WO2019239374A1 - Inhibiteurs imidazopyrazines de kinase de lymphocytes t inductible par l'interleukine-2 - Google Patents

Inhibiteurs imidazopyrazines de kinase de lymphocytes t inductible par l'interleukine-2 Download PDF

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WO2019239374A1
WO2019239374A1 PCT/IB2019/054971 IB2019054971W WO2019239374A1 WO 2019239374 A1 WO2019239374 A1 WO 2019239374A1 IB 2019054971 W IB2019054971 W IB 2019054971W WO 2019239374 A1 WO2019239374 A1 WO 2019239374A1
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cancer
group
alkyl
optionally substituted
amino
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PCT/IB2019/054971
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English (en)
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Tjeerd Barf
Edwin DE ZWART
Saskia VERKAIK
Niels Hoogenboom
Dennis DEMONT
Allard Kaptein
Todd Covey
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Acerta Pharma B.V.
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Publication of WO2019239374A1 publication Critical patent/WO2019239374A1/fr

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    • 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
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the present invention relates to heterocyclic compounds, to
  • compositions comprising these compounds, and to their use in therapy.
  • pharmaceutical compositions comprising these compounds, and to their use in therapy.
  • the present invention relates to the use of imidazopyrazine compounds in the
  • ITK interleukin-2-inducible T-cell kinase
  • Interleukin-2-inducible T-cell kinase is a Tec family non-receptor protein kinase
  • the Tec family kinases which include ITK, Tec,
  • Bruton’s tyrosine kinase (ITK), Txk/Rlk and Bmx/Etk, are primarily expressed in
  • ITK is an intracellular tyrosine kinase expressed in T cells.
  • ITK plays a key role in antigen receptor signalling and cell
  • PLCy-l which cleaves phosphatidyl inositol (4,5) bisphosphate (PIP2) into the second messengers inositol 1,4,5-trisphosphate (IP3)
  • T cell malignancies such as acute lymphoblastic T cell leukemia and cutaneous T cell
  • ITK inhibitors have been developed and evaluated as potential therapies
  • inhibitors that selectively inhibit ITK with minimal effects on other kinases are urgently needed for effective therapies.
  • the invention includes a compound of Formula (I):
  • L is selected from the group consisting of–C(O)NH–,–NHC(O)–,–S(O)NH–,–NHS(O)–,– SO 2 NH–, and–NHSO 2 –;
  • V is selected from the group consisting of CH, C(R 5 ), and N;
  • W is selected from the group consisting of CH, C(R 6 ), and N;
  • X is selected from the group consisting of CH, C(R 7 ), and N;
  • Y is selected from the group consisting of CH, C(R 8 ), N, S, and a bond;
  • Z is selected from the group consisting of CH, C(R 9 ), N, O, and S;
  • R 5 is selected from the group consisting of a halogen, a (C 1-6 )alkyl optionally substituted with one or more halogens, (C 1-6 )alkoxyl optionally substituted with one or more halogens, and a (C 5-6 )heteroaryl;
  • R 6 is selected from the group consisting of a halogen, a (C 1-6 )alkyl optionally substituted with one or more halogens, a (C 1-6 )alkoxyl optionally substituted with one or more halogens, C(O)R 2 , a (C 5-6 )heteroaryl optionally substituted with a (C 1-6 )alkyl or (C 1-6 )alkoxyl, and a N(R 2 ) 2 ;
  • R 7 is selected from the group consisting of a halogen, a (C 1-6 )alkyl optionally substituted with one or more halogens, (C 1-6 )alkoxyl optionally substituted with one or more halogens, C(O)R 2 , a (C 5-6 )heteroaryl optionally substituted with a (C 1-6 )alkyl or (C 1-6 )alkoxyl, and a N(R 2 ) 2 ; or R 6 and R 7 form, together with the C or N atom they are attached to, an optionally substituted (C 5-6 )cycloaryl ring, an optionally substituted (C 5-6 )heteroaryl ring, an optionally substituted (C 5-6 )heterocyclyl ring or an optionally substituted (C 5- 6 )cycloalkyl ring;
  • R 8 is selected from the group consisting of a halogen, a (C 1-6 )alkyl or (C 1-6 )alkoxyl optionally substituted with one or more halogens, or a (C 5-6 )heteroaryl and
  • R 9 is selected from the group consisting of a halogen, a (C 1-6 )alkyl or (C 1-6 )alkoxyl optionally substituted with one or more halogens, or a (C 5-6 )heteroaryl and
  • B 1 is selected from the group consisting of CH, C(R 10 ), S, O and N;
  • B 2 is selected from the group consisting of CH, C(R 10 ), S, O, N, and a bond;
  • B 3 is selected from the group consisting of CH, C(R 10 ), N, and a bond;
  • B 4 is selected from the group consisting of CH, C(R 10 ), S, O, N, and a bond; with the privso that when B 1 , B 2 and B 4 are S or O, B 3 is a bond;
  • R 10 is selected from the group consisting of (C 1-6 )alkyl and (C 1-6 )alkoxyl;
  • R 1 is selected from the group consisting of C(O)R 11 , S(O)R 12 , and SO 2 R 13 ;
  • R 2 is selected from the group consisting of H, (C 1-3 )alkyl, and (C 3-7 )cycloalkyl;
  • R 3 is selected from the group consisting of H, (C 1-6 )alkyl, (C 1-6 )alkoxyl, and (C 3-7 )cycloalkyl; or
  • R 2 and R 3 form, together with the N and C atom they are attached to, a (C 3-7 )heterocycloalkyl ring optionally substituted with one or more fluorine, hydroxyl, (C 1-3 )alkyl, (C 1-3 )alkoxy or oxo;
  • R 4 is selected from a group consisting of H, (C 1-6 )alkoxyl, and (C 1-3 )alkyl;
  • R 11 , R 12 , and R 13 are selected from a group consisting of (C 1-6 )alkyl, (C 2-6 )alkenyl and (C 2- 6 )alkynyl, wherein each alkyl, alkenyl or alkynyl is optionally substituted with one or more groups selected from hydroxyl, (C 1-4 )alkyl optionally substituted with one or more halogens, (C 3-7 )cycloalkyl optionally substituted with one or more halogens, (C 1- 4 )alkylamino, di(C 1-4 )alkylamino, (C 1-4 )alkyl(C 1-6 )alkoxylamino, (C 1-3 )alkoxy, (C 3- 7 )cycloalkoxy, (C 6-10 )aryl, and (C 3-7 )
  • V, W, X, Y, and Z are O, S, or N;
  • V, W, X, Y, or Z is O, S, or N, then the nearest adjoining atom is not O, S, or N.
  • the invention includes a compound of Formula (II):
  • L is selected from the group consisting of–C(O)NH–,–NHC(O)–,–S(O)NH–,–NHS(O)–,– SO 2 NH–, and–NHSO 2 –;
  • V is selected from the group consisting of CH, C(R 5 ), and N;
  • W is selected from the group consisting of CH, C(R 6 ), and N;
  • X is selected from the group consisting of CH, C(R 7 ), and N;
  • Y is selected from the group consisting of CH, C(R 8 ), N, S, and a bond;
  • Z is selected from the group consisting of CH, C(R 9 ), N, O, and S;
  • R 5 is selected from the group consisting of a halogen, a (C 1-6 )alkyl optionally substituted with one or more halogens, (C 1-6 )alkoxyl optionally substituted with one or more halogens, and a (C 5-6 )heteroaryl;
  • R 6 is selected from the group consisting of a halogen, a (C 1-6 )alkyl optionally substituted with one or more halogens, a (C 1-6 )alkoxyl optionally substituted with one or more halogens, C(O)R 2 , a (C 5-6 )heteroaryl optionally substituted with a (C 1-6 )alkyl or (C 1-6 )alkoxyl, and a N(R 2 ) 2 ;
  • R 7 is selected from the group consisting of a halogen, a (C 1-6 )alkyl optionally substituted with one or more halogens, (C 1-6 )alkoxyl optionally substituted with one or more halogens, C(O)R 2 , a (C 5-6 )heteroaryl optionally substituted with a (C 1-6 )alkyl or (C 1-6 )alkoxyl, and a N(R 2 ) 2 ; or R 6 and R 7 form, together with the C or N atom they are attached to, an optionally substituted (C 5-6 )cycloaryl ring, an optionally substituted (C 5-6 )heteroaryl ring, an optionally substituted (C 5-6 )heterocyclyl ring or an optionally substituted (C 5- 6 )cycloalkyl ring;
  • R 8 is selected from the group consisting of a halogen, a (C 1-6 )alkyl or (C 1-6 )alkoxyl optionally substituted with one or more halogens, or a (C 5-6 )heteroaryl and
  • R 9 is selected from the group consisting of a halogen, a (C 1-6 )alkyl or (C 1-6 )alkoxyl optionally substituted with one or more halogens, or a (C 5-6 )heteroaryl and
  • B 1 is selected from the group consisting of CH, C(R 10 ), S, O and N;
  • B 2 is selected from the group consisting of CH, C(R 10 ), S, O, N, and a bond;
  • B 3 is selected from the group consisting of CH, C(R 10 ), N, and a bond;
  • B 4 is selected from the group consisting of CH, C(R 10 ), S, O, N, and a bond; with the privso that when B 1 , B 2 and B 4 are S or O, B 3 is a bond;
  • R 10 is selected from the group consisting of (C 1-6 )alkyl and (C 1-6 )alkoxyl;
  • R 1 is selected from the group consisting of C(O)R 11 , S(O)R 12 , and SO 2 R 13 ;
  • R 2 is selected from the group consisting of H, (C 1-3 )alkyl, and (C 3-7 )cycloalkyl;
  • R 3 is selected from the group consisting of H, (C 1-6 )alkyl, (C 1-6 )alkoxyl, and (C 3-7 )cycloalkyl; or
  • R 2 and R 3 form, together with the N and C atom they are attached to, a (C 3-7 )heterocycloalkyl ring optionally substituted with one or more fluorine, hydroxyl, (C 1-3 )alkyl, (C 1-3 )alkoxy or oxo;
  • R 4 is selected from a group consisting of H, (C 1-6 )alkoxyl, and (C 1-3 )alkyl;
  • R 11 , R 12 , and R 13 are selected from a group consisting of (C 1-6 )alkyl, (C 2-6 )alkenyl and (C 2- 6 )alkynyl, wherein each alkyl, alkenyl or alkynyl is optionally substituted with one or more groups selected from hydroxyl, (C 1-4 )alkyl optionally substituted with one or more halogens, (C 3-7 )cycloalkyl optionally substituted with one or more halogens, (C 1- 4 )alkylamino, di(C 1-4 )alkylamino, (C 1-4 )alkyl(C 1-6 )alkoxylamino, (C 1-3 )alkoxy, (C 3- 7 )cycloalkoxy, (C 6-10 )aryl, and (C 3-7 )heterocycloalkyl; or R 11 is (C 1-3 )alkyl-C(O)-S-(C 1- 3 )al
  • V, W, X, Y, and Z are O, S, or N;
  • V, W, X, Y, or Z is O, S, or N, then the nearest adjoining atom is not O, S, or N.
  • the invention includes a compound of Formula (III):
  • L is selected from the group consisting of–C(O)NH–,–NHC(O)–,–S(O)NH–,–NHS(O)–,– SO 2 NH–, and–NHSO 2 –;
  • R 5 is selected from the group consisting of a halogen, a (C 1-6 )alkyl optionally substituted with one or more halogens, (C 1-6 )alkoxyl optionally substituted with one or more halogens, and a (C 5-6 )heteroaryl;
  • R6 is selected from the group consisting of a halogen, a (C1-6)alkyl optionally substituted with one or more halogens, a (C 1-6 )alkoxyl optionally substituted with one or more halogens, C(O)R 2 , a (C 5-6 )heteroaryl optionally substituted with a (C 1-6 )alkyl or (C 1-6 )alkoxyl, and a N(R 2 ) 2 ;
  • R 7 is selected from the group consisting of a halogen, a (C 1-6 )alkyl optionally substituted with one or more halogens, (C 1-6 )alkoxyl optionally substituted with one or more halogens, C(O)R 2 , a (C 5-6 )heteroaryl optionally substituted with a (C 1-6 )alkyl or (C 1-6 )alkoxyl, and a N(R 2 ) 2 ; or R 6 and R 7 form, together with the C or N atom they are attached to, an optionally substituted (C 5-6 )cycloaryl ring, an optionally substituted (C 5-6 )heteroaryl ring, an optionally substituted (C 5-6 )heterocyclyl ring or an optionally substituted (C 5- 6)cycloalkyl ring; R 8 is selected from the group consisting of a halogen, a (C 1-6 )alkyl or (C 1-6 )
  • R 9 is selected from the group consisting of a halogen, a (C 1-6 )alkyl or (C 1-6 )alkoxyl optionally substituted with one or more halogens, or a (C 5-6 )heteroaryl and
  • B 1 is selected from the group consisting of CH, C(R 10 ), S, O and N;
  • B 2 is selected from the group consisting of CH, C(R 10 ), S, O, N, and a bond;
  • B 3 is selected from the group consisting of CH, C(R 10 ), N, and a bond;
  • B 4 is selected from the group consisting of CH, C(R 10 ), S, O, N, and a bond; with the privso that when B 1 , B 2 and B 4 are S or O, B 3 is a bond;
  • R 10 is selected from the group consisting of (C 1-6 )alkyl and (C 1-6 )alkoxyl;
  • R 1 is selected from the group consisting of C(O)R 11 , S(O)R 12 , and SO 2 R 13 ;
  • R 2 is selected from the group consisting of H, (C 1-3 )alkyl, and (C 3-7 )cycloalkyl;
  • R 3 is selected from the group consisting of H, (C 1-6 )alkyl, (C 1-6 )alkoxyl, and (C 3-7 )cycloalkyl; or
  • R 2 and R 3 form, together with the N and C atom they are attached to, a (C 3-7 )heterocycloalkyl ring optionally substituted with one or more fluorine, hydroxyl, (C 1-3 )alkyl, (C 1-3 )alkoxy or oxo;
  • R 4 is selected from a group consisting of H, (C 1-6 )alkoxyl, and (C 1-3 )alkyl;
  • R 11 , R 12 , and R 13 are selected from a group consisting of (C 1-6 )alkyl, (C 2-6 )alkenyl and (C 2- 6 )alkynyl, wherein each alkyl, alkenyl or alkynyl is optionally substituted with one or more groups selected from hydroxyl, (C 1-4 )alkyl optionally substituted with one or more halogens, (C 3-7 )cycloalkyl optionally substituted with one or more halogens, (C 1- 4 )alkylamino, di(C 1-4 )alkylamino, (C 1-4 )alkyl(C 1-6 )alkoxylamino, (C 1-3 )alkoxy, (C 3- 7 )cycloalkoxy, (C 6-10 )aryl, and (C 3-7 )heterocycloalkyl; or R 11 is (C 1-3 )alkyl-C(O)-S-(C 1- 3 )al
  • the invention includes a compound of Formula (IV):
  • L is selected from the group consisting of–C(O)NH–,–NHC(O)–,–S(O)NH–,–NHS(O)–,– SO 2 NH–, and–NHSO 2 –;
  • R 5 is selected from the group consisting of a halogen, a (C 1-6 )alkyl optionally substituted with one or more halogens, (C 1-6 )alkoxyl optionally substituted with one or more halogens, and a (C 5-6 )heteroaryl;
  • R 6 is selected from the group consisting of a halogen, a (C 1-6 )alkyl optionally substituted with one or more halogens, a (C 1-6 )alkoxyl optionally substituted with one or more halogens, C(O)R 2 , a (C 5-6 )heteroaryl optionally substituted with a (C 1-6 )alkyl or (C 1-6 )alkoxyl, and a N(R 2 ) 2 ;
  • R 7 is selected from the group consisting of a halogen, a (C 1-6 )alkyl optionally substituted with one or more halogens, (C 1-6 )alkoxyl optionally substituted with one or more halogens, C(O)R 2 , a (C 5-6 )heteroaryl optionally substituted with a (C 1-6 )alkyl or (C 1-6 )alkoxyl, and a N(R 2 ) 2 ; or R 6 and R 7 form, together with the C or N atom they are attached to, an optionally substituted (C 5-6 )cycloaryl ring, an optionally substituted (C 5-6 )heteroaryl ring, an optionally substituted (C 5-6 )heterocyclyl ring or an optionally substituted (C 5- 6 )cycloalkyl ring; R 8 is selected from the group consisting of a halogen, a (C 1-6 )alkyl or (C 1-6
  • R 9 is selected from the group consisting of a halogen, a (C 1-6 )alkyl or (C 1-6 )alkoxyl optionally substituted with one or more halogens, or a (C 5-6 )heteroaryl and
  • B 1 is selected from the group consisting of CH, C(R 10 ), S, O and N;
  • B 2 is selected from the group consisting of CH, C(R 10 ), S, O, N, and a bond;
  • B 3 is selected from the group consisting of CH, C(R 10 ), N, and a bond;
  • B 4 is selected from the group consisting of CH, C(R 10 ), S, O, N, and a bond; with the privso that when B 1 , B 2 and B 4 are S or O, B 3 is a bond;
  • R 10 is selected from the group consisting of (C 1-6 )alkyl and (C 1-6 )alkoxyl;
  • R 1 is selected from the group consisting of C(O)R 11 , S(O)R 12 , and SO 2 R 13 ;
  • R 4 is selected from a group consisting of H, (C 1-6 )alkoxyl, and (C 1-3 )alkyl;
  • n is selected from the group consisting of 2, 3, 4, and 5;
  • R r is C
  • R r is selected from the group consisting of C, N, O, and S, optionally substituted with one or more fluorine, hydroxyl, (C 1-3 )alkyl, (C 1-3 )alkoxy, or oxo, with the proviso that no direct N-N, O-O, S-S, N-C-N, O-C-O, or S-C-S bonds may be formed;
  • R 11 , R 12 , and R 13 are selected from a group consisting of (C 1-6 )alkyl, (C 2-6 )alkenyl and (C 2- 6 )alkynyl, wherein each alkyl, alkenyl or alkynyl is optionally substituted with one or more groups selected from hydroxyl, (C 1-4 )alkyl optionally substituted with one or more halogens, (C 3- 7 )cycloalkyl optionally substituted with one or more halogens, (C 1-4 )alkylamino, di(C 1- 4 )alkylamino, (C 1-4 )alkyl(C 1-6 )alkoxylamino, (C 1-3 )alkoxy, (C 3-7 )cycloalkoxy, (C 6-10 )aryl, and (C 3-7 )heterocycloalkyl; or R 11 is (C 1-3 )alkyl-C(O)-S-(C 1-3 )al
  • the invention includes a compound of Formula (V):
  • L is selected from the group consisting of–C(O)NH–,–NHC(O)–,–S(O)NH–,–NHS(O)–,– SO 2 NH–, and–NHSO 2 –;
  • R 5 is selected from the group consisting of a halogen, a (C 1-6 )alkyl optionally substituted with one or more halogens, (C 1-6 )alkoxyl optionally substituted with one or more halogens, and a (C 5-6 )heteroaryl;
  • R 6 is selected from the group consisting of a halogen, a (C 1-6 )alkyl optionally substituted with one or more halogens, a (C 1-6 )alkoxyl optionally substituted with one or more halogens, C(O)R 2 , a (C 5-6 )heteroaryl optionally substituted with a (C 1-6 )alkyl or (C 1-6 )alkoxyl, and a N(R 2 ) 2 ;
  • R 7 is selected from the group consisting of a halogen, a (C 1-6 )alkyl optionally substituted with one or more halogens, (C 1-6 )alkoxyl optionally substituted with one or more halogens, C(O)R 2 , a (C 5-6 )heteroaryl optionally substituted with a (C 1-6 )alkyl or (C 1-6 )alkoxyl, and a N(R 2 ) 2 ; or R 6 and R 7 form, together with the C or N atom they are attached to, an optionally substituted (C 5-6 )cycloaryl ring, an optionally substituted (C 5-6 )heteroaryl ring, an optionally substituted (C 5-6 )heterocyclyl ring or an optionally substituted (C 5- 6 )cycloalkyl ring;
  • R 8 is selected from the group consisting of a halogen, a (C 1-6 )alkyl or (C 1-6 )alkoxyl optionally substituted with one or more halogens, or a (C 5-6 )heteroaryl and
  • R 9 is selected from the group consisting of a halogen, a (C 1-6 )alkyl or (C 1-6 )alkoxyl optionally substituted with one or more halogens, or a (C 5-6 )heteroaryl and
  • B 1 is selected from the group consisting of CH, C(R 10 ), S, O and N;
  • B 2 is selected from the group consisting of CH, C(R 10 ), S, O, N, and a bond;
  • B 3 is selected from the group consisting of CH, C(R 10 ), N, and a bond;
  • B 4 is selected from the group consisting of CH, C(R 10 ), S, O, N, and a bond; with the privso that when B 1 , B 2 and B 4 are S or O, B 3 is a bond;
  • R 10 is selected from the group consisting of (C 1-6 )alkyl and (C 1-6 )alkoxyl;
  • R 1 is selected from the group consisting of C(O)R 11 , S(O)R 12 , and SO 2 R 13 ;
  • R 2 is selected from the group consisting of H, (C 1-3 )alkyl, and (C 3-7 )cycloalkyl;
  • R 3 is selected from the group consisting of H, (C 1-6 )alkyl, (C 1-6 )alkoxyl, and (C 3-7 )cycloalkyl; or
  • R 2 and R 3 form, together with the N and C atom they are attached to, a (C 3-7 )heterocycloalkyl ring optionally substituted with one or more fluorine, hydroxyl, (C 1-3 )alkyl, (C 1-3 )alkoxy or oxo;
  • R 4 is selected from a group consisting of H, (C 1-6 )alkoxyl, and (C 1-3 )alkyl;
  • R 11 , R 12 , and R 13 are selected from a group consisting of (C 1-6 )alkyl, (C 2-6 )alkenyl and (C 2- 6 )alkynyl, wherein each alkyl, alkenyl or alkynyl is optionally substituted with one or more groups selected from hydroxyl, (C 1-4 )alkyl optionally substituted with one or more halogens, (C 3-7 )cycloalkyl optionally substituted with one or more halogens, (C 1- 4 )alkylamino, di(C 1-4 )alkylamino, (C 1-4 )alkyl(C 1-6 )alkoxylamino, (C 1-3 )alkoxy, (C 3- 7 )cycloalkoxy, (C 6-10 )aryl, and (C 3-7 )heterocycloalkyl; or R 11 is (C 1-3 )alkyl-C(O)-S-(C 1- 3 )al
  • the invention includes a compound of Formula (VI):
  • L is selected from the group consisting of–C(O)NH– and–NHC(O)–;
  • C 1 is selected from the group consisting of CH and N, with the proviso that when C 2 is N, then C 1 is CH;
  • C 2 is selected from the group consisting of CH and N, with the proviso that when C 1 is N, then C 2 is CH;
  • R 1 is selected from the group consisting of C(O)R 11 , S(O)R 12 , and SO 2 R 13 ;
  • R 2 is selected from the group consisting of H, (C 1-3 )alkyl, (C 3-7 )alkyoxyl, and (C 3-7 )cycloalkyl
  • R 3 is selected from the group consisting of H, (C 1-6 )alkyl, (C 3-7 )alkyoxyl, and (C 3-7 )cycloalkyl); or R 2 and R 3 form, together with the N and C atom they are attached to, a (C 3-7 )heterocycloalkyl ring optionally substituted with one or more fluorine, hydroxyl, (C 1-3 )alkyl, (C 1-3 )alkoxy or oxo;
  • R 4 is selected from a group consisting of H, (C 1-6 )alkoxyl, and (C 1-3 )alkyl;
  • R 11 , R 12 , and R 13 are selected from a group consisting of (C 1-6 )alkyl, (C 2-6 )alkenyl and (C 2- 6 )alkynyl, wherein each alkyl, alkenyl or alkynyl is optionally substituted with one or more groups selected from hydroxyl, (C 1-4 )alkyl optionally substituted with one or more halogens, (C 3- 7 )cycloalkyl optionally substituted with one or more halogens, (C 1-4 )alkylamino, di(C 1- 4 )alkylamino, (C 1-4 )alkyl(C 1-6 )alkoxylamino, (C 1-3 )alkoxy, (C 3-7 )cycloalkoxy, (C 6-10 )aryl or (C 3- 7 )heterocycloalkyl; or R 11 is (C 1-3 )alkyl-C(O)-S-(C 1-3 )alky
  • co-administration encompass administration of two or more agents to a subject so that both agents and/or their metabolites are present in the subject at the same time.
  • Co-administration includes simultaneous administration in separate
  • compositions administration at different times in separate compositions, or administration in a composition in which two or more agents are present.
  • the term“effective amount” or“therapeutically effective amount” refers to that amount of a compound or combination of compounds as described herein that is sufficient to effect the intended application including, but not limited to, disease treatment.
  • a therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated (e.g., the weight, age and gender of the subject), the severity of the disease condition, the manner of administration, etc. which can readily be determined by one of ordinary skill in the art.
  • the term also applies to a dose that will induce a particular response in target cells (e.g., the reduction of platelet adhesion and/or cell migration).
  • A“therapeutic effect” as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above.
  • a prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
  • salts refers to salts derived from a variety of organic and inorganic counter ions known in the art.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins. Specific examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
  • cocrystal refers to a molecular complex derived from a number of cocrystal formers known in the art. Unlike a salt, a cocrystal typically does not involve hydrogen transfer between the cocrystal and the drug, and instead involves
  • intermolecular interactions such as hydrogen bonding, aromatic ring stacking, or dispersive forces, between the cocrystal former and the drug in the crystal structure.
  • “Pharmaceutically acceptable carrier” or“pharmaceutically acceptable excipient” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions of the invention is contemplated. Supplementary active ingredients can also be incorporated into the described compositions.
  • Prodrug is intended to describe a compound that may be converted under
  • prodrug refers to a precursor of a biologically active compound that is pharmaceutically acceptable.
  • a prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis.
  • the prodrug compound often offers the advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgaard, Design of Prodrugs, Elsevier, Amsterdam, 1985).
  • the term “prodrug” is also intended to include any covalently bonded carriers, which release the active compound in vivo when administered to a subject.
  • Prodrugs of an active compound may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to yield the active parent compound.
  • Prodrugs include, for example, compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
  • prodrugs include, but are not limited to, acetates, formates and benzoate derivatives of an alcohol, various ester derivatives of a carboxylic acid, or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound.
  • in vivo refers to an event that takes place in a subject's body.
  • in vitro refers to an event that takes places outside of a subject's body.
  • in vitro assays encompass cell-based assays in which cells alive or dead are employed and may also encompass a cell-free assay in which no intact cells are employed.
  • ranges are used herein to describe, for example, physical or chemical properties such as molecular weight or chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.
  • Use of the term“about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary from, for example, between 1% and 15% of the stated number or numerical range.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms (e.g., (C 1 - 10 )alkyl or C 1 - 10 alkyl).
  • a numerical range such as“1 to 10” refers to each integer in the given range - e.g.,“1 to 10 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the definition is also intended to cover the occurrence of the term“alkyl” where no numerical range is specifically designated.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl and decyl.
  • the alkyl moiety may be attached to the rest of the molecule by a single bond, such as for example, methyl (Me), ethyl (Et), n-propyl (Pr), 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl) and 3-methylhexyl.
  • an alkyl group is optionally substituted by one or more of substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , - OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , - N(R a )C(O)R a , -N(R a )C(O)OR
  • Alkylaryl refers to an -(alkyl)aryl radical where aryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.
  • Alkylhetaryl refers to an -(alkyl)hetaryl radical where hetaryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.
  • Alkylheterocycloalkyl refers to an -(alkyl) heterocycyl radical where alkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heterocycloalkyl and alkyl respectively.
  • An“alkene” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond
  • an“alkyne” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond.
  • the alkyl moiety, whether saturated or unsaturated, may be branched, straight chain, or cyclic.
  • Alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from two to ten carbon atoms (i.e., (C 2 - 10 )alkenyl or C 2 - 10 alkenyl).
  • a numerical range such as“2 to 10” refers to each integer in the given range - e.g.,“2 to 10 carbon atoms” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms.
  • the alkenyl moiety may be attached to the rest of the molecule by a single bond, such as for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl and penta-1,4-dienyl.
  • ethenyl i.e., vinyl
  • prop-1-enyl i.e., allyl
  • but-1-enyl i.e., pent-1-enyl and penta-1,4-dienyl.
  • an alkenyl group is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, - OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , - N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )
  • Alkenyl-cycloalkyl refers to an -(alkenyl)cycloalkyl radical where alkenyl and cyclo alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for alkenyl and cycloalkyl respectively.
  • Alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to ten carbon atoms (i.e., (C 2 - 10 )alkynyl or C 2 - 10 alkynyl).
  • a numerical range such as“2 to 10” refers to each integer in the given range - e.g.,“2 to 10 carbon atoms” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms.
  • the alkynyl may be attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl and hexynyl.
  • an alkynyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,
  • Alkynyl-cycloalkyl refers to an -(alkynyl)cycloalkyl radical where alkynyl and cycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for alkynyl and cycloalkyl respectively.
  • Cyano refers to a -CN radical.
  • Cycloalkyl refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and may be saturated, or partially unsaturated. Cycloalkyl groups include groups having from 3 to 10 ring atoms (i.e. (C 3 - 10 )cycloalkyl or C 3 - 10 cycloalkyl). Whenever it appears herein, a numerical range such as“3 to 10” refers to each integer in the given range - e.g.,“3 to 10 carbon atoms” means that the cycloalkyl group may consist of 3 carbon atoms, etc., up to and including 10 carbon atoms.
  • cycloalkyl groups include, but are not limited to the following moieties: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloseptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, and the like.
  • Cycloalkyl-alkenyl refers to a -(cycloalkyl)alkenyl radical where cycloalkyl and alkenyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and alkenyl, respectively.
  • Cycloalkyl-heterocycloalkyl refers to a -(cycloalkyl)heterocycloalkyl radical where cycloalkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and
  • Cycloalkyl-heteroaryl refers to a -(cycloalkyl)heteroaryl radical where cycloalkyl and heteroaryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and heteroaryl, respectively.
  • alkoxy or“alkoxyl” refers to the group -O-alkyl or–alkylene-O-alkyl, including from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and
  • “Lower alkoxy” refers to alkoxy groups containing one to six carbons.
  • substituted alkoxy refers to alkoxy wherein the alkyl constituent is substituted (i.e., -O-(substituted alkyl)).
  • the alkyl moiety of an alkoxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2
  • a (C 1 - 6 )alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atoms attached through its oxygen to a carbonyl linker.
  • “Lower alkoxycarbonyl” refers to an alkoxycarbonyl group wherein the alkoxy group is a lower alkoxy group.
  • substituted alkoxycarbonyl refers to the group (substituted alkyl)-O-C(O)- wherein the group is attached to the parent structure through the carbonyl functionality.
  • alkyl moiety of an alkoxycarbonyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , - OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O
  • Acyl refers to the groups (alkyl)-C(O)-, (aryl)-C(O)-, (heteroaryl)-C(O)-,
  • heteroalkyl C(O)- and (heterocycloalkyl)-C(O)-, wherein the group is attached to the parent structure through the carbonyl functionality.
  • R radical is heteroaryl or heterocycloalkyl, the hetero ring or chain atoms contribute to the total number of chain or ring atoms.
  • the alkyl, aryl or heteroaryl moiety of the acyl group is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , - OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , -N(R a )C(O)OR a ,
  • the“R” of an acyloxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , - OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , - N(R a )C(O)R a ,
  • Amino or“amine” refers to a -N(R a ) 2 radical group, where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, unless stated otherwise specifically in the specification.
  • R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, unless stated otherwise specifically in the specification.
  • R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl
  • -N(R a ) 2 is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl.
  • an amino group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,
  • substituted amino also refers to N-oxides of the groups -NHR d , and NR d R d each as described above. N-oxides can be prepared by treatment of the corresponding amino group with, for example, hydrogen peroxide or m-chloroperoxybenzoic acid.
  • Amide or“amido” refers to a chemical moiety with formula -C(O)N(R) 2
  • R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), each of which moiety may itself be optionally substituted.
  • the R 2 of -N(R) 2 of the amide may optionally be taken together with the nitrogen to which it is attached to form a 4-, 5-, 6- or 7- membered ring.
  • an amido group is optionally substituted independently by one or more of the substituents as described herein for alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl.
  • An amide may be an amino acid or a peptide molecule attached to a compound disclosed herein, thereby forming a prodrug.
  • the procedures and specific groups to make such amides are known to those of skill in the art and can readily be found in seminal sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein by reference in its entirety.
  • “Aromatic” or“aryl” or“Ar” refers to an aromatic radical with six to ten ring atoms (e.g., C 6 -C 10 aromatic or C 6 -C 10 aryl) which has at least one ring having a conjugated pi electron system which is carbocyclic (e.g., phenyl, fluorenyl, and naphthyl).
  • Bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals.
  • Bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in“-yl” by removal of one hydrogen atom from the carbon atom with the free valence are named by adding“-idene” to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene.
  • a numerical range such as“6 to 10” refers to each integer in the given range; e.g.,“6 to 10 ring atoms” means that the aryl group may consist of 6 ring atoms, 7 ring atoms, etc., up to and including 10 ring atoms.
  • an aryl moiety is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , - OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a )
  • R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
  • alkyl or“arylalkyl” refers to an (aryl)alkyl-radical where aryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.
  • Ester refers to a chemical radical of formula -COOR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon).
  • R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon).
  • the procedures and specific groups to make esters are known to those of skill in the art and can readily be found in seminal sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein by reference in its entirety.
  • an ester group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,
  • Fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, 2,2,2- trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the fluoroalkyl radical may be optionally substituted as defined above for an alkyl group.
  • Halo “Halo”,“halide”, or, alternatively,“halogen” is intended to mean fluoro, chloro, bromo or iodo.
  • the terms“haloalkyl,”“haloalkenyl,”“haloalkynyl” and“haloalkoxy” include alkyl, alkenyl, alkynyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof.
  • the terms“fluoroalkyl” and“fluoroalkoxy” include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine.
  • Heteroalkyl “heteroalkenyl” and“heteroalkynyl” include optionally substituted alkyl, alkenyl and alkynyl radicals and which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof.
  • a numerical range may be given - e.g., C 1 -C 4 heteroalkyl which refers to the chain length in total, which in this example is 4 atoms long.
  • a heteroalkyl group may be substituted with one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , - OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , -N(R a )C(O)OR a , -N(R a )C(O)R a
  • R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
  • Heteroalkylaryl refers to an -(heteroalkyl)aryl radical where heteroalkyl and aryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and aryl, respectively.
  • Heteroalkylheteroaryl refers to an -(heteroalkyl)heteroaryl radical where heteroalkyl and heteroaryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and heteroaryl, respectively.
  • Heteroalkylheterocycloalkyl refers to an -(heteroalkyl)heterocycloalkyl radical where heteroalkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and
  • Heteroalkylcycloalkyl refers to an -(heteroalkyl)cycloalkyl radical where heteroalkyl and cycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and cycloalkyl, respectively.
  • Heteroaryl or“heteroaromatic” or“HetAr” refers to a 5- to 18-membered aromatic radical (e.g., C 5 -C 13 heteroaryl) that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur, and which may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system.
  • a numerical range such as“5 to 18” refers to each integer in the given range - e.g.,“5 to 18 ring atoms” means that the heteroaryl group may consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms.
  • Bivalent radicals derived from univalent heteroaryl radicals whose names end in“-yl” by removal of one hydrogen atom from the atom with the free valence are named by adding“-idene” to the name of the corresponding univalent radical - e.g., a pyridyl group with two points of attachment is a pyridylidene.
  • a N-containing“heteroaromatic” or“heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom.
  • the polycyclic heteroaryl group may be fused or non-fused.
  • the heteroatom(s) in the heteroaryl radical are optionally oxidized.
  • heteroaryl may be attached to the rest of the molecule through any atom of the ring(s).
  • heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benz
  • a heteroaryl moiety is optionally substituted by one or more substituents which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR a , -SR a , -OC(O)- R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , - N(R a )C(O)R a ,
  • Substituted heteroaryl also includes ring systems substituted with one or more oxide (-O-) substituents, such as, for example, pyridinyl N-oxides.
  • Heteroarylalkyl refers to a moiety having an aryl moiety, as described herein, connected to an alkylene moiety, as described herein, wherein the connection to the remainder of the molecule is through the alkylene group.
  • Heterocycloalkyl refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Whenever it appears herein, a numerical range such as“3 to 18” refers to each integer in the given range - e.g.,“3 to 18 ring atoms” means that the heterocycloalkyl group may consist of 3 ring atoms, 4 ring atoms, etc., up to and including 18 ring atoms.
  • the heterocycloalkyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems.
  • the heteroatoms in the heterocycloalkyl radical may be optionally oxidized.
  • One or more nitrogen atoms, if present, are optionally quaternized.
  • the heterocycloalkyl radical is partially or fully saturated.
  • the heterocycloalkyl may be attached to the rest of the molecule through any atom of the ring(s).
  • heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2- oxopiperazinyl, 3-oxopiperazinyl, 2-oxomorpholinyl, 3-oxomorpholinyl, 2-oxopiperidinyl, 2- oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl,
  • heterocycloalkyl moiety is optionally substituted by one or more substituents which
  • Heterocycloalkyl also includes bicyclic ring systems wherein one non-aromatic ring, usually with 3 to 7 ring atoms, contains at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms; and the other ring, usually with 3 to 7 ring atoms, optionally contains 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen and is not aromatic.
  • Niro refers to the -NO 2 radical.
  • Oxa refers to the -O- radical.
  • “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space - i.e., having a different stereochemical configuration.“Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term“( ⁇ )” is used to designate a racemic mixture where appropriate. “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn- Ingold-Prelog R-S system.
  • stereochemistry at each chiral carbon can be specified by either (R) or (S).
  • Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
  • Certain of the compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R) or (S).
  • the present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures.
  • Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
  • Enantiomeric purity refers to the relative amounts, expressed as a percentage, of the presence of a specific enantiomer relative to the other enantiomer. For example, if a compound, which may potentially have an (R)- or an (S)-isomeric configuration, is present as a racemic mixture, the enantiomeric purity is about 50% with respect to either the (R)- or (S)-isomer. If that compound has one isomeric form predominant over the other, for example, 80% (S)-isomer and 20% (R)-isomer, the enantiomeric purity of the compound with respect to the (S)-isomeric form is 80%.
  • the enantiomeric purity of a compound can be determined in a number of ways known in the art, including but not limited to chromatography using a chiral support, polarimetric measurement of the rotation of polarized light, nuclear magnetic resonance spectroscopy using chiral shift reagents which include but are not limited to lanthanide containing chiral complexes or Pirkle’s reagents, or derivatization of a compounds using a chiral compound such as Mosher’s acid followed by chromatography or nuclear magnetic resonance spectroscopy.
  • the enantiomerically enriched composition has a higher potency with respect to therapeutic utility per unit mass than does the racemic mixture of that composition.
  • Enantiomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred enantiomers can be prepared by asymmetric syntheses. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions, Wiley Interscience, New York, 1981; Eliel, Stereochemistry of Carbon Compounds, McGraw-Hill, NY, 1962; and Eliel and Wilen, Stereochemistry of Organic Compounds, Wiley, New York, 1994.
  • an enantiomerically enriched preparation of the (S)-enantiomer means a preparation of the compound having greater than 50% by weight of the (S)-enantiomer relative to the (R)-enantiomer, such as at least 75% by weight, or such as at least 80% by weight.
  • the enrichment can be significantly greater than 80% by weight, providing a “substantially enantiomerically enriched” or a“substantially non-racemic” preparation, which refers to preparations of compositions which have at least 85% by weight of one enantiomer relative to other enantiomer, such as at least 90% by weight, or such as at least 95% by weight.
  • the terms“enantiomerically pure” or“substantially enantiomerically pure” refers to a composition that comprises at least 98% of a single enantiomer and less than 2% of the opposite enantiomer.
  • “Moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
  • Tautomers are structurally distinct isomers that interconvert by tautomerization. “Tautomerization” is a form of isomerization and includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry.“Prototropic
  • A“leaving group or atom” is any group or atom that will, under selected reaction conditions, cleave from the starting material, thus promoting reaction at a specified site.
  • Examples of such groups include halogen atoms and mesyloxy, p- nitrobenzensulphonyloxy and tosyloxy groups.
  • Protecting group is intended to mean a group that selectively blocks one or more reactive sites in a multifunctional compound such that a chemical reaction can be carried out selectively on another unprotected reactive site and the group can then be readily removed after the selective reaction is complete.
  • a variety of protecting groups are disclosed, for example, in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York, 1999.
  • Solvate refers to a compound in physical association with one or more molecules of a pharmaceutically acceptable solvent.
  • “Substituted” means that the referenced group may have attached one or more additional groups, radicals or moieties individually and independently selected from, for example, acyl, alkyl, alkylaryl, cycloalkyl, aralkyl, aryl, carbohydrate, carbonate, heteroaryl, heterocycloalkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, ester, thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, oxo, perhaloalkyl, perfluoroalkyl, phosphate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, and amino, including mono- and di-substituted amino groups, and protected
  • substituents themselves may be substituted, for example, a cycloalkyl substituent may itself have a halide substituent at one or more of its ring carbons.
  • optionally substituted means optional substitution with the specified groups, radicals or moieties.
  • “Sulfanyl” refers to groups that include -S-(optionally substituted alkyl), -S-(optionally substituted aryl), -S-(optionally substituted heteroaryl) and -S-(optionally substituted
  • “Sulfinyl” refers to groups that include -S(O)-H, -S(O)-(optionally substituted alkyl), -S(O)-(optionally substituted amino), -S(O)-(optionally substituted aryl), -S(O)- (optionally substituted heteroaryl) and -S(O)-(optionally substituted heterocycloalkyl).
  • “Sulfonyl” refers to groups that include -S(O 2 )-H, -S(O 2 )-(optionally substituted alkyl), -S(O 2 )-(optionally substituted amino), -S(O 2 )-(optionally substituted aryl), -S(O 2 )- (optionally substituted heteroaryl), and -S(O 2 )-(optionally substituted heterocycloalkyl).
  • a sulfonamido group is optionally substituted by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl, respectively.
  • a sulfonate group is optionally substituted on R by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl, respectively.
  • the term“IC 50 ” is the half maximal inhibitory concentration, which can be measured by techniques known to those of skill in the art, including IMAP (immobilized metal ion affinity- based fluorescence polarization) assays, and which provides information on the inhibition of a particular enzyme by a substance.
  • the term“EC 50 ” is the half maximal effective concentration, which can be measured by techniques known to those of skill in the art, and which provides information on the cellular effects or functional activity of a substance.
  • Compounds of the invention also include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.“Crystalline form” and“polymorph” are intended to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to.
  • ITK Inhibitors include, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or
  • ITK inhibitors of the present invention may include ITK inhibitors that bind covalently to the target in an irreversible manner, and ITK inhibitors that bind non-covalently to the target in a reversible manner.
  • the ITK inhibitor is an irreversible inhibitor of ITK that forms a covalent bond to Cys442 of ITK.
  • the invention includes an ITK inhibitor, wherein the ITK inhibitor is more potent or selective for ITK than for an enzyme selected from the group consisting of BTK, TEC, Txk, Bmx, EGFR WT, ErbB 2 , ErbB 4 , Blk 1, Jak3, and combinations thereof.
  • the ITK inhibitor is more potent or selective for ITK than for an enzyme selected from the group consisting of BTK, TEC, Txk, Bmx, EGFR WT, ErbB 2 , ErbB 4 , Blk 1, Jak3, and combinations thereof by a factor selected from the group consisting of 1000:1, 500:1; 250:1, 100:1, 50:1, 25:1, 10:1, 5:1, 4:1, 3:1, 2:1, and 1.5:1.
  • the ITK inhibitor is more potent or selective for ITK than for an enzyme selected from the group consisting of BTK, TEC, Txk, Bmx, EGFR WT, ErbB 2 , ErbB 4 , Blk 1, Jak3, and combinations thereof by a factor selected from the group consisting of 1000:1, 500:1; 250:1, 100:1, 50:1, 25:1, 10:1, 5:1, 4:1, 3:1, 2:1, 1.5:1, 1.4:1, 1.3:1, 1.2:1, and 1.1:1, wherein potency is determined by a comparison of IC 50 values obtained by a biochemical assay.
  • the ITK inhibitor is more potent or selective for ITK than for an enzyme selected from the group consisting of BTK, TEC, Txk, Bmx, EGFR WT, ErbB 2 , ErbB 4 , Blk 1, Jak3, and combinations thereof by a factor selected from the group consisting of 1000:1, 500:1; 250:1, 100:1, 50:1, 25:1, 10:1, 5:1, 4:1, 3:1, 2:1, and 1.5:1, wherein potency is determined by a comparison of EC 50 values obtained by a functional or cellular assay.
  • the invention includes a compound of Formula (I):
  • L is selected from the group consisting of–C(O)NH–,–NHC(O)–,–S(O)NH–,–NHS(O)–,– SO 2 NH–, and–NHSO 2 –;
  • V is selected from the group consisting of CH, C(R 5 ), and N;
  • W is selected from the group consisting of CH, C(R 6 ), and N;
  • X is selected from the group consisting of CH, C(R 7 ), and N;
  • Y is selected from the group consisting of CH, C(R 8 ), N, S, and a bond;
  • Z is selected from the group consisting of CH, C(R 9 ), N, O, and S;
  • R 5 is selected from the group consisting of a halogen, a (C 1-6 )alkyl optionally substituted with one or more halogens, (C 1-6 )alkoxyl optionally substituted with one or more halogens, and a (C 5-6 )heteroaryl;
  • R6 is selected from the group consisting of a halogen, a (C1-6)alkyl optionally substituted with one or more halogens, a (C 1-6 )alkoxyl optionally substituted with one or more halogens, C(O)R 2 , a (C 5-6 )heteroaryl optionally substituted with a (C 1-6 )alkyl or (C 1-6 )alkoxyl, and a N(R 2 ) 2 ;
  • R 7 is selected from the group consisting of a halogen, a (C 1-6 )alkyl optionally substituted with one or more halogens, (C 1-6 )alkoxyl optionally substituted with one or more halogens, C(O)R 2 , a (C 5-6 )heteroaryl optionally substituted with a (C 1-6 )alkyl or (C 1-6 )alkoxyl, and a N(R 2 ) 2 ; or R 6 and R 7 form, together with the C or N atom they are attached to, an optionally substituted (C 5-6 )cycloaryl ring, an optionally substituted (C 5-6 )heteroaryl ring, an optionally substituted (C 5-6 )heterocyclyl ring or an optionally substituted (C 5- 6 )cycloalkyl ring;
  • R 8 is selected from the group consisting of a halogen, a (C 1-6 )alkyl or (C 1-6 )alkoxyl optionally substituted with one or more halogens, or a (C 5-6 )heteroaryl and
  • R 9 is selected from the group consisting of a halogen, a (C 1-6 )alkyl or (C 1-6 )alkoxyl optionally substituted with one or more halogens, or a (C 5-6 )heteroaryl and
  • B 1 is selected from the group consisting of CH, C(R 10 ), S, O and N;
  • B 2 is selected from the group consisting of CH, C(R 10 ), S, O, N, and a bond;
  • B 3 is selected from the group consisting of CH, C(R 10 ), N, and a bond;
  • B 4 is selected from the group consisting of CH, C(R 10 ), S, O, N, and a bond; with the privso that when B 1 , B 2 and B 4 are S or O, B 3 is a bond;
  • R 10 is selected from the group consisting of (C 1-6 )alkyl and (C 1-6 )alkoxyl;
  • R 1 is selected from the group consisting of C(O)R 11 , S(O)R 12 , and SO 2 R 13 ;
  • R 2 is selected from the group consisting of H, (C 1-3 )alkyl, and (C 3-7 )cycloalkyl;
  • R 3 is selected from the group consisting of H, (C 1-6 )alkyl, (C 1-6 )alkoxyl, and (C 3-7 )cycloalkyl; or
  • R 2 and R 3 form, together with the N and C atom they are attached to, a (C 3-7 )heterocycloalkyl ring optionally substituted with one or more fluorine, hydroxyl, (C 1-3 )alkyl, (C 1-3 )alkoxy or oxo;
  • R 4 is selected from a group consisting of H, (C 1-6 )alkoxyl, and (C 1-3 )alkyl;
  • R 11 , R 12 , and R 13 are selected from a group consisting of (C 1-6 )alkyl, (C 2-6 )alkenyl and (C 2- 6 )alkynyl, wherein each alkyl, alkenyl or alkynyl is optionally substituted with one or more groups selected from hydroxyl, (C 1-4 )alkyl optionally substituted with one or more halogens, (C 3-7 )cycloalkyl optionally substituted with one or more halogens, (C 1- 4 )alkylamino, di(C 1-4 )alkylamino, (C 1-4 )alkyl(C 1-6 )alkoxylamino, (C 1-3 )alkoxy, (C 3- 7 )cycloalkoxy, (C 6-10 )aryl, and (C 3-7 )heterocycloalkyl; or R 11 is (C 1-3 )alkyl-C(O)-S-(C 1- 3 )al
  • V, W, X, Y, and Z are O, S, or N;
  • V, W, X, Y, or Z is O, S, or N, then the nearest adjoining atom is not O, S, or N.
  • the invention includes a compound of Formula (II):
  • L is selected from the group consisting of–C(O)NH–,–NHC(O)–,–S(O)NH–,–NHS(O)–,– SO 2 NH–, and–NHSO 2 –;
  • V is selected from the group consisting of CH, C(R 5 ), and N;
  • W is selected from the group consisting of CH, C(R6), and N;
  • X is selected from the group consisting of CH, C(R 7 ), and N;
  • Y is selected from the group consisting of CH, C(R 8 ), N, S, and a bond;
  • Z is selected from the group consisting of CH, C(R 9 ), N, O, and S;
  • R 5 is selected from the group consisting of a halogen, a (C 1-6 )alkyl optionally substituted with one or more halogens, (C 1-6 )alkoxyl optionally substituted with one or more halogens, and a (C 5-6 )heteroaryl;
  • R 6 is selected from the group consisting of a halogen, a (C 1-6 )alkyl optionally substituted with one or more halogens, a (C 1-6 )alkoxyl optionally substituted with one or more halogens, C(O)R 2 , a (C 5-6 )heteroaryl optionally substituted with a (C 1-6 )alkyl or (C 1-6 )alkoxyl, and a N(R 2 ) 2 ;
  • R 7 is selected from the group consisting of a halogen, a (C 1-6 )alkyl optionally substituted with one or more halogens, (C 1-6 )alkoxyl optionally substituted with one or more halogens, C(O)R 2 , a (C 5-6 )heteroaryl optionally substituted with a (C 1-6 )alkyl or (C 1-6 )alkoxyl, and a N(R 2 ) 2 ; or R 6 and R 7 form, together with the C or N atom they are attached to, an optionally substituted (C 5-6 )cycloaryl ring, an optionally substituted (C 5-6 )heteroaryl ring, an optionally substituted (C 5-6 )heterocyclyl ring or an optionally substituted (C 5- 6 )cycloalkyl ring;
  • R 8 is selected from the group consisting of a halogen, a (C 1-6 )alkyl or (C 1-6 )alkoxyl optionally substituted with one or more halogens, or a (C 5-6 )heteroaryl and
  • R 9 is selected from the group consisting of a halogen, a (C 1-6 )alkyl or (C 1-6 )alkoxyl optionally substituted with one or more halogens, or a (C 5-6 )heteroaryl and
  • B 1 is selected from the group consisting of CH, C(R 10 ), S, O and N;
  • B 2 is selected from the group consisting of CH, C(R 10 ), S, O, N, and a bond;
  • B 3 is selected from the group consisting of CH, C(R 10 ), N, and a bond;
  • B 4 is selected from the group consisting of CH, C(R 10 ), S, O, N, and a bond; with the privso that when B 1 , B 2 and B 4 are S or O, B 3 is a bond;
  • R 10 is selected from the group consisting of (C 1-6 )alkyl and (C 1-6 )alkoxyl;
  • R 1 is selected from the group consisting of C(O)R 11 , S(O)R 12 , and SO 2 R 13 ;
  • R 2 is selected from the group consisting of H, (C 1-3 )alkyl, and (C 3-7 )cycloalkyl;
  • R 3 is selected from the group consisting of H, (C 1-6 )alkyl, (C 1-6 )alkoxyl, and (C 3-7 )cycloalkyl; or
  • R 2 and R 3 form, together with the N and C atom they are attached to, a (C 3-7 )heterocycloalkyl ring optionally substituted with one or more fluorine, hydroxyl, (C 1-3 )alkyl, (C 1-3 )alkoxy or oxo;
  • R 4 is selected from a group consisting of H, (C 1-6 )alkoxyl, and (C 1-3 )alkyl;
  • R 11 , R 12 , and R 13 are selected from a group consisting of (C 1-6 )alkyl, (C 2-6 )alkenyl and (C 2- 6 )alkynyl, wherein each alkyl, alkenyl or alkynyl is optionally substituted with one or more groups selected from hydroxyl, (C 1-4 )alkyl optionally substituted with one or more halogens, (C 3-7 )cycloalkyl optionally substituted with one or more halogens, (C 1- 4 )alkylamino, di(C 1-4 )alkylamino, (C 1-4 )alkyl(C 1-6 )alkoxylamino, (C 1-3 )alkoxy, (C 3- 7 )cycloalkoxy, (C 6-10 )aryl, and (C 3-7 )heterocycloalkyl; or R 11 is (C 1-3 )alkyl-C(O)-S-(C 1- 3 )al
  • V, W, X, Y, and Z are O, S, or N;
  • V, W, X, Y, or Z is O, S, or N, then the nearest adjoining atom is not O, S, or N.
  • the invention includes a compound of Formula (III):
  • L is selected from the group consisting of–C(O)NH–,–NHC(O)–,–S(O)NH–,–NHS(O)–,– SO 2 NH–, and–NHSO 2 –;
  • R 5 is selected from the group consisting of a halogen, a (C 1-6 )alkyl optionally substituted with one or more halogens, (C 1-6 )alkoxyl optionally substituted with one or more halogens, and a (C 5-6 )heteroaryl;
  • R 6 is selected from the group consisting of a halogen, a (C 1-6 )alkyl optionally substituted with one or more halogens, a (C 1-6 )alkoxyl optionally substituted with one or more halogens, C(O)R 2 , a (C 5-6 )heteroaryl optionally substituted with a (C 1-6 )alkyl or (C 1-6 )alkoxyl, and a N(R 2 ) 2 ;
  • R 7 is selected from the group consisting of a halogen, a (C 1-6 )alkyl optionally substituted with one or more halogens, (C 1-6 )alkoxyl optionally substituted with one or more halogens, C(O)R 2 , a (C 5-6 )heteroaryl optionally substituted with a (C 1-6 )alkyl or (C 1-6 )alkoxyl, and a N(R 2 ) 2 ; or R 6 and R 7 form, together with the C or N atom they are attached to, an optionally substituted (C 5-6 )cycloaryl ring, an optionally substituted (C 5-6 )heteroaryl ring, an optionally substituted (C 5-6 )heterocyclyl ring or an optionally substituted (C 5- 6 )cycloalkyl ring;
  • R 8 is selected from the group consisting of a halogen, a (C 1-6 )alkyl or (C 1-6 )alkoxyl optionally substituted with one or more halogens, or a (C 5-6 )heteroaryl and
  • R 9 is selected from the group consisting of a halogen, a (C 1-6 )alkyl or (C 1-6 )alkoxyl optionally substituted with one or more halogens, or a (C 5-6 )heteroaryl and
  • B 1 is selected from the group consisting of CH, C(R 10 ), S, O and N;
  • B 2 is selected from the group consisting of CH, C(R 10 ), S, O, N, and a bond;
  • B 3 is selected from the group consisting of CH, C(R 10 ), N, and a bond;
  • B 4 is selected from the group consisting of CH, C(R 10 ), S, O, N, and a bond; with the privso that when B 1 , B 2 and B 4 are S or O, B 3 is a bond;
  • R 10 is selected from the group consisting of (C 1-6 )alkyl and (C 1-6 )alkoxyl;
  • R 1 is selected from the group consisting of C(O)R 11 , S(O)R 12 , and SO 2 R 13 ;
  • R 2 is selected from the group consisting of H, (C 1-3 )alkyl, and (C 3-7 )cycloalkyl; is selected from the group consisting of H, (C 1-6 )alkyl, (C 1-6 )alkoxyl, and (C 3-7 )cycloalkyl; or
  • R 2 and R 3 form, together with the N and C atom they are attached to, a (C 3-7 )heterocycloalkyl ring optionally substituted with one or more fluorine, hydroxyl, (C 1-3 )alkyl, (C 1-3 )alkoxy or oxo;
  • R 4 is selected from a group consisting of H, (C 1-6 )alkoxyl, and (C 1-3 )alkyl;
  • R 11 , R 12 , and R 13 are selected from a group consisting of (C 1-6 )alkyl, (C 2-6 )alkenyl and (C 2- 6 )alkynyl, wherein each alkyl, alkenyl or alkynyl is optionally substituted with one or more groups selected from hydroxyl, (C 1-4 )alkyl optionally substituted with one or more halogens, (C 3-7 )cycloalkyl optionally substituted with one or more halogens, (C 1- 4 )alkylamino, di(C 1-4 )alkylamino, (C 1-4 )alkyl(C 1-6 )alkoxylamino, (C 1-3 )alkoxy, (C 3- 7 )cycloalkoxy, (C 6-10 )aryl, and (C 3-7 )heterocycloalkyl; or R 11 is (C 1-3 )alkyl-C(O)-S-(C 1- 3 )al
  • the invention includes a compound of Formula (IV):
  • L is selected from the group consisting of–C(O)NH–,–NHC(O)–,–S(O)NH–, – SO 2 NH–, and–NHSO 2 –;
  • R 5 is selected from the group consisting of a halogen, a (C 1-6 )alkyl optionally substituted with one or more halogens, (C 1-6 )alkoxyl optionally substituted with one or more halogens, and a (C 5-6 )heteroaryl;
  • R 6 is selected from the group consisting of a halogen, a (C 1-6 )alkyl optionally substituted with one or more halogens, a (C 1-6 )alkoxyl optionally substituted with one or more halogens, C(O)R 2 , a (C 5-6 )heteroaryl optionally substituted with a (C 1-6 )alkyl or (C 1-6 )alkoxyl, and a N(R 2 ) 2 ;
  • R 7 is selected from the group consisting of a halogen, a (C 1-6 )alkyl optionally substituted with one or more halogens, (C 1-6 )alkoxyl optionally substituted with one or more halogens, C(O)R 2 , a (C 5-6 )heteroaryl optionally substituted with a (C 1-6 )alkyl or (C 1-6 )alkoxyl, and a N(R 2 ) 2 ; or R 6 and R 7 form, together with the C or N atom they are attached to, an optionally substituted (C 5-6 )cycloaryl ring, an optionally substituted (C 5-6 )heteroaryl ring, an optionally substituted (C 5-6 )heterocyclyl ring or an optionally substituted (C 5- 6 )cycloalkyl ring;
  • R 8 is selected from the group consisting of a halogen, a (C 1-6 )alkyl or (C 1-6 )alkoxyl optionally substituted with one or more halogens, or a (C 5-6 )heteroaryl and
  • R 9 is selected from the group consisting of a halogen, a (C 1-6 )alkyl or (C 1-6 )alkoxyl optionally substituted with one or more halogens, or a (C 5-6 )heteroaryl and
  • B 1 is selected from the group consisting of CH, C(R 10 ), S, O and N;
  • B 2 is selected from the group consisting of CH, C(R 10 ), S, O, N, and a bond;
  • B 3 is selected from the group consisting of CH, C(R 10 ), N, and a bond;
  • B 4 is selected from the group consisting of CH, C(R 10 ), S, O, N, and a bond; with the privso that when B 1 , B 2 and B 4 are S or O, B 3 is a bond;
  • R 10 is selected from the group consisting of (C 1-6 )alkyl and (C 1-6 )alkoxyl;
  • R 1 is selected from the group consisting of C(O)R 11 , S(O)R 12 , and SO 2 R 13 ;
  • R 4 is selected from a group consisting of H, (C 1-6 )alkoxyl, and (C 1-3 )alkyl; n is selected from the group consisting of 2, 3, 4, and 5;
  • R r is C
  • R r is selected from the group consisting of C, N, O, and S, optionally substituted with one or more fluorine, hydroxyl, (C 1-3 )alkyl, (C 1-3 )alkoxy, or oxo, with the proviso that no direct N-N, O-O, S-S, N-C-N, O-C-O, or S-C-S bonds may be formed;
  • R 11 , R 12 , and R 13 are selected from a group consisting of (C 1-6 )alkyl, (C 2-6 )alkenyl and (C 2- 6 )alkynyl, wherein each alkyl, alkenyl or alkynyl is optionally substituted with one or more groups selected from hydroxyl, (C 1-4 )alkyl optionally substituted with one or more halogens, (C 3- 7 )cycloalkyl optionally substituted with one or more halogens, (C 1-4 )alkylamino, di(C 1- 4 )alkylamino, (C 1-4 )alkyl(C 1-6 )alkoxylamino, (C 1-3 )alkoxy, (C 3-7 )cycloalkoxy, (C 6-10 )aryl, and (C 3-7 )heterocycloalkyl; or R 11 is (C 1-3 )alkyl-C(O)-S-(C 1-3 )al
  • the invention includes a compound of Formula (V):
  • L is selected from the group consisting of–C(O)NH–,–NHC(O)–,–S(O)NH–,–NHS(O)–,– SO 2 NH–, and–NHSO 2 –;
  • R 5 is selected from the group consisting of a halogen, a (C 1-6 )alkyl optionally substituted with one or more halogens, (C 1-6 )alkoxyl optionally substituted with one or more halogens, and a (C 5-6 )heteroaryl;
  • R 6 is selected from the group consisting of a halogen, a (C 1-6 )alkyl optionally substituted with one or more halogens, a (C 1-6 )alkoxyl optionally substituted with one or more halogens, C(O)R 2 , a (C 5-6 )heteroaryl optionally substituted with a (C 1-6 )alkyl or (C 1-6 )alkoxyl, and a N(R 2 ) 2 ;
  • R 7 is selected from the group consisting of a halogen, a (C 1-6 )alkyl optionally substituted with one or more halogens, (C 1-6 )alkoxyl optionally substituted with one or more halogens, C(O)R 2 , a (C 5-6 )heteroaryl optionally substituted with a (C 1-6 )alkyl or (C 1-6 )alkoxyl, and a N(R 2 ) 2 ; or R 6 and R 7 form, together with the C or N atom they are attached to, an optionally substituted (C 5-6 )cycloaryl ring, an optionally substituted (C 5-6 )heteroaryl ring, an optionally substituted (C 5-6 )heterocyclyl ring or an optionally substituted (C 5- 6 )cycloalkyl ring;
  • R 8 is selected from the group consisting of a halogen, a (C 1-6 )alkyl or (C 1-6 )alkoxyl optionally substituted with one or more halogens, or a (C 5-6 )heteroaryl and
  • R 9 is selected from the group consisting of a halogen, a (C 1-6 )alkyl or (C 1-6 )alkoxyl optionally substituted with one or more halogens, or a (C 5-6 )heteroaryl and
  • B 1 is selected from the group consisting of CH, C(R 10 ), S, O and N;
  • B 2 is selected from the group consisting of CH, C(R 10 ), S, O, N, and a bond;
  • B 3 is selected from the group consisting of CH, C(R 10 ), N, and a bond;
  • B 4 is selected from the group consisting of CH, C(R 10 ), S, O, N, and a bond; with the privso that when B 1 , B 2 and B 4 are S or O, B 3 is a bond;
  • R 10 is selected from the group consisting of (C 1-6 )alkyl and (C 1-6 )alkoxyl;
  • R 1 is selected from the group consisting of C(O)R 11 , S(O)R 12 , and SO 2 R 13 ;
  • R 2 is selected from the group consisting of H, (C 1-3 )alkyl, and (C 3-7 )cycloalkyl;
  • R 3 is selected from the group consisting of H, (C 1-6 )alkyl, (C 1-6 )alkoxyl, and (C 3-7 )cycloalkyl; or R 2 and R 3 form, together with the N and C atom they are attached to, a (C 3-7 )heterocycloalkyl ring optionally substituted with one or more fluorine, hydroxyl, (C 1-3 )alkyl, (C 1-3 )alkoxy or oxo;
  • R 4 is selected from a group consisting of H, (C 1-6 )alkoxyl, and (C 1-3 )alkyl;
  • R 11 , R 12 , and R 13 are selected from a group consisting of (C 1-6 )alkyl, (C 2-6 )alkenyl and (C 2- 6 )alkynyl, wherein each alkyl, alkenyl or alkynyl is optionally substituted with one or more groups selected from hydroxyl, (C 1-4 )alkyl optionally substituted with one or more halogens, (C 3-7 )cycloalkyl optionally substituted with one or more halogens, (C 1- 4 )alkylamino, di(C 1-4 )alkylamino, (C 1-4 )alkyl(C 1-6 )alkoxylamino, (C 1-3 )alkoxy, (C 3- 7 )cycloalkoxy, (C 6-10 )aryl, and (C 3-7 )heterocycloalkyl; or R 11 is (C 1-3 )alkyl-C(O)-S-(C 1- 3 )al
  • the invention includes a compound of Formula (VI):
  • L is selected from the group consisting of–C(O)NH– and–NHC(O)–;
  • C 1 is selected from the group consisting of CH and N, with the proviso that when C 2 is N, then C 1 is CH;
  • C 2 is selected from the group consisting of CH and N, with the proviso that when C 1 is N, then C 2 is CH;
  • R 1 is selected from the group consisting of C(O)R 11 , S(O)R 12 , and SO 2 R 13 ;
  • R 2 is selected from the group consisting of H, (C 1-3 )alkyl, (C 3-7 )alkyoxyl, and (C 3-7 )cycloalkyl
  • R 3 is selected from the group consisting of H, (C 1-6 )alkyl, (C 3-7 )alkyoxyl, and (C 3-7 )cycloalkyl); or R 2 and R 3 form, together with the N and C atom they are attached to, a (C 3-7 )heterocycloalkyl ring optionally substituted with one or more fluorine, hydroxyl, (C 1-3 )alkyl, (C 1-3 )alkoxy or oxo;
  • R 4 is selected from a group consisting of H, (C 1-6 )alkoxyl, and (C 1-3 )alkyl;
  • R 11 , R 12 , and R 13 are selected from a group consisting of (C 1-6 )alkyl, (C 2-6 )alkenyl and (C 2- 6 )alkynyl, wherein each alkyl, alkenyl or alkynyl is optionally substituted with one or more groups selected from hydroxyl, (C 1-4 )alkyl optionally substituted with one or more halogens, (C 3- 7 )cycloalkyl optionally substituted with one or more halogens, (C 1-4 )alkylamino, di(C 1- 4 )alkylamino, (C 1-4 )alkyl(C 1-6 )alkoxylamino, (C 1-3 )alkoxy, (C 3-7 )cycloalkoxy, (C 6-10 )aryl or (C 3- 7 )heterocycloalkyl; or R 11 is (C 1-3 )alkyl-C(O)-S-(C 1-3 )alky
  • the ITK inhibitor is a compound selected from the group consisting of:
  • the ITK inhibitor is a compound selected from the group consisting of:
  • the ITK inhibitor is a compound selected from the group consisting of:
  • the invention provides pharmaceutical compositions for treating solid tumor cancers, lymphomas and leukemia.
  • the pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of an ITK inhibitor as the active ingredients, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
  • the pharmaceutical compositions contain a pharmaceutically acceptable salt and/or coordination complex thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
  • the pharmaceutical compositions are administered as an ITK inhibitor.
  • other agent(s) may be mixed into a preparation or both components may be formulated into separate preparations for use in combination separately or at the same time.
  • the concentration of each of the ITK inhibitors provided in the pharmaceutical compositions of the invention is independently less than, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w/w, w/v or v/v, relative to the total mass or volume of
  • the concentration of each of the ITK inhibitors provided in the pharmaceutical compositions of the invention is independently greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25%
  • the concentration of each of the ITK inhibitors of the invention is independently in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40%, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12% or approximately 1% to approximately 10% w/w, w/v or v/v, relative to the total mass or volume of the pharmaceutical composition.
  • the concentration of each of the ITK inhibitors of the invention is independently in the range from approximately 0.001% to approximately 10%, approximately 0.01% to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, approximately 0.1% to approximately 0.9% w/w, w/v or v/v, relative to the total mass or volume of the pharmaceutical composition.
  • the amount of each of the ITK inhibitors of the invention is independently equal to or less than 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007
  • the amount of each of the ITK inhibitors of the invention is independently more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.
  • each of the ITK inhibitors according to the invention is effective over a wide dosage range.
  • dosages independently range from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used.
  • the exact dosage will depend upon the route of administration, the form in which the compound is administered, the gender and age of the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.
  • compositions for Oral Administration are provided.
  • the invention provides a pharmaceutical composition for oral administration containing an ITK inhibitor disclosed herein and a pharmaceutical excipient suitable for oral administration.
  • the invention provides a solid pharmaceutical composition for oral administration containing: (i) an effective amount of an ITK inhibitor disclosed herein and (ii) a pharmaceutical excipient suitable for oral administration.
  • the composition further contains (iii) an effective amount of a fourth compound.
  • the pharmaceutical composition may be a liquid
  • compositions of the invention suitable for oral administration can be presented as discrete dosage forms, such as capsules, cachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion.
  • dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient(s) into association with the carrier, which constitutes one or more necessary ingredients.
  • compositions are prepared by uniformly and intimately admixing the active ingredient(s) with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the invention further encompasses anhydrous pharmaceutical compositions and dosage forms since water can facilitate the degradation of some compounds.
  • water may be added (e.g., 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time.
  • Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • Pharmaceutical compositions and dosage forms of the invention which contain lactose can be made anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
  • An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained.
  • anhydrous compositions may be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits.
  • suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.
  • each of the ITK inhibitors as active ingredients can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier can take a wide variety of forms depending on the form of preparation desired for administration.
  • any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose.
  • suitable carriers include powders, capsules, and tablets, with the solid oral preparations. If desired, tablets can be coated by standard aqueous or nonaqueous techniques.
  • Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre- gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.
  • natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrol
  • suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • Disintegrants may be used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which disintegrate in the bottle. Too little may be insufficient for disintegration to occur, thus altering the rate and extent of release of the active ingredients from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art.
  • Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.
  • Lubricants which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethylaureate, agar, or mixtures thereof.
  • Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof.
  • a lubricant can optionally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition.
  • the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.
  • the tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
  • Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • Surfactants which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed.
  • a suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10.
  • An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of non- ionic amphiphilic compounds is the hydrophilic-lipophilic balance (“HLB” value).
  • HLB hydrophilic-lipophilic balance
  • Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions.
  • Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable.
  • lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10.
  • HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions.
  • Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids,
  • oligopeptides, and polypeptides lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.
  • ionic surfactants include, by way of example:
  • lecithins lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di- glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.
  • Ionic surfactants may be the ionized forms of lecithin, lysolecithin,
  • phosphatidylcholine phosphatidylethanolamine
  • phosphatidylglycerol phosphatidic acid
  • phosphatidylserine lysophosphatidylcholine
  • lysophosphatidylethanolamine phosphatidylethanolamine
  • lysophosphatidylglycerol lysophosphatidic acid, lysophosphatidylserine, PEG- phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl carn
  • Hydrophilic non-ionic surfactants may include, but not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterol
  • hydrophilic-non-ionic surfactants include, without limitation, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG- 15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl ole
  • Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil- soluble vitamins/vitamin derivatives; and mixtures thereof.
  • preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.
  • the composition may include a solubilizer to ensure good solubilization and/or dissolution of the compound of the present invention and to minimize precipitation of the compound of the present invention. This can be especially important for compositions for non-oral use - e.g., compositions for injection.
  • a solubilizer may also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.
  • solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol,
  • alcohols and polyols such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol,
  • solubilizers may also be used. Examples include, but not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.
  • the amount of solubilizer that can be included is not particularly limited.
  • the amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art.
  • the solubilizer can be in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by weight, based on the combined weight of the drug, and other excipients.
  • very small amounts of solubilizer may also be used, such as 5%, 2%, 1% or even less.
  • the solubilizer may be present in an amount of about 1% to about 100%, more typically about 5% to about 25% by weight.
  • the composition can further include one or more pharmaceutically acceptable additives and excipients.
  • additives and excipients include, without limitation, detackifiers, anti- foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.
  • an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons.
  • pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like.
  • bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like.
  • a pharmaceutically acceptable acid such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids
  • Salts of polyprotic acids such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used.
  • the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals and alkaline earth metals.
  • Example may include, but not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium.
  • Suitable acids are pharmaceutically acceptable organic or inorganic acids.
  • suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like.
  • suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p- toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid and uric acid.
  • compositions may also be prepared from compositions described herein and one or more pharmaceutically acceptable excipients suitable for intravenous, intramuscular, topical, sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration.
  • pharmaceutically acceptable excipients suitable for intravenous, intramuscular, topical, sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration.
  • Preparations for such pharmaceutical compositions are well-known in the art. See, e.g., Anderson, et al., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; and Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, N.Y., 1990, each of which is incorporated by reference herein in its entirety.
  • Administration of the ITK inhibitors or pharmaceutical compositions of these compounds can be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (e.g., transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation.
  • the combination of compounds can also be administered intraadiposally or intrathecally.
  • Parenteral administration forms include solutions or suspensions of active compound in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.
  • kits include each the ITK inhibitors, either alone or in combination in suitable packaging, and written material that can include instructions for use, discussion of clinical studies and listing of side effects.
  • kits may also include information, such as scientific literature references, package insert materials, clinical trial results, and/or summaries of these and the like, which indicate or establish the activities and/or advantages of the composition, and/or which describe dosing, administration, side effects, drug interactions, or other information useful to the health care provider. Such information may be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials.
  • the kit may further contain another agent.
  • the ITK inhibitors and the agent are provided as separate compositions in separate containers within the kit.
  • the ITK inhibitors and the agent are provided as a single composition within a container in the kit.
  • Kits described herein can be provided, marketed and/or promoted to health providers, including physicians, nurses, pharmacists, formulary officials, and the like. Kits may also, in selected embodiments, be marketed directly to the consumer.
  • the amounts of the ITK inhibitors administered will be dependent on the mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compounds and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, such as about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g/day, such as about 0.05 to about 2.5 g/day.
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect - e.g., by dividing such larger doses into several small doses for administration throughout the day.
  • the ITK inibitor is administered in a single dose.
  • such administration will be by injection, for example by intravenous injection, in order to introduce the agents quickly.
  • other routes may be used as appropriate.
  • a single dose of the ITK inhibitor may also be used for treatment of an acute condition.
  • the ITK inhibitor is administered in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be about once a month, once every two weeks, once a week, or once every other day. In other embodiments, the ITK inhibitor is administered about once per day to about 6 times per day. In another embodiment the administration of the ITK inhibitor continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary.
  • the ITK inhibitor is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the ITK inhibitor is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In selected embodiments, the ITK inhibitor is administered chronically on an ongoing basis - e.g., for the treatment of chronic effects.
  • An effective amount of the combination of the ITK inhibitor may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.
  • the invention relates to a method of treating a hyperproliferative disorder in a mammal that comprises administering to said mammal a therapeutically effective amount of an ITK inhibitor, or a pharmaceutically acceptable salt, ester, prodrug, cocrystal, solvate, or hydrate of the ITK inhibitor.
  • the hyperproliferative disorder may be a cancer, including a hematoligical malignancy (such as a T cell cancer) and a solid tumor cancer, or may be a non-cancerous hyperproliferative disorder.
  • the hyperproliferative disorder may also be an inflammatory disorder, an immune disorder, or an autoimmune disorder, including a dermatosis.
  • the hyperproliferative disorder may also be an immune activation, such as graft-versus-host- disease, rejection of an allograft, or the development or persistence of anti-allogeneic antibodies.
  • the hyperproliferative disorder could be a neuroinflammatory condition.
  • the hyperproliferative disorder could also be a reaction to an allergen, such as a Type I or Type 2 sensitization, or an allergic reaction.
  • the mammal is a human. In a preferred
  • the mammal is a companion animal.
  • the mammal is a companion animal selected from the group consisting of a canine, a feline, and an equine.
  • the invention relates to a method of treating a T cell cancer with an ITK inhibitor.
  • the invention relates to a method of treating, with an ITK inhibitor, a hyperproliferative disorder in a mammal that is a T cell cancer selected from the group consisting of classical Hodgkin lymphoma, nodular sclerosis or lymphocyte rich subsets of classical Hodgkin lymphoma, nodular lymphocyte-predominant Hodgkin lymphoma, lymphocyte depleted Hodgkin lymphoma, T cell non-Hodgkin’s lymphoma, precursor T lymphoblastic lymphoma/leukemia, T cell acute lymphoytic lymphoma, angioimmunoblastic T cell lymphoma, peripheral T cell lymphoma, mature T cell lymphoma, cutaneous T cell lymphoma, adult T cell leukemia/lymphoma, extranodal natural killer/T cell lymphoma
  • the invention relates to a method of treating, with an ITK inhibitor, a cutaneous T cell lymphoma or lymphoproliferative disorder selected from the group consisting of mycosis fungoides, lymphomatous papulosis, and Sezary syndrome.
  • the invention relates to treating an lymphoproliferative disorder resulting from viral activation. Efficacy of the compounds and combinations of compounds described herein in treating, preventing and/or managing hematological
  • malignancies including T cell cancers
  • the SCL-LMO1, OLIG2- LMO1, and NUP98-HOXD1 mouse models reproduce many features of human disease.
  • Other suitable models are known in the art.
  • the invention relates to a method of treating, with an ITK inhibitor, a hyperproliferative disorder that is an aggressive NK cell leukemia or lymphoma.
  • a hyperproliferative disorder that is an aggressive NK cell leukemia or lymphoma.
  • Aggressive NK cell leumemia is described in Chan, et al., Aggressive NK-cell leukaemia, in Jaffe, et al., eds., Tumours of Haematopoietic and Lymphoid Tissues. World Health Organization Classification of Tumours. Lyon: IARC Press, 2001, pp.198-200.
  • Efficacy of the compounds and combinations of compounds described herein in treating, preventing and/or managing hematological malignancies, including NK cell cancers may be assessed using animal models known in the art.
  • the invention relates to a method of treating, with an ITK inhibitor, a hyperproliferative disorder in a mammal that is a solid tumor cancer selected from the group consisting of bladder cancer, non-small cell lung cancer, cervical cancer, anal cancer, pancreatic cancer, squamous cell carcinoma including head and neck cancer, renal cell carcinoma, melanoma, ovarian cancer, small cell lung cancer, glioblastoma, gastrointestinal stromal tumor, breast cancer, lung cancer, colorectal cancer, thyroid cancer, bone sarcoma, stomach cancer, oral cavity cancer, oropharyngeal cancer, gastric cancer, kidney cancer, liver cancer, prostate cancer, esophageal cancer, testicular cancer, gynecological cancer, colon cancer, brain cancer, adrenal cancer, and adrenocortical tumor.
  • a solid tumor cancer selected from the group consisting of bladder cancer, non-small cell lung cancer, cervical cancer, anal cancer, pancreatic cancer, squamous cell carcinoma including head and neck
  • Efficacy of the compounds and combinations of compounds described herein in treating, preventing and/or managing solid tumor cancers may be assessed using animal models known in the art. For example, models for determining efficacy of treatments for pancreatic cancer are described in Herreros-Villanueva, et al., World J. Gastroenterol.2012, 18, 1286-1294. Models for determining efficacy of treatments for breast cancer are described, e.g., in Fantozzi, Breast Cancer Res.2006, 8, 212. Models for determining efficacy of treatments for ovarian cancer are described, e.g., in Mullany, et al., Endocrinology 2012, 153, 1585-92; and Fong, et al., J.
  • Models for determining efficacy of treatments for melanoma are described, e.g., in Damsky, et al., Pigment Cell & Melanoma Res.2010, 23, 853–859.
  • Models for determining efficacy of treatments for lung cancer are described, e.g., in Meu Giveaway, et al., Genes & Development, 2005, 19, 643-664.
  • Models for determining efficacy of treatments for lung cancer are described, e.g., in Kim, Clin. Exp. Otorhinolaryngol.2009, 2, 55-60; and Sano, Head Neck Oncol.2009, 1, 32.
  • the invention relates to a method of treating, with an ITK inhibitor, a hyperproliferative disorder in a mammal that is a solid tumor cancer selected from the group consisting of fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma,
  • lymphangioendotheliosarcoma synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas,
  • cystadenocarcinoma medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms’ tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma,
  • medulloblastoma craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, uveal melanoma, neuroblastoma, retinoblastoma, malignant hemangioendothelioma, malignant schwannoma, osteosarcoma, alveolar soft part sarcoma, cystosarcoma phylloides, dermatofibrosarcoma, desmoid tumor, extraskeletal osteosarcoma, hemangiopericytoma, hemangiosarcoma, Kaposi’s sarcoma, lymphosarcoma, malignant fibrous histiocytoma, neurofibrosarcoma, primary central nervous system lymphoma, Hodgkin’s lymphoma, diffuse large B cell lymphoma
  • the invention relates to a method of treating, with an ITK inhibitor, a hyperproliferative disorder in a mammal that is a cancer selected from the group consisting of bladder cancer, head and neck cancer, pancreatic ductal adenocarcinoma (PDA), pancreatic cancer, colon carcinoma, mammary carcinoma, breast cancer, fibrosarcoma, mesothelioma, renal cell carcinoma, lung carcinoma, thyoma, prostate cancer, colorectal cancer, ovarian cancer, acute myeloid leukemia, thymus cancer, brain cancer, squamous cell cancer, skin cancer, eye cancer, retinoblastoma, melanoma, intraocular melanoma, oral cavity and
  • a cancer selected from the group consisting of bladder cancer, head and neck cancer, pancreatic ductal adenocarcinoma (PDA), pancreatic cancer, colon carcinoma, mammary carcinoma, breast cancer, fibrosarcoma, mesothelio
  • oropharyngeal cancers gastric cancer, stomach cancer, cervical cancer, head, neck, renal cancer, kidney cancer, liver cancer, ovarian cancer, prostate cancer, colorectal cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, Kaposi’s sarcoma, viral-induced cancer, esophogeal tumors, hematological neoplasms, non-small-cell lung cancer (NSCLC), chronic myelocytic leukemia, esophagus tumor, follicle center lymphoma, head and neck tumor, hepatitis C virus infection, hepatocellular carcinoma, Hodgkin’s disease, metastatic colon cancer, multiple myeloma, non-Hodgkin’s lymphoma, ovary tumor, pancreas tumor, renal cell carcinoma, small-cell lung cancer, or stage IV melanoma.
  • the invention relates to a method of treating, with an ITK inhibitor, a non-cancerous hyperproliferative disorder in a mammal that is selected from the group consisting of benign hyperplasia of the skin, restenosis, and benign hyperplasia of the prostate (e.g., benign prostatic hypertrophy (BPH)).
  • a non-cancerous hyperproliferative disorder in a mammal that is selected from the group consisting of benign hyperplasia of the skin, restenosis, and benign hyperplasia of the prostate (e.g., benign prostatic hypertrophy (BPH)).
  • BPH benign prostatic hypertrophy
  • combinations of compounds described herein in treating, preventing and/or managing non- cancerous hyperproliferative disorders may be assessed using animal models known in the art.
  • the invention relates to a method of treating, with an ITK inhibitor, a hyperproliferative disorder in a mammal that is an inflammatory, immune, or autoimmune disorder selected from the group consisting of tumor angiogenesis, chronic inflammatory disease, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, psoriasis, eczema, scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, autoimmune uveitis, age-related macular degeneration, hemangioma, ulcerative colitis, atopic dermatitis, contact dermatitis, pouchitis, whipple, spondylarthritis, uveitis, Behcet’s disease, polymyalgia rheumatica, giant-cell arteritis, sarcoidosis, Kawasaki disease, discoid lupus, systemic lupus erythemato
  • Efficacy of the compounds and combinations of compounds described herein in treating, preventing and/or managing inflammatory, immune, or autoimmune disorders may be assessed using animal models known in the art.
  • efficacy in treating, preventing and/or managing arthritis e.g., rheumatoid or psoriatic arthritis
  • arthritis can be assessed using the autoimmune animal models described in, for example, Williams, et al., Chem. Biol.2010, 17, 123-34, WO 2009/088986, WO 2009/088880, and WO 2011/008302.
  • Efficacy in treating, preventing and/or managing fibrosis or fibrotic conditions can be assessed using the unilateral ureteral obstruction model of renal fibrosis, which is described, for example, in Chevalier, et al., Kidney International 2009, 75, 1145-1152; the bleomycin induced model of pulmonary fibrosis described in, for example, Moore, et al., Am. J. Physiol. Lung. Cell. Mol. Physiol.2008, 294, L152-L160; a variety of liver/biliary fibrosis models described in, for example, Chuang, et al., Clin.
  • Efficacy in treating, preventing and/or managing scleroderma can be assessed using a mouse model induced by repeated local injections of bleomycin described, for example, in Yamamoto, et al., J. Invest. Dermatol.1999, 112, 456-462.
  • Efficacy in treating, preventing and/or managing dermatomyositis can be assessed using a myositis mouse model induced by immunization with rabbit myosin as described, for example, in Phyanagi, et al., Arthritis & Rheumatism, 2009, 60(10), 3118-3127.
  • Efficacy in treating, preventing and/or managing lupus can be assessed using various animal models described, for example, in Ghoreishi, et al., Lupus, 2009, 19, 1029-1035; Ohl, et al., J. Biomed.
  • Efficacy in treating, preventing, and/or managing Sjögren’s syndrome can be assessed using various mouse models described, for example, in Chiorini, et al., J. Autoimmunity, 2009, 33, 190-196.
  • Efficacy in treating, preventing, and/or managing pemphigus vulgaris can be assessed using methods and models described, for example, in Takahashi, et al., J Clin.
  • the invention relates to a method of treating, with an ITK inhibitor, a hyperproliferative disorder in a mammal that is a dermatosis selected from the group consisting of psoriasis vulgaris, guttate psoriasis, erythrodermic psoriasis, psoriatic nails, annular pustular psoriasis, pustular psoriasis, inverse psoriasis, psoriatic arthritis, keratoderma blennorrhagicum, parapsoriasis, erythema nodosum, palmoplantar hidradentitis, atopic dermatitis, atopic eczema, seborrheic eczema, seborrheic dermatitis, dyshidrosis, rosacea, cutaneous lupus erythematosus, acute cutaneous lupus erythe
  • Efficacy of the compounds and combinations of compounds described herein in treating, preventing and/or managing dermatoses may be assessed using animal models known in the art.
  • efficacy in treating, preventing and/or managing psoriasis can be assessed using transgenic or knockout mouse model with targeted mutations in epidermis, vasculature or immune cells, mouse model resulting from spontaneous mutations, and immuno- deficient mouse model with xenotransplantation of human skin or immune cells, all of which are described, for example, in Boehncke, et al., Clinics in Dermatology, 2007, 25, 596-605.
  • Other suitable models are known in the art.
  • the invention relates to a method of treating a solid tumor cancer with a composition including an ITK inhibitor, wherein the dose is effective to inhibit signaling between the solid tumor cells and at least one microenvironment selected from the group consisting of macrophages, monocytes, mast cells, helper T cells, cytotoxic T cells, regulatory T cells, natural killer cells, myeloid-derived suppressor cells, regulatory B cells, neutrophils, dendritic cells, and fibroblasts.
  • a composition including an ITK inhibitor wherein the dose is effective to inhibit signaling between the solid tumor cells and at least one microenvironment selected from the group consisting of macrophages, monocytes, mast cells, helper T cells, cytotoxic T cells, regulatory T cells, natural killer cells, myeloid-derived suppressor cells, regulatory B cells, neutrophils, dendritic cells, and fibroblasts.
  • the invention relates to a method of treating pancreatic cancer, breast cancer, ovarian cancer, melanoma, lung cancer, head and neck cancer, and colorectal cancer using an ITK inhibitor, wherein the dose is effective to inhibit signaling between the solid tumor cells and at least one microenvironment selected from the group consisting of macrophages, monocytes, mast cells, helper T cells, cytotoxic T cells, regulatory T cells, natural killer cells, myeloid-derived suppressor cells, regulatory B cells, neutrophils, dendritic cells, and fibroblasts.
  • ITK inhibition can polarize CD4 + T cells to the Th1 phenotype, potentially restoring anti-tumor immunity. Dubovsky, et al., Blood 2013, 122, 2539- 49.
  • the inflammatory, immune, or autoimmune disorder is the treatment, prevention, and/or management of asthma.
  • asthma encompasses airway constriction regardless of the cause, including reactive airway disease.
  • Common triggers of asthma include, but are not limited to, exposure to an environmental stimulants (e.g., allergens), cold air, warm air, perfume, moist air, exercise or exertion, and emotional stress.
  • an environmental stimulants e.g., allergens
  • cold air e.g., warm air, perfume, moist air, exercise or exertion, and emotional stress.
  • a method of treating, preventing and/or managing one or more symptoms associated with asthma examples of the symptoms include, but are not limited to, severe coughing, airway constriction, and mucus production.
  • the inflammatory, immune, or autoimmune disorder is the treatment, prevention, and/or management of allograft rejection.
  • Tissue grafts from related or non-related donors, or hematopoetic stem cell grafts from related or non-related donors are subject to anti-allogenic immune responses, despite attention to MHC matchinb between donor and recipient.
  • Both CD4 + and CD8 + T cells are important for mediating anti-allograft responses, through development of anti-allo antibodies and generation for effector CD8 + T cells that directly target the graft. Inflammation and antibody opsonization of grafted tissue leads to the engagement of other cell types, including innate pro-inflammatory and effector cells.
  • Provided herein is a method of treating, preventing and/or managing graft rejection and anti-graft immune responses by administration of a systemic ITK inhibitor.
  • the inflammatory, immune, or autoimmune disorder is the treatment, prevention, and/or management of acute or chronic graft-versus-host disease.
  • the ITK inhibitors included in the present invention can be prepared by methods well known in the art of organic chemistry. See, for example, March, Advanced Organic Chemistry, 4th Edition, John Wiley & Sons, 2001. During synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This is achieved by means of conventional protecting groups, such as those described in Greene and Wutts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, 1999. The protective groups are optionally removed at a convenient subsequent stage using methods well known in the art.
  • the products of the reactions are optionally isolated and purified, if desired, using conventional techniques, but not limited to, filtration, distillation, crystallization,
  • Such materials are optionally characterized using conventional means, including the measurement of physical constants and spectral data.
  • ITK inhibitors included in the present invention may be synthesized by the following routes.
  • Boronic acid or pinacol esters may be prepared as follows:
  • Substituted imidazopyrazines may be prepared as follows (wherein CBz refers to carboxybenzyl):
  • the present invention also includes within its scope all stereoisomeric forms of the ITK inhibitors according to the present invention resulting, for example, because of configurational or geometrical isomerism.
  • stereoisomeric forms include enantiomers, diastereoisomers, cis and trans isomers, etc.
  • the present invention also includes the aforementioned stereoisomers substantially free, i.e., associated with less than 5%, preferably less than 2% and in particular less than 1% of the other stereoisomer. Mixtures of stereoisomers in any proportion, for example a racemic mixture comprising substantially equal amounts of two enantiomers are also included within the scope of the present invention.
  • stereoisomers are obtained are well known in the art, e.g. synthesis with chiral induction, synthesis starting from chiral intermediates, enantioselective enzymatic conversions, separation of stereoisomers using chromatography on chiral media. Such methods are described in Collins, et al., eds., Chirality in Industry, John Wiley & Sons, 1992. Likewise, methods for synthesis of geometrical isomers are also well known in the art. [00166]
  • the compounds of the present invention which can be in the form of a free base, may be isolated from the reaction mixture in the form of a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salts may also be obtained by treating the free base of the ITK inhibitors disclosed herein with an organic or inorganic acid such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methanesulphonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, and ascorbic acid.
  • an organic or inorganic acid such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methanesulphonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, and ascorbic acid.
  • the compounds of the present invention disclosed herein may also exist as amorphous forms or as multiple crystalline forms, also known as polymorphic forms. All physical forms are included within the scope of the present invention.
  • Preparation of solvates is generally known.
  • Caira, et al., J. Pharm. Sci., 2004, 93, 601-611 describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water.
  • Similar preparations of solvates, hydrates and the like are described by van Tonder, et al., AAPS PharmSciTech.2004, 5(1), article 12; and Bingham, et al., Chem. Commun.2001, 603-604.
  • a typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods.
  • the present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 32 P, 35 S, and 36 Cl, respectively.
  • Radioisotopically-labelled forms of the compounds disclosed herein are useful in compound and/or substrate tissue distribution assays.
  • Tritium ( 3 H) and carbon-14 ( 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium ( 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Isotopically-labelled forms of the compounds disclosed herein can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples described below, by substituting an appropriate isotopically labeled reagent for a non- isotoplically labeled reagent.
  • Mass detector API-ES (100-1000 amu, pos./neg. ion mode)
  • Eluents (mobile phase): A: 0.1% trifluoroacetic acid (TFA) in water; B: acetonitrile
  • UV/Vis (210/240 nm)
  • HPLC Waters analytical HPLC system; Column: SunFire-C18 (46 x 50 mm, 5 mm),
  • HPLC Waters analytical HPLC system; Column: X-Bridge Shield-RP-18 (46 x 250 mm, 5 mm), Detector: UV/Vis (210/240 nm), Flow: 1 mL/min.
  • HPLC Alliance Waters 2695 ; Detector: Waters 2996 PDA (214 nm)
  • N-(4-isopropyl-3-methyl-phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide A solution of 4-dimethyl-aminopyridine (0.3 g, 2.42 mmol), N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide (4.3 g, 22.17 mmol), 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzoic acid (5.0 g, 20.15 mmol) and 4-isopropyl-3-methyl-aniline hydrochloride (4.1 g, 22.17 mmol) in DCM (100 mL) was stirred at room temperature overnight.
  • 4-dimethyl-aminopyridine 0.3 g, 2.42 mmol
  • N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide 4.3
  • N,N-Diisopropylethylamine (19.35 mL, 111.09 mmol) was added dropwise in ten minutes to a mixture of (2S)-2-[benzyloxycarbonyl(methyl)amino]propanoic acid (6.59 g, 27.77 mmol), (3-chloropyrazin-2-yl)methanamine hydrochloride (5.00 g, 27.77 mmol) and HATU (15.84 g, 41.66 mmol) in dichloromethane (250 mL) and the resulting mixture was stirred for three hours at 20 °C. The mixture was washed once with aqueous saturated.
  • the aqueous phase was made basic (pH ⁇ 8) with solid sodium carbonate and extracted four times with 2-methyl-THF (75 mL). The combined organic extracts were dried over sodium sulfate and concentrated to give 5-[8-amino-3-[(1S)-1- (methylamino)ethyl]imidazo[1,5-a]pyrazin-1-yl]-N-(4-isopropyl-3-methyl-phenyl)pyridine-3- carboxamide (193 mg,0.44 mmol, 100% crude yield) as a light yellow solid.

Abstract

Dans certains modes de réalisation, l'invention concerne un inhibiteur de kinase de lymphocytes T inductible par l'interleukine-2 (kinase ITK) de formule (I) ou un sel pharmaceutiquement acceptable de celui-ci, ou des compositions pharmaceutiques comprenant ces composés et leur utilisation dans le traitement de troubles médiés par la kinase ITK. (I)
PCT/IB2019/054971 2018-06-13 2019-06-13 Inhibiteurs imidazopyrazines de kinase de lymphocytes t inductible par l'interleukine-2 WO2019239374A1 (fr)

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CN113264938A (zh) * 2021-07-21 2021-08-17 北京鑫开元医药科技有限公司 一种咪唑并[1,5-a]吡嗪-8-胺类化合物、制备方法、药物组合物和应用
CN113264938B (zh) * 2021-07-21 2021-11-02 北京鑫开元医药科技有限公司 一种咪唑并[1,5-a]吡嗪-8-胺类化合物、制备方法、药物组合物和应用
WO2023071973A1 (fr) * 2021-10-26 2023-05-04 Shenzhen Targetrx, Inc. Composé bicyclique fusionné pour inhiber l'activité de la tyrosine kinase

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