WO2017133663A1 - Phosphorus containing compounds as protein kinase inhibitors - Google Patents

Phosphorus containing compounds as protein kinase inhibitors Download PDF

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Publication number
WO2017133663A1
WO2017133663A1 PCT/CN2017/072828 CN2017072828W WO2017133663A1 WO 2017133663 A1 WO2017133663 A1 WO 2017133663A1 CN 2017072828 W CN2017072828 W CN 2017072828W WO 2017133663 A1 WO2017133663 A1 WO 2017133663A1
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Prior art keywords
alkyl
cycloalkyl
independently selected
heterocyclyl
heteroaryl
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PCT/CN2017/072828
Other languages
French (fr)
Inventor
Meiyu Geng
Jian Ding
Jing AI
Xia PENG
Chuiliang YU
Xingdong ZHAO
Yue RONG
Hongbin Liu
Zhifang Chen
Rui Tan
Lijun Yang
Xianlong WANG
Qihong Liu
Zhifu Li
Weipeng Zhang
Jing Sun
Weibo Wang
Original Assignee
Shanghai Fochon Pharmaceutical Co., Ltd.
Shanghai Institute Of Materia Medica Chinese Academy Of Sciences
Chongqing Fochon Pharmaceutical Co., Ltd.
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Application filed by Shanghai Fochon Pharmaceutical Co., Ltd., Shanghai Institute Of Materia Medica Chinese Academy Of Sciences, Chongqing Fochon Pharmaceutical Co., Ltd. filed Critical Shanghai Fochon Pharmaceutical Co., Ltd.
Priority to CN201780009722.5A priority Critical patent/CN109071512A/en
Publication of WO2017133663A1 publication Critical patent/WO2017133663A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/50—Organo-phosphines
    • C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
    • C07F9/5325—Aromatic phosphine oxides or thioxides (P-C aromatic linkage)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Novel pyrimidine derivatives or pharmaceutical compositions thereof which can inhibit kinase activity of ALK, and may be useful for the treatment of hyper-proliferative diseases like cancer and inflammation.
  • Hyper-proliferative diseases like cancer and inflammation are attracting the scientific community to provide therapeutic benefits. In this regard efforts have been made to identify and target specific mechanisms which play a role in proliferating the diseases.
  • 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 Anaplastic lymphoma kinase
  • 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. Mol. Life. Sci. 61: 2939-2953 (2004) ) .
  • ALK inhibitors are provided herein.
  • each R 1 is independently selected from hydrogen, halogen, hydroxyl, CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, C 1-10 alkylamino, C 3-10 cycloalkylamino, di (C 1-10 alkyl) amino, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from R X ;
  • each R 2 is independently selected from hydrogen, halogen, hydroxyl, CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, C 1-10 alkylamino, C 3-10 cycloalkylamino, di (C 1-10 alkyl) amino, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents
  • R 3 is independently selected from hydrogen, halogen, CN, -NR A R B and C 1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from R X ;
  • R 4 is independently selected from hydrogen, halogen, CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl and C 3-10 cycloalkyl, wherein alkyl, alkenyl, alkynyl, and cycloalkyl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from R X ;
  • R 3 and R 4 together with the carbon atoms to which they are attached form a 5-6 membered ring containing 0, 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2 or 3 R X groups;
  • each R 5 is independently selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, CN, NO 2 , -NR A1 R B1 , -OR A1 , -S (O) r R A1 , -S (O) 2 OR A1 , -OS (O) 2 R A1 , -P (O) R A1 R B1 , -P (O) (OR A1 ) (OR B1 ) , -C (O) R A1 , -C (O) OR A1 , -OC (O) R A1 , -C (O) NR A1 R B1 ,
  • R 6 and R 7 are independently selected from hydrogen, hydroxyl, C 1-10 alkyl, C 3-10 cycloalkyl and C 1-10 alkoxyl, wherein alkyl, cycloalkyl, and alkoxyl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from R X ;
  • each R A , R A1 , R B and R B1 are independently selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from R X ;
  • each R E1 is independently selected from hydrogen, C 1-10 alkyl, CN, NO 2 , -OR a1 , -SR a1 , -S (O) r R a1 , -C (O) R a1 , -C (O) OR a1 , -C (O) NR a1 R b1 and -S (O) r NR a1 R b1 ;
  • each R X is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, halogen, CN, NO 2 , - (CR c1 R d1 ) t NR a1 R b1 , - (CR c1 R d1 ) t OR b1 , - (CR c1 R d1 ) t S (O) r R b1 , - (CR c1 R d1 ) t S (O) 2 OR b1 , - (CR c1 R d1 ) t OS (O) 2 R b1 , - (CR c1 R d1
  • each R a1 and each R b1 are independently selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from R Y ;
  • R a1 and R b1 together with the atom (s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R Y groups;
  • each R c1 and each R d1 are independently selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from R Y ;
  • R c1 and R d1 together with the carbon atom (s) to which they are attached form a ring of 3 to 12 members containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2 or 3 R Y groups;
  • each R e1 is independently selected from hydrogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, CN, NO 2 , -OR a2 , -SR a2 , -S (O) r R a2 , -C (O) R a2 , -C (O) OR a2 , -S (O) r NR a2 R b2 and -C (O) NR a2 R b2 ;
  • each R Y is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, halogen, CN, NO 2 , - (CR c2 R d2 ) t NR a2 R b2 , - (CR c2 R d2 ) t OR b2 , - (CR c2 R d2 ) t S (O) r R b2 , - (CR c2 R d2 ) t S (O) 2 OR b2 , - (CR c2 R d2 ) t OS (O) 2 R b2 , - (CR c2 R d2
  • each R a2 and each R b2 are independently selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, C 1-10 alkylamino, C 3-10 cycloalkylamino, di (C 1-10 alkyl) amino, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl
  • R a2 and R b2 together with the atom (s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1 or 2 substituents, independently selected from halogen, CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, OH, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, amino, C 1-10 alkylamino, C 3-10 cycloalkylamino and di (C 1-10 alkyl) amino;
  • each R c2 and each R d2 are independently selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, C 1-10 alkylamino, C 3-10 cycloalkylamino, di (C 1-10 alkyl) amino, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino,
  • R c2 and R d2 together with the carbon atom (s) to which they are attached form a ring of 3 to 12 members containing 0, 1, or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1 or 2 substituents, independently selected from halogen, CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, OH, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, amino, C 1-10 alkylamino, C 3-10 cycloalkylamino and di (C 1-10 alkyl) amino;
  • each R e2 is independently selected from hydrogen, CN, NO 2 , C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, C 3-10 cycloalkoxy, -C (O) C 1-4 alkyl, -C (O) C 3-10 cycloalkyl, -C (O) OC 1-4 alkyl, -C (O) OC 3-10 cycloalkyl, -C (O) N (C 1-4 alkyl) 2 , -C (O) N (C 3-10 cycloalkyl) 2 , -S (O) 2 C 1-4 alkyl, -S (O) 2 C 3-10 cycloalkyl, -S (O) 2 C 1-4 alkyl, -S (O) 2 C 3-10 cycloalkyl, -S (O) 2 N (C 1-4 alkyl) 2 and -S (O)
  • n is independently selected from 0, 1 and 2;
  • n is independently selected from 1, 2 and 3;
  • p is independently selected from 0, 1, 2 and 3;
  • q is independently selected from 0, 1, 2 and 3;
  • each r is independently selected from 1 and 2;
  • each t is independently selected from 0, 1, 2, 3 and 4.
  • composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • a method for modulating ALK comprising administering to a system or a subject in need thereof, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or pharmaceutical compositions thereof, thereby modulating said ALK.
  • a method to treat, ameliorate or prevent a condition which responds to inhibition of ALK comprising administering to a system or subject in need of such treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or pharmaceutical compositions thereof, and optionally in combination with a second therapeutic agent, thereby treating said condition.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a condition mediated by ALK.
  • the compound of the disclosure may be used alone or in combination with a second therapeutic agent to treat a condition mediated by ALK.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating a condition mediated by ALK is disclosed herein.
  • the condition herein includes but not limited to, is an autoimmune disease, a transplantation disease, an infectious disease or a cell proliferative disorder.
  • a method for treating a cell proliferative disorder comprising administering to a system or subject in need of such treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or pharmaceutical compositions thereof, and optionally in combination with a second therapeutic agent, thereby treating said condition.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a cell-proliferative disorder.
  • the compounds of the disclosure may be used alone or in combination with a chemotherapeutic agent to treat a cell proliferative disorder.
  • the cell proliferative disorder disclosed herein includes 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 of formula (I) or a pharmaceutically acceptable salt thereof may be administered to a system comprising cells or tissues, or to a subject including a mammalian subject such as a human or animal subject.
  • Reactions and purification techniques can be performed e.g., using kits of manufacturer's specifications or as commonly accomplished in the art or as described herein.
  • the foregoing techniques and procedures can be generally performed of conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification.
  • groups and substituents thereof can be chosen by one skilled in the field to provide stable moieties and compounds.
  • substituent groups are specified by their conventional chemical formulas, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left.
  • CH 2 O is equivalent to OCH 2 .
  • the term “optionally substituted” means unsubstituted or substituted.
  • substituted means that a hydrogen atom is removed and replaced by a substituent. It is to be understood that substitution at a given atom is limited by valency.
  • C i-j indicates a range which includes the endpoints, wherein i and j are integers and indicate the number of carbons. Examples include C 1-4 , C 1-10 , C 3-10 , and the like.
  • alkyl refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Unless otherwise specified, “alkyl” refers to C l-10 alkyl. For example, C 1-6 , as in “C l-6 alkyl” is defined to include groups having 1, 2, 3, 4, 5, or 6 carbons in a linear or branched arrangement.
  • C l-8 alkyl includes but is not limited to methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl, hexyl, heptyl, and octyl.
  • cycloalkyl employed alone or in combination with other terms, refers to a monocyclic or bridged hydrocarbon ring system.
  • the monocyclic cycloalkyl is a carbocyclic ring system containing three to ten carbon atoms, zero heteroatoms and zero double bonds. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • the monocyclic ring may contain one or two alkylene bridges, each consisting of one, two, or three carbon atoms, each linking two non-adjacent carbon atoms of the ring system.
  • bridged cycloalkyl ring systems include, but are not limited to, bicyclo [3.1.1] heptane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, bicyclo [3.3.1] nonane, bicyclo [4.2.1] nonane, tricyclo [3.3.1.03, 7] nonane, and tricyclo [3.3.1.13, 7] decane (adamantane) .
  • the monocyclic and bridged cycloalkyl can be attached to the parent molecular moiety through any substitutable atom contained within the ring system.
  • alkenyl refers to a non-aromatic hydrocarbon radical, straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. In some embodiments, one carbon to carbon double bond is present, and up to four non-aromatic carbon-carbon double bonds may be present.
  • C 2-6 alkenyl means an alkenyl radical having from 2 to 6 carbon atoms.
  • Alkenyl groups include but are not limited to ethenyl, propenyl, butenyl, 2-methylbutenyl and cyclohexenyl. The straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated.
  • alkynyl refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond. In some embodiments, up to three carbon-carbon triple bonds may be present.
  • C 2-6 alkynyl means an alkynyl radical having from 2 to 6 carbon atoms.
  • Alkynyl groups include but are not limited to ethynyl, propynyl, butynyl, and 3-methylbutynyl. The straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is indicated.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • alkoxy refers to an alkyl radical that is single bonded to an oxygen atom. The attachment point of an alkoxy radical to a molecule is through the oxygen atom. An alkoxy radical may be depicted as -O-alkyl.
  • C 1-10 alkoxy refers to an alkoxy radical containing from one to ten carbon atoms, having straight or branched moieties. Alkoxy groups, includes but is not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, hexyloxy, and the like.
  • cycloalkoxy refers to cycloalkyl radical that is single bonded to an oxygen atom. The attachment point of a cycloalkoxy radical to a molecule is through the oxygen atom. A cycloalkoxy radical may be depicted as -O-cycloalkyl. "C 3-10 cycloalkoxy” refers to a cycloalkoxy radical containing from three to ten carbon atoms. Cycloalkoxy groups, includes but is not limited to, cyclopropoxy, cyclobutoxy, cyclohexyloxy, and the like.
  • alkylthio refers to an alkyl radical that is single bonded to a sulfur atom. The attachment point of an alkylthio radical to a molecule is through the sulfur atom. An alkylthio radical may be depicted as -S-alkyl.
  • C 1-10 alkylthio refers to an alkylthio radical containing from one to ten carbon atoms, having straight or branched moieties. Alkylthio groups, includes but is not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, hexylthio, and the like.
  • cycloalkylthio refers to cycloalkyl radical that is single bonded to a sulfur atom. The attachment point of a cycloalkylthio radical to a molecule is through the sulfur atom.
  • a cycloalkylthio radical may be depicted as -S-cycloalkyl.
  • C 3-10 cycloalkylthio refers to a cycloalkylthio radical containing from three to ten carbon atoms. Cycloalkylthio groups, includes but is not limited to, cyclopropylthio, cyclobutylthio, cyclohexylthio, and the like.
  • alkylamino refers to an alkyl radical that is single bonded to a nitrogen atom. The attachment point of an alkylamino radical to a molecule is through the nitrogen atom. An alkylamino radical may be depicted as -NH (alkyl) .
  • C 1-10 alkylamino refers to an alkylamino radical containing from one to ten carbon atoms, having straight or branched moieties.
  • Alkylamino groups includes but is not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, hexylamoino, and the like.
  • cycloalkylamino refers to cycloalkyl radical that is single bonded to a nitrogen atom. The attachment point of a cycloalkylamino radical to a molecule is through the nitrogen atom.
  • a cycloalkylamino radical may be depicted as -NH (cycloalkyl) .
  • C 3-10 cycloalkylamino refers to a cycloalkylamino radical containing from three to ten carbon atoms. Cycloalkylamino groups, includes but is not limited to, cyclopropylamino, cyclobutylamino, cyclohexylamino, and the like.
  • di (alkyl) amino refers to two alkyl radicals that are single bonded to a nitrogen atom. The attachment point of an di(alkyl) amino radical to a molecule is through the nitrogen atom. A di (alkyl) amino radical may be depicted as -N (alkyl) 2 .
  • di (C 1-10 alkyl) amino refers to a di (C 1-10 alkyl) amino radical wherein the alkyl radicals each independently contains from one to ten carbon atoms, having straight or branched moieties.
  • aryl employed alone or in combination with other terms, encompasses: 5-and 6-membered carbocyclic aromatic rings, for example, benzene; bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, naphthalene, indane, and 1, 2, 3, 4-tetrahydroquinoline; and tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, fluorene.
  • the aryl substituent is bicyclic or tricyclic and at least one ring is non-aromatic, it is understood that attachment is via the aromatic ring.
  • aryl includes 5-and 6-membered carbocyclic aromatic rings fused to a 5-to 7-membered heterocyclic ring containing one or more heteroatoms selected from N, O, and S, provided that the point of attachment is at the carbocyclic aromatic ring.
  • Bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals.
  • Bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in "-yl” by removal of one hydrogen atom from the carbon atom with the free valence are named by adding "-idene” to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene.
  • Aryl does not encompass or overlap in any way with heteroaryl, separately defined below. Hence, if one or more carbocyclic aromatic rings are fused with a heterocyclic aromatic ring, the resulting ring system is heteroaryl, not aryl, as defined herein.
  • heteroaryl employed alone or in combination with other terms, refers to
  • 8-to 12-membered bicyclic rings containing one or more, for example, from 1 to 4, or, in some embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring; and
  • 11-to 14-membered tricyclic rings containing one or more, for example, from 1 to 4, or in some embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring.
  • the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1.
  • heteroaryl groups include, but are not limited to, (as numbered from the linkage position assigned priority 1) , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2, 3-pyrazinyl, 3, 4-pyrazinyl, 2, 4-pyrimidinyl, 3, 5-pyrimidinyl, 1-pyrazolyl, 2, 3-pyrazolyl, 2, 4-imidazolinyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothienyl, furyl, benzofuryl, benzoimidazolinyl, indolinyl, pyridizinyl, triazolyl, quinolinyl, pyrazolyl, and 5, 6, 7, 8-tetrahydroisoquinoline.
  • heteroaryl groups include but are not limited to pyrrolyl, isothiazolyl, triazinyl, pyrazinyl, pyridazinyl, indolyl, benzotriazolyl, quinoxalinyl, and isoquinolinyl, .
  • heteroaryl is also understood to include the N-oxide derivative of any nitrogen-containing heteroaryl.
  • Bivalent radicals derived from univalent heteroaryl radicals whose names end in "-yl” by removal of one hydrogen atom from the atom with the free valence are named by adding "-idene" to the name of the corresponding univalent radical, e.g., a pyridyl group with two points of attachment is a pyridylidene.
  • Heteroaryl does not encompass or overlap with aryl as defined above.
  • heteroaryl substituent is bicyclic or tricyclic and at least one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively.
  • heterocycle employed alone or in combination with other terms, (and variations thereof such as “heterocyclic” , or “heterocyclyl” ) broadly refers to a single aliphatic ring, usually with 3 to 12 ring atoms, containing at least 2 carbon atoms in addition to one or more, preferably one to three heteroatoms independently selected from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms.
  • a heterocycle as defined above may be multicyclic ring system (e.g.
  • Heterocycle also refers to 5-to 7-membered heterocyclic ring containing one or more heteroatoms selected from N, O, and S fused with 5-and 6-membered carbocyclic aromatic ring, provided that the point of attachment is at the heterocyclic ring.
  • the rings may be saturated or have one or more double bonds (i.e. partially unsaturated) .
  • the heterocycle can be substituted by oxo.
  • the point of the attachment may be carbon or heteroatom in the heterocyclic ring, provided that attachment results in the creation of a stable structure.
  • heterocyclic ring has substituents
  • substituents may be attached to any atom in the ring, whether a heteroatom or a carbon atom, provided that a stable chemical structure results.
  • Heterocycle does not overlap with heteroaryl.
  • Suitable heterocycles include, for example (as numbered from the linkage position assigned priority 1) , 1-pyrrolidinyl, 2-pyrrolidinyl, 2, 4-imidazolidinyl, 2, 3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2, 5-piperazinyl. 1, 4-piperazinyl, and 2, 3-pyridazinyl.
  • Morpholinyl groups are also contemplated, including 2-morpholinyl and 3-morpholinyl (numbered wherein the oxygen is assigned priority 1) .
  • Substituted heterocycle also includes ring systems substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and 1, 1-dioxo-1-thiomorpholinyl.
  • Bicyclic heterocycles include, for example:
  • aryl-alkyl refers to an alkyl moiety substituted by an aryl group.
  • Example aryl-alkyl groups include benzyl, phenethyl, and naphthylmethyl groups. In some embodiments, aryl-alkyl groups have from 7 to 20 or 7 to 11 carbon atoms.
  • aryl-C l-4 alkyl the term “C 1-4 ” refers to the alkyl portion of the moiety and does not describe the number of atoms in the aryl portion of the moiety.
  • heterocyclyl-alkyl refers to alkyl substituted by heterocyclyl.
  • C 1-4 alkyl refers to the alkyl portion of the moiety and does not describe the number of atoms in the heterocyclyl portion of the moiety.
  • cycloalkyl-alkyl refers to alkyl substituted by cycloalkyl.
  • C 3-10 cycloalkyl-C l-4 alkyl refers to the term “C 3-10 ” refers to the cycloalkyl portion of the moiety and does not describe the number of atoms in the alkyl portion of the moiety
  • C 1-4 refers to the alkyl portion of the moiety and does not describe the number of atoms in the cycloalkyl portion of the moiety.
  • heteroaryl-alkyl refers to alkyl substituted by heteroaryl.
  • C 1-4 refers to the alkyl portion of the moiety and does not describe the number of atoms in the heteroaryl portion of the moiety.
  • substitution of alkyl, cycloalkyl, heterocyclyl, aryl, and/or heteroaryl refers to substitution of each of those groups individually as well as to substitutions of combinations of those groups. That is, if R 1 is aryl-C l-4 alkyl, the aryl portion may be unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R X and the alkyl portion may also be unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R X .
  • salts derived from inorganic bases may be selected, for example, from aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, and zinc salts. Further, for example, the pharmaceutically acceptable salts derived from inorganic bases may be selected from ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in one or more crystal structures, and may also be in the form of hydrates.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases may be selected, for example, from salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, and tripropylamine, tromethamine.
  • salts may be prepared using at least one pharmaceutically acceptable non-toxic acid, selected from inorganic and organic acids.
  • acid may be selected, for example, from acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, and p-toluenesulfonic acids.
  • such acid may be selected, for example, from citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.
  • administering should be understood to mean providing a compound or a pharmaceutically acceptable salt thereof to the individual in recognized need of treatment.
  • the term "effective amount” means the amount of the a compound or a pharmaceutically acceptable salt that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • composition in relation to a pharmaceutical composition is intended to encompass a product comprising the active ingredient (s) , and the inert ingredient (s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • pharmaceutically acceptable it is meant compatible with the other ingredients of the formulation and not unacceptably deleterious to the recipient thereof.
  • subject in reference to individuals suffering from a disorder, a condition, and the like, encompasses mammals and non-mammals.
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • non-mammals include, but are not limited to, birds, fish and the like.
  • the mammal is a human.
  • treat, “ “treating” or “treatment, “ and other grammatical equivalents as used herein, include alleviating, abating or ameliorating a disease or condition, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition, and are intended to include prophylaxis.
  • the terms further include achieving a therapeutic benefit and/or a prophylactic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
  • protecting group refers to a substituent that can be commonly employed to block or protect a certain functionality while reacting other functional groups on the compound.
  • an "amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include but are not limited to acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC) , benzyloxycarbonyl (CBZ) and 9-fluorenylmethylenoxycarbonyl (Fmoc) .
  • a "hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality.
  • Suitable protecting groups include but are not limited to acetyl and silyl.
  • a "carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Common carboxy-protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenylsulfenyl) ethyl, 2- (diphenylphosphino) -ethyl, nitroethyl and the like.
  • protecting groups and their use see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley &Sons, New York, 1991.
  • NH protecting group includes, but not limited to, trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, para-nitrobenzylcarbonyl, ortho-bromobenzyloxycarbonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-amyloxycarbonyl, tert-butoxycarbonyl, para-methoxybenzyloxycarbonyl, 3, 4-dimethoxybenzyl-oxycarbonyl, 4- (phenylazo) -benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1, 1-dimethylpropoxy-carbonyl, isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leu
  • C (O) OH protecting group includes, but not limited to, methyl, ethyl, n-propyl, isopropyl, 1, 1-dimethylpropyl, n-butyl, tert-butyl, phenyl, naphthyl, benzyl, diphenylmethyl, triphenylmethyl, para-nitrobenzyl, para-methoxybenzyl, bis(para-methoxyphenyl) methyl, acetylmethyl, benzoylmethyl, para-nitrobenzoylmethyl, para-bromobenzoylmethyl, para-methanesulfonylbenzoylmethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 2, 2, 2-trichloro-ethyl, 2- (trimethylsilyl) ethyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, phthalimidomethyl, succinimid
  • OH or SH protecting group includes, but not limited to, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3, 4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1, 1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2, 2, 2-trichloroethoxycarbonyl, 2, 2, 2-tribromoethoxycarbonyl, 2- (trimethylsilyl) ethoxycarbonyl, 2- (phenylsulfonyl) ethoxycarbonyl, 2- (triphenylphosphonio) ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyl
  • Geometric isomers may exist in the present compounds.
  • Compounds of this invention may contain carbon-carbon double bonds or carbon-nitrogen double bonds in the E or Z configuration, wherein the term “E” represents higher order substituents on opposite sides of the carbon-carbon or carbon-nitrogen double bond and the term “Z” represents higher order substituents on the same side of the carbon-carbon or carbon-nitrogen double bond as determined by the Cahn-Ingold-Prelog Priority Rules.
  • the compounds of this invention may also exist as a mixture of "E” and "Z” isomers. Substituents around a cycloalkyl or heterocycloalkyl are designated as being of cis or trans configuration.
  • the invention contemplates the various isomers and mixtures thereof resulting from the disposal of substituents around an adamantane ring system.
  • Two substituents around a single ring within an adamantane ring system are designated as being of Z or E relative configuration.
  • C. D. Jones, M. Kaselj, R. N. Salvatore, W. J. le Noble J. Org. Chem. 1998, 63, 2758-2760 See C. D. Jones, M. Kaselj, R. N. Salvatore, W. J. le Noble J. Org. Chem. 1998, 63, 2758-2760.
  • Compounds of this invention may contain asymmetrically substituted carbon atoms in the R or S configuration, in which the terms "R” and “S” are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-10.
  • Compounds having asymmetrically substituted carbon atoms with equal amounts of R and S configurations are racemic at those carbon atoms. Atoms with an excess of one configuration over the other are assigned the configuration present in the higher amount, preferably an excess of about 85-90%, more preferably an excess of about 95-99%, and still more preferably an excess greater than about 99%.
  • this invention includes racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.
  • Compounds of the invention can exist in isotope-labeled or -enriched form containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most abundantly found in nature.
  • Isotopes can be radioactive or non-radioactive isotopes.
  • Isotopes of atoms such as hydrogen, carbon, nitrogen, phosphorous, sulfur, fluorine, chlorine, and iodine include, but are not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 32 P, 35 S, 18 F, 36 Cl, and 125 I.
  • Compounds that contain other isotopes of these and/or other atoms are within the scope of this invention.
  • the isotope-labeled compounds contain deuterium ( 2 H) , tritium ( 3 H) or 14 C isotopes.
  • Isotope-labeled compounds of this invention can be prepared by the general methods well known to persons having ordinary skill in the art. Such isotope-labeled compounds can be conveniently prepared by carrying out the procedures disclosed in the Examples disclosed herein and Schemes by substituting a readily available isotope-labeled reagent for a non-labeled reagent.
  • compounds may be treated with isotope-labeled reagents to exchange a normal atom with its isotope, for example, hydrogen for deuterium can be exchanged by the action of a deuterated acid such as D 2 SO 4 /D 2 O.
  • a deuterated acid such as D 2 SO 4 /D 2 O.
  • the isotope-labeled compounds of the invention may be used as standards to determine the effectiveness of ALK inhibitors in binding assays.
  • Isotope containing compounds have been used in pharmaceutical research to investigate the in vivo metabolic fate of the compounds by evaluation of the mechanism of action and metabolic pathway of the nonisotope-labeled parent compound (Blake et al. J. Pharm. Sci. 64, 3, 367-391 (1975) ) .
  • Such metabolic studies are important in the design of safe, effective therapeutic drugs, either because the in vivo active compound administered to the patient or because the metabolites produced from the parent compound prove to be toxic or carcinogenic (Foster et al., Advances in Drug Research Vol. 14, pp.
  • non-radio active isotope containing drugs such as deuterated drugs called “heavy drugs” can be used for the treatment of diseases and conditions related to ALK activity.
  • Increasing the amount of an isotope present in a compound above its natural abundance is called enrichment.
  • Examples of the amount of enrichment include from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96, to about 100 mol %.
  • Stable isotope labeling of a drug can alter its physico-chemical properties such as pKa and lipid solubility. These effects and alterations can affect the pharmacodynamic response of the drug molecule if the isotopic substitution affects a region involved in a ligand-receptor interaction. While some of the physical properties of a stable isotope-labeled molecule are different from those of the unlabeled one, the chemical and biological properties are the same, with one important exception: because of the increased mass of the heavy isotope, any bond involving the heavy isotope and another atom will be stronger than the same bond between the light isotope and that atom. Accordingly, the incorporation of an isotope at a site of metabolism or enzymatic transformation will slow said reactions potentially altering the pharmacokinetic profile or efficacy relative to the non-isotopic compound.
  • this invention relates to a compound of formula (I)
  • each R 1 is independently selected from hydrogen, halogen, hydroxyl, CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, C 1-10 alkylamino, C 3-10 cycloalkylamino, di (C 1-10 alkyl) amino, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, and heteroaryl-C 1-4 alkyl, wherein alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from R X ;
  • each R 2 is independently selected from hydrogen, halogen, hydroxyl, CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, C 1-10 alkylamino, C 3-10 cycloalkylamino, di (C 1-10 alkyl) amino, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituent
  • R 3 is independently selected from hydrogen, halogen, CN, -NR A R B , and C 1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from R X ;
  • R 4 is independently selected from hydrogen, halogen, CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, and C 3-10 cycloalkyl, wherein alkyl, alkenyl, alkynyl, and cycloalkyl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from R X ;
  • R 3 and R 4 together with the carbon atoms to which they are attached form a 5-6 membered ring containing 0, 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2 or 3 R X groups;
  • each R 5 is independently selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, CN, NO 2 , -NR A1 R B1 , -OR A1 , -S (O) r R A1 , -S (O) 2 OR A1 , -OS (O) 2 R A1 , -P (O) R A1 R B1 , -P (O) (OR A1 ) (OR B1 ) , -C (O) R A1 , -C (O) OR A1 , -OC (O) R A1 , -C (O) NR A1 R B1 ,
  • R 6 and R 7 are independently selected from hydrogen, hydroxyl, C 1-10 alkyl, C 3-10 cycloalkyl, and C 1-10 alkoxyl, wherein alkyl, cycloalkyl, and alkoxyl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from R X ;
  • each R A , R A1 , R B and R B1 are independently selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from R X ;
  • each R E1 is independently selected from hydrogen, C 1-10 alkyl, CN, NO 2 , OR a1 , SR a1 , -S (O) r R a1 , -C (O) R a1 , -C (O) OR a1 , -C (O) NR a1 R b1 , and -S (O) r NR a1 R b1 ;
  • each R X is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, halogen, CN, NO 2 , - (CR c1 R d1 ) t NR a1 R b1 , - (CR c1 R d1 ) t OR b1 , - (CR c1 R d1 ) t S (O) r R b1 , - (CR c1 R d1 ) t S (O) 2 OR b1 , - (CR c1 R d1 ) t OS (O) 2 R b1 , - (CR c1 R d1
  • each R a1 and each R b1 are independently selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from R Y ;
  • R a1 and R b1 together with the atom (s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2, or 3 R Y groups;
  • each R c1 and each R d1 are independently selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from R Y ;
  • R c1 and R d1 together with the carbon atom (s) to which they are attached form a ring of 3 to 12 members containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2 or 3 R Y groups;
  • each R e1 is independently selected from hydrogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, CN, NO 2 , -OR a2 , -SR a2 , -S (O) r R a2 , -C (O) R a2 , -C (O) OR a2 , -S (O) r NR a2 R b2 and -C (O) NR a2 R b2 ;
  • each R Y is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, halogen, CN, NO 2 , - (CR c2 R d2 ) t NR a2 R b2 , - (CR c2 R d2 ) t OR b2 , - (CR c2 R d2 ) t S (O) r R b2 , - (CR c2 R d2 ) t S (O) 2 OR b2 , - (CR c2 R d2 ) t OS (O) 2 R b2 , - (CR c2 R d2
  • each R a2 and each R b2 are independently selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, C 1-10 alkylamino, C 3-10 cycloalkylamino, di (C 1-10 alkyl) amino, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl
  • R a2 and R b2 together with the atom (s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1 or 2 substituents, independently selected from halogen, CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, OH, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, amino, C 1-10 alkylamino, C 3-10 cycloalkylamino and di (C 1-10 alkyl) amino;
  • each R c2 and each R d2 are independently selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, C 1-10 alkylamino, C 3-10 cycloalkylamino, di (C 1-10 alkyl) amino, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl and heteroaryl-C 1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino,
  • R c2 and R d2 together with the carbon atom (s) to which they are attached form a ring of 3 to 12 members containing 0, 1, or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1 or 2 substituents, independently selected from halogen, CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, OH, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, amino, C 1-10 alkylamino, C 3-10 cycloalkylamino and di (C 1-10 alkyl) amino;
  • each R e2 is independently selected from hydrogen, CN, NO 2 , C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, C 3-10 cycloalkoxy, -C (O) C 1-4 alkyl, -C (O) C 3-10 cycloalkyl, -C (O) OC 1-4 alkyl, -C (O) OC 3-10 cycloalkyl, -C (O) N (C 1-4 alkyl) 2 , -C (O) N (C 3-10 cycloalkyl) 2 , -S (O) 2 C 1-4 alkyl, -S (O) 2 C 3-10 cycloalkyl, -S (O) 2 C 1-4 alkyl, -S (O) 2 C 3-10 cycloalkyl, -S (O) 2 N (C 1-4 alkyl) 2 and -S (O)
  • n is independently selected from 0, 1 and 2;
  • n is independently selected from 1, 2 and 3;
  • p is independently selected from 0, 1, 2 and 3;
  • q is independently selected from 0, 1, 2 and 3;
  • each r is independently selected from 1 and 2;
  • each t is independently selected from 0, 1, 2, 3 and 4.
  • the invention provides a compound of Embodiment (1) or a pharmaceutically acceptable salt thereof, wherein each R 1 is independently selected from C 1-10 alkyl.
  • the invention provides a compound of Embodiment (2) or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl.
  • the invention provides a compound of any one of Embodiments (1) - (3) or a pharmaceutically acceptable salt thereof, wherein m is 1.
  • the invention provides a compound of any one of Embodiments (1) - (4) or a pharmaceutically acceptable salt thereof, wherein n is 1.
  • the invention provides a compound of any one of Embodiments (1) - (5) or a pharmaceutically acceptable salt thereof, wherein p is 2.
  • the invention provides a compound of any one of Embodiments (1) - (6) or a pharmaceutically acceptable salt thereof, wherein one R 2 is independently selected from C 1-10 alkyl; and the other R 2 is independently selected from heterocyclyl, wherein alkyl and heterocyclyl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from R X .
  • the invention provides a compound of Embodiment (7) or a pharmaceutically acceptable salt thereof, wherein one R 2 is methyl; and the other R 2 is piperidinyl, which is unsubstituted or substituted with methyl or ethyl.
  • the invention provides a compound of any one of Embodiments (1) - (8) or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.
  • the invention provides a compound of any one of Embodiments (1) - (9) or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from halogen.
  • the invention provides a compound of Embodiment (10) or a pharmaceutically acceptable salt thereof, wherein R 4 is chlorine.
  • the invention provides a compound of Embodiments any one of (1) - (11) or a pharmaceutically acceptable salt thereof, wherein each R 5 is hydrogen.
  • the invention provides a compound of any one of Embodiments (1) - (12) or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from C 1-10 alkyl.
  • the invention provides a compound of Embodiment (13) or a pharmaceutically acceptable salt thereof, wherein R 6 is methyl.
  • the invention provides a compound of any one of Embodiments (1) - (14) or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from C 1-10 alkyl.
  • the invention provides a compound of Embodiment (15) or a pharmaceutically acceptable salt thereof, wherein R 7 is methyl.
  • the invention provides a compound selected from
  • a pharmaceutical composition comprising a compound of any one of Embodiments (1) - (17) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • Embodiment (19) A method of treating, ameliorating or preventing a condition, which responds to inhibition of ALK, comprising administering to a subject in need of such treatment an effective amount of a compound of any one of Embodiments (1) - (17) or a pharmaceutically acceptable salt thereof, or of at least one pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent.
  • Embodiment (20) Use of a compound of any one of Embodiments (1) - (17) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a cell-proliferative disorder.
  • kits comprising a compound disclosed herein, or a pharmaceutically acceptable salts thereof; and instructions which comprise one or more forms of information selected from the group consisting of indicating a disease state for which the composition is to be administered, storage information for the composition, dosing information and instructions regarding how to administer the composition.
  • the kit comprises the compound in a multiple dose form.
  • an article of manufacture comprising a compound disclosed herein, or a pharmaceutically acceptable salts thereof; and packaging materials.
  • the packaging material comprises a container for housing the compound.
  • the container comprises a label indicating one or more members of the group consisting of a disease state for which the compound is to be administered, storage information, dosing information and/or instructions regarding how to administer the compound.
  • the article of manufacture comprises the compound in a multiple dose form.
  • a therapeutic method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salts thereof.
  • a method of inhibiting a ALK kinase comprising contacting ALK with a compound disclosed herein, or a pharmaceutically acceptable salts thereof.
  • a method of inhibiting ALK comprising causing a compound disclosed herein, or a pharmaceutically acceptable salts thereof to be present in a subject in order to inhibit the ALK in vivo.
  • a method of inhibiting ALK comprising administering a first compound to a subject that is converted in vivo to a second compound wherein the second compound inhibits the ALK in vivo, the second compound being a compound according to any one of the above embodiments and variations.
  • a method of treating a disease state for which a ALK possesses activity that contributes to the pathology and/or symptomology of the disease state comprising causing a compound disclosed herein, or a pharmaceutically acceptable salts thereof to be present in a subject in a therapeutically effective amount for the disease state.
  • a method of treating a disease state for which a ALK possesses activity that contributes to the pathology and/or symptomology of the disease state comprising administering a first compound to a subject that is converted in vivo to a second compound wherein the second compound inhibits the ALK in vivo.
  • the compounds of the present invention may be the first or second compounds.
  • the disease state is selected from the group consisting of cancerous hyperproliferative disorders (e.g., brain, lung, squamous cell, bladder, gastric, pancreatic, breast, head, neck, renal, kidney, ovarian, prostate, colorectal, epidermoid, esophageal, testicular, gynecological or thyroid cancer) ; non-cancerous hyperproliferativedisorders (e.g., benign hyperplasia of the skin (e.g., psoriasis) , restenosis, and benign prostatic hypertrophy (BPH) ) ; pancreatitis; kidney disease; pain; preventing blastocyte implantation; treating diseases related to vasculogenesis or angiogenesis (e.g., tumor angiogenesis, acute and chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, exzema,
  • a method of treating a disease state for which a mutation in the ALK gene contributes to the pathology and/or symptomology of the disease state including, for example, melanomas, lung cancer, colon cancer and other tumor types.
  • the present invention relates to the use of a compound of any of the above embodiments and variations as a medicament. In yet another of its aspects, the present invention relates to the use of a compound according to any one of the above embodiments and variations in the manufacture of a medicament for inhibiting a ALK.
  • the present invention relates to the use of a compound according to any one of the above embodiments and variations in the manufacture of a medicament for treating a disease state for which a ALK possesses activity that contributes to the pathology and/or symptomology of the disease state.
  • compounds of the disclosure 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 1000 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 disclosure 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 disclosure 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 disclosure 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, M 2375, (polyoxyethylene glycerol) , M 1944 CS (unsaturated polyglycolized glycerides prepared by alcoholysis of apricot kernel oil and comprising glycerides and polyethylene glycol ester) , LABRASOL TM (saturated polyglycolized glycerides prepared by alcoholysis of TCM and comprising glycerides and polyethylene glycol ester; all available from GaKefosse, France) , and/or 812 (triglyceride of saturated fatty acids of chain length C8 to C12 from Hüls 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 oil, castor oil, ses
  • 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.
  • kits comprising a) a first agent which is a compound of the disclosure 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.
  • the compounds or pharmaceutical acceptable salts of the disclosure may be administered as the sole therapy, or together with other therapeutic agent or agents.
  • the therapeutic effectiveness of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e. by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the individual is enhanced) .
  • the benefit experienced by an individual may be increased by administering one of the compounds described herein with another therapeutic agent that also has therapeutic benefit.
  • increased therapeutic benefit may result by also providing the individual with another therapeutic agent for gout.
  • the additional therapy or therapies include, but are not limited to physiotherapy, psychotherapy, radiation therapy, application of compresses to a diseased area, rest, altered diet, and the like. Regardless of the disease, disorder or condition being treated, the overall benefit experienced by the individual may be additive of the two therapies or the individual may experience a synergistic benefit.
  • the compounds described herein may be administered in the same pharmaceutical composition as other therapeutic agents, or because of different physical and chemical characteristics, be administered by a different route.
  • the compounds described herein may be administered orally to generate and maintain good blood levels thereof, while the other therapeutic agent may be administered intravenously.
  • the compounds described herein may be administered concurrently, sequentially or dosed separately to other therapeutic agents.
  • Compounds having Formula (I) are expected to be useful when used with alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors, other apoptosis promoters (for example, Bcl-xL, Bcl-w and Bfl-1) inhibitors, activators of death receptor pathway, Bcr-Abl kinase inhibitors, BiTE (Bi-Specific T cell Engager) antibodies, antibody drug conjugates, biologic response modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVDs, leukemia viral oncogene homolog (ErbB2) receptor inhibitors, growth factor inhibitors, heat shock protein (HSP) -90 inhibitors, histone deacetylase (HDAC) inhibitors, hormonal therapies, immunologicals, inhibitors of inhibitors of apoptosis proteins (IAPs) , intercal
  • BiTE antibodies are bi-specific antibodies that direct T-cells to attack cancer cells by simultaneously binding the two cells. The T-cell then attacks the target cancer cell.
  • Examples of BiTE antibodies include adecatumumab (Micromet MT201) , blinatumomab (Micromet MT103) and the like.
  • adecatumumab Movable MT201
  • blinatumomab Micromet MT103
  • one of the mechanisms by which T-cells elicit apoptosis of the target cancer cell is by exocytosis of cytolytic granule components, which include perforin and granzyme B.
  • Bcl-2 has been shown to attenuate the induction of apoptosis by both perforin and granzyme B.
  • SiRNAs are molecules having endogenous RNA bases or chemically modified nucleotides. The modifications do not abolish cellular activity, but rather impart increased stability and/or increased cellular potency. Examples of chemical modifications include phosphorothioate groups, 2'-deoxynucleotide, 2'-OCH 3 -containing ribonucleotides, 2'-F-ribonucleotides, 2'-methoxyethyl ribonucleotides, combinations thereof and the like.
  • the siRNA can have varying lengths (e.g., 10-200 bps) and structures (e.g., hairpins, single/double strands, bulges, nicks/gaps, mismatches) and are processed in cells to provide active gene silencing.
  • a double-stranded siRNA can have the same number of nucleotides on each strand (blunt ends) or asymmetric ends (overhangs) .
  • the overhang of 1-2 nucleotides can be present on the sense and/or the antisense strand, as well as present on the 5'-and/or the 3 '-ends of a given strand.
  • siRNAs targeting Mcl-1 have been shown to enhance the activity of ABT-263, (i.e., N- (4- (4- ( (2- (4-chlorophenyl) -5, 5-dimethyl-1-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoyl) -4- ( ( (1R) -3- (morpholin-4-yl) -1- ( (phenylsulfanyl) methyl) -propyl) amino) -3- ( (trifluoromethyl) sulf onyl) benzenesulfonamide) or ABT-737 (i.e., N- (4- (4- ( (4'-chloro (l, r-biphenyl) -2-yl) methyl) piperazin-l-yl) benzoyl) -4- ( ( (1R) -3- (dimethylamino ) -1- ( (phenylsulfanyl) methyl) propyl)
  • Multivalent binding proteins are binding proteins comprising two or more antigen binding sites. Multivalent binding proteins are engineered to have the three or more antigen binding sites and are generally not naturally occurring antibodies.
  • the term "multispecific binding protein” means a binding protein capable of binding two or more related or unrelated targets.
  • Dual variable domain (DVD) binding proteins are tetravalent or multivalent binding proteins binding proteins comprising two or more antigen binding sites. Such DVDs may be monospecific (i.e., capable of binding one antigen) or multispecific (i.e., capable of binding two or more antigens) .
  • DVD binding proteins comprising two heavy chain DVD polypeptides and two light chain DVD polypeptides are referred to as DVD Ig's .
  • Each half of a DVD Ig comprises a heavy chain DVD polypeptide, a light chain DVD polypeptide, and two antigen binding sites.
  • Each binding site comprises a heavy chain variable domain and a light chain variable domain with a total of 6 CDRs involved in antigen binding per antigen binding site.
  • Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone, bendamustine, brostallicin, busulfan, carboquone, carmustine (BCNU) , chlorambucil, (laromustine, VNP 40101M) , cyclophosphamide, decarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine (CCNU) , mafosfamide, melphalan, mitobronitol, mitolactol, nimustine, nitrogen mustard N-oxide, ranimustine, temozolomide, thiotepa, (bendamustine) , treosulfan, rofosfamide and the like.
  • Angiogenesis inhibitors include endothelial-specific receptor tyrosine kinase (Tie-2) inhibitors, epidermal growth factor receptor (EGFR) inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrix metalloproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9 (MMP-9) inhibitors, platelet-derived growth factor receptor (PDGFR) inhibitors, thrombospondin analogs, vascular endothelial growth factor receptor tyrosine kinase (VEGFR) inhibitors and the like.
  • Tie-2 endothelial-specific receptor tyrosine kinase
  • EGFR epidermal growth factor receptor
  • IGFR-2 insulin growth factor-2 receptor
  • MMP-2 matrix metalloproteinase-2
  • MMP-9 matrix metalloproteinase-9
  • PDGFR platelet-derived growth factor receptor
  • VEGFR vascular endothelial growth factor receptor tyrosine
  • Antimetabolites include (pemetrexed disodium, LY231514, MTA) , 5-azacitidine, (capecitabine) , carmofur, (cladribine) , clofarabine, cytarabine, cytarabine ocfosfate, cytosine arabinoside, decitabine, deferoxamine, doxifluridine, eflornithine, EICAR (5-ethynyl-l-P -D-ribofuranosylimidazole-4-carboxamide) , enocitabine, ethnylcytidine, fludarabine, 5-fluorouracil alone or in combination with leucovorin, (gemcitabine) , hydroxyurea, (melphalan) , mercaptopurine, 6-mercaptopurine riboside, methotrexate, mycophenolic acid, nelarabine, nolatrexed
  • Antivirals include ritonavir, hydroxychloroquine and the like.
  • Aurora kinase inhibitors include ABT-348, AZD-1152, MLN-8054, VX-680, Aurora A-specific kinase inhibitors, Aurora B-specific kinase inhibitors and pan-Aurora kinase inhibitors and the like.
  • Bcl-2 protein inhibitors include AT-101 ( (-) gossypol) , (G3139 or oblimersen (Bcl-2 -targeting antisense oligonucleotide) ) , IPI-194, IPI-565, N- (4- (4- ( (4'-chloro (1, 1'-biphenyl) -2-yl) methyl) piperazin-1-yl) benzoyl) -4- ( ( (1R) -3- (dimethylamin o) -1- ( (phenylsulfanyl) methyl) propyl) amino) -3-nitrobenzenesulfonamide) (ABT-737) , N- (4- (4- ( (2- (4-chlorophenyl) -5, 5-dimethyl-1-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoyl) -4- ( ( (1R) -3- (morpholin-4-yl) -1-
  • Bcr-Abl kinase inhibitors include (BMS-354825) , (imatinib) and the like.
  • CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584, flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib (CYC-202, R-roscovitine) , ZK-304709 and the like.
  • COX-2 inhibitors include ABT-963 , ARCOXI (etoricoxib) , (valdecoxib) , BMS347070, (celecoxib) , COX-189 (lumiracoxib) , CT-3, (deracoxib) , JTE-522, 4-methyl-2- (3, 4-dimethylphenyl) -l- (4-sulfamoylphenyl-lH-pyrrole) , MK-663 (etoricoxib) , NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016, S-2474, T-614, (rofecoxib) and the like.
  • EGFR inhibitors include ABX-EGF, anti-EGFR immuno liposomes, EGF-vaccine, EMD-7200, (cetuximab) , HR3, IgA antibodies, (gefitinib) , (erlotinib or OSI-774) , TP-38, EGFR fusion protein, (lapatinib) and the like.
  • ErbB2 receptor inhibitors include CP-724-714, CI-1033 (canertinib) , (trastuzumab) , (lapatinib) , (2C4, petuzumab) , TAK-165, GW-572016 (ionafarnib) , GW-282974, EKB-569, PI-166, dHER2 (HER2 vaccine) , APC-8024 (HER-2 vaccine) , anti-HER/2neu bispecific antibody, B7. her2IgG3, AS HER2 trifunctional bispecfic antibodies, mAB AR-209, mAB 2B-1 and the like.
  • Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275, trapoxin, suberoylanilide hydroxamic acid (SAHA) , TSA, valproic acid and the like.
  • HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010, CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, (human recombinant antibody to HSP-90) , NCS-683664, PU24FC1, PU-3, radicicol, SNX-2112, STA-9090 VER49009 and the like.
  • Inhibitors of inhibitors of apoptosis proteins include HGS1029, GDC-0145, GDC-0152, LCL-161, LBW-242 and the like.
  • Antibody drug conjugates include anti-CD22-MC-MMAF, anti-CD22-MC-MMAE, anti-CD22-MCC-DMl, CR-011-vcMMAE, PSMA-ADC, MEDI-547, SGN-19Am SGN-35, SGN-75 and the like
  • Activators of death receptor pathway include TRAIL, antibodies or other agents that target TRAIL or death receptors (e.g., DR4 and DR5) such as Apomab, conatumumab, ETR2-ST01, GDC0145 (lexatumumab) , HGS-1029, LBY-135, PRO-1762 and trastuzumab.
  • Kinesin inhibitors include Eg5 inhibitors such as AZD4877, ARRY-520; CENPE inhibitors such as GSK923295A and the like.
  • JAK-2 inhibitors include CEP-701 (lesaurtinib) , XL019 and INCBO 18424 and the like.
  • MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059 and the like.
  • mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001, rapamycin, temsirolimus, ATP-competitive TORC1/TORC2 inhibitors, including PI-103, PP242, PP30, Torin 1 and the like.
  • Non-steroidal anti-inflammatory drugs include (salsalate) , (difiunisal) , (ibuprofen) , (ketoprofen) , (nabumetone) , (piroxicam) , ibuprofen cream, (naproxen) and (naproxen) , (diclofenac) , (indomethacin) , (sulindac) , (tolmetin) , (etodolac) , (ketorolac) , (oxaprozin) and the like.
  • PDGFR inhibitors include C-451, CP-673, CP-868596 and the like.
  • Platinum chemotherapeutics include cisplatin, (oxaliplatin) eptaplatin, lobaplatin, nedaplatin, (carboplatin) , satraplatin, picoplatin and the like.
  • Polo-like kinase inhibitors include BI-2536 and the like.
  • Phosphoinositide-3 kinase (PI3K) inhibitors include wortmannin, LY294002, XL-147, CAL-120, ONC-21, AEZS-127, ETP-45658, PX-866, GDC-0941, BGT226, BEZ235, XL765 and the like.
  • Thrombospondin analogs include ABT-510, ABT-567, ABT-898, TSP-1 and the like.
  • VEGFR inhibitors include (bevacizumab) , ABT-869, AEE-788, ANGIOZYME TM (a ribozyme that inhibits angiogenesis (Ribozyme Pharmaceuticals (Boulder, CO.) and Chiron, (Emeryville, CA) ) , axitinib (AG-13736) , AZD-2171, CP-547, 632, IM-862, MACUGEN (pegaptamib) , (sorafenib, BAY43-9006) , pazopanib (GW-786034) , vatalanib (PTK-787, ZK-222584) , (sunitinib, SU-11248) , VEGF trap, ZACTIMA TM (vandetanib, ZD-6474) and the like.
  • ANGIOZYME TM a ribozyme that inhibits angiogenesis
  • axitinib AG-13736
  • Antibiotics include intercalating antibiotics aclarubicin, actinomycin D, amrubicin, annamycin, adriamycin, (bleomycin) , daunorubicin, or (liposomal doxorubicin) , elsamitrucin, epirbucin, glarbuicin, (idarubicin) , mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin, (valrubicin) , zinostatin and the like.
  • Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin, amonafide, amsacrine, becatecarin, belotecan, BN-80915, (irinotecan hydrochloride) , camptothecin, (dexrazoxine) , diflomotecan, edotecarin, or (epirubicin) , etoposide, exatecan, 10-hydroxycamptothecin, gimatecan, lurtotecan, mitoxantrone, orathecin, pirarbucin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide, topotecan and the like.
  • Antibodies include (bevacizumab) , CD40-specific antibodies, chTNT-1/B, denosumab, (cetuximab) , (zanolimumab) , IGFlR-specific antibodies, lintuzumab, (edrecolomab) , (WX G250) , (rituximab) , ticilimumab, trastuzimab, CD20 antibodies types I and II and the like.
  • Hormonal therapies include (anastrozole) , (exemestane) , arzoxifene, (bicalutamide) , (cetrorelix) , degarelix, deslorelin, (trilostane) , dexamethasone, (flutamide) , (raloxifene) , AFEMA TM (fadrozole) , (toremifene) , (fulvestrant) , (letrozole) , formestane, glucocorticoids, (doxercalciferol) , (sevelamer carbonate) , lasofoxifene, leuprolide acetate, (megesterol) , (mifepristone) , NILANDRON TM (nilutamide) , (tamoxifen citrate) , PLENAXIS TM (abarelix) , prednisone, (finasteride) , rilostane
  • Deltoids and retinoids include seocalcitol (EB1089, CB1093) , lexacalcitrol (KH1060) , fenretinide, (aliretinoin) , (liposomal tretinoin) , (bexarotene) , LGD-1550 and the like.
  • PARP inhibitors include ABT-888 (veliparib) , olaparib, KU-59436, AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231 and the like.
  • Plant alkaloids include, but are not limited to, vincristine, vinblastine, vindesine, vinorelbine and the like.
  • Proteasome inhibitors include (bortezomib) , MG132, NPI-0052, PR-171 and the like.
  • immunologicals include interferons and other immune-enhancing agents.
  • Interferons include interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-la, (interferon gamma-lb) or interferon gamma-nl, combinations thereof and the like.
  • agents include (IFN-a) , BAM-002 (oxidized glutathione) , (tasonermin) , (tositumomab) , (alemtuzumab) , CTLA4 (cytotoxic lymphocyte antigen 4) , decarbazine, denileukin, epratuzumab, (lenograstim) , lentinan, leukocyte alpha interferon, imiquimod, MDX-010 (anti-CTLA-4) , melanoma vaccine, mitumomab, molgramostim, MYLOTARG TM (gemtuzumab ozogamicin) , (filgrastim) , OncoVAC-CL, (oregovomab) , pemtumomab (Y-muHMFGl) , (sipuleucel-T) , sargaramostim, sizofilan, teceleukin, (Baci
  • Biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth or differentiation of tissue cells to direct them to have anti-tumor activity and include krestin, lentinan, sizofiran, picibanil PF-3512676 (CpG-8954) , ubenimex and the like.
  • Pyrimidine analogs include cytarabine (ara C or Arabinoside C) , cytosine arabinoside, doxifluridine, (fludarabine) , 5-FU (5-fluorouracil) , floxuridine, (gemcitabine) , (ratitrexed) , TROXATYL TM (triacetyluridine troxacitabine) and the like.
  • Purine analogs include (thioguanine) and (mercaptopurine) .
  • Antimitotic agents include batabulin, epothilone D (KOS-862) , N- (2- ( (4-hydroxyphenyl) amino) pyridin-3 -yl) -4-methoxybenzenesulfonamide, ixabepilone (BMS 247550) , paclitaxel, (docetaxel) , PNU100940 (109881) , patupilone, XRP-9881 (larotaxel) , vinflunine, ZK-EPO (synthetic epothilone) and the like.
  • Ubiquitin ligase inhibitors include MDM2 inhibitors, such as nutlins, NEDD8 inhibitors such as MLN4924 and the like.
  • Compounds of this invention can also be used as radiosensitizers that enhance the efficacy of radiotherapy. Examples of radiotherapy include external beam radiotherapy, teletherapy, brachytherapy and sealed, unsealed source radiotherapy and the like.
  • compounds having Formula (I) may be combined with other chemotherapeutic agents such as ABRAXANE TM (ABI-007) , ABT-100 (farnesyl transferase inhibitor) , (Ad5CMV-p53 vaccine) , or (lovastatin) , (poly Lpoly C12U, a synthetic RNA) , (exisulind) , (pamidronic acid) , arglabin, L-asparaginase, atamestane (l-methyl-3, 17-dione-androsta-l, 4-diene) , (tazarotene) , AVE-8062 (combreastatin derivative) BEC2 (mitumomab) , cachectin or cachexin (tumor necrosis factor) , canvaxin (vaccine) , (cancer vaccine) , (celmoleukin) , (histamine dihydrochloride) , (human papillomavirus vaccine)
  • Ae compound of formula (I) can also be prepared as a pharmaceutically acceptable acid addition salt by, for example, reacting the free base form of a compound with a pharmaceutically acceptable inorganic or organic acid.
  • a pharmaceutically acceptable base addition salt of the a compound of formula (I) can be prepared by, for example, reacting the free acid form of the a compound with a pharmaceutically acceptable inorganic or organic base.
  • Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compounds of formula (I) are set forth in the definitions section of this Application.
  • the salt forms of the compounds of formula (I) can be prepared using salts of the starting materials or intermediates.
  • the free acid or free base forms of the compounds of formula (I) can be prepared from the corresponding base addition salt or acid addition salt form.
  • a compound of formula (I) in an acid addition salt form can be converted to the corresponding free base thereof by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like) .
  • a compound of formula (I) in a base addition salt form can be converted to the corresponding free acid thereof by, for example, treating with a suitable acid (e.g., hydrochloric acid, etc) .
  • N-oxides of the a compound of formula (I) or a pharmaceutically acceptable salt thereof can be prepared by methods known to those of ordinary skill in the art.
  • N-oxides can be prepared by treating an unoxidized form of the compound of formula (I) with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at approximately 0 to 80 °C.
  • an oxidizing agent e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or the like
  • a suitable inert organic solvent e.g., a halogenated hydrocarbon such as dichloromethane
  • Compounds of formula (I) in an unoxidized form can be prepared from N-oxides of compounds of formula (I) by, for example, treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, and the like) in an suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, and the like) at 0 to 80 °C.
  • a reducing agent e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, and the like
  • an inert organic solvent e.g., acetonitrile, ethanol, aqueous dioxane, and the like
  • Protected derivatives of the compounds of formula (I) can be made by methods known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley &Sons, Inc. 1999.
  • references to ether or Et 2 O are to diethyl ether; brine refers to a saturated aqueous solution of NaCl. Unless otherwise indicated, all temperatures are expressed in °C (degrees Centigrade) . All reactions were conducted under an inert atmosphere at RT unless otherwise noted.
  • MS mass spectra
  • ESI electrospray ionization
  • UV detector 220 and 254 nm
  • ELSD evaporative light scattering detector
  • Thin-layer chromatography was performed on 0.25 mm Superchemgroup silica gel plates (60F-254) , visualized with UV light, 5%ethanolic phosphomolybdic acid, ninhydrin, or p-anisaldehyde solution. Flash column chromatography was performed on silica gel (200-300 mesh, Branch of Qingdao Haiyang Chemical Co., Ltd ) .
  • At least one compound of formula I and/or at least one pharmaceutically acceptable salt thereof may be synthesized according to a variety of reaction schemes. Some illustrative schemes are provided below and in the examples. Other reaction schemes could be readily devised by those skilled in the art in view of the present disclosure.
  • Phosphine oxide of formula IIa-b is prepared by reacting iodides of formula IIa-awith phosphine A in the presence of a palladium reagents such as Pd (OAc) 2 and a ligand such as Xantphos. Reaction of IIa-b with dichloropyrimidine B in the presence of a base such as NaH in a solvent such as DMF furnishes intermediates of formula IIa-c as a result of the regio-selective displacement of one of the chloride in compound B by the amino group in analine IIa-b.
  • a palladium reagents such as Pd (OAc) 2
  • a ligand such as Xantphos
  • Dimethylphosphine oxide (1a) was prepared according to the method described in J. Org. Chem. 1968, Vol. 33, No. 10, 3690-3694.
  • the reaction mixture was stirred at 95°Covernight.
  • the reaction was quenched with addition of water (4 mL) , 3 N HCl (1 mL) at room temperature and extracted with EtOAc (2 ⁇ 10 mL) .
  • the combined organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure.
  • the kinase reaction was initiated by the addition of purified or commercial tyrosine kinase proteins diluted in 49 ⁇ L of kinase reaction buffer. After incubation for 60 min at 37 °C, the plate was washed three times with phosphate-buffered saline (PBS) containing 0.1%Tween 20 (T-PBS) . Anti-phosphotyrosine (PY99) antibody (100 ⁇ L; 1: 500, diluted in 5 mg/mL BSA T-PBS) was then added.
  • PBS phosphate-buffered saline
  • T-PBS 0.1%Tween 20
  • the reaction was terminated by the addition of 50 ⁇ L of 2 mol/L H 2 SO 4 as the color changed, and the plate was analyzed using a multi-well spectrophotometer at 490 nm.
  • the inhibition rate (%) was calculated using the following equation: [1 - (A490/A490 control) ] ⁇ 100%.
  • the IC 50 values were calculated by concentration–response curve fitting using a SoftMax pro-based four-parameter method.
  • Kinase IC 50 (nM) Kinase IC 50 (nM) ALK 2.4 ⁇ 0.9 ALK F1174L 27.6 ⁇ 13.3 ALK L1196M 2.1 ⁇ 0.3 ALK R1275Q 3.6 ⁇ 0.2
  • NCI-H3122 cell line ATCC, Cat. No. CC-Y1574) , SU-DHL-1 (DSMZ, Cat. No. ACC-356) .
  • IC 50 values were calculated by concentration–response curve fitting using a SoftMax pro-based four-parameter method.
  • mice Female SCID Mouse (4–6 weeks old) were housed and maintained under specific-pathogen free conditions. Animal procedures were performed according to institutional ethical guidelines of animal care. Human NCI-H3122 lung cancer xenografts were maintained in SCID mice. In this study, under a sterilization condition, well growth tumors were cut into 1mm 3 fragments and the fragments were transplanted subcutaneously into the right flank by trocar in nude mice. When tumor reached a volume of 150-180 mm 3 , the mice were randomized to control and treated groups, and received vehicle, and compounds at indicated doses and schedule. The size of tumors were measured individually twice per week with microcalipers.

Abstract

Provided are certain ALK inhibitors, pharmaceutical compositions thereof, and methods of use thereof.

Description

PHOSPHORUS CONTAINING COMPOUNDS AS PROTEIN KINASE INHIBITORS
This application claims the priority to the U. S. provisional application No. 62/290,465, which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
Disclosed herein are certain novel pyrimidine derivatives or pharmaceutical compositions thereof which can inhibit kinase activity of ALK, and may be useful for the treatment of hyper-proliferative diseases like cancer and inflammation.
BACKGROUND OF THE INVENTION
Hyper-proliferative diseases like cancer and inflammation are attracting the scientific community to provide therapeutic benefits. In this regard efforts have been made to identify and target specific mechanisms which play a role in proliferating the diseases.
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. Mol. Life. Sci. 61: 2939-2953 (2004) ) .
Because of the emerging disease-related roles of ALK, there is a continuing need for compounds which may be useful for treating and preventing a disease which responds to inhibition of ALK and have at least one advantageous property selected from potency, stability, selectivity, toxicity, pharmacodynamics properties and pharmacokinetics properties as an alternative. In this regard, a novel class of ALK inhibitors is provided herein.
DISCLOSURE OF THE INVENTION
Disclosed herein are certain novel pyrimidine derivatives, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, and their use as pharmaceuticals.
In one aspect, disclosed herein is a compound of formula (I)
Figure PCTCN2017072828-appb-000001
or a pharmaceutically acceptable salt thereof, wherein
each R1 is independently selected from hydrogen, halogen, hydroxyl, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, C1-10 alkylamino, C3-10 cycloalkylamino, di (C1-10 alkyl) amino, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl and heteroaryl-C1-4 alkyl, wherein alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RX；
each R2 is independently selected from hydrogen, halogen, hydroxyl, CN, C1-10 alkyl, C2-10 alkenyl, C2-10alkynyl, C3-10cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, C1-10 alkylamino, C3-10 cycloalkylamino, di (C1-10 alkyl) amino, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl and heteroaryl-C1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RX；
R3 is independently selected from hydrogen, halogen, CN, -NRARB and C1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RX；
R4 is independently selected from hydrogen, halogen, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl and C3-10cycloalkyl, wherein alkyl, alkenyl, alkynyl, and cycloalkyl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RX；
or R3 and R4 together with the carbon atoms to which they are attached form a 5-6 membered ring containing 0, 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2 or 3 RX groups；
each R5 is independently selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10cycloalkyl, C3-10cycloalkyl-C1-4alkyl, heterocyclyl, heterocyclyl-C1-4alkyl, aryl, aryl-C1-4alkyl, heteroaryl, heteroaryl-C1-4alkyl, CN, NO2, -NRA1RB1, -ORA1, -S (O) rRA1, -S (O) 2ORA1, -OS (O) 2RA1, -P (O) RA1RB1, -P (O) (ORA1) (ORB1) , -C (O) RA1, -C (O) ORA1, -OC (O) RA1,  -C (O) NRA1RB1, -NRA1C (O) RB1, -OC (O) NRA1RB1, -NRA1C (O) ORB1, -NRA1C (O) NRA1RB1, -NRA1C (S) NRA1RB1, -S (O) rNRA1RB1, -NRA1S (O) rRB1, -NRA1S (O) 2NRA1RB1, -S (O) (＝NRE1) RB1, -N＝S (O) RA1RB1, -NRA1S (O) (＝NRE1) RB1, -S (O) (＝NRE1) NRA1RB1, -NRA1S (O) (＝NRE1) NRA1RB1, -C (＝NRE1) RA1, -C (＝N-ORB1) RA1, -C (＝NRE1) NRA1RB1, -NRA1C (＝NRE1) RB1 and -NRA1C (＝NRE1) NRA1RB1, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RX；
R6 and R7 are independently selected from hydrogen, hydroxyl, C1-10 alkyl, C3-10 cycloalkyl and C1-10alkoxyl, wherein alkyl, cycloalkyl, and alkoxyl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RX；
each RA, RA1, RB and RB1 are independently selected from hydrogen, C1-10alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl and heteroaryl-C1-4alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RX；
or each “RA and RB” or “RA1 and RB1” together with the atom (s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 RX groups；
each RE1 is independently selected from hydrogen, C1-10alkyl, CN, NO2, -ORa1, -SRa1, -S (O) rRa1, -C (O) Ra1, -C (O) ORa1, -C (O) NRa1Rb1 and -S (O) rNRa1Rb1；
each RX is independently selected from C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, heteroaryl-C1-4alkyl, halogen, CN, NO2, - (CRc1Rd1) tNRa1Rb1, - (CRc1Rd1) tORb1, - (CRc1Rd1) tS (O) rRb1, - (CRc1Rd1) tS (O) 2ORb1, - (CRc1Rd1) tOS (O) 2Rb1, - (CRc1Rd1) tP (O) Ra1Rb1, - (CRc1Rd1) tP (O) (ORa1) (ORb1) , - (CRc1Rd1) tC (O) Ra1, - (CRc1Rd1) tC (O) ORb1, - (CRc1Rd1) tOC (O) Rb1, - (CRc1Rd1) tC (O) NRa1Rb1, - (CRc1Rd1) tNRa1C (O) Rb1, - (CRc1Rd1) tOC (O) NRa1Rb1, - (CRc1Rd1) tNRa1C (O) ORb1, - (CRc1Rd1) tNRa1C (O) NRa1Rb1, - (CRc1Rd1) tNRa1C (S) NRa1Rb1, - (CRc1Rd1) tS (O) rNRa1Rb1, - (CRc1Rd1) tNRa1S (O) rRb1, - (CRc1Rd1) tNRa1S (O) 2NRa1Rb1, - (CRc1Rd1) tS (O) (＝NRe1) Rb1, - (CRc1Rd1) tN＝S (O) Ra1Rb1, - (CRc1Rd1) tNRa1S (O) (＝NRe1) Rb1, - (CRc1Rd1) tS (O) (＝NRe1) NRa1Rb1, - (CRc1Rd1) tNRa1S (O) (＝NRe1) NRa1Rb1, - (CRc1Rd1) tC (＝NRe1) Ra1, - (CRc1Rd1) tC (＝N-ORb1) Ra1, - (CRc1Rd1) tC (＝NRe1) NRa1Rb1, - (CRc1Rd1) tNRa1C (＝NRe1) Rb1 and - (CRc1Rd1) tNRa1C (＝NRe1) NRa1Rb1, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RY；
each Ra1 and each Rb1 are independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4alkyl, heteroaryl and heteroaryl-C1-4alkyl, wherein alkyl, alkenyl, alkynyl,  cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RY；
or Ra1 and Rb1 together with the atom (s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 RY groups；
each Rc1 and each Rd1 are independently selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl and heteroaryl-C1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RY；
or Rc1 and Rd1 together with the carbon atom (s) to which they are attached form a ring of 3 to 12 members containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2 or 3 RY groups；
each Re1 is independently selected from hydrogen, C1-10alkyl, C3-10cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, CN, NO2, -ORa2, -SRa2, -S (O) rRa2, -C (O) Ra2, -C (O) ORa2, -S (O) rNRa2Rb2 and -C (O) NRa2Rb2；
each RY is independently selected from C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, heteroaryl-C1-4alkyl, halogen, CN, NO2, - (CRc2Rd2) tNRa2Rb2, - (CRc2Rd2) tORb2, - (CRc2Rd2) tS (O) rRb2, - (CRc2Rd2) tS (O) 2ORb2, - (CRc2Rd2) tOS (O) 2Rb2, - (CRc2Rd2) tP (O) Ra2Rb2, - (CRc2Rd2) tP (O) (ORa2) (ORb2) , - (CRc2Rd2) tC (O) Ra2, - (CRc2Rd2) tC (O) ORb2, - (CRc2Rd2) tOC (O) Rb2, - (CRc2Rd2) tC (O) NRa2Rb2, - (CRc2Rd2) tNRa2C (O) Rb2, - (CRc2Rd2) tOC (O) NRa2Rb2, - (CRc2Rd2) tNRa2C (O) ORb2, - (CRc2Rd2) tNRa2C (O) NRa2Rb2, - (CRc2Rd2) tNRa2C (S) NRa2Rb2, - (CRc2Rd2) tS (O) rNRa2Rb2, - (CRc2Rd2) tNRa2S (O) rRb2, - (CRc2Rd2) tNRa2S (O) 2NRa2Rb2, - (CRc2Rd2) tS (O) (＝NRe2) Rb2, - (CRc2Rd2) tN＝S (O) Ra2Rb2, - (CRc2Rd2) tNRa2S (O) (＝NRe2) Rb2, - (CRc2Rd2) tS (O) (＝NRe2) NRa2Rb2, - (CRc2Rd2) tNRa2S (O) (＝NRe2) NRa2Rb2, - (CRc2Rd2) tC (＝NRe2) Ra2, - (CRc2Rd2) tC (＝N-ORb2) Ra2, - (CRc2Rd2) tC (＝NRe2) NRa2Rb2, - (CRc2Rd2) tNRa2C (＝NRe2) Rb2 and - (CRc2Rd2) tNRa2C (＝NRe2) NRa2Rb2, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from OH, CN, amino, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, C1-10 alkylamino, C3-10 cycloalkylamino and di (C1-10 alkyl) amino；
each Ra2 and each Rb2 are independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, C1-10 alkylamino, C3-10 cycloalkylamino, di (C1-10 alkyl) amino, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl and heteroaryl-C1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents,  independently selected from halogen, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, OH, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, amino, C1-10 alkylamino, C3-10 cycloalkylamino and di (C1-10 alkyl) amino；
or Ra2 and Rb2 together with the atom (s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1 or 2 substituents, independently selected from halogen, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, OH, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, amino, C1-10 alkylamino, C3-10 cycloalkylamino and di (C1-10 alkyl) amino；
each Rc2 and each Rd2 are independently selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, C1-10 alkylamino, C3-10 cycloalkylamino, di (C1-10 alkyl) amino, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl and heteroaryl-C1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from halogen, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, OH, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, amino, C1-10 alkylamino, C3-10 cycloalkylamino and di (C1-10 alkyl) amino；
or Rc2 and Rd2 together with the carbon atom (s) to which they are attached form a ring of 3 to 12 members containing 0, 1, or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1 or 2 substituents, independently selected from halogen, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, OH, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, amino, C1-10 alkylamino, C3-10 cycloalkylamino and di (C1-10 alkyl) amino；
each Re2 is independently selected from hydrogen, CN， NO2， C1-10 alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4alkyl, C1-10 alkoxy, C3-10 cycloalkoxy, -C (O) C1-4 alkyl, -C (O) C3-10 cycloalkyl, -C (O) OC1-4alkyl, -C (O) OC3-10 cycloalkyl, -C (O) N (C1-4alkyl) 2, -C (O) N (C3-10cycloalkyl) 2, -S (O) 2C1-4 alkyl, -S (O) 2C3-10 cycloalkyl, -S (O) 2N (C1-4 alkyl) 2 and -S (O) 2N (C3-10 cycloalkyl) 2；
m is independently selected from 0, 1 and 2；
n is independently selected from 1, 2 and 3；
p is independently selected from 0, 1, 2 and 3；
q is independently selected from 0, 1, 2 and 3；
each r is independently selected from 1 and 2；
each t is independently selected from 0, 1, 2, 3 and 4.
In yet another aspect, disclosed herein is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
In yet another aspect, disclosed herein is a method for modulating ALK, comprising administering to a system or a subject in need thereof, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or pharmaceutical compositions thereof, thereby modulating said ALK.
In yet another aspect, disclosed herein is a method to treat, ameliorate or prevent a condition which responds to inhibition of ALK comprising administering to a system or subject in need of such treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or pharmaceutical compositions thereof, and optionally in combination with a second therapeutic agent, thereby treating said condition.
Alternatively, disclosed herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a condition mediated by ALK. In particular embodiments, the compound of the disclosure may be used alone or in combination with a second therapeutic agent to treat a condition mediated by ALK.
Alternatively, disclosed herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating a condition mediated by ALK.
Specifically, the condition herein includes but not limited to, is an autoimmune disease, a transplantation disease, an infectious disease or a cell proliferative disorder.
Furthermore, disclosed herein is a method for treating a cell proliferative disorder, comprising administering to a system or subject in need of such treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or pharmaceutical compositions thereof, and optionally in combination with a second therapeutic agent, thereby treating said condition.
Alternatively, disclosed herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a cell-proliferative disorder. In particular examples, the compounds of the disclosure may be used alone or in combination with a chemotherapeutic agent to treat a cell proliferative disorder.
Specifically, the cell proliferative disorder disclosed herein includes but not limited to, lymphoma, osteosarcoma, melanoma, or a tumor of breast, renal, prostate, colorectal, thyroid, ovarian, pancreatic, neuronal, lung, uterine or gastrointestinal tumor.
In the above methods for using the compounds of the disclosure, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered to a system comprising cells or tissues, or to a subject including a mammalian subject such as a human or animal subject.
Certain Terminology
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter  belongs. All patents, patent applications, published materials referred to throughout the entire disclosure herein, unless noted otherwise, are incorporated by reference in their entirety. In the event that there is a plurality of definitions for terms herein, those in this section prevail.
It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms "a" , "an" and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that use of "or" means "and/or" unless stated otherwise. Furthermore, use of the term "including" as well as other forms, suchas "include" , "includes" , and "included" is not limiting. Likewise, use of the term “comprising” as well as other forms, such as "comprise" , "comprises" , and "comprised" is not limiting.
Definition of standard chemistry terms may be found in reference works, including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED. " Vols. A (2000) and B (2001) , Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, IR and UV/Vis spectroscopy and pharmacology, within the skill of the art are employed. Unless specific definitions are provided, the nomenclature employed in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those known in the art. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Reactions and purification techniques can be performed e.g., using kits of manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures can be generally performed of conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. Throughout the specification, groups and substituents thereof can be chosen by one skilled in the field to provide stable moieties and compounds.
Where substituent groups are specified by their conventional chemical formulas, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left. As a non-limiting example, CH2O is equivalent to OCH2.
As used herein, the term "optionally substituted" means unsubstituted or substituted. The term "substituted" means that a hydrogen atom is removed and replaced by a substituent. It is to be understood that substitution at a given atom is limited by valency. Throughout the definitions, the term “Ci-j” indicates a range which includes the endpoints, wherein i and j are integers and indicate the number of carbons. Examples include C1-4, C1-10, C3-10, and the like.
The term "alkyl" , employed alone or in combination with other terms, refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Unless otherwise specified, “alkyl” refers to Cl-10 alkyl. For example, C1-6, as in "Cl-6 alkyl" is defined to include groups having 1, 2, 3, 4, 5, or 6 carbons in a linear or  branched arrangement. For example, "Cl-8 alkyl" includes but is not limited to methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl, hexyl, heptyl, and octyl.
The term "cycloalkyl" , employed alone or in combination with other terms, refers to a monocyclic or bridged hydrocarbon ring system. The monocyclic cycloalkyl is a carbocyclic ring system containing three to ten carbon atoms, zero heteroatoms and zero double bonds. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The monocyclic ring may contain one or two alkylene bridges, each consisting of one, two, or three carbon atoms, each linking two non-adjacent carbon atoms of the ring system. Representative examples of such bridged cycloalkyl ring systems include, but are not limited to, bicyclo [3.1.1] heptane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, bicyclo [3.3.1] nonane, bicyclo [4.2.1] nonane, tricyclo [3.3.1.03, 7] nonane, and tricyclo [3.3.1.13, 7] decane (adamantane) . The monocyclic and bridged cycloalkyl can be attached to the parent molecular moiety through any substitutable atom contained within the ring system.
The term "alkenyl" , employed alone or in combination with other terms, refers to a non-aromatic hydrocarbon radical, straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. In some embodiments, one carbon to carbon double bond is present, and up to four non-aromatic carbon-carbon double bonds may be present. Thus, "C2-6 alkenyl" means an alkenyl radical having from 2 to 6 carbon atoms. Alkenyl groups include but are not limited to ethenyl, propenyl, butenyl, 2-methylbutenyl and cyclohexenyl. The straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated.
The term "alkynyl" , employed alone or in combination with other terems, refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond. In some embodiments, up to three carbon-carbon triple bonds may be present. Thus, "C2-6 alkynyl" means an alkynyl radical having from 2 to 6 carbon atoms. Alkynyl groups include but are not limited to ethynyl, propynyl, butynyl, and 3-methylbutynyl. The straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is indicated.
The term "halogen" (or "halo" ) refers to fluorine, chlorine, bromine and iodine.
The term "alkoxy" , employed alone or in combination with other terms, refers to an alkyl radical that is single bonded to an oxygen atom. The attachment point of an alkoxy radical to a molecule is through the oxygen atom. An alkoxy radical may be depicted as -O-alkyl. The term "C1-10 alkoxy" refers to an alkoxy radical containing from one to ten carbon atoms, having straight or branched moieties. Alkoxy groups, includes but is not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, hexyloxy, and the like.
The term "cycloalkoxy" , employed alone or in combination with other terms, refers to cycloalkyl radical that is single bonded to an oxygen atom. The attachment point of a cycloalkoxy radical to a molecule is through the oxygen atom. A cycloalkoxy radical may be  depicted as -O-cycloalkyl. "C3-10 cycloalkoxy" refers to a cycloalkoxy radical containing from three to ten carbon atoms. Cycloalkoxy groups, includes but is not limited to, cyclopropoxy, cyclobutoxy, cyclohexyloxy, and the like.
The term "alkylthio" , employed alone or in combination with other terms, refers to an alkyl radical that is single bonded to a sulfur atom. The attachment point of an alkylthio radical to a molecule is through the sulfur atom. An alkylthio radical may be depicted as -S-alkyl. The term "C1-10 alkylthio" refers to an alkylthio radical containing from one to ten carbon atoms, having straight or branched moieties. Alkylthio groups, includes but is not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, hexylthio, and the like.
The term "cycloalkylthio" , employed alone or in combination with other terms, refers to cycloalkyl radical that is single bonded to a sulfur atom. The attachment point of a cycloalkylthio radical to a molecule is through the sulfur atom. A cycloalkylthio radical may be depicted as -S-cycloalkyl. "C3-10 cycloalkylthio" refers to a cycloalkylthio radical containing from three to ten carbon atoms. Cycloalkylthio groups, includes but is not limited to, cyclopropylthio, cyclobutylthio, cyclohexylthio, and the like.
The term "alkylamino" , employed alone or in combination with other terms, refers to an alkyl radical that is single bonded to a nitrogen atom. The attachment point of an alkylamino radical to a molecule is through the nitrogen atom. An alkylamino radical may be depicted as -NH (alkyl) . The term "C1-10 alkylamino" refers to an alkylamino radical containing from one to ten carbon atoms, having straight or branched moieties. Alkylamino groups, includes but is not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, hexylamoino, and the like.
The term "cycloalkylamino" , employed alone or in combination with other terms, refers to cycloalkyl radical that is single bonded to a nitrogen atom. The attachment point of a cycloalkylamino radical to a molecule is through the nitrogen atom. A cycloalkylamino radical may be depicted as -NH (cycloalkyl) . "C3-10 cycloalkylamino" refers to a cycloalkylamino radical containing from three to ten carbon atoms. Cycloalkylamino groups, includes but is not limited to, cyclopropylamino, cyclobutylamino, cyclohexylamino, and the like.
The term "di (alkyl) amino" , employed alone or in combination with other terms, refers to two alkyl radicals that are single bonded to a nitrogen atom. The attachment point of an di(alkyl) amino radical to a molecule is through the nitrogen atom. A di (alkyl) amino radical may be depicted as -N (alkyl) 2. The term "di (C1-10 alkyl) amino" refers to a di (C1-10 alkyl) amino radical wherein the alkyl radicals each independently contains from one to ten carbon atoms, having straight or branched moieties.
The term "aryl" , employed alone or in combination with other terms, encompasses: 5-and 6-membered carbocyclic aromatic rings, for example, benzene； bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, naphthalene, indane, and 1, 2, 3, 4-tetrahydroquinoline； and tricyclic ring systems wherein at least one ring is carbocyclic and  aromatic, for example, fluorene. In cases where the aryl substituent is bicyclic or tricyclic and at least one ring is non-aromatic, it is understood that attachment is via the aromatic ring.
For example, aryl includes 5-and 6-membered carbocyclic aromatic rings fused to a 5-to 7-membered heterocyclic ring containing one or more heteroatoms selected from N, O, and S, provided that the point of attachment is at the carbocyclic aromatic ring. Bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals. Bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in "-yl" by removal of one hydrogen atom from the carbon atom with the free valence are named by adding "-idene" to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene. Aryl, however, does not encompass or overlap in any way with heteroaryl, separately defined below. Hence, if one or more carbocyclic aromatic rings are fused with a heterocyclic aromatic ring, the resulting ring system is heteroaryl, not aryl, as defined herein.
The term “heteroaryl” , employed alone or in combination with other terms, refers to
5-to 8-membered aromatic, monocyclic rings containing one or more, for example, from 1 to 4, or, in some embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon；
8-to 12-membered bicyclic rings containing one or more, for example, from 1 to 4, or, in some embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring； and
11-to 14-membered tricyclic rings containing one or more, for example, from 1 to 4, or in some embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring.
When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heteroaryl groups include, but are not limited to, (as numbered from the linkage position assigned priority 1) , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2, 3-pyrazinyl, 3, 4-pyrazinyl, 2, 4-pyrimidinyl, 3, 5-pyrimidinyl, 1-pyrazolyl, 2, 3-pyrazolyl, 2, 4-imidazolinyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothienyl, furyl, benzofuryl, benzoimidazolinyl, indolinyl, pyridizinyl, triazolyl, quinolinyl, pyrazolyl, and 5, 6, 7, 8-tetrahydroisoquinoline.
Further heteroaryl groups include but are not limited to pyrrolyl, isothiazolyl, triazinyl, pyrazinyl, pyridazinyl, indolyl, benzotriazolyl, quinoxalinyl, and isoquinolinyl, . As with the definition of heterocycle below, "heteroaryl" is also understood to include the N-oxide derivative of any nitrogen-containing heteroaryl.
Bivalent radicals derived from univalent heteroaryl radicals whose names end in "-yl" by removal of one hydrogen atom from the atom with the free valence are named by adding "-idene" to the name of the corresponding univalent radical, e.g., a pyridyl group with two points of attachment is a pyridylidene. Heteroaryl does not encompass or overlap with aryl as defined above.
In cases where the heteroaryl substituent is bicyclic or tricyclic and at least one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively.
The term "heterocycle" , employed alone or in combination with other terms, (and variations thereof such as "heterocyclic" , or "heterocyclyl" ) broadly refers to a single aliphatic ring, usually with 3 to 12 ring atoms, containing at least 2 carbon atoms in addition to one or more, preferably one to three heteroatoms independently selected from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms. Alternatively , a heterocycle as defined above may be multicyclic ring system (e.g. bicyclic) in which two or more rings may be fused or bridged or spiro together, wherein at least one such ring contains one or more heteroatoms independently selected from oxygen, sulfur, and nitrogen. “Heterocycle” also refers to 5-to 7-membered heterocyclic ring containing one or more heteroatoms selected from N, O, and S fused with 5-and 6-membered carbocyclic aromatic ring, provided that the point of attachment is at the heterocyclic ring. The rings may be saturated or have one or more double bonds (i.e. partially unsaturated) . The heterocycle can be substituted by oxo. The point of the attachment may be carbon or heteroatom in the heterocyclic ring, provided that attachment results in the creation of a stable structure. When the heterocyclic ring has substituents, it is understood that the substituents may be attached to any atom in the ring, whether a heteroatom or a carbon atom, provided that a stable chemical structure results. Heterocycle does not overlap with heteroaryl.
Suitable heterocycles include, for example (as numbered from the linkage position assigned priority 1) , 1-pyrrolidinyl, 2-pyrrolidinyl, 2, 4-imidazolidinyl, 2, 3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2, 5-piperazinyl. 1, 4-piperazinyl, and 2, 3-pyridazinyl. Morpholinyl groups are also contemplated, including 2-morpholinyl and 3-morpholinyl (numbered wherein the oxygen is assigned priority 1) . Substituted heterocycle also includes ring systems substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and 1, 1-dioxo-1-thiomorpholinyl. Bicyclic heterocycles include, for example:
Figure PCTCN2017072828-appb-000002
Figure PCTCN2017072828-appb-000003
As used herein, “aryl-alkyl” refers to an alkyl moiety substituted by an aryl group. Example aryl-alkyl groups include benzyl, phenethyl, and naphthylmethyl groups. In some embodiments, aryl-alkyl groups have from 7 to 20 or 7 to 11 carbon atoms. When used in the phrase "aryl-Cl-4 alkyl” , the term "C1-4” refers to the alkyl portion of the moiety and does not describe the number of atoms in the aryl portion of the moiety.
As used herein, “heterocyclyl-alkyl” refers to alkyl substituted by heterocyclyl. When used in the phrase "heterocyclyl-C1-4 alkyl” , the term "C1-4” refers to the alkyl portion of the moiety and does not describe the number of atoms in the heterocyclyl portion of the moiety.
As used herein, "cycloalkyl-alkyl" refers to alkyl substituted by cycloalkyl. When used in the phrase "C3-10 cycloalkyl-Cl-4 alkyl” , the term "C3-10” refers to the cycloalkyl portion of the moiety and does not describe the number of atoms in the alkyl portion of the moiety, and the term "C1-4” refers to the alkyl portion of the moiety and does not describe the number of atoms in the cycloalkyl portion of the moiety.
As used herein, "heteroaryl-alkyl" refers to alkyl substituted by heteroaryl. When used in the phrase "heteroaryl-Cl-4 alkyl” , the term "C1-4” refers to the alkyl portion of the moiety and does not describe the number of atoms in the heteroaryl portion of the moiety.
For avoidance of doubt, reference, for example, to substitution of alkyl, cycloalkyl, heterocyclyl, aryl, and/or heteroaryl refers to substitution of each of those groups individually as well as to substitutions of combinations of those groups. That is, if R1 is aryl-Cl-4 alkyl, the aryl portion may be unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from RX and the alkyl portion may also be unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from RX.
The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases may be selected, for example, from aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, and zinc salts. Further, for example, the pharmaceutically acceptable salts derived from inorganic bases may be selected from ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in one or more crystal structures, and may also be in the form of hydrates. Salts derived from pharmaceutically acceptable organic non-toxic bases may be selected, for example, from salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, and tripropylamine, tromethamine.
When the compound disclosed herein is basic, salts may be prepared using at least one pharmaceutically acceptable non-toxic acid, selected from inorganic and organic acids. Such acid may be selected, for example, from acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, and p-toluenesulfonic acids. In some embodiments, such acid may be selected, for example, from citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.
The terms "administration of" and or "administering" a compound or a pharmaceutically acceptable salt should be understood to mean providing a compound or a pharmaceutically acceptable salt thereof to the individual in recognized need of treatment.
The term "effective amount" means the amount of the a compound or a pharmaceutically acceptable salt that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which  results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such term in relation to a pharmaceutical composition is intended to encompass a product comprising the active ingredient (s) , and the inert ingredient (s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
The term "pharmaceutically acceptable" it is meant compatible with the other ingredients of the formulation and not unacceptably deleterious to the recipient thereof.
The term "subject" as used herein in reference to individuals suffering from a disorder, a condition, and the like, encompasses mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species； farm animals such as cattle, horses, sheep, goats, swine； domestic animals such as rabbits, dogs, and cats； laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.
The terms "treat, " "treating" or "treatment, " and other grammatical equivalents as used herein, include alleviating, abating or ameliorating a disease or condition, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition, and are intended to include prophylaxis. The terms further include achieving a therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder. For prophylactic benefit, the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
The term "protecting group" or "Pg" refers to a substituent that can be commonly employed to block or protect a certain functionality while reacting other functional groups on the compound. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include but are not limited to acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC) , benzyloxycarbonyl (CBZ) and 9-fluorenylmethylenoxycarbonyl (Fmoc) . Similarly, a "hydroxy-protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include but are not limited to acetyl and silyl. A "carboxy-protecting group" refers to a substituent of the carboxy group that blocks or protects the  carboxy functionality. Common carboxy-protecting groups include -CH2CH2SO2Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenylsulfenyl) ethyl, 2- (diphenylphosphino) -ethyl, nitroethyl and the like. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley &Sons, New York, 1991.
The term "NH protecting group" as used herein includes， but not limited to, trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, para-nitrobenzylcarbonyl, ortho-bromobenzyloxycarbonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-amyloxycarbonyl, tert-butoxycarbonyl, para-methoxybenzyloxycarbonyl, 3, 4-dimethoxybenzyl-oxycarbonyl, 4- (phenylazo) -benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1, 1-dimethylpropoxy-carbonyl, isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl, 1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl, benzyl, diphenylmethyl, triphenylmethyl, 2-nitrophenylthio, methanesulfonyl, para-toluenesulfonyl, N, N-dimethylaminomethylene, benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-l-naphthylmethylene, 3-hydroxy-4-pyridylmethylene, cyclohexylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3, 3-dimethyl-5-oxycyclo-hexylidene, diphenylphosphoryl, dibenzylphosphoryl, 5-methyl-2-oxo-2H-l, 3-dioxol-4-yl-methyl, trimethylsilyl, triethylsilyl, and triphenylsilyl.
The term "C (O) OH protecting group" as used herein includes， but not limited to, methyl, ethyl, n-propyl, isopropyl, 1, 1-dimethylpropyl, n-butyl, tert-butyl, phenyl, naphthyl, benzyl, diphenylmethyl, triphenylmethyl, para-nitrobenzyl, para-methoxybenzyl, bis(para-methoxyphenyl) methyl, acetylmethyl, benzoylmethyl, para-nitrobenzoylmethyl, para-bromobenzoylmethyl, para-methanesulfonylbenzoylmethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 2, 2, 2-trichloro-ethyl, 2- (trimethylsilyl) ethyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, phthalimidomethyl, succinimidomethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, benzyloxymethyl, methylthiomethyl, 2-methylthioethyl, phenylthiomethyl, 1, 1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, and tert-butylmethoxyphenylsilyl.
The term "OH or SH protecting group" as used herein includes， but not limited to, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3, 4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1, 1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2, 2, 2-trichloroethoxycarbonyl, 2, 2, 2-tribromoethoxycarbonyl, 2- (trimethylsilyl) ethoxycarbonyl, 2- (phenylsulfonyl) ethoxycarbonyl, 2- (triphenylphosphonio) ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 4-ethoxy-1-naphthyloxycarbonyl, 8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl,  dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl, benzoyl, methyl, tert-butyl, 2, 2, 2-trichloroethyl, 2-trimethylsilylethyl, 1, 1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl (phenylmethyl) , para-methoxybenzyl, 3, 4-dimethoxybenzyl, diphenylmethyl, triphenylmethyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2, 2, 2-trichloro-ethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, 1-ethoxyethyl, methanesulfonyl, para-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, and tert-butylmethoxyphenylsilyl.
Geometric isomers may exist in the present compounds. Compounds of this invention may contain carbon-carbon double bonds or carbon-nitrogen double bonds in the E or Z configuration, wherein the term "E" represents higher order substituents on opposite sides of the carbon-carbon or carbon-nitrogen double bond and the term "Z" represents higher order substituents on the same side of the carbon-carbon or carbon-nitrogen double bond as determined by the Cahn-Ingold-Prelog Priority Rules. The compounds of this invention may also exist as a mixture of "E" and "Z" isomers. Substituents around a cycloalkyl or heterocycloalkyl are designated as being of cis or trans configuration. Furthermore, the invention contemplates the various isomers and mixtures thereof resulting from the disposal of substituents around an adamantane ring system. Two substituents around a single ring within an adamantane ring system are designated as being of Z or E relative configuration. For examples, see C. D. Jones, M. Kaselj, R. N. Salvatore, W. J. le Noble J. Org. Chem. 1998, 63, 2758-2760.
Compounds of this invention may contain asymmetrically substituted carbon atoms in the R or S configuration, in which the terms "R" and "S" are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-10. Compounds having asymmetrically substituted carbon atoms with equal amounts of R and S configurations are racemic at those carbon atoms. Atoms with an excess of one configuration over the other are assigned the configuration present in the higher amount, preferably an excess of about 85-90％, more preferably an excess of about 95-99％, and still more preferably an excess greater than about 99％. Accordingly, this invention includes racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.
Isotope Enriched or Labeled Compounds.
Compounds of the invention can exist in isotope-labeled or -enriched form containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most abundantly found in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, nitrogen, phosphorous, sulfur, fluorine, chlorine, and iodine include, but are not limited to, 2H, 3H, 13C, 14C, 15N, 18O, 32P, 35S, 18F, 36Cl, and 125I. Compounds that contain other isotopes of these and/or other atoms are within the scope of this invention.
In another embodiment, the isotope-labeled compounds contain deuterium (2H) , tritium (3H) or 14C isotopes. Isotope-labeled compounds of this invention can be prepared by the general methods well known to persons having ordinary skill in the art. Such isotope-labeled compounds can be conveniently prepared by carrying out the procedures disclosed in the Examples disclosed herein and Schemes by substituting a readily available isotope-labeled reagent for a non-labeled reagent. In some instances, compounds may be treated with isotope-labeled reagents to exchange a normal atom with its isotope, for example, hydrogen for deuterium can be exchanged by the action of a deuterated acid such as D2SO4/D2O. In addition to the above, relevant procedures and intermediates are disclosed, for instance, in Lizondo, J et al, Drugs Fut, 21 (11) , 1116 (1996) ； Brickner, S J et al., J Med Chem, 39 (3) , 673 (1996) ； Mallesham, B et al, Org Lett, 5 (7) , 963 (2003) ； PCT publications WO1997010223, WO2005099353, WO1995007271, WO2006008754； US Patent Nos. 7538189； 7534814； 7531685； 7528131； 7521421； 7514068； 7511013； and US Patent Application Publication Nos. 20090137457； 20090131485； 20090131363； 20090118238； 20090111840； 20090105338； 20090105307； 20090105147； 20090093422； 20090088416； and 20090082471, the methods are hereby incorporated by reference.
The isotope-labeled compounds of the invention may be used as standards to determine the effectiveness of ALK inhibitors in binding assays. Isotope containing compounds have been used in pharmaceutical research to investigate the in vivo metabolic fate of the compounds by evaluation of the mechanism of action and metabolic pathway of the nonisotope-labeled parent compound (Blake et al. J. Pharm. Sci. 64, 3, 367-391 (1975) ) . Such metabolic studies are important in the design of safe, effective therapeutic drugs, either because the in vivo active compound administered to the patient or because the metabolites produced from the parent compound prove to be toxic or carcinogenic (Foster et al., Advances in Drug Research Vol. 14, pp. 2-36, Academic press, London, 1985； Kato et al, J. Labelled Comp. Radiopharmaceut., 36 (10) : 927-932 (1995) ； Kushner et al., Can. J. Physiol. Pharmacol, 77, 79-88 (1999) .
In addition, non-radio active isotope containing drugs, such as deuterated drugs called "heavy drugs" can be used for the treatment of diseases and conditions related to ALK activity. Increasing the amount of an isotope present in a compound above its natural abundance is called enrichment. Examples of the amount of enrichment include from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96, to about 100 mol ％. Replacement of up to about 15％of normal atom with a heavy isotope has been effected and maintained for a period of days to weeks in mammals, including rodents and dogs, with minimal observed adverse effects (Czajka D M and Finkel A J, Ann. N. Y. Acad. Sci. 1960 84: 770； Thomson J F, Ann. New York Acad. Sci 1960 84: 736； Czakja D M et al., Am. J. Physiol. 1961 201 : 357) . Acute replacement of as high as 15％-23％in human fluids with deuterium was found not to cause toxicity (Blagojevic N et al. in "Dosimetry &Treatment Planning for Neutron Capture Therapy″ , Zamenhof R, Solares G and Harling O Eds. 1994. Advanced Medical Publishing, Madison Wis. pp. 125-134； Diabetes Metab. 23: 251 (1997) ) .
Stable isotope labeling of a drug can alter its physico-chemical properties such as pKa and lipid solubility. These effects and alterations can affect the pharmacodynamic response of the drug molecule if the isotopic substitution affects a region involved in a ligand-receptor interaction. While some of the physical properties of a stable isotope-labeled molecule are different from those of the unlabeled one, the chemical and biological properties are the same, with one important exception: because of the increased mass of the heavy isotope, any bond involving the heavy isotope and another atom will be stronger than the same bond between the light isotope and that atom. Accordingly, the incorporation of an isotope at a site of metabolism or enzymatic transformation will slow said reactions potentially altering the pharmacokinetic profile or efficacy relative to the non-isotopic compound.
In embodiment (1) ， this invention relates to a compound of formula (I)
Figure PCTCN2017072828-appb-000004
or a pharmaceutically acceptable salt thereof, wherein
each R1 is independently selected from hydrogen, halogen, hydroxyl, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, C1-10 alkylamino, C3-10 cycloalkylamino, di (C1-10 alkyl) amino, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, and heteroaryl-C1-4 alkyl, wherein alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RX；
each R2 is independently selected from hydrogen, halogen, hydroxyl, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, C1-10 alkylamino, C3-10 cycloalkylamino, di (C1-10 alkyl) amino, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, and heteroaryl-C1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RX；
R3 is independently selected from hydrogen, halogen, CN, -NRARB, and C1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RX；
R4 is independently selected from hydrogen, halogen, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, and C3-10 cycloalkyl, wherein alkyl, alkenyl, alkynyl, and cycloalkyl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RX；
or R3 and R4 together with the carbon atoms to which they are attached form a 5-6 membered ring containing 0, 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2 or 3 RX groups；
each R5 is independently selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, heteroaryl-C1-4 alkyl, CN, NO2, -NRA1RB1, -ORA1, -S (O) rRA1, -S (O) 2ORA1, -OS (O) 2RA1, -P (O) RA1RB1, -P (O) (ORA1) (ORB1) , -C (O) RA1, -C (O) ORA1, -OC (O) RA1, -C (O) NRA1RB1, -NRA1C (O) RB1, -OC (O) NRA1RB1, -NRA1C (O) ORB1, -NRA1C (O) NRA1RB1, -NRA1C (S) NRA1RB1, -S (O) rNRA1RB1, -NRA1S (O) rRB1, -NRA1S (O) 2NRA1RB1, -S (O) (＝NRE1) RB1, -N＝S (O) RA1RB1, -NRA1S (O) (＝NRE1) RB1, -S (O) (＝NRE1) NRA1RB1, -NRA1S (O) (＝NRE1) NRA1RB1, -C (＝NRE1) RA1, -C (＝N-ORB1) RA1, -C (＝NRE1) NRA1RB1, -NRA1C (＝NRE1) RB1 and -NRA1C (＝NRE1) NRA1RB1, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RX；
R6 and R7 are independently selected from hydrogen, hydroxyl, C1-10 alkyl, C3-10 cycloalkyl, and C1-10 alkoxyl, wherein alkyl, cycloalkyl, and alkoxyl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RX；
each RA, RA1, RB and RB1 are independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, and heteroaryl-C1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RX；
or each “RA and RB” or “RA1 and RB1” together with the atom (s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 RX groups；
each RE1 is independently selected from hydrogen, C1-10 alkyl, CN, NO2, ORa1, SRa1, -S (O) rRa1, -C (O) Ra1, -C (O) ORa1, -C (O) NRa1Rb1, and -S (O) rNRa1Rb1；
each RX is independently selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, heteroaryl-C1-4 alkyl, halogen, CN, NO2, - (CRc1Rd1) tNRa1Rb1, - (CRc1Rd1) tORb1, - (CRc1Rd1) tS (O) rRb1, - (CRc1Rd1) tS (O) 2ORb1, - (CRc1Rd1) tOS (O) 2Rb1, - (CRc1Rd1) tP (O) Ra1Rb1, - (CRc1Rd1) tP (O) (ORa1) (ORb1) , - (CRc1Rd1) tC (O) Ra1, - (CRc1Rd1) tC (O) ORb1, - (CRc1Rd1) tOC (O) Rb1, - (CRc1Rd1) tC (O) NRa1Rb1, - (CRc1Rd1) tNRa1C (O) Rb1, - (CRc1Rd1) tOC (O) NRa1Rb1,  - (CRc1Rd1) tNRa1C (O) ORb1, - (CRc1Rd1) tNRa1C (O) NRa1Rb1, - (CRc1Rd1) tNRa1C (S) NRa1Rb1, - (CRc1Rd1) tS (O) rNRa1Rb1, - (CRc1Rd1) tNRa1S (O) rRb1, - (CRc1Rd1) tNRa1S (O) 2NRa1Rb1, - (CRc1Rd1) tS (O) (＝NRe1) Rb1, - (CRc1Rd1) tN＝S (O) Ra1Rb1, - (CRc1Rd1) tNRa1S (O) (＝NRe1) Rb1, - (CRc1Rd1) tS (O) (＝NRe1) NRa1Rb1, - (CRc1Rd1) tNRa1S (O) (＝NRe1) NRa1Rb1, - (CRc1Rd1) tC (＝NRe1) Ra1, - (CRc1Rd1) tC (＝N-ORb1) Ra1, - (CRc1Rd1) tC (＝NRe1) NRa1Rb1, - (CRc1Rd1) tNRa1C (＝NRe1) Rb1 and - (CRc1Rd1) tNRa1C (＝NRe1) NRa1Rb1, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RY；
each Ra1 and each Rb1 are independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, and heteroaryl-C1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RY；
or Ra1 and Rb1 together with the atom (s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2, or 3 RY groups；
each Rc1 and each Rd1 are independently selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl and heteroaryl-C1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RY；
or Rc1 and Rd1 together with the carbon atom (s) to which they are attached form a ring of 3 to 12 members containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2 or 3 RY groups；
each Re1 is independently selected from hydrogen, C1-10 alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, CN, NO2, -ORa2, -SRa2, -S (O) rRa2, -C (O) Ra2, -C (O) ORa2, -S (O) rNRa2Rb2 and -C (O) NRa2Rb2；
each RY is independently selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, heteroaryl-C1-4 alkyl, halogen, CN, NO2, - (CRc2Rd2) tNRa2Rb2, - (CRc2Rd2) tORb2, - (CRc2Rd2) tS (O) rRb2, - (CRc2Rd2) tS (O) 2ORb2, - (CRc2Rd2) tOS (O) 2Rb2, - (CRc2Rd2) tP (O) Ra2Rb2, - (CRc2Rd2) tP (O) (ORa2) (ORb2) , - (CRc2Rd2) tC (O) Ra2, - (CRc2Rd2) tC (O) ORb2, - (CRc2Rd2) tOC (O) Rb2, - (CRc2Rd2) tC (O) NRa2Rb2, - (CRc2Rd2) tNRa2C (O) Rb2, - (CRc2Rd2) tOC (O) NRa2Rb2, - (CRc2Rd2) tNRa2C (O) ORb2, - (CRc2Rd2) tNRa2C (O) NRa2Rb2, - (CRc2Rd2) tNRa2C (S) NRa2Rb2, - (CRc2Rd2) tS (O) rNRa2Rb2, - (CRc2Rd2) tNRa2S (O) rRb2, - (CRc2Rd2) tNRa2S (O) 2NRa2Rb2, - (CRc2Rd2) tS (O) (＝NRe2) Rb2, - (CRc2Rd2) tN＝S (O) Ra2Rb2, - (CRc2Rd2) tNRa2S (O) (＝NRe2) Rb2, - (CRc2Rd2) tS (O) (＝NRe2) NRa2Rb2, - (CRc2Rd2) tNRa2S (O) (＝NRe2) NRa2Rb2, - (CRc2Rd2) tC (＝NRe2) Ra2, - (CRc2Rd2) tC (＝N-ORb2) Ra2, - (CRc2Rd2) tC (＝NRe2) NRa2Rb2, - (CRc2Rd2) tNRa2C (＝NRe2) Rb2 and - (CRc2Rd2) tNRa2C (＝NRe2) NRa2Rb2, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl  and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from OH, CN, amino, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, C1-10 alkylamino, C3-10 cycloalkylamino and di (C1-10 alkyl) amino；
each Ra2 and each Rb2 are independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, C1-10 alkylamino, C3-10 cycloalkylamino, di (C1-10 alkyl) amino, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl and heteroaryl-C1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from halogen, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, OH, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, amino, C1-10 alkylamino, C3-10 cycloalkylamino and di (C1-10 alkyl) amino；
or Ra2 and Rb2 together with the atom (s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1 or 2 substituents, independently selected from halogen, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, OH, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, amino, C1-10 alkylamino, C3-10 cycloalkylamino and di (C1-10 alkyl) amino；
each Rc2 and each Rd2 are independently selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, C1-10 alkylamino, C3-10 cycloalkylamino, di (C1-10 alkyl) amino, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl and heteroaryl-C1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from halogen, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, OH, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, amino, C1-10 alkylamino, C3-10 cycloalkylamino and di (C1-10 alkyl) amino；
or Rc2 and Rd2 together with the carbon atom (s) to which they are attached form a ring of 3 to 12 members containing 0, 1, or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1 or 2 substituents, independently selected from halogen, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, OH, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, amino, C1-10 alkylamino, C3-10 cycloalkylamino and di (C1-10 alkyl) amino；
each Re2 is independently selected from hydrogen, CN， NO2， C1-10 alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, C1-10 alkoxy, C3-10 cycloalkoxy, -C (O) C1-4 alkyl, -C (O) C3-10 cycloalkyl, -C (O) OC1-4 alkyl, -C (O) OC3-10 cycloalkyl, -C (O) N (C1-4 alkyl) 2, -C (O) N (C3-10 cycloalkyl) 2, -S (O) 2C1-4 alkyl, -S (O) 2C3-10 cycloalkyl, -S (O) 2N (C1-4 alkyl) 2 and -S (O) 2N (C3-10 cycloalkyl) 2；
m is independently selected from 0, 1 and 2；
n is independently selected from 1, 2 and 3；
p is independently selected from 0, 1, 2 and 3；
q is independently selected from 0, 1, 2 and 3；
each r is independently selected from 1 and 2；
each t is independently selected from 0, 1, 2, 3 and 4.
In another Embodiment (2) , the invention provides a compound of Embodiment (1) or a pharmaceutically acceptable salt thereof, wherein each R1 is independently selected from C1-10 alkyl.
In another Embodiment (3) , the invention provides a compound of Embodiment (2) or a pharmaceutically acceptable salt thereof, wherein R1 is methyl.
In another Embodiment (4) , the invention provides a compound of any one of Embodiments (1) - (3) or a pharmaceutically acceptable salt thereof, wherein m is 1.
In another Embodiment (5) , the invention provides a compound of any one of Embodiments (1) - (4) or a pharmaceutically acceptable salt thereof, wherein n is 1.
In another Embodiment (6) , the invention provides a compound of any one of Embodiments (1) - (5) or a pharmaceutically acceptable salt thereof, wherein p is 2.
In another Embodiment (7) , the invention provides a compound of any one of Embodiments (1) - (6) or a pharmaceutically acceptable salt thereof, wherein one R2 is independently selected from C1-10 alkyl； and the other R2 is independently selected from heterocyclyl, wherein alkyl and heterocyclyl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RX.
In another Embodiment (8) , the invention provides a compound of Embodiment (7) or a pharmaceutically acceptable salt thereof, wherein one R2 is methyl； and the other R2 is piperidinyl, which is unsubstituted or substituted with methyl or ethyl.
In another Embodiment (9) , the invention provides a compound of any one of Embodiments (1) - (8) or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen.
In another Embodiment (10) , the invention provides a compound of any one of Embodiments (1) - (9) or a pharmaceutically acceptable salt thereof, wherein R4 is selected from halogen.
In another Embodiment (11) , the invention provides a compound of Embodiment (10) or a pharmaceutically acceptable salt thereof, wherein R4 is chlorine.
In another Embodiment (12) , the invention provides a compound of Embodiments any one of (1) - (11) or a pharmaceutically acceptable salt thereof, wherein each R5 is hydrogen.
In another Embodiment (13) , the invention provides a compound of any one of Embodiments (1) - (12) or a pharmaceutically acceptable salt thereof, wherein R6 is selected from C1-10 alkyl.
In another Embodiment (14) , the invention provides a compound of Embodiment (13) or a pharmaceutically acceptable salt thereof, wherein R6 is methyl.
In another Embodiment (15) , the invention provides a compound of any one of Embodiments (1) - (14) or a pharmaceutically acceptable salt thereof, wherein R7 is selected from C1-10 alkyl.
In another Embodiment (16) , the invention provides a compound of Embodiment (15) or a pharmaceutically acceptable salt thereof, wherein R7 is methyl.
In another Embodiment (17) , the invention provides a compound selected from
(R) - (2- ( (5-chloro-2- ( (2, 5-dimethyl-4- (piperidin-4-yl) -2, 3-dihydrobenzofuran-7-yl) amino) py rimidin-4-yl) amino) phenyl) dimethylphosphine oxide,
(R) - (2- ( (5-chloro-2- ( (2, 5-dimethyl-4- (1-methylpiperidin-4-yl) -2, 3-dihydrobenzofuran-7-yl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide,
(R) - (2- ( (5-chloro-2- ( (4- (1-ethylpiperidin-4-yl) -2, 5-dimethyl-2, 3-dihydrobenzofuran-7-yl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide,
or pharmaceutically acceptable salts thereof.
In another Embodiment (18) , A pharmaceutical composition, comprising a compound of any one of Embodiments (1) - (17) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
In another Embodiment (19) , A method of treating, ameliorating or preventing a condition, which responds to inhibition of ALK, comprising administering to a subject in need of such treatment an effective amount of a compound of any one of Embodiments (1) - (17) or a pharmaceutically acceptable salt thereof, or of at least one pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent.
In another Embodiment (20) , Use of a compound of any one of Embodiments (1) - (17) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a cell-proliferative disorder.
In yet another of its aspects, there is provided a kit comprising a compound disclosed herein, or a pharmaceutically acceptable salts thereof； and instructions which comprise one or more forms of information selected from the group consisting of indicating a disease state for which the composition is to be administered, storage information for the composition, dosing information and instructions regarding how to administer the composition. In one particular variation, the kit comprises the compound in a multiple dose form.
In still another of its aspects, there is provided an article of manufacture comprising a compound disclosed herein, or a pharmaceutically acceptable salts thereof； and  packaging materials. In one variation, the packaging material comprises a container for housing the compound. In one particular variation, the container comprises a label indicating one or more members of the group consisting of a disease state for which the compound is to be administered, storage information, dosing information and/or instructions regarding how to administer the compound. In another variation, the article of manufacture comprises the compound in a multiple dose form.
In a further of its aspects, there is provided a therapeutic method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salts thereof.
In another of its aspects, there is provided a method of inhibiting a ALK kinase comprising contacting ALK with a compound disclosed herein, or a pharmaceutically acceptable salts thereof.
In yet another of its aspects, there is provided a method of inhibiting ALK comprising causing a compound disclosed herein, or a pharmaceutically acceptable salts thereof to be present in a subject in order to inhibit the ALK in vivo.
In a further of its aspects, there is provided a method of inhibiting ALK comprising administering a first compound to a subject that is converted in vivo to a second compound wherein the second compound inhibits the ALK in vivo, the second compound being a compound according to any one of the above embodiments and variations.
In another of its aspects, there is provided a method of treating a disease state for which a ALK possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising causing a compound disclosed herein, or a pharmaceutically acceptable salts thereof to be present in a subject in a therapeutically effective amount for the disease state.
In a further of its aspects, there is provided a method of treating a disease state for which a ALK possesses activity that contributes to the pathology and/or symptomology of the disease state, the method comprising administering a first compound to a subject that is converted in vivo to a second compound wherein the second compound inhibits the ALK in vivo. It is noted that the compounds of the present invention may be the first or second compounds.
In one variation of each of the above methods the disease state is selected from the group consisting of cancerous hyperproliferative disorders (e.g., brain, lung, squamous cell, bladder, gastric, pancreatic, breast, head, neck, renal, kidney, ovarian, prostate, colorectal, epidermoid, esophageal, testicular, gynecological or thyroid cancer) ； non-cancerous hyperproliferativedisorders (e.g., benign hyperplasia of the skin (e.g., psoriasis) , restenosis, and benign prostatic hypertrophy (BPH) ) ； pancreatitis； kidney disease； pain； preventing blastocyte implantation； treating diseases related to vasculogenesis or angiogenesis (e.g., tumor angiogenesis, acute and chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, exzema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung,  pancreatic, prostate, colon and epidermoid cancer) ； asthma； neutrophil chemotaxis (e.g., reperfusion injury in myocardial infarction and stroke and inflammatory arthritis) ； septic shock； T-cell mediateddiseases where immune suppression would be of value (e.g., the prevention of organ transplant rejection, graft versus host disease, lupus erythematosus, multiple sclerosis, and rheumatoid arthritis) ； atherosclerosis； inhibition of keratinocyte responses to growth factor cocktails； chronic obstructive pulmonary disease (COPD) and other diseases.
In another of its aspects, there is provided a method of treating a disease state for which a mutation in the ALK gene contributes to the pathology and/or symptomology of the disease state including, for example, melanomas, lung cancer, colon cancer and other tumor types.
In still another of its aspects, the present invention relates to the use of a compound of any of the above embodiments and variations as a medicament. In yet another of its aspects, the present invention relates to the use of a compound according to any one of the above embodiments and variations in the manufacture of a medicament for inhibiting a ALK.
In a further of its aspects, the present invention relates to the use of a compound according to any one of the above embodiments and variations in the manufacture of a medicament for treating a disease state for which a ALK possesses activity that contributes to the pathology and/or symptomology of the disease state.
Administration and Pharmaceutical Compositions
In general, compounds of the disclosure 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.
In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.001 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 1000 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 disclosure 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.
Pharmaceutical compositions comprising a compound of the present disclosure 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 disclosure 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.
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) .
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.
Other suitable fatty acid esters include but are not limited ethyl-oleate, isopropyl myristate, isopropyl palmitate, 
Figure PCTCN2017072828-appb-000005
M 2375, (polyoxyethylene glycerol) , 
Figure PCTCN2017072828-appb-000006
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 
Figure PCTCN2017072828-appb-000007
812 (triglyceride of saturated fatty acids of chain length C8 to C12 from Hüls AG, Germany) , and vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil, or groundnut oil.
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.
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.
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.
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.
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.
The disclosure also provides for a pharmaceutical combinations, e.g. a kit, comprising a) a first agent which is a compound of the disclosure 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.
Combination therapies
The compounds or pharmaceutical acceptable salts of the disclosure may be administered as the sole therapy, or together with other therapeutic agent or agents.
For example, the therapeutic effectiveness of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e. by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the individual is enhanced) . Or, by way of example only, the benefit experienced by an individual may be increased by administering one of the compounds described herein with another therapeutic agent that also has therapeutic benefit. By way of example only, in a treatment for gout involving administration of one of the compounds described herein, increased therapeutic benefit may result by also providing the individual with another therapeutic agent for gout. Or, by way of example only, if one of the side effects experienced by an individual upon receiving one of the compounds described herein is nausea, then it may be appropriate to administer an anti-nausea agent in combination with the compound. Or, the additional therapy or therapies include, but are not limited to physiotherapy, psychotherapy, radiation therapy, application of compresses to a diseased area, rest, altered diet, and the like. Regardless of the disease, disorder or condition being treated, the overall benefit experienced by the individual may be additive of the two therapies or the individual may experience a synergistic benefit.
In the instances where the compounds described herein are administered in combination with other therapeutic agents, the compounds described herein may be administered in the same pharmaceutical composition as other therapeutic agents, or because of different physical and chemical characteristics, be administered by a different route. For example, the compounds described herein may be administered orally to generate and maintain good blood levels thereof, while the other therapeutic agent may be administered intravenously. Thus the compounds described herein may be administered concurrently, sequentially or dosed separately to other therapeutic agents.
Compounds having Formula (I) are expected to be useful when used with alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors, other apoptosis promoters (for example, Bcl-xL, Bcl-w and Bfl-1) inhibitors, activators of death receptor pathway, Bcr-Abl kinase inhibitors, BiTE (Bi-Specific T cell Engager) antibodies, antibody drug conjugates, biologic  response modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVDs, leukemia viral oncogene homolog (ErbB2) receptor inhibitors, growth factor inhibitors, heat shock protein (HSP) -90 inhibitors, histone deacetylase (HDAC) inhibitors, hormonal therapies, immunologicals, inhibitors of inhibitors of apoptosis proteins (IAPs) , intercalating antibiotics, kinase inhibitors, kinesin inhibitors, Jak2 inhibitors, mammalian target of rapamycin inhibitors, microRNA's , mitogen-activated extracellular signal-regulated kinase inhibitors, multivalent binding proteins, non-steroidal anti-inflammatory drugs (NSAIDs) , poly ADP (adenosine diphosphate) -ribose polymerase (PARP) inhibitors, platinum chemotherapeutics, polo-like kinase (Plk) inhibitors, phosphoinositide-3 kinase (PI3K) inhibitors, proteosome inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors, retinoids/deltoids plant alkaloids, small inhibitory ribonucleic acids (siRNAs) , topoisomerase inhibitors, ubiquitin ligase inhibitors, and the like, and in combination with one or more of these agents .
BiTE antibodies are bi-specific antibodies that direct T-cells to attack cancer cells by simultaneously binding the two cells. The T-cell then attacks the target cancer cell. Examples of BiTE antibodies include adecatumumab (Micromet MT201) , blinatumomab (Micromet MT103) and the like. Without being limited by theory, one of the mechanisms by which T-cells elicit apoptosis of the target cancer cell is by exocytosis of cytolytic granule components, which include perforin and granzyme B. In this regard, Bcl-2 has been shown to attenuate the induction of apoptosis by both perforin and granzyme B. These data suggest that inhibition of Bcl-2 could enhance the cytotoxic effects elicited by T-cells when targeted to cancer cells (V. R. Sutton, D. L. Vaux and J. A. Trapani, J. of Immunology 1997, 158 (12) , 5783) .
SiRNAs are molecules having endogenous RNA bases or chemically modified nucleotides. The modifications do not abolish cellular activity, but rather impart increased stability and/or increased cellular potency. Examples of chemical modifications include phosphorothioate groups, 2'-deoxynucleotide, 2'-OCH3-containing ribonucleotides, 2'-F-ribonucleotides, 2'-methoxyethyl ribonucleotides, combinations thereof and the like. The siRNA can have varying lengths (e.g., 10-200 bps) and structures (e.g., hairpins, single/double strands, bulges, nicks/gaps, mismatches) and are processed in cells to provide active gene silencing. A double-stranded siRNA (dsRNA) can have the same number of nucleotides on each strand (blunt ends) or asymmetric ends (overhangs) . The overhang of 1-2 nucleotides can be present on the sense and/or the antisense strand, as well as present on the 5'-and/or the 3 '-ends of a given strand. For example, siRNAs targeting Mcl-1 have been shown to enhance the activity of ABT-263, (i.e., N- (4- (4- ( (2- (4-chlorophenyl) -5, 5-dimethyl-1-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoyl) -4- ( ( (1R) -3- (morpholin-4-yl) -1- ( (phenylsulfanyl) methyl) -propyl) amino) -3- ( (trifluoromethyl) sulf onyl) benzenesulfonamide) or ABT-737 (i.e., N- (4- (4- ( (4'-chloro (l, r-biphenyl) -2-yl) methyl) piperazin-l-yl) benzoyl) -4- ( ( (1R) -3- (dimethylamino ) -1- ( (phenylsulfanyl) methyl) propyl) amino) -3-nitrobenzenesulfonamide) in multiple tumor cell lines (Tse et. al, Cancer Research 2008, 68 (9) , 3421 and references therein) .
Multivalent binding proteins are binding proteins comprising two or more antigen binding sites. Multivalent binding proteins are engineered to have the three or more antigen binding sites and are generally not naturally occurring antibodies. The term "multispecific binding protein" means a binding protein capable of binding two or more related or unrelated targets. Dual variable domain (DVD) binding proteins are tetravalent or multivalent binding proteins binding proteins comprising two or more antigen binding sites. Such DVDs may be monospecific (i.e., capable of binding one antigen) or multispecific (i.e., capable of binding two or more antigens) . DVD binding proteins comprising two heavy chain DVD polypeptides and two light chain DVD polypeptides are referred to as DVD Ig's . Each half of a DVD Ig comprises a heavy chain DVD polypeptide, a light chain DVD polypeptide, and two antigen binding sites. Each binding site comprises a heavy chain variable domain and a light chain variable domain with a total of 6 CDRs involved in antigen binding per antigen binding site.
Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone, bendamustine, brostallicin, busulfan, carboquone, carmustine (BCNU) , chlorambucil, 
Figure PCTCN2017072828-appb-000008
(laromustine, VNP 40101M) , cyclophosphamide, decarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine (CCNU) , mafosfamide, melphalan, mitobronitol, mitolactol, nimustine, nitrogen mustard N-oxide, ranimustine, temozolomide, thiotepa, 
Figure PCTCN2017072828-appb-000009
 (bendamustine) , treosulfan, rofosfamide and the like.
Angiogenesis inhibitors include endothelial-specific receptor tyrosine kinase (Tie-2) inhibitors, epidermal growth factor receptor (EGFR) inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrix metalloproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9 (MMP-9) inhibitors, platelet-derived growth factor receptor (PDGFR) inhibitors, thrombospondin analogs, vascular endothelial growth factor receptor tyrosine kinase (VEGFR) inhibitors and the like.
Antimetabolites include
Figure PCTCN2017072828-appb-000010
 (pemetrexed disodium, LY231514, MTA) , 5-azacitidine, 
Figure PCTCN2017072828-appb-000011
 (capecitabine) , carmofur, 
Figure PCTCN2017072828-appb-000012
 (cladribine) , clofarabine, cytarabine, cytarabine ocfosfate, cytosine arabinoside, decitabine, deferoxamine, doxifluridine, eflornithine, EICAR (5-ethynyl-l-P -D-ribofuranosylimidazole-4-carboxamide) , enocitabine, ethnylcytidine, fludarabine, 5-fluorouracil alone or in combination with leucovorin, 
Figure PCTCN2017072828-appb-000013
(gemcitabine) , hydroxyurea, 
Figure PCTCN2017072828-appb-000014
 (melphalan) , mercaptopurine, 6-mercaptopurine riboside, methotrexate, mycophenolic acid, nelarabine, nolatrexed, ocfosfate, pelitrexol, pentostatin, raltitrexed, Ribavirin, triapine, trimetrexate, S-1, tiazofurin, tegafur, TS-1, vidarabine, UFT and the like.
Antivirals include ritonavir, hydroxychloroquine and the like.
Aurora kinase inhibitors include ABT-348, AZD-1152, MLN-8054, VX-680, Aurora A-specific kinase inhibitors, Aurora B-specific kinase inhibitors and pan-Aurora kinase inhibitors and the like.
Bcl-2 protein inhibitors include AT-101 ( (-) gossypol) , 
Figure PCTCN2017072828-appb-000015
 (G3139 or oblimersen (Bcl-2 -targeting antisense oligonucleotide) ) , IPI-194, IPI-565,  N- (4- (4- ( (4'-chloro (1, 1'-biphenyl) -2-yl) methyl) piperazin-1-yl) benzoyl) -4- ( ( (1R) -3- (dimethylamin o) -1- ( (phenylsulfanyl) methyl) propyl) amino) -3-nitrobenzenesulfonamide) (ABT-737) , N- (4- (4- ( (2- (4-chlorophenyl) -5, 5-dimethyl-1-cyclohex-1-en-1-yl) methyl) piperazin-1-yl) benzoyl) -4- ( ( (1R) -3- (morpholin-4-yl) -1- ( (phenylsulfanyl) methyl) propyl) amino) -3- ( (trifluoromethyl) -sulf onyl) benzenesulfonamide (ABT-263) , GX-070 (obatoclax) and the like.
Bcr-Abl kinase inhibitors include
Figure PCTCN2017072828-appb-000016
 (BMS-354825) , 
Figure PCTCN2017072828-appb-000017
(imatinib) and the like.
CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584, flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib (CYC-202, R-roscovitine) , ZK-304709 and the like.
COX-2 inhibitors include ABT-963 , ARCOXI
Figure PCTCN2017072828-appb-000018
 (etoricoxib) , 
Figure PCTCN2017072828-appb-000019
(valdecoxib) , BMS347070, 
Figure PCTCN2017072828-appb-000020
 (celecoxib) , COX-189 (lumiracoxib) , CT-3, 
Figure PCTCN2017072828-appb-000021
(deracoxib) , JTE-522, 4-methyl-2- (3, 4-dimethylphenyl) -l- (4-sulfamoylphenyl-lH-pyrrole) , MK-663 (etoricoxib) , NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016, S-2474, T-614, 
Figure PCTCN2017072828-appb-000022
 (rofecoxib) and the like.
EGFR inhibitors include ABX-EGF, anti-EGFR immuno liposomes, EGF-vaccine, EMD-7200, 
Figure PCTCN2017072828-appb-000023
 (cetuximab) , HR3, IgA antibodies, 
Figure PCTCN2017072828-appb-000024
 (gefitinib) , 
Figure PCTCN2017072828-appb-000025
(erlotinib or OSI-774) , TP-38, EGFR fusion protein, 
Figure PCTCN2017072828-appb-000026
 (lapatinib) and the like.
ErbB2 receptor inhibitors include CP-724-714, CI-1033 (canertinib) , 
Figure PCTCN2017072828-appb-000027
(trastuzumab) , 
Figure PCTCN2017072828-appb-000028
 (lapatinib) , 
Figure PCTCN2017072828-appb-000029
 (2C4, petuzumab) , TAK-165, GW-572016 (ionafarnib) , GW-282974, EKB-569, PI-166, dHER2 (HER2 vaccine) , APC-8024 (HER-2 vaccine) , anti-HER/2neu bispecific antibody, B7. her2IgG3, AS HER2 trifunctional bispecfic antibodies, mAB AR-209, mAB 2B-1 and the like.
Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275, trapoxin, suberoylanilide hydroxamic acid (SAHA) , TSA, valproic acid and the like.
HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010, CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, 
Figure PCTCN2017072828-appb-000030
 (human recombinant antibody to HSP-90) , NCS-683664, PU24FC1, PU-3, radicicol, SNX-2112, STA-9090 VER49009 and the like.
Inhibitors of inhibitors of apoptosis proteins include HGS1029, GDC-0145, GDC-0152, LCL-161, LBW-242 and the like.
Antibody drug conjugates include anti-CD22-MC-MMAF, anti-CD22-MC-MMAE, anti-CD22-MCC-DMl, CR-011-vcMMAE, PSMA-ADC, MEDI-547, SGN-19Am SGN-35, SGN-75 and the like Activators of death receptor pathway include TRAIL, antibodies or other agents that target TRAIL or death receptors (e.g., DR4 and DR5) such as Apomab, conatumumab, ETR2-ST01, GDC0145 (lexatumumab) , HGS-1029, LBY-135, PRO-1762 and trastuzumab.
Kinesin inhibitors include Eg5 inhibitors such as AZD4877, ARRY-520； CENPE inhibitors such as GSK923295A and the like.
JAK-2 inhibitors include CEP-701 (lesaurtinib) , XL019 and INCBO 18424 and the like.
MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059 and the like.
mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001, rapamycin, temsirolimus, ATP-competitive TORC1/TORC2 inhibitors, including PI-103, PP242, PP30, Torin 1 and the like.
Non-steroidal anti-inflammatory drugs include
Figure PCTCN2017072828-appb-000031
 (salsalate) , 
Figure PCTCN2017072828-appb-000032
(difiunisal) , 
Figure PCTCN2017072828-appb-000033
 (ibuprofen) , 
Figure PCTCN2017072828-appb-000034
 (ketoprofen) , 
Figure PCTCN2017072828-appb-000035
(nabumetone) , 
Figure PCTCN2017072828-appb-000036
 (piroxicam) , ibuprofen cream, 
Figure PCTCN2017072828-appb-000037
 (naproxen) and 
Figure PCTCN2017072828-appb-000038
(naproxen) , 
Figure PCTCN2017072828-appb-000039
 (diclofenac) , 
Figure PCTCN2017072828-appb-000040
 (indomethacin) , 
Figure PCTCN2017072828-appb-000041
(sulindac) , 
Figure PCTCN2017072828-appb-000042
 (tolmetin) , 
Figure PCTCN2017072828-appb-000043
 (etodolac) , 
Figure PCTCN2017072828-appb-000044
 (ketorolac) , 
Figure PCTCN2017072828-appb-000045
(oxaprozin) and the like.
PDGFR inhibitors include C-451, CP-673, CP-868596 and the like.
Platinum chemotherapeutics include cisplatin, 
Figure PCTCN2017072828-appb-000046
 (oxaliplatin) eptaplatin, lobaplatin, nedaplatin, 
Figure PCTCN2017072828-appb-000047
 (carboplatin) , satraplatin, picoplatin and the like.
Polo-like kinase inhibitors include BI-2536 and the like.
Phosphoinositide-3 kinase (PI3K) inhibitors include wortmannin, LY294002, XL-147, CAL-120, ONC-21, AEZS-127, ETP-45658, PX-866, GDC-0941, BGT226, BEZ235, XL765 and the like.
Thrombospondin analogs include ABT-510, ABT-567, ABT-898, TSP-1 and the like.
VEGFR inhibitors include
Figure PCTCN2017072828-appb-000048
 (bevacizumab) , ABT-869, AEE-788, ANGIOZYMETM (a ribozyme that inhibits angiogenesis (Ribozyme Pharmaceuticals (Boulder, CO.) and Chiron, (Emeryville, CA) ) , axitinib (AG-13736) , AZD-2171, CP-547, 632, IM-862, MACUGEN (pegaptamib) , 
Figure PCTCN2017072828-appb-000049
 (sorafenib, BAY43-9006) , pazopanib (GW-786034) , vatalanib (PTK-787, ZK-222584) , 
Figure PCTCN2017072828-appb-000050
 (sunitinib, SU-11248) , VEGF trap, ZACTIMATM(vandetanib, ZD-6474) and the like. Antibiotics include intercalating antibiotics aclarubicin, actinomycin D, amrubicin, annamycin, adriamycin, 
Figure PCTCN2017072828-appb-000051
 (bleomycin) , daunorubicin, 
Figure PCTCN2017072828-appb-000052
or
Figure PCTCN2017072828-appb-000053
 (liposomal doxorubicin) , elsamitrucin, epirbucin, glarbuicin, 
Figure PCTCN2017072828-appb-000054
(idarubicin) , mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin, 
Figure PCTCN2017072828-appb-000055
 (valrubicin) , zinostatin and the like.
Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin, amonafide, amsacrine, becatecarin, belotecan, BN-80915, 
Figure PCTCN2017072828-appb-000056
 (irinotecan hydrochloride) , camptothecin, 
Figure PCTCN2017072828-appb-000057
 (dexrazoxine) , diflomotecan, edotecarin, 
Figure PCTCN2017072828-appb-000058
or 
Figure PCTCN2017072828-appb-000059
(epirubicin) , etoposide, exatecan, 10-hydroxycamptothecin, gimatecan, lurtotecan, mitoxantrone, orathecin, pirarbucin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide, topotecan and the like.
Antibodies include
Figure PCTCN2017072828-appb-000060
 (bevacizumab) , CD40-specific antibodies, chTNT-1/B, denosumab, 
Figure PCTCN2017072828-appb-000061
 (cetuximab) , 
Figure PCTCN2017072828-appb-000062
 (zanolimumab) , IGFlR-specific antibodies, lintuzumab, 
Figure PCTCN2017072828-appb-000063
 (edrecolomab) , 
Figure PCTCN2017072828-appb-000064
 (WX G250) , 
Figure PCTCN2017072828-appb-000065
(rituximab) , ticilimumab, trastuzimab, CD20 antibodies types I and II and the like.
Hormonal therapies include
Figure PCTCN2017072828-appb-000066
 (anastrozole) , 
Figure PCTCN2017072828-appb-000067
(exemestane) , arzoxifene, 
Figure PCTCN2017072828-appb-000068
 (bicalutamide) , 
Figure PCTCN2017072828-appb-000069
 (cetrorelix) , degarelix, deslorelin, 
Figure PCTCN2017072828-appb-000070
 (trilostane) , dexamethasone, 
Figure PCTCN2017072828-appb-000071
 (flutamide) , 
Figure PCTCN2017072828-appb-000072
(raloxifene) , AFEMATM (fadrozole) , 
Figure PCTCN2017072828-appb-000073
 (toremifene) , 
Figure PCTCN2017072828-appb-000074
(fulvestrant) , 
Figure PCTCN2017072828-appb-000075
 (letrozole) , formestane, glucocorticoids, 
Figure PCTCN2017072828-appb-000076
(doxercalciferol) , 
Figure PCTCN2017072828-appb-000077
 (sevelamer carbonate) , lasofoxifene, leuprolide acetate, 
Figure PCTCN2017072828-appb-000078
 (megesterol) , 
Figure PCTCN2017072828-appb-000079
 (mifepristone) , NILANDRONTM (nilutamide) , 
Figure PCTCN2017072828-appb-000080
(tamoxifen citrate) , PLENAXISTM (abarelix) , prednisone, 
Figure PCTCN2017072828-appb-000081
(finasteride) , rilostane, 
Figure PCTCN2017072828-appb-000082
 (buserelin) , 
Figure PCTCN2017072828-appb-000083
 (luteinizing hormone releasing hormone (LHRH) ) , 
Figure PCTCN2017072828-appb-000084
 (Histrelin implant) , 
Figure PCTCN2017072828-appb-000085
 (trilostane or modrastane) , 
Figure PCTCN2017072828-appb-000086
 (fosrelin, goserelin) and the like.
Deltoids and retinoids include seocalcitol (EB1089, CB1093) , lexacalcitrol (KH1060) , fenretinide, 
Figure PCTCN2017072828-appb-000087
 (aliretinoin) , 
Figure PCTCN2017072828-appb-000088
 (liposomal tretinoin) , 
Figure PCTCN2017072828-appb-000089
(bexarotene) , LGD-1550 and the like.
PARP inhibitors include ABT-888 (veliparib) , olaparib, KU-59436, AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231 and the like.
Plant alkaloids include, but are not limited to, vincristine, vinblastine, vindesine, vinorelbine and the like. Proteasome inhibitors include
Figure PCTCN2017072828-appb-000090
 (bortezomib) , MG132, NPI-0052, PR-171 and the like.
Examples of immunologicals include interferons and other immune-enhancing agents. Interferons include interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-la, 
Figure PCTCN2017072828-appb-000091
 (interferon gamma-lb) or interferon gamma-nl, combinations thereof and the like. Other agents include
Figure PCTCN2017072828-appb-000092
 (IFN-a) , BAM-002 (oxidized glutathione) , 
Figure PCTCN2017072828-appb-000093
 (tasonermin) , 
Figure PCTCN2017072828-appb-000094
 (tositumomab) , 
Figure PCTCN2017072828-appb-000095
(alemtuzumab) , CTLA4 (cytotoxic lymphocyte antigen 4) , decarbazine, denileukin, epratuzumab, 
Figure PCTCN2017072828-appb-000096
 (lenograstim) , lentinan, leukocyte alpha interferon, imiquimod, MDX-010 (anti-CTLA-4) , melanoma vaccine, mitumomab, molgramostim, MYLOTARGTM (gemtuzumab ozogamicin) , 
Figure PCTCN2017072828-appb-000097
 (filgrastim) , OncoVAC-CL, 
Figure PCTCN2017072828-appb-000098
(oregovomab) , pemtumomab (Y-muHMFGl) , 
Figure PCTCN2017072828-appb-000099
 (sipuleucel-T) , sargaramostim, sizofilan, teceleukin, 
Figure PCTCN2017072828-appb-000100
 (Bacillus Calmette-Guerin) , ubenimex, 
Figure PCTCN2017072828-appb-000101
(immunotherapeutic, Lorus Pharmaceuticals) , Z-100 (Specific Substance of Maruyama (SSM) ) , WF-10 (Tetrachlorodecaoxide (TCDO) ) , 
Figure PCTCN2017072828-appb-000102
 (aldesleukin) , 
Figure PCTCN2017072828-appb-000103
(thymalfasin) , 
Figure PCTCN2017072828-appb-000104
 (daclizumab) , 
Figure PCTCN2017072828-appb-000105
 (90Y-Ibritumomab tiuxetan) and the like.
Biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth or differentiation of tissue cells to direct them to have anti-tumor activity and include krestin, lentinan, sizofiran, picibanil PF-3512676 (CpG-8954) , ubenimex and the like.
Pyrimidine analogs include cytarabine (ara C or Arabinoside C) , cytosine arabinoside, doxifluridine, 
Figure PCTCN2017072828-appb-000106
 (fludarabine) , 5-FU (5-fluorouracil) , floxuridine, 
Figure PCTCN2017072828-appb-000107
(gemcitabine) , 
Figure PCTCN2017072828-appb-000108
 (ratitrexed) , TROXATYLTM (triacetyluridine troxacitabine) and the like.
Purine analogs include
Figure PCTCN2017072828-appb-000109
 (thioguanine) and
Figure PCTCN2017072828-appb-000110
(mercaptopurine) .
Antimitotic agents include batabulin, epothilone D (KOS-862) , N- (2- ( (4-hydroxyphenyl) amino) pyridin-3 -yl) -4-methoxybenzenesulfonamide, ixabepilone (BMS 247550) , paclitaxel, 
Figure PCTCN2017072828-appb-000111
 (docetaxel) , PNU100940 (109881) , patupilone, XRP-9881 (larotaxel) , vinflunine, ZK-EPO (synthetic epothilone) and the like.
Ubiquitin ligase inhibitors include MDM2 inhibitors, such as nutlins, NEDD8 inhibitors such as MLN4924 and the like. Compounds of this invention can also be used as radiosensitizers that enhance the efficacy of radiotherapy. Examples of radiotherapy include external beam radiotherapy, teletherapy, brachytherapy and sealed, unsealed source radiotherapy and the like.
Additionally, compounds having Formula (I) may be combined with other chemotherapeutic agents such as ABRAXANETM (ABI-007) , ABT-100 (farnesyl transferase inhibitor) , 
Figure PCTCN2017072828-appb-000112
 (Ad5CMV-p53 vaccine) , 
Figure PCTCN2017072828-appb-000113
or
Figure PCTCN2017072828-appb-000114
 (lovastatin) , 
Figure PCTCN2017072828-appb-000115
(poly Lpoly C12U, a synthetic RNA) , 
Figure PCTCN2017072828-appb-000116
 (exisulind) , 
Figure PCTCN2017072828-appb-000117
(pamidronic acid) , arglabin, L-asparaginase, atamestane (l-methyl-3, 17-dione-androsta-l, 4-diene) , 
Figure PCTCN2017072828-appb-000118
 (tazarotene) , AVE-8062 (combreastatin derivative) BEC2 (mitumomab) , cachectin or cachexin (tumor necrosis factor) , canvaxin (vaccine) , 
Figure PCTCN2017072828-appb-000119
 (cancer vaccine) , 
Figure PCTCN2017072828-appb-000120
 (celmoleukin) , 
Figure PCTCN2017072828-appb-000121
 (histamine dihydrochloride) , 
Figure PCTCN2017072828-appb-000122
 (human papillomavirus vaccine) , 
Figure PCTCN2017072828-appb-000123
 (C: 
Figure PCTCN2017072828-appb-000124
(cyclophosphamide) ； H: 
Figure PCTCN2017072828-appb-000125
 (hydroxy doxorubicin) ； O: Vincristine 
Figure PCTCN2017072828-appb-000126
P: prednisone) , CYPATTM (cyproterone acetate) , combrestatin A4P, DAB(389) EGF (catalytic and translocation domains of diphtheria toxin fused via a His-Ala linker to human epidermal growth factor) or TransMID-107RTM (diphtheria toxins) , dacarbazine, dactinomycin, 5, 6-dimethylxanthenone-4-acetic acid (DMXAA) , eniluracil, EVIZONTM(squalamine lactate) , 
Figure PCTCN2017072828-appb-000127
 (T4N5 liposome lotion) , discodermolide, DX-8951f (exatecan mesylate) , enzastaurin, EPO906 (epithilone B) , 
Figure PCTCN2017072828-appb-000128
 (quadrivalent human papillomavirus (Types 6, 11, 16, 18) recombinant vaccine) , 
Figure PCTCN2017072828-appb-000129
GMK (ganglioside conjugate vaccine) , 
Figure PCTCN2017072828-appb-000130
 (prostate cancer vaccine) , halofuginone,  histerelin, hydroxycarbamide, ibandronic acid, IGN-101, IL-13-PE38, IL-13-PE38QQR (cintredekin besudotox) , IL-13-pseudomonas exotoxin, interferon-a, interferon-γ, JUNO VANTM or MEPACTTM (mifamurtide) , lonafarnib, 5, 10-methylenetetrahydro folate, miltefosine (hexadecylphosphocholine) , 
Figure PCTCN2017072828-appb-000131
 (AE-941 ) , 
Figure PCTCN2017072828-appb-000132
 (trimetrexate glucuronate) , 
Figure PCTCN2017072828-appb-000133
 (pentostatin) , 
Figure PCTCN2017072828-appb-000134
 (aribonuclease enzyme) , 
Figure PCTCN2017072828-appb-000135
(melanoma vaccine treatment) , 
Figure PCTCN2017072828-appb-000136
 (IL-2 Vaccine) , ORATHECINTM (rubitecan) , 
Figure PCTCN2017072828-appb-000137
(antibody-based cell drug) , 
Figure PCTCN2017072828-appb-000138
MAb (murine monoclonal antibody) , paclitaxel, PANDIMEXTM (aglycone saponins from ginseng comprising 20 (S) protopanaxadiol (aPPD) and 20 (S) protopanaxatriol (aPPT) ) , panitumumab, 
Figure PCTCN2017072828-appb-000139
-VF (investigational cancer vaccine) , pegaspargase, PEG Interferon A, phenoxodiol, procarbazine, rebimastat, 
Figure PCTCN2017072828-appb-000140
(catumaxomab) , 
Figure PCTCN2017072828-appb-000141
 (lenalidomide) , RSR13 (efaproxiral) , 
Figure PCTCN2017072828-appb-000142
LA (lanreotide) , 
Figure PCTCN2017072828-appb-000143
 (acitretin) , staurosporine (Streptomyces staurospores) , talabostat (PT100) , 
Figure PCTCN2017072828-appb-000144
 (bexarotene) , 
Figure PCTCN2017072828-appb-000145
(DHA-paclitaxel) , 
Figure PCTCN2017072828-appb-000146
 (canfosfamide, TLK286) , temilifene, 
Figure PCTCN2017072828-appb-000147
(temozolomide) , tesmilifene, thalidomide, 
Figure PCTCN2017072828-appb-000148
 (STn-KLH) , thymitaq (2-amino-3, 4-dihydro-6-methyl-4-oxo-5- (4-pyridylthio) quinazoline dihydrochloride) , TNFERADETM (adenovector: DNA carrier containing the gene for tumor necrosis factor-a) , 
Figure PCTCN2017072828-appb-000149
or
Figure PCTCN2017072828-appb-000150
 (bosentan) , tretinoin (Retin-A) , tetrandrine, 
Figure PCTCN2017072828-appb-000151
 (arsenic trioxide) , ukrain (derivative of alkaloids from the greater celandine plant) , vitaxin (anti-alphavbeta3 antibody) , 
Figure PCTCN2017072828-appb-000153
 (motexafm gadolinium) , XINLAYTM (atrasentan) , XYOTAXTM (paclitaxel poliglumex) , 
Figure PCTCN2017072828-appb-000154
 (trabectedin) , ZD-6126, 
Figure PCTCN2017072828-appb-000155
(dexrazoxane) , 
Figure PCTCN2017072828-appb-000156
 (zolendronic acid) , zorubicin and the like.
EXAMPLES
Various methods may be developed for synthesizing a compound of formula (I) or a pharmaceutically acceptable salt thereof. Representative methods for synthesizing a compound of formula (I) or a pharmaceutically acceptable salt thereof are provided in the Examples. It is noted, however, that a compound of formula (I) or a pharmaceutically acceptable salt thereof may also be synthesized by other synthetic routes that others may devise.
It will be readily recognized that certain compounds of formula (I) have atoms with linkages to other atoms that confer a particular stereochemistry to the compound (e.g., chiral centers) . It is recognized that synthesis of a compound of formula (I) or a pharmaceutically acceptable salt thereof may result in the creation of mixtures of different stereoisomers (enantiomers, diastereomers) . Unless a particular stereochemistry is specified, recitation of a compound is intended to encompass all of the different possible stereoisomers.
Ae compound of formula (I) can also be prepared as a pharmaceutically acceptable acid addition salt by, for example, reacting the free base form of a compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of the a compound of formula (I) can be prepared by, for example, reacting the free acid form of the a compound with a pharmaceutically acceptable inorganic or  organic base. Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compounds of formula (I) are set forth in the definitions section of this Application. Alternatively, the salt forms of the compounds of formula (I) can be prepared using salts of the starting materials or intermediates.
The free acid or free base forms of the compounds of formula (I) can be prepared from the corresponding base addition salt or acid addition salt form. For example, a compound of formula (I) in an acid addition salt form can be converted to the corresponding free base thereof by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like) . A compound of formula (I) in a base addition salt form can be converted to the corresponding free acid thereof by, for example, treating with a suitable acid (e.g., hydrochloric acid, etc) .
The N-oxides of the a compound of formula (I) or a pharmaceutically acceptable salt thereof can be prepared by methods known to those of ordinary skill in the art. For example, N-oxides can be prepared by treating an unoxidized form of the compound of formula (I) with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at approximately 0 to 80 ℃. Alternatively, the N-oxides of the compounds of formula (I) can be prepared from the N-oxide of an appropriate starting material.
Compounds of formula (I) in an unoxidized form can be prepared from N-oxides of compounds of formula (I) by, for example, treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, and the like) in an suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, and the like) at 0 to 80 ℃.
Protected derivatives of the compounds of formula (I) can be made by methods known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley &Sons, Inc. 1999.
As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Standard single-letter or three-letter abbreviations are generally used to designate amino acid residues, which are assumed to be in the L-configuration unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. For example, the following abbreviations may be used in the examples and throughout the specification: g (grams) ； mg (milligrams) ； L (liters) ； mL (milliliters) ； μL (microliters) ； psi (pounds per square inch) ； M (molar) ； mM (millimolar) ； i. v. (intravenous) ； Hz (Hertz) ； MHz (megahertz) ； mol (moles) ； mmol (millimoles) ； RT (room temperature) ； min (minutes) ； h (hours) ； mp (melting point) ； TLC (thin layer chromatography) ； Rt (retention time) ； RP (reverse phase) ； MeOH (methanol) ； i-PrOH (isopropanol) ； TEA (triethylamine) ； TFA  (trifluoroacetic acid) ； TFAA (trifluoroacetic anhydride) ； THF (tetrahydrofuran) ； DMSO (dimethyl sulfoxide) ； EtOAc (ethyl acetate) ； DME (1, 2-dimethoxyethane) ； DCM (dichloromethane) ； DCE (dichloroethane) ； DMF (N, N-dimethylformamide) ； DMPU (N, N'-dimethylpropyleneurea) ； CDI (1, 1-carbonyldiimidazole) ； IBCF (isobutyl chloroformate) ； HOAc (acetic acid) ； HOSu (N-hydroxysuccinimide) ； HOBT (1-hydroxybenzotriazole) ； Et2O (diethyl ether) ； EDCI (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride) ； BOC (tert-butyloxycarbonyl) ； FMOC (9-fluorenylmethoxycarbonyl) ； DCC (dicyclohexylcarbodiimide) ； CBZ (benzyloxycarbonyl) ； Ac (acetyl) ； atm (atmosphere) ； TMSE (2- (trimethylsilyl) ethyl) ； TMS (trimethylsilyl) ； TIPS (triisopropylsilyl) ； TBS (t-butyldimethylsilyl) ； DMAP (4-dimethylaminopyridine) ； Me (methyl) ； OMe (methoxy) ； Et (ethyl) ； tBu (tert-butyl) ； HPLC (high pressure liquid chomatography) ； BOP (bis (2-oxo-3-oxazolidinyl) phosphinic chloride) ； TBAF (tetra-n-butylammonium fluoride) ； m-CPBA (meta-chloroperbenzoic acid) .
References to ether or Et2O are to diethyl ether； brine refers to a saturated aqueous solution of NaCl. Unless otherwise indicated, all temperatures are expressed in ℃ (degrees Centigrade) . All reactions were conducted under an inert atmosphere at RT unless otherwise noted.
1H NMR spectra were recorded on a Varian Mercury Plus 400. Chemical shifts are expressed in parts per million (ppm) . Coupling constants are in units of hertz (Hz) . Splitting patterns describe apparent multiplicities and are designated as s (singlet) , d (doublet) , t (triplet) , q (quartet) , m (multiplet) , and br (broad) .
Low-resolution mass spectra (MS) and compound purity data were acquired on a Shimadzu LC/MS single quadrapole system equipped with electrospray ionization (ESI) source, UV detector (220 and 254 nm) , and evaporative light scattering detector (ELSD) . Thin-layer chromatography was performed on 0.25 mm Superchemgroup silica gel plates (60F-254) , visualized with UV light, 5％ethanolic phosphomolybdic acid, ninhydrin, or p-anisaldehyde solution. Flash column chromatography was performed on silica gel (200-300 mesh, Branch of Qingdao Haiyang Chemical Co., Ltd ) .
Synthetic Schemes
At least one compound of formula I and/or at least one pharmaceutically acceptable salt thereof may be synthesized according to a variety of reaction schemes. Some illustrative schemes are provided below and in the examples. Other reaction schemes could be readily devised by those skilled in the art in view of the present disclosure.
In the reactions described hereinafter it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice, for examples see T. W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991.
Synthetic methods for preparing the compounds of the present invention are illustrated in the following Schemes and Examples. Starting materials are commercially available or may be made according to procedures known in the art or as illustrated herein.
The intermediates shown in the following schemes are either known in the literature or may be prepared by a variety of methods familiar to those skilled in the art.
As an illustration, one of the synthetic approach to the compounds of formula I of the present disclosure is outlined in Scheme 1. As shown in the Scheme, the compounds of formula I can be disassembled into the intermediates of formula II and III, which are either known in the literature or may be prepared by a variety of methods familiar to those skilled in the art. Coupling of pyrimidines of formula II with analines such as those of formula III using such coupling conditions as Buchwald amination reaction, acid catalyzed nucleophilic amination reaction or other amination conditions known in the literature leads to compound of formula I or II respectively.
Figure PCTCN2017072828-appb-000157
Scheme 1
As an illustration of the preparation of compound I, one synthetic route of Ia is shown in Scheme 2. Phosphine oxide of formula IIa-b is prepared by reacting iodides of formula IIa-awith phosphine A in the presence of a palladium reagents such as Pd (OAc) 2 and a ligand such as Xantphos. Reaction of IIa-b with dichloropyrimidine B in the presence of a base such as NaH in a solvent such as DMF furnishes intermediates of formula IIa-c as a result of the regio-selective displacement of one of the chloride in compound B by the amino group in analine IIa-b. Cleavage of the Boc group in IIa-c results in intermediation IIa. Acid catalyzed cross coupling of intermediate IIa with analine C, which can be prepared according to the method described in US20140128387, provides compounds of formula Ia.
Figure PCTCN2017072828-appb-000158
Scheme 2
In some cases the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way.
Example 1
(R) - (2- ( (5-chloro-2- ( (2, 5-dimethyl-4- (piperidin-4-yl) -2, 3-dihydrobenzofuran-7-yl)  amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (1)
Figure PCTCN2017072828-appb-000159
dimethylphosphine oxide (1a)
Dimethylphosphine oxide (1a) was prepared according to the method described in J. Org. Chem. 1968, Vol. 33, No. 10, 3690-3694.
tert-butyl (2-iodophenyl) carbamate (1b)
A mixture of 2-iodoaniline (35.0 g, 0.160 mol) and (Boc) 2O (93.0 g, 0.427 mol) in dioxane (105 mL) was stirred at 100℃ for 24 hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EtOAc (200: 1) to give tert-butyl (2-iodophenyl) -carbamate (1b) . MS-ESI (m/z) : 264 [M + 1 -56] +.
tert-butyl (2- (dimethylphosphoryl) phenyl) carbamate (1c)
A mixture of tert-butyl (2-iodophenyl) -carbamate (1b) (6.90 g, 21.6 mmol) , dimethylphosphine oxide (1a) (3.40 g, 43.6 mmol) , Pd (OAc) 2 (0.97 g, 4.31 mmol) , Xantphos (2.50 g, 4.33 mmol) and K3PO4·3H2O (11.5 g, 43.2 mmol) in N, N-dimethylformamide (70 mL) was stirred under N2 atmosphere at 120℃ for 1 hour. The reaction mixture was cooled to ambient temperature and filtered through celite pad. The pad was washed with EtOAc (400 mL) . The filtrate was washed with water (3 × 200 mL) , brine (200 mL) , dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with DCM /EtOAc (1: 1) to give tert-butyl (2- (dimethylphosphoryl) phenyl) carbamate (1c) . MS-ESI (m/z) : 270 [M + 1] +.
tert-butyl (2, 5-dichloropyrimidin-4-yl) (2- (dimethylphosphoryl) phenyl) carbamate  (1d)
To a mixture of tert-butyl (2- (dimethylphosphoryl) phenyl) carbamate (1c) (14.2 g, 52.8 mmol) and 2, 4, 5-trichloropyrimidine (11.7 g, 63.9 mmol) in N, N-dimethylformamide (140 mL) was added NaH at room temperature. The reaction mixture was stirred at 60℃ for 1 hour. The reaction was quenched with aq. NH4Cl (1400 mL) at ambient temperature. The mixture was extracted with EtOAc (3 × 500 mL) . The combined organic layer was washed with brine (2 × 500 mL) , dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with DCM/MeOH (30: 1) to give tert-butyl (2,5-dichloropyrimidin-4-yl) (2- (dimethylphosphoryl) phenyl) carbamate (1d) . MS-ESI (m/z) : 416 [M + 1] +.
(R) -2, 5-dimethyl-4- (piperidin-4-yl) -2, 3-dihydrobenzofuran-7-amine (1e)
(R) -2, 5-dimethyl-4- (piperidin-4-yl) -2, 3-dihydrobenzofuran-7-amine (1e) was prepared according to the method described in WO2014071832.
(R) - (2- ( (5-chloro-2- ( (2, 5-dimethyl-4- (piperidin-4-yl) -2, 3-dihydrobenzofuran-7-yl)  amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (1)
A mixture of tert-butyl (2,5-dichloropyrimidin-4-yl) (2- (dimethylphosphoryl) -phenyl) carbamate 11.0 g (1d) (100 mg, 0.240 mmol) and TFA (0.7 mL) in DCM (0.7 mL) was stirred at room temperature for 0.5 hour. The reaction mixture was concentrated under reduced pressure. The residue was added to i-PrOH  (1.2 mL) , followed by (R) -2, 5-dimethyl-4- (piperidin-4-yl) -2, 3-dihydrobenzofuran-7-amine (1e) (56 mg, 0.227 mmol) , TFA (0.021 mL, 0.288 mmol) . The reaction mixture was stirred at 95℃overnight. The reaction was quenched with addition of water (4 mL) , 3 N HCl (1 mL) at room temperature and extracted with EtOAc (2 × 10 mL) . The aqueous layer was adjusted to pH ＝ 9 using NaOH and extracted with DCM (3 × 10 mL) . The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by pre-TLC with DCM /MeOH /NH3·H2O (100: 10: 1) to give (R) - (2- ( (5-chloro-2- ( (2, 5-dimethyl-4- (piperidin-4-yl) -2, 3-dihydrobenzofuran-7-yl) amino) pyrimid in-4-yl) amino) phenyl) dimethylphosphine oxide (1) . MS-ESI (m/z) : 526 [M + 1] +.
Example 2
(R) - (2- ( (5-chloro-2- ( (2, 5-dimethyl-4- (1-methylpiperidin-4-yl) -2, 3-dihydrobenzofur  an-7-yl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (2)
Figure PCTCN2017072828-appb-000160
A mixture of (R) - (2- ( (5-chloro-2- ( (2, 5-dimethyl-4- (piperidin-4-yl) -2, 3-dihydrobenzofuran-7-yl) amino) pyrimid in-4-yl) amino) phenyl) dimethylphosphine oxide (1) (55 mg, 0.105 mmol) , formaldehyde (40 uL, 0.524 mmol) and NaBH (OAc) 3 (111 mg, 0.524 mmol) in 1, 2-Dichloroethane (1 mL) was stirred at ambient temperature for 3 hours. The reaction was quenched with aq. NaHCO3 (10 mL) , and the mixture was extracted with DCM (3 × 10 mL) , washed with brine (10 mL) , dried and concentrated. The residue was purified by pre-TLC with DCM/MeOH/NH3·H2O (100: 6.7: 1) to give (R) - (2- ( (5-chloro-2- ( (2, 5-dimethyl-4- (1-methyl-piperidin-4-yl) -2, 3-dihydrobenzofuran-7-yl) amin o) pyrimidin-4-yl) amino) phenyl) dimethyl-phosphine oxide (2) . MS-ESI (m/z) : 540 [M + 1] +.
Example 3
(R) - (2- ( (5-chloro-2- ( (4- (1-ethylpiperidin-4-yl) -2, 5-dimethyl-2, 3-dihydrobenzofura n-7-yl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (3)
Figure PCTCN2017072828-appb-000161
The title compound (R) - (2- ( (5-chloro-2- ( (4- (1-ethylpiperidin-4-yl) -2, 5-dimethyl-2, 3-dihydrobenzofuran-7-yl) amino) p yrimidin-4-yl) amino) phenyl) dimethylphosphine oxide (3) was prepared according to the synthetic method of 2 by replacing formaldehyde with acetaldehyde . MS-ESI (m/z) : 554 [M +1] +.
In vitro effects against a panel of recombinant human protein kinases
Materials: Poly (Glu, Tyr) 4: 1 (Sigma, Cat, No, P7244) , PY99 (Santa Cruz, Cat. No. SC-7020) , Goat Anti-Mouse IgG Antibody, H&L Chain Specific Peroxidase Conjugate (Calbiochem, Cat. No. 401215) , The recombinant kinase proteins was commercial: ALK (Millipore, Cat. No. 14-614) , ALK L1196M (Carna, Cat. No. 08-529) , ALK F1174L (Carna, Cat. No. 08-519) , ALK R1275Q (Carna, Cat. No. 08-520) . Multi-well spectrophotometer (Molecular Device, Cat. No. SpectraMax 190) .
The effects of indicated compound on the activities of receptor tyrosine kinases were determined using enzyme-linked immunosorbent assays (ELISAs) with commercial recombinant kinase proteins. Briefly, 20 μg/mL poly (Glu, Tyr) 4: 1 was pre-coated in 96-well plates as a substrate. A 50-μL aliquot of 10 μmol/L ATP solution diluted in kinase reaction buffer (50 mmol/L HEPES [pH 7.4] , 50 mmol/L MgCl2, 0.5 mmol/L MnCl2, 0.2 mmol/L Na3VO4, and 1 mmol/L DTT) was added to each well； 1 μL of various concentrations of indicated compound diluted in DMSO (Sigma) were then added to each reaction well. DMSO (1％, v/v) was used as the negative control. The kinase reaction was initiated by the addition of purified or commercial tyrosine kinase proteins diluted in 49 μL of kinase reaction buffer. After incubation for 60 min at 37 ℃, the plate was washed three times with phosphate-buffered saline (PBS) containing 0.1％Tween 20 (T-PBS) . Anti-phosphotyrosine (PY99) antibody (100 μL； 1: 500, diluted in 5 mg/mL BSA T-PBS) was then added. After a 30-min incubation at 37 ℃, the plate was washed three times, and 100 μL horseradish peroxidase-conjugated goat anti-mouse IgG (1: 2000, diluted in 5 mg/mL BSA T-PBS) was added. The plate was then incubated at 37 ℃ for 30 min and washed 3 times. A 100-μL aliquot of a solution containing 0.03％H2O2 and 2 mg/ml o-phenylenediamine in 0.1 mol/L citrate buffer (pH 5.5) was added. The reaction was terminated by the addition of 50 μL of 2 mol/L H2SO4 as the color changed, and the plate was analyzed using a multi-well  spectrophotometer at 490 nm. The inhibition rate (％) was calculated using the following equation: [1 - (A490/A490 control) ]× 100％. The IC50 values were calculated by concentration–response curve fitting using a SoftMax pro-based four-parameter method.
Select compounds prepared as described above were assayed according to the biological procedures described herein. The kinase profile of Example 3 are given in Table 1.
Table 1 Kinase Profile of Example 3
Kinase IC50 (nM) Kinase IC50 (nM)
ALK 2.4 ± 0.9 ALK F1174L 27.6 ± 13.3
ALK L1196M 2.1 ± 0.3 ALK R1275Q 3.6 ± 0.2
Inhibition of ALK-Addicted Proliferation of Human Cancer Cells
Cell Line: NCI-H3122 cell line (ATCC, Cat. No. CC-Y1574) , SU-DHL-1 (DSMZ, Cat. No. ACC-356) . 
Cells were seeded in 96-well tissue culture plates. On the next day, cells were exposed to various concentrations of compounds and further cultured for 72 h. Finally, cell proliferation was determined using sulforhodamine B (SRB) assay or Cell Counting Kit (CCK-8) assay. IC50 values were calculated by concentration–response curve fitting using a SoftMax pro-based four-parameter method. 
Select compounds prepared as described above were assayed according to the biological procedures described herein. The anti-proliferative activity of compounds are given in Table 2.
Table 2 Anti-proliferative activity of compounds on ALK-addicted cell lines
Figure PCTCN2017072828-appb-000162
Tumor Growth Inhibition Study of Compounds in ALK positive human NCI-H3122 lung cancer xenograft model
Animals (female SCID Mouse, 4-6 weeks) were obtained from Beijing HFK Bioscience Co.， Ltd. Female SCID Mouse (4–6 weeks old) were housed and maintained under specific-pathogen free conditions. Animal procedures were performed according to institutional ethical guidelines of animal care. Human NCI-H3122 lung cancer xenografts were maintained in SCID mice. In this study, under a sterilization condition, well growth tumors were cut into 1mm3 fragments and the fragments were transplanted subcutaneously into the right flank by trocar in  nude mice. When tumor reached a volume of 150-180 mm3, the mice were randomized to control and treated groups, and received vehicle, and compounds at indicated doses and schedule. The size of tumors were measured individually twice per week with microcalipers. Tumor volume (TV) was calculated as V＝ (length×width2) /2. The individual relative tumor volume (RTV) was calculated as follows: RTV＝ Vt/V0, where Vt is the volume on each day of measurement and V0 is the volume on the day of initial treatment. Therapeutic effect of compound was expressed in terms of T/C ％and the calculation formula is: T/C (％) ＝ mean RTV of the treated group /mean RTV of the control group×100％. The weight of mice also was measured twice per week. The experiment was repeated.
Statistical Analysis. Data of in vitro and in vivo efficacy are presented as the mean ± SE, and significance was determined by Student’s t-test. Differences were considered statistically significant at **P<0.01, ***P<0.001.
Table 3 Effect of Compounds on NCI-H3122 xenograft growth in SCID mice
Figure PCTCN2017072828-appb-000163
t student’s test vs Vehicle, **p < 0.01 ***p < 0.001

Claims (20)

  1. A compound of formula (I)
    Figure PCTCN2017072828-appb-100001
    or a pharmaceutically acceptable salt thereof, wherein
    each R1 is independently selected from hydrogen, halogen, hydroxyl, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, C1-10 alkylamino, C3-10 cycloalkylamino, di (C1-10 alkyl) amino, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl and heteroaryl-C1-4 alkyl, wherein alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RX；
    each R2 is independently selected from hydrogen, halogen, hydroxyl, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, C1-10 alkylamino, C3-10 cycloalkylamino, di (C1-10 alkyl) amino, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl and heteroaryl-C1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RX；
    R3 is independently selected from hydrogen, halogen, CN, -NRARB and C1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RX；
    R4 is independently selected from hydrogen, halogen, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl and C3-10 cycloalkyl, wherein alkyl, alkenyl, alkynyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RX；
    or R3 and R4 together with the carbon atoms to which they are attached form a 5-6 membered ring containing 0, 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2 or 3 RX groups；
    each R5 is independently selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10  alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, heteroaryl-C1-4 alkyl, CN, NO2, -NRA1RB1, -ORA1, -S (O) rRA1, -S (O) 2ORA1, -OS (O) 2RA1, -P (O) RA1RB1, -P (O) (ORA1) (ORB1) , -C (O) RA1, -C (O) ORA1, -OC (O) RA1, -C (O) NRA1RB1, -NRA1C (O) RB1, -OC (O) NRA1RB1, -NRA1C (O) ORB1, -NRA1C (O) NRA1RB1, -NRA1C (S) NRA1RB1, -S (O) rNRA1RB1, -NRA1S (O) rRB1, -NRA1S (O) 2NRA1RB1, -S (O) (＝NRE1) RB1, -N＝S (O) RA1RB1, -NRA1S (O) (＝NRE1) RB1, -S (O) (＝NRE1) NRA1RB1, -NRA1S (O) (＝NRE1) NRA1RB1, -C (＝NRE1) RA1, -C (＝N-ORB1) RA1, -C (＝NRE1) NRA1RB1, -NRA1C (＝NRE1) RB1 and -NRA1C (＝NRE1) NRA1RB1, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RX；
    R6 and R7 are independently selected from hydrogen, hydroxyl, C1-10 alkyl, C3-10 cycloalkyl and C1-10 alkoxyl, wherein alkyl, cycloalkyl and alkoxyl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RX；
    each RA, RA1, RB and RB1 are independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl and heteroaryl-C1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RX；
    or each “RA and RB” or “RA1 and RB1” and together with the atom (s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 RX groups；
    each RE1 is independently selected from hydrogen, C1-10 alkyl, CN, NO2, ORa1, SRa1, -S (O) rRa1, -C (O) Ra1, -C (O) ORa1 , -C (O) NRa1Rb1, and -S (O) rNRa1Rb1；
    each RX is independently selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, heteroaryl-C1-4 alkyl, halogen, CN, NO2, - (CRc1Rd1) tNRa1Rb1, - (CRc1Rd1) tORb1, - (CRc1Rd1) tS (O) rRb1, - (CRc1Rd1) tS (O) 2ORb1, - (CRc1Rd1) tOS (O) 2Rb1, - (CRc1Rd1) tP (O) Ra1Rb1, - (CRc1Rd1) tP (O) (ORa1) (ORb1) , - (CRc1Rd1) tC (O) Ra1, - (CRc1Rd1) tC (O) ORb1, - (CRc1Rd1) tOC (O) Rb1, - (CRc1Rd1) tC (O) NRa1Rb1, - (CRc1Rd1) tNRa1C (O) Rb1, - (CRc1Rd1) tOC (O) NRa1Rb1, - (CRc1Rd1) tNRa1C (O) ORb1, - (CRc1Rd1) tNRa1C (O) NRa1Rb1, - (CRc1Rd1) tNRa1C (S) NRa1Rb1, - (CRc1Rd1) tS (O) rNRa1Rb1, - (CRc1Rd1) tNRa1S (O) rRb1, - (CRc1Rd1) tNRa1S (O) 2NRa1Rb1, - (CRc1Rd1) tS (O) (＝NRe1) Rb1, - (CRc1Rd1) tN＝S (O) Ra1Rb1, - (CRc1Rd1) tNRa1S (O) (＝NRe1) Rb1, - (CRc1Rd1) tS (O) (＝NRe1) NRa1Rb1, - (CRc1Rd1) tNRa1S (O) (＝NRe1) NRa1Rb1, - (CRc1Rd1) tC (＝NRe1) Ra1, - (CRc1Rd1) tC (＝N-ORb1) Ra1, - (CRc1Rd1) tC (＝NRe1) NRa1Rb1, - (CRc1Rd1) tNRa1C (＝NRe1) Rb1 and - (CRc1Rd1) tNRa1C (＝NRe1) NRa1Rb1, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RY；
    each Ra1 and each Rb1 are independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl and heteroaryl-C1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RY；
    or Ra1 and Rb1 together with the atom (s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 RY groups；
    each Rc1 and each Rd1 are independently selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl and heteroaryl-C1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RY；
    or Rc1 and Rd1 together with the carbon atom (s) to which they are attached form a ring of 3 to 12 members containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2 or 3 RY groups；
    each Re1 is independently selected from hydrogen, C1-10 alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, CN, NO2, ORa2, SRa2, -S (O) rRa2, -C (O) Ra2, -C (O) ORa2, -C (O) NRa2Rb2, and -S (O) rNRa2Rb2；
    each RY is independently selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, heteroaryl-C1-4 alkyl, halogen, CN, NO2, - (CRc2Rd2) tNRa2Rb2, - (CRc2Rd2) tORb2, - (CRc2Rd2) tS (O) rRb2, - (CRc2Rd2) tS (O) 2ORb2, - (CRc2Rd2) tOS (O) 2Rb2, - (CRc2Rd2) tP (O) Ra2Rb2, - (CRc2Rd2) tP (O) (ORa2) (ORb2) , - (CRc2Rd2) tC (O) Ra2, - (CRc2Rd2) tC (O) ORb2, - (CRc2Rd2) tOC (O) Rb2, - (CRc2Rd2) tC (O) NRa2Rb2, - (CRc2Rd2) tNRa2C (O) Rb2, - (CRc2Rd2) tOC (O) NRa2Rb2, - (CRc2Rd2) tNRa2C (O) ORb2, - (CRc2Rd2) tNRa2C (O) NRa2Rb2, - (CRc2Rd2) tNRa2C (S) NRa2Rb2, - (CRc2Rd2) tS (O) rNRa2Rb2, - (CRc2Rd2) tNRa2S (O) rRb2, - (CRc2Rd2) tNRa2S (O) 2NRa2Rb2, - (CRc2Rd2) tS (O) (＝NRe2) Rb2, - (CRc2Rd2) tN＝S (O) Ra2Rb2, - (CRc2Rd2) tNRa2S (O) (＝NRe2) Rb2, - (CRc2Rd2) tS (O) (＝NRe2) NRa2Rb2, - (CRc2Rd2) tNRa2S (O) (＝NRe2) NRa2Rb2, - (CRc2Rd2) tC (＝NRe2) Ra2, - (CRc2Rd2) tC (＝N-ORb2) Ra2, - (CRc2Rd2) tC (＝NRe2) NRa2Rb2, - (CRc2Rd2) tNRa2C (＝NRe2) Rb2 and - (CRc2Rd2) tNRa2C (＝NRe2) NRa2Rb2, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from OH, CN, amino, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, C1-10 alkylamino, C3-10 cycloalkylamino and di (C1-10 alkyl) amino；
    each Ra2 and each Rb2 are independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, C1-10 alkylamino, C3-10 cycloalkylamino, di (C1-10 alkyl) amino, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl and heteroaryl-C1-4 alkyl,  wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from halogen, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, OH, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, amino, C1-10 alkylamino, C3-10 cycloalkylamino and di (C1-10 alkyl) amino；
    or Ra2 and Rb2 together with the atom (s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1 or 2 substituents, independently selected from halogen, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, OH, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, amino, C1-10 alkylamino, C3-10 cycloalkylamino and di (C1-10 alkyl) amino；
    each Rc2 and each Rd2 are independently selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, C1-10 alkylamino, C3-10 cycloalkylamino, di (C1-10 alkyl) amino, heterocyclyl, heterocyclyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl and heteroaryl-C1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from halogen, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, OH, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, amino, C1-10 alkylamino, C3-10 cycloalkylamino and di (C1-10 alkyl) amino；
    or Rc2 and Rd2 together with the carbon atom (s) to which they are attached form a ring of 3 to 12 members containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1 or 2 substituents, independently selected from halogen, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, OH, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, amino, C1-10 alkylamino, C3-10 cycloalkylamino and di (C1-10 alkyl) amino；
    each Re2 is independently selected from hydrogen, CN， NO2， C1-10 alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, C1-10 alkoxy, C3-10 cycloalkoxy, -C (O) C1-4 alkyl, -C (O) C3-10 cycloalkyl, -C (O) OC1-4 alkyl, -C (O) OC3-10 cycloalkyl, -C (O) N (C1-4 alkyl) 2, -C (O) N (C3-10 cycloalkyl) 2, -S (O) 2C1-4 alkyl, -S (O) 2C3-10 cycloalkyl, -S (O) 2N (C1-4 alkyl) 2 and -S (O) 2N (C3-10 cycloalkyl) 2；
    m is independently selected from 0, 1 and 2；
    n is independently selected from 1, 2 and 3；
    p is independently selected from 0, 1, 2 and 3；
    q is independently selected from 0, 1, 2 and 3；
    each r is independently selected from 1 and 2；
    each t is independently selected from 0, 1, 2, 3 and 4.
  2. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R1 is independently selected from C1-10 alkyl.
  3. A compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein each R1 is methyl.
  4. A compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein m is 1.
  5. A compound of any one of claims 1-4 or a pharmaceutically acceptable salt thereof, wherein n is 1.
  6. A compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof, wherein p is 2.
  7. A compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, wherein one R2 is independently selected from C1-10 alkyl, and the other R2 is independently selected from heterocyclyl, wherein alkyl and heterocyclyl are each unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RX.
  8. A compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein one R2 is methyl； and the other R2 is piperidinyl, which is unsubstituted or substituted with methyl or ethyl.
  9. A compound of any one of claims 1-8 or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen.
  10. A compound of any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein R4 is selected from halogen.
  11. A compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein R4 is chlorine.
  12. A compound of any one of claims 1-11 or a pharmaceutically acceptable salt thereof, wherein each R5 is hydrogen.
  13. A compound of any one of claims 1-12 or a pharmaceutically acceptable salt thereof, wherein R6 is selected from C1-10 alkyl.
  14. A compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein R6 is methyl.
  15. A compound of any one of claims 1-14 or a pharmaceutically acceptable salt thereof, wherein R7 is selected from C1-10 alkyl.
  16. A compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein R7 is methyl.
  17. A compound, selected from
    (R) - (2- ( (5-chloro-2- ( (2, 5-dimethyl-4- (piperidin-4-yl) -2, 3-dihydrobenzofuran-7-yl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide,
    (R) - (2- ( (5-chloro-2- ( (2, 5-dimethyl-4- (1-methylpiperidin-4-yl) -2, 3-dihydrobenzofuran-7-y l) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide,
    (R) - (2- ( (5-chloro-2- ( (4- (1-ethylpiperidin-4-yl) -2, 5-dimethyl-2, 3-dihydrobenzofuran-7-yl) amino) pyrimidin-4-yl) amino) phenyl) dimethylphosphine oxide,
    or pharmaceutically acceptable salts thereof.
  18. A pharmaceutical composition, comprising a compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  19. A method of treating, ameliorating or preventing a condition, which responds to inhibition of ALK, comprising administering to a subject in need of such treatment an effective amount of a compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, or of at least one pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent.
  20. Use of a compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a cell-proliferative disorder.
PCT/CN2017/072828 2016-02-03 2017-02-03 Phosphorus containing compounds as protein kinase inhibitors WO2017133663A1 (en)

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US11555042B2 (en) * 2018-03-28 2023-01-17 Fochon Biosciences, Ltd. Macrocyclic compounds as TRK kinases inhibitors
WO2022199589A1 (en) * 2021-03-23 2022-09-29 南京明德新药研发有限公司 Pyrimidine derivatives

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WO2009143389A1 (en) * 2008-05-21 2009-11-26 Ariad Pharmaceuticals, Inc. Phosphorous derivatives as kinase inhibitors
WO2012051587A1 (en) * 2010-10-14 2012-04-19 Ariad Pharmaceuticals, Inc. Methods for inhibiting cell proliferation in egfr-driven cancers
CN104854101A (en) * 2012-11-06 2015-08-19 上海复尚慧创医药研究有限公司 Alk kinase inhibitors

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US20160145244A1 (en) * 2014-11-25 2016-05-26 Fochon Pharma, Inc. Certain protein kinase inhibitors

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WO2009143389A1 (en) * 2008-05-21 2009-11-26 Ariad Pharmaceuticals, Inc. Phosphorous derivatives as kinase inhibitors
WO2012051587A1 (en) * 2010-10-14 2012-04-19 Ariad Pharmaceuticals, Inc. Methods for inhibiting cell proliferation in egfr-driven cancers
CN104854101A (en) * 2012-11-06 2015-08-19 上海复尚慧创医药研究有限公司 Alk kinase inhibitors

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