WO2008073687A2 - Compounds and compositions as protein kinase inhibitors - Google Patents

Compounds and compositions as protein kinase inhibitors Download PDF

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Publication number
WO2008073687A2
WO2008073687A2 PCT/US2007/085304 US2007085304W WO2008073687A2 WO 2008073687 A2 WO2008073687 A2 WO 2008073687A2 US 2007085304 W US2007085304 W US 2007085304W WO 2008073687 A2 WO2008073687 A2 WO 2008073687A2
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WO
WIPO (PCT)
Prior art keywords
phenyl
isopropoxy
isopropylsulfonyl
ylamino
methyl
Prior art date
Application number
PCT/US2007/085304
Other languages
French (fr)
Other versions
WO2008073687A3 (en
Inventor
Pierre-Yves Michellys
Wei Pei
Thomas H. Marsilje
Wenshuo Lu
Bei Chen
Tetsuo Uno
Yunho Jin
Tao Jiang
Original Assignee
Irm Llc
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Priority to PL07864693T priority Critical patent/PL2091918T3/en
Application filed by Irm Llc filed Critical Irm Llc
Priority to BRPI0720264-4A priority patent/BRPI0720264B1/en
Priority to DK07864693.2T priority patent/DK2091918T3/en
Priority to JP2009540379A priority patent/JP5208123B2/en
Priority to CA2671744A priority patent/CA2671744C/en
Priority to KR1020097014175A priority patent/KR101149295B1/en
Priority to KR1020117019463A priority patent/KR101364277B1/en
Priority to SI200731554T priority patent/SI2091918T1/en
Priority to MX2009006081A priority patent/MX2009006081A/en
Priority to RSP20140601 priority patent/RS53588B1/en
Priority to EA200970557A priority patent/EA017405B9/en
Priority to NZ577197A priority patent/NZ577197A/en
Priority to MEP-2009-216A priority patent/ME00811B/en
Priority to AU2007333394A priority patent/AU2007333394C1/en
Priority to EP07864693.2A priority patent/EP2091918B1/en
Priority to ES07864693.2T priority patent/ES2524009T3/en
Priority to UAA200905803A priority patent/UA100846C2/en
Publication of WO2008073687A2 publication Critical patent/WO2008073687A2/en
Publication of WO2008073687A3 publication Critical patent/WO2008073687A3/en
Priority to ZA2009/03601A priority patent/ZA200903601B/en
Priority to IL198936A priority patent/IL198936A0/en
Priority to TNP2009000225A priority patent/TN2009000225A1/en
Priority to CU2009000102A priority patent/CU23829B1/en
Priority to NO20092472A priority patent/NO338069B1/en
Priority to SM200900058T priority patent/SMP200900058B/en
Priority to HK10101751A priority patent/HK1134290A1/en
Priority to AU2010210018A priority patent/AU2010210018B2/en
Priority to AU2010210019A priority patent/AU2010210019C1/en
Priority to IL230972A priority patent/IL230972A/en
Priority to HRP20141260TT priority patent/HRP20141260T1/en
Priority to FR15C0058C priority patent/FR15C0058I2/en
Priority to LTPA2015034C priority patent/LTC2091918I2/en
Priority to NL300763C priority patent/NL300763I2/nl
Priority to CY2015043C priority patent/CY2015043I1/en
Priority to NO20160333A priority patent/NO20160333A1/en
Priority to NO2016014C priority patent/NO2016014I2/en

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    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D487/08—Bridged systems

Definitions

  • the invention relates to protein kinase inhibitors, more particularly novel pyrimidine and pyridine derivatives and pharmaceutical compositions thereof, and their use as pharmaceuticals.
  • Anaplastic lymphoma kinase (ALK), a member of the insulin receptor superfamily of receptor tyrosine kinases, has been implicated in oncogenesis in hematopoietic and non- hematopoietic tumors.
  • ALK insulin receptor superfamily of receptor tyrosine kinases
  • the aberrant expression of full-length ALK receptor proteins has been reported in neuroblastomas and glioblastomas; and ALK fusion proteins have occurred in anaplastic large cell lymphoma.
  • the study of ALK fusion proteins has also raised the possibility of new therapeutic treatments for patients with ALK-positive malignancies. (Pulford et al., Cell. MoI. Life Sci. 61:2939-2953 (2004)).
  • Focal Adhesion Kinase is a key enzyme in the integrin-mediated outside-in signal cascade (D. Schlaepfer et al., Prog Biophys MoI Biol 1999, 71, 43578).
  • the trigger in the signal transduction cascade is the autophosphorylation of Y397.
  • Phosphorylated Y397 is a SH2 docking site for Src family tyrosine kinases; the bound c-Src kinase phosphorylates other tyrosine residues in FAK.
  • phsophorylated Y925 becomes a binding site for the SH2 site of Grb2 small adaptor protein. This direct binding of Grb2 to FAK is one of the key steps for the activation of down stream targets such as the Ras-ERK2/MAP kinase cascade.
  • ZAP-70 Zeta-chain-associated protein kinase 70
  • CLL chronic lymphocytic leukemia
  • ZAP-70 known to be of importance in T and NK cell signaling but absent in normal peripheral B cells, is expressed in the majority of the poorer prognosis unmutated CLL and absent in most cases with mutated IgVH genes. ZAP-70 is also expressed in a minority of other B cell tumors.
  • IGF-I Insulin- like growth factor
  • IGF-IR IGF-I receptor
  • the invention relates to novel pyrimidine and pyridine derivatives and pharmaceutical compositions thereof, and their use as pharmaceuticals. [0009] In one aspect, the invention provides a having Formula (1):
  • a 1 and A 4 are independently C or N; each A 2 and A 3 is C, or one of A 2 and A 3 is N when R 6 and R 7 form a ring;
  • B and C are independently an optionally substituted 5-7 membered carbocyclic ring, aryl, heteroaryl or heterocyclic ring containing N, O or S;
  • R 1 and R 2 are independently halo, OR 12 , NR(R 12 ), SR 12 , or an optionally substituted Ci_ 6 alkyl, C 2 -6 alkenyl or C 2 -6 alkynyl; or one of R 1 and R 2 is H;
  • R 3 is (CR 2 )o-2S0 2 R 12 , (CR 2 V 2 SO 2 NRR 12 , (CR 2 )o-2COi_ 2 R 12 , (CR 2 )o- 2 CONRR 12 or cyano;
  • R 4 , R , R 7 and R 10 are independently an optionally substituted Ci_ 6 alkyl, C 2 _ 6 alkenyl or C 2 -6 alkynyl; OR 12 , NR(R 12 ), halo, nitro, SO 2 R 12 , (CR 2 ) P R 13 or X; or R 4 , R 7 and R 10 are independently H;
  • R, R 5 and R 5 are independently H or Ci_ 6 alkyl
  • R 8 and R 9 are independently C 1-6 alkyl, C 2 -6 alkenyl, C 2 _6 alkynyl, halo or X, or one of R 8 and R 9 is H when R 1 and R 2 form a ring; and provided one of R 8 and R 9 is X; alternatively, R 1 and R 2 , or R 6 and R 7 , R 7 and R 8 , or R 9 and R 10 , when attached to a carbon atom may form an optionally substituted 5-7 membered monocyclic or fused carbocyclic ring, aryl, or heteroaryl or heterocyclic ring comprising N, O and/or S; or R 7 , R 8 , R 9 and R 10 are absent when attached to N;
  • R 11 is H, Ci_6 alkyl, C 2-6 alkenyl, (CR 2 ) P COi_ 2 R, (CR 2 ) P 0R, (CR 2 ) P R 13 , (CR 2 ) P NRR 12 , (CR 2 ) P CONRR 12 or (CR 2 ) p SOi_ 2 R 12 ;
  • R 12 and R 13 are independently an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, or a 5-7 membered heterocyclic ring comprising N, O and/or S; aryl or heteroaryl; or R 12 is H, C 1-6 alkyl;
  • X is (CR 2 ) q Y, cyano, COi_ 2 R 12 , CONR(R 12 ), CONR(CR 2 ) P NR(R 12 ), CONR(CR 2 ) P OR 12 , CONR(CR 2 ) P SR 12 , CONR(CR 2 ) p S(O)i_ 2 R 12 or (CR 2 )i_ 6 NR(CR 2 ) p OR 12 ;
  • Y is an optionally substituted 3-12 membered carbocyclic ring, a 5-12 membered aryl, or a 5-12 membered heteroaryl or heterocyclic ring comprising N, O and/or S and attached to A or A 3 or both via a carbon atom of said heteroaryl or heterocyclic ring when q in (CR 2 ) q Y is 0; and n, p and q are independently 0-4.
  • R 1 may be halo or Ci_ 6 alkyl
  • R 2 is H or NH 2
  • R 1 and R 2 together form an optionally substituted 5-6 membered aryl, or heteroaryl or heterocyclic ring comprising 1-3 nitrogen atoms.
  • R 3 in Formula (1) may be SO 2 R 12 , SO 2 NH 2 , SO 2 NRR 12 , CO 2 NH 2 , CONRR 12 , COi_ 2 R 12 , or cyano; and R 12 is Ci_ 6 alkyl, an optionally substituted cycloalkyl, cycloalkenyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl or azetidinyl.
  • R , R , R 7 and R 10 in Formula (1) are independently H, and n is 0.
  • R 6 in Formula (1) may be halo or OR 12 , and R 12 is C 1-6 alkyl.
  • R 1 is halo or C]_ 6 alkyl
  • R 2 is H
  • R 1 and R 2 together form an optionally substituted 5-6 membered heteroaryl or heterocyclic ring comprising one or two nitrogen atoms;
  • R 6 is isopropoxy or methoxy; one of R 8 and R 9 is (CR 2 ) q Y and the other is Ci_ 6 alkyl, cyano, COi_ 2 R 12 , CONR(R 12 ) or CONR(CR 2 ) p NR(R 12 );
  • Y is an optionally substituted C 3 - 7 cycloalkyl, C 3 - 7 cycloalkenyl, or phenyl; or Y is pyridyl, pyrazolyl, isoxazolyl, imidazolyl, thiazolyl, benzimidazolyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, azetidinyl, heptamethyleneimine or octamethyleneimine, each of which is attached to the phenyl ring via a carbon atom when q in (CR 2 ) q Y is 0; n is 0- 1 ; and q is 0-4.
  • one of R 8 and R 9 may be (CR 2 ) q Y and the other is Ci_ 6 alkyl; and n and q are independently 0.
  • Y is pyrrolidinyl, piperidinyl, azetidinyl.
  • R 1 is halo or C 1-6 alkyl; and R 2 is H.
  • the invention provides compounds having Formula (3A) or (3B): wherein B and C together form
  • R 2 is H
  • R 1 and R 2 together form an optionally substituted 5-7 membered carbocyclic ring, aryl, or heteroaryl or heterocyclic ring comprising N, O and/or S;
  • R is isopropoxy or methoxy.
  • each R 11 may be (CR 2 ) P COi_ 2 R, (CR 2 ) P OR, (CR 2 ) p R 13 , (CR 2 ) P NRR 12 or (CR 2 ) P CONRR 12 ;
  • R and R 12 are independently H or Ci_ 6 alkyl
  • R 13 is an optionally substituted piperidinyl, azetidiyl, tetrahydropyranyl, cyclohexyl, morpholinyl, pyrrolidinyl, heptamethyleneimine, octamethyleneimine, a bicyclic amine or diamine derivative, quinuclidin-3-yl, 8-methyl-8-aza-bicyclo[3.2.1]oct-6-yl], or 9-methyl-9-aza- bicyclo[4.2.1]nonan-7-yl.
  • the invention provides compounds having Formula (4A) or Formula (4B):
  • R 1 is halo or C 1-6 alkyl
  • R is H
  • R 1 and R 2 together form an optionally substituted 5-7 membered carbocyclic ring, aryl, or heteroaryl or heterocyclic ring comprising N, O and/or S;
  • R is isopropoxy or methoxy
  • B 2 and B 3 are independently an optionally substituted 5-6 membered aryl or heteroaryl containing N, O or S.
  • the invention provides compounds having Formula (5):
  • a 1 and A 4 are independently C or N; each A 2 and A 3 is C, or one of A 2 and A 3 is N when R and R 7 form a ring; B and C are independently an optionally substituted 5-7 membered carbocyclic ring, aryl, heteroaryl or heterocyclic ring containing N, O or S;
  • R 1 and R 2 are independently halo, OR 12 , NR(R 12 ), SR 12 , or an optionally substituted C 1-6 alkyl, C 2 _ 6 alkenyl or C 2 _ 6 alkynyl; or one of R 1 and R 2 is H;
  • R 3 is (CR 2 )o- 2 S0 2 R 12 , (CR 2 )o- 2 S0 2 NRR 12 , (CR ⁇ CO ⁇ R 12 , (CR 2 ) 0 - 2 CONRR 12 or cyano;
  • R 4 , R 6 , and R 7 and R 10 when attached to a carbon atom, are independently H, an optionally substituted Ci_ 6 alkyl, C 2 _ 6 alkenyl or C 2 _ 6 alkynyl; OR 12 , NR(R 12 ), halo, nitro, SO 2 R 12 , (CR 2 ) p R 13 or X; provided R 6 and R 7 are not both H;
  • R, R 5 and R 5 are independently H or C 1-6 alkyl
  • R 8 and R 9 are independently Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, halo or X, or one of R 8 and R 9 is H; and provided one of R 8 and R 9 is X; alternatively, R 1 and R 2 , or R 6 and R 7 , R 7 and R 8 , or R 9 and R 10 , when attached to a carbon atom may form an optionally substituted 5-7 membered monocyclic or fused carbocyclic ring, aryl, or heteroaryl or heterocyclic ring comprising N, O and/or S; or R 7 , R 8 , R 9 and R 10 are absent when attached to N;
  • R 11 is H, Ci_6 alkyl, C 2-6 alkenyl, (CR 2 ) p COi_ 2 R, (CR 2 ) P OR, (CR 2 ) P R 13 , (CR 2 ) P NRR 12 , (CR 2 ) P CONRR 12 or (CR 2 ) p SOi_ 2 R 12 ;
  • R 12 and R 13 are independently an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, or a 5-7 membered heterocyclic ring comprising N, O and/or S; aryl or heteroaryl; or R 12 is H, C]_ 6 alkyl;
  • X is (CR 2 ) q Y, cyano, COi_ 2 R 12 , CONR(R 12 ), CONR(CR 2 ) P NR(R 12 ), CONR(CR 2 ) P OR 12 , CONR(CR 2 ) P SR 12 , CONR(CR 2 ) p S(O)i_ 2 R 12 or (CR 2 )i_ 6 NR(CR 2 ) p OR 12 ;
  • Y is an optionally substituted 3-12 membered carbocyclic ring, a 5-12 membered aryl, or a 5-12 membered heteroaryl or heterocyclic ring comprising N, O and/or S and attached to A 2 or A 3 or both via a carbon atom of said heteroaryl or heterocyclic ring when q in (CR 2 ) q Y is 0; and n, p and q are independently 0-4.
  • the present invention provides pharmaceutical compositions comprising a compound having Formula (1), (2), (3A), (3B), (4A), (4B) or (5), and a pharmaceutically acceptable excipient.
  • the invention provides methods for modulating ALK, FAK, ZAP-70 and/or IGF-IR, comprising administering to a system or a subject in need thereof, a therapeutically effective amount of a compound having Formula (1), (2), (3A), (3B), (4A), (4B) or (5), or pharmaceutically acceptable salts or pharmaceutical compositions thereof, thereby modulating said ALK, FAK, ZAP-70 and/or IGF-IR.
  • the invention also provides methods to treat, ameliorate or prevent a condition which responds to inhibition of ALK, FAK, ZAP-70 and/or IGF-IR, comprising administering to a system or subject in need of such treatment an effective amount of a compound having Formula (1), (2), (3A), (3B), (4A), (4B) or (5), or pharmaceutically acceptable salts or pharmaceutical compositions thereof, and optionally in combination with a second therapeutic agent, thereby treating said condition.
  • the present invention provides the use of a compound having Formula (1), (2), (3A), (3B), (4A), (4B) or (5) in the manufacture of a medicament for treating a condition mediated by ALK, FAK, ZAP-70 and/or IGF-IR.
  • the compounds of the invention may be used alone or in combination with a second therapeutic agent to treat a condition mediated by ALK, wherein said condition is an autoimmune disease, a transplantation disease, an infectious disease or a cell proliferative disorder.
  • the invention provides methods for treating a cell proliferative disorder, comprising administering to a system or subject in need of such treatment an effective amount of a compound having Formula (1), (2), (3A), (3B), (4A), (4B) or (5), or pharmaceutically acceptable salts or pharmaceutical compositions thereof, and optionally in combination with a second therapeutic agent, thereby treating said condition.
  • the present invention provides the use of a compound having Formula (1), (2), (3A), (3B), (4A), (4B) or (5) in the manufacture of a medicament for treating a cell-proliferative disorder.
  • the compounds of the invention may be used alone or in combination with a chemotherapeutic agent to treat a cell proliferative disorder, including but not limited to, lymphoma, osteosarcoma, melanoma, or a tumor of breast, renal, prostate, colorectal, thyroid, ovarian, pancreatic, neuronal, lung, uterine or gastrointestinal tumor.
  • a chemotherapeutic agent to treat a cell proliferative disorder, including but not limited to, lymphoma, osteosarcoma, melanoma, or a tumor of breast, renal, prostate, colorectal, thyroid, ovarian, pancreatic, neuronal, lung, uterine or gastrointestinal tumor.
  • a compound having Formula (1), (2), (3A), (3B), (4A), (4B) or (5) may be administered to a system comprising cells or tissues, or to a mammalian subject such as a human or animal subject.
  • Alkyl refers to a moiety and as a structural element of other groups, for example halo-substituted-alkyl and alkoxy, and may be straight-chained or branched.
  • An optionally substituted alkyl, alkenyl or alkynyl as used herein may be optionally halogenated (e.g., CF 3 ), or may have one or more carbons that is substituted or replaced with a heteroatom, such as NR, O or S (e.g., -OCH 2 CH 2 O-, alkylthiols, thioalkoxy, alkylamines, etc).
  • Aryl refers to a monocyclic or fused bicyclic aromatic ring containing carbon atoms.
  • Arylene means a divalent radical derived from an aryl group.
  • an aryl group may be phenyl, indenyl, indanyl, naphthyl, or 1,2,3,4-tetrahydronaphthalenyl, which may be optionally substituted in the ortho, meta or para position.
  • Heteroaryl as used herein is as defined for aryl above, where one or more of the ring members is a heteroatom.
  • heteroaryls include but are not limited to pyridyl, pyrazinyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl, benzopyranyl, benzothiopyranyl, benzo[l,3]dioxole, imidazolyl, benzo-imidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl, benzotriazolyl, tetrazolyl, pyrazolyl, thienyl, pyrrolyl, isoquinolinyl, purinyl, thiazolyl, tetrazinyl, benzothiazolyl, oxadiazolyl, benzoxadiazolyl, etc.
  • Examples of carbocyclic rings include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylene, cyclohexanone, etc.
  • a "heterocyclic ring” as used herein is as defined for a carbocyclic ring above, wherein one or more ring carbons is a heteroatom.
  • heterocyclic rings include but are not limited to morpholino, pyrrolidinyl, pyrrolidinyl-2-one, piperazinyl, piperidinyl, piperidinylone, l,4-dioxa-8-aza-spiro[4.5]dec-8-yl, 1,2,3,4-tetrahydroquinolinyl, etc.
  • Heterocyclic rings as used herein may encompass bicyclic amines and bicyclic diamines.
  • co- administration or “combined administration” or the like as used herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • the term "pharmaceutical combination” as used herein refers to a product obtained from mixing or combining active ingredients, and includes both fixed and non-fixed combinations of the active ingredients.
  • the term "fixed combination” means that the active ingredients, e.g. a compound of Formula (1) and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • the term “non-fixed combination” means that the active ingredients, e.g. a compound of Formula (1) and a co-agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the active ingredients in the body of the patient.
  • cocktail therapy e.g. the administration of three or more active ingredients.
  • terapéuticaally effective amount means the amount of the subject compound that will elicit a biological or medical response in a cell, tissue, organ, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • administration means providing a compound of the invention and prodrugs thereof to a subject in need of treatment.
  • the invention provides novel pyrimidine and pyridine derivatives and pharmaceutical compositions thereof, and methods for using such compounds.
  • the invention provides a having Formula (1):
  • a 1 and A 4 are independently C or N; each A 2 and A 3 is C, or one of A 2 and A 3 is N when R and R 7 form a ring;
  • B and C are independently an optionally substituted 5-7 membered carbocyclic ring, aryl, heteroaryl or heterocyclic ring containing N, O or S;
  • R 1 and R 2 are independently halo, OR 12 , NR(R 12 ), SR 12 , or an optionally substituted Ci_ 6 alkyl, C 2 -6 alkenyl or C 2 -6 alkynyl; or one of R 1 and R 2 is H;
  • R 3 is (CR 2 )o- 2 S0 2 R 12 , (CR 2 V 2 SO 2 NRR 12 , (CR 2 ) 0 - 2 COi_ 2 R 12 , (CR 2 ) 0 - 2 CONRR 12 or cyano;
  • R 4 , R 6 , R 7 and R 10 are independently an optionally substituted C 1-6 alkyl, C 2 _ 6 alkenyl or C 2 _ 6 alkynyl; OR 12 , NR(R 12 ), halo, nitro, SO 2 R 12 , (CR 2 ) p R 13 or X; or R 4 , R 7 and R 10 are independently H;
  • R, R 5 and R 5 are independently H or C 1-6 alkyl
  • R and R are independently Ci_6 alkyl, C 2 _6 alkenyl, C 2 _6 alkynyl, halo or X, or one of R and R 9 is H when R 1 and R 2 form a ring; and provided one of R 8 and R 9 is X; alternatively, R 1 and R 2 , or R 6 and R 7 , R 7 and R 8 , or R 9 and R 10 , when attached to a carbon atom may form an optionally substituted 5-7 membered monocyclic or fused carbocyclic ring, aryl, or heteroaryl or heterocyclic ring comprising N, O and/or S; or R 7 , R 8 , R 9 and R 10 are absent when attached to N;
  • R 11 is H, Ci_6 alkyl, C 2 _ 6 alkenyl, (CR 2 ) p COi_ 2 R, (CR 2 ) p 0R, (CR 2 ) P R 13 , (CR 2 ) P NRR 12 , (CR 2 ) P CONRR 12 or (CR 2 ) p SOi_ 2 R 12 ;
  • R 12 and R 13 are independently an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, or a 5-7 membered heterocyclic ring comprising N, O and/or S; aryl or heteroaryl; or R 12 i •s H, Ci_ 6 alkyl;
  • X is (CR 2 ) q Y, cyano, COi , CONR(CR 2 ) P SR 12 , CONR(CR 2 ) P S(O) ! _ 2 R 12 or (CR 2 ;h_ 6 NR(CR 2 ) p OR 12 ;
  • Y is an optionally substituted 3-12 membered carbocyclic ring, a 5-12 membered aryl, or a 5-12 membered heteroaryl or heterocyclic ring comprising N, O and/or S and attached to A 2 or A 3 or both via a carbon atom of said heteroaryl or heterocyclic ring when q in (CR 2 ) q Y is 0; and n, p and q are independently 0-4. [0032] In one embodiment, the invention provides compounds having Formula (2):
  • R 1 is halo or Ci_ 6 alkyl; R is H; or
  • R 1 and R 2 together form an optionally substituted 5-6 membered heteroaryl or heterocyclic ring comprising one or two nitrogen atoms;
  • R 6 is isopropoxy or methoxy; one of R 8 and R 9 is (CR 2 ) q Y and the other is Ci_ 6 alkyl, cyano, COi_ 2 R 12 , CONR(R 12 ) or CONR(CR 2 ) p NR(R 12 );
  • Y is an optionally substituted C 3 - 7 cycloalkyl, C 3 - 7 cycloalkenyl, or phenyl; or Y is pyridyl, pyrazolyl, isoxazolyl, imidazolyl, thiazolyl, benzimidazolyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, azetidinyl, heptamethyleneimine or octamethyleneimine, each of which is attached to the phenyl ring via a carbon atom when q in (CR 2 ) q Y is 0; n is 0- 1 ; and q is 0-4.
  • the invention provides compounds having Formula (3A) or (3B):
  • R 1 is halo or C 1-6 alkyl
  • R 2 is H
  • R 1 and R 2 together form an optionally substituted 5-7 membered carbocyclic ring, aryl, or heteroaryl or heterocyclic ring comprising N, O and/or S;
  • R is isopropoxy or methoxy.
  • the invention provides compounds having Formula (4A) or Formula (4B):
  • R 1 is halo or C 1-6 alkyl
  • R is H
  • R 1 and R 2 together form an optionally substituted 5-7 membered carbocyclic ring, aryl, or heteroaryl or heterocyclic ring comprising N, O and/or S;
  • R is isopropoxy or methoxy
  • B 2 and B 3 are independently an optionally substituted 5-6 membered aryl or heteroaryl containing N, O or S.
  • the invention provides compounds having Formula (5):
  • a 1 and A 4 are independently C or N; each A 2 and A 3 is C, or one of A 2 and A 3 is N when R and R 7 form a ring; B and C are independently an optionally substituted 5-7 membered carbocyclic ring, aryl, heteroaryl or heterocyclic ring containing N, O or S;
  • R 1 and R 2 are independently halo, OR 12 , NR(R 12 ), SR 12 , or an optionally substituted C 1-6 alkyl, C 2 _ 6 alkenyl or C 2 _ 6 alkynyl; or one of R 1 and R 2 is H;
  • R 3 is (CR 2 )o- 2 S0 2 R 12 , (CR 2 )o- 2 S0 2 NRR 12 , (CR ⁇ CO ⁇ R 12 , (CR 2 ) 0 - 2 CONRR 12 or cyano;
  • R 4 , R 6 , and R 7 and R 10 when attached to a carbon atom, are independently H, an optionally substituted Ci_ 6 alkyl, C 2 _ 6 alkenyl or C 2 _ 6 alkynyl; OR 12 , NR(R 12 ), halo, nitro, SO 2 R 12 , (CR 2 ) p R 13 or X; provided R 6 and R 7 are not both H;
  • R, R 5 and R 5 are independently H or C 1-6 alkyl
  • R 8 and R 9 are independently Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, halo or X, or one of R 8 and R 9 is H; and provided one of R 8 and R 9 is X; alternatively, R 1 and R 2 , or R 6 and R 7 , R 7 and R 8 , or R 9 and R 10 , when attached to a carbon atom may form an optionally substituted 5-7 membered monocyclic or fused carbocyclic ring, aryl, or heteroaryl or heterocyclic ring comprising N, O and/or S; or R 7 , R 8 , R 9 and R 10 are absent when attached to N;
  • R 11 is H, Ci_6 alkyl, C 2-6 alkenyl, (CR 2 ) p COi_ 2 R, (CR 2 ) P OR, (CR 2 ) P R 13 , (CR 2 ) P NRR 12 , (CR 2 ) P CONRR 12 or (CR 2 ) p SOi_ 2 R 12 ;
  • R 12 and R 13 are independently an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, or a 5-7 membered heterocyclic ring comprising N, O and/or S; aryl or heteroaryl; or R 12 is H, C]_ 6 alkyl;
  • X is (CR 2 ) q Y, cyano, COi_ 2 R 12 , CONR(R 12 ), CONR(CR 2 ) P NR(R 12 ), CONR(CR 2 ) P OR 12 , CONR(CR 2 ) P SR 12 , CONR(CR 2 ) p S(O)i_ 2 R 12 or (CR 2 )i_ 6 NR(CR 2 ) p OR 12 ;
  • Y is an optionally substituted 3-12 membered carbocyclic ring, a 5-12 membered aryl, or a 5-12 membered heteroaryl or heterocyclic ring comprising N, O and/or S and attached to A 2 or A 3 or both via a carbon atom of said heteroaryl or heterocyclic ring when q in (CR 2 ) q Y is 0; and n, p and q are independently 0-4.
  • Y or R 13 may independently be heterocyclic rings, which may be a bicyclic amine or bicyclic diamine.
  • bicyclic amine and bicyclic diamines include but are not limited to an optionally substituted hexanemethyleneimine; heptamethyleneimine; quinuclidine; 3-azabicyclo(3,3,0)octane; 3,8-diazabicyclo[3,2,l]octane; octahydro-lH-pyrido[3,4-C]azepine; octahydropyrrolizine; 6-azabicyclo[3,2,l]octane; 3- azabicyclo[3,2,l]octane; 2,5-diazabicyclo[2,2,l]heptane; l-azabicyclo[2,2,l]heptane; 2- azabicyclo[2,2,l]heptane; l,4-
  • any asymmetric carbon atoms may be present in the (R)-, (S)-or (R,S)-configuration.
  • the compounds may thus be present as mixtures of isomers or as pure isomers, for example, as pure enantiomers or diastereomers.
  • the invention further encompasses possible tautomers of the inventive compounds.
  • each optionally substituted moiety may be substituted with Ci_6 alkyl, C 2 -6 alkenyl or C3_6 alkynyl, each of which may be optionally halogenated or optionally having a carbon that may be replaced or substituted with N, S, O, or a combination thereof (for example, hydroxylCi-Cgalkyl, Ci-CgalkoxyCi-Cgalkyl); halo, amino, amidino, C]_ 6 alkoxy; hydroxyl, methylenedioxy, carboxy; Ci-s alkylcarbonyl, Ci-s alkoxycarbonyl, carbamoyl, Ci- 8 alkylcarbamoyl, sulfamoyl, cyano, oxo, nitro, or an optionally substituted carbocyclic ring, heterocyclic ring, aryl or heteroaryl as previously described.
  • the compounds of the invention and their pharmaceutically acceptable salts exhibit valuable pharmacological properties when tested in vitro in cell-free kinase assays and in cellular assays, and are therefore useful as pharmaceuticals.
  • compounds of Formula (1), (2), (3A), (3B), (4A), (4B) or (5) may inhibit the tyrosine kinase activity of anaplastic lymphoma kinase (ALK) and the fusion protein of NPM-ALK.
  • ALK anaplastic lymphoma kinase
  • NPM-ALK fusion protein of NPM-ALK
  • NPM-ALK plays a key role in signal transmission in a number of hematopoetic and other human cells leading to hematological and neoplastic diseases, for example in anaplastic large-cell lymphoma (ALCL) and non-Hodgkin's lymphomas (NHL), specifically in ALK+NHL or Alkomas, in inflammatory myofibroblastic tumors (IMT) and neuroblastomas.
  • ACL anaplastic large-cell lymphoma
  • NHL non-Hodgkin's lymphomas
  • IMT myofibroblastic tumors
  • neuroblastomas Duyster et al. 2001 Oncogene 20, 5623-5637.
  • TPM3-ALK a fusion of nonmuscle tropomyosin with ALK
  • ALK tyrosine kinase activity may be demonstrated using known methods, for example using the recombinant kinase domain of the ALK in analogy to the VEGF-R kinase assay described in J. Wood et al. Cancer Res. 60, 2178-2189 (2000).
  • Reactions are terminated by adding 50 ⁇ l of 125 mM EDTA, and the reaction mixture is transferred onto a MAIP Multiscreen plate (Millipore, Bedford, MA, USA), previously wet with methanol, and rehydrated for 5 min with H 2 O. Following washing (0.5 % H 3 PO 4 ), plates are counted in a liquid scintillation counter. IC 50 values are calculated by linear regression analysis of the percentage inhibition.
  • Compounds of Formula (1), (2), (3A), (3B), (4A), (4B) or (5) may potently inhibit the growth of human NPM-ALK overexpressing murine BaF3 cells (DSMZ Deutsche Sammiung von Mikroorganismen und Zelikulturen GmbH, Germany).
  • the expression of NPM- ALK may be achieved by transfecting the BaF3 cell line with an expression vector pClneoTM (Promega Corp., Madison WI, USA) coding for NPM-ALK and subsequent selection of G418 resistant cells.
  • Non-transfected BaF3 cells depend on IL-3 for cell survival.
  • NPM- ALK expressing BaF3 cells can proliferate in the absence of IL-3 because they obtain proliferative signal through NPM-ALK kinase.
  • Putative inhibitors of the NPM-ALK kinase therefore abolish the growth signal and may result in antiproliferative activity.
  • the antiproliferative activity of putative inhibitors of the NPM-ALK kinase can however be overcome by addition of IL-3, which provides growth signals through an NPM- ALK independent mechanism.
  • An analogous cell system using FLT3 kinase has also been described (see, E Weisberg et al. Cancer Cell; 1, 433-443 (2002)).
  • the inhibitory activity of the compounds of the invention may be determined as follows.
  • BaF3-NPM-ALK cells (15,000/microtitre plate well) are transferred to 96- well microtitre plates.
  • Test compounds dissolved in dimethyl sulfoxide (DMSO) are added in a series of concentrations (dilution series) in such a manner that the final concentration of DMSO is not greater than 1 % (v/v).
  • DMSO dimethyl sulfoxide
  • the plates are incubated for two days during which the control cultures without test compound are able to undergo two cell-division cycles.
  • the growth of the BaF3-NPM-ALK cells is measured by means of YOPROTM staining [T Idziorek et al. J. Immunol.
  • IC 50 values may be determined by a computer-aided system using the formula:
  • IC 50 value in those experiments is given as that concentration of the test compound in question that results in a cell count that is 50 % lower than that obtained using the control without inhibitor.
  • the compounds of the invention in free form or in pharmaceutically acceptable salt form may exhibit valuable pharmacological properties, for example, as indicated by the in vitro tests described in this application.
  • compounds of the invention have IC 50 values from 1 nM to 10 ⁇ M.
  • compounds of the invention have IC 50 values from 0.01 ⁇ M to 5 ⁇ M.
  • compounds of the invention have IC 50 values from 0.01 ⁇ M to 1 ⁇ M, or more particularly from 1 nM to 1 ⁇ M.
  • compounds of the invention have IC 50 values of less than 1 nM or more than 10 ⁇ M.
  • the compounds of the invention may exhibit a percentage inhibition of greater than 50%, or in other embodiments, may exhibit a percentage inhibition greater than about 70%, against ALK at 10 ⁇ M.
  • the antiproliferative action of the inventive compounds may also be determined in the human KARPAS-299 lymphoma cell line (DSMZ Manual Sammiung von Mikroorganismen und Zelikulturen GmbH, Braunschweig, Germany, described in WG Dirks et al. Int. J. Cancer 100, 49-56 (2002)) using the same methodology described above for the BaF3- NPM-ALK cell line.
  • compounds of the invention may exhibit inhibitory activity with an IC 50 in the range from approximately 0.01 to 1 ⁇ M.
  • the action of the inventive compounds on autophosphorylation of the ALK may be determined in the human KARPAS-299 lymphoma cell line by means of an immunoblot as described in WG Dirks et al. Int. J. Cancer 100, 49-56 (2002).
  • the compounds of the invention may inhibit Focal Adhesion Kinase (FAK), and may be useful as pharmaceuticals to treat conditions caused by a malfunction of signal cascades connected with FAK, such as in the treatment of particular tumors.
  • FAK Focal Adhesion Kinase
  • the inhibition of endogenous FAK signaling results in reduced motility, and in some cases induces cell death.
  • enhancing FAK signaling by exogenous expression increases cell motility.
  • FAK is overexpressed in invasive and metastatic epithelial, mesenchymal, thyroid and prostate cancers. Consequently, an inhibitor of FAK is likely to be a drug for antitumor growth and metastasis.
  • the compounds of the invention may thus be useful to prevent and/or treat a vertebrate and more particularly a mammal, affected by a neoplastic disease, in particular breast tumor, cancer of the bowel (colon and rectum), stomach cancer and cancer of the ovary and prostate, non-small cell lung cancer, small cell lung cancer, cancer of liver, melanoma, bladder tumor and cancer of head and neck.
  • a neoplastic disease in particular breast tumor, cancer of the bowel (colon and rectum), stomach cancer and cancer of the ovary and prostate
  • non-small cell lung cancer small cell lung cancer
  • cancer of liver melanoma
  • bladder tumor cancer of head and neck.
  • the compounds of the invention are, for example, useful to prevent and/or treat a vertebrate and more particularly a mammal, affected by immune system disorders, diseases or disorders mediated by T lymphocytes, B lymphocytes, mast cells and/or eosinophils e.g.
  • vascular occlusion due to vascular injury such as angioplasty, restenosis, hypertension, heart failure, chronic obstructive pulmonary disease, CNS disease such as Alzheimer disease or amyotrophic lateral sclerosis; cancer; infectious disease such as AIDS; septic shock or adult respiratory distress syndrome, ischemia/reperfusion injury e.g. myocardial infarction, stroke, gut ischemia, renal failure or hemorrhage shock, or traumatic shock.
  • the compounds of the invention may inhibit zeta chain- associate protein 70 (ZAP-70).
  • ZAP-70 protein tyrosine kinase interaction of the agents of the invention may be demonstrated, for example, by their ability to prevent phosphorylation of LAT- 11 (linker for activation of T cell) by human ZAP-70 protein tyrosine kinase in aqueous solution. Therefore, the compounds of the invention may be useful for the prevention or treatment of disorders or diseases where ZAP-70 inhibition plays a role.
  • the compounds of the invention may also inhibit insulin like growth-factor receptor 1 (IGF-IR), and may be useful in the treatment of IGF-I R mediated diseases.
  • IGF-IR mediated diseases include but are not limited to proliferative diseases, such as tumors, for example breast, renal, prostate, colorectal, thyroid, ovarian, pancreas, neuronal, lung, uterine and gastro intestinal tumors, as well as osteosarcomas and melanomas.
  • the efficacy of the compounds of the invention as inhibitors of IGF-IR tyrosine kinase activity may be demonstrated using a cellular capture ELISA. In this assay, the activity of the compounds of the invention against (IGF-I) -induced autophosphorylation of the IGF-IR is determined.
  • the compounds of the invention may also be useful in the treatment and/or prevention of acute or chronic inflammatory diseases or disorders or autoimmune diseases e.g. rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, diabetes (type I and II) and the disorders associated therewith, respiratory diseases such as asthma or inflammatory liver injury, inflammatory glomerular injury, cutaneous manifestations of immunologically-mediated disorders or illnesses, inflammatory and hyperproliferative skin diseases (such as psoriasis, atopic dermatitis, allergic contact dermatitis, irritant contact dermatitis and further eczematous dermatitis, seborrhoeic dermatitis), s inflammatory eye diseases, e.g. Sjoegren's syndrome, keratoconjunctivitis or uveitis, inflammatory bowel disease, Crohn's disease or ulcerative
  • the present invention provides:
  • a compound of the invention for use as an ALK inhibitor, FAK inhibitor, ZAP-70 inhibitor and/or IGF-IR inhibitor, for example for use in any of the particular indications hereinbefore set forth;
  • compositions e.g. for use in any of the indications herein before set forth, comprising a compound of the invention as active ingredient together with one or more pharmaceutically acceptable diluents or carriers;
  • a method for the treatment of any particular indication set forth hereinbefore in a subject in need thereof which comprises administering an effective amount of a compound of the invention or a pharmaceutical composition comprising same; (5) the use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of a disease or condition in which ALK, FAK, ZAP-70 and/or IGF-IR activation plays a role or is implicated;
  • the disease to be treated is selected from anaplastic large cell lymphoma, non-Hodgkin's lymphomas, inflammatory myofibroblastic tumors, neuroblastomas and neoplastic diseases;
  • (11) a method for the treatment of a disease which responds to inhibition of the anaplastic lymphoma kinase, especially a disease selected from anaplastic large-cell lymphoma, non Hodgkin's lymphomas, inflammatory myofibroblastic tumors, neuroblastomas and neoplastic diseases, comprising administering an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.
  • compounds of the invention will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents.
  • a therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors known to those of ordinary skill in the art.
  • the required dosage will also vary depending on the mode of administration, the particular condition to be treated and the effect desired.
  • an indicated daily dosage in the larger mammal may be in the range from about 0.5 mg to about 2000 mg, or more particularly, from about 0.5 mg to about 100 mg, conveniently administered, for example, in divided doses up to four times a day or in retard form.
  • Suitable unit dosage forms for oral administration comprise from ca. 1 to 50 mg active ingredient.
  • Compounds of the invention may be administered as pharmaceutical compositions by any conventional route; for example, enterally, e.g., orally, e.g., in the form of tablets or capsules; parenterally, e.g., in the form of injectable solutions or suspensions; or topically, e.g., in the form of lotions, gels, ointments or creams, or in a nasal or suppository form.
  • enterally e.g., orally, e.g., in the form of tablets or capsules
  • parenterally e.g., in the form of injectable solutions or suspensions
  • topically e.g., in the form of lotions, gels, ointments or creams, or in a nasal or suppository form.
  • compositions comprising a compound of the present invention in free form or in a pharmaceutically acceptable salt form in association with at least one pharmaceutically acceptable carrier or diluent may be manufactured in a conventional manner by mixing, granulating, coating, dissolving or lyophilizing processes.
  • pharmaceutical compositions comprising a compound of the invention in association with at least one pharmaceutical acceptable carrier or diluent may be manufactured in conventional manner by mixing with a pharmaceutically acceptable carrier or diluent.
  • Unit dosage forms for oral administration contain, for example, from about 0.1 mg to about 500 mg of active substance.
  • the pharmaceutical compositions are solutions of the active ingredient, including suspensions or dispersions, such as isotonic aqueous solutions.
  • suspensions or dispersions such as isotonic aqueous solutions.
  • dispersions or suspensions can be made up before use.
  • the pharmaceutical compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers.
  • Suitable preservatives include but are not limited to antioxidants such as ascorbic acid, or microbicides, such as sorbic acid or benzoic acid.
  • solutions or suspensions may further comprise viscosity-increasing agents, including but not limited to, sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone, gelatins, or solubilizers, e.g. Tween 80 (polyoxyethylene(20)sorbitan mono-oleate).
  • viscosity-increasing agents including but not limited to, sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone, gelatins, or solubilizers, e.g. Tween 80 (polyoxyethylene(20)sorbitan mono-oleate).
  • Suspensions in oil may comprise as the oil component the vegetable, synthetic, or semi- synthetic oils customary for injection purposes.
  • oils customary for injection purposes.
  • Examples include liquid fatty acid esters that contain as the acid component a long-chained fatty acid having from 8 to 22 carbon atoms, or in some embodiments, from 12 to 22 carbon atoms.
  • Suitable liquid fatty acid esters include but are not limited to lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid or corresponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, brassidic acid and linoleic acid, and if desired, may contain antioxidants, for example vitamin E, 3-carotene or 3,5-di-tert-butyl-hydroxytoluene.
  • the alcohol component of these fatty acid esters may have six carbon atoms and may be monovalent or polyvalent, for example a mono-, di- or trivalent, alcohol. Suitable alcohol components include but are not limited to methanol, ethanol, propanol, butanol or pentanol or isomers thereof; glycol and glycerol.
  • Suitable fatty acid esters include but are not limited ethyl-oleate, isopropyl myristate, isopropyl palmitate, LABRAFIL® M 2375, (polyoxyethylene glycerol), LABRAFIL® M 1944 CS (unsaturated polyglycolized glycerides prepared by alcoholysis of apricot kernel oil and comprising glycerides and polyethylene glycol ester), LABRASOLTM (saturated polyglycolized glycerides prepared by alcoholysis of TCM and comprising glycerides and polyethylene glycol ester; all available from GaKefosse, France), and/or MIGLYOL® 812 (triglyceride of saturated fatty acids of chain length Cg to C 12 from H ⁇ ls AG, Germany), and vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil, or groundnut oil.
  • vegetable oils such as cottonseed oil, almond oil, olive
  • compositions for oral administration may be obtained, for example, by combining the active ingredient with one or more solid carriers, and if desired, granulating a resulting mixture, and processing the mixture or granules by the inclusion of additional excipients, to form tablets or tablet cores.
  • Suitable carriers include but are not limited to fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations, and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starches, for example corn, wheat, rice or potato starch, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, carboxymethyl starch, crosslinked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate.
  • Additional excipients include flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, or derivatives thereof.
  • Tablet cores may be provided with suitable, optionally enteric, coatings through the use of, inter alia, concentrated sugar solutions which may comprise gum arable, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments may be added to the tablets or tablet coatings, for example for identification purposes or to indicate different doses of active ingredient.
  • concentrated sugar solutions which may comprise gum arable, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate.
  • Dyes or pigments may be added to the tablets or tablet coatings,
  • compositions for oral administration may also include hard capsules comprising gelatin or soft-sealed capsules comprising gelatin and a plasticizer, such as glycerol or sorbitol.
  • the hard capsules may contain the active ingredient in the form of granules, for example in admixture with fillers, such as corn starch, binders, and/or glidants, such as talc or magnesium stearate, and optionally stabilizers.
  • the active ingredient may be dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilizers and detergents, for example of the polyoxyethylene sorbitan fatty acid ester type, may also be added.
  • suitable liquid excipients such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilizers and detergents, for example of the polyoxyethylene sorbitan fatty acid ester type, may also be added.
  • compositions suitable for rectal administration are, for example, suppositories comprising a combination of the active ingredient and a suppository base.
  • Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
  • compositions suitable for parenteral administration may comprise aqueous solutions of an active ingredient in water-soluble form, for example of a water-soluble salt, or aqueous injection suspensions that contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if desired, stabilizers.
  • the active ingredient optionally together with excipients, can also be in the form of a lyophilizate and can be made into a solution before parenteral administration by the addition of suitable solvents. Solutions such as are used, for example, for parenteral administration can also be employed as infusion solutions.
  • the manufacture of injectable preparations is usually carried out under sterile conditions, as is the filling, for example, into ampoules or vials, and the sealing of the containers.
  • the compounds of the invention may be administered as the sole active ingredient, or together with other drugs useful against neoplastic diseases or useful in immunomodulating regimens.
  • the compounds of the invention may be used in accordance with the invention in combination with pharmaceutical compositions effective in various diseases as described above, e.g.
  • cyclophosphamide 5-fluorouracil, fludarabine, gemcitabine, cisplatinum, carboplatin, vincristine, vinblastine, etoposide, irinotecan, paclitaxel, docetaxel, rituxan, doxorubicine, gefitinib, or imatinib; or also with cyclosporins, rapamycins, ascomycins or their immunosuppressive analogs, e.g. cyclosporin A, cyclosporin G, FK-506, sirolimus or everolimus, corticosteroids, e.g.
  • prednisone cyclophosphamide, azathioprene, methotrexate, gold salts, sulfasalazine, antimalarials, brequinar, leflunomide, mizoribine, mycophenolic acid, mycophenolate, mofetil, 15-deoxyspergualine, immuno-suppressive monoclonal antibodies, e.g. monoclonal antibodies to leukocyte receptors, e.g.
  • the invention also provides for a pharmaceutical combinations, e.g. a kit, comprising a) a first agent which is a compound of the invention as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent.
  • a pharmaceutical combination e.g. a kit, comprising a) a first agent which is a compound of the invention as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent.
  • the kit can comprise instructions for its administration.
  • a compound of Formula (1) may be synthesized by reacting a compound of formula (6) with a compound of formula (7) in the presence of palladium catalyst (for example palladium acetate and the like), ligand (for example xantphos and the like) and base (for example cesium carbonate and the like) in a suitable solvent (for example, THF, and the like).
  • palladium catalyst for example palladium acetate and the like
  • ligand for example xantphos and the like
  • base for example cesium carbonate and the like
  • THF a suitable solvent
  • a compound of Formula (1) may be synthesized by reacting a compound of formula (6) with a compound of formula (7) in the presence of acid (for example HCl, TsOH and the like), in a suitable solvent (for example, 2-propanol, and the like). The reaction proceeds in a temperature range of about 70 0 C to about 150 0 C and can take up to 12 hours to complete.
  • acid for example HCl, TsOH and the like
  • a suitable solvent for example, 2-propanol, and the like
  • the compounds of the invention are also obtainable in the form of hydrates, or their crystals may include for example the solvent used for crystallization (present as solvates).
  • Salts can usually be converted to compounds in free form, e.g., by treating with suitable basic agents, for example with alkali metal carbonates, alkali metal hydrogen carbonates, or alkali metal hydroxides, such as potassium carbonate or sodium hydroxide.
  • suitable basic agents for example with alkali metal carbonates, alkali metal hydrogen carbonates, or alkali metal hydroxides, such as potassium carbonate or sodium hydroxide.
  • Salts of the inventive compounds with a salt-forming group may be prepared in a manner known per se. Acid addition salts of compounds of Formula (1), (2), (3A), (3B), (4A), (4B) or (5) may thus be obtained by treatment with an acid or with a suitable anion exchange reagent. Pharmaceutically acceptable salts of the compounds of the invention may be formed, for example, as acid addition salts, with organic or inorganic acids, from compounds of Formula (1), (2), (3A), (3B), (4A), (4B) or (5) with a basic nitrogen atom.
  • Suitable inorganic acids include, but are not limited to, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid.
  • Suitable organic acids include, but are not limited to, carboxylic, phosphoric, sulfonic or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid,-malic acid, tartaric acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4 aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid,
  • Compounds of the invention in unoxidized form may be prepared from N-oxides of compounds of the invention by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in a suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 8O 0 C.
  • a reducing agent e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like
  • a suitable inert organic solvent e.g. acetonitrile, ethanol, aqueous dioxane, or the like
  • Prodrug derivatives of the compounds of the invention may be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985).
  • appropriate prodrugs may be prepared by reacting a non-derivatized compound of the invention with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like).
  • Protected derivatives of the compounds of the invention may be made by means known to those of ordinary skill in the art. A detailed description of techniques applicable to the creation of protecting groups and their removal may be found in T. W. Greene, "Protecting Groups in Organic Chemistry", 3 rd edition, John Wiley and Sons, Inc., 1999.
  • Compounds of the invention may be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers.
  • Resolution of enantiomers may be carried out using covalent diastereomeric derivatives of the compounds of the invention, or by using dissociable complexes (e.g., crystalline diastereomeric salts).
  • Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and may be readily separated by taking advantage of these dissimilarities.
  • the diastereomers may be separated by fractionated crystallization, chromatography, or by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • a more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture may be found in Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981.
  • the compounds of the invention may be made by a process, which involves:
  • the reaction is quenched at 0 0 C with 100 mL of saturated aqueous NH 4 Cl and filtered through Celite. The filtrate is added to 100 mL of EtOAc and the layers are separated. The organic layer is washed with H 2 O, dried over MgSO 4 and concentrated.
  • the crude product is purified by silica flash column chromatography (0-30% EtOAc in Hexanes as eluent and checked by TLC stained with 2% of KMnO 4 in EtOH) to afford 4-Trifluoromethanesulfonyloxy-3,6-dihydro-2H- pyridine-1-carboxylic acid tert-butyl ester as a yellow oil.
  • Steps 1 and 2 4-(2-Chloro-4-isopropoxy-5-nitro-benzoylamino)-piperidine-l-carboxylic acid tert-butyl ester
  • Step 3 4-(4-Isopropoxy-5-nitro-2-vinyl-benzoylamino)-piperidine-l-carboxylic acid tert-butyl ester
  • the mixture is cooled to room temperature and poured into saturated aqueous ammonia chloride solution.
  • the mixture is extracted with ethyl acetate (3 x 100 mL).
  • the organic extracts are combined, washed with brine and concentrated.
  • the crude product is purified with silica gel column chromatography (40% ethyl acetate in hexanes) to afford 4-(4-isopropoxy-5-nitro-2-vinyl-benzoylamino)-piperidine-l-carboxylic acid tert-butyl ester as white solid.
  • Steps 4, 5 and 6 4-(5 -Isopropoxy-6-nitro- 1 -oxo- 1 ,3 -dihydro-isoindol-2-yl)-piperidine- 1 - carboxylic acid tert-butyl ester
  • Step 1 4-(4-Chloro-5-methyl-2-nitro-phenoxy)-piperidine-l-carboxylic acid tert-butyl ester
  • Step 2 4-r5-Methyl-4-(l-methyl-lH-pyrazol-4-yl)-2-nitro-phenoxyl-piperidine-l-carboxylic acid tert-butyl ester
  • the crude product is purified with silica gel column chromatography (10% ethyl acetate in hexanes) to afford l-methyl-5-nitro-4-propoxy-2- vinyl-benzene as a yellow solid.
  • l-Methyl-5-nitro-4-propoxy-2-vinyl-benzene obtained from the previous step (360 mg, 1.63mmol) is dissolved in DCM (20 mL) and is cooled to -78 0 C. O 3 (g) is bubbled into the solution until the solution's color turns blue/gray. The solution is then purged with N 2 (g) until the blue color disappears.
  • Tris(dibenzylidene acetone)dipalladium (0) (100 mg, 0.109 mmol, 0.1 equiv.), 2- dicyclohexylphosphine-2'-6'-dimethoxy biphenyl (112 mg, 0.272 mmol, 0.25 equiv.), 1-chloro- 5-isopropoxy-2-methyl-4-nitro-benzene (Intermediate 4, 250 mg, 1.09 mmol, 1.0 equiv.) and K 3 PO 4 (462 mg, 2.18 mmol, 2.0 equiv.) are added under a N 2 blanket. The reaction vessel is sealed and heated with microwave irradiation to 150 0 C for 20 min.
  • Steps 2 and 3 4-(4-Amino-5-isopropoxy-2-methyl-phenyl)-piperidine-l-carboxylic acid tert- butyl ester
  • Step 1 N2-(2-Isopropoxv-4-methvl-5-trimethvlsilanvlethvnvl-phenvl)-5-methyl-N4-r2- (propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine
  • reaction mixture is filtered through a small Celite plug and concentrated.
  • residue is purified over a 4 g SiO 2 column (ISCO) using a gradient of 0 to 20% ethyl acetate in hexanes as eluent, affording N2-(2-Isopropoxy-4- methyl-5-trimethylsilanylethynyl-phenyl)-5-methyl-N4-[2-(propane-2-sulfonyl)-phenyl]- pyrimidine-2,4-diamine as a yellow viscous oil.
  • ISCO SiO 2 column
  • Step 1 4-(l-Hvdroxv-6-isopropoxv-5-m ' tro-3-oxo-l,3-dihvdro-isoindol-2-vl)-piperidine-l- carboxylic acid tert-butyl ester oc
  • Step 1 (2S, 4Sj-4-(6- ⁇ 5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino ⁇ - 5-isopropoxy-l-oxo-l,3-dihydro-isoindol-2-yl)-pyrrolidine-2-carboxylic acid methyl ester
  • Step 1 l,4-dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate
  • a solution of 0.5 M KHMDS in toluene (4.7 mL, 2.34 mmol) is added to a solution of l,4-dioxaspiro[4.5]decan-8-one (1.80 mmol) and N-phenyltrifluoromethanesulfonimide (2.34 mmol) in dry THF (18 mL) at -78 0 C under argon. After stirring at -78 0 C for 4 hours, the mixture is quenched with H 2 O, extracted with diethyl ether and dried with MgSO 4 .
  • Step 5 4-(4-(dimethylamino)cyclohexyl)-2-isopropoxy-5-methylaniline
  • Table 1 shows exemplary compounds of Formula (IA).
  • Table 2 shows exemplary compounds of Formula (1C).
  • Methyl 4'-amino-5'-methoxy-2'-methylbiphenyl-4-carboxylate may be synthesized following the procedures previously described (Example 7, Steps 1 and 2) using appropriate reagents.
  • Step 2 Methyl 4'-(4-bromo-5-chloropyridin-2-ylamino)-5'-methoxy-2'-methylbiphenyl- 4-carboxylate
  • Step 3 Methyl 4'-(5-chloro-4-(2-(isopropylsulfonyl)phenylamino)pyridin-2-ylamino)-5'- methoxy-2'-methylbiphenyl-4-carboxylate (254)
  • Table 3 shows exemplary compounds of Formula (5).
  • Table 4 shows other compounds which may be useful treating, ameliorating or preventing a condition which responds to inhibition of anaplastic lymphoma kinase (ALK) activity, focal adhesion kinase (FAK), zeta-chain-associated protein kinase 70 (ZAP-70), insulin-like growth factor (IGF-IR).
  • ALK anaplastic lymphoma kinase
  • FAK focal adhesion kinase
  • ZAP-70 zeta-chain-associated protein kinase 70
  • IGF-IR insulin-like growth factor
  • Compounds of the present invention may be assessed for their ability to inhibit ALK using assays described below, as well as other assays known in the art.
  • Ba/F3 is a murine IL-3 -dependent pro-B lymphoma cell line.
  • Parental Ba/F3 cells are used to generate a panel of sublines whose proliferation and survival is rendered IL-3- independent by stable transduction with individual tyrosine kinases activated by fusion with the amino-terminal portion of TEL (amino acid 1-375) or BCR.
  • TEL amino acid 1-375
  • BCR BCR.
  • TK Tel-Tyrosine Kinase
  • Each transformed Ba/F3 cells are cultured in RPMI- 1640 media (Gibco Cat #11875093, Carlsbad, CA) supplemented with 10% FBS (Hyclone Cat #SV30014.03, Logan, UT), 4.5 g/L glucose (Sigma #G5400, St.Louis, MO), 1.5 g/L sodium bicarbonate (Biowhittaker #17-613E, Walkersville, MD) and Pen/Strep (Gibco #10378-016, Carlsbad, CA). Cells are splitted twice weekly.
  • the potency of test compounds against various TeI-TK transformed Ba/F3 lines is determined as follows. Exponentially growing BaF3 TeI-TK cells are diluted in fresh medium to 75,000 cells/mL and seeded into 384-well plates (3750 cells/well) at 50 ⁇ L/well using a ⁇ Fill liquid dispenser (BioTek, Winooski, VT, USA). Duplicate plates are run for each cell line. Test and control compounds are serially diluted with DMSO and arrayed in a polypropylene 384-well plate. 50 nL of compound is transferred into the assay plates using a pin-transfer device, and the plates are incubated at 37 0 C (5% CO2) for 48 hours.
  • Luciferized Karpas 299 (Karpas299-Luc) is generated by infecting retrovirus encoding luciferase gene, and cultured in RPMI-1649 medium supplemented with 10% FBS, 1% P/S/L-Glu. At day 1, cells are harvested and resuspended at density of 150,000 cells/ml (cell number is measured using ViCeIl (BD). Cells are dispensed from a diluted suspension into a 384-well assay plate in 50 ⁇ l volume using ⁇ Fill (Bio-TEK). Serially diluted compounds (in DMSO) are transferred into plate using 50 nL pinhead. Assay plates are incubated at 37 0 C for 48 hours.
  • ALK enzyme and IGFlR and INSR are purchased from Upstate. Following reagents are prepared in-house; 10 x kinas buffer (KB) (200 mM Tris (pH 7.0), 100 mM MgCl 2 , 30 mM MnCl 2 , 50 nM NaVO 4 ), 10 mM ATP, 100 mg/ml BSA, 0.5 M EDTA, 4 M KF. Proxiplate-384 from Perkin-Elmer is used for set up assay.
  • HTRF reagents including substrate (Biotin- poly-GT (61GT0BLB), Mab PT66-K, (61T66KLB), Streptavidin-XL ent (611SAXLB)) are purchased from CIS-US, Inc.
  • the substrate/ ATP mix is prepared by adding ATP (final concentration, 3 ⁇ M) and biotinylated poly-GT (final concentration, 10 ng/ ⁇ l) into Ix KB, and dispensed into Proxiplate- 384 at 5 ⁇ l/well using ⁇ Fill (Bio-TEK). Serially diluted compounds (in DMSO) are transferred into plate using 50 nL pinhead. 5 ⁇ L of prepared Enzyme mix (enzyme (final concentration, 5 ng/ ⁇ l), mixed with BSA and DTT in Ix KB) is added to initiate kinase reaction using ⁇ Fill (Bio- TEK). Assay plate is incubated at room temperature for 2 hours.
  • Detection mix is prepared by adding both Mab PT66-K and Streptavidin-XL ent into 0.5 x KB solution containing KF (final concentration, 125 mM), EDTA (final concentration, 50 mM) and BSA (final concentration, 100 ⁇ g/ml) in. At the end of reaction, 10 ⁇ L of detection mix is added and incubated for 30 minutes at room temperature before measurement. HTRF signal is detected using Analyst-GT (molecular dynamic).

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Abstract

The invention provides novel pyrimidine and pyridine derivatives of formula (I) and pharmaceutical compositions thereof, and methods for using such compounds. For example, the pyrimidine and pyridine derivatives of the invention may be used to treat, ameliorate or prevent a condition which responds to inhibition of anaplastic lymphoma kinase (ALK) activity, focal adhesion kinase (FAK), zeta-chain-associated protein kinase 70 ZAP-70), insulin-like growth factor (IGF- 1R), or a combination thereof.

Description

COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS
Cross-Reference to Related Applications
[0001] This application claims the benefit of U.S. provisional application serial no. 60/869,299, filed December 8, 2006, which is incorporated by reference herein in its entirety.
Technical Field
[0002] The invention relates to protein kinase inhibitors, more particularly novel pyrimidine and pyridine derivatives and pharmaceutical compositions thereof, and their use as pharmaceuticals.
Background Art
[0003] Anaplastic lymphoma kinase (ALK), a member of the insulin receptor superfamily of receptor tyrosine kinases, has been implicated in oncogenesis in hematopoietic and non- hematopoietic tumors. The aberrant expression of full-length ALK receptor proteins has been reported in neuroblastomas and glioblastomas; and ALK fusion proteins have occurred in anaplastic large cell lymphoma. The study of ALK fusion proteins has also raised the possibility of new therapeutic treatments for patients with ALK-positive malignancies. (Pulford et al., Cell. MoI. Life Sci. 61:2939-2953 (2004)).
[0004] Focal Adhesion Kinase (FAK) is a key enzyme in the integrin-mediated outside-in signal cascade (D. Schlaepfer et al., Prog Biophys MoI Biol 1999, 71, 43578). The trigger in the signal transduction cascade is the autophosphorylation of Y397. Phosphorylated Y397 is a SH2 docking site for Src family tyrosine kinases; the bound c-Src kinase phosphorylates other tyrosine residues in FAK. Among them, phsophorylated Y925 becomes a binding site for the SH2 site of Grb2 small adaptor protein. This direct binding of Grb2 to FAK is one of the key steps for the activation of down stream targets such as the Ras-ERK2/MAP kinase cascade.
[0005] Zeta-chain-associated protein kinase 70 (ZAP-70), a member of the protein tyrosine kinase family, is of potential prognostic importance in chronic lymphocytic leukemia (CLL). ZAP-70, known to be of importance in T and NK cell signaling but absent in normal peripheral B cells, is expressed in the majority of the poorer prognosis unmutated CLL and absent in most cases with mutated IgVH genes. ZAP-70 is also expressed in a minority of other B cell tumors. (Orchard et al., Leuk. Lymphoma 46:1689-98 (2005)). [0006] Insulin- like growth factor (IGF-I) signaling is highly implicated in cancer, with the IGF-I receptor (IGF-IR) as the predominating factor. IGR-IR is important for tumor transformation and survival of malignant cells, but is only partially involved in normal cell growth. Targeting of IGF-IR has been suggested to be a promising option for cancer therapy. (Larsson et al., Br. J. Cancer 92:2097-2101 (2005)).
[0007] Because of the emerging disease-related roles of ALK, FAK, ZAP-70 and IGF-IR, there is a continuing need for compounds which may be useful for treating and preventing a disease which responds to inhibition of ALK, FAK, ZAP-70 and/or IGF-IR.
Disclosure of the Invention
[0008] The invention relates to novel pyrimidine and pyridine derivatives and pharmaceutical compositions thereof, and their use as pharmaceuticals. [0009] In one aspect, the invention provides a having Formula (1):
Figure imgf000003_0001
or pharmaceutically acceptable salts thereof; wherein
Figure imgf000003_0002
A1 and A4 are independently C or N; each A2 and A3 is C, or one of A2 and A3 is N when R6 and R7 form a ring;
B and C are independently an optionally substituted 5-7 membered carbocyclic ring, aryl, heteroaryl or heterocyclic ring containing N, O or S;
Z1, Z2 and Z3 are independently NR11, C=O, CR-OR, (CR2)I-2 or =C-R12;
R1 and R2 are independently halo, OR12, NR(R12), SR12, or an optionally substituted Ci_6 alkyl, C2-6 alkenyl or C2-6 alkynyl; or one of R1 and R2 is H;
R3 is (CR2)o-2S02R12, (CR2V2SO2NRR12, (CR2)o-2COi_2R12, (CR2)o-2CONRR12 or cyano; R4, R , R7 and R10 are independently an optionally substituted Ci_6 alkyl, C2_6 alkenyl or C2-6 alkynyl; OR12, NR(R12), halo, nitro, SO2R12, (CR2)PR13 or X; or R4, R7 and R10 are independently H;
R, R5 and R5 are independently H or Ci_6 alkyl;
R8 and R9 are independently C1-6 alkyl, C2-6 alkenyl, C2_6 alkynyl, halo or X, or one of R8 and R9 is H when R1 and R2 form a ring; and provided one of R8 and R9 is X; alternatively, R1 and R2, or R6 and R7, R7 and R8, or R9 and R10, when attached to a carbon atom may form an optionally substituted 5-7 membered monocyclic or fused carbocyclic ring, aryl, or heteroaryl or heterocyclic ring comprising N, O and/or S; or R7, R8, R9 and R10 are absent when attached to N;
R11 is H, Ci_6 alkyl, C2-6 alkenyl, (CR2)PCOi_2R, (CR2)P0R, (CR2)PR13, (CR2)PNRR12, (CR2)PCONRR12 or (CR2)pSOi_2R12;
R12 and R13 are independently an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, or a 5-7 membered heterocyclic ring comprising N, O and/or S; aryl or heteroaryl; or R12 is H, C1-6 alkyl;
X is (CR2)qY, cyano, COi_2R12, CONR(R12), CONR(CR2)PNR(R12), CONR(CR2)POR12, CONR(CR2)PSR12, CONR(CR2)pS(O)i_2R12 or (CR2)i_6NR(CR2)pOR12;
Y is an optionally substituted 3-12 membered carbocyclic ring, a 5-12 membered aryl, or a 5-12 membered heteroaryl or heterocyclic ring comprising N, O and/or S and attached to A or A3 or both via a carbon atom of said heteroaryl or heterocyclic ring when q in (CR2)qY is 0; and n, p and q are independently 0-4.
[0010] In the above Formula (1), R1 may be halo or Ci_6 alkyl; R2 is H or NH2; or R1 and R2 together form an optionally substituted 5-6 membered aryl, or heteroaryl or heterocyclic ring comprising 1-3 nitrogen atoms. In other examples, R3 in Formula (1) may be SO2R12, SO2NH2, SO2NRR12, CO2NH2, CONRR12, COi_2R12, or cyano; and R12 is Ci_6 alkyl, an optionally substituted cycloalkyl,
Figure imgf000004_0001
cycloalkenyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl or azetidinyl. In yet other examples, R , R , R7 and R10 in Formula (1) are independently H, and n is 0. In other examples, R6 in Formula (1) may be halo or OR12, and R12 is C1-6 alkyl. [0011] In one embodiment, the invention provides compounds having Formula (2):
Figure imgf000005_0001
wherein R1 is halo or C]_6 alkyl;
R2 is H; or
R1 and R2 together form an optionally substituted 5-6 membered heteroaryl or heterocyclic ring comprising one or two nitrogen atoms;
R6 is isopropoxy or methoxy; one of R8 and R9 is (CR2)qY and the other is Ci_6 alkyl, cyano, COi_2R12, CONR(R12) or CONR(CR2)pNR(R12);
Y is an optionally substituted C3-7 cycloalkyl, C3-7 cycloalkenyl, or phenyl; or Y is pyridyl, pyrazolyl, isoxazolyl, imidazolyl, thiazolyl, benzimidazolyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, azetidinyl, heptamethyleneimine or octamethyleneimine, each of which is attached to the phenyl ring via a carbon atom when q in (CR2)qY is 0; n is 0- 1 ; and q is 0-4.
[0012] In the above Formula (2), one of R8 and R9 may be (CR2)qY and the other is Ci_6 alkyl; and n and q are independently 0. In some examples, Y is pyrrolidinyl, piperidinyl, azetidinyl. In other examples, R1 is halo or C1-6 alkyl; and R2 is H.
[0013] In another embodiment, the invention provides compounds having Formula (3A) or (3B):
Figure imgf000006_0001
wherein B and C together form
Figure imgf000006_0002
Z1, Z2 and Z3 together form
Figure imgf000007_0001
or tautomers thereof;
R » 1 i •s halo or Ci_6 alkyl;
R2 is H; or
R1 and R2 together form an optionally substituted 5-7 membered carbocyclic ring, aryl, or heteroaryl or heterocyclic ring comprising N, O and/or S; and
R is isopropoxy or methoxy.
11
[0014] In the above Formula (3A) or (3B), each R11 may be (CR2)PCOi_2R, (CR2)POR, (CR2)pR13, (CR2)PNRR12 or (CR2)PCONRR12;
R and R12 are independently H or Ci_6 alkyl; and
R13 is an optionally substituted piperidinyl, azetidiyl, tetrahydropyranyl, cyclohexyl, morpholinyl, pyrrolidinyl, heptamethyleneimine, octamethyleneimine, a bicyclic amine or diamine derivative, quinuclidin-3-yl, 8-methyl-8-aza-bicyclo[3.2.1]oct-6-yl], or 9-methyl-9-aza- bicyclo[4.2.1]nonan-7-yl.
[0015] In yet another embodiment, the invention provides compounds having Formula (4A) or Formula (4B):
Figure imgf000007_0002
(4A)
Figure imgf000008_0001
wherein R1 is halo or C1-6 alkyl;
R is H; or
R1 and R2 together form an optionally substituted 5-7 membered carbocyclic ring, aryl, or heteroaryl or heterocyclic ring comprising N, O and/or S;
R is isopropoxy or methoxy; and
B2 and B3 are independently an optionally substituted 5-6 membered aryl or heteroaryl containing N, O or S.
[0016] In another aspect, the invention provides compounds having Formula (5):
Figure imgf000008_0002
or pharmaceutically acceptable salts thereof; wherein
Figure imgf000008_0003
A1 and A4 are independently C or N; each A2 and A3 is C, or one of A2 and A3 is N when R and R7 form a ring; B and C are independently an optionally substituted 5-7 membered carbocyclic ring, aryl, heteroaryl or heterocyclic ring containing N, O or S;
Z1, Z2 and Z3 are independently NR11, C=O, CR-OR, (CR2)I-2 or =C-R12; R1 and R2 are independently halo, OR12, NR(R12), SR12, or an optionally substituted C1-6 alkyl, C2_6 alkenyl or C2_6 alkynyl; or one of R1 and R2 is H;
R3 is (CR2)o-2S02R12, (CR2)o-2S02NRR12, (CR^CO^R12, (CR2)0-2CONRR12 or cyano;
R4, R6, and R7 and R10 when attached to a carbon atom, are independently H, an optionally substituted Ci_6 alkyl, C2_6 alkenyl or C2_6 alkynyl; OR12, NR(R12), halo, nitro, SO2R12, (CR2)pR13 or X; provided R6 and R7 are not both H;
R, R5 and R5 are independently H or C1-6 alkyl;
R8 and R9 are independently Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, halo or X, or one of R8 and R9 is H; and provided one of R8 and R9 is X; alternatively, R1 and R2, or R6 and R7, R7 and R8, or R9 and R10, when attached to a carbon atom may form an optionally substituted 5-7 membered monocyclic or fused carbocyclic ring, aryl, or heteroaryl or heterocyclic ring comprising N, O and/or S; or R7, R8, R9 and R10 are absent when attached to N;
R11 is H, Ci_6 alkyl, C2-6 alkenyl, (CR2)pCOi_2R, (CR2)POR, (CR2)PR13, (CR2)PNRR12, (CR2)PCONRR12 or (CR2)pSOi_2R12;
R12 and R13 are independently an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, or a 5-7 membered heterocyclic ring comprising N, O and/or S; aryl or heteroaryl; or R12 is H, C]_6 alkyl;
X is (CR2)qY, cyano, COi_2R12, CONR(R12), CONR(CR2)PNR(R12), CONR(CR2)POR12, CONR(CR2)PSR12, CONR(CR2)pS(O)i_2R12 or (CR2)i_6NR(CR2)pOR12;
Y is an optionally substituted 3-12 membered carbocyclic ring, a 5-12 membered aryl, or a 5-12 membered heteroaryl or heterocyclic ring comprising N, O and/or S and attached to A2 or A3 or both via a carbon atom of said heteroaryl or heterocyclic ring when q in (CR2)qY is 0; and n, p and q are independently 0-4.
[0017] In yet another aspect, the present invention provides pharmaceutical compositions comprising a compound having Formula (1), (2), (3A), (3B), (4A), (4B) or (5), and a pharmaceutically acceptable excipient.
[0018] In yet another aspect, the invention provides methods for modulating ALK, FAK, ZAP-70 and/or IGF-IR, comprising administering to a system or a subject in need thereof, a therapeutically effective amount of a compound having Formula (1), (2), (3A), (3B), (4A), (4B) or (5), or pharmaceutically acceptable salts or pharmaceutical compositions thereof, thereby modulating said ALK, FAK, ZAP-70 and/or IGF-IR. The invention also provides methods to treat, ameliorate or prevent a condition which responds to inhibition of ALK, FAK, ZAP-70 and/or IGF-IR, comprising administering to a system or subject in need of such treatment an effective amount of a compound having Formula (1), (2), (3A), (3B), (4A), (4B) or (5), or pharmaceutically acceptable salts or pharmaceutical compositions thereof, and optionally in combination with a second therapeutic agent, thereby treating said condition. Alternatively, the present invention provides the use of a compound having Formula (1), (2), (3A), (3B), (4A), (4B) or (5) in the manufacture of a medicament for treating a condition mediated by ALK, FAK, ZAP-70 and/or IGF-IR. In particular embodiments, the compounds of the invention may be used alone or in combination with a second therapeutic agent to treat a condition mediated by ALK, wherein said condition is an autoimmune disease, a transplantation disease, an infectious disease or a cell proliferative disorder.
[0019] Furthermore, the invention provides methods for treating a cell proliferative disorder, comprising administering to a system or subject in need of such treatment an effective amount of a compound having Formula (1), (2), (3A), (3B), (4A), (4B) or (5), or pharmaceutically acceptable salts or pharmaceutical compositions thereof, and optionally in combination with a second therapeutic agent, thereby treating said condition. Alternatively, the present invention provides the use of a compound having Formula (1), (2), (3A), (3B), (4A), (4B) or (5) in the manufacture of a medicament for treating a cell-proliferative disorder. In particular examples, the compounds of the invention may be used alone or in combination with a chemotherapeutic agent to treat a cell proliferative disorder, including but not limited to, lymphoma, osteosarcoma, melanoma, or a tumor of breast, renal, prostate, colorectal, thyroid, ovarian, pancreatic, neuronal, lung, uterine or gastrointestinal tumor.
[0020] In the above methods for using the compounds of the invention, a compound having Formula (1), (2), (3A), (3B), (4A), (4B) or (5) may be administered to a system comprising cells or tissues, or to a mammalian subject such as a human or animal subject.
Definitions
[0021] "Alkyl" refers to a moiety and as a structural element of other groups, for example halo-substituted-alkyl and alkoxy, and may be straight-chained or branched. An optionally substituted alkyl, alkenyl or alkynyl as used herein may be optionally halogenated (e.g., CF3), or may have one or more carbons that is substituted or replaced with a heteroatom, such as NR, O or S (e.g., -OCH2CH2O-, alkylthiols, thioalkoxy, alkylamines, etc). [0022] "Aryl" refers to a monocyclic or fused bicyclic aromatic ring containing carbon atoms. "Arylene" means a divalent radical derived from an aryl group. For example, an aryl group may be phenyl, indenyl, indanyl, naphthyl, or 1,2,3,4-tetrahydronaphthalenyl, which may be optionally substituted in the ortho, meta or para position.
[0023] "Heteroaryl" as used herein is as defined for aryl above, where one or more of the ring members is a heteroatom. Examples of heteroaryls include but are not limited to pyridyl, pyrazinyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl, benzopyranyl, benzothiopyranyl, benzo[l,3]dioxole, imidazolyl, benzo-imidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl, benzotriazolyl, tetrazolyl, pyrazolyl, thienyl, pyrrolyl, isoquinolinyl, purinyl, thiazolyl, tetrazinyl, benzothiazolyl, oxadiazolyl, benzoxadiazolyl, etc.
[0024] A "carbocyclic ring" as used herein refers to a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring containing carbon atoms, which may optionally be substituted, for example, with =0. Examples of carbocyclic rings include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylene, cyclohexanone, etc.
[0025] A "heterocyclic ring" as used herein is as defined for a carbocyclic ring above, wherein one or more ring carbons is a heteroatom. For example, a heterocyclic ring may contain N, O, S, -N=, -S-, -S(O), -S(O)2-, or -NR- wherein R may be hydrogen, Ci^alkyl or a protecting group. Examples of heterocyclic rings include but are not limited to morpholino, pyrrolidinyl, pyrrolidinyl-2-one, piperazinyl, piperidinyl, piperidinylone, l,4-dioxa-8-aza-spiro[4.5]dec-8-yl, 1,2,3,4-tetrahydroquinolinyl, etc. Heterocyclic rings as used herein may encompass bicyclic amines and bicyclic diamines.
[0026] The terms "co- administration" or "combined administration" or the like as used herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
[0027] The term "pharmaceutical combination" as used herein refers to a product obtained from mixing or combining active ingredients, and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, e.g. a compound of Formula (1) and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g. a compound of Formula (1) and a co-agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the active ingredients in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of three or more active ingredients.
[0028] The term "therapeutically effective amount" means the amount of the subject compound that will elicit a biological or medical response in a cell, tissue, organ, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
[0029] The term "administration" or "administering" of the subject compound means providing a compound of the invention and prodrugs thereof to a subject in need of treatment.
Modes of Carrying Out the Invention
[0030] The invention provides novel pyrimidine and pyridine derivatives and pharmaceutical compositions thereof, and methods for using such compounds.
[0031] In one aspect, the invention provides a having Formula (1):
R3 ' I
R5 W (1) or pharmaceutically acceptable salts thereof; wherein
Figure imgf000012_0001
A1 and A4 are independently C or N; each A2 and A3 is C, or one of A2 and A3 is N when R and R7 form a ring;
B and C are independently an optionally substituted 5-7 membered carbocyclic ring, aryl, heteroaryl or heterocyclic ring containing N, O or S;
Z1, Z2 and Z3 are independently NR11, C=O, CR-OR, (CR2)I-2 or =C-R12;
R1 and R2 are independently halo, OR12, NR(R12), SR12, or an optionally substituted Ci_6 alkyl, C2-6 alkenyl or C2-6 alkynyl; or one of R1 and R2 is H; R3 is (CR2)o-2S02R12, (CR2V2SO2NRR12, (CR2)0-2COi_2R12, (CR2)0-2CONRR12 or cyano;
R4, R6, R7 and R10 are independently an optionally substituted C1-6 alkyl, C2_6 alkenyl or C2_6 alkynyl; OR12, NR(R12), halo, nitro, SO2R12, (CR2)pR13 or X; or R4, R7 and R10 are independently H;
R, R5 and R5 are independently H or C1-6 alkyl;
R and R are independently Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, halo or X, or one of R and R9 is H when R1 and R2 form a ring; and provided one of R8 and R9 is X; alternatively, R1 and R2, or R6 and R7, R7 and R8, or R9 and R10, when attached to a carbon atom may form an optionally substituted 5-7 membered monocyclic or fused carbocyclic ring, aryl, or heteroaryl or heterocyclic ring comprising N, O and/or S; or R7, R8, R9 and R10 are absent when attached to N;
R11 is H, Ci_6 alkyl, C2_6 alkenyl, (CR2)pCOi_2R, (CR2)p0R, (CR2)PR13, (CR2)PNRR12, (CR2)PCONRR12 or (CR2)pSOi_2R12;
R12 and R13 are independently an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, or a 5-7 membered heterocyclic ring comprising N, O and/or S; aryl or heteroaryl; or R 12 i •s H, Ci_6 alkyl;
X is (CR2)qY, cyano, COi
Figure imgf000013_0001
, CONR(CR2)PSR12, CONR(CR2)PS(O)!_2R12 or (CR2;h_6NR(CR2)pOR12;
Y is an optionally substituted 3-12 membered carbocyclic ring, a 5-12 membered aryl, or a 5-12 membered heteroaryl or heterocyclic ring comprising N, O and/or S and attached to A2 or A3 or both via a carbon atom of said heteroaryl or heterocyclic ring when q in (CR2)qY is 0; and n, p and q are independently 0-4. [0032] In one embodiment, the invention provides compounds having Formula (2):
Figure imgf000013_0002
wherein R1 is halo or Ci_6 alkyl; R is H; or
R1 and R2 together form an optionally substituted 5-6 membered heteroaryl or heterocyclic ring comprising one or two nitrogen atoms;
R6 is isopropoxy or methoxy; one of R8 and R9 is (CR2)qY and the other is Ci_6 alkyl, cyano, COi_2R12, CONR(R12) or CONR(CR2)pNR(R12);
Y is an optionally substituted C3-7 cycloalkyl, C3-7 cycloalkenyl, or phenyl; or Y is pyridyl, pyrazolyl, isoxazolyl, imidazolyl, thiazolyl, benzimidazolyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, azetidinyl, heptamethyleneimine or octamethyleneimine, each of which is attached to the phenyl ring via a carbon atom when q in (CR2)qY is 0; n is 0- 1 ; and q is 0-4.
[0033] In another embodiment, the invention provides compounds having Formula (3A) or (3B):
Figure imgf000014_0001
wherein B and C together form
Figure imgf000015_0001
Z2 and Z3 together form
Figure imgf000015_0002
or tautomers thereof;
R1 is halo or C1-6 alkyl; R2 is H; or
R1 and R2 together form an optionally substituted 5-7 membered carbocyclic ring, aryl, or heteroaryl or heterocyclic ring comprising N, O and/or S; and
R is isopropoxy or methoxy.
[0034] In yet another embodiment, the invention provides compounds having Formula (4A) or Formula (4B):
Figure imgf000015_0003
Figure imgf000016_0001
wherein R1 is halo or C1-6 alkyl;
R is H; or
R1 and R2 together form an optionally substituted 5-7 membered carbocyclic ring, aryl, or heteroaryl or heterocyclic ring comprising N, O and/or S;
R is isopropoxy or methoxy; and
B2 and B3 are independently an optionally substituted 5-6 membered aryl or heteroaryl containing N, O or S.
[0035] In another aspect, the invention provides compounds having Formula (5):
Figure imgf000016_0002
or pharmaceutically acceptable salts thereof; wherein
Figure imgf000016_0003
A1 and A4 are independently C or N; each A2 and A3 is C, or one of A2 and A3 is N when R and R7 form a ring; B and C are independently an optionally substituted 5-7 membered carbocyclic ring, aryl, heteroaryl or heterocyclic ring containing N, O or S;
Z1, Z2 and Z3 are independently NR11, C=O, CR-OR, (CR2)I-2 or =C-R12; R1 and R2 are independently halo, OR12, NR(R12), SR12, or an optionally substituted C1-6 alkyl, C2_6 alkenyl or C2_6 alkynyl; or one of R1 and R2 is H;
R3 is (CR2)o-2S02R12, (CR2)o-2S02NRR12, (CR^CO^R12, (CR2)0-2CONRR12 or cyano;
R4, R6, and R7 and R10 when attached to a carbon atom, are independently H, an optionally substituted Ci_6 alkyl, C2_6 alkenyl or C2_6 alkynyl; OR12, NR(R12), halo, nitro, SO2R12, (CR2)pR13 or X; provided R6 and R7 are not both H;
R, R5 and R5 are independently H or C1-6 alkyl;
R8 and R9 are independently Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, halo or X, or one of R8 and R9 is H; and provided one of R8 and R9 is X; alternatively, R1 and R2, or R6 and R7, R7 and R8, or R9 and R10, when attached to a carbon atom may form an optionally substituted 5-7 membered monocyclic or fused carbocyclic ring, aryl, or heteroaryl or heterocyclic ring comprising N, O and/or S; or R7, R8, R9 and R10 are absent when attached to N;
R11 is H, Ci_6 alkyl, C2-6 alkenyl, (CR2)pCOi_2R, (CR2)POR, (CR2)PR13, (CR2)PNRR12, (CR2)PCONRR12 or (CR2)pSOi_2R12;
R12 and R13 are independently an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, or a 5-7 membered heterocyclic ring comprising N, O and/or S; aryl or heteroaryl; or R12 is H, C]_6 alkyl;
X is (CR2)qY, cyano, COi_2R12, CONR(R12), CONR(CR2)PNR(R12), CONR(CR2)POR12, CONR(CR2)PSR12, CONR(CR2)pS(O)i_2R12 or (CR2)i_6NR(CR2)pOR12;
Y is an optionally substituted 3-12 membered carbocyclic ring, a 5-12 membered aryl, or a 5-12 membered heteroaryl or heterocyclic ring comprising N, O and/or S and attached to A2 or A3 or both via a carbon atom of said heteroaryl or heterocyclic ring when q in (CR2)qY is 0; and n, p and q are independently 0-4.
[0036] In each of the above formula, Y or R13 may independently be heterocyclic rings, which may be a bicyclic amine or bicyclic diamine. Examples of bicyclic amine and bicyclic diamines include but are not limited to an optionally substituted hexanemethyleneimine; heptamethyleneimine; quinuclidine; 3-azabicyclo(3,3,0)octane; 3,8-diazabicyclo[3,2,l]octane; octahydro-lH-pyrido[3,4-C]azepine; octahydropyrrolizine; 6-azabicyclo[3,2,l]octane; 3- azabicyclo[3,2,l]octane; 2,5-diazabicyclo[2,2,l]heptane; l-azabicyclo[2,2,l]heptane; 2- azabicyclo[2,2,l]heptane; l,4-diazabicyclo[4,4,0]decane; l,4-diazabicyclo[4,3,0]nonane; 1- azabicyclo[3,2,l]octane; 3-azabicyclo[3,3,0]octane; 8-azabicyclo[3,2,l]octane; 3,9- diazabicyclo[4,2,l]nonane; octahydropyrrolo[3,4-C]pyrrole; octahydropyrrolo[3,4-B]pyrrole; hexahydropyrrolo[3,2-B]pyrrole; hexahydropyrrolo[3,2-C]pyrrole; 1,4-diazacyclooctane; 1,5- diazacyclooctane; 3,7-diazabicyclo[4,2,0]octane; 3,7-diazabicyclo[3,3,l]nonane; octahydropyrrolo[3,4-C]pyridine; octahydropyrrolo[3,4-B]pyridine; octahydrocyclopenta[C]pyrrolidine; hexahydrocyclopentafClpyrrolidine; 8- azabicyclo[3,2,l]octane; decahydroquinoline; decahydroisoquinoline; decahydropyrido[3,4- B]azepine; decahydropyrido[4,3-B]azepine; 9-azabicyclo[3,3,l]nonane; bispidine; 3- azabicyclo[3,l,0]hexane; 8-azabicyclo[3,2,l]octane; 2-azabicyclo[3.3.1]nonane; tetrahydroquinoline; tetrahydroisoquinoline; 2,5-diazabicyclo[2,2,2]octane; decahydro-2,7- naphthyridine; 1,4-diazepane; azonane; octahydro-lH-indole; octahydro-lH-isoindole; 2- azabicyclo[3,3,0]octane; 6-azabicyclo[3,2,l]octane; 7-aza-bicyclo[2.2.1]heptane; decahydropyrazino[l,2-a]azepine; 3,8-diaza-bicyclo[3,2,l]octane; 3-azabicyclo[3,2,l]octane; 3- aza-tricyclo[4,2,l,0(2,5)]nonane; 2,6-diazaspiro[3,5]nonane; 6-azabicyclo[2,l,0]hexane, etc.
[0037] In each of the above formula, any asymmetric carbon atoms may be present in the (R)-, (S)-or (R,S)-configuration. The compounds may thus be present as mixtures of isomers or as pure isomers, for example, as pure enantiomers or diastereomers. The invention further encompasses possible tautomers of the inventive compounds.
[0038] In each of the above formula, each optionally substituted moiety may be substituted with Ci_6 alkyl, C2-6 alkenyl or C3_6 alkynyl, each of which may be optionally halogenated or optionally having a carbon that may be replaced or substituted with N, S, O, or a combination thereof (for example, hydroxylCi-Cgalkyl, Ci-CgalkoxyCi-Cgalkyl); halo, amino, amidino, C]_6 alkoxy; hydroxyl, methylenedioxy, carboxy; Ci-s alkylcarbonyl, Ci-s alkoxycarbonyl, carbamoyl, Ci-8 alkylcarbamoyl, sulfamoyl, cyano, oxo, nitro, or an optionally substituted carbocyclic ring, heterocyclic ring, aryl or heteroaryl as previously described.
Pharmacology and Utility
[0039] The compounds of the invention and their pharmaceutically acceptable salts exhibit valuable pharmacological properties when tested in vitro in cell-free kinase assays and in cellular assays, and are therefore useful as pharmaceuticals.
[0040] In one aspect, compounds of Formula (1), (2), (3A), (3B), (4A), (4B) or (5) may inhibit the tyrosine kinase activity of anaplastic lymphoma kinase (ALK) and the fusion protein of NPM-ALK. This protein tyrosine kinase results from a gene fusion of nucleophosmin (NPM) and ALK, rendering the protein tyrosine kinase activity of ALK ligand independent. NPM-ALK plays a key role in signal transmission in a number of hematopoetic and other human cells leading to hematological and neoplastic diseases, for example in anaplastic large-cell lymphoma (ALCL) and non-Hodgkin's lymphomas (NHL), specifically in ALK+NHL or Alkomas, in inflammatory myofibroblastic tumors (IMT) and neuroblastomas. (Duyster et al. 2001 Oncogene 20, 5623-5637). In addition to NPM-ALK, other gene fusions have been identified in human hematological and neoplastic diseases; for example, TPM3-ALK (a fusion of nonmuscle tropomyosin with ALK).
[0041] The inhibition of ALK tyrosine kinase activity may be demonstrated using known methods, for example using the recombinant kinase domain of the ALK in analogy to the VEGF-R kinase assay described in J. Wood et al. Cancer Res. 60, 2178-2189 (2000). In general, in vitro enzyme assays using GST-ALK protein tyrosine kinase are performed in 96- well plates as a filter binding assay in 20 mM Tris HCl, pH = 7.5, 3 mM MgCl2, 10 mM MnCl2, 1 mM DTT, 0.1 μCi/assay (=30 μl) [γ-33P]-ATP, 2 μM ATP, 3 μg/mL poly (GIu, Tyr 4:1) PoIy- EY (Sigma P-0275), 1 % DMSO, 25 ng ALK enzyme. Assays are incubated for 10 min at ambient temperature. Reactions are terminated by adding 50 μl of 125 mM EDTA, and the reaction mixture is transferred onto a MAIP Multiscreen plate (Millipore, Bedford, MA, USA), previously wet with methanol, and rehydrated for 5 min with H2O. Following washing (0.5 % H3PO4), plates are counted in a liquid scintillation counter. IC50 values are calculated by linear regression analysis of the percentage inhibition.
[0042] Compounds of Formula (1), (2), (3A), (3B), (4A), (4B) or (5) may potently inhibit the growth of human NPM-ALK overexpressing murine BaF3 cells (DSMZ Deutsche Sammiung von Mikroorganismen und Zelikulturen GmbH, Germany). The expression of NPM- ALK may be achieved by transfecting the BaF3 cell line with an expression vector pClneo™ (Promega Corp., Madison WI, USA) coding for NPM-ALK and subsequent selection of G418 resistant cells. Non-transfected BaF3 cells depend on IL-3 for cell survival. In contrast, NPM- ALK expressing BaF3 cells (named BaF3-NPM-ALK hereinafter) can proliferate in the absence of IL-3 because they obtain proliferative signal through NPM-ALK kinase. Putative inhibitors of the NPM-ALK kinase therefore abolish the growth signal and may result in antiproliferative activity. The antiproliferative activity of putative inhibitors of the NPM-ALK kinase can however be overcome by addition of IL-3, which provides growth signals through an NPM- ALK independent mechanism. An analogous cell system using FLT3 kinase has also been described (see, E Weisberg et al. Cancer Cell; 1, 433-443 (2002)).
[0043] The inhibitory activity of the compounds of the invention may be determined as follows. In general, BaF3-NPM-ALK cells (15,000/microtitre plate well) are transferred to 96- well microtitre plates. Test compounds dissolved in dimethyl sulfoxide (DMSO) are added in a series of concentrations (dilution series) in such a manner that the final concentration of DMSO is not greater than 1 % (v/v). After the addition, the plates are incubated for two days during which the control cultures without test compound are able to undergo two cell-division cycles. The growth of the BaF3-NPM-ALK cells is measured by means of YOPRO™ staining [T Idziorek et al. J. Immunol. Methods; 185: 249-258 (1995)]: 25 μl of lysis buffer comprising 20 mM sodium citrate, pH 4.0, 26.8 mM sodium chloride, 0.4 % NP40, 20 mM EDTA and 20 mM is added to each well. Cell lysis is completed within 60 min at room temperature and total amount of YOPRO™ bound to DNA is determined by measurement using the Cytofluor II 96- well reader (PerSeptive Biosystems) with the following settings: Excitation (nm) 485/20 and Emission (nm) 530/25.
[0044] IC50 values may be determined by a computer-aided system using the formula:
IC50 = [(ABStest-ABSstarO/CABScontoi-ABSstert)] x 100. (ABS = absorption)
[0045] The IC50 value in those experiments is given as that concentration of the test compound in question that results in a cell count that is 50 % lower than that obtained using the control without inhibitor. The compounds of the invention in free form or in pharmaceutically acceptable salt form, may exhibit valuable pharmacological properties, for example, as indicated by the in vitro tests described in this application. In general, compounds of the invention have IC50 values from 1 nM to 10 μM. In some examples, compounds of the invention have IC50 values from 0.01 μM to 5 μM. In other examples, compounds of the invention have IC50 values from 0.01 μM to 1 μM, or more particularly from 1 nM to 1 μM. In yet other examples, compounds of the invention have IC50 values of less than 1 nM or more than 10 μM. The compounds of the invention may exhibit a percentage inhibition of greater than 50%, or in other embodiments, may exhibit a percentage inhibition greater than about 70%, against ALK at 10 μM.
[0046] The antiproliferative action of the inventive compounds may also be determined in the human KARPAS-299 lymphoma cell line (DSMZ Deutsche Sammiung von Mikroorganismen und Zelikulturen GmbH, Braunschweig, Germany, described in WG Dirks et al. Int. J. Cancer 100, 49-56 (2002)) using the same methodology described above for the BaF3- NPM-ALK cell line. In some embodiments, compounds of the invention may exhibit inhibitory activity with an IC50 in the range from approximately 0.01 to 1 μM. The action of the inventive compounds on autophosphorylation of the ALK may be determined in the human KARPAS-299 lymphoma cell line by means of an immunoblot as described in WG Dirks et al. Int. J. Cancer 100, 49-56 (2002).
[0047] In another aspect, the compounds of the invention may inhibit Focal Adhesion Kinase (FAK), and may be useful as pharmaceuticals to treat conditions caused by a malfunction of signal cascades connected with FAK, such as in the treatment of particular tumors. The inhibition of endogenous FAK signaling results in reduced motility, and in some cases induces cell death. On the other hand, enhancing FAK signaling by exogenous expression increases cell motility. In addition, FAK is overexpressed in invasive and metastatic epithelial, mesenchymal, thyroid and prostate cancers. Consequently, an inhibitor of FAK is likely to be a drug for antitumor growth and metastasis. The compounds of the invention may thus be useful to prevent and/or treat a vertebrate and more particularly a mammal, affected by a neoplastic disease, in particular breast tumor, cancer of the bowel (colon and rectum), stomach cancer and cancer of the ovary and prostate, non-small cell lung cancer, small cell lung cancer, cancer of liver, melanoma, bladder tumor and cancer of head and neck.
[0048] The relation between FAK inhibition and immuno-system is described e.g. in G.A. van Seventer et al., Eur. J. Immunol. 2001, 31, 1417-1427. Therefore, the compounds of the invention are, for example, useful to prevent and/or treat a vertebrate and more particularly a mammal, affected by immune system disorders, diseases or disorders mediated by T lymphocytes, B lymphocytes, mast cells and/or eosinophils e.g. acute or chronic rejection of organ or tissue allo-or xenografts, atherosclerosis, vascular occlusion due to vascular injury such as angioplasty, restenosis, hypertension, heart failure, chronic obstructive pulmonary disease, CNS disease such as Alzheimer disease or amyotrophic lateral sclerosis; cancer; infectious disease such as AIDS; septic shock or adult respiratory distress syndrome, ischemia/reperfusion injury e.g. myocardial infarction, stroke, gut ischemia, renal failure or hemorrhage shock, or traumatic shock.
[0049] In yet another aspect, the compounds of the invention may inhibit zeta chain- associate protein 70 (ZAP-70). ZAP-70 protein tyrosine kinase interaction of the agents of the invention may be demonstrated, for example, by their ability to prevent phosphorylation of LAT- 11 (linker for activation of T cell) by human ZAP-70 protein tyrosine kinase in aqueous solution. Therefore, the compounds of the invention may be useful for the prevention or treatment of disorders or diseases where ZAP-70 inhibition plays a role.
[0050] The compounds of the invention may also inhibit insulin like growth-factor receptor 1 (IGF-IR), and may be useful in the treatment of IGF-I R mediated diseases. Examples of IGF-IR mediated diseases include but are not limited to proliferative diseases, such as tumors, for example breast, renal, prostate, colorectal, thyroid, ovarian, pancreas, neuronal, lung, uterine and gastro intestinal tumors, as well as osteosarcomas and melanomas. The efficacy of the compounds of the invention as inhibitors of IGF-IR tyrosine kinase activity may be demonstrated using a cellular capture ELISA. In this assay, the activity of the compounds of the invention against (IGF-I) -induced autophosphorylation of the IGF-IR is determined.
[0051] The compounds of the invention may also be useful in the treatment and/or prevention of acute or chronic inflammatory diseases or disorders or autoimmune diseases e.g. rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, diabetes (type I and II) and the disorders associated therewith, respiratory diseases such as asthma or inflammatory liver injury, inflammatory glomerular injury, cutaneous manifestations of immunologically-mediated disorders or illnesses, inflammatory and hyperproliferative skin diseases (such as psoriasis, atopic dermatitis, allergic contact dermatitis, irritant contact dermatitis and further eczematous dermatitis, seborrhoeic dermatitis), s inflammatory eye diseases, e.g. Sjoegren's syndrome, keratoconjunctivitis or uveitis, inflammatory bowel disease, Crohn's disease or ulcerative colitis.
[0052] In accordance with the foregoing, the present invention provides:
(1) a compound of the invention for use as a pharmaceutical;
(2) a compound of the invention for use as an ALK inhibitor, FAK inhibitor, ZAP-70 inhibitor and/or IGF-IR inhibitor, for example for use in any of the particular indications hereinbefore set forth;
(3) a pharmaceutical composition, e.g. for use in any of the indications herein before set forth, comprising a compound of the invention as active ingredient together with one or more pharmaceutically acceptable diluents or carriers;
(4) a method for the treatment of any particular indication set forth hereinbefore in a subject in need thereof which comprises administering an effective amount of a compound of the invention or a pharmaceutical composition comprising same; (5) the use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of a disease or condition in which ALK, FAK, ZAP-70 and/or IGF-IR activation plays a role or is implicated;
(6) the method as defined above under (4) comprising co-administration, e.g. concomitantly or in sequence, of a therapeutically effective amount of a compound of the invention and one or more further drug substances, said further drug substance being useful in any of the particular indications set forth hereinbefore;
(7) a combination comprising a therapeutically effective amount of a compound of the invention and one or more further drug substances, said further drug substance being useful in any of the particular indications set forth hereinbefore;
(8) use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of a disease which responds to inhibition of the anaplastic lymphoma kinase;
(9) the use according to (8), wherein the disease to be treated is selected from anaplastic large cell lymphoma, non-Hodgkin's lymphomas, inflammatory myofibroblastic tumors, neuroblastomas and neoplastic diseases;
(10) the use according to (8) or (9), wherein the compound is or a pharmaceutically acceptable; salt of any one of the examples;
(11) a method for the treatment of a disease which responds to inhibition of the anaplastic lymphoma kinase, especially a disease selected from anaplastic large-cell lymphoma, non Hodgkin's lymphomas, inflammatory myofibroblastic tumors, neuroblastomas and neoplastic diseases, comprising administering an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.
Administration and Pharmaceutical Compositions
[0053] In general, compounds of the invention will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents. A therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors known to those of ordinary skill in the art. For example, for the treatment of neoplastic diseases and immune system disorders, the required dosage will also vary depending on the mode of administration, the particular condition to be treated and the effect desired.
[0054] In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.01 to about 100 mg/kg per body weight, or particularly, from about 0.03 to 2.5 mg/kg per body weight. An indicated daily dosage in the larger mammal, e.g. humans, may be in the range from about 0.5 mg to about 2000 mg, or more particularly, from about 0.5 mg to about 100 mg, conveniently administered, for example, in divided doses up to four times a day or in retard form. Suitable unit dosage forms for oral administration comprise from ca. 1 to 50 mg active ingredient.
[0055] Compounds of the invention may be administered as pharmaceutical compositions by any conventional route; for example, enterally, e.g., orally, e.g., in the form of tablets or capsules; parenterally, e.g., in the form of injectable solutions or suspensions; or topically, e.g., in the form of lotions, gels, ointments or creams, or in a nasal or suppository form.
[0056] Pharmaceutical compositions comprising a compound of the present invention in free form or in a pharmaceutically acceptable salt form in association with at least one pharmaceutically acceptable carrier or diluent may be manufactured in a conventional manner by mixing, granulating, coating, dissolving or lyophilizing processes. For example, pharmaceutical compositions comprising a compound of the invention in association with at least one pharmaceutical acceptable carrier or diluent may be manufactured in conventional manner by mixing with a pharmaceutically acceptable carrier or diluent. Unit dosage forms for oral administration contain, for example, from about 0.1 mg to about 500 mg of active substance.
[0057] In one embodiment, the pharmaceutical compositions are solutions of the active ingredient, including suspensions or dispersions, such as isotonic aqueous solutions. In the case of lyophilized compositions comprising the active ingredient alone or together with a carrier such as mannitol, dispersions or suspensions can be made up before use. The pharmaceutical compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. Suitable preservatives include but are not limited to antioxidants such as ascorbic acid, or microbicides, such as sorbic acid or benzoic acid. The solutions or suspensions may further comprise viscosity-increasing agents, including but not limited to, sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone, gelatins, or solubilizers, e.g. Tween 80 (polyoxyethylene(20)sorbitan mono-oleate).
[0058] Suspensions in oil may comprise as the oil component the vegetable, synthetic, or semi- synthetic oils customary for injection purposes. Examples include liquid fatty acid esters that contain as the acid component a long-chained fatty acid having from 8 to 22 carbon atoms, or in some embodiments, from 12 to 22 carbon atoms. Suitable liquid fatty acid esters include but are not limited to lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid or corresponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, brassidic acid and linoleic acid, and if desired, may contain antioxidants, for example vitamin E, 3-carotene or 3,5-di-tert-butyl-hydroxytoluene. The alcohol component of these fatty acid esters may have six carbon atoms and may be monovalent or polyvalent, for example a mono-, di- or trivalent, alcohol. Suitable alcohol components include but are not limited to methanol, ethanol, propanol, butanol or pentanol or isomers thereof; glycol and glycerol.
[0059] Other suitable fatty acid esters include but are not limited ethyl-oleate, isopropyl myristate, isopropyl palmitate, LABRAFIL® M 2375, (polyoxyethylene glycerol), LABRAFIL® M 1944 CS (unsaturated polyglycolized glycerides prepared by alcoholysis of apricot kernel oil and comprising glycerides and polyethylene glycol ester), LABRASOL™ (saturated polyglycolized glycerides prepared by alcoholysis of TCM and comprising glycerides and polyethylene glycol ester; all available from GaKefosse, France), and/or MIGLYOL® 812 (triglyceride of saturated fatty acids of chain length Cg to C12 from Hϋls AG, Germany), and vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil, or groundnut oil.
[0060] Pharmaceutical compositions for oral administration may be obtained, for example, by combining the active ingredient with one or more solid carriers, and if desired, granulating a resulting mixture, and processing the mixture or granules by the inclusion of additional excipients, to form tablets or tablet cores.
[0061] Suitable carriers include but are not limited to fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations, and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starches, for example corn, wheat, rice or potato starch, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, carboxymethyl starch, crosslinked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate. Additional excipients include flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, or derivatives thereof.
[0062] Tablet cores may be provided with suitable, optionally enteric, coatings through the use of, inter alia, concentrated sugar solutions which may comprise gum arable, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments may be added to the tablets or tablet coatings, for example for identification purposes or to indicate different doses of active ingredient.
[0063] Pharmaceutical compositions for oral administration may also include hard capsules comprising gelatin or soft-sealed capsules comprising gelatin and a plasticizer, such as glycerol or sorbitol. The hard capsules may contain the active ingredient in the form of granules, for example in admixture with fillers, such as corn starch, binders, and/or glidants, such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient may be dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilizers and detergents, for example of the polyoxyethylene sorbitan fatty acid ester type, may also be added.
[0064] Pharmaceutical compositions suitable for rectal administration are, for example, suppositories comprising a combination of the active ingredient and a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
[0065] Pharmaceutical compositions suitable for parenteral administration may comprise aqueous solutions of an active ingredient in water-soluble form, for example of a water-soluble salt, or aqueous injection suspensions that contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if desired, stabilizers. The active ingredient, optionally together with excipients, can also be in the form of a lyophilizate and can be made into a solution before parenteral administration by the addition of suitable solvents. Solutions such as are used, for example, for parenteral administration can also be employed as infusion solutions. The manufacture of injectable preparations is usually carried out under sterile conditions, as is the filling, for example, into ampoules or vials, and the sealing of the containers.
[0066] The compounds of the invention may be administered as the sole active ingredient, or together with other drugs useful against neoplastic diseases or useful in immunomodulating regimens. For example, the compounds of the invention may be used in accordance with the invention in combination with pharmaceutical compositions effective in various diseases as described above, e.g. with cyclophosphamide, 5-fluorouracil, fludarabine, gemcitabine, cisplatinum, carboplatin, vincristine, vinblastine, etoposide, irinotecan, paclitaxel, docetaxel, rituxan, doxorubicine, gefitinib, or imatinib; or also with cyclosporins, rapamycins, ascomycins or their immunosuppressive analogs, e.g. cyclosporin A, cyclosporin G, FK-506, sirolimus or everolimus, corticosteroids, e.g. prednisone, cyclophosphamide, azathioprene, methotrexate, gold salts, sulfasalazine, antimalarials, brequinar, leflunomide, mizoribine, mycophenolic acid, mycophenolate, mofetil, 15-deoxyspergualine, immuno-suppressive monoclonal antibodies, e.g. monoclonal antibodies to leukocyte receptors, e.g. MHC, CD2, CD3, CD4, CD7, CD25, CD28, 1 CD40, CD45, CD58, CD80, CD86, CD152, CD137, CD154, ICOS, LFA-I, VLA-4 or their ligands, or other immunomodulatory compounds, e.g. CTLA41g.
[0067] The invention also provides for a pharmaceutical combinations, e.g. a kit, comprising a) a first agent which is a compound of the invention as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent. The kit can comprise instructions for its administration.
Processes for Making Compounds of the Invention
[0068] Compounds of Formula (1) may be prepared following Reaction Scheme I, in which each substituent is as defined in the Summary of the Invention:
Figure imgf000027_0001
[0069] A compound of Formula (1) may be synthesized by reacting a compound of formula (6) with a compound of formula (7) in the presence of palladium catalyst (for example palladium acetate and the like), ligand (for example xantphos and the like) and base (for example cesium carbonate and the like) in a suitable solvent (for example, THF, and the like). The reaction proceeds in a temperature range of about 700C to about 1800C and can take 10 min. to 8 hours to complete.
[0070] Alternatively, a compound of Formula (1) may be synthesized by reacting a compound of formula (6) with a compound of formula (7) in the presence of acid (for example HCl, TsOH and the like), in a suitable solvent (for example, 2-propanol, and the like). The reaction proceeds in a temperature range of about 700C to about 1500C and can take up to 12 hours to complete.
Additional Processes for Making Compounds of the Invention
[0071] The compounds of the invention, including their salts, are also obtainable in the form of hydrates, or their crystals may include for example the solvent used for crystallization (present as solvates). Salts can usually be converted to compounds in free form, e.g., by treating with suitable basic agents, for example with alkali metal carbonates, alkali metal hydrogen carbonates, or alkali metal hydroxides, such as potassium carbonate or sodium hydroxide. In view of the close relationship between the novel compounds in free form and those in the form of their salts, including those salts that may be used as intermediates, for example in the purification or identification of the novel compounds, any reference to the free compounds hereinbefore and hereinafter is to be understood as referring also to the corresponding salts, as appropriate.
[0072] Salts of the inventive compounds with a salt-forming group may be prepared in a manner known per se. Acid addition salts of compounds of Formula (1), (2), (3A), (3B), (4A), (4B) or (5) may thus be obtained by treatment with an acid or with a suitable anion exchange reagent. Pharmaceutically acceptable salts of the compounds of the invention may be formed, for example, as acid addition salts, with organic or inorganic acids, from compounds of Formula (1), (2), (3A), (3B), (4A), (4B) or (5) with a basic nitrogen atom.
[0073] Suitable inorganic acids include, but are not limited to, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids include, but are not limited to, carboxylic, phosphoric, sulfonic or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid,-malic acid, tartaric acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4 aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane-or ethane-sulfonic acid, 2-hydroxyethanesulfonic acid, ethane- 1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalene-disuifonic acid, 2-, 3-or 4 methylbenzenesulfonic acid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid, N cyclohexylsulfamic acid, N-methyl-, N-ethyl-or N-propyl-sulfamic acid, or other organic protonic acids, such as ascorbic acid.
[0074] For isolation or purification purposes, it is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates. For therapeutic use, only pharmaceutically acceptable salts or free compounds are employed (where applicable in the form of pharmaceutical preparations).
[0075] Compounds of the invention in unoxidized form may be prepared from N-oxides of compounds of the invention by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in a suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 8O0C.
[0076] Prodrug derivatives of the compounds of the invention may be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985). For example, appropriate prodrugs may be prepared by reacting a non-derivatized compound of the invention with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like).
[0077] Protected derivatives of the compounds of the invention may be made by means known to those of ordinary skill in the art. A detailed description of techniques applicable to the creation of protecting groups and their removal may be found in T. W. Greene, "Protecting Groups in Organic Chemistry", 3rd edition, John Wiley and Sons, Inc., 1999.
[0078] Compounds of the invention may be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. Resolution of enantiomers may be carried out using covalent diastereomeric derivatives of the compounds of the invention, or by using dissociable complexes (e.g., crystalline diastereomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and may be readily separated by taking advantage of these dissimilarities. The diastereomers may be separated by fractionated crystallization, chromatography, or by separation/resolution techniques based upon differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. A more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture may be found in Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981.
[0079] In summary, the compounds of the invention may be made by a process, which involves:
(a) that of Reaction Scheme I; and
(b) optionally converting a compound of the invention into a pharmaceutically acceptable salt;
(c) optionally converting a salt form of a compound of the invention to a non-salt form;
(d) optionally converting an unoxidized form of a compound of the invention into a pharmaceutically acceptable N-oxide;
(e) optionally converting an N-oxide form of a compound of the invention to its unoxidized form;
(f) optionally resolving an individual isomer of a compound of the invention from a mixture of isomers;
(g) optionally converting a non-derivatized compound of the invention into a pharmaceutically acceptable prodrug derivative; and
(h) optionally converting a prodrug derivative of a compound of the invention to its non- derivatized form.
[0080] Insofar as the production of the starting materials is not particularly described, the compounds are known or can be prepared analogously to methods known in the art or as disclosed in the Examples hereinafter. One of skill in the art will appreciate that the above transformations are only representative of methods for preparation of the compounds of the present invention, and that other well known methods can similarly be used. The present invention is further exemplified, but not limited, by the following and Examples that illustrate the preparation of the compounds of the invention.
Preparation of Intermediates
Intermediate 1
2-chloro-N-(2-fao-propylsulfonyl)phenyl)-5-methylpyrimidin-4-amine
Figure imgf000031_0001
[0081] To a suspension of 730 mg of NaH in a mixture of DMF/DMSO (25/2.5 ml) is added drop-wise at 00C, 2.53 g (12.69 mmol) of 2-(Jso-propylsulfonyl)benzenamine in DMF/DMSO (10 ml, ratio 9/1). The solution is stirred 30 minutes at 00C and 4.11 g (25.3 mmol, 2 eq.) of 2,4- dichloro-5-methylpyrimidine diluted in 10 ml of DMF/DMSO (ratio: 9/1) is added dropwise. The solution is warmed-up to room temperature and stirred overnight. After work-up, the crude product is directly crystallized from cold CH3CN in several batches to afford 2-chloro-N-(2-(/,so- propylsulfonyl)phenyl)-5-methylpyrimidin-4-amine as pale creamy colored crystals: ESMS m/z 326.1 (M + H+).
Intermediate 2
Synthesis of 2,5-dichloro-N-(2-(/so-propylsulfonyl)phenyl)pyrimidin-4-amine
Figure imgf000031_0002
[0082] Using the same procedure described for the synthesis of 2-chloro-N-(2-(/sø- propylsulfonyl)phenyl)-5-methylpyrimidin-4-amine, 2,5-dichloro-N-(2-Q',so- propylsulfonyl)phenyl)pyrimidin-4-amine is isolated as a creamy colored solid: ESMS m/z 346.0 (M + H+).
Intermediate 3
2-chloro-4-fluoro-5-nitrotoluene
Figure imgf000032_0001
[0083] To a solution of 100 g (0.7 mol) of 2-chloro-4-fluorotoluene in 250 ml of concentrated H2SO4 is added portion-wise 85 g (0.875 mol) of KNO3 at 00C (addition of the whole amount of KNO3 is finished in about 1 hour). The reddish mixture is slowly warmed-up at room temperature overnight and quenched over crushed ice and extracted with EtOAc. The organic layers are combined, dried over MgSO4 and concentrated. The crude oil is then purified over a large silica plug (eluent: 97/3 hexanes/EtOAc) to afford 2-chloro-4-fluoro-5-nitrotoluene as a pale yellow oil that solidifies upon standing. 1H NMR (CDCl3, 400 Mz): 7.97 (d, J = 8.0 Hz, IH), 7.32 (d, J = 10.4 Hz, IH), 2.43 (s, 3H).
Intermediate 4
2-chloro-4-/,sopropoxv-5-nitrotoluene
Figure imgf000032_0002
[0084] To a solution of 25 g (0.131 mol) of 2-chloro-4-fluoro-5-nitrotoluene in 250 ml of 2- propanol is added 208 g (0.659 mol, 5 eq.) of Cs2CO3. The mixture is stirred at 6O0C overnight and most of the 2-propanol is evaporated under reduced pressure. Water is added and the solution is extracted with EtOAc. The organic layers are combined, dried over MgSO4, concentrated and the crude product filtrated over a silica plug (eluent: 95/5 hexanes/EtOAc) to afford 2-chloro-4-/,sopropoxy-5-nitrotoluene as a pale yellow fluffy solid.
Intermediate 5
2-methyl-4-nitro-5-z',sopropoxy-phenylboronic acid pinacol ester
Figure imgf000033_0001
[0085] A mixture of 5.09 g 2-chloro-4-/søpropoxy-5-nitrotoluene (0.02216 mol), 6.20 g (0.02437 mol) of pinacol diborane, 595 mg (0.00212 mol) Of PCy3, 1.014 g (0.00108 mol) of Pd2dba3 and 3.16 g (0.0322 mol) of KOAc in 100 ml of dry dioxane is heated to 100°C overnight. After cooling to RT, the dark solution is filtered over Celite and the solvent evaporated under reduced pressure. The crude oil is purified with silica gel column chromatography (eluent: 95/5 hexanes/EtOAc) to afford 2-methyl-4-nitro-5-/,sopropoxy- phenylboronic acid pinacol ester as an oil that solidifies upon standing. 1H NMR (CDCl3, 400 Mz): 7.51 (s, IH), 7.44 (s, IH), 4.70 (m, IH), 2.48 (s, 3H), 1.36 (d, J = 7.6 Hz, 6H), 1.35 (s, 12H).
Intermediate 6
4-Trifluoromethanesulfonyloxy-3,6-dihvdro-2H-pyridine-l-carboxylic acid tert-butyl ester
Figure imgf000033_0002
[0086] A solution of N-feτt-Butoxycarbonyl-4-piperidone (10.17 g, 0.05 mol) in THF (100 mL) is added dropwise into a cooled (-780C), vigorously stirring solution of LDA (40 mL of 1.5 M solution in cyclohexanes, 0.06 mol) in THF (100 mL), under N2. The reaction mixture is left at -780C for 30 min before adding a solution of phenyl trifluorosulfonimide (19.85 g, 0.055 mol) in THF (50 mL). Then the reaction mixture is warmed to room temperature and stirred for 3 h. The reaction is quenched at 0 0C with 100 mL of saturated aqueous NH4Cl and filtered through Celite. The filtrate is added to 100 mL of EtOAc and the layers are separated. The organic layer is washed with H2O, dried over MgSO4 and concentrated. The crude product is purified by silica flash column chromatography (0-30% EtOAc in Hexanes as eluent and checked by TLC stained with 2% of KMnO4 in EtOH) to afford 4-Trifluoromethanesulfonyloxy-3,6-dihydro-2H- pyridine-1-carboxylic acid tert-butyl ester as a yellow oil.
Intermediate 7
4-(5-Isopropoxy-2-methyl-4-nitro-phenyl)-3,6-dihvdro-2H-pyridine-l-carboxylic acid tert-butyl ester
Figure imgf000034_0001
[0087] To a solution of 2-methyl-4-nitro-5-/søpropoxy-phenylboronic acid pinacol ester (2.04 g, 6.4 mmol) and 4-Trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester (3.2 g, 9.6 mmol) in 110 mL of DME/H20 (10:1 V/V) is added Pd(PPh3)4 (365 mg, 0.32 mmol) and Cs2CO3 (4.2 g, 12.8 mmol). The reaction mixture is heated under N2 at 80 0C overnight. After cooling to room temperature, the reaction is filtered through Celite and the filtrate is diluted with 100 mL of EtOAc, sequentially washed with H2O, brine, and finally concentrated in vacuo. The crude product is purified by silica gel flash chromatography (5%- 15% EtOAc in Hexanes as eluent) to afford 4-(5-Isopropoxy-2-methyl-4-nitro-phenyl)-3,6- dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester as a yellow oil. 1H NMR (CD3OD, 400 Mz): 7.59 (s, IH), 6.96 (s, IH), 5.67 (broad s, IH), 4.73 (m, IH), 4.06 (m, 2H), 3.65 (m, 2H), 2.37 (m, 2H), 2.25 (s, 3H), 1.50 (s, 9H), 1.33 (d, J = 6.0 Hz, 6H).
Intermediate 8
2-Chloro-4-isopropoxy-5-nitro-benzoic acid
Figure imgf000034_0002
[0088] A mixture of 2-chloro-4-fluoro-5-nitro-benzoic acid (5.0 g, 22.8 mmol) and cesium carbonate (29.7 g, 91.1 mmol) in 2-propanol (100 mL) is heated at 500C overnight. The solvent is removed in vacuo and 100 mL of water is added. Concentrated aqueous HCl is added dropwise to this solution at 00C until pH=2. The product precipitate which forms is isolated by filtration, washed by water and dried under vacuum to give 2-chloro-4-isopropoxy-5-nitro- benzoic acid-
Example 1
6- { 5 -Chloro-4- r2-(propane-2-sulfonyl)-phenylaminol -pyrimidin-2- ylamino I -5 -isopropoxy-2- piperidin-4-yl-2,3-dihydro-isoindol-l-one (178)
Figure imgf000035_0001
Steps 1 and 2: 4-(2-Chloro-4-isopropoxy-5-nitro-benzoylamino)-piperidine-l-carboxylic acid tert-butyl ester
Figure imgf000035_0002
[0089] To a solution of 2-chloro-4-isopropoxy-5-nitro-benzoic acid (Intermediate 8, 1O g, 38.5 mmol) in DCM (200 mL) and DMF (ImL), is slowly added thionyl chloride (9.17 g, 77 mmol) via a syringe. The mixture is stirred for 3 hours, and is then concentrated to dryness. The obtained white solid, 2-chloro-4-isopropoxy-5-nitro-benzoyl chloride, is dried under vacuum. To a mixture of 4-amino-piperidine-l-carboxylic acid tert-butyl ester (1.44g, 7.2 mmol) and triethylamine (3 mL, 21.6 mmol) in DCM (100 mL), is slowly added 2-chloro-4-isopropoxy-5- nitro-benzoyl chloride (2g, 7.2 mmol) dissolved in DCM (10 mL) via syringe. The mixture is stirred at room temperature for 3 hours, and then is concentrated. The obtained solid is dissolved in ethyl acetate and is washed with water and brine respectively. After evaporation of the solvent, the title compound is obtained as light yellow solid, and is directly used for the next step without further purification. Step 3 : 4-(4-Isopropoxy-5-nitro-2-vinyl-benzoylamino)-piperidine-l-carboxylic acid tert-butyl ester
Figure imgf000036_0001
[0090] To a mixture of 4-(2-chloro-4-isopropoxy-5-nitro-benzoylamino)-piperidine-l- carboxylic acid tert-butyl ester (7.2 mmol) obtained in the previous step, vinylboronic acid dibutyl ester (1.72 g, 9.4 mmol) and sodium carbonate (5.34 g, 50.4 mmol) in THF/H2O (100/25 mL) is added dichlorobis(triphenylphospine) palladium (II) (442 mg, 5% mmol). The mixture is purged with N2 for 3 min and heated at 900C under N2 for overnight in a round bottom flask equipped with a condenser. The mixture is cooled to room temperature and poured into saturated aqueous ammonia chloride solution. The mixture is extracted with ethyl acetate (3 x 100 mL). The organic extracts are combined, washed with brine and concentrated. The crude product is purified with silica gel column chromatography (40% ethyl acetate in hexanes) to afford 4-(4-isopropoxy-5-nitro-2-vinyl-benzoylamino)-piperidine-l-carboxylic acid tert-butyl ester as white solid.
Steps 4, 5 and 6: 4-(5 -Isopropoxy-6-nitro- 1 -oxo- 1 ,3 -dihydro-isoindol-2-yl)-piperidine- 1 - carboxylic acid tert-butyl ester
Figure imgf000036_0002
[0091] 4-(4-Isopropoxy-5-nitro-2-vinyl-benzoylamino)-piperidine-l-carboxylic acid tert- butyl ester obtained from previous step (1.9 g, 4.38mmol) is dissolved in DCM (100 mL) and is cooled to -78 0C. O3 (g) is bubbled into the solution until the solution's color turns blue/gray. The solution is then purged with N2 (g) until the blue color disappears. The solution is warmed to room temperature and treated with triphenyl phosphine resin (5 g) pre-s welled in DCM (100 mL). After 30 min, the mixture is filtered, the filtrate is concentrated, and the resulting residue dissolved in DCM/TFA (10OmL / 25 mL). To this mixture is added triethyl silane (4.6 mL, 17.5 mmol). The resulting mixture is stirred at room temperature overnight. The reaction mixture is concentrated and re-dissolved in DCM. The DCM solution is washed with IN aqueous HCl (3 x 20 mL). The combined aqueous layer is treated with cone, aqueous NaOH until pH =12. The aqueous layer is extracted with ethyl acetate (3 x 30 mL). The combined organic layers are washed with brine, and dried over sodium sulfate. A light yellow solid is obtained after evaporation of the organic solvent.
[0092] The solid is dissolved in a mixture of methanol and triethylamine (10OmL, 9:1 v/v). To this mixture is added di-tert-butyl dicarbonate (680 mg, 3.1mmol). After stirring at 50 0C for 30 minutes, the mixture is concentrated and purified by silica gel flash column chromatography (eluent: 40-50% ethyl acetate in hexanes) to afford 4-(5-Isopropoxy-6-nitro-l-oxo-l,3-dihydro- isoindol-2-yl)-piperidine-l-carboxylic acid tert-butyl ester as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.19 (s, IH), 7.11 (s, IH), 4.74 (q, IH), 4.45-4.38 (m, IH), 4.35 (s, 2H), 2.90-2.80 (m, 2H), 1.85-1.81 (m, 2H), 1.66-1.63 (m, 2H), 1.48 (s, 9H), 1.42 (d, 6H).
Steps 7, 8 and 9
[0093] To a solution of 4-(5-isopropoxy-6-nitro-l-oxo-l,3-dihydro-isoindol-2-yl)- piperidine-1-carboxylic acid tert-butyl ester from the previous step (850 mg, 2mmol) in methanol, is added Pd/C (10% on carbon, 100 mg). The mixture is hydrogenated under 1 atm of hydrogen gas. After 4 hours, the mixture is filtered and concentrated. The obtained aniline, as yellow solid, is used for next step without additional purification. To a mixture of the crude product (2 mmol) from previous step, (2,5-dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)- phenyl]-amine (Intermediate 2, 770mg, 2.2 mmol), cesium carbonate (1.3g, 4mmol), and xantphos (115 mg, 0.2mmol) in THF (20 mL), is added palladium acetate (22mg, 5% mmol) in a microwave tube. The mixture is purged with N2 for 3 min. The sealed tube is heated at 1500C for 20 min under microwave irradiation. The mixture is cooled, filtered and concentrated. The residue is purified by silica gel flash column chromatography (eluent: 65% ethyl acetate in hexanes) to afford a yellow solid. The solid is treated with DCM/TFA (1/1, 1OmL) for 1 hour followed by concentration under vacuum. Final purification using preparative RP LC-MS affords 6-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5- isopropoxy-2-piperidin-4-yl-2,3-dihydro-isoindol-l-one (178) as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.38 (s, IH), 10.13 (s, IH), 9.60-9.50 (br, IH), 9.34-9.21 (br, IH), 8.46 (d, IH), 8.26 (s, IH), 8.08 (s, IH), 7.91 (dd, IH), 7.71 (m, IH), 7.34 (t, IH), 7.03 (s, IH), 4.30 (m, IH), 4.53 (m, IH), 4.33 (s, 2H), 3.62 (m, 2H), 3.21-3.09 (m, 3H), 2.31-2.21 (m, 2H), 2.09-2.05 (m, 2H), 1.41 (d, 6H), 2.30 (d, 6H); ESMS m/z 599.2 (M + H+).
Example 2
6-{5-Chloro-4-r2-(propane-2-sulfonyl)-phenylaminol-pyrimidin-2-ylamino|-5-isopropoxy-2-(l- methyl-piperidin-4-yl)-2,3-dihydro-isoindol-l-one (181)
Figure imgf000038_0001
Jj 5-Isopropoxy-2-(l-methyl-piperidin-4-yl)-6-nitro-indan-l-one
Figure imgf000038_0002
[0094] To a solution of 5-isopropoxy-6-nitro-2-piperidin-4-yl-indan-l-one (Example 1, Step
5) in THF (5 mL) and methanol (5 mL) is added formaldehyde (104.2 uL, 1.39 mmol) and 10 drops of AcOH sequentially. The reaction mixture is stirred at room temperature for Ih, then sodium cyanoborohydride (175.1 mg, 2.78 mmol) is added in one portion, and the reaction is stirred for an additional 30 min. The reaction is quenched by saturated aqueous NH4Cl and concentrated in vacuo to give an oily residue. This oil is partitioned between EtOAc and brine, the organic extract is dried over Na2SO4, filtered and concentrated under vacuum. Silica gel chromatography (5% MeOH in DCM) affords 5-isopropoxy-2-(l-methyl-piperidin-4-yl)-6-nitro- indan-1-one; MS m/z 333.2 (M+l). Steps 2 and 3
[0095] Following the procedures previously described (Example 1, Steps 7 and 8) using the product from Step 1 generates the title compound 6-{5-Chloro-4-[2-(propane-2-sulfonyl)- phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-2-(l-methyl-piperidin-4-yl)-2,3-dihydro- isoindol-1-one (181) as a white solid. 1H NMR 400 MHz (DMSOd6 with trace D2O) δ 8.46 (d, IH), 8.35 (s, IH), 8.09(s, IH), 7.82(d, IH), 7.74(t, IH), 7.36(t,lH), 7.33(s, IH), 4.75 (m, IH), 4.41(s, 2H), 4,29(m, IH), 3.65(m, 2H), 3.44(m, IH), 3.17(t, 2H), 2,79(s, 3H), 2.07(m, 2H), l,98(d, 2H), 1.28(d, 6H), 1.14(d, 6H); MS m/z 613 (M+l).
Example 3
5-Methyl-N2-r4-methyl-5-(l-methyl-lH-pyrazol-4-yl)-2-(piperidin-4-yloxy)-phenyll-N4-r2- (propane-2-sulfonyl)-phenyll-pyrimidine-2,4-diamine (35)
Figure imgf000039_0001
Step 1: 4-(4-Chloro-5-methyl-2-nitro-phenoxy)-piperidine-l-carboxylic acid tert-butyl ester
Figure imgf000039_0002
[0096] To a mixture of 4-Chloro-5-methyl-2-nitro-phenol (3.752 g, 20.0 mmol), 4-Hydroxy- piperidine-1-carboxylic acid tert-butyl ester (4.83 g, 24 mmol), and triphenylphosphine (6.23 g, 24 mmol) in 75 mL THF is added diisopropyl asodicarboxylate (4.73 mL, 245 mmol) in several portions at 22 0C for 1 h. The reaction is stirred at the same temperature for an additional 2 hrs. The reaction mixture is concentrated in vacuo. The residue is taken up in 50 mL ether, and let stand at 22 0C for 14 hrs. The resulting crystals are removed by filtration. The filtrate is concentrated in vacuo, and the residue is purified over a 330 g SiO2 column (ISCO) using a gradient of 20 to 40% ethyl acetate in hexanes as eluent, affording 4-(4-Chloro-5-methyl-2- nitro-phenoxy)-piperidine-l-carboxylic acid tert-butyl ester as dark yellow viscous oil. MS (ES+); 315.1 (MH+ - C4H8), 393.1 (MNa+).
Step 2: 4-r5-Methyl-4-(l-methyl-lH-pyrazol-4-yl)-2-nitro-phenoxyl-piperidine-l-carboxylic acid tert-butyl ester
Figure imgf000040_0001
[0097] A mixture of 4-(4-Chloro-5-methyl-2-nitro-phenoxy)-piperidine-l-carboxylic acid tert-butyl ester from the previous step (375.8 mg, 1.01 mmol), l-Methyl-4-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-lH-pyrazole (Boron Molecular, 224.4 mg 1.08 mmol), potassium phosphate tribasic monohydrate (392 mg), Pd2(dba)3 (45 mg), and dicyclophosphinobiphenyl (43 mg) in 4 mL of l,4-dioxane/H2θ (3/1) is heated in a sealed tube at 150 0C for 20 min under microwave radiation. The reaction mixture is filtered through a small plug of Celite, dried over Na2SO4 and concentrated. The residue is purified using a SiO2 column (ISCO), affording 4-[5- Methyl-4-(l-methyl-lH-pyrazol-4-yl)-2-nitro-phenoxy]-piperidine-l-carboxylic acid tert-butyl ester. MS (ES+); 417.3 (MH+), 439.2 (MNa+).
Steps 3, 4 and 5
[0098] Utilizing the same procedures described in the synthesis of Example 1 (Steps 7, 8 and 9) and final purification using preparative RP LC-MS affords 5-Methyl-N2-[4-methyl-5-(l- methyl-lH-pyrazol-4-yl)-2-(piperidin-4-yloxy)-phenyl]-N4-[2-(propane-2-sulfonyl)-phenyl]- pyrimidine-2,4-diamine (35). MS (ES+): 576.3 (MH+). Example 4 l-(5-{5-Chloro-4-r2-(propane-2-sulfonyl)-phenylaminol-pyrimidin-2-ylamino|-4-isopropoxy-2- methyl-phenvD-ethanone (36)
Figure imgf000041_0001
Step 1: 2-(4-Isopropoxv-2-methvl-5-nitro-phenvl)-2-methyl-ri,31dioxolane
Figure imgf000041_0002
[0100] A mixture of l-(4-Isopropoxy-2-methyl-5-nitro-phenyl)-ethanone (0.788 g, 3.32 mmol), ethyleneglycol (1.8 mL), and p-toluenesulfonic acid monohydrate (6.3 mg) in 60 mL of benzene is heated at reflux with a Dean-Stark trap for 18 hrs. The reaction mixture is diluted with 100 mL of ethyl acetate and successively washed with 100 mL each of aqueous saturated NaHCU3, H2O, and saturated brine. The organic phase is dried over anhydrous Na2SO4, filtered and concentrated in vacuo, affording 2-(4-Isopropoxy-2-methyl-5-nitro-phenyl)-2-methyl- [l,3]dioxolane as yellow crystals. MS (ES+): 282.2 (MH+).
Steps 2 and 3: 5-Chloro-N2-[2-isopropoxy-4-methyl-5-(2-methyl-[l,3]dioxolan-2-yl)-phenyl]- N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine
Figure imgf000041_0003
[0101] Utilizing the same procedures described in the synthesis of Example 1 (Steps 7 and 8), using 2-(4-Isopropoxy-2-methyl-5-nitro-phenyl)-2-methyl-[l,3]dioxolane from the previous step as starting material and purification using silica gel chromatography (gradient 2% to 20% EtOAc in hexanes) affords 5-Chloro-N2-[2-isopropoxy-4-methyl-5-(2-methyl-[l,3]dioxolan-2- yl)-phenyl]-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine as a white solid. MS (ES+): 561.2 (MH+).
Step 4
[0102] A solution of 5-Chloro-N2-[2-isopropoxy-4-methyl-5-(2-methyl-[l,3]dioxolan-2-yl> phenyl]-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine from the previous step (84 mg, 0.15 mmol) in 5 mL 1,4-dioxane is treated with 1 mL of aqueous IN HCl at 22 0C for 2 hrs. The reaction is worked up and affords l-(5-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]- pyrimidin-2-ylamino}-4-isopropoxy-2-methyl-phenyl)-ethanone (36). MS (ES+): 517.2 (MH+).
Example 5
N2-{2-Isopropoxy-4-methyl-5-ri-(2-morpholin-4-yl-ethyl)-lH-pyrazol-4-yll-phenyl|-5-methyl- N4-r2-(propane-2-sulfonyl)-phenyH-pyrimidine-2,4-diamine (37)
Figure imgf000042_0001
1 : 4-Bromo-5-methyl-2-nitro-phenol
Figure imgf000042_0002
[0103] 4-Bromo-3 -methyl-phenol (1.122 g, 6.00 mmol) and Yb(CF3SO3)3 (372 mg) in 30 mL dichloromethane is treated with 0.38 mL of cone. HNO3 at 22 0C. After stirring at the same temperature for 1 hr, an additional 0.1 mL of cone. HNO3 is added, and the reaction is stirred for an additional hour. The reaction mixture is washed with H2O, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is purified using a SiO2 column (ISCO), affording a mixture of 4-Bromo-5-methyl-2-nitro-phenol as yellow crystals and its regioisomer by-product as orange crystals.
Step 2: l-Bromo-4-isopropoxy-2-methyl-5-nitro-benzene
Figure imgf000043_0001
[0104] To a mixture of 4-Bromo-5-methyl-2-nitro-phenol from the previous step (0.66 g, 2.84 mmol), 2-propanol (0.262 niL), and triphenylphosphine (894 mg) in 10 mL THF is added diisopropyl asodicarboxylate (0.671 mL) at 22 0C. The reaction mixture is concentrated in vacuo. The residue is purified using a SiO2 column (ISCO), affording l-Bromo-4-isopropoxy-2- methyl-5-nitro-benzene as a bright yellow solid.
Step 3: 5-Bromo-2-isopropoxy-4-methyl-phenylamine
Figure imgf000043_0002
[0105] To l-Bromo-4-isopropoxy-2-methyl-5-nitro-benzene from the previous step (0.734 g, 2.68 mmol) and iron (powder, 325 mesh, 1.05 g) in 20 mL ethanol is added 1 mL of IN aqueous HCl with cooling in an ice bath. Following this addition, the reaction is heated at reflux for 2 hrs. Then an additional 0.5 g of iron is added and the reaction is heated at reflux for an additional 2 hrs. The reaction mixture is cooled down and filtered though a pad of Celite. The filtrate is concentrated in vacuo, affording 5-Bromo-2-isopropoxy-4-methyl-phenylamine as an orange oil. The product is used for the next step without further purification. Ste2_4i N2-(5-Bromo-2-isopropoxy-4-methyl-phenyl)-5-methyl-N4-[2-(propane-2-sulfonyl)- phenyl] -pyrimidine-2,4-diamine
Figure imgf000044_0001
[0106] 5-Bromo-2-isopropoxy-4-methyl-phenylamine from the previous step (537 mg, 2.20 mmol) and 2-chloro-N-(2-(/sø-propylsulfonyl)phenyl)-5-methylpyrimidin-4-amine (Intermediate 1, 652 mg, 2.00 mmol) in the presence of methanesulfonic acid (0.143 mL) in 4 mL 2-propanol are condensed at 140 0C for 30 min in a sealed tube under microwave irradiation. Following workup, Ν2-(5-Bromo-2-isopropoxy-4-methyl-phenyl)-5-methyl-Ν4-[2-(propane-2- sulfonyl)-phenyl]-pyrimidine-2,4-diamine is obtained. MS (ES+): 535.1 (MH+).
Step 5
[0107] A mixture of N2-(5-Bromo-2-isopropoxy-4-methyl-phenyl)-5-methyl-N4-[2- (propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine from the previous step (53 mg, 0.099 mmol), 4-{2-[4-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-pyrazol-l-yl]-ethyl}-morpholine (Boron Molecular, 61 mg 0.20 mmol), K3PO4 (58 mg), Pd2(dba)3 (10 mg), and tricyclohexylphosphine (8 mg) in 1 mL of l,4-dioxane/H2O (3/1 v/v) is heated in a sealed tube at 150 0C for 20 min under microwave radiation. The reaction mixture is filtered through a small plug of Celite and concentrated. Final purification using preparative RP LC-MS affords N2- { 2-Isopropoxy-4-methyl-5 - [ 1 -(2-morpholin-4-yl-ethyl)- 1 H-pyrazol-4-yl] -phenyl } -5-methyl- N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine (37). MS (ES+): 634.3 (MH+).
Example 6
5-Chloro-N2-(2-isopropoxy-5-methyl-4-morpholin-4-ylmethyl-phenyl)-N4-r2-(propane-2- sulfonyl)-phenyll-pyrimidine-2,4-diamine (60)
Figure imgf000044_0002
Steps 1 and 2: l-Chloro-5-isopropoxy-2-methyl-4-nitro-benzene
Figure imgf000045_0001
[0108] To a mixture of l-chloro-2-methyl-4-nitro-5-isopropoxy-benzene (Intermediate 4,
870 mg, 3.77mmol), vinylboronic acid dibutyl ester (1.24 mL, 5.6 mmol), and sodium carbonate (2.8 g, 26.4mmol) in THF/H2O (20/5 mL) is added dichlorobis(triphenylphospine) palladium (II) (132 mg, 5% mmol). The reaction tube is sealed, the mixture is purged with N2 for 3 min and then heated at 900C under N2 for overnight. The reaction is cooled to room temperature and poured into saturated aqueous ammonia chloride solution. The crude reaction mixture is extracted with ethyl acetate (3 x 100 mL). The organic extracts are combined, washed with brine and concentrated. The crude product is purified with silica gel column chromatography (10% ethyl acetate in hexanes) to afford l-methyl-5-nitro-4-propoxy-2- vinyl-benzene as a yellow solid. l-Methyl-5-nitro-4-propoxy-2-vinyl-benzene obtained from the previous step (360 mg, 1.63mmol) is dissolved in DCM (20 mL) and is cooled to -78 0C. O3 (g) is bubbled into the solution until the solution's color turns blue/gray. The solution is then purged with N2 (g) until the blue color disappears. The solution is warmed to room temperature and treated with triphenylphospine resin (2 g) pre-swelled in DCM (30 mL). After 30 min, the mixture is filtered, and the filtrate is concentrated to afford 2-methyl-4-nitro-5-propoxy-benzaldehyde as yellow solid.
Steps 3 and 4: 2-Isopropoxv-5-methvl-4-morpholin-4-vlmethvl-phenylamine
Figure imgf000045_0002
[0109] To a solution of 2-methyl-4-nitro-5-propoxy-benzaldehyde obtained in the previous step (34 mg, 0.152 mmol) in MeOH/THF (0.5/0.5 mL), is added acetic acid (5 drops). The mixture is stirred at room temperature for 1 hour. Sodium cyanoborohydride (20 mg, 0.30 mmol) is then added. After stirring for 30 min, the reaction is quenched by adding saturated aqueous ammonium chloride solution. The reaction mixture is extracted with ethyl acetate (3 x 5 mL). The organic phases are combined and concentrated to afford the amine product as an yellow oil which is directly used for the next step without further purification. To a solution of the product obtained in the previous step in methanol (5 mL), is added Pd/C (10% on carbon, 2 mg). The mixture is hydrogenated under 1 atm hydrogen. After 4 hours, the mixture is filtered and concentrated. The aniline product obtained (yellow solid), is used in the next step without further purification.
Step 5
[0110] To a mixture of the aniline product obtained in the previous step (0.152 mmol), (2,5- dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine (Intermediate 2, 52 mg, 0.152 mmol), cesium carbonate (99 mg, 0.30 mmol) and xantphos (8 mg, 0.02mmol) in THF (2 mL), is added palladium acetate (2 mg, 5% mmol) in a microwave tube. The mixture is purged with N2 for 3 min and then the sealed tube is heated at 150 0C for 20 min. under microwave irradiation. The reaction is filtered, concentrated, and purified by mass-trigger preparative RP LC-MS to afford the title compound 5-Chloro-N2-(2-isopropoxy-5-methyl-4-morpholin-4- ylmethyl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine (60) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 10.35(s, IH), 8.38 (d, IHO, 7.93 (d, IH), 7.59 (m, 2H), 7.41-7.36 (m, 2H), 4.70-4.63(br, IH), 4.30-4.18 (br, 2H), 4.15-4.10 (br, 2H), 4.00-3.97 (br, 2H), 3.52-3.46 (br, 2H), 3.20 (m, IH), 2.95-2.84 (br, 2H), 2.24 (s, 3H), 1.31 (d, 12H); ESMS m/z 574.2 (M + H+).
Example 7
5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-r2-(propane-2-sulfonyl)- phenvH-pyrimidine-2,4-diamine (66)
Figure imgf000046_0001
1 : 4-(5-Isopropoxv-2-methvl-4-nitro-phenyl)-pvridine
Figure imgf000047_0001
[0111] 4-Pyridineboronic acid (147 mg, 1.20 mmol, 1.1 equiv.) is dissolved in a 2:1 v/v mixture of dioxane and H2O (15 mL) and N2 is bubbled through for 5 minutes. Tris(dibenzylidene acetone)dipalladium (0) (100 mg, 0.109 mmol, 0.1 equiv.), 2- dicyclohexylphosphine-2'-6'-dimethoxy biphenyl (112 mg, 0.272 mmol, 0.25 equiv.), 1-chloro- 5-isopropoxy-2-methyl-4-nitro-benzene (Intermediate 4, 250 mg, 1.09 mmol, 1.0 equiv.) and K3PO4 (462 mg, 2.18 mmol, 2.0 equiv.) are added under a N2 blanket. The reaction vessel is sealed and heated with microwave irradiation to 150 0C for 20 min. After cooling to room temperature, the reaction is diluted with ethyl acetate and washed with 1 N aqueous NaOH (2x), the organic layer is then dried over Na2SO4 and filtered. After concentration, the crude product is purified by silica gel chromatography (gradient from hexanes to 30% ethyl acetate in hexanes) to give 4-(5-Isopropoxy-2-methyl-4-nitro-phenyl)-pyridine as a brown solid: ESMS m/z 273.1 (M + H+).
Steps 2 and 3 : 4-(4-Amino-5-isopropoxy-2-methyl-phenyl)-piperidine-l-carboxylic acid tert- butyl ester
Figure imgf000047_0002
[0112] 4-(5-Isopropoxy-2-methyl-4-nitro-phenyl)-pyridine from the previous step(438 mg, 1.61 mmol) dissolved in acetic acid (30 mL) is treated with TFA (0.24 mL, 3.22 mmol) and PtO2 (176 mg, 40% w/w). The reaction mixture is vigorously stirred under 1 atm. H2 for 36 hours. The reaction mixture is filtered and the filtrate is concentrated under vacuum. The resulting residue is diluted with ethyl acetate and washed with 1 N aqueous NaOH (2x), the organic layer is then dried over Na2SO4 and filtered. After concentration, the crude product (391 mg) is dissolved in anhydrous CH2Cl2 (30 mL). TEA is added (0.44 mL, 3.15, 2 equiv.) followed by Boc2O (344 mg, 1.57 equiv, 1 equiv.). The reaction is stirred at room temperature for 30 min. The reaction is concentrated under vacuum. The resulting residue is purified by silica gel chromatography (gradient from hexanes to 30% ethyl acetate in hexanes) to give 4-(4-amino-5- isopropoxy-2-methyl-phenyl)-piperidine-l-carboxylic acid tert-butyl ester as a sticky foam: ESMS m/z 293.1 (M-?Bu+H)+.
Steps 4 and 5
[0113] 4-(4-Amino-5-isopropoxy-2-methyl-phenyl)-piperidine-l-carboxylic acid tert-butyl ester (170 mg, 0.488 mmol) from the previous step, (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane- 2-sulfonyl)-phenyl]-amine (Intermediate 2, 169 mg, 0.488 mmol, 1 equiv.), xantphos (28 mg, 0.049 mmol, 0.1 equiv.), palladium acetate (5.5 mg, 0.024 mmol, 0.05 equiv.), and Cs2CO3 (477 mg, 1.46 mmol, 3 equiv.) are dissolved in anhydrous THF (6 mL). N2 is bubbled through the reaction mixture for 5 minutes and then the reaction vessel is sealed and heated with microwave irradiation to 150 0C for 20 min. The reaction is filtered and the filtrate concentrated under vacuum. After concentration, the crude product is purified by silica gel chromatography (gradient from hexanes to 30% ethyl acetate in hexanes) to give 4-(4-{5-chloro-4-[2-(propane-2- sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-2-methyl-phenyl)-piperidine-l- carboxylic acid tert-butyl ester as a yellow film: ESMS m/z 658.3 (M + H+). This product (105 mg, 0.160 mmol) is dissolved in CH2Cl2 (3 mL) and treated with TFA (3 mL). After 45 min., the reaction is concentrated under vacuum. 1 N HCl in Et2O (5 mL x 2) is added causing the product HCl salt to precipitate. The solvent is removed by decantation. The resulting 5- Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)- phenyl]-pyrimidine-2,4-diamine (66) is dried under high vacuum, generating an off-white powder: 1H NMR (400 MHz, DMSO-J6 + trace D2O) δ 8.32 (s, IH), 8.27 (d, IH), 7.88 (d, IH), 7.67 (dd, IH), 7.45 (dd, IH), 7.42 (s, IH), 6.79 (s, IH), 4.56-4.48 (m, IH), 3.49-3.32 (m, 3H), 3.10-2.91 (m, 3H), 2.09 (s, 3H), 1.89-1.77 (m, 4H), 1.22 (d, 6H), 1.13 (d, 6H); ESMS m/z 558.1 (M + H+).
Example 8
5-Chloro-N2-r2-isopropoxy-5-methyl-4- ((1l --mmeetthhyyll --ppiiperidin-4-yl)-phenyll-N4-r2-(propane-2- sulfonyl)-phenyll-pyrimidine-2,4-diamine (67)
Figure imgf000049_0001
Jj.4-(5-Isopropoxy-2-methyl-4-nitro-phenyl)-l-methyl-pyridinium iodide
Figure imgf000049_0002
[0114] 4-(5-Isopropoxy-2-methyl-4-nitro-phenyl)-pyridine (Example 7, Step 1, 217 mg,
0.797 mmol) is dissolved in anhydrous THF (9 mL). Iodomethane (0.10 mL, 1.61 mmol, 2 equiv.) is added and the reaction is stirred at 40 0C in a sealed tube for 2 days. The volatiles are removed under vacuum generating 4-(5-Isopropoxy-2-methyl-4-nitro-phenyl)-l-methyl- pyridinium iodide as a brown solid: ESMS m/z 287.1 (M+).
Steps 2 and 3 : 2-Isopropoxy-5-methyl-4-(l-methyl-piperidin-4-yl)-phenylamine
Figure imgf000049_0003
[0115] 4-(5-Isopropoxy-2-methyl-4-nitro-phenyl)-l-methyl-pyridinium iodide from the previous step (0.697 mmol) is dissolved in CH3OH (20 mL) and cooled to 0 0C. NaBH4 (264 mg, 6.97 mmol, 10 equiv.) is slowly added. After this addition is complete, the cooling bath is removed and the reaction is stirred at room temperature for 1 h. The reaction is quenched by the slow addition of IN aqueous HCl (14 mL). The CH3OH is partially removed by vacuum. The resulting residue is partitioned between EtOAc and 1 N aqueous NaOH. Additional 50 % aqueous NaOH is added until the aqueous layer pH >12. The EtOAc layer is washed with 1 N aqueous NaOH (2x), the organic layer is then dried over Na2SO4, filtered, and concentrated under vacuum. After concentration, the crude product (175 mg) is dissolved in acetic acid (10 mL). TFA (0.15 mL, 3 equiv.) and PtO2 (53 mg, 30% w/w) are added and the reaction is placed under 50 psi H2 gas in a Parr Shaker for 14 h. The reaction mixture is filtered and the filtrate is concentrated under vacuum. The resulting residue is partitioned between EtOAc and 1 N aqueous NaOH. Additional 50% aqueous NaOH is added until the aqueous layer pH >12. The EtOAc layer is washed with 1 N aqueous NaOH (2x), the organic layer is then dried over Na2SO4, filtered, and concentrated under vacuum to give 2-Isopropoxy-5-methyl-4-(l-methyl- piperidin-4-yl)-phenylamine which is used in Step 4 without further purification: ESMS m/z 263.2 (M + H+).
Step 4
[0116] Utilizing the same procedures described in the synthesis of Example 7 (Step 4) and final purification using preparative RP LC-MS affords 5-Chloro-N2-[2-isopropoxy-5-methyl-4- (l-methyl-piperidin-4-yl)-phenyl]-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine (67) as a pale yellow powder: (HCl salt, DMSO-J6 + trace D2O) δ 8.28 (s, IH), 8.19 (d, IH), 7.86 (d, IH), 7.66 (dd, IH), 7.45 (dd, IH), 7.37 (s, IH), 6.77 (s, IH), 4.56-4.49 (m, IH), 3.51- 3.37 (m, 3H), 3.16-3.08 (m, 2H), 2.98-2.88 (m, IH), 2.77 (s, 3H), 2.05 (s, 3H), 1.90-1.81 (m, 4H), 1.19 (d, 6H), 1.11 (d, 6H); ESMS m/z 572.2 (M + H+).
Example 9
2- [4-(4- { 5 -Chloro-4- r2-(propane-2-sulfonyl)-phenylaminol -pyrimidin-2-ylamino I -5 - isopropoxy-2-methyl-phenyl)-piperidin-l-yll-ethanol (72)
Figure imgf000050_0001
[0117] 5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2- sulfonyl)-phenyl]-pyrimidine-2,4-diamine (Example 7, 0.087 mmol) is dissolved in anhydrous DMF (1 mL). TEA (0.04 mL, 0.262 mmol, 3 equiv.) is added followed by 2-bromo-ethanol (0.019 mL, 0.262 mmol, 3 equiv.) dissolved in anhydrous DMF (0.7 mL). The reaction vessel is sealed and heated at 70 0C for 12 h. After cooling to room temperature, the reaction is diluted with ethyl acetate and washed with 1 N aqueous NaOH (5x), the organic layer is then dried over Na2SO4 and filtered. After concentration, the crude product is purified using preparative RP LC-MS to give 2-[4-(4-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2- ylamino}-5-isopropoxy-2-methyl-phenyl)-piperidin-l-yl]-ethanol (72) as a yellow powder: ESMS m/z 602.2 (M + H+).
Example 10
2- [4-(6- 15 -Chloro-4- r2-(propane-2-sulfonyl)-phenylaminol -pyrimidin-2-ylamino 1 -5 - isopropoxy- 1 -oxo- 1 ,3 -dihydro-isoindol-2- yl)-piperidin- 1 -yll -acetamide (149)
Figure imgf000051_0001
[0118] To a mixture of 6-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2- ylamino}-5-isopropoxy-2-piperidin-4-yl-2,3-dihydro-isoindol-l-one (Example 1, 20 mg, 0.033 mmol) and triethylamine (23 uL, 0.165 mmol) in DMF (1.5 mL), is added 2-bromo-acetamide (10 mg, 0.066 mmol). The mixture is stirred at 60 0C for 4 hours. The reaction is filtered and the filtrate is purified by mass-trigger preparative RP LC-MS to afford the title compound 2-[4-(6- {5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-l-oxo- 1, 3 -dihydro-isoindol-2-yl)-piperidin-l-yl] -acetamide (136) as a white solid: 1H NMR (400 MHz, MeOD-J4) δ 8.41 (d, IH), 8.27 (s, IH), 8.21 (br, IH), 7.93 (dd, IH), 7.73 (m, IH), 7.40 (dd, IH), 7.30 (s, IH), 4.52 (s, 2H), 4.45-4.37 (m, IH), 4.19-4.15 (br, 2H), 3.87-3.78 (br, 2H), 2.37- 2.19 (m, 2H), 2.20-2.15 (m, IH), 1.40 (d, 6H), 1.25 (d, 6H); ESMS m/z 656.2 (M + H+).
Example 11
4-(6-{5-Chloro-4-r2-(propane-2-sulfonyl)-phenylaminol-pyrimidin-2-ylamino|-5-isopropoxy-l- oxo-l,3-dihydro-isoindol-2-yl)-piperidine-l-carboxylic acid dimethylamide ( 155)
Figure imgf000052_0001
[0119] To a mixture of 6-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2- ylamino}-5-isopropoxy-2-piperidin-4-yl-2,3-dihydro-isoindol-l-one (Example 1, 20 mg, 0.033 mmol) and triethylamine (23 uL, 0.165 mmol) in DMF (1.5 mL) is added dimethylcarbamyl chloride (11 mg, 0.1 mmol). The mixture is stirred at room temperature for 1 hour. The reaction is filtered and the filtrate is purified by mass-trigger preparative RP LC-MS to afford the title compound 4-(6-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5- isopropoxy-l-oxo-l,3-dihydro-isoindol-2-yl)-piperidine-l-carboxylic acid dimethylamide (155) as a white solid: 1H NMR (400 MHz, MeOD-d4) δ 8.29 (s, IH), 8.26 (br, IH), 7.96 (dd, IH), 7.93 (s, IH), 7.72(dd, IH), 7.48 (dd, IH), 7.35 (s, IH), 4.50 (s, 2H), 4.35-4.29 (m, IH), 3.83 (d, 2H), 3.38-3.30 (m, 2H), 3.02-2.95 (m, 3H), 2.88 (s, 6H), 1.88-1.84 (m, 3H), 1.36 (d, 6H), 1.25 (d, 6H); ESMS m/z 670.2 (M + H+).
Example 12
N2-(5-Ethynyl-2-isopropoxy-4-methyl-phenyl)-5-methyl-N4-r2-(propane-2-sulfonyl)-phenyll- pyrimidine-2,4-diamine (257)
Figure imgf000052_0002
Step 1 : N2-(2-Isopropoxv-4-methvl-5-trimethvlsilanvlethvnvl-phenvl)-5-methyl-N4-r2- (propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine
Figure imgf000053_0001
[0120] A mixture of N2-(5-Bromo-2-isopropoxy-4-methyl-phenyl)-5-methyl-N4-[2- (propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine (Example 5, Step 4, 110 mg, 0.21 mmol), ethynyl-trimethyl-silane (0.14 niL), N,N-diisopropyl ethylamine (0.10 niL), PdCl2(PhCN)2 (12 mg), 1Bu3PHBF4 (17 mg), and CuI (4 mg) in 1 mL 1,4-dioxane is stirred at 22 0C for 20 hrs followed by heating at 60 0C for an additional 2 hrs. The reaction mixture is filtered through a small Celite plug and concentrated. The residue is purified over a 4 g SiO2 column (ISCO) using a gradient of 0 to 20% ethyl acetate in hexanes as eluent, affording N2-(2-Isopropoxy-4- methyl-5-trimethylsilanylethynyl-phenyl)-5-methyl-N4-[2-(propane-2-sulfonyl)-phenyl]- pyrimidine-2,4-diamine as a yellow viscous oil.
Step 2
[0121] A solution of N2-(2-Isopropoxy-4-methyl-5-trimethylsilanylethynyl-phenyl)-5- methyl-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine from the previous step (0.102 g, 0.18 mmol) in 2.5 mL THF is treated with TBAF (0.5 mL, IM in THF) and 30 μL AcOH at 22 0C for 2 hrs. The reaction mixture is concentrated and the residue is purified using a 4 g SiO2 column (ISCO), affording N2-(5-Ethynyl-2-isopropoxy-4-methyl-phenyl)-5-methyl- N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine (257). MS (ES+): 479.2 (MH+).
Example 13
4-(6-{5-Chloro-4-r2-(propane-2-sulfonyl)-phenylaminol-pyrimidin-2-ylamino|-5-isopropoxy-l- oxo-l,3-dihvdro-isoindol-2-yl)-piperidine-l-carboxyric acid ethyl ester (175)
Figure imgf000054_0001
[0122] To a mixture of 6- { 5-Chloro-4- [2-(propane-2-sulfonyl)-phenylamino] -pyrimidin-2- ylamino}-5-isopropoxy-2-piperidin-4-yl-2,3-dihydro-isoindol-l-one (Example 1, 15 mg, 0.025 mmol) and triethylamine (37.5 uL, 0.25 mmol) in DMF (0.5 mL), is added ethyl chloroformate (5.4 mg, 0.05 mmol). The mixture is stirred at room temperature for 1 hour. The crude reaction mixture is purified by mass-trigger preparative RP LC-MS to afford the title compound 4-(6-{5- chloro-4- [2-(propane-2-sulfonyl)-phenylamino] -pyrimidin-2-ylamino } -5 -isopropoxy- 1 -oxo- 1,3- dihydro-isoindol-2-yl)-piperidine-l-carboxylic acid ethyl ester (175) as a white solid. 1H NMR 400 MHz (DMSOd6 with trace D2O) δ 8.55 (d, IH), 8.32 (s, IH), 8.14 (s, IH), 7.82 (dd,lH), 7.74 (t, IH), 7.34 (t, IH), 7.28 (s, IH), 4.73 (m, 2H), 4.39 (s, 2H), 4.12 (m, 2H), 4.06 (q, 2H), 3.46 (m, IH), 2.92 (m 2H), 1.76 (m, 2H), 1.68 (m, 2H), 1.29 (d, 6H), 1.20 (t, 3H), 1.17 (d, 6H); MS m/z 671 (M+l).
Example 14
5-{5-Chloro-4-r2-(propane-2-sulfonyl)-phenylaminol-pyrimidin-2-ylaminol-6-isopropoxy-2-(l- methyl-piperidin-4-yl)-isoindole-l,3-dione (176)
Figure imgf000054_0002
Step 1: 4-(l-Hvdroxv-6-isopropoxv-5-m'tro-3-oxo-l,3-dihvdro-isoindol-2-vl)-piperidine-l- carboxylic acid tert-butyl ester oc
Figure imgf000055_0001
[0123] 4-(4-Isopropoxy-5-nitro-2-vinyl-benzoylamino)-piperidine-l-carboxylic acid tert- butyl ester (Example 1, Step 3, 1.2 g, 2.77 mmol) dissolved in 50 mL of DCM is cooled to -78 0C. Ozone gas is bubbled through this solution until the starting material is consumed and then nitrogen gas is bubbled through the solution for 5 min. The reaction mixture is warmed to room temperature. Triphenylphosphine -resin (2.77 g) in 10 mL of DCM is added and the resulting mixture is stirred for 1.5 h. The resin is removed by filtration and the filtrate is concentrated. Silica gel chromatography (5% MeOH in DCM) affords 4-(l-hydroxy-6-isopropoxy-5-nitro-3- oxo-1, 3-dihydro-isoindol-2-yl)-piperidine-l-carboxylic acid tert-butyl ester; MS m/z 336.2 (M- Boc + H+).
Steps 2, 3 and 4: 5-Isopropoxy-2-(l-methyl-piperidin-4-yl)-6-nitro-indan-l,3-dione
Figure imgf000055_0002
[0124] To the solution of 4-(l-hydroxy-6-isopropoxy-5-nitro-3-oxo-l,3-dihydro-isoindol-2- yl)-piperidine-l-carboxylic acid tert-butyl ester from the previous step (173.9 mg, 0.4 mmol) in DMF (4 mL) is added pyridinum dichromate (286.5 mg, 0.8 mmol) in one portion. After stirring at room temperature for 2 h, the reaction mixture is poured into 25 mL of water and the product is extracted with EtOAc. The organic extracts are dried over Na2SO4, filtered and concentrated in vacuo to give crude 4-(5-isopropoxy-6-nitro-l,3-dioxo-l,3-dihydro-isoindol-2- yl)-piperidine-l-carboxylic acid tert-butyl ester, which is directly used in the next step without further purification.
[0125] To a solution of 4-(5-isopropoxy-6-nitro-l,3-dioxo-l,3-dihydro-isoindol-2-yl)- piperidine-1-carboxylic acid tert-butyl ester generated in the previous step in 3 mL of DCM is added TFA (3 mL). The reaction mixture is stirred at room temperature for 1 h. After concentration, water (5 mL) is added to the crude reaction mixture, the resulting mixture is neutralized to pH=8 by adding NaHCθ3, and the product is extracted with DCM. The organic extracts are dried over Na2SO4, filtered and concentrated in vacuo to give crude 5-isopropoxy-6- nitro-2-piperidin-4-yl-isoindole-l,3-dione, which is directly used in the next step without further purification.
[0126] To a solution of the 5-isopropoxy-6-nitro-2-piperidin-4-yl-isoindole-l,3-dione generated in the previous step in THF (5 mL) and methanol (5 mL) are added formaldehyde (30 uL, 0.4 mmol) and 2 drops of AcOH sequentially. The reaction mixture is stirred at room temperature for Ih, then sodium cyanoborohydride (50.4 mg, 0.8 mmol) is added in one portion and the resulting mixture is stirred for an additional 30 min. The reaction is quenched by the addition of saturated aqueous NH4Cl followed by concentration in vacuo to give an oily residue. This oil is partitioned between EtOAc and brine. The organic extract is dried over Na2SO4, filtered and concentrated. Silica gel chromatography (5% MeOH in DCM) affords 5- isopropoxy-2-(l-methyl-piperidin-4-yl)-6-nitro-indan-l,3-dione; MS m/z 347.2 (M+l).
Steps 5 and 6
[0127] Following the procedures previously described (Example 1, Steps 7 and 8) using the product from Step 4 generates the title compound 5-{5-Chloro-4-[2-(propane-2-sulfonyl)- phenylamino]-pyrimidin-2-ylamino}-6-isopropoxy-2-(l-methyl-piperidin-4-yl)-isoindole-l,3- dione (176) as a yellow solid. 1H NMR 400 MHz (DMSO-d6 with trace D2O) δ 8.44 (s, 2H), 8.39 (s, IH), 7.87 (dd, IH), 7.78 (dt, IH), 7.45 (s, IH), 7.41 (m, IH), 4.91(m, 2H), 4.25(m, 2H), 3.51 (m, 3H), 3.10(m, 2H), 2.77(s, 3H), 1.80(m, 2H), 1.35(d, 6H), 1.13(d, 6H); MS m/z 627 (M+l). Example 15
(2S, 45)-4-(6-{5-Chloro-4-r2-(propane-2-sulfonyl)-phenylaminol-pyrimidin-2-ylamino|-5- isopropoxy-l-oxo-l,3-dihvdro-isoindol-2-yl)-pyrrolidine-2-carboxylic acid amide (177)
Figure imgf000057_0001
Step 1: (2S, 4Sj-4-(6-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}- 5-isopropoxy-l-oxo-l,3-dihydro-isoindol-2-yl)-pyrrolidine-2-carboxylic acid methyl ester
Figure imgf000057_0002
[0128] Following the procedures previously described (Example 1) using N-Boc-ds-4- amino-L-proline methyl ester in place of 4-amino-piperidine-l-carboxylic acid tert-butyl ester, generates (2S, 4S )-4-(6- { 5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2- ylamino}-5-isopropoxy-l-oxo-l,3-dihydro-isoindol-2-yl)-pyrrolidine-2-carboxylic acid methyl ester; MS m/z 643.2 (M+l).
Step 2
[0129] (2S, 4Sj-4-(6-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2- ylamino}-5-isopropoxy-l-oxo-l,3-dihydro-isoindol-2-yl)-pyrrolidine-2-carboxylic acid methyl ester generated in Step 1 (20 mg, 0.03 mmol) is dissolved in 7 Ν ammonia solution in MeOH ( 3 mL, 21 mmol). The resulting solution is heated using microwave irradiation to 120 0C for 1 h. After cooling to room temperature, the reaction mixture is concentrated in vacuo, neutralized to pH=8 with saturated aqueous ΝaHCθ3, and extracted with DCM. The organic extracts are dried over Na2SO4, filtered, and concentrated in vacuo to give (2S, 4S)-4-(6-{5-Chloro-4-[2-(propane- 2-sulfonyl)-phenylamino] -pyrimidin-2-ylamino } -5 -isopropoxy- 1 -oxo- 1 ,3 -dihydro-isoindol-2- yl)-pyrrolidine-2-carboxylic acid amide (177) as a yellow solid. 1H NMR 400 MHz (DMSO-d6 with trace D2O) δ 8.47(d, IH), 8.25 (s, IH), 8.07 (s, IH), 7.78 (dd, IH), 7.68 (m, IH), 7.31(t, IH), 7,24 (s, IH), 4,71 (m, 2H), 4.43 (dd, 2H), 3.60 (m, IH), 3.44 (m, IH), 3.35 (m,lH), 2.63 (m, IH), 2.28 (m, IH), 1.22 (d, 6H), 1.10 (d, 6H); MS m/z 628 (M+l).
Example 16
5-Chloro-N2-r4-(4-dimethylamino-cyclohexyl)-2-isopropoxy-5-methyl-phenyll-N4-r2- (propane-2-sulfonyl)-phenyll-pyrimidine-2,4-diamine (21)
Figure imgf000058_0001
Step 1: l,4-dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate
Figure imgf000058_0002
[0130] A solution of 0.5 M KHMDS in toluene (4.7 mL, 2.34 mmol) is added to a solution of l,4-dioxaspiro[4.5]decan-8-one (1.80 mmol) and N-phenyltrifluoromethanesulfonimide (2.34 mmol) in dry THF (18 mL) at -780C under argon. After stirring at -780C for 4 hours, the mixture is quenched with H2O, extracted with diethyl ether and dried with MgSO4. After workup and silica flash chromatography (hexane/EtOAc 90:10), l,4-dioxaspiro[4.5]dec-7-en-8- yl trifluoromethanesulfonate is isolated: 1H NMR (CDCl3, 400 MHz) δ 5.66 (m, IH), 3.98 (m. 4H), 2.53 (m, 2H), 2.40 (m, 2H), 1.90 (t, 2H). MS (ES+): 289.0 (M+l)+. i 2: 8-(5-isopropoxy-2-methyl-4-nitrophenyl)-l,4-dioxaspiro[4.5]dec-7-ene
Figure imgf000059_0001
[0131] A stirred solution of the l,4-dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate (0.03 mmol) and 2-(5-isopropoxy-2-methyl-4-nitrophenyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (Intermediate 5, 0.04 mmol) in THF (3 niL), containing [Pd(PPh3)4] (0.013 mmol) and K3PO4Η2O (0.045 mmol), is heated to 8O0C under argon for 16 hours. After workup and silica flash chromatography (hexane/EtOAc 4:1), 8-(5-isopropoxy-2-methyl-4-nitrophenyl)- l,4-dioxaspiro[4.5]dec-7-ene is obtained. 1H NMR (CDCl3, 400 MHz) δ 7.62 (s, IH), 6.82 (s, IH), 5.74 (m, IH), 4.65 (m, IH), 4.04 (m. 4H), 2.47 (m, 4H), 2.27 (s, 3H), 1.89 (t, 2H), 1.29 (d. 6H). MS (ES+): 334.16 (M+l)+.
> 3: 4-(5-isopropoxv-2-methvl-4-nitrophenvl)cyclohex-3-enone
Figure imgf000059_0002
[0132] A solution of 8-(5-isopropoxy-2-methyl-4-nitrophenyl)-l,4-dioxaspiro[4.5]dec-7-ene (0.1 mmol) in 2.5 mL of TFA and CH2CI2 (1:4 v/v), is stirred at room temperature for 6 hours. After workup and silica flash chromatography (hexane/EtOAc 4: 1), 4-(5-isopropoxy-2-methyl- 4-nitrophenyl)cyclohex-3-enone is obtained. 1H NMR (CDCl3, 400 MHz) δ 7.63 (s, IH), 6.81 (s, IH), 5.73 (m, IH), 4.62 (m, IH), 3.07 (m, 2H), 2.68 (m, 4H), 2.27 (s, 3H), 1.37 (d. 6H). MS (ES+): 290.13 (M+l)+.
> 4: 4-(5-isopropoxv-2-methvl-4-nitrophenvl)-N,N-dimethvlcyclohex-3-enamine
Figure imgf000059_0003
[0133] To a solution of 4-(5-isopropoxy-2-methyl-4-nitrophenyl)cyclohex-3-enone (0.1 mmol) and dimethylamine (0.11 mmol) in 2 mL of 1 ,2-dicholoroethane, is added AcOH (0.1 mmol) and NaBH(OAc)3 (0.11 mmol). The reaction mixture is stirred at room temperature for 10 hours. After workup and silica flash chromatography (CH2Cl2/Me0H 9: 1), 4-(5-isopropoxy- 2-methyl-4-nitrophenyl)-N,N-dimethylcyclohex-3-enamine is obtained. MS (ES+): 319.19 (M+ 1)+.
Step 5 : 4-(4-(dimethylamino)cyclohexyl)-2-isopropoxy-5-methylaniline
Figure imgf000060_0001
[0134] To a solution of 4-(5-isopropoxy-2-methyl-4-nitrophenyl)-N,N-dimethylcyclohex-3- enamine (0.1 mmol) in 10 mL of MeOH, is added Pd/C (5 mg) under argon. The suspension is stirred under 1 atm. H2 for 6 hours. After filtering, solvent is removed and 4-(4- (dimethylamino)cyclohexyl)-2-isopropoxy-5-methylaniline is obtained. MS (ES+): 291.24 (M+ 1)+.
Step 6
[0135] Following the procedure previously described (Example 7, Step 4) using the product from Step 5 generates the title compound 5-Chloro-N2-[4-(4-dimethylamino-cyclohexyl)-2- isopropoxy-5-methyl-phenyl]-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine (21). 1H NMR (CD3OD, 400 MHz) δ 8.36-8.38 (d, IH), 8.20 (s, IH), 7.97-7.99 (m, IH), 7.69-7.73 (m, IH), 7.46-7.52 (m, 2H), 6.89-7.02 (d, IH), 4.60-4.66 (m, IH), 3.37-3.39 (m, IH), 3.00 (s, 3H), 2.90 (s, 3H), 2.17-2.22 (m, 4H), 1.64-2.01 (m, 8H), 1.25-1.32 (m, 12H); MS (ES+): 600.3 (M+ 1)+.
[0136] Exemplary compounds of the invention are set forth below. Table 1 shows exemplary compounds of Formula (IA). Table 1
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Ill
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
[0137] Table 2 shows exemplary compounds of Formula (1C).
Table 2
Figure imgf000115_0002
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0003
Example 17
Methyl 4'-(5-chloro-4-(2-(isopropylsulfonyl)phenylamino)pyridin-2-ylamino)-5'-methoxy-2'- methylbiphenyl-4-carboxylate (254)
Figure imgf000130_0001
Step 1: Methyl 4'-amino-5'-methoxy-2'-methylbiphenyl-4-carboxylate
Figure imgf000130_0002
[0138] Methyl 4'-amino-5'-methoxy-2'-methylbiphenyl-4-carboxylate; MS m/z 272.1 (M+l), may be synthesized following the procedures previously described (Example 7, Steps 1 and 2) using appropriate reagents. Step 2: Methyl 4'-(4-bromo-5-chloropyridin-2-ylamino)-5'-methoxy-2'-methylbiphenyl- 4-carboxylate
Figure imgf000131_0001
[0139] Methyl 4'-amino-5'-methoxy-2'-methylbiphenyl-4-carboxylate generated in Step 1 (200 mg, 0.75 mmol), 2,4-dibromo-5-chloropyridine (222 mg, 0.82 mmol, 1.1 equiv), Pd2(dba)3 (17 mg, 0.02 mmol, 0.025 equiv.), xantphos (22 mg, 0.04 mmol, 0.05 equiv.), and Cs2CO3 (365 mg, 1.1 mmol, 1.5 equiv.) are added to THF (5 mL). The resulting mixture is bubbled with N2 gas for 5 minutes and then heated at 150 0C for 4 hours. After cooling to room temperature, the reaction mixture is diluted into EtOAc and washed with H2O. The EtOAc layer is dried over Mg2SO4 and concentrated in vacuo. Silica gel chromatography (hexanes-EtOAc) affords Methyl 4'-(4-bromo-5-chloropyridin-2-ylamino)-5'-methoxy-2'-methylbiphenyl-4-carboxylate; MS m/z 461.0 (M+l).
Step 3: Methyl 4'-(5-chloro-4-(2-(isopropylsulfonyl)phenylamino)pyridin-2-ylamino)-5'- methoxy-2'-methylbiphenyl-4-carboxylate (254)
[0140] Methyl 4'-(4-bromo-5-chloropyridin-2-ylamino)-5'-methoxy-2'-methylbiphenyl-4- carboxylate generated in Step 2 (9 mg, 0.022 mmol), 2-(isopropylsulfonyl)aniline (4 mg, 0.022 mmol, 1 equiv), Pd2(dba)3 (1.7 mg, 0.002 mmol, 0.1 equiv.), 2-(Dicyclohexylphosphino)- 2',4',6'-tri-i-propyl-l,l'-biphenyl (1.8 mg, 0.004 mmol, 0.2 equiv.), and Sodium tert-butoxide (2.7 mg, 0.028 mmol, 1.3 equiv.) are added to THF (1 mL). The resulting mixture is bubbled with N2 gas for 5 minutes and then heated at 150 0C for 4 hours. After cooling to room temperature, the reaction mixture is diluted into EtOAc and washed with H2O. The EtOAc layer is dried over Mg2SO4 and concentrated in vacuo. Silica gel chromatography (hexanes-EtOAc) affords Methyl 4'-(5-chloro-4-(2-(isopropylsulfonyl)phenylamino)pyridin-2-ylamino)-5'- methoxy-2'-methylbiphenyl-4-carboxylate (254); MS m/z 580.2 (M+l).
[0141] Exemplary compounds of the invention are set forth below. Table 3 shows exemplary compounds of Formula (5). Table 3
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
[0142] Table 4 shows other compounds which may be useful treating, ameliorating or preventing a condition which responds to inhibition of anaplastic lymphoma kinase (ALK) activity, focal adhesion kinase (FAK), zeta-chain-associated protein kinase 70 (ZAP-70), insulin-like growth factor (IGF-IR).
Table 4
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
[0143] Compounds of the present invention may be assessed for their ability to inhibit ALK using assays described below, as well as other assays known in the art.
Ba/F3 cell line panel and reagents
[0144] Ba/F3 is a murine IL-3 -dependent pro-B lymphoma cell line. Parental Ba/F3 cells are used to generate a panel of sublines whose proliferation and survival is rendered IL-3- independent by stable transduction with individual tyrosine kinases activated by fusion with the amino-terminal portion of TEL (amino acid 1-375) or BCR. In order to generate Ba/F3 cell lines transformed by Tel-Tyrosine Kinase (TK) fusions, parental Ba/F3 cells are infected with a retrovirus harboring each kinase domain and subjected to puromycin selection and IL-3 withdrawal to obtain IL- 3 -independent, transformed Ba/F3 cells.
[0145] Each transformed Ba/F3 cells are cultured in RPMI- 1640 media (Gibco Cat #11875093, Carlsbad, CA) supplemented with 10% FBS (Hyclone Cat #SV30014.03, Logan, UT), 4.5 g/L glucose (Sigma #G5400, St.Louis, MO), 1.5 g/L sodium bicarbonate (Biowhittaker #17-613E, Walkersville, MD) and Pen/Strep (Gibco #10378-016, Carlsbad, CA). Cells are splitted twice weekly.
Ba/F3 cell viability inhibition assay
[0146] The potency of test compounds against various TeI-TK transformed Ba/F3 lines is determined as follows. Exponentially growing BaF3 TeI-TK cells are diluted in fresh medium to 75,000 cells/mL and seeded into 384-well plates (3750 cells/well) at 50 μL/well using a μFill liquid dispenser (BioTek, Winooski, VT, USA). Duplicate plates are run for each cell line. Test and control compounds are serially diluted with DMSO and arrayed in a polypropylene 384-well plate. 50 nL of compound is transferred into the assay plates using a pin-transfer device, and the plates are incubated at 37 0C (5% CO2) for 48 hours. 25 μL Bright-Glo (Promega, Madison, WI, USA) is added and luminescence is quantified using Analyst GT (Perkin Elmer, Wellesley, MA). Custom curve-fitting software is used to produce a logistic fit of percent cell viability as a function of the logarithm of inhibitor concentration. The IC50 is interpolated as the concentration of compound needed to reduce cell viability to 50% of a DMSO control. Parental Ba/F3 cells that are maintained and cultured in presence of IL- 3 (1 ng/ml in final) are diluted in fresh medium containing IL-3 (1 ng/ml in final) to 75,000 cells/mL following the same procedure as described above.
Kapas 299 cellular assay
[0147] Luciferized Karpas 299 (Karpas299-Luc) is generated by infecting retrovirus encoding luciferase gene, and cultured in RPMI-1649 medium supplemented with 10% FBS, 1% P/S/L-Glu. At day 1, cells are harvested and resuspended at density of 150,000 cells/ml (cell number is measured using ViCeIl (BD). Cells are dispensed from a diluted suspension into a 384-well assay plate in 50 μl volume using μFill (Bio-TEK). Serially diluted compounds (in DMSO) are transferred into plate using 50 nL pinhead. Assay plates are incubated at 37 0C for 48 hours. At day 4, 25 μl/well of Bright-Glo reagent (Promega) is added using μFill (Bio-TEK). Within 30 minutes, a luciferase signal is measured using Analyst GT in default setting for luminescence detection. Enzymatic HTRF assay
[0148] ALK enzyme and IGFlR and INSR are purchased from Upstate. Following reagents are prepared in-house; 10 x kinas buffer (KB) (200 mM Tris (pH 7.0), 100 mM MgCl2, 30 mM MnCl2 , 50 nM NaVO4), 10 mM ATP, 100 mg/ml BSA, 0.5 M EDTA, 4 M KF. Proxiplate-384 from Perkin-Elmer is used for set up assay. All the HTRF reagents including substrate (Biotin- poly-GT (61GT0BLB), Mab PT66-K, (61T66KLB), Streptavidin-XLent (611SAXLB)) are purchased from CIS-US, Inc.
[0149] The substrate/ ATP mix is prepared by adding ATP (final concentration, 3 μM) and biotinylated poly-GT (final concentration, 10 ng/μl) into Ix KB, and dispensed into Proxiplate- 384 at 5 μl/well using μFill (Bio-TEK). Serially diluted compounds (in DMSO) are transferred into plate using 50 nL pinhead. 5 μL of prepared Enzyme mix (enzyme (final concentration, 5 ng/μl), mixed with BSA and DTT in Ix KB) is added to initiate kinase reaction using μFill (Bio- TEK). Assay plate is incubated at room temperature for 2 hours. Detection mix is prepared by adding both Mab PT66-K and Streptavidin-XLent into 0.5 x KB solution containing KF (final concentration, 125 mM), EDTA (final concentration, 50 mM) and BSA (final concentration, 100 μg/ml) in. At the end of reaction, 10 μL of detection mix is added and incubated for 30 minutes at room temperature before measurement. HTRF signal is detected using Analyst-GT (molecular dynamic).
Reporter assay in U2OS cells using REl-pGL3 for IGF1-S3-5 or INSR-S3-5 [0150] Seed 1OM cells / T175 Flask in Mc Coy 10% FBS and 4 days later, suck off media and add fresh media. Next day (5 days after seeding), trypsinize cells, wash once with PBS, then resuspend cells in Mc-Coy media 4% delipidated serum with P/S/G. Count cells and dilute to 400,000 cells/ml.
[0151] For 95 ml of cells (400000 cells/ml (40M)), prepare the following DNA/Fugene6 mix: 5 ml Mc-Coy media without serum; 120 μg DNA mix (20 μg IGF1R-S3-5 or INSR-S3- 5+100 μg REl-pGL3); and 240 μL Fugeneό reagent. Incubate DNA/ Fugeneό mix for 15 min before adding it to cells in 4% delipidated serum. Dispense 50 μL / well in 384 well plate. 22- 24h later, add 50 nL of serially diluted compounds using pinhead. 30 min later, add 2 μL of 26X IGFl (or IOOX Insulin) dose diluted in Mc-Coy 4% delipidated serum using μ-Fill. 30 hours later, add 25 μL 100% bright-glo and read on Analyst-GT for measuring luminescence. [0152] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference for all purposes.

Claims

Claims
1. A compound having Formula (1):
Figure imgf000147_0001
or pharmaceutically acceptable salts thereof; wherein
Figure imgf000147_0002
A1 and A4 are independently C or N; each A2 and A3 is C, or one of A2 and A3 is N when R6 and R7 form a ring;
B and C are independently an optionally substituted 5-7 membered carbocyclic ring, aryl, heteroaryl or heterocyclic ring containing N, O or S;
Z1, Z2 and Z3 are independently NR11, C=O, CR-OR, (CR2)I-2 or =C-R12;
R1 and R2 are independently halo, OR12, NR(R12), SR12, or an optionally substituted C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl; or one of R1 and R2 is H;
R3 is (CR2)o-2S02R12, (CR2V2SO2NRR12, (CR2)o-2COi_2R12, (CR2)0-2CONRR12 or cyano;
R4, R6, R7 and R10 are independently an optionally substituted Ci_6 alkyl, C2-6 alkenyl or C2_6 alkynyl; OR12, NR(R12), halo, nitro, SO2R12, (CR2)pR13 or X; or R4, R7 and R10 are independently H;
R, R5 and R5 are independently H or C1-6 alkyl;
R8 and R9 are independently Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, halo or X, or one of R8 and R9 is H when R1 and R2 form a ring; and provided one of R8 and R9 is X; alternatively, R1 and R2, or R6 and R7, R7 and R8, or R9 and R10, when attached to a carbon atom may form an optionally substituted 5-7 membered monocyclic or fused carbocyclic ring, aryl, or heteroaryl or heterocyclic ring comprising N, O and/or S; or R7, R8, R9 and R10 are absent when attached to N; R11 is H, Ci_6 alkyl, C2-6 alkenyl, (CR2)PCOi_2R, (CR2)POR, (CR2)PR13, (CR2)PNRR12, (CR2)PCONRR12 or (CR2)pSOi_2R12;
R12 and R13 are independently an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, or a 5-7 membered heterocyclic ring comprising N, O and/or S; aryl or heteroaryl; or R12 is H, Ci_6 alkyl;
X is (CR2)qY, cyano, COi_2R12, CONR(R12), CONR(CR2)PNR(R12), CONR(CR2)POR12, CONR(CR2)PSR12, CONR(CR2)pS(O)i_2R12 or (CR2)i_6NR(CR2)pOR12;
Y is an optionally substituted 3-12 membered carbocyclic ring, a 5-12 membered aryl, or a 5-12 membered heteroaryl or heterocyclic ring comprising N, O and/or S and attached to A or A3 or both via a carbon atom of said heteroaryl or heterocyclic ring when q in (CR2)qY is 0; and n, p and q are independently 0-4.
2. The compound of claim 1, wherein R1 is halo or Ci_6 alkyl; R2 is H or NH2; or
R1 and R2 together form an optionally substituted 5-6 membered aryl, or heteroaryl or heterocyclic ring comprising 1-3 nitrogen atoms.
3. The compound of claim 1 or claim 2, wherein R3 is SO2R12, SO2NH2, SO2NRR12, CO2NH2, CONRR12, COi_2R12, or cyano; and
R12 is Ci_6 alkyl, an optionally substituted C3_7 cycloalkyl, C3_7 cycloalkenyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl or azetidinyl.
4. The compound of any one of claims 1-3, wherein R5, R5 , R7 and R10 are independently H, and n is 0.
5. The compound of any one of claims 1-3, wherein R is OR12, and R12 is Ci_6 alkyl.
6. The compound of any one of claims 1-3, wherein said compound is of Formula
(2):
Figure imgf000149_0001
wherein R1 is halo or C]_6 alkyl;
R2 is H; or
R1 and R2 together form an optionally substituted 5-6 membered heteroaryl or heterocyclic ring comprising one or two nitrogen atoms;
R6 is isopropoxy or methoxy; one of R8 and R9 is (CR2)qY and the other is Ci_6 alkyl, cyano, COi_2R12, CONR(R12) or CONR(CR2)pNR(R12);
Y is an optionally substituted C3-7 cycloalkyl, C3-7 cycloalkenyl, or phenyl; or Y is pyridyl, pyrazolyl, isoxazolyl, imidazolyl, thiazolyl, benzimidazolyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, azetidinyl, heptamethyleneimine or octamethyleneimine, each of which is attached to the phenyl ring via a carbon atom when q in (CR2)qY is 0; n is 0- 1 ; and q is 0-4.
7. The compound of claim 6, wherein one of R8 and R9 is (CR2)qY and the other is Ci_6 alkyl; and n and q are independently 0.
8. The compound of claim 1, wherein said compound is of Formula (3A) or (3B):
Figure imgf000150_0001
wherein B and C together form
Figure imgf000150_0002
Z1, Z2 and Z3 together form
Figure imgf000151_0001
or tautomers thereof;
R » i i •s halo or Ci_6 alkyl;
R2 is H; or
R1 and R2 together form an optionally substituted 5-7 membered carbocyclic ring, aryl, or heteroaryl or heterocyclic ring comprising N, O and/or S; and R6 is isopropoxy or methoxy.
9. The compound of claim 8, wherein each R11 is (CR2)pCOi_2R, (CR2)POR, (CR2)pR13, (CR2)pNRR12 or (CR2)PCONRR12;
R and R12 are independently H or C1-6 alkyl; and
R13 is an optionally substituted piperidinyl, azetidiyl, tetrahydropyranyl, cyclohexyl, morpholinyl, pyrrolidinyl, heptamethyleneimine, octamethyleneimine, a bicyclic amine or diamine derivative, quinuclidin-3-yl, 8-methyl-8-aza-bicyclo[3.2.1]oct-6-yl], or 9-methyl-9-aza- bicyclo[4.2.1]nonan-7-yl.
10. The compound of claim 1, wherein said compound is of Formula (4A) or Formula (4B):
Figure imgf000151_0002
Figure imgf000152_0001
wherein R1 is halo or C1-6 alkyl; R is H; or
R1 and R2 together form an optionally substituted 5-7 membered carbocyclic ring, aryl, or heteroaryl or heterocyclic ring comprising N, O and/or S;
R is isopropoxy or methoxy; and BB22 aanndd BB33 aarree independently an optionally substituted 5-6 membered aryl or heteroaryl containing N, O or S.
11. The compound of claim 1, wherein said compound is selected from the group consisting of
Figure imgf000152_0002
N2-(4-((lr,4r)-4-(N-(2-methoxyethyl)-N-
(2-(5-chloro-2-(2-isopropoxy-5-methyl-4-(l- methylamino)cyclohexyl)-2-isopropoxy-5- methylpiperidin-4-yl)phenylamino) methylphenyl)-5-chloro-N4-(2- pyrimidin-4-ylamino)phenyl)(pyrrolidin- 1 - (isopropylsulfonyl)phenyl)pyrimidine-2,4- yl)methanone diamine
Figure imgf000152_0003
2-(5-chloro-2-(2-isopropoxy-5-methyl-4-(l- 5-(4-(2-(isopropylsulfonyl)phenylamino)- methylpiperidin-4-yl)phenylamino) 5-chlorop3τimidin-2-ylamino)-4- P3τimidin-4-ylamino)-N- isopropoxy-N-methyl-2-((R)-4-(4- cyclopentylbenzamide methylpiperazin- 1 -yl)cyclohex- 1 - enyl)benzamide
Figure imgf000153_0001
5-(4-(2-(isopropylsulfonyl)phenylamino)-
Figure imgf000153_0002
5-chloropyrimidin-2-ylamino)-4- isopropoxy-N-methyl-2-((S)-4-(4-
N2-(4-((lR,2S,4R)-2,4-bis(dimethylamino) methylpiperazin- 1 -yl)cyclohex- 1 - cyclohexyl)-2-isopropoxy-5-methylphenyl)-5- enyl)benzamide chloro-N4-(2-(isopropylsulfonyl) phenyl)pyrimidine-2,4-diamine
Figure imgf000153_0003
2-(4-((R)-I -hydroxypropan-2-
Figure imgf000153_0004
ylamino)cyclohex-l-enyl)-5-(4-(2-
(isopropylsulfonyl)phenylamino)-5-
N2-(4-((lR,2S,4S)-2,4-bis(dimethylamino) chloropyrimidin-2-ylamino)-4-isopropoxy- cyclohexyl)-2-isopropoxy-5-methylphenyl)-5- N-methylbenzamide chloro-N4-(2-(isopropylsulfonyl) phenyl)pyrimidine-2,4-diamine
Figure imgf000153_0005
2-(4-((S)-l-hydroxypropan-2-
Figure imgf000153_0006
ylamino)cyclohex-l-enyl)-5-(4-(2-
(isopropylsulfonyl)phenylamino)-5-
2-(5-chloro-2-(4-((ls,4s)-4-(dimethylamino) chloropyrimidin-2-ylamino)-4-isopropoxy- cyclohexyl)-2-isopropoxy-5 - N-methylbenzamide methylphenylamino) pyrimidin-4-ylamino)- N,Ndimethylbenzenesulfonamide
Figure imgf000154_0001
5-(4-(2-(isopropylsulfonyl)phenylamino)-
Figure imgf000154_0002
5-chloropyrimidin-2-ylamino)-4- isopropoxy-N-methyl-2-(4-oxocyclohex- 1 -
2-(5-chloro-2-(4-((lr,4r)-4- enyl)benzamide (dimethylamino)cyclohexyl)-2-isopropoxy-5- methylphenylamino) pyrimidin-4-ylamino)- N,N-dimethylbenzenesulfonamide
Figure imgf000154_0003
5-chloro-N4-(2-(isopropylsulfony)phenyl)-
N2-(2-isopropoxy-5-(N-
2-(5-chloro-2-(2-isopropoxy-5-methyl-4-(l- methylcarboxamido)-4-(3-methyl-4-(3- methylpiperidin-4-yl)phenylamino) morpholinomethyl)-phenyl)pyrimidine- pyrimidin-4-ylamino)-N-
2,4-diamine cyclobutylbenzamide
Figure imgf000154_0004
5-chloro-N2-(2-isopropoxy-5-methyl-4- azetidin-l-yl(2-(5-chloro-2-(2-isopropoxy-5- (piperidin-3-yl)phenyl)-N4-(2- methyl-4-(l-methylpiperidin-4- (isopropylsulfonyl) phenyl)pyrimidine-2,4- yl)phenylamino) pyrimidin-4- diamine ylamino)phenyl)methanone
Figure imgf000155_0001
5-chloro-N2-(4-((lr,4r)-4-(dimethylamino) cyclohexyl)-2-isopropoxy-5-methylphenyl)- (2-(5-chloro-2-(2-isopropoxy-5-methyl-4- N4-(2-(pyrrolidin-l-ylsulfonyl)phenyl) ( 1 -methylpiperidin-4 - pyrimidine-2,4-diamine yl)phenylamino)pyrimidin-4- ylamino)phenyl)(morpholino)methanone
Figure imgf000155_0002
2-((2-(4-(5-chloro-4-(2- (isopropylsulfonyl)phenylamino)
5-chloro-N2-(4-((ls,4s)-4-(dimethylamino) pyrimidin-2-ylamino)-5-isopropoxy-2- cyclohexyl)-2-isopropoxy-5-methylphenyl)- methylphenyl) propyl)(methyl)amino) N4-(2-(pyrrolidin-l-ylsulfonyl)phenyl) ethanol pyrimidine-2,4-diamine
Figure imgf000155_0003
N2-(4-((lr,4r)-4-(dimethylamino)cyclohexyl)- 5-chloro-N2-(4-((lr,4r)-4-(dimethylamino) 2-isopropoxy-5-methylphenyl)-N4-(2- cyclohexyl)-2-methoxy-5-methylphenyl)- (isopropylsulfonyl) phenyl) -5- N4-(2-(isopropylsulfonyl) methylpyrimidine-2,4-diamine phenyl)pyrimidine-2,4-diamine
Figure imgf000156_0001
N2-(4-((ls,4s)-4-(dimethylamino) 5-chloro-N2-(4-((ls,4s)-4-(dimethylamino) cyclohexyl)-2-isopropoxy-5-methylphenyl)- cyclohexyl)-2-methoxy-5-methylphenyl)- N4-(2-(isopropylsulfonyl) phenyl)-5- N4-(2-(isopropylsulfonyl) methylpyrimidine-2,4-diamine phenyl)pyrimidine-2,4-diamine
2-(5-chlor
Figure imgf000156_0002
o-2-(2-isopropoxy-5-methyl-4- (1- methylpiperidin-4-yl)phenylamino)
N2-(2-isopropoxy-5-methyl-4-(piperidin- pyrimidin-4-ylamino)-N-
4-yl)phenyl)-N4-(2-(isopropylsulfonyl) cyclopropylbenzamide phenyl)-5-methylpyrimidine-2,4,6-triamine
Figure imgf000156_0003
5-(4-(2-(isopropylsulfonyl)phenylamino)-
(2-(5-chloro-2-(2-isopropoxy-5-methyl-4-(l- 5-chloropyrimidin-2-ylamino)-2-chloro-N- methylpiperidin-4-yl)phenylamino) (2-(dimethylamino)ethyl)-4- pyrimidin-4-ylamino)phenyl)(piperidin-l- isopropoxybenzamide yl)methanone
Figure imgf000157_0001
(S)-5-chloro-N2-(2-isopropoxy-5-methyl-4- (piperidin-2-yl)phenyl)-N4-(2- 5-chloro-N2-(4-chloro-2-isopropoxy-5-(3- (isopropylsulfonyl)phenyl)pyrimidine-2,4- methylisoxazol-5-yl)phenyl)-N4-(2- diamine (isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine
Figure imgf000157_0002
(R)-5-chloro-N2-(2-isopropoxy-5-methyl-4- (piperidin-2-yl)phenyl)-N4-(2-
Figure imgf000157_0003
(isopropylsulfonyl)phenyl) pyrimidine-2,4- diamine 6-(4-(2-(isopropylsulfonyl)phenylamino)- 5-chloropyrimidin-2-ylamino)-5- isopropoxy-2-((R)-piperidin-3- yl)isoindolin- 1 -one
Figure imgf000157_0004
(cis, trans) 5-Chloro-N2- { 2-isopropoxy-5- 6-(4-(2-(isopropylsulfonyl)phenylamino)- methyl-4- [4-(4-methyl-piperazin- 1 -yl)- 5-chloropyrimidin-2-ylamino)-5- cyclohexyl]-phenyl}-N4-[2-(propane-2- isopropoxy-2-((S)-piperidin-3- sulfonyl)-phenyl]-pyrimidine-2,4-diamine yl)isoindolin- 1 -one -
Figure imgf000158_0001
5-{5-Chloro-4-[2-(propane-2-sulfonyl)- Ethyl 6-(4-(2- phenylamino] -pyrimidin-2-ylamino } -A- (isopropylsulfonyl)phenylamino)-5- isopropoxy-N-methyl-2-[4-(4-methyl- chloropyrimidin-2-ylamino)-5-isopropoxy- piperazin- 1 -yl)-cyclohex- 1 -enyl] -benzamide 1 -oxoisoindoline-2-carboxylate
Figure imgf000158_0002
4_ [4.(4. { 5-Chloro-4- [2-(propane-2-sulfonyl)-
Figure imgf000158_0003
phenylamino] -pyrimidin-2-ylamino } -5- isopropoxy-2-methyl-phenyl)-cyclohexyl]- 6-(4-(2-(isopropylsulfonyl)phenylamino)- piperazin-2-one 5-chloropyrimidin-2-ylamino)-2- (tetrahydro-2H-pyran-4-yl)-5- isopropoxyisoindolin- 1 -one
Figure imgf000159_0001
5-Chloro-N2-[4-(4-dimethylamino- 6-(4-(2-(isopropylsulfonyl)phenylamino)- cyclohexyl)-2-isopropoxy-5 -methyl-phenyl] - 5-chloro pyrimidin-2-ylamino)-2- N4-[2-(propane-2-sulfonyl)-phenyl]- cyclohexyl-5 -isopropoxy-isoindolin- 1 -one pyrimidine-2,4-diamine
Figure imgf000159_0002
5-Chloro-N2-[2-isopropoxy-5-methyl-4-(4- 6-(4-(2-(isopropylsulfonyl)phenylamino)- methylamino-cyclohexyl)-phenyl]-N4-[2- 5-chloro pyrimidin-2-ylamino)-5- (propane-2-sulfonyl)-phenyl]-pyrimidine-2,4- isopropoxy-2-morpholino-isoindolin- 1 -one diamine
Figure imgf000159_0003
5-(4-(2-(isopropylsulfonyl)phenylamino)-5-
Figure imgf000159_0004
chloropyrimidin-2-ylamino)-4-isopropoxy-N- methyl-2-(2-(4-methylpiperazin- 1 - 6-(4-(2-(isopropylsulfonyl)phenylamino)- yl)ethyl)benzamide 5-chloropyrimidin-2-ylamino)-5- isopropoxy-2-((S)-pyrrolidin-3- yl)isoindolin- 1 -one
Figure imgf000159_0005
3-(4-(6-(4-(2-(isopropylsulfonyl)
5-Chloro-N2-[2-isopropoxy-5-methyl-4-(4- phenylamino)-5-chloropyrimidin-2- pyrrolidin- 1 -yl-cyclohexyl)-phenyl] -N4- [2- ylamino)-5-isopropoxy- 1 -oxoisoindolin-2- (propane-2-sulfonyl)-phenyl]-pyrimidine-2,4- yl)piperidin-l-yl)propanoic acid diamine
Figure imgf000160_0001
5-Chloro-N2-(2-isopropoxy-4-{4-[(2- 6-(4-(2-(isopropylsulfonyl)phenylamino)- methoxy-ethyl)-methyl-amino] -cyclohexyl } - 5-chloropyrimidin-2-ylamino)-5- 5-methyl-phenyl)-N4-[2-(propane-2- isopropoxy-2-((R)-pyrrolidin-3- sulfonyl)-phenyl]-pyrimidine-2,4-diamine yl)isoindolin- 1 -one
Figure imgf000160_0002
5-{5-Chloro-4-[2-(propane-2-sulfonyl)- 2-[4-(6-{5-Chloro-4-[2-(propane-2- phenylamino] -pyrimidin-2-ylamino } -A- sulfonyl)-phenyl-amino]-pyrimidin-2- isopropoxy-N-methyl-2-[3-(4-methyl- ylamino } -5 -isopropoxy- 1 -oxo- 1 , 3 - piperazin-l-yl)-propyl]-benzamide dihydro-isoindol-2-yl)-piperidin- 1 -yl] - acetamide
Figure imgf000160_0003
5-chloro-N2-(4-((ls,4s)-4-(dimethylamino)
Figure imgf000160_0004
cyclohexyl)-2-isopropoxy-5-methylphenyl)- 6-(4-(2-(isopropylsulfonyl)phenylamino)- N4-(2-(isopropylsulfonyl)phenyl)pyrimidine- 5-chloropyrimidin-2-ylamino)-2-acetyl-5- 2,4-diamine isopropoxyisoindolin- 1 -one
Figure imgf000160_0005
5-chloro-N2-(2-isopropoxy-5-methyl-4-
Figure imgf000160_0006
(piperidin-2-yl)phenyl)-N4-(2- (isopropylsulfonyl)phenyl)pyrimidine-2,4- 6-(4-(2-(isopropylsulfonyl)phenylamino)- diamine 5-chloropyrimidin-2-ylamino)-2-(2- hydroxyethyl)-5-isopropoxyisoindolin-l- one
Figure imgf000161_0001
5-chloro-N2-(2-isopropoxy-4-methyl-5-
Figure imgf000161_0002
(piperidin-4-yl)phenyl)-N4-(2- (isopropylsulfonyl)phenyl) pyrimidine-2,4- (2S,4S)-methyl 4-(6-(4-(2- diamine (isopropylsulfonyl) phenylamino)-5- chloropyrimidin-2-ylamino)-5-isopropoxy- l-oxoisoindolin-2-yl)pyrrolidine-2- carboxylate
Figure imgf000161_0003
5-chloro-N2-(2-isopropoxy-4-methyl-5-
Figure imgf000161_0004
(piperidin-4-yl)phenyl)-N4- (2(morpholinosulfonamido) 2-(6-(4-(2-(isopropylsulfonyl) phenyl)pyrimidine-2,4-diamine phenylamino)-5-chloropyrimidin-2- ylamino)-5-isopropoxy- 1 -oxoisoindolin-2- yl) acetic acid
Figure imgf000161_0005
2-(2-(2-isopropoxy-4-methyl-5-(piperidin-4- yl)phenylamino) -5 -chloropyrimidin-4 - (2S,4R)-methyl 4-(6-(4-(2- ylamino) -N-isopropylbenzamide (isopropylsulfonyl) phenylamino)-5- chloropyrimidin-2-ylamino)-5-isopropoxy- l-oxoisoindolin-2-yl)pyrrolidine-2- carboxylate
Figure imgf000162_0001
5-chloro-N2-(4-((lr,4r)-4-(dimethylamino)
Figure imgf000162_0002
cyclohexyl)-2-isopropoxy-5-methylphenyl)- N4-(2-(isopropylsulfonyl)phenyl)pyrimidine- 4-(6-{5-Chloro-4-[2-(propane-2-sulfonyl)- 2,4-diamine phenylamino]-pyrimidin-2-ylamino}-5- isopropoxy- 1 -oxo- 1 ,3-dihydro-isoindol-2- yl)-piperidine-l-carboxylic acid dimethylamide
Figure imgf000162_0003
5-chloro-N2-(2-isopropoxy-5-methyl-4-
Figure imgf000162_0004
(( 1 s,4s)-4-(4-methylpiperazin- 1 - yl)cyclohexyl)phenyl)-N4-(2- (2S,4S)-4-(6-(4-(2-(isopropylsulfonyl) (isopropylsulfonyl)phenyl)pyrimidine-2,4- phenylamino)-5-chloropyrimidin-2- diamine ylamino)-5-isopropoxy- 1 -oxoisoindolin-2- yl)pyrrolidine-2-carboxylic acid
Figure imgf000162_0005
5-chloro-N2-(2-isopropoxy-5-methyl-4-
Figure imgf000162_0006
((lr,4r)-4-(4-methylpiperazin-l- yl)cyclohexyl)phenyl)-N4-(2- (2S,4R)-4-(6-(4-(2-(isopropylsulfonyl)
(isopropylsulfonyl)phenyl)pyrimidine-2,4- phenylamino)-5-chloropyrimidin-2- diamine ylamino)-5-isopropoxy- 1 -oxoisoindolin-2- yl)pyrrolidine-2-carboxylic acid
Figure imgf000163_0001
5-Methyl-N2-[4-methyl-5-(l-methyl-lH- pyrazol-4-yl)-2-(piperidin-4-yloxy)-phenyl]- 6-(4-(2-(isopropylsulfonyl)phenylamino)- N4-[2-(propane-2-sulfonyl)-phenyl]- 5-chloropyrimidin-2-ylamino)-2- pyrimidine-2,4-diamine ((azetidin-3-yl)methyl)-5- isopropoxyisoindolin- 1 -one
Figure imgf000163_0002
l-(5-{5-Chloro-4-[2-(propane-2-sulfonyl)- phenylamino] -pyrimidin-2-ylamino } -A-
Figure imgf000163_0003
isopropoxy-2-methyl-phenyl)-ethanone 6-(4-(2-(isopropylsulfonyl)phenylamino)- 5-chloropyrimidin-2-ylamino)-5- isopropoxy-2-((S)-quinuclidin-3- yl)isoindolin- 1 -one
Figure imgf000163_0004
6-{5-Chloro-4-[2-(propane-2-sulfonyl)-
Figure imgf000163_0005
phenylamino]-pyrimidin-2-ylamino}-5-
N2- { 2-Isopropoxy-4-methyl-5- [ 1 -(2- isopropoxy-2-(8-methyl-8-aza- morpholin-4-yl-ethyl)-lH-pyrazol-4-yl]- bicyclo[3.2.1]oct-6-yl)-2,3-dihydro- phenyl}-5-methyl-N4-[2-(propane-2- isoindol- 1 -one sulfonyl)-phenyl]-pyrimidine-2,4-diamine
Figure imgf000164_0001
N2-(5-(6-(3-(dimethylamino)propoxy)
Figure imgf000164_0002
pyridin-3-yl)-2-isopropoxy-4-methylphenyl)- N4-(2-(isopropyl sulfonyl)phenyl)-5- 4-(6-(4-(2-(isopropylsulfonyl) methylpyrimidine-2,4-diamine phenylamino)-5-chloropyrimidin-2- ylamino)-5-isopropoxy- 1 -oxoisoindolin-2- yl)-N-ethylpiperidine-l-carboxamide
Figure imgf000164_0003
N2-(2-isopropoxy-4-methyl-5-(6-(4- methylpiperazin-l-yl)pyridin-3-yl)phenyl)- 4-(6-(4-(2-(isopropylsulfonyl) N4-(2-(isopropylsulfonyl) phenyl)-5- phenylamino)-5-chloropyrimidin-2- methylpyrimidine-2,4-diamine ylamino)-5-isopropoxy- 1 -oxoisoindolin-2- yl)piperidine- 1 -carboxamide
Figure imgf000164_0004
N2-(2-isopropoxy-4-methyl-5-(6- 6-(4-(2-(isopropylsulfonyl)phenylamino)- morpholinopyridin-3-yl)phenyl)-N4-(2- 5-chloropyrimidin-2-ylamino)-5- (isopropylsulf onyl)phenyl) -5 - fluoroisoindolin- 1 -one methylpyrimidine-2,4-diamine
Figure imgf000165_0001
6-(4-(2-(isopropylsulfonyl)phenylamino)-
N2-(2-isopropoxy-4-methyl-5-(6-(piperazin- 5 -methylpyrimidin-2 -ylamino) -5 - l-yl)pyridin-3-yl)phenyl)-N4-(2- fluoroisoindolin- 1 -one (isopropylsulfonyl) phenyl) -5- methylpyrimidine-2,4-diamine
Figure imgf000165_0002
N2-(5-(6-(2-morpholinoethylamino) pyridin- 3-yl)-2-isopropoxy-4-methylphenyl)-N4-(2-
Figure imgf000165_0003
(isopropyl-sulfonyl)phenyl)-5- methylpyrimidine-2,4-diamine Ethyl 7-(4-(2-(isopropylsulfonyl) phenylamino)-5-methylpyrimidin-2- ylamino)- 1 ,4-dihydro-6- isopropoxyindeno[l,2-c]pyrazole-3- carboxylate
Figure imgf000165_0004
N2-(2-isopropoxy-4-methyl-5-(2-(4- methylpiperazin- 1 -yl)pyridin-4-yl)phenyl)-
Figure imgf000165_0005
N4-(2-(isopropylsulfonyl) phenyl)-5- methylpyrimidine-2,4-diamine (7-(4-(2-(isopropylsulfonyl)phenylamino)- 5 -methylpyrimidin-2 -ylamino) -1,4- dihydro-6-isopropoxyindeno[l ,2- c]pyrazol-3-yl)methanol
164
Figure imgf000166_0001
5-chloro-N2-(2-isopropoxy-5-methyl-4- ((ls,4s)-4-(methylamino)cyclohexyl) phenyl)-
Figure imgf000166_0002
N4-(2-(isopropylsulfonyl) phenyl)pyrimidine- 2,4-diamine Ethyl 7-(4-(2-(isopropylsulfonyl) phenylamino)-5-chloropyrimidin-2- ylamino)- 1 ,4-dihydro-6- isopropoxyindeno[l,2-c]pyrazole-3- carboxylate
Figure imgf000166_0003
5-chloro-N2-(2-isopropoxy-5-methyl-4-
Figure imgf000166_0004
((lr,4r)-4-(methylamino)cyclohexyl) phenyl)- N4-(2-(isopropylsulfonyl)phenyl) pyrimidine- N2-(l,4-dihydro-6-isopropoxy-3-((4- 2,4-diamine methylpiperazin- 1 -yl)methyl)indeno [1,2- c]pyrazol-7-yl)-N4-(2- (isopropylsulfonyl)phenyl)-5 - methylpyrimidine-2,4-diamine
Figure imgf000166_0005
5-chloro-N2-(2-isopropoxy-4-methyl-5-(3- methylisoxazol-5-yl)phenyl)-N4-(2-
Figure imgf000166_0006
(isopropylsulfonyl)phenyl)pyrimidine-2,4- N2-( 1 ,4-dihydro-6-isopropoxy-3- diamine (morpholinomethyl) indeno[ 1 ,2-c]pyrazol- 7-yl)-N4-(2-(isopropylsulfonyl) phenyl)-5- methylpyrimidine-2,4-diamine
Figure imgf000167_0001
2-(5-chloro-2-(2-isopropoxy-4-methyl-5-(3- methylisoxazol-5-yl)phenylamino)pyrimidin-
Figure imgf000167_0002
4-ylamino)-N,N-dimethylbenzenesulfonamide
N2-(3-((4-aminopiperidin- 1 -yl)methyl)- l,4-dihydro-6-isopropoxyindeno[l,2- c]pyrazol-7-yl)-N4-(2- (isopropylsulfonyl)phenyl)-5 - methylpyrimidine-2,4-diamine
Figure imgf000167_0003
5-chloro-N2-(2-isopropoxy-4-methyl-5-(5- methyl-lH-pyrazol-3-yl)phenyl)-N4-(2-
Figure imgf000167_0004
(isopropylsulfonyl) phenyl)pyrimidine-2,4- diamine N2-( 1 ,4-dihydro-6-isopropoxy-3- ((piperidin-4-ylamino)methyl)indeno [ 1 ,2- c]pyrazol-7-yl)-N4-(2- (isopropylsulfonyl)phenyl)-5 - methylpyrimidine-2,4-diamine
Figure imgf000167_0005
5-chloro-N2-(2-isopropoxy-4-methyl-5-(lH- pyrazol-3-yl)phenyl)-N4-(2- 6-(4-(2-(isopropylsulfonyl)phenylamino)- (isopropylsulfonyl) phenyl)pyrimidine-2,4- 5-chloropyrimidin-2-ylamino)-2,3- diamine dihydro-5-isopropoxyinden- 1 -one
Figure imgf000168_0001
6-(4-(2-(isopropylsulfonyl)phenylamino)-
2-(5-chloro-2-(2-isopropoxy-5-(isoxazol-5- 5 -methylpyrimidin-2 -ylamino) -2,3- yl) -4 - methylpheny lamino )pyrimidin-4 - dihydro-5-isopropoxyinden- 1 -one ylamino)-N,N-dimethylbenzenesulfonamide
Figure imgf000168_0002
6-(4-(2-(isopropylsulfonyl)phenylamino)-
2-(5-chloro-2-(2-isopropoxy-4-methyl-5-(2- 5-methyl pyrimidin-2-ylamino)-2,3- methyl-lH-imidazol-4-yl) dihydro-5-isopropoxy- 1 H-inden- 1 -ol phenylamino)pyrimidin-4-ylamino)-N,N- dimethylbenzenesulfonamide
Figure imgf000168_0003
5-chloro-N2-(2-isopropoxy-4-methyl-5-(2- methyl-lH-imidazol-4-yl)phenyl)-N4-(2- 4-(6-{5-Chloro-4-[2-(propane-2-sulfonyl)- (isopropylsulfonyl) phenyl)pyrimidine-2,4- phenylamino] -pyrimidin-2-ylamino } -5- diamine isopropoxy- 1 -oxo- 1 ,3-dihydro -isoindol-2- yl)-piperidine-l-carboxylic acid ethyl ester
Figure imgf000168_0004
(5-(5-(4-(2-(isopropylsulfonyl) phenylamino)-
Figure imgf000168_0005
5-methylpyrimidin-2-ylamino)-4-isopropoxy- 5-{5-Chloro-4-[2-(propane-2-sulfonyl)- 2-methylphenyl)isoxazol-3-yl)methanol phenylamino] -pyrimidin-2-ylamino } -6- isopropoxy-2-(l-methyl-piperidin-4-yl)- isoindole-1 ,3-dione
Figure imgf000169_0001
N2-(2-isopropoxy-4-methyl-5-(3-((piperazin- (2S, 4^-4-(6-{5-Chloro-4-[2-(propane-2- l-yl)methyl)isoxazol-5-yl)phenyl)-N4-(2- sulfonyl)-phenylamino]-pyrimidin-2- (isopropyl-sulfonyl)phenyl)-5- ylamino } -5 -isopropoxy- 1 -oxo- 1 , 3 - methylpyrimidine-2,4-diamine dihydro-isoindol-2-yl)-pyrrolidine-2- carboxylic acid amide
Figure imgf000169_0002
N2-(5-(3-((diethylamino)methyl) isoxazol-5- 6-{5-Chloro-4-[2-(propane-2-sulfonyl)- yl)-2-isopropoxy-4-methylphenyl)-N4-(2- phenylamino]-pyrimidin-2-ylamino}-5- (isopropyl-sulfonyl)phenyl)-5- isopropoxy-2-piperidin-4-yl-2,3-dihydro- methylpyrimidine-2,4-diamine isoindol- 1 -one
Figure imgf000169_0003
N2-(2-isopropoxy-4-methyl-5-(3-((4-(2- morpholinoethyl)piperazin- 1 - 6-(4-(2-(isopropylsulfonyl)phenylamino)- yl)methyl)isoxazol-5-yl)phenyl)-N4-(2- 5-chloropyrimidin-2-ylamino)-5- (isopropylsulf onyl)phenyl) -5 - isopropoxy-2-(l-isopropylpiperidin-4- methylpyrimidine-2,4-diamine yl)isoindolin- 1 -one
Figure imgf000170_0001
6-(4-(2-(isopropylsulfonyl)phenylamino)- 5-chloropyrimidin-2-ylamino)-5-
Figure imgf000170_0002
isopropoxy-2-(2-(4-(piperidin-l-
5-(5-(4-(2-(isopropylsulfonyl) phenylamino)- yl)piperidin- 1 -yl)ethyl)isoindolin- 1 -one 5-chloropyrimidin-2-ylamino)-4-isopropoxy- 2-methylphenyl)-N-(2- morpholinoethyl)isoxazole-3-carboxamide
Figure imgf000170_0003
6-{5-Chloro-4-[2-(propane-2-sulfonyl)-
(5-(5-(4-(2-(isopropylsulfonyl) phenylamino)- phenylamino]-pyrimidin-2-ylamino}-5- 5-chloropyrimidin-2-ylamino)-4-isopropoxy- isopropoxy-2-(l-methyl-piperidin-4-yl)- 2-methylphenyl)isoxazol-3-yl)(4- 2,3-dihydro-isoindol- 1 -one ethylpiperazin- 1 -yl)methanone
Figure imgf000170_0004
Figure imgf000170_0005
6-(4-(2-(isopropylsulfonyl)phenylamino)- 5-chloro pyrimidin-2-ylamino)-2-(l -(2-
5-(5-(4-(2-(isopropylsulfonyl)phenylamino)- (dimethylamino)ethyl) piperidin-4-yl)-5- 5-chloropyrimidin-2-ylamino)-4-isopropoxy- isopropoxyisoindolin- 1 -one 2-methylphenyl)-N-methoxyisoxazole-3- carboxamide
Figure imgf000171_0001
5-Chloro-N2-(2-isopropoxy-5-methyl-4-
Figure imgf000171_0002
morpholin-4-ylmethyl-phenyl)-N4-[2- (propane-2-sulfonyl)-phenyl]-pyrimidine-2,4- 6-(4-(2-(isopropylsulfonyl)phenylamino)- diamine 5-chloropyrimidin-2-ylamino)-5- isopropoxy-2-( 1 -(2-(pyrrolidin- 1 - yl)ethyl)piperidin-4-yl)isoindolin- 1 -one
Figure imgf000171_0003
N2-(4-(lH-benzo[d]imidazol-2-yl)-2-
6-(4-(2-(isopropylsulfonyl)phenylamino)- isopropoxy-5-methylphenyl)-5-chloro-N4-(2- 5-chloropyrimidin-2-ylamino)-5- (isopropylsulfonyl) phenyl)pyrimidine-2,4- isopropoxy-2-methylisoindolin- 1 -one diamine
Figure imgf000171_0004
5-(4-(2-(isopropylsulfonyl)phenylamino)-5-
Figure imgf000171_0005
chloropyrimidin-2-ylamino)-4-isopropoxy-N- methyl-2-((pyrrolidin- 1 -yl)methyl)benzamide 8-(5-chloro-4-(2-(isopropylsulfonyl) phenylamino) pyrimidin-2-ylamino)-9- isopropoxy-3-methyl-l,2,3,4- tetrahydrobenzo [c] [ 1 ,7]naphthyridin- 6(5H)-one
Figure imgf000171_0006
5-(4-(2-(isopropylsulfonyl)phenylamino)-5-
Figure imgf000171_0007
chloropyrimidin-2-ylamino)-4-isopropoxy-N- methyl-2-(piperidin-4-yl)benzamide (S)-6-(5-chloro-4-(2-(isopropylsulfonyl) phenylamino) pyrimidin-2-ylamino)-2-(l- (2-hydroxyethyl)piperidin-3-yl)-5- isopropoxyisoindolin- 1 -one
Figure imgf000172_0001
5-(4-(2-(isopropylsulfonyl)phenylamino)-5-
Figure imgf000172_0002
chloropyrimidin-2-ylamino)-4-isopropoxy-N- methyl-2-(morpholinomethyl)benzamide (R)-6-(5-chloro-4-(2- (isopropylsulfonyl)phenylamino) pyrimidin-2-ylamino)-2-(l-(2- hydroxyethyl)piperidin-3 -yl) -5 - isopropoxyisoindolin- 1 -one
Figure imgf000172_0003
4-(4-(2-(isopropylsulfonyl)phenylamino)-5- chloropyrimidin-2-ylamino)-5-isopropoxy-2- methylbenzoic acid
Figure imgf000172_0004
6-(5-chloro-4-(2-(isopropylsulfonyl) phenylamino) pyrimidin-2-ylamino)-5- isopropoxy-2-(l,2,2,6,6-pentamethyl piperidin-4-yl)isoindolin- 1 -one
Figure imgf000172_0005
5-chloro-N2-(2-isopropoxy-5-methyl-4-
(piperidin-4-yl)phenyl)-N4-[2-(propane-2- sulfonyl)-phenyl]-pyrimidine-2,4-diamine
Figure imgf000172_0006
(2S,4S)-4-(6-(5-chloro-4-(2- (isopropylsulfonyl) phenylamino) pyrimidin-2-ylamino)-5-isopropoxy- 1 - oxoisoindolin-2-yl)- 1 -methylpyrrolidine-2- carboxamide
Figure imgf000173_0001
5-chloro-N2-(2-isopropoxy-5-methyl-4-(l- methylpiperidin-4-yl)phenyl)-N4-[2- (propane-2-sulfonyl)phenyl]-pyrimidine-2,4- diamine
Figure imgf000173_0002
5-(5-chloro-4-(2-(isopropylsulfonyl) phenylamino) pyrimidin-2-ylamino)-2-(l- (2-hydroxyethyl)piperidin-4-yl)-6- isopropoxyisoindoline- 1 , 3 -dione
Figure imgf000173_0003
(4-(4-(2-(isopropylsulfonyl) phenylamino) -5- chloropyrimidin-2-ylamino)-5-isopropoxy-2- methylphenyl)(4-methylpiperazin- 1 - yl)methanone
Figure imgf000173_0004
2-(4-(5-(5-chloro-4-(2-(isopropylsulfonyl) phenylamino) pyrimidin-2-ylamino)-6- isopropoxy-l,3-dioxoisoindolin-2- yl)piperidin- 1 -yl)acetamide
Figure imgf000173_0005
5-chloro-N2-(2-isopropoxy-5-methyl-4-(l-(l- methylpiperidin-4-yl)piperidin-4-yl)phenyl)- N4-(2-(isopropylsulfonyl) phenyl)pyrimidine- 2,4-diamine
Figure imgf000173_0006
3-(4-(5-(5-chloro-4-(2-(isopropylsulfonyl) phenylamino)pyrimidin-2-ylamino)-6- isopropoxy-l,3-dioxoisoindolin-2- yl)piperidin- 1 -yl)propanenitrile
Figure imgf000174_0001
5-chloro-N2-(2-isopropoxy-5-methyl-4-(6-(4- methylpiperazin-l-yl)pyridin-3-yl)phenyl)-
Figure imgf000174_0002
N4-(2-(isopropylsulfonyl) phenyl)pyrimidine- 2,4-diamine
(S)-5-(5-chloro-4-(2-(isopropylsulfonyl) phenylamino) pyrimidin-2-ylamino)-6- isopropoxy-2-(l-methylpyrrolidin-3- yl)isoindoline- 1 ,3-dione
Figure imgf000174_0003
5-chloro-N2-(2-cyclobutoxy-5-methyl-4- (piperidin-4-yl)phenyl)-N4-(2- (isopropylsulfonyl)phenyl)pyrimidine-2,4-
Figure imgf000174_0004
diamine
(S)-5-(5-chloro-4-(2-(isopropylsulfonyl) phenylamino) pyrimidin-2-ylamino)-2-(l- (2-hydroxyethyl)pyrrolidin-3-yl)-6- isopropoxyisoindoline- 1 , 3 -dione
Figure imgf000174_0005
2- [4-(4- { 5-Chloro-4- [2-(propane-2-sulfonyl)-
Figure imgf000174_0006
phenylamino] -pyrimidin-2-ylamino } -5- isopropoxy-2-methyl-phenyl)-piperidin- 1 -yl] - (S)-5-(5-chloro-4-(2-(isopropylsulfonyl) ethanol phenylamino) pyrimidin-2-ylamino)-6- isopropoxy-2-(l-methylpyrrolidin-3- yl)isoindoline- 1 ,3-dione
Figure imgf000175_0001
5-chloro-N2-(2-isopropoxy-4-(l-(2- methoxyethyl)piperidin-4-yl)-5-
Figure imgf000175_0002
methylphenyl)-N4-(2-(isopropylsulfonyl)
6-(4-(2-(isopropylsulfonyl)phenylamino)- phenyl)pyrimidine-2,4-diamine 5-chloropyrimidin-2-ylamino)-5- isopropoxy-2-(l-methylpiperidin-4- yl)isoindolin- 1 -one
Figure imgf000175_0003
N2-(2-isopropoxy-5-methyl-4-(l- methylpiperidin-4-yl)phenyl)-N4-(2- 6-(4-(2-(isopropylsulfonyl)phenylamino)- (isopropylsulf onyl)phenyl) -5 - 5-chloropyrimidin-2-ylamino)-5- methylpyrimidine-2,4-diamine isopropoxy-2-((6S,7R)-9-methyl-9-aza- bicyclo[4.2.1]nonan-7-yl)isoindolin-l-one
Figure imgf000175_0004
4-{5-Chloro-4-[2-(propane-2-sulfonyl)-
5-chloro-N2-(2-isopropoxy-5-methyl-4-(l- phenylamino] -pyrimidin-2-ylamino } -6- methylpiperidin-4-yl)phenyl)-N4-(2- methyl-quinoline-2-carboxylic acid amide (propylsulfonyl)phenyl)pyrimidine-2,4- diamine
Figure imgf000175_0005
2-(5-chloro-2-(2-isopropoxy-5-methyl-4-(l-
4-{5-Chloro-4-[2-(propane-2-sulfonyl)- methylpiperidin-4-yl)phenylamino) phenylamino] -pyrimidin-2-ylamino } -6- pyrimidin-4-ylamino)-N,N- methyl-quinoline-2-carboxylic acid dimethylbenzenesulfonamide methylamide
Figure imgf000176_0001
5-chloro-N2-(2-isopropoxy-5-methyl-4-(l- methylpiperidin-4-yl)phenyl)-N4-(2- 4-{5-Chloro-4-[2-(propane-2-sulfonyl)- (pyrrolidin- 1 -ylsulfonyl)phenyl) pyrimidine- phenylamino] -pyrimidin-2-ylamino } - 2,4-diamine quinoline-2-carboxylic acid (2-morpholin- 4-yl-ethyl)-amide
Figure imgf000176_0002
5-chloro-N4-(2-
(cyclobutylaminosulfonyl)phenyl)-N2-(2- 4-{5-Chloro-4-[2-(propane-2-sulfonyl)- isopropoxy-5-methyl-4-( 1 -methylpiperidin-4- phenylamino] -pyrimidin-2-ylamino } - yl)phenyl)pyrimidine-2,4-diamine quinoline-2-carboxylic acid [2-(4-methyl- piperazin- 1 -yl)-ethyl] -amide
Figure imgf000176_0003
2-(2-(2-isopropoxy-5-methyl-4-(l-
4-{5-Chloro-4-[2-(propane-2-sulfonyl)- methylpiperidin-4-yl)phenylamino)-5- phenylamino] -pyrimidin-2-ylamino } - chloropyrimidin-4-ylamino)-N,N- quinoline-2-carboxylic acid piperidin-4- dimethylbenzamide ylamide
Figure imgf000176_0004
2-(2-(2-isopropoxy-5-methyl-4-(l- methylpiperidin-4-yl)phenylamino)-5- N2-(2-isopropoxy-5-methyl-4-(piperidin- chloropyrimidin-4-ylamino) benzamide 4-yl)phenyl)-N4-(2-
(methylsulfonyl)phenyl)-7H-pyrrolo[2,3- d]pyrimidine-2,4-diamine
Figure imgf000177_0001
5-chloro-N2-(2-isopropoxy-5-methyl-4-(l- methylpiperidin-4-yl)phenyl)-N4-(2- (aminosulfonyl)phenyl)pyrimidine-2,4-
Figure imgf000177_0002
diamine
N2-(4-(l-ethylpiperidin-4-yl)-2- isopropoxy-5-methylphenyl)-N4-(2- (isopropylsulfonyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidine-2,4-diamine
Figure imgf000177_0003
5-chloro-N2-(2-isopropoxy-5-methyl-4-(l- methylpiperidin-4-yl)phenyl)-N4-(2-
Figure imgf000177_0004
(methylsulfonyl)phenyl)pyrimidine-2,4- diamine 2-(4-(5-isopropoxy-4-(4-(2- (isopropylsulfonyl) phenylamino)-7H- pyrrolo[2,3-d]pyrimidin-2-ylamino)-2- methylphenyl)piperidin- 1 -yl)propan- 1 -
Figure imgf000177_0005
5-chloro-N2-(2-fluoro-5-methyl-4-(l- methylpiperidin-4-yl)phenyl)-N4-(2- (aminosulfonyl)phenyl)pyrimidine-2,4- diamine
Figure imgf000177_0006
N2-(2-isopropoxy-4-(l-isopropylpiperidin- 4-yl)-5-methylphenyl)-N4-(2- (isopropylsulfonyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidine-2,4-diamine
Figure imgf000178_0001
5-chloro-N4-(2-(cyclobutylsulfonyl)phenyl)- N2-(2-isopropoxy-5-methyl-4-(l-
Figure imgf000178_0002
methylpiperidin-4-yl)phenyl)pyrimidine-2,4- diamine 2-(4-(5-isopropoxy-4-(4-(2- (isopropylsulfonyl) phenylamino)-7H- pyrrolo[2,3-d]pyrimidin-2-ylamino)-2- methylphenyl)piperidin- 1 -yl)ethanol
Figure imgf000178_0003
5-chloro-N4-(2-(isopropylsulfonyl) phenyl)-
N2-(2-methoxy-5-methyl-4-phenyl)- phenyl)pyrimidine-2,4-diamine
Figure imgf000178_0004
N2-(2-isopropoxy-5-methyl-4-(l'-methyl- l,4'-bipiperidin-4-yl)phenyl)-N4-(2- (isopropylsulfonyl) phenyl)-7H- pyrrolo[2,3-d]pyrimidine-2,4-diamine
Figure imgf000178_0005
5-chloro-N4-(2-cyanophenyl)-N2-(2- methoxy-5 -methyl-4-phenyl) - phenyl)pyrimidine-2,4-diamine
Figure imgf000178_0006
N2-(2-isopropoxy-5-methyl-4-(l- methylpiperidin-4-yl)phenyl)-N6-(2- (isopropylsulfonyl)phenyl)-9H-purine-2,6- diamine
Figure imgf000179_0001
2-(5-chloro-2-(5-methoxy-2-methylbiphenyl-
4-ylamino)pyrimidin-4-ylamino)-N,N- dimethylbenzenesulfonamide
Figure imgf000179_0002
N2-(2-isopropoxy-5-methyl-4-(l- methylpiperidin-4-yl)phenyl)-N4-(2- (isopropylsulfonyl)phenyl)quinazoline-2,4- diamine
Figure imgf000179_0003
5-chloro-N4-(2-(isopropylsulfonyl) phenyl)- N2-(2-methoxy-5-methyl-4-(4- methylphenyl) -pheny l)p yrimidine -2,4-
Figure imgf000179_0004
diamine
N2-(2-isopropoxy-5-methyl-4-(l- methylpiperidin-4-yl)phenyl)-N4-(2- (isopropylsulfonyl)phenyl)-6- methoxyquinazoline-2,4-diamine
Figure imgf000179_0005
5-chloro-N4-(2-(isopropylsulfonyl) phenyl)-
N2-(2-methoxy-5-methyl-4-(4-fluorophenyl)- phenyl)pyrimidine-2,4-diamine
Figure imgf000179_0006
N2-(2-isopropoxy-5-methyl-4-(l- methylpiperidin-4-yl)phenyl)-N4-(2- (isopropylsulfonyl)phenyl)-6,7- dimethoxyquinazoline-2,4-diamine
Figure imgf000180_0001
5-chloro-N4-(2-(isopropylsulfonyl) phenyl)- N2-(2-methoxy-5-methyl-4-(2,4-
Figure imgf000180_0002
difluorophenyl)-phenyl)pyrimidine-2,4- diamine 5-isopropoxy-6-(4-(2-(isopropylsulfonyl) phenylamino)-7H-pyrrolo[2,3-d]pyrimidin- 2-ylamino)-2-(piperidin-4-yl)isoindolin- 1 - one
Figure imgf000180_0003
2-(5-chloro-2-(4'-(dimethylamino)-5- methoxy-2,3'-dimethylbiphenyl-4- ylamino)pyrimidin-4-ylamino)-N,N- dimethylbenzenesulfonamide
Figure imgf000180_0004
N2-(4-(4-(dimethylamino)cyclohexyl)-2- isopropoxy-5-methylphenyl)-N6-(2- (isopropylsulfonyl)phenyl)-9H-purine-2,6- diamine
Figure imgf000180_0005
5-chloro-N2-(2-isopropoxy-5-methyl-4- (( 1 s,4s)-4-(pyrrolidin- 1 - N2-(2-isopropoxy-4-methyl-5-(3- yl)cyclohexyl)phenyl)-N4-(2- methylisoxazol-5-yl)phenyl)-N4-(2- (isopropylsulfonyl)phenyl)pyrimidine-2,4- (isopropylsulfonyl)phenyl)-7H- diamine pyrrolo[2,3-d]pyrimidine-2,4-diamine
Figure imgf000181_0001
2-(5-chloro-2-(5-methoxy-2-methyl-4'- morpholinobiphenyl-4-ylamino) pyrimidin-4-
Figure imgf000181_0002
ylamino)-N,N-dimethylbenzenesulfonamide
N2-(2-isopropoxy-5-methyl-4-(piperidin- 2-yl)phenyl)-N4-(2-(isopropylsulfonyl) phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4- diamine
Figure imgf000181_0003
2-(5-chloro-2-(5-methoxy-2-methyl-4'- (methylsulfonyl)biphenyl-4-
Figure imgf000181_0004
ylamino)pyrimidin-4-ylamino)-N,N- dimethylbenzenesulfonamide N2-(2-isopropoxy-4-(l-(2- methoxyethyl)piperidin-4-yl) -5 - methylphenyl)-N4-(2-(isopropylsulfonyl) phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4- diamine
Figure imgf000181_0005
4'-(5-chloro-4-(2-(N,N-dimethylsulfamoyl) phenylamino) pyrimidin-2-ylamino)-5'- methoxy-2'-methylbiphenyl-4-carboxamide
Figure imgf000181_0006
3-(4-(5-isopropoxy-4-(4-(2- (isopropylsulfonyl) phenylamino)-7H- pyrrolo[2,3-d]pyrimidin-2-ylamino)-2- methylphenyl)piperidin- 1 -yl)propan- 1 -ol
Figure imgf000182_0001
2-(2-(4'-acetyl-5-methoxy-2-methylbiphenyl-
4-ylamino)-5-chloropyrimidin-4-ylamino)-
N,N-dimethylbenzenesulfonamide
Figure imgf000182_0002
2-(4-(5-isopropoxy-4-(4-(2- (isopropylsulfonyl) phenylamino)-7H- pyrrolo[2,3-d]pyrimidin-2-ylamino)-2- methylphenyl)piperidin- 1 -yl) acetic acid
Figure imgf000182_0003
4'-(5-chloro-4-(2-(N,N-dimethylsulfamoyl) phenylamino) pyrimidin-2-ylamino)-5'-
3-(4-(5-isopropoxy-4-(4-(2- methoxy-N,2'-dimethylbiphenyl-4- (isopropylsulfonyl) phenylamino)-7H- carboxamide pyrrolo[2,3-d]pyrimidin-2-ylamino)-2- methylphenyl)piperidin- 1 -yl)propanoic acid
Figure imgf000182_0004
4'-(5-chloro-4-(2-(N,N-dimethylsulfamoyl) phenylamino) pyrimidin-2-ylamino)-5'- methoxy-2'-methylbiphenyl-4-carboxylic acid
Figure imgf000182_0005
2-(4-(5-isopropoxy-4-(4-(2- (isopropylsulfonyl) phenylamino)-7H- pyrrolo[2,3-d]pyrimidin-2-ylamino)-2- methylphenyl)piperidin- 1 -yl)acetamide
Figure imgf000183_0001
2-(5-chloro-2-(2-methoxy-5-methyl-4-
(pyridin-4-yl)phenylamino)pyrimidin-4-
Figure imgf000183_0002
ylamino)-N,N-dimethylbenzenesulfonamide
3-(4-(5-isopropoxy-4-(4-(2- (isopropylsulfonyl) phenylamino)-7H- pyrrolo[2,3-d]pyrimidin-2-ylamino)-2- methylphenyl)piperidin- 1 -yl)propanamide
Figure imgf000183_0003
2-(5-chloro-2-(2-isopropoxy-5-methyl-4-
(pyridin-4-yl)phenylamino)pyrimidin-4-
Figure imgf000183_0004
ylamino)-N,N-dimethylbenzenesulfonamide
4-(5 -isopropoxy-4-(4-(2- (isopropylsulfonyl) phenylamino)-7H- pyrrolo[2,3-d]pyrimidin-2-ylamino)-2- methylphenyl)-N,N-dimethylpiperidine-l- carboxamide
Figure imgf000183_0005
2-(5-chloro-2-(5-methyl-2-(l- methylpiperidin-4-yloxy)-4-(pyridin-4- yl)phenylamino)pyrimidin-4-ylamino)-N,N- N2-(2-isopropoxy-5-methyl-4-(piperidin- dimethylbenzenesulfonamide 3-yl)phenyl)-N4-(2- (isopropylsulfonyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidine-2,4-diamine
Figure imgf000184_0001
5-(5-chloro-4-(2-(N,N-dimethylsulfamoyl) phenylamino) pyrimidin-2-ylamino)-4- N2-(2-isopropoxy-5-methyl-4-(l- isopropoxy-N-methyl-2-(pyridin-4- methylpiperidin-3-yl)phenyl)-N4-(2- yl)benzamide (isopropylsulfonyl)phenyl)-7H- pyrrolo[2,3-d]pyrimidine-2,4-diamine
Figure imgf000184_0002
5-(5-chloro-4-(2-(N,N-dimethylsulfamoyl) 2-(3-(5-isopropoxy-4-(4-(2- phenylamino) pyrimidin-2-ylamino)-2-(2- (isopropylsulfonyl) phenylamino)-7H- fluoropyridin-4-yl)-4-isopropoxy-N- pyrrolo[2,3-d]pyrimidin-2-ylamino)-2- methylbenzamide methylphenyl)piperidin- 1 -yl)ethanol
Figure imgf000184_0003
5-(4-(2-(isopropylsulfonyl)phenylamino)-5-
Figure imgf000184_0004
chloropyrimidin-2-ylamino)-4-isopropoxy-
N,2-dimethylbenzamide N2-(2-isopropoxy-4-(l-(2- methoxyethyl)piperidin-3 -yl) -5 - methylphenyl)-N4-(2-(isopropylsulfonyl) phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4- diamine
Figure imgf000185_0001
5-(4-(2-(isopropylsulfonyl)phenylamino)-5- chloropyrimidin-2-ylamino)-4-isopropoxy-N-
Figure imgf000185_0002
methyl-2-(3-methyl-lH-pyrazol-5- yl)benzamide 5-(5-isopropoxy-4-(4-(2-
(isopropylsulfonyl)phenylamino)-7H- pyrrolo[2,3-d]pyrimidin-2-ylamino)-2- methylphenyl)-N-methylpiperidine-2- carboxamide
Figure imgf000185_0003
5-(4-(2-(isopropylsulfonyl)phenylamino)-5- chloropyrimidin-2-ylamino)-4-isopropoxy-N-
Figure imgf000185_0004
methyl-2-(2-methylthiazol-5-yl)benzamide
N6-(2-isopropoxy-5-methyl-4-(piperidin- 4-yl)phenyl)-N4-(2-(isopropylsulfonyl) phenyl)-lH-pyrazolo[3,4-d]pyrimidine- 4,6-diamine
Figure imgf000185_0005
5-(4-(2-(isopropylsulfonyl)phenylamino)-5-
Figure imgf000185_0006
chloropyrimidin-2-ylamino)-4-isopropoxy-2- methyl-N-( 1 -methylpiperidin-4-yl)benzamide N6-(4-(l-ethylpiperidin-4-yl)-2- isopropoxy-5-methylphenyl)-N4-(2- (isopropylsulfonyl)phenyl)- IH- pyrazolo[3,4-d]pyrimidine-4,6-diamine
Figure imgf000186_0001
5-(4-(2-(isopropylsulfonyl)phenylamino)-5- chloropyrimidin-2-ylamino)-2-cyclopropyl-4- N6-(2-isopropoxy-5-methyl-4-(l- isopropoxy-N-methylbenzamide methylpiperidin-4-yl)phenyl)-N4-(2- (isopropylsulfonyl)phenyl)- IH- pyrazolo[3,4-d]pyrimidine-4,6-diamine
Figure imgf000186_0002
4'-(5-chloro-4-(2-(N,N- dimethylsulfamoyl)phenylamino) pyrimidin- 2-ylamino)-2'-cyano-5'-isopropoxy-N-
Figure imgf000186_0003
methylbiphenyl-4 -carboxamide
2-(4-(5-isopropoxy-4-(4-(2- (isopropylsulfonyl) phenylamino)- IH- pyrazolo[3,4-d]pyrimidin-6-ylamino)-2- methylphenyl)piperidin- 1 -yl)ethanol
Figure imgf000186_0004
5-chloro-N4-(2-(sulfonylamino)phenyl)-N2- (2-methoxy-5-methyl-4-(3-methyl-4- (methylacetamidophenyl)-phenyl)pyrimidine-
Figure imgf000186_0005
2,4-diamine
N6-(2-isopropoxy-4-(l-(2-methoxyethyl) piperidin-4-yl)-5-methylphenyl)-N4-(2- (isopropylsulfonyl)phenyl)- IH- pyrazolo[3,4-d]pyrimidine-4,6-diamine
Figure imgf000187_0001
4'-(5-chloro-4-(2-(N,N-
Figure imgf000187_0002
dimethylsulfamoyl)phenylamino) pyrimidin- 2-ylamino)-N-cyclopropyl-5'-methoxy-2'- N6-(4-(4-(dimethylamino)cyclohexyl)-2- methylbiphenyl-4 -carboxamide isopropoxy-5-methylphenyl)-N4-(2- (isopropylsulfonyl)phenyl)- IH- pyrazolo[3,4-d]pyrimidine-4,6-diamine
Figure imgf000187_0003
N-((4'-(5-chloro-4-(2-(N,N-
Figure imgf000187_0004
dimethylsulfamoyl) phenylamino) pyrimidin- 2-ylamino)-5'-methoxy-2'-methylbiphenyl-4- N6-(2-isopropoxy-5-methyl-4-(piperidin- yl)methyl)acetamide 2-yl)phenyl)-N4-(2-(isopropylsulfonyl) phenyl)-lH-pyrazolo[3,4-d]pyrimidine- 4,6-diamine
Figure imgf000187_0005
5-chloro-N4-(2-(morpholinosulfonyl) phenyl)-N2-(2-methoxy-5-methyl-4-(4 5-isopropoxy-6-(4-(2-(isopropylsulfonyl) (methylacetamidophenyl)-phenyl)pyrimidine- phenylamino)- 1 H-pyrazolo[3 ,4- 2,4-diamine d]pyrimidin-6-ylamino)-2-(piperidin-4- yl)isoindolin- 1 -one
Figure imgf000188_0001
4'-(5-chloro-4-(2-(N-(cyclopropylmethyl) sulfamoyl)phenylamino)pyrimidin-2-
N2-(2-isopropoxy-5-methyl-4-(piperidin- ylamino)-5'-methoxy-N,2'-dimethylbiphenyl- 4-carboxamide 4-yl)phenyl)-N4-(2-(isopropylsulfonyl) phenyl)-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidine-2,4-diamine
Figure imgf000188_0002
4'-(5-chloro-4-(2-(N-cyclobutyl sulfamoyl)phenylamino)pyrimidin-2-
Figure imgf000188_0003
ylamino)-5'-methoxy-N,2'-dimethylbiphenyl- 4-carboxamide N2-(2-isopropoxy-5-methyl-4-(piperidin- 4-yl)phenyl)-N4-(2-(isopropylsulfonyl) phenyl)pyrido[2,3-d]pyrimidine-2,4- diamine
Figure imgf000188_0004
5-chloro-N4-(2-(pyrrolidinosulfonyl) phenyl)- N2-(2-methoxy-5-methyl-4-(4-
Figure imgf000188_0005
acetamidomethylphenyl)-phenyl)pyrimidine- 2,4-diamine 5-isopropoxy-6-(4-(2-(isopropylsulfonyl) phenylamino)- 1 H-pyrazolo[3 ,4- d]pyrimidin-6-ylamino)-2-(l- methylpiperidin-4-yl)isoindolin- 1 -one
Figure imgf000189_0001
4'-(5-chloro-4-(2-(N,N-dimethylsulfamoyl) phenylamino) pyrimidin-2-ylamino)-5'-
5-isopropoxy-6-(4-(2-(isopropylsulfonyl)- methoxy-2'-methylbiphenyl-3-carboxylic acid 5-methylphenylamino)-lH-pyrazolo[3,4- d]pyrimidin-6-ylamino)-2-(l- methylpiperidin-4-yl)isoindolin- 1 -one
Figure imgf000189_0002
4'-(4-(2-(N,N-dimethylsulfamoyl)
Figure imgf000189_0003
phenylamino)-5-fluoropyrimidin-2-ylamino)- 5'-methoxy-N,2'-dimethylbiphenyl-4- 5-isopropoxy-6-(4-(2-(isopropylsulfonyl)- carboxamide 5-methylphenylamino)-lH-pyrazolo[3,4- d]pyrimidin-6-ylamino)-2-(l-(2-methoxy ethyl)piperidin-4-yl)isoindolin- 1 -one
Figure imgf000189_0004
2-(5-chloro-2-(5-methoxy-2-methyl-4'- (morpholinosulfonyl)biphenyl-4-
N6-(2-isopropoxy-5-methyl-4-(piperidin- ylamino)pyrimidin-4-ylamino)-N,N- 2-yl)phenyl)-N4-(2-(isopropylsulfonyl)-5- dimethylbenzenesulfonamide methylphenyl)-lH-pyrazolo[3,4- d]pyrimidine-4,6-diamine
Figure imgf000190_0001
2-(5-chloro-2-(5-methoxy-2-methyl-4'-(4-
Figure imgf000190_0002
methylpiperazin-l-yl)biphenyl-4- ylamino)pyrimidin-4-ylamino)-N,N- N6-(2-isopropoxy-5-methyl-4-(piperidin- dimethylbenzenesulfonamide 3-yl)phenyl)-N4-(2-(isopropylsulfonyl)-5- methylphenyl)-lH-pyrazolo[3,4- d]pyrimidine-4,6-diamine
Figure imgf000190_0003
5-chloro-N2-(2-isopropoxy-5-methyl-4- ((lr,4r)-4-(pyrrolidin-l-yl)cyclohexyl)
Figure imgf000190_0004
phenyl)-N4-(2-(isopropylsulfonyl) phenyl)pyrimidine-2,4-diamine N2-(2-isopropoxy-4-(l-methylpiperidin-4- yl)phenyl)-N4-(2-(isopropylsulfonyl) phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4- diamine
Figure imgf000190_0005
2-(N-((lr,4r)-4-(4-(4-(2-(isopropylsulfonyl) phenylamino)-5-chloropyrimidin-2-ylamino)- 5-isopropoxy-2-methylphenyl)cyclohexyl)-N- methylamino)ethanol
Figure imgf000190_0006
2-(4-(3-isopropoxy-4-(6-(2- (isopropylsulfonyl) phenylamino)-9H- purin-2-ylamino)phenyl)piperidin- 1 - yl)ethanol; and
Figure imgf000191_0001
N2-(4-((ls,4s)-4-(N-(2-methoxyethyl)-N- methylamino)cyclohexyl)-2-isopropoxy-5-
Figure imgf000191_0002
methylphenyl)-5-chloro-N4-(2- (isopropylsulfonyl) phenyl)pyrimidine-2,4- N2-(2-isopropoxy-4-(l-methylpiperidin-4- diamine yl)phenyl)-N6-(2-(isopropylsulfonyl) phenyl)-9H-purine-2,6-diamine.
12. A compound having Formula (5):
Figure imgf000191_0003
or pharmaceutically acceptable salts thereof; wherein
Figure imgf000191_0004
A1 and A4 are independently C or N; each A2 and A3 is C, or one of A2 and A3 is N when R6 and R7 form a ring;
B and C are independently an optionally substituted 5-7 membered carbocyclic ring, aryl, heteroaryl or heterocyclic ring containing N, O or S;
Z1, Z2 and Z3 are independently NR11, C=O, CR-OR, (CR2)I-2 or =C-R12;
R1 and R2 are independently halo, OR12, NR(R12), SR12, or an optionally substituted C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl; or one of R1 and R2 is H;
R3 is (CR2)o-2S02R12, (CR2V2SO2NRR12, (CR2)o-2COi_2R12, (CR2)o-2CONRR12 or cyano; R4, R , and R7 and R10 when attached to a carbon atom, are independently H, an optionally substituted Ci_6 alkyl, C2_6 alkenyl or C2-6 alkynyl; OR12, NR(R12), halo, nitro, SO2R12, (CR2)pR13 or X; provided R6 and R7 are not both H;
R, R5 and R5 are independently H or Ci_6 alkyl;
R8 and R9 are independently Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, halo or X, or one of R8 and R9 is H; and provided one of R8 and R9 is X; alternatively, R1 and R2, or R6 and R7, R7 and R8, or R9 and R10, when attached to a carbon atom may form an optionally substituted 5-7 membered monocyclic or fused carbocyclic ring, aryl, or heteroaryl or heterocyclic ring comprising N, O and/or S; or R7, R8, R9 and R10 are absent when attached to N;
R11 is H, Ci_6 alkyl, C2-6 alkenyl, (CR2)pCOi_2R, (CR2)POR, (CR2)PR13, (CR2)PNRR12, (CR2)PCONRR12 or (CR2)pSOi_2R12;
R12 and R13 are independently an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, or a 5-7 membered heterocyclic ring comprising N, O and/or S; aryl or heteroaryl; or R12 is H, Ci_6 alkyl;
X is (CR2)qY, cyano, COi_2R12, CONR(R12), CONR(CR2)PNR(R12), CONR(CR2)POR12, CONR(CR2)PSR12, CONR(CR2)pS(O)i_2R12 or (CR2)i_6NR(CR2)pOR12;
Y is an optionally substituted 3-12 membered carbocyclic ring, a 5-12 membered aryl, or a 5-12 membered heteroaryl or heterocyclic ring comprising N, O and/or S and attached to A or A3 or both via a carbon atom of said heteroaryl or heterocyclic ring when q in (CR2)qY is 0; and n, p and q are independently 0-4.
13. The compound of claim 12, wherein R1 is halo or Ci_6 alkyl; R2 is H or NH2; or
R1 and R2 together form an optionally substituted 5-6 membered aryl, or heteroaryl or heterocyclic ring comprising 1-3 nitrogen atoms.
14. The compound of claim 12, selected from the group consisting of
Figure imgf000193_0001
4'-(5-chloro-4-(2-(isopropylsulfonyl)
5-chloro-N2-(3-isopropoxy-5-(piperidin-4- phenylamino) pyridin-2-ylamino)-3'-fluoro- yl)pyridin-2-yl)-N4-(2-(isopropylsulfonyl) N-methylbiphenyl-4-carboxamide phenyl)pyridine-2,4-diamine
Figure imgf000193_0002
5-chloro-N2-(3-isopropoxy-5-(l- methylpiperidin-4-yl)pyridin-2-yl)-N4-(2-
5-chloro-N4-(2-(isopropylsulfonyl)phenyl)- (isopropylsulfonyl) phenyl)pyridine-2,4- N2-(2-methyl-3'-(methylsulfonyl)biphenyl- diamine 4-yl)pyridine-2,4-diamine
Figure imgf000193_0003
5-chloro-N2-(5-(l-ethylpiperidin-4-yl)-3- isopropoxypyridin-2-yl)-N4-(2- Methyl 4'-(5-chloro-4-(2- (isopropylsulfonyl) phenyl)pyridine-2,4- (isopropylsulfonyl) phenylamino )pyridin-2- diamine ylamino)-5'-methoxy-2'-methylbiphenyl-4- carboxylate
Figure imgf000194_0001
N2-(3-isopropoxy-5-(piperidin-4- yl)pyridin-2-yl)-5-methyl-N4-(2-
2-(4-(6-(5-chloro-4-(2-(isopropylsulfonyl) (methylsulfonyl)phenyl)pyridine-2,4- phenylamino)pyridin-2-ylamino)-5- diamine; and isopropoxypyridin-3-yl)piperidin- 1 - yl)ethanol
Figure imgf000194_0002
6-(3-isopropoxy-5-(piperidin-4-yl)pyridin-
4'-(5-chloro-4-(2-(isopropylsulfonyl) 2-ylamino)-4-(2-(isopropylsulfonyl) phenylamino) pyridin-2-ylamino)-N,2'- phenylamino) nicotinonitrile. dimethylbiphenyl-4-carboxamide
15. A compound selected from the group consisting of
Figure imgf000194_0003
N2-(5-Ethynyl-2-isopropoxy-4-methyl- phenyl)-5-methyl-N4-[2-(propane-2-
Figure imgf000194_0004
sulfonyl)-phenyl]-pyrimidine-2,4-diamine
5-chloro-N4-(5-fluoro-2- (isopropylsulfonyl) phenyl)-N2-(2- isopropoxy-4-( 1 -methyl piperidin-4- yl)phenyl)pyrimidine-2,4-diamine 2 -(2- (5 -ethy
Figure imgf000195_0001
nyl-2-isopropoxy-4 - methylphenylamino)-5-methylpyrimidin-4- 5-chloro-N2-(2-isopropoxy-4-(piperidin-4- ylamino)-N-isopropylbenzamide yl)phenyl) - N4 - (2 - (pyrro lidin - 1 - ylsulfonyl)phenyl)pyrimidine-2,4-diamine
Figure imgf000195_0002
5-chloro-N2-(2-isopropoxy-4-(piperidin-4-
4-(4-(2-(isopropylsulfonyl)phenylamino)-5- yl)phenyl)-N4-(2-(isopropylsulfonyl) chloropyrimidin-2-ylamino)-2,3-dihydro-5- phenyl)pyrimidine-2,4-diamine isopropoxyinden- 1 -one
Figure imgf000195_0003
5-chloro-N2-(2-isopropoxy-4-(l-(l-
Figure imgf000195_0004
methylpiperidin-4-yl)piperidin-4-
5-chloro-N4-(2-(isopropylsulfonyl) phenyl)- yl)phenyl)-N4-(2-(isopropylsulfonyl) N2 -(5 - (piperidin-4-yl)isoquinolin- 8 - phenyl)pyrimidine-2,4-diamine yl)pyrimidine-2,4-diamine
Figure imgf000195_0005
2-[5-Chloro-2-(6-chloro-2-methyl-quinolin- 4-(4-(4_(2-
4-ylamino)-pyrimidin-4-ylamino]-N,N- (isopropylsulf onyl)phenylamino) -5 - dimethyl-benzenesulfonamide chloropyrimidin-2-ylamino)-3- isopropoxyphenyl)cyclohexanone
Figure imgf000196_0001
Figure imgf000196_0002
N2-(2-isopropoxy-4-(piperidin-4- yl)phenyl)-N4-(2-
N4-(2-(isopropylsulfonyl)phenyl)-N2-(2- (isopropylsulf onyl)phenyl) -5 - methylpyrimidine-2,4-diamine methoxy-5-methylphenyl)-7H-pyrrolo[2,3- d]pyrimidine-2,4-diamine
Figure imgf000196_0003
-
5-chloro-N2-(2-isopropoxy-4-(l-methyl methylpyrimidin-2-ylamino)-3-isopropoxy piperidin-2-yl)phenyl)-N4-(2-(isopropyl phenyl)piperidin- 1 -yl)ethanol sulfonyl)phenyl)pyrimidine-2,4-diamine
Figure imgf000196_0004
5-chloro-N2-(2-isopropoxy-4-(l- methylpiperidin-4-yl)phenyl)-N4-(2- (isopropylsulfonyl)phenyl)pyrimidine-2,4-
Figure imgf000196_0005
diamine
5-chloro-N2-(2-isopropoxy-4-(l-(4- methylpiperazin- 1 -yl)propan-2-yl)phenyl)- N4-(2-(isopropylsulfonyl)phenyl) pyrimidine-2,4-diamine
Figure imgf000196_0006
N2-(2-isopropoxy-4-(l-methylpiperidin-4-
Figure imgf000196_0007
yl)phenyl)-N4-(2-
3-(4-(5-chloro-4-(2-(isopropylsulfonyl) (isopropylsulf onyl)phenyl) -5 - phenylamino) pyrimidin-2-ylamino)-3- methylpyrimidine-2,4-diamine isopropoxyphenyl)butan- 1 -ol
Figure imgf000197_0001
2-(2-(2-isopropoxy-4-(l-methylpiperidin-4-
Figure imgf000197_0002
yl)phenylamino)-5-chloropyrimidin-4- ylamino)-N,N-dimethylbenzamide
5 -chloro-N2-(2-isopropoxy-4-( 1 - methylpiperidin-4-yl)phenyl)-N4-(2- (methylsulfonylmethyl) phenyl)pyrimidine- 2,4-diamine
Figure imgf000197_0003
Figure imgf000197_0004
2-(4-(4-(4-(2-(isopropylsulfonyl) phenylamino)-5-chloropyrimidin-2-
2-(5-chloro-2-(2-isopropoxy-4-(l -methyl ylamino)-3-isopropoxyphenyl) piperidin- 1 - piperidin-4-yl)phenylamino) pyrimidin-4- yl)acetamide ylamino)-N,N-dimethylbenzenesulfonamide
Figure imgf000197_0005
2-(4-(5-chloro-4-(2-(isopropylsulfonyl) 5-chloro-N2-(4-isopropoxy-2-(piperidin-4- phenylamino) pyrimidin-2-ylamino)-3- yl)pyrimidin-5-yl)-N4-(2-(isopropyl isopropoxyphenyl)-2-methylpropan- 1 -ol sulfonyl)phenyl)pyrimidine-2,4-diamine
Figure imgf000197_0006
5-chloro-N4-(2-(isopropylsulfonyl)phenyl)-
5-chloro-N2-(2-isopropoxy-4-(2-methyl-l- N2-(2-methoxy-6-(piperidin-4-yl)pyridin- (4-methylpiperazin- 1 -yl)propan-2- 3-yl) pyrimidine-2,4-diamine yl)phenyl)-N4-(2-(isopropylsulfonyl) phenyl)pyrimidine-2,4-diamine
Figure imgf000198_0001
5-chloro-N2-(2-isopropoxy-4-(l-(pyrrolidin- 1 -yl)propan-2-yl)phenyl)-N4-(2- (isopropylsulfonyl) phenyl)pyrimidine-2,4-
Figure imgf000198_0002
diamine
5-chloro-N4-(2-(isopropylsulfonyl)phenyl)- N2-(2-methoxy-6-(4-(piperazin- 1 - yl)phenyl)pyridin-3-yl)pyrimidine-2,4- diamine
Figure imgf000198_0003
Methyl 2-(4-(5-chloro-4-(2- (isopropylsulfonyl) phenylamino)pyrimidin- 2-(5-chloro-2-(2-methoxy-6-phenylpyridin- 2-ylamino)-3-isopropoxyphenyl)-2- 3-ylamino)pyrimidin-4-ylamino)-N,N- methylpropanoate dimethylbenzenesulfonamide; and
Figure imgf000198_0004
5 -chloro-N2-(2-isopropoxy-4-( 1 -
Figure imgf000198_0005
morpholinopropan-2-yl)phenyl)-N4-(2- (isopropylsulfonyl)phenyl)pyrimidine-2,4- 2-(4-(5-chloro-4-(2- diamine (isopropylsulfonyl)phenylamino) pyrimidin-2-ylamino)-3- isopropoxyphenyl)-2-methylpropane-l,3- diol.
Figure imgf000199_0001
5-chloro-N4-(5-fluoro-2- (isopropylsulfonyl)phenyl)-N2-(2- isopropoxy-4-(piperidin-4- yl)phenyl)pyrimidine-2,4-diamine
16. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-15 and a pharmaceutically acceptable carrier.
17. A method for inhibiting anaplastic lymphoma kinase, comprising administering to a cell or tissue system or to a mammalian subject, a therapeutically effective amount of a compound of any one of claims 1-15, or pharmaceutically acceptable salts thereof, thereby inhibiting said kinase.
18. The use of a compound of any one of claims 1-15, or a pharmaceutical composition thereof, for the manufacture of a medicament for treating a condition mediated by anaplastic lymphoma kinase, and optionally in combination with a second therapeutic agent, wherein said condition is an autoimmune disease, a transplantation disease, an infectious disease or a cell proliferative disorder.
19. The use of a compound of any one of claims 1-15, or a pharmaceutical composition thereof, for the manufacture of a medicament for treating a cell proliferative disorder, and optionally in combination with a second therapeutic agent, wherein said cell proliferative disorder is lymphoma, osteosarcoma, melanoma, or a tumor of breast, renal, prostate, colorectal, thyroid, ovarian, pancreatic, neuronal, lung, uterine or gastrointestinal tumor.
20. The use of claim 19, wherein said second therapeutic agent is a chemotherapeutic agent.
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