 H), 7.34 (s, 1H). Preparation of 9b: (2S)-Azetidine-2-carboxamide hydrochloride Compound 9b was obtained from ferf-butyl (2S)-2-(aminocarbonyl)azetidine-1- carboxylate compound 9a (2.33 g, 11.64 mmol) following the same procedure used to prepare (2S)-N-methylazetidine-2-carboxamide hydrochloride compound 8c from compound 8b. Compound 9b was obtained as a white crystalline solid (1.32 g, 83%). 1H NMR (400MHz, MeOD): δ 2.49-2.59 (m, 1H), 2.79-2.89 (m, 1H), 3.90-3.97 (m, 1H), 4.10- 4.15 (m, 1 H), 4.97-5.01 (m, 1H). MS(ES) 101 (M+H). IR 1711 1421, 1361, 1266, 1222 cm"1.
2-Chloro-Λ/-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methylthieno[3,2-d]pyrimidin-4-amine 4e (0.21 g, 0.68 mmol), was dissolved in NMP (3.50 mL) in a microwave reaction vessel. After addition of (2S)-azetidine-2-carboxamide hydrochloride 9b (0.14 g, 1.02 mmol) and AgBF4 (0.66 g, 3.41 mmol), the reaction was sealed and placed in a Biotage Smith Synthesizer microwave reactor at 15O0C for 60 minutes. The reaction was heated for an additional 60 minutes at 17O0C. The solvent was removed under reduced pressure, and the product purified by preparative HPLC to give compound 9 as a tan solid (0.004 g). 1H NMR (400MHz, MeOD): δ 0.78-0.80 (m, 2H), 0.99-1.01 (m, 2H), 1.28-1.36 (m, 1H), 1.92- 1.98 (m, 1 H), 2.42-2.47 (m, 2H), 2.59-2.63 (m, 4H), 2.75-2.85 (m, 1H), 6.66 (s, 1 H), 6.97 (s, 1H). LCMS 370 (M+H).
Example 10: (1 R,5S,6s)-3-(4-(3-cyanobenzyl)-6-(5-ethyI-1 H-pyrazol-3- ylaminoJpyrimidin^-ylJ-S-aza-bicyclop.i.Olhexan-e-ylcarbamate
Figure imgf000072_0001
10e
Figure imgf000073_0001
Preparation of 10c: 3-((2,6-dichloropyrimidin-4-yl)methyl)benzonitrile
Pd(PPh3)4 (132 mg, 0.114 mmol) was added to a solution of 2,4,6-trichloropyrimidine compound 10b (1.40 g, 7.63 mmol) in THF (25 mL) and sub/ect to three cycles of vacuum/N2 flushes. 2-Cyanobenzylzinc bromide compound 10a (0.5 M solution in THF, 16.8 mL, 8.40 mmol) was slowly added to the suspension. The reaction mixture was stirred at 5O0C for 2 hours. Solvent was removed by vacuum. Ethyl acetate and saturated sodium bicarbonate were added to the residue. The suspension was sonicated and filtered. The EA phase was separated, washed with brine and dried over sodium sulfate. It was then filtered and the filtrate was concentrated. Purification by Biotage (0 to 50% ethyl acetate in hexane) gave compound 10c (1.75 g, 88%). LCMS (APCI, M+H+): 264.0. Preparation of compound 10e: 3-((2-Chloro-6-(5-ethyl-1H-pyrazoI-3- ylarnino)pyrimidin-4-yl)methyl)benzonitrile
3-((2,6-Dichloropyrimidin-4-yl)methyl)benzonitrile 10c (646 mg, 2.46 mmol), 5-Ethyl-1H- pyrazol-3-ylamine 10d (300 mg, 2.70 mmol) and TEA (0.60 mL, 4.3 mmol) were dissolved in isopropanol (25 mL) and refluxed for overnight. Solvent was removed by vacuum. Ethyl acetate and water were added to the residue. The EA phase was separated, washed with brine and dried over sodium sulfate. Purification by Biotage (0 to 60% ethyl acetate in hexane) gave compound 10e (443 mg, 53%). LCMS (APCI, M+H+): 339.0. 1H NMR (400MHz, DMSO-d6): δ 1.10 (t, J=7.5 Hz, 3H), 2.50 (q, J=7.9 Hz, 2H), 3.91 (s, 2H), 7.47 (t, J=7.6 Hz, 1 H), 7.55 (d, J=8.4 Hz, 1 H), 7.66 (d, J=7.9 Hz, 1 H), 7.70 (s, 1 H), 10.18 (s, 1 H), 12.06 (s, 1 H).
A microwave reaction vessel was charged with 3-((2-Chloro-6-(5-ethyl-1H-pyrazol-3- ylamino)pyrimidin-4-yl)methyl)benzonitrile 10e (140 mg, 0.414 mmol), AXL012352 (86 mg, 0.435 mmol) compound 1f, TEA (0.12 mL, 0.83 mmol) and amyl alcohol (3 mL). It was sealed and then heated in a Biotage Smith Synthesizer microwave at 2000C for 20 minutes. Purification by Biotage (0 to 80% ethyl acetate in hexane) gave compound 10 as a light yellow solid (78 mg, 38%). LCMS (APCI, M+H+): 501.3. 1H NMR (400MHz, DMSO- d6): δ 1.21 (t, J=7.6 Hz, 3H), 1.42 (s, 9H), 2.18 (s, 1 H), 2.56-2.65 (m, 2H), 3.43-3.53 (m, 2H), 3.80 (s, 4H), 7.65 (t, J=7.8 Hz, 1H), 7.69 (d, J=7.8 Hz1 1H), 7.73 (d, J=7.6 Hz, 1H),
7.80 (S, 1 H), 9.38 (s, 1 H), 11.89 (s, 1 H).
Example 11 : 3-((2-((1 R,5S,6s)-6-Amino-3-aza-bicyclo[3.1.0]hexan-3-yl)-6-(5-ethyl-1 H- pyrazol-3-ylamino)pyrimidin-4-yl)methyl)benzonitriIe
Figure imgf000074_0001
11
Tert-Butyl (1R,5S,6s) -3-(4-(3-cyanobenzyl) -6-(5-ethyl-1 H- pyrazol-3-ylamino)pyrimidin-2- yl)-3-aza-bicyclo[3.1.0]hexan-6-ylcarbamate 10 (75 mg, 0.15 mmol) was dissolved in dichloromethane (3 mL). At O0C, TFA (0.8 mL) was introduced to the solution slowly and stirred at room temperature for 2 hours. Purification by prep. HPLC gave compound 1.1 as a white solid (51 mg). LCMS (APCI, M+H+): 401.3. 1H NMR (400MHz, DMSOd6): δ 1.13 (t, J=7.3 Hz, 3H), 2.11 (s, 2H), 2.46-2.58 (m, 3H), 3.65 (bs, 2H), 3.78 (bs, 2H), 3.97 (s, 2H), 5.93 (bs, 1 H), 6.37 (bs, 1H), 7.49-7.62 (m, 2H), 7.70-7.77 (m, 1 H), 8.20 (bs, 3H). Anal. Calcd. For C22H24N82.94TFA0.56H2O: C, 44.90; H, 3.79; N, 15.02. Found: C, 44.90; H, 3.76; N, 14.97.
Example 12: 2-((1S,4S)-5-Oxa-2-aza-bicyclo[2.2.1]heptan-2-yl)-6-benzyl-N-(5- cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine
Figure imgf000074_0002
12c
Figure imgf000075_0001
12
Preparation of 12b: 4-Benzyl-2,6-dichloropyrimidine
2,4,6-Trichloropyrimidine 10b (97%, 23.0 mL, 200 mmol) was dissolved in THF and cooled to -780C. Benzylmagnesium chloride 12a (2M in THF, 100 mL, 200 mmol) was added to the reaction which was then warmed to room temperature overnight. The solvent was removed under reduced pressure, and the residue partitioned between CH2CI2 and water. The organic layer was separated, washed with brine, dried (MgSO4), and evaporated. The resulting liquid was distilled under vacuum to give compound 12b (43.14g (90%) as a gold liquid (bp 151-1540C, 2.4 mmHg): Rf = 0.39 (15% EtOAc/hexane). 1H NMR (400MHz, DMSO-d6): δ 4.10 (s, 2H), 7.23-7.34 (m, 5H), 7.72 (s, 1H). LCMS 239, 241 (M+H).
Preparation of 12c: 6-Benzyl-2-chloro-Λf-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4- amine
4-benzyl-2,6-dichloropyrimidine 12b (11.78 g, 49.29 mmol) and 3-cyclopropylpyrazol-5- amine 1d (6.07 g, 49.29 mmol) and 1.2 equivalents of triethylamine were refluxed in isopropanol (150 mL) overnight. The solvent was removed under reduced pressure, and the product purified by flash silica gel chromatography eluting with 10-50% EtOAc/hexane to give compound 12c as a light yellow solid (7.58 g, 47%). Rf = 0.16 (50% EtOAc/hexane). 1H NMR (400MHz, DMSO-d6): δ 0.63-0.67 (m, 2H), 0.90-0.94 (m, 2H), 1.84-1.88 (m, 1 H), 3.87 (s, 2H), 7.21-7.33 (m, 6H), 10.17 (s, 1 H), 12.13 (s, 1 H). LCMS 326 (M+H). Anal. Calcd. For C17H16N5CI.0.20 hexane.0.10 H2O C, 63.39; H, 5.55; N, 20.31. Found: C, 63.35; H, 5.65; N, 20.07.
A microwave reaction vessel was charged with 6-Benzyl-2-chloro-Λ/-(5-cyclopropyl-1H- pyrazol-3-yl)pyrimidin-4-amine 12c (139 mg, 0.428 mmol), (1S,4S)-5-oxa-2-aza- bicyclo[2.2.1]heptane 12d (61 mg, 0.449 mmol), TEA (0.15 mL, 1.1 mmol) and amyl alcohol (3 mL). It was sealed and then heated in a Biotage Smith Synthesizer microwave at 2000C for 20 minutes. Purification by prep. HPLC gave compound 12 as a white solid (98 mg). LCMS (APCI, M+H+): 389.1. 1H NMR (400MHz, DMSO-d6): δ 0.60 (bs, 2H), 0.86 (dd, J=2.3, 8.4 Hz, 2H), 1.78-1.87 (m, 1H), 1.88-1.98 (m, 2H), 3.36-3.63 (m, 4H), 3.91 (s, 2H), 4.72 (bs, 1 H), 4.98 (bs, 1 H), 5.88 (bs, 1 H), 6.23 (bs, 1 H), 7.22-7.35 (m, 5H). Anal. Calcd. FOr C22H24N6OHTTFAOJI H2O: C, 54.68; H, 5.01; N, 15.72. Found: C, 54.68; H,
5.00; N, 15.65.
Preparation of intermediate 12g: θ-β-fluorobenzyl^-chloro-N-fδ-cyclopropyl-IH- pyrazol-3-yl)pyrimidin-4-amine
Figure imgf000076_0001
Compound 12g was prepared using the same method used to prepare 12c except that compound 12e was used in place of 12a. LCMS (APCI, M+H+): 344.0. 1H NMR (400MHz, DMSO-de): δ 0.56-0.62 (m, 2H), 0.81-0.88 (m, 2H), 1.76-1.84 (m, 1 H), 3.85 (s, 2H), 6.98-7.07 (m, 3H), 7.26-7.33 (m, 1H)1 10.13 (s, 1 H). Anal. Calcd. For C17H15CIFN50.13TFA0.07H2O: C, 57.61 ; H, 4.28; N, 19.46. Found: C, 57.61 ; H, 4.31 ; N, 19.81.
Compound 12f: 2,4-Dichloro-6-(3-fluoro-benzyl)-pyrimidine, 1H NMR (400MHz, CDCI3): δ 4.07 (s, 2H), 6.9-7.05 (m, 3H), 7.02 (s, 1H), 7.30-7.35 (m, 1H). LCMS 258 (M+H). Preparation of intermediate 12h: 6-Benzyl-2-chloro-/V-(5-ethyl-1W-pyrazol-3- yl)pyrimidin-4-amine
Figure imgf000076_0002
12h
Compound 12h was prepared following the method used in preparing compound 12c except that 3-ethylpyrazol-5-amine was used in place of 3-cyclopropylpyrazol-5-amine compound 1d. 1H NMR (400MHz, DMSO-d6): δ 1.16 (t, J = 7.5 Hz, 3H), 2.52-2.59 (m, 2H), 3.88 (s, 2H), 5.80-6.30 (br, 1 H), 7.20-7.34 (m, 6H), 10.20 (s, 1 H), 12.11 (s, 1 H). IR 1587, 1515, 1484, 1265, 1222, 1178 cm"1. LCMS 314 (M+H).
Preparation of intermediate 12i: 6-Benzyl-Λ/-(5-tert-butyl-1W-pyrazol-3-yl)-2- chloropyrimidin -4-amine
Figure imgf000077_0001
12i
Compound 12i was prepared following the same method used to prepare compound 12c except that 3-tert-butyllpyrazol-5-amine was used in place of 3-cyclopropylpyrazol-5- amine compound 1d. 1H NMR (300MHz, CDCI3 -cQ: δ ppm 1.29 (s, 9 H) 3.95 (s, 2 H) 5.85 (s, 1 H) 6.72 (s, 1 H) 7.16 - 7.39 (m, 5 H) 8.21 (s, 1 H) 9.79 (s, 1 H). Anal. Calcd. For C18H20CIN5: C, 63.24; H, 5.90; N, 20.49; Cl, 10.37. Found: C, 63.39; H, 5.89; N, 20.44; Cl, 10.26.
Figure imgf000077_0002
1H), (bs, 1H),
N,
Hz, (s, 1H),
N,
and 5- of
Figure imgf000078_0001
(m, (m, 1 H),
C,
(d, ,4, 33.4 1H), (m, 5H). H, 4.39;
16 used salt of obtain
Figure imgf000079_0001
of
(m, 1 H), 2H), (m, 48.35; H,
(t, J =
3.87 (d, H)1 6.16 418 C, 22.39.
cis-
Figure imgf000080_0001
(m, 3.69- (d, J
66.78;
place
(m, (m, 1 H), Hz, (M+H). 65.62;
2H),
was
Figure imgf000081_0001
(m, 1H),
C,
1 H), J=4.8, (bm, C, 14.72.
26 uL,
for 5 the
Figure imgf000082_0001
(m, 5.84
H,
(t, J =
1H),
H,
cis-
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
acid
2H)1 3.10 (s,
of
2H), (t, H),
in
solid
Figure imgf000087_0001
1 H), (d, Hz, Hz, 7.58 For
in
(m, 3.82 (d, 4.36 (d, (m,
4.45; N,
4-
in the
Figure imgf000088_0001
0.84- (m, 5.79 Hz, For
at
3H),
7.72 Anal. N,
5-
was
Figure imgf000089_0001
Preparation of 34a: 3-Aza-bicyclo[3.1.0]hexane-6-carboxylic acid diethylamide
Figure imgf000090_0001
To a diisopropylethylamine (2.3mL, 13.2mmol) solution in DMF (2OmL) was added 3-Aza- bicyclo[3.1.0]hexane-3,6-dicarboxylic acid 3-tert-butyl ester 34b (1g, 4.4mmol), dimethylamine hydrochloride (0.431, 5.28mmol) and HATU (2g, 5.28mmol). The suspension was stirred at 250C for 18h. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (5OmL). The solution was washed with NH4CI solution (sat'd 2x50mL). After being dried and concentrated, compound 34c 6- Dimethylcarbamoyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester was obtained as an off-white gum (1.5g, quantitative). 1H NMR (400MHz, DMSOd6): δ 1.37 (s, 9H), 1.66 (t, J=3.2Hz, 1H), 1.87 (m, 2H), 2.80 (s, 3H), 3.08 (s, 3H), 3.35 (m, 2H), 3.44 (dd, J=10.9, 5.1 Hz, 2H). LCMS: 255 (M+H+).
To a CH2CI2 solution (2OmL) of δ-Dimethylcarbamoyl-S-aza-bicyclotS.I.Olhexane-S- carboxylic acid tert-butyl ester 34c (1.12g, 4.40mmol) was added trifluoroacetic acid (3mL) drop-wise. The mixture was stirred at 250C for 18h. The reaction solution was concentrated in vacuo. The residue was dissolved in CH2CI2 (5OmL). The solution was washed with ice cool NaOH solution (10%, 2x50mL). After being dried and concentrated, the title compound 34a was obtained as an yellow solid (0.9, 76.3% yield). 1H NMR (400MHz, DMSOd6): δ 1.66 (m, 2H), 1.82 (t, J=3.2 Hz, 1 H), 2.64 (d, J=11.4 Hz, 2H), 2.78 (s, 3H), 2.85 (d, J=11.3Hz, 2H), 3.05 (s, 3H).. LCMS: 155 (M+H+). Preparation of 36a: 4-((1S,4S)-2,5-Diaza-bicyclo[2.2.1]heptan-2-ylmethyl)benzamide
Figure imgf000090_0002
36b 36c 36d
Figure imgf000091_0001
36e 36a
A 100 mL round bottom flask was charged with (1S,4S)-tert-butyl 2,5-diaza- bicyclo[2.2.1]heptane-2-carboxylate 36b (735 mg, 3.71 mmol), methyl-4- (chloromethyl)benzoate 36c (1.03 g, 5.56 mmol), DIEA (1.3 mL, 7.4 mmol) and THF (20 mL). The reaction mixture was refluxed for 6 days. Solvent was removed by vacuum. The residue was dissolved in ethyl acetate and washed with water and brine. Purification by Biotage (0 to 75% ethyl acetate in hexane) gave 36d 5-(4-(methoxycarbonyl)benzyl)-2,5- diaza-bicyclo[2.2.1]heptane-2-carboxylate as a white solid (1.03g, 80%). LCMS (APCI, M+H+): 347.2. 1H NMR (400MHz, methanol-d4): δ 1.49 (s, 9H), 1.76 (t, J=11.9 Hz, 1 H), 1.95 (d, J=9.9 Hz, 1 H), 2.67 (dd, J=9.9, 26.0 Hz, 1 H), 2.88 (t, J=8.6 Hz, 1 H), 3.20 (t, J=11.4 Hz, 1 H), 3.54 (d, J=12.9 Hz, 2H), 3.83 (s, 2H), 3.91 (s, 3H), 4.82 (s, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.99 (d, J=8.3 Hz, 2H).
At O0C, ammonia was bubbled into a 100 mL round bottom flask charged with (1S.4S)- tert-Butyl 5-(4-(methoxycarbonyl)benzyl)-2,5-diaza-bicyclo[2.2.1 ]heptane-2-carboxylate 36d (652 mg, 1.88 mmol) in methanol (20 mL) for 30 minutes. The reaction mixture was sealed and stirred at room temperature for 6 weeks. Most solvent was removed by vacuum. 2 mL ethyl acetate was added to the residue. Large excess of ether was added while stirring. Filtration followed by an either wash gave 36e (1S,4S)-tert-Butyl 5-(4- carbamoylbenzyl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylate as a solid (392 mg, 63%). LCMS (APCI, M+H+): 332.2. 1H NMR (400MHz, methanol-d4): δ 1.28 (s, 9H), 1.54 (t, J=11.4 Hz, 1H), 1.74 (d, J=10.1 Hz, 1 H), 2.47 (dd, J=9.9, 26.0 Hz, 1 H), 2.66 (t, J=9.9 Hz, 1 H), 2.99 (t, J=10.6 Hz, 1 H), 3.33 (d, J=13.6 Hz, 2H), 3.61 (s, 2H), 4.11 (s, 1 H), 7.27 (d, J=8.3 Hz, 2H), 7.64 (d, J=8.3 Hz, 2H).
(1 S,4S)-tert-Butyl 5-(4-carbamoylbenzyl)-2,5-diaza-bicyclo[2.2.1 ]heptane-2-carboxylate 36e (389 mg, 1.18 mmol) was dissolved in dichioromethane (10 mL). At O0C, TFA (2.5 mL) was introduced to the solution slowly and stirred at room temperature for 2 hours. Evaporation of solvent gave title compound 36a as oil. LCMS (APCI, M+H+): 232.1. 1H NMR (400MHz, methanol-d6): δ 2.28 (d, J=12.9 Hz, 1 H), 2.69 (d, J=13.1 Hz, 1 H), 3.55 (dd, J=2.8, 13.4 Hz, 2H), 3.67 (dd, J=1.8, 13.1 Hz, 1H), 3.84 (dd, J=2.0, 13.4 Hz, 1 H), 4.48 (d, J=13.1 Hz, 1 H), 4.52 (s, 1H), 4.60 (d, J=13.1 Hz, 1 H), 7.68 (d, J=8.3 Hz, 2H), 7.99 (d, J=8.3 Hz, 2H). Example 40: N-(5-methyl-1 H-pyrazol-3-yl)-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept- 5-yl]thieno[3,2-d]pyrimidin-4-amine
Figure imgf000092_0001
In a glove box, the following were added to a 2.0 mL Personal Chemistry Microwave reaction tube: one triangular stir bar, the 0.25M compound 1h solution in NMP (320 DL, 80 Dmol), 0.25M solution of compound 12d in NMP (640 DL, 160 Dmol), and a 0.5M solution of TEA in NMP (240 DL, 120 Dmol). The microwave tube was sealed with a septum cap, and outside the glove box, the reaction mixtures were heated in a Personal Chemistry Microwave Synthesizer for 15 minutes at 200 0C. The reaction mixtures were transferred into a 10 x 75 mm test tube. The microwave tubes were washed with DMF (0.5 mL) and the wash DMF was combined with the originally transferred material. The solvents were removed, and the residues were reconstituted in DMSO to give compound 40. 1 H NMR: (500 MHz, DEUTERIUM OXIDE) d ppm 1.96 (dd, 2 H) 2.23 (s, 3 H) 3.55 - 3.66 (m, 2 H) 3.77 - 3.85 (m, 2 H) 4.75 (s, 1 H) 4.99 (s, 1 H) 6.41 (br. s., 1 H) 7.22 (d, 1 H) 8.20 (d, 1 H) 11.43 (br. s., 1 H).
Figure imgf000092_0002
2 H) 1 H) s., 1
of
2 H) 2.86 (s, 1 H)
place of
Figure imgf000093_0001
0.90 - - (m, 4 (s, 1
2 H) 2 H) (d, 3
in
of
Figure imgf000094_0001
Figure imgf000095_0001
Biological testing and Ki data
Cloning, expression, and purification of recombinant PAK4 Kinase domain (PAK4 KD): The cDNA coding for PAK4 was amplified from the EST clone (#12) (purchased from Research Genetics) by using PCR. P33 (ACATATG TCC CATGAGCAGT TCCGGGCTGC CCTGCAGCT) and P34 (CTCA TGGGTGCTTC AGCAGCTCGG CTGCCGTGGC) were used as the 5' primer and 3' primer in PCR respectively. The PCR amplified product was cloned into Topo vector (Invitrogen Inc.), and verified by DNA sequencing. PAK4 KD was then subcloned into expression plasmid pET28a(+), pET24a(+), or pGST4.5. The recombinant plasmids containing PAK4 KD was transformed into BL21(DE3) cells for recombinant protein expression. The production of PAK4 KD was induced at 37°C by the addition of IPTG into the cells. The cells were then harvested and lyzed for protein purification. Ni-NTA column (pET28a(+), pET24a(+)) and glutathione column (pGST4.5) were used for the purification. The purified protein was then subjected to thrombin to cleave the N-terminal tags that were inherited from the expression plasmids, and thus gave the PAK4 KD that were used for the Ki assay of this invention.
PAK4 kinase domain enzymatic assay conditions: the enzymatic activity of PAK4 KD was measured by its ability to catalyze the transfer of a phosphate residue from a nucleoside triphosphate to an amino acid side chain of a commercially available peptide (amino acid sequence EVPRRKSLVGTPYWM). The conversion of ATP to ADP accompanies the catalytic reaction. The PAK4 KD catalyzed production of ADP from ATP was coupled to the oxidation of NADH through the activities of pyruvate kinase (PK) and lactate dehydrogenase (LDH). The conversion of NADH to NAD+ is monitored by the decrease in absorbance at 340 nm (e340 = 6.22 cm"1mM"1) using a Molecular Devices SPECTRAMAX 190 in conjunction with the Biomec FX. Typical reaction solutions contain 2 mM phosphoenolpyruvate, 0.35 mM NADH, 10 mM MgCI2, 1 mM DTT1 0.4mM peptide (EVPRRKSLVGTPYWM) 0.4 mM ATP, 1 units/mL PK, 1 units/mL LDH, 0.01 % Tween 20 in 50 mM HEPES, pH 7.5. Assays are initiated with the addition of 25nM PAK4 KD. The PAK KD Ki of each compound of the invention (the inhibitor) was calculated based on multiple of Percent Inhibition numbers of the inhibitor at different inhibitor concentrations. The peptide (amino sequence EVPRRKSLVGTPYWM) was purchased from American Peptide Company. NADH, MgCI2 , HEPES, DTT, ATP and PK/LDH were purchased from Sigma. Tween 20 was purchased from Calbiochem. PAK4 Kinase Domain Ki data of the compounds of Examples 1-47:
Figure imgf000096_0001
Figure imgf000097_0001
All patents, patent applications and publications referred to are incorporated herein by reference in their entireties.

Claims

ClaimsWe claim:
1. A compound of formula I1
Figure imgf000098_0001
wherein:
Z1, Z2, Z3 and Z4 are independently CH or N, provided that at least one of Z1, Z2, Z3 and Z4 is CH and at least one of Z1, Z2, Z3 and Z4 is N, and the ring formed by Z1, Z2, Z3, Z4 and the two intervening carbons is optionally further substituted by 1 to 3 R4 groups; R1 represents 1 or 2 optional substituents;
Ring A is 3-4 member cycloalkyl, 3-4 member heterocyclyl, 5-7 member bicyclic heterocyclyl or 5-7 member bicyclic nonaromatic carbocyclyl, and Ring A is optionally further substituted by 1-6 groups selected from R7 and oxo; each R1, R4, and R7 is independently R, and each R1, R4 and R7 is optionally independently further substituted by 1-6 groups selected from Rx and oxo, provided that when Rx is a substitutent of R7, Rx is optionally further substituted by 1-6 groups selected from Ry and oxo;
R is selected from the group consisting of C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, -(C1-C3 alkylene)m-(C3-C12 cycloalkyl), -(C1-C3 alkylene)m-phenyl, -(C1-C3 alkylene)m-(5-10 member heteroaryl), -(C1-C3 alkylene)m-(3-10 member heterocyclyl), - (C1-C3 alkylene)m-(3-12 member unsaturated non-aromatic carbocyclyl), -(C1-C6 perfluoroaklyl), -(C1-C3 alkylene)m-halide, -(C1-C3 alkylene)m-CN, -(C1-C3 alkylene)m- C(O)R3, -(C1-C3 alkylene)m-C(O)ORa, -(C1-C3 aIkylene)m-C(O)NRaRb, -(C1-C3 alkylene)m- ORa, -(C1-C3 alkylene)m-OC(O)Ra, -(C1-C3 alkylene)m-OC(O)NRaRb, -(C1-C3 alkylene)m-O- S(O)R3, -(C1-C3 alkylene)m-OS(O)2Ra, -(C1-C3 alkylene)m-OS(O)2NRaRb, -(C1-C3 alkylene)m-OS(O)NRaRb, -(C1-C3 alkylene)m-NO2, -(C1-C3 alkylene)m-NRaRb -(C1-C3 alkylene)m-N(Ra)C(O)Rb, -(C1-C3 alkylene)m-N(Ra)C(O)ORb, -(C1-C3 alkylene)m- N(Rc)C(O)NRaRb, -(C1-C3 alkylene)m-N(Ra)S(O)2Rb, -(C1-C3 alkylene)m-N(Ra)S(O)Rb, -(C1- C3 alkylene)m-SRa, -(C1-C3 alkylene)m-S(O)Ra, -(C1-C3 alkylene)m-S(O)2Ra, -(C1-C3 alkylene)m-S(O)NRaRb, and -(C1-C3 alkylene)m-S(O)2NRaRb, wherein each Ra, Rb and R0 is independently H, C1-C8 alkyl, C2-C8 alkenyl, -(C1-C3 alkylene)m-(C3-C8 cycloalkyl), -(C1- C3 alkylene)m-(C3-C8 cycloalkenyl), C2-C8 alkynyl, -(C1-C3 alkylene)m-phenyl, -(C1-C3 alkylene)m-(5-7 member heteroaryl) or -(C1-C3 alkylene)m-(3-8 member heterocyclyl), and when connected to the same atom, Ra and Rb may optionally form a ring selected from- (5-7 member heteroaryl) and -(3-8 member heterocyclyl); each Rx and Ryis independently R; two R4 on adjacent atoms may optionally form a ring selected from phenyl, 4-7 member nonaromatic carbocyclyl, 5-7 member heteroaryl containing 1-4 atoms selected from O, N, and S, and 4-7 member heterocyclyl containing 1-4 atoms selected from O, N and S, wherein the said ring is optionally further substituted by 1-6 groups selected from Rx and oxo; and each m is independently O or 1 , or a pharmaceutically acceptable salt, solvate or hydrate thereof.
2. The compounds of claim 1, wherein the ring formed by Z1, Z2' Z3, Z4 and the two intervening carbons is selected from
Figure imgf000099_0001
wherein the said ring is optionally further substituted by 1 to 3 R4, and wherein 1 indicates the point of attachment to the aminopyrazole in formula I1 and 2 indicates the point of attachment to Ring A in formula I.
3. A compound of formula II,
Figure imgf000100_0001
wherein: each R2, R3, R5 and R6 is independently H or R;
Ring A is 3-4 member cycloalkyl, 3-4 member heterocyclyl, 5-7 member bicyclic heterocyclyl or 5-7 member bicyclic nonaromatic carbocyclyl, and Ring A is optionally further substituted by 1-6 groups selected from R7 and oxo;
R7 is R;
R is selected from the group consisting of C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, -(C1-C3 alkylene)m-(C3-Ci2 cycloalkyl), -(C1-C3 alkylene)m-phenyl, -(C1-C3 alkylene)m-(5-10 member heteroaryl), -(C1-C3 alkylene)m-(3-10 member heterocyclyl), - (C1-C3 alkylene)m-(3-12 member unsaturated non-aromatic carbocyclyl), -(C1-C6 perfluoroaklyl), -(C1-C3 alkylene)m-halide, -(CrC3 alkylene)m-CN, -(C1-C3 alkylene)m- C(O)R3, -(C1-C3 alkylene)m-C(O)ORa, -(C1-C3 alkylene)m-C(O)NRaRb, -(C1-C3 alkylene)m- ORa, -(C1-C3 alkylene)m-OC(O)Ra, -(C1-C3 alkylene)m-OC(O)NRaRb, -(C1-C3 alkylene)m-O- S(O)Ra, -(C1-C3 alkylene)m-OS(O)2Ra, -(C1-C3 alkylene)m-OS(O)2NRaRb, -(C1-C3 alkylene)m-OS(O)NRaRb, -(C1-C3 alkylene)m-NO2, -(C1-C3 alkylene)m-NRaRb -(C1-C3 alkylene)m-N(Ra)C(O)Rb, -(C1-C3 alkylene)m-N(Ra)C(O)ORb, -(C1-C3 alkylene)m- N(Rc)C(O)NRaRb, -(C1-C3 alkylene)m-N(Ra)S(O)2Rb, -(C1-C3 alkylene)m-N(Ra)S(O)Rb, -(C1- C3 alkylene)m-SRa, -(C1-C3 alkylene)m-S(O)Ra, -(C1-C3 alkylene)m-S(O)2Ra, -(C1-C3 alkylene)m-S(O)NRaRb and -(C1-C3 alkylene)m-S(O)2NRaRb, wherein each Ra, Rb and Rc is independently H, C1-C8 alkyl, C2-C8 alkenyl, -(C1-C3 alkylene)m-(C3-C8 cycloalkyl), -(C1-C3 alkylene)m-(C3-C8 cycloalkenyl), C2-C8 alkynyl, -(C1-C3 alkylene)m-phenyl, -(C1-C3 alkylene)m-(5-7 member heteroaryl) or -(C1-C3 alkylene)m-(3-8 member heterocyclyl), and when connected to the same atom, Ra and Rb may optionally form a ring selected from- (5-7 member heteroaryl) and -(3-8 member heterocyclyl); each R2, R3, R5, R6 and R7 is independently optionally further substituted by 1-6 groups selected from Rx and oxo, provided that when Rx is an substituent of R7, Rx is optionally further substituted by 1-6 groups selected from Ry and oxo; each Rx and Ry is independently R; and each m is independently 0 or 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
4. The compound of claim 3, wherein:
R2 and R3 are independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, -(C1-C3 alkylene)m-(C3-C6 cycloalkyl), -(C1-C3 alkylene)m-(C3-C6 cycloalkenyl), C2-C6 alkynyl and -(C1-C6 perfluoroalkyl), and that each R2 and R3 is optionally independently further substituted by 1-6 groups selected from oxo, -(C1-C3 alkylene)m-halide, -(C1-C3 alkylene)m-CN, -(C1-C3 alkylene)m-C(O)Ra, -(C1-C3 alkylene)m- C(O)OR3, -(C1-C3 alkylene)m-C(O)NRaRb, -(C1-C3 alkylene)m-ORa, -(C1-C3 alkylene)m- OC(O)R3 and -(C1-C3 alkylene)m-OC(O)NRaRb, wherein each Ra and Rb is independently H, C1-C6 alkyl or -(C1-C3 alkylene)m-(C3-C6 cycloalkyl), and when connecting to the same atom, Ra and Rb, may optionally form a ring selected from -(5-7 member heteroaryl) and - (3-8 member heterocyclyl);
R5 is selected from the group consisting of H, C1-C6 alkyl, and -(C1-C3 alkylene)m- (C3-C6 cycloalkyl); and
R5 is independently optionally further substituted by 1-6 groups selected from Rx and oxo.
5. The compound of claim 3, wherein:
R2 is H, C1-C6 alkyl or -(C1-C3 alkylene)m-(C3-C6 cycloalkyl),
R3 is H, C1-C6 alkyl or -(C1-C3 alkylene)m-(C3-C6 cycloalkyl);
R2 and R3 are optionally further substituted by 1-6 groups selected from halide, oxo, -CN, -ORa and -NRaRb, wherein each Ra and Rb is independently H, C1-C6 alkyl or - (C1-C3 alkylene)m-(C3-C6 cycloalkyl), and when connected to the same atom, Ra and Rb may optionally form a ring selected from -(5-7 member heteroaryl) and -(3-8 member heterocyclyl);
R5 is H, unsubstituted C1-C6 alkyl, unsubstituted -(C1-C3 alkylene)m-(C3-C6 cycloalkyl) or halide; and
R6 is selected from the group consisting of (C1-C3 alkylene)m-phenyl, (C1-C3 alkylene)m -(5-10 member heteroaryl), (C1-C3 alkylene)m (3-8 member heterocyclyl), (C1- C3 alkylene)m-(5-12 member bicyclic non-aromatic carbocyclyl) and -(Ci-C6 perfluoroaklyl), and R6 is optionally further substituted by 1-6 groups selected from Rx and oxo wherein Rx is R.
6. The compound of claim 3, wherein:
R2 is unsubstituted C1-C6 alkyl or unsubstituted -(C1-C3 alkylene)m-(C3-C6 cycloalkyl); R3 is H;
R5 is H1 unsubstituted C1-C6 alkyl, unsubstituted -(C1-C3 alkylene)m-(C3-C6 cycloalkyl) or halide;
R6 is selected from the group consisting of (C1-C3 alkylene)m-phenyl, (C1-C3 alkylene)n -(5-10 member heteroaryl), (C1-C3 alkylene)m (3-8 member heterocyclyl), (C1- C3 alkylene)m-(5-12 member bicyclic non-aromatic carbocyclyl) and -(C1-C6 perfluoroaklyl), and R6 is optionally further substituted by 1-6 groups selected from Rx and oxo wherein Rx is R; and
Ring A is selected from the group consisting of NG
Figure imgf000102_0001
Figure imgf000102_0002
i wherein — indicates the point of attachment to the pyrimidine ring 2 position, and Ring A is optonally further substituted by 1-6 groups selected from R7 and oxo.
7. The compound of claim 3, wherein R7 is selected from halide, C1-C6 alkyl, C2-C6 alkenyl, -(C1-C3 alkylene)m-(C3-C6 cycloalkyl), C1-C6 perfluroalkyl, -(C1-C3 alkylene)m- C(O)NRaRb, -(C1-C3 alkylene)m-C(O)ORa, -(C1-C3 alkylene)m-C(O)Ra, -(C1-C3 alkylene)m- NRaRb, -(C1-C3 alkylene)m-NRc-C(O)Ra, -(C1-C3 alkylene)m-NRc-C(O)NRaRb, -(C1-C3 alkylene)m -ORa, wherein each Ra Rb and Rc is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, and that R7 is unsubstituted.
8. The compound of claim 6, wherein R7 is selected from halide, C1-C6 alkyl, C2-C6 alkenyl, -(C1-C3 alkylene)m-(C3-C6 cycloalkyl), C1-C6 perfluroalkyl, -(C1-C3 alkylene)m- C(O)NRaRb, -(C1-C3 alkylene)m-C(O)ORa, -(C1-C3 alkylene)m-C(O)Ra, -(C1-C3 alkylene)m- NRaRb, -(C1-C3 alkylene)m-NRc-C(O)Ra, -(C1-C3 alkylene)m-NRG-C(O)NRaRb, -(C1-C3 alkylene)m -ORa, wherein each Ra Rb and Rc is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, and that R7 is unsubstituted.
9. The compound of claim 3, of formula III,
Figure imgf000102_0003
Hl wherein:
R2 is unsubstituted C1-C6 alkyl or unsubstituted -(C1-C3 alkylene)m-(C3-C6 cycloalkyl); R R88 represents 1-3 optional substituents, and each R8 is independently R.
10. The compound of claim 9, wherein:
Ring A is selected from the group consiissttiinngg ooff
Figure imgf000103_0001
, ^ Λ-O ,
Figure imgf000103_0002
, wherein — indicates the point of attachment to the pyrimidine ring 2 position, and Ring A is optonally further substituted by 1-6 groups selected from R7 and oxo; and
R7 is selected from halide, C1-C6 alkyl, C2-C6 alkenyl, -(C1-C3 alkylene)m-(C3-C6 cycloalkyl), C1-C6 perfluroalkyl, -(C1-C3 alkylene)m-C(O)NRaRb, -(C1-C3 alkylene)m- C(O)OR3, -(C1-C3 alkylene)m-C(O)Ra, -(C1-C3 alkylene)m-NRaRb, -(C1-C3 alkylene)m-NRc- C(O)Ra, -(C1-C3 alkylene)m-NRc-C(O)NRaRb, -(C1-C3 alkylene)m -ORa, wherein each Ra Rb and Rc is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, and that R7 is unsubstituted.
11. A compound of formula IV,
Figure imgf000103_0003
IV wherein:
Ring A is 3-4 member cycloalkyl, 3-4 member heterocyclyl, 5-7 member bicyclic heterocyclyl or 5-7 member bicyclic nonaromatic carbocyclyl, and Ring A is optionally further substituted by 1-6 groups selected from R7 and oxo;
B represents a ring selected from phenyl, 4-7 member nonaromatic carbocyclyl, 5-7 member heteroaryl containing 1-4 atoms selected from O, N, and S, and 4-7 member heterocyclyl containing 1-4 atoms selected from O, N and S, and the said ring is fused to the pyrimidine ring in formula IV; each R2 and R3 is independently H or R;
R7 is R; each R2, R3, R7 and B is independently optionally further substituted by 1-6 groups selected from Rx and oxo, provided that when Rx is an substituent of R7, Rx is optionally further substituted by 1-6 groups selected from Ry and oxo;
R is selected from the group consisting of C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, -(C1-C3 alkylene)m-(C3-C12 cycloalkyl), -(CrC3 alkylene)m-phenyl, -(C1-C3 alkylene)m-(5-10 member heteroaryl), -(C1-C3 alkylene)m-(3-10 member heterocyclyl), - (C1-C3 alkylene)m-(3-12 member unsaturated non-aromatic carbocyclyl), -(C1-C6 perfluoroaklyl), -(C1-C3 alkylene)m-halide, -(C1-C3 alkylene)m-CN, -(C1-C3 alkylene)m- C(O)Ra, -(C1-C3 alkylene)m-C(O)ORa, -(C1-C3 alkylene)m-C(O)NRaRb, -(C1-C3 alkylene)m- ORa, -(C1-C3 alkylene)m-OC(O)Ra, -(C1-C3 alkylene)m-OC(O)NRaRb, -(C1-C3 aikylene)m-O- S(O)Ra, -(C1-C3 alkylene)m-OS(O)2Ra, -(C1-C3 alkylene)m-OS(O)2NRaRb, -(C1-C3 alkylene)m-OS(O)NRaRb, -(C1-C3 alkylene)m-NO2, -(C1-C3 alkylene)m-NRaRb, -(C1PC3 alkylene)m-N(Ra)C(O)Rb, -(C1-C3 alkylene)m-N(Ra)C(O)ORb, -(C1-C3 alkylene)m- N(R°)C(O)NRaRb, -(C1-C3 alkylene)m-N(Ra)S(O)2Rb, -(C1-C3 alkylene)m-N(Ra)S(O)Rb 1 -(C1- C3 alkylene)m-SRa, -(C1-C3 alkylene)m-S(O)Ra, -(C1-C3 alkylene)m-S(O)2Ra, -(C1-C3 alkylene)m-S(O)NRaRb and -(C1-C3 alkylene)m-S(O)2NRaRb, wherein each Ra, Rb and Rc is independently H, C1-C8 alkyl, C2-C8 alkenyl, -(C1-C3 alkylene)m-(C3-C8 cycloalkyl), -(C1-C3 alkylene)m-(C3-C8 cycloalkenyl), C2-C8 alkynyl, -(C1-C3 alkylene)m-phenyl, -(C1-C3 alkylene)m-(5-7 member heteroaryl) or -(C1-C3 alkylene)m-(3-8 member heterocyclyl), and when connected to the same atom, Ra and Rb may optionally form a ring selected from- (5-7 member heteroaryl) and -(3-8 member heterocyclyl); each Rx and Ry is independently R; and each m is independently 0 or 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
12. The compound of claim 11 , wherein:
R2 is H, C1-C6 alkyl, or -(C1-C3 alkylene)m-(C3-C6 cycloalkyl); R3 is H, C1-C6 alkyl, Or -(C1-C3 aikylene)m-(C3-C6 cycloalkyl);and each R2 and R3 is independently optionally further substituted by 1-6 groups selected from halide, oxo, -CN, -ORa, and -NRaRb, wherein each Ra and Rb is independently H, C1-C6 alkyl or -(C1-C3 alkylene)m-(C3-C6 cycloalkyl).
13, The compound of claim 11 , of formula V,
Figure imgf000105_0001
V wherein R9 represents 1-2 optional substituents and that R 39a : is, R.
14. The compound of claim 11 , wherein R7, optional substitutents of Ring A, is selected from halide, C1-C6 alkyl, C2-C6 alkenyl, -(C1-C3 alkylene)m-(C3-C6 cycloalkyl), C1- C6 perfluroalkyl, -(C1-C3 alkylene)m-C(O)NRaRb, -(C1-C3 alkylene)m-C(O)ORa, -(C1-C3 alkylene)m-C(O)Ra, -(C1-C3 alkylene)m-NRaRb, -(C1-C3 alkylene)m-NR°-C(O)Ra, -(C1-C3 alkylene)m-NRc-C(O)NRaRb, -(C1-C3 alkylene)m -ORa, wherein each Ra Rb and Rc is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, and that R7 is unsubstituted.
15. The compound of claim 11 , wherein Ring A is selected from the group consisting of
Figure imgf000105_0002
wherein — indicates the point of attachment to the pyrimidine ring 2 position, and Ring A is optionally further substituted by 1-6 groups selected from oxo and R7.
16. The compound of claim 11 , wherein:
R2 is H, C1-C6 alkyl, or -(C1-C3 alkylene)m-(C3-C6 cycloalkyl);
R3 is H, C1-C6 alkyl, Or -(C1-C3 alkylene)m-(C3-C6 cycloalkyl); each R2 and R3 is independently optionally further substituted by 1-6 groups selected from halide, oxo, -CN, -ORa, and -NRaRb, wherein each Ra and Rb is independently H, C1-C6 alkyl or -(C1-C3 alkylene)m-(C3-C6 cycloalkyl);
B represents a ring selected from 5-6 member heteroaryl containing 1-2 atoms selected from O, N and S, 5-6 member heterocyclyl containing 1-2 atoms selected from O, N and S, phenyl and 5-6 member nonaromatic carbocyclyl, the said ring is fused to the pyrimidine ring in formula IV; and
Ring A is selected from the group consisting of I — I ,
Figure imgf000106_0001
. wherein — indicates the point of attachment to the pyrimidine ring 2 position, and Ring A is optionally further substituted by 1-6 groups selected from oxo and R7.
17. The compound of claim 16, wherein B represents a ring selected from thiophenyl, pyrrolyl, furanyl, phenyl.
18. The compound of claim 17, wherein R7 is selected from halide, C1-C6 alkyl, C2-C6 alkenyl, -(C1-C3 alkylene)m-(C3-C6 cycloalkyl), C1-C6 perfluroalkyl, -(C1-C3 alkylene)m- C(O)NRaRb, -(C1-C3 alkylene)m-C(O)ORa, -(C1-C3 alkylene)m-C(O)Ra, -(C1-C3 alkylene)m- NRaRb, -(C1-C3 alkylene)m-NRc-C(O)Ra, -(C1-C3 alkylene)m-NR°-C(O)NRaRb, -(C1-C3 alkylene)m -ORa, wherein each Ra Rb and R0 is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, and that R7 is unsubstituted.
19. A compound selected from the group consisting of
Figure imgf000106_0002
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
18. A method of modulating the activity of PAK4 protein kinase, comprising contacting the protein kinase with an effective amount of a compound, pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt, solvate of any of claims of 1-17.
19. A method of treating abnormal cell growth in a mammal, comprising administering to a mammal a therapeutically acceptable amount of a compound, salt, hydrate or solvate of any of claims 1-17.
20. The method of claim 19, wherein abnormal cell growth is cancer.
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