WO2017133701A1 - Certain protein kinase inhibitors - Google Patents

Certain protein kinase inhibitors Download PDF

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Publication number
WO2017133701A1
WO2017133701A1 PCT/CN2017/072958 CN2017072958W WO2017133701A1 WO 2017133701 A1 WO2017133701 A1 WO 2017133701A1 CN 2017072958 W CN2017072958 W CN 2017072958W WO 2017133701 A1 WO2017133701 A1 WO 2017133701A1
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Prior art keywords
pyridin
methyl
pyrimidin
fluoro
amine
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PCT/CN2017/072958
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French (fr)
Inventor
Xingdong ZHAO
Tongshuang Li
Zuwen ZHOU
Xianlong WANG
Ling Chen
Yue RONG
Qihong Liu
Zhifang Chen
Huajie Zhang
Rui Tan
Haohan TAN
Zhifu Li
Weipeng Zhang
Lihua Jiang
Yanxin Liu
Li LINGHU
Min Lin
Jing Sun
Weibo Wang
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Shanghai Fochon Pharmaceutical Co., Ltd.
Chongqing Fochon Pharmaceutical Co., Ltd.
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Application filed by Shanghai Fochon Pharmaceutical Co., Ltd., Chongqing Fochon Pharmaceutical Co., Ltd. filed Critical Shanghai Fochon Pharmaceutical Co., Ltd.
Priority to CN201780010075.XA priority Critical patent/CN108602799B/en
Publication of WO2017133701A1 publication Critical patent/WO2017133701A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • certain compounds and/or pharmaceutically acceptable salts thereof which can inhibit kinase activity of CDK4/6 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.
  • CDKs cyclin-dependent kinases
  • CDKs are serine/threonine protein kinases, which are the driving force behind the cell cycle and cell proliferation. CDKs regulate initiation, progression, and completion of mammalian cell cycle, and they are critical for cell growth. Most of the known CDK's , including CDK1 through CDK9, are involved either directly or indirectly in cell cycle progression. Those directly involved with cell cycle progression, such as CDK1-4 and 6, can be classified as G1, S, or G2M phase enzymes. Uncontrolled proliferation is a hallmark of cancer cells and the alteration of CDK function occurs with high frequency in many solid tumors.
  • CDK inhibitors could conceivably also be used to treat other conditions such as viral infections, autoimmune diseases and neuro-degenerative diseases, amongst others.
  • CDKs targeted therapeutics may also provide clinical benefits in the treatment of the previously described diseases when used in combination therapy with either existing, or new, therapeutic agents.
  • CDK4/6 inhibitors were disclosed in the arts, e.g., WO2010075074, many suffer from having short half-life or toxicity. Therefore, there is a need for new CDK4/6 inhibitors that have at least one advantageous property selected from potency, stability, selectivity, toxicity and pharmacodynamics properties as an alternative for the treatment of hyper-proliferative diseases.
  • a novel class of CDK4/6 inhibitors is provided herein.
  • Q is selected from aryl and heteroaryl
  • 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, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino di (
  • each R 2 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 ,
  • each R 3 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 A2 R B2 , -OR A2 , -S (O) r R A2 , -S (O) 2 OR A2 , -OS (O) 2 R A2 , -P (O) R A2 R B2 , -P (O) (OR A2 ) (OR B2 ) , -C (O) R A2 , -C (O) OR A2 , -OC (O) R A2 , -C (O) NR A2 R B2 ,
  • each R 4 is 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 A3 R B3 , -OR A3 , -S (O) r R A3 , -S (O) 2 OR A3 , -OS (O) 2 R A3 , -P (O) R A3 R B3 , -P (O) (OR A3 ) (OR B3 ) , -C (O) R A3 , -C (O) OR A3 , -OC (O) R A3 , -C (O) NR A3 R B3 ,
  • 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 A4 R B4 , - (CH 2 ) t NR A4 R B4 , -OR A4 , -S (O) r R A4 , -S (O) 2 OR A4 , -OS (O) 2 R A4 , -P (O) R A4 R B4 , -P (O) (OR A4 ) (OR A4 ) (OR B4 ) , -C (O) R A4 , -C (O) OR A4 , -
  • each R A1 , R A2 , R A3 , R A4 , R B1 , R B2 , R B3 and R B4 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 , R E2 , R E3 and R E4 are 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 selected from 0, 1, 2, 3 and 4;
  • n is selected from 0, 1 and 2;
  • p is selected from 0, 1 and 2;
  • each r is independently selected from 0, 1 and 2;
  • each t is independently selected from 0, 1, 2, 3 and 4.
  • composition comprising a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • a method for modulating CDK4/6 comprising administering to a system or a subject in need thereof, a therapeutically effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof or pharmaceutical compositions thereof, thereby modulating said CDK4/6.
  • a method to treat, ameliorate or prevent a condition which responds to inhibition of CDK4/6 comprising administering to a system or subject in need of such treatment an effective amount of a compound of formula (I) or (II) 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 (II) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a condition mediated by CDK4/6.
  • the compounds of the disclosure may be used alone or in combination with a second therapeutic agent to treat a condition mediated by CDK4/6.
  • condition herein includes but is not limited to, 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 (II) or a pharmaceutically acceptable salt thereof or pharmaceutical compositions thereof, and optionally in combination with a second therapeutic agent, thereby treating said condition.
  • the present disclosure provides the use of a compound of formula (I) or (II) 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 is 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 (II) 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 refers to aryl
  • 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.
  • 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 substituens, 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 CDK4/6 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 CDK4/6 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 provides a compound of formula (I) or (II) ,
  • Q is selected from aryl and heteroaryl
  • 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, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino di (
  • each R 2 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 ,
  • each R 3 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 A2 R B2 , -OR A2 , -S (O) r R A2 , -S (O) 2 OR A2 , -OS (O) 2 R A2 , -P (O) R A2 R B2 , -P (O) (OR A2 ) (OR B2 ) , -C (O) R A2 , -C (O) OR A2 , -OC (O) R A2 , -C (O) NR A2 R B2 ,
  • each R 4 is 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 A3 R B3 , -OR A3 , -S (O) r R A3 , -S (O) 2 OR A3 , -OS (O) 2 R A3 , -P (O) R A3 R B3 , -P (O) (OR A3 ) (OR B3 ) , -C (O) R A3 , -C (O) OR A3 , -OC (O) R A3 , -C (O) NR A3 R B3 ,
  • 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 A4 R B4 , - (CH 2 ) t NR A4 R B4 , -OR A4 , -S (O) r R A4 , -S (O) 2 OR A4 , -OS (O) 2 R A4 , -P (O) R A4 R B4 , -P (O) (OR A4 ) (OR A4 ) (OR B4 ) , -C (O) R A4 , -C (O) OR A4 , -
  • each R A1 , R A2 , R A3 , R A4 , R B1 , R B2 , R B3 and R B4 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 , R E2 , R E3 and R E4 are 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 selected from 0, 1, 2, 3 and 4;
  • n is selected from 0, 1 and 2;
  • p is selected from 0, 1 and 2;
  • each r is independently selected from 0, 1 and 2;
  • each t is independently selected from 0, 1, 2, 3 and 4.
  • Embodiment (2) the invention provides a compound of Embodiment (1) or a pharmaceutically acceptable salt thereof, wherein the formula is
  • the invention provides a compound of Embodiment (1) or a pharmaceutically acceptable salt thereof, wherein the formula is
  • the invention provides a compound of any one of Embodiments (1) - (3) or a pharmaceutically acceptable salt thereof, wherein Q is heteroaryl.
  • the invention provides a compound of Embodiment (4) or a pharmaceutically acceptable salt thereof, wherein Q is independently selected from
  • the invention provides a compound of any one of Embodiments (1) - (5) or a pharmaceutically acceptable salt thereof, wherein each R 5 is independently selected from C 1-10 alkyl, heterocycle, heterocyclyl-C 1-4 alkyl, -S (O) r R A4 , -C (O) R A4 and -CH 2 NR A4 R B4 , 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 (6) or a pharmaceutically acceptable salt thereof, wherein each R 5 is independently selected from methyl, ethyl,
  • the invention provides a compound of Embodiment (6) or a pharmaceutically acceptable salt thereof, wherein each R 5 is independently selected from -S (O) 2 R A4 and -C (O) R A4 , wherein each R A4 is independently selected from heterocyclyl and heterocyclyl-C 1-4 alkyl, 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 , and each R B4 is independently selected from C 1-10 alkyl.
  • the invention provides a compound of Embodiment (8) or a pharmaceutically acceptable salt thereof, wherein each R 5 is independently selected from -S (O) 2 R A4 and -C (O) R A4 , wherein each R A4 is independently selected from
  • each R B4 is methyl.
  • the invention provides a compound of Embodiment (6) or a pharmaceutically acceptable salt thereof, wherein each R 5 is independently selected from -CH 2 NR A4 R B4 , wherein each R A4 is which is unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from R X , and each R B4 is methyl.
  • the invention provides a compound of any one of Embodiments (6) - (10) or a pharmaceutically acceptable salt thereof, wherein each R X is independently selected from methyl, ethyl, methoxymethyl, cyanoethyl and oxetan-3-yl.
  • the invention provides a compound of any one of Embodiments (1) - (11) or a pharmaceutically acceptable salt thereof, wherein m is 1.
  • the invention provides a compound of any one of Embodiments (1) - (12) or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen.
  • the invention provides a compound of any one of Embodiments (1) - (13) or a pharmaceutically acceptable salt thereof, wherein each R 2 is hydrogen.
  • the invention provides a compound of any one of Embodiments (1) - (14) or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently selected from C 1-10 alkyl.
  • the invention provides a compound of Embodiment (15) or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently selected from methyl, isopropyl and tert-butyl.
  • the invention provides a compound of any one of Embodiments (15) - (16) or a pharmaceutically acceptable salt thereof, wherein p is 2.
  • the invention provides a compound of any one of Embodiments (1) - (17) or a pharmaceutically acceptable salt thereof, wherein R 4 is halogen.
  • the invention provides a compound of (18) or a pharmaceutically acceptable salt thereof, wherein each R 4 is independently selected from fluorine and chlorine.
  • the invention provides a compound selected from
  • the invention provides a pharmaceutical composition comprising a compound of any one of Embodiments (1) - (20) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • the invention provides a method of treating, ameliorating or preventing a condition, which responds to inhibition of cyclin-dependent kinase 4/6, comprising administering to a subject in need of such treatment an effective amount of a compound of any one of Embodiments (1) to (20) , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent.
  • the invention provides a use of a compound of any one of Embodiments (1) to (20) 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 CDK4/6 kinase comprising contacting the CDK4/6 with a compound disclosed herein, or a pharmaceutically acceptable salts thereof.
  • a method of inhibiting a CDK4/6 comprising causing a compound disclosed herein, or a pharmaceutically acceptable salts thereof to be present in a subject in order to inhibit the CDK4/6 in vivo.
  • a method of inhibiting CDK4/6 comprising administering a first compound to a subject that is converted in vivo to a second compound wherein the second compound inhibits the CDK4/6 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 CDK4/6 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 CDK4/6 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 CDK4/6 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 hyperproliferative disorders (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 s
  • a method of treating a disease state for which a mutation in the CDK4/6 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 CDK4/6.
  • 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 CDK4/6 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) , LABRASOLTM (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, sesam
  • 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) or (II) 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
  • a compound of formula (I) or (II) can also be prepared as a pharmaceutically acceptable acid addition salt by, for example, reacting the free base form of the at least one compound with a pharmaceutically acceptable inorganic or organic acid.
  • a pharmaceutically acceptable base addition salt of the at least one compound of formula (I) or (II) can be prepared by, for example, reacting the free acid form of the at least one 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) or (II) are set forth in the definitions section of this Application.
  • the salt forms of the compounds of formula (I) or (II) can be prepared using salts of the starting materials or intermediates.
  • the free acid or free base forms of the compounds of formula (I) or (II) can be prepared from the corresponding base addition salt or acid addition salt form.
  • a compound of formula (I) or (II) 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) or (II) 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) .
  • a suitable acid e.g., hydrochloric acid, etc
  • N-oxides of the a compound of formula (I) or (II) 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) or (II) 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) or (II) in an unoxidized form can be prepared from N-oxides of compounds of formula (I) or (II) 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
  • 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 ) .
  • a compound of formula (I) or (II) or a 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.
  • the compound of formula I or II of the present disclosure is outlined in Scheme 1.
  • the compound of formula I or II can be disassembled into the intermediates III to VIII, 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 pyrimidine intermediates such as those of formula VI with hetero-arene intermediates such as those of formula VII or VIII using such palladium catalyzed coupling conditions as Suzuki reaction or other coupling conditions known in the literature provides pyrimidine intermediates of formula IV or V.
  • Reaction of IV or V with amino-arene such as those of formula III using such coupling conditions as Buchwald amination reaction or amination conditions known in the literature leads to compound of formula I or II respectively.
  • intermediate IVa one synthetic route of IVa is shown in Scheme 2.
  • intermediate IVa is prepared by a sequence of reductive amination, imidazole formation and conversion of halide group into a group such as B or Sn followed by palladium catalyzed coupling reaction.
  • the title compound (C-2) was prepared according to the synthetic method of B-8 by replacing 5-bromo-3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridine (B-7) with 5-bromo-3-isopropyl-1-methyl-1H-pyrazolo [3, 4-b] pyridine (C-1) .
  • MS-ESI (m/z) 220 [M + 1] + .
  • Examples 9-81 listed in Table 1 were prepared from appropriate starting materials which are commercially available or known in the literature and sequential modifications as necessary. The structures and names of Examples 9-81 are given in Table 1.
  • Examples 83-87 Examples 88-156 listed in Table 2 were prepared from the corresponding substituted aminopyridines and sequential modifications as necessary, or using similar synthetic strategies or methods.
  • BE (2) -C Cells were plated in 96-well plates with 150 ⁇ l culture medium at cell density of 5000 cells/well. Compounds dilution: 20 mM stock solution of all compounds in DMSO. On the day of treatment, compounds were fresh diluted from the stock solution to a working solution (4 ⁇ of final concentrations) in culture medium. 50 ⁇ l of compound mixtures were added to duplicate wells along with 150 ⁇ l of cells. 24 hours after BE (2) -C cells were plated, testing compounds were added. Cell proliferation was measured by MTS assay following manufacturer’s instruction after compound treatment for 72 hours.
  • Example IC 50 (nM) Example IC 50 (nM)
  • Example IC 50 (nM) Example IC 50 (nM)
  • Example IC 50 (nM) 1 857 49 728 91 574 126 192 2 343 54 58 92 124 129 464 3 204 56 740 93 96 134 323 4 19 57 456 94 68 135 418 5 49 58 279 95 768 136 46 7 583 59 37 96 51 137 28 8 811 60 435 97 55 138 18 10 82 61 217 99 176 139 26 11 60 62 251 100 74 140 38 13 546 63 91 102 74 141 102 14 392 65 58 103 99 142 26 16 751 66 51 105 640 143 20 19 396 68 58 106 177 144 31 20 272 69 31 107 178 145 16 22 840 70 148 108 456 146 37 23 514 71 38 109 297 147 535

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Abstract

Provided are certain CDK4/6 inhibitors, pharmaceutical compositions thereof, and methods of use therefor.

Description

CERTAIN PROTEIN KINASE INHIBITORS
This application claims the priority to the U.S. provisional application No. 62/292,259, which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
Provided are certain compounds and/or pharmaceutically acceptable salts thereof which can inhibit kinase activity of CDK4/6 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.
Tumor development is closely associated with genetic alteration and deregulation of cyclin-dependent kinases (CDKs) and their regulators, suggesting that inhibitors of CDKs may be useful anti-cancer therapeutics.
CDKs are serine/threonine protein kinases, which are the driving force behind the cell cycle and cell proliferation. CDKs regulate initiation, progression, and completion of mammalian cell cycle, and they are critical for cell growth. Most of the known CDK's , including CDK1 through CDK9, are involved either directly or indirectly in cell cycle progression. Those directly involved with cell cycle progression, such as CDK1-4 and 6, can be classified as G1, S, or G2M phase enzymes. Uncontrolled proliferation is a hallmark of cancer cells and the alteration of CDK function occurs with high frequency in many solid tumors.
The development of monotherapies for the treatment of proliferative disorders, such as cancers, using therapeutics targeted generically at CDKs, or at specific CDKs, is therefore potentially highly desirable. CDK inhibitors could conceivably also be used to treat other conditions such as viral infections, autoimmune diseases and neuro-degenerative diseases, amongst others. CDKs targeted therapeutics may also provide clinical benefits in the treatment of the previously described diseases when used in combination therapy with either existing, or new, therapeutic agents.
Therefore, a compound having an inhibitory activity on CDK will be useful for the prevention or treatment of cancer. Although CDK4/6 inhibitors were disclosed in the arts, e.g., WO2010075074, many suffer from having short half-life or toxicity. Therefore, there is a need for new CDK4/6 inhibitors that have at least one advantageous property selected from potency, stability, selectivity, toxicity and pharmacodynamics properties as an alternative for the treatment of hyper-proliferative diseases. In this regard, a novel class of CDK4/6 inhibitors is provided herein.
DISCLOSURE OF THE INVENTION
Disclosed herein are certain novel 6-5 membered fused azole ring 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) or (II) :
Figure PCTCN2017072958-appb-000001
or
Figure PCTCN2017072958-appb-000002
or a pharmaceutically acceptable salt thereof, wherein
Q is selected from aryl and heteroaryl；
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, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino di (alky) amino, 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, 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；
each R3 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, -NRA2RB2, -ORA2, -S (O) rRA2, -S (O) 2ORA2, -OS (O) 2RA2, -P (O) RA2RB2, -P (O) (ORA2) (ORB2) , -C (O) RA2, -C (O) ORA2, -OC (O) RA2, -C (O) NRA2RB2, -NRA2C (O) RB2, -OC (O) NRA2RB2, -NRA2C (O) ORB2, -NRA2C (O) NRA2RB2, -NRA2C (S) NRA2RB2, -S (O) rNRA2RB2, -NRA2S (O) rRB2, -NRA2S (O) 2NRA2RB2, -S (O) (＝NRE2) RB2, -N＝S (O) RA2RB2, -NRA2S (O) (＝NRE2) RB2, -S (O) (＝NRE2) NRA2RB2, -NRA2S (O) (＝NRE2) NRA2RB2, -C (＝NRE2) RA2, -C (＝N-ORB2) RA2, -C (＝NRE2) NRA2RB2, -NRA2C (＝NRE2) RB2 and -NRA2C (＝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 RX；
each R4 is 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, -NRA3RB3, -ORA3, -S (O) rRA3, -S (O) 2ORA3, -OS (O) 2RA3, -P (O) RA3RB3, -P (O) (ORA3) (ORB3) , -C (O) RA3, -C (O) ORA3, -OC (O) RA3, -C (O) NRA3RB3, -NRA3C (O) RB3, -OC (O) NRA3RB3, -NRA3C (O) ORB3, -NRA3C (O) NRA3RB3, -NRA3C (S) NRA3RB3, -S (O) rNRA3RB3, -NRA3S (O) rRB3, -NRA3S (O) 2NRA3RB3, -S (O) (＝NRE3) RB3, -N＝S (O) RA3RB3, -NRA3S (O) (＝NRE3) RB3, -S (O) (＝NRE3) NRA3RB3, -NRA3S (O) (＝NRE3) NRA3RB3, -C (＝NRE3) RA3, -C (＝N-ORB3) RA3, -C (＝NRE3) NRA3RB3, -NRA3C (＝NRE3) RB3 and -NRA3C (＝NRE3) NRA3RB3, 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；
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, -NRA4RB4, - (CH2) tNRA4RB4, -ORA4, -S (O) rRA4, -S (O) 2ORA4, -OS (O) 2RA4, -P (O) RA4RB4, -P (O) (ORA4) (ORB4) , -C (O) RA4, -C (O) ORA4, -OC (O) RA4, -C (O) NRA4RB4, -NRA4C (O) RB4, -OC (O) NRA4RB4, -NRA4C (O) ORB4, -NRA4C (O) NRA4RB4, -NRA4C (S) NRA4RB4, -S (O) rNRA4RB4, -NRA4S (O) rRB4, -NRA4S (O) 2NRA4RB4, -S ( O) (＝NRE4) RB4, -N＝S (O) RA4RB4, -NRA4S (O) (＝NRE4) RB4, -S (O) (＝NRE4) NRA4RB4, -NRA4S (O) (＝NRE4) NRA4RB4, -C (＝NRE4) RA4, -C (＝N-ORB4) RA4, -C (＝NRE4) NRA4RB4, -NRA4C (＝NRE4) RB4 and -NRA4C (＝NRE4) NRA4RB4, 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；
each RA1, RA2, RA3, RA4, RB1, RB2, RB3 and RB4 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 “RA1 and RB1” , “RA2 and RB2” , “RA3 and RB3” or “RA4 and RB4” 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, RE2, RE3 and RE4 are 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 selected from 0, 1, 2, 3 and 4；
n is selected from 0, 1 and 2；
p is selected from 0, 1 and 2；
each r is independently selected from 0, 1 and 2；
each t is independently selected from 0, 1, 2, 3 and 4.
In another aspect, disclosed herein is a pharmaceutical composition comprising a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
In yet another aspect, disclosed herein is a method for modulating CDK4/6, comprising administering to a system or a subject in need thereof, a therapeutically effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof or pharmaceutical compositions thereof, thereby modulating said CDK4/6.
In yet another aspect, disclosed is a method to treat, ameliorate or prevent a condition which responds to inhibition of CDK4/6 comprising administering to a system or subject in need of such treatment an effective amount of a compound of formula (I) or (II) 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 (II) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a condition mediated by CDK4/6. In particular embodiments, the compounds of the disclosure may be used alone or in combination with a second therapeutic agent to treat a condition mediated by CDK4/6.
Alternatively, disclosed herein is a compound of formula (I) or (II) or a pharmaceutically acceptable salt for treating a condition mediated by CDK4/6.
Specifically, the condition herein includes but is not limited to, 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 (II) or a pharmaceutically acceptable salt thereof or pharmaceutical compositions thereof, and optionally in combination with a second therapeutic agent, thereby treating said condition.
Alternatively, the present disclosure provides the use of a compound of formula (I) or (II) 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 is 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 (II) 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, such as "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” 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 PCTCN2017072958-appb-000003
Figure PCTCN2017072958-appb-000004
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 substituens, 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 CDK4/6 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 CDK4/6 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 an embodiment (1) , this invention provides a compound of formula (I) or (II) ,
Figure PCTCN2017072958-appb-000005
or
Figure PCTCN2017072958-appb-000006
or a pharmaceutically acceptable salt thereof, wherein
Q is selected from aryl and heteroaryl；
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, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino di (alky) amino, 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, 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；
each R3 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, -NRA2RB2, -ORA2, -S (O) rRA2,  -S (O) 2ORA2, -OS (O) 2RA2, -P (O) RA2RB2, -P (O) (ORA2) (ORB2) , -C (O) RA2, -C (O) ORA2, -OC (O) RA2, -C (O) NRA2RB2, -NRA2C (O) RB2, -OC (O) NRA2RB2, -NRA2C (O) ORB2, -NRA2C (O) NRA2RB2, -NRA2C (S) NRA2RB2, -S (O) rNRA2RB2, -NRA2S (O) rRB2, -NRA2S (O) 2NRA2RB2, -S (O) (＝NRE2) RB2, -N＝S (O) RA2RB2, -NRA2S (O) (＝NRE2) RB2, -S (O) (＝NRE2) NRA2RB2, -NRA2S (O) (＝NRE2) NRA2RB2, -C (＝NRE2) RA2, -C (＝N-ORB2) RA2, -C (＝NRE2) NRA2RB2, -NRA2C (＝NRE2) RB2 and -NRA2C (＝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 RX；
each R4 is 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, -NRA3RB3, -ORA3, -S (O) rRA3, -S (O) 2ORA3, -OS (O) 2RA3, -P (O) RA3RB3, -P (O) (ORA3) (ORB3) , -C (O) RA3, -C (O) ORA3, -OC (O) RA3, -C (O) NRA3RB3, -NRA3C (O) RB3, -OC (O) NRA3RB3, -NRA3C (O) ORB3, -NRA3C (O) NRA3RB3, -NRA3C (S) NRA3RB3, -S (O) rNRA3RB3, -NRA3S (O) rRB3, -NRA3S (O) 2NRA3RB3, -S (O) (＝NRE3) RB3, -N＝S (O) RA3RB3, -NRA3S (O) (＝NRE3) RB3, -S (O) (＝NRE3) NRA3RB3, -NRA3S (O) (＝NRE3) NRA3RB3, -C (＝NRE3) RA3, -C (＝N-ORB3) RA3, -C (＝NRE3) NRA3RB3, -NRA3C (＝NRE3) RB3 and -NRA3C (＝NRE3) NRA3RB3, 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；
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, -NRA4RB4, - (CH2) tNRA4RB4, -ORA4, -S (O) rRA4, -S (O) 2ORA4, -OS (O) 2RA4, -P (O) RA4RB4, -P (O) (ORA4) (ORB4) , -C (O) RA4, -C (O) ORA4, -OC (O) RA4, -C (O) NRA4RB4, -NRA4C (O) RB4, -OC (O) NRA4RB4, -NRA4C (O) ORB4, -NRA4C (O) NRA4RB4, -NRA4C (S) NRA4RB4, -S (O) rNRA4RB4, -NRA4S (O) rRB4, -NRA4S (O) 2NRA4RB4, -S (O) (＝NRE4) RB4, -N＝S (O) RA4RB4, -NRA4S (O) (＝NRE4) RB4, -S (O) (＝NRE4) NRA4RB4, -NRA4S (O) (＝NRE4) NRA4RB4, -C (＝NRE4) RA4, -C (＝N-ORB4) RA4, -C (＝NRE4) NRA4RB4, -NRA4C (＝NRE4) RB4 and -NRA4C (＝NRE4) NRA4RB4, 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；
each RA1, RA2, RA3, RA4, RB1, RB2, RB3 and RB4 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 “RA1 and RB1” , “RA2 and RB2” , “RA3 and RB3” or “RA4 and RB4” 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, RE2, RE3 and RE4 are 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 selected from 0, 1, 2, 3 and 4；
n is selected from 0, 1 and 2；
p is selected from 0, 1 and 2；
each r is independently selected from 0, 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 the formula is
Figure PCTCN2017072958-appb-000007
In another Embodiment (3) , the invention provides a compound of Embodiment (1) or a pharmaceutically acceptable salt thereof, wherein the formula is
Figure PCTCN2017072958-appb-000008
In another Embodiment (4) , the invention provides a compound of any one of Embodiments (1) - (3) or a pharmaceutically acceptable salt thereof, wherein Q is heteroaryl.
In another Embodiment (5) , the invention provides a compound of Embodiment (4) or a pharmaceutically acceptable salt thereof, wherein Q is independently selected from
Figure PCTCN2017072958-appb-000009
Figure PCTCN2017072958-appb-000010
In another Embodiment (6) , the invention provides a compound of any one of Embodiments (1) - (5) or a pharmaceutically acceptable salt thereof, wherein each R5 is independently selected from C1-10 alkyl, heterocycle, heterocyclyl-C1-4 alkyl, -S (O) rRA4, -C (O) RA4 and -CH2NRA4RB4, 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 (7) , the invention provides a compound of Embodiment (6) or a pharmaceutically acceptable salt thereof, wherein each R5 is independently selected from methyl, ethyl, 
Figure PCTCN2017072958-appb-000011
Figure PCTCN2017072958-appb-000012
which is 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 (6) or a pharmaceutically acceptable salt thereof, wherein each R5 is independently selected from -S (O) 2RA4 and -C (O) RA4, wherein each RA4 is independently selected from heterocyclyl and heterocyclyl-C1-4 alkyl, 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, and each RB4 is independently selected from C1-10 alkyl.
In another Embodiment (9) , the invention provides a compound of Embodiment (8) or a pharmaceutically acceptable salt thereof, wherein each R5 is independently selected from -S (O) 2RA4 and -C (O) RA4, wherein each RA4 is independently selected from
Figure PCTCN2017072958-appb-000013
which is unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RX, and each RB4 is methyl.
In another Embodiment (10) , the invention provides a compound of Embodiment (6) or a pharmaceutically acceptable salt thereof, wherein each R5 is independently selected from -CH2NRA4RB4, wherein each RA4 is
Figure PCTCN2017072958-appb-000014
which is unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RX, and each RB4 is methyl.
In another Embodiment (11) , the invention provides a compound of any one of Embodiments (6) - (10) or a pharmaceutically acceptable salt thereof, wherein each RX is independently selected from methyl, ethyl, methoxymethyl, cyanoethyl and oxetan-3-yl.
In another Embodiment (12) , the invention provides a compound of any one of Embodiments (1) - (11) or a pharmaceutically acceptable salt thereof, wherein m is 1.
In another Embodiment (13) , the invention provides a compound of any one of Embodiments (1) - (12) or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen.
In another Embodiment (14) , the invention provides a compound of any one of Embodiments (1) - (13) or a pharmaceutically acceptable salt thereof, wherein each R2 is hydrogen.
In another Embodiment (15) , the invention provides a compound of any one of Embodiments (1) - (14) or a pharmaceutically acceptable salt thereof, wherein each R3 is independently selected from C1-10 alkyl.
In another Embodiment (16) , the invention provides a compound of Embodiment (15) or a pharmaceutically acceptable salt thereof, wherein each R3 is independently selected from methyl, isopropyl and tert-butyl.
In another Embodiment (17) , the invention provides a compound of any one of Embodiments (15) - (16) or a pharmaceutically acceptable salt thereof, wherein p is 2.
In another Embodiment (18) , the invention provides a compound of any one of Embodiments (1) - (17) or a pharmaceutically acceptable salt thereof, wherein R4 is halogen.
In another Embodiment (19) , the invention provides a compound of (18) or a pharmaceutically acceptable salt thereof, wherein each R4 is independently selected from fluorine and chlorine.
In another Embodiment (20) , the invention provides a compound selected from
5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- (piperazin-1-ylme thyl) pyridin-2-yl) pyrimidin-2-amine,
5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (4-methylpiperaz in-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
N- (5- ( (4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-i midazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
(S) -5-fluoro-N- (5- ( (hexahydropyrrolo [1, 2-a] pyrazin-2 (1H) -yl) methyl) pyridin-2-yl) -4- (1-i sopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
(R) -5-fluoro-N- (5- ( (hexahydropyrrolo [1, 2-a] pyrazin-2 (1H) -yl) methyl) pyridin-2-yl) -4- (1-i sopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
N- (5- ( ( (1S, 4S) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-iso propyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( ( (1S, 4S) -5-methy l-2, 5-diazabicyclo [2.2.1] heptan-2-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
N- (5- ( ( (1S, 4S) -5-ethyl-2, 5-diazabicyclo [2.2.1] heptan-2-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
N- (5- ( (3, 8-diazabicyclo [3.2.1] octan-8-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (3-methyl-3, 8-di azabicyclo [3.2.1] octan-8-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
N- (5- ( (3-ethyl-3, 8-diazabicyclo [3.2.1] octan-8-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopr opyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
N- (5- ( (3, 8-diazabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (8-methyl-3, 8-di azabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
N- (5- ( (8-ethyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopr opyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
5-fluoro-N- (5- ( (hexahydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) methyl) pyridin-2-yl) -4- (1-isopro pyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (5-methylhexahy dropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
N- (5- ( (5-ethylhexahydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) methyl) pyridin-2-yl) -5-fluoro-4- (1 -isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
N- (5- ( (2, 7-diazaspiro [3.5] nonan-2-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-met hyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (7-methyl-2, 7-di azaspiro [3.5] nonan-2-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
N- (5- ( (7-ethyl-2, 7-diazaspiro [3.5] nonan-2-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropy l-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
N- (5- ( (2, 6-diazaspiro [3.3] heptan-2-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-met hyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (6-methyl-2, 6-di azaspiro [3.3] heptan-2-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
N- (5- ( (6-ethyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isoprop yl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
N- (5- ( (3, 9-diazaspiro [5.5] undecan-3-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-m ethyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (9-methyl-3, 9-di azaspiro [5.5] undecan-3-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
N- (5- ( (9-ethyl-3, 9-diazaspiro [5.5] undecan-3-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopro pyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
N- (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-yl) -5, 6, 7,8-tetrahydro-1, 6-naphthyridin-2-amine,
N- (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-yl) -6-m ethyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-amine,
6-ethyl-N- (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-yl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-amine,
(6- ( (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-yl) ami no) pyridin-3-yl) (piperazin-1-yl) methanone,
(6- ( (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-yl) ami no) pyridin-3-yl) (4-methylpiperazin-1-yl) methanone,
(4-ethylpiperazin-1-yl) (6- ( (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6 -yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,
(3, 8-diazabicyclo [3.2.1] octan-3-yl) (6- ( (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5 -b] pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,
(6- ( (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-yl) ami no) pyridin-3-yl) (8-methyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) methanone,
(8-ethyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) (6- ( (5-fluoro-4- (1-isopropyl-2-methyl-1H-imid azo [4, 5-b] pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,
(6- ( (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-yl) ami no) pyridin-3-yl) (2, 7-diazaspiro [3.5] nonan-2-yl) methanone,
(6- ( (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-yl) ami no) pyridin-3-yl) (7-methyl-2, 7-diazaspiro [3.5] nonan-2-yl) methanone,
(7-ethyl-2, 7-diazaspiro [3.5] nonan-2-yl) (6- ( (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b] pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,
(6- ( (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-yl) ami no) pyridin-3-yl) (hexahydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) methanone,
(6- ( (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-yl) ami no) pyridin-3-yl) (5-methylhexahydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) methanone,
(5-ethylhexahydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) (6- ( (5-fluoro-4- (1-isopropyl-2-methyl-1 H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,
5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- (piperazin-1-ylsul fonyl) pyridin-2-yl) pyrimidin-2-amine,
5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (4-methylpiperaz in-1-yl) sulfonyl) pyridin-2-yl) pyrimidin-2-amine,
N- (5- ( (4-ethylpiperazin-1-yl) sulfonyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
N- (5- ( (3, 8-diazabicyclo [3.2.1] octan-3-yl) sulfonyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2 -methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (8-methyl-3, 8-di azabicyclo [3.2.1] octan-3-yl) sulfonyl) pyridin-2-yl) pyrimidin-2-amine,
N- (5- ( (8-ethyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) sulfonyl) pyridin-2-yl) -5-fluoro-4- (1-isop ropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
5-fluoro-N- (5- ( (hexahydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) sulfonyl) pyridin-2-yl) -4- (1-isopr opyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (5-methylhexahy dropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) sulfonyl) pyridin-2-yl) pyrimidin-2-amine,
N- (5- ( (5-ethylhexahydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) sulfonyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
N- (5- ( (2, 7-diazaspiro [3.5] nonan-2-yl) sulfonyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-me thyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (7-methyl-2, 7-di azaspiro [3.5] nonan-2-yl) sulfonyl) pyridin-2-yl) pyrimidin-2-amine,
N- (5- ( (7-ethyl-2, 7-diazaspiro [3.5] nonan-2-yl) sulfonyl) pyridin-2-yl) -5-fluoro-4- (1-isoprop yl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (4- (oxetan-3-yl) p iperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
(S) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (2-methyl-4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
(R) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (2-methyl-4-(oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
(R) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (3-methyl-4-(oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine.
(S) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (3-methyl-4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-fluoro-N- (5- ( (4- (oxetan-3-yl ) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
(S) -4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-fluoro-N- (5- ( (2-methyl-4 - (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
(R) -4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-fluoro-N- (5- ( (2-methyl-4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
(R) -4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-fluoro-N- (5- ( (3-methyl-4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
(S) -4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-fluoro-N- (5- ( (3-methyl-4 - (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-fluoro-N- (5- (piperazin-1-yl methyl) pyridin-2-yl) pyrimidin-2-amine,
4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-fluoro-N- (5- ( (4-methylpiper azin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (4-ethylpiperazin-1-yl) m ethyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine,
N- (5- ( (3, 8-diazabicyclo [3.2.1] octan-8-yl) methyl) pyridin-2-yl) -4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-fluoropyrimidin-2-amine,
4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-fluoro-N- (5- ( (3-methyl-3, 8-diazabicyclo [3.2.1] octan-8-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (3-ethyl-3, 8-diazabicycl o [3.2.1] octan-8-yl) methyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine,
(S) -4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-fluoro-N- (5- ( (3- (methox ymethyl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
(S) -4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-fluoro-N- (5- ( (3- (methox ymethyl) -4-methylpiperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
(S) -4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (4-ethyl-3- (methoxy methyl) piperazin-1-yl) methyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine,
N- (5- ( (3, 8-diazabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) -4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-fluoropyrimidin-2-amine,
4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-fluoro-N- (5- ( (8-methyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (8-ethyl-3, 8-diazabicycl o [3.2.1] octan-3-yl) methyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine,
4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-fluoro-N- (5- (1- (piperazin-1-yl) ethyl) pyridin-2-yl) pyrimidin-2-amine,
4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-fluoro-N- (5- (1- (4-methylpip erazin-1-yl) ethyl) pyridin-2-yl) pyrimidin-2-amine,
4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- (1- (4-ethylpiperazin-1-yl ) ethyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine,
4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-chloro-N- (5- (piperazin-1-yl methyl) pyridin-2-yl) pyrimidin-2-amine,
4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-chloro-N- (5- ( (4-methylpiper azin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-chloro-N- (5- ( (4-ethylpiperaz in-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- (piperazin-1-ylm ethyl) pyridin-2-yl) pyrimidin-2-amine,
5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (4-methylpipera zin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
N- (5- ( (4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-p yrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
5-fluoro-4- (3-isopropyl-1-methyl-1H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (4-methylpipera zin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
N- (5- ( (4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-1-methyl-1H-p yrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
N- (5- ( (3, 8-diazabicyclo [3.2.1] octan-8-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (3-methyl-3, 8-di azabicyclo [3.2.1] octan-8-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
N- (5- ( (3-ethyl-3, 8-diazabicyclo [3.2.1] octan-8-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopr opyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
N- (5- ( (3, 8-diazabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (8-methyl-3, 8-di azabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
N- (5- ( (8-ethyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopr opyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
(R) -5-fluoro-N- (5- ( (hexahydropyrrolo [1, 2-a] pyrazin-2 (1H) -yl) methyl) pyridin-2-yl) -4- (3-i sopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
N- (5- ( (2, 7-diazaspiro [3.5] nonan-2-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-met hyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (7-methyl-2, 7-di azaspiro [3.5] nonan-2-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
N- (5- ( (7-ethyl-2, 7-diazaspiro [3.5] nonan-2-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropy l-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
5-fluoro-N- (5- ( (hexahydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) methyl) pyridin-2-yl) -4- (3-isopro pyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (5-methylhexah ydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
N- (5- ( (5-ethylhexahydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) methyl) pyridin-2-yl) -5-fluoro-4- (3 -isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
N- (5- ( (2, 7-diazaspiro [3.5] nonan-7-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-met hyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (2-methyl-2, 7-di azaspiro [3.5] nonan-7-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
N- (5- ( (2-ethyl-2, 7-diazaspiro [3.5] nonan-7-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropy l-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
N- ( 5- ( (3, 9-diazaspiro [5.5] undecan-3-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-m ethyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (9-methyl-3, 9-di azaspiro [5.5] undecan-3-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
N- (5- ( (9-ethyl-3, 9-diazaspiro [5.5] undecan-3-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopro pyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
(S) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (2-methyl-4-(oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
(R) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (2-methyl-4-(oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
(R) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (3-methyl-4-(oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
(S) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (3-methyl-4-(oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
(6- ( (5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-yl) am ino) pyridin-3-yl) (piperazin-1-yl) methanone,
(6- ( (5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-yl) am ino) pyridin-3-yl) (4-methylpiperazin-1-yl) methanone,
(4-ethylpiperazin-1-yl) (6- ( (5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5 -yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,
(3, 8-diazabicyclo [3.2.1] octan-8-yl) (6- ( (5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,
(6- ( (5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-yl) am ino) pyridin-3-yl) (3-methyl-3, 8-diazabicyclo [3.2.1] octan-8-yl) methanone,
(3-ethyl-3, 8-diazabicyclo [3.2.1] octan-8-yl) (6- ( (5-fluoro-4- (3-isopropyl-2-methyl-2H-pyra zolo [3, 4-b] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,
(3, 8-diazabicyclo [3.2.1] octan-3-yl) (6- ( (5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,
(6- ( (5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-yl) am ino) pyridin-3-yl) (8-methyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) methanone,
(8-ethyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) (6- ( (5-fluoro-4- (3-isopropyl-2-methyl-2H-pyra zolo [3, 4-b] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,
(6- ( (5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-yl) am ino) pyridin-3-yl) (2, 7-diazaspiro [3.5] nonan-2-yl) methanone,
(6- ( (5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-yl) am ino) pyridin-3-yl) (7-methyl-2, 7-diazaspiro [3.5] nonan-2-yl) methanone,
(7-ethyl-2, 7-diazaspiro [3.5] nonan-2-yl) (6- ( (5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazol o [3, 4-b] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,
(6- ( (5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-yl) am ino) pyridin-3-yl) (hexahydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) methanone,
(6- ( (5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-yl) am ino) pyridin-3-yl) (5-methylhexahydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) methanone,
(5-ethylhexahydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) (6- ( (5-fluoro-4- (3-isopropyl-2-methyl-2 H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,
N- (5- ( (3, 8-diazabicyclo [3.2.1] octan-3-yl) sulfonyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2 -methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (8-methyl-3, 8-di azabicyclo [3.2.1] octan-3-yl) sulfonyl) pyridin-2-yl) pyrimidin-2-amine,
N- (5- ( (8-ethyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) sulfonyl) pyridin-2-yl) -5-fluoro-4- (3-isop ropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
N- (5- ( (2, 7-diazaspiro [3.5] nonan-2-yl) sulfonyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-me thyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (7-methyl-2, 7-di azaspiro [3.5] nonan-2-yl) sulfonyl) pyridin-2-yl) pyrimidin-2-amine,
N- (5- ( (7-ethyl-2, 7-diazaspiro [3.5] nonan-2-yl) sulfonyl) pyridin-2-yl) -5-fluoro-4- (3-isoprop yl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
5-fluoro-N- (5- ( (hexahydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) sulfonyl) pyridin-2-yl) -4- (3-isopr opyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (5-methylhexah ydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) sulfonyl) pyridin-2-yl) pyrimidin-2-amine,
N- (5- ( (5-ethylhexahydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) sulfonyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoro-N- (5- ( (4- (oxetan-3-y l) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoro-N- (5- ( (4-methylpiper azin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine,
(R) -4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoro-N- (5- ( (methyl ( (1 -methylpyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) pyrimidin-2-amine,
(R) -4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoro-N- (5- ( (hexahydr opyrrolo [1, 2-a] pyrazin-2 (1H) -yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
N- (5- ( (3, 8-diazabicyclo [3.2.1] octan-8-yl) methyl) pyridin-2-yl) -4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoropyrimidin-2-amine,
4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoro-N- (5- ( (3-methyl-3, 8-diazabicyclo [3.2.1] octan-8-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (3-ethyl-3, 8-diazabicycl o [3.2.1] octan-8-yl) methyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine,
(S) -4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoro-N- (5- ( (3- (methox ymethyl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
(S) -4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoro-N- (5- ( (3- (methox ymethyl) -4-methylpiperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
(S) -4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (4-ethyl-3- (methoxy methyl) piperazin-1-yl) methyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine,
N- (5- ( ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) -4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoropyrimidin-2-amine,
4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoro-N- (5- ( ( (1R, 5S) -8-met hyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( ( (1R, 5S) -8-ethyl-3, 8-dia zabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine,
4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoro-N- (5- (1- (piperazin-1-yl) ethyl) pyridin-2-yl) pyrimidin-2-amine,
4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoro-N- (5- (1- (4-methylpip erazin-1-yl) ethyl) pyridin-2-yl) pyrimidin-2-amine,
4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- (1- (4-ethylpiperazin-1-yl ) ethyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine,
N- (4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoropyrimidin-2-yl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-amine,
N- (4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoropyrimidin-2-yl) -6-methyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-amine,
N- (4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoropyrimidin-2-yl) -6-ethyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-amine,
4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoro-N- (5- (morpholinome thyl) pyridin-2-yl) pyrimidin-2-amine,
3- (4- ( (6- ( (4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoropyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazin-1-yl) propanenitrile,
N- (4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoropyrimidin-2-yl) -6-(piperidin-4-yl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-amine,
N- (4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoropyrimidin-2-yl) -6-(1-methylpiperidin-4-yl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-amine,
N- (4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoropyrimidin-2-yl) -6-(1-ethylpiperidin-4-yl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-amine,
or pharmaceutically acceptable salts thereof.
In another Embodiment (21) , the invention provides a pharmaceutical composition comprising a compound of any one of Embodiments (1) - (20) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
In another Embodiment (22) , the invention provides a method of treating, ameliorating or preventing a condition, which responds to inhibition of cyclin-dependent kinase 4/6, comprising administering to a subject in need of such treatment an effective amount of a compound of any one of Embodiments (1) to (20) , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent.
In another Embodiment (23) , the invention provides a use of a compound of any one of Embodiments (1) to (20) 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 CDK4/6 kinase comprising contacting the CDK4/6 with a compound disclosed herein, or a pharmaceutically acceptable salts thereof.
In yet another of its aspects, there is provided a method of inhibiting a CDK4/6 comprising causing a compound disclosed herein, or a pharmaceutically acceptable salts thereof to be present in a subject in order to inhibit the CDK4/6 in vivo.
In a further of its aspects, there is provided a method of inhibiting CDK4/6 comprising administering a first compound to a subject that is converted in vivo to a second compound wherein the second compound inhibits the CDK4/6 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 CDK4/6 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 CDK4/6 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 CDK4/6 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 hyperproliferative disorders (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 mediated diseases 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 CDK4/6 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 CDK4/6.
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 CDK4/6 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 PCTCN2017072958-appb-000015
M 2375, (polyoxyethylene glycerol) , 
Figure PCTCN2017072958-appb-000016
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 PCTCN2017072958-appb-000017
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) or (II) 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 .
EXAMPLES
Various methods may be developed for synthesizing a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof. Representative methods for synthesizing a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof are provided in the Examples. It is noted, however, that a compound of formula (I) or (II) 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) or (II) 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 (II) 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.
A compound of formula (I) or (II) can also be prepared as a pharmaceutically acceptable acid addition salt by, for example, reacting the free base form of the at least one compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of the at least one compound of formula (I) or (II) can be prepared by, for example, reacting the free acid form of the at least one 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) or (II) are set forth in the definitions section of this Application. Alternatively, the salt forms of the compounds of formula (I) or (II) can be prepared using salts of the starting materials or intermediates.
The free acid or free base forms of the compounds of formula (I) or (II) can be prepared from the corresponding base addition salt or acid addition salt form. For example, a compound of formula (I) or (II) 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) or (II) 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 (II) 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) or (II) 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) or (II) can be prepared from the N-oxide of an appropriate starting material.
Compounds of formula (I) or (II) in an unoxidized form can be prepared from N-oxides of compounds of formula (I) or (II) 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) or (II) 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
A compound of formula (I) or (II) or a 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 disclosure 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 the compound of formula I or II of the present disclosure is outlined in Scheme 1. As shown in the Scheme, the compound of formula I or II can be disassembled into the intermediates III to VIII, 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 pyrimidine intermediates such as those of formula VI with hetero-arene intermediates such as those of formula VII or VIII using such palladium catalyzed coupling conditions as Suzuki reaction or other coupling conditions known in the literature provides pyrimidine intermediates of formula IV or V. Reaction of IV or V with amino-arene such as those of formula III using such coupling conditions as Buchwald amination reaction or amination conditions known in the literature leads to compound of formula I or II respectively.
Figure PCTCN2017072958-appb-000018
Scheme 1
As an illustration of the preparation of intermediate IV, one synthetic route of IVa is shown in Scheme 2. Starting from commercially available pyridine diamine A, intermediate IVa is prepared by a sequence of reductive amination, imidazole formation and conversion of halide group into a group such as B or Sn followed by palladium catalyzed coupling reaction.
Figure PCTCN2017072958-appb-000019
Scheme 2
A synthetic route to intermediate Vb is shown in Scheme 3. Reaction of ketone N with hydrazine lead to intermediate O, alkylation of intermediate O provides intermediate P, conversion of halide group in intermediate P into a group such as B or Sn followed by palladium catalyzed coupling reaction give intermediate Vb.
Figure PCTCN2017072958-appb-000020
Scheme 3
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.
Preparation of Intermediates
Intermediate A
6- (2-chloro-5-fluoropyrimidin-4-yl) -1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyrid ine (Intermediate A)
Figure PCTCN2017072958-appb-000021
5-Bromo-N3-isopropylpyridine-2, 3-diamine (A-1)
To a solution of commercial available 5-bromopyridine-2, 3-diamine (1.88 g, 10 mmol) and acetone (0.7 g, 12 mmol) in i-PrOAc (15 mL) was added TFA (2.51 g, 22 mmol) , followed by NaBH (OAc) 3 (3.18g, 15 mmol) at 0℃. The mixture was stirred at r. t. for 2 h. EtOAc (50 mL) was added to quench the reaction. The solution was washed with saturated NaHCO3 (30 mL) , brine (30 mL) , dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with PE/EtOAc (9: 1～2: 1) to give 5-Bromo-N3-isopropylpyridine-2, 3-diamine (A-1) as yellow solid. MS-ESI (m/z) : 230, 232 [M +1] +.
6-Bromo-1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridine (A-2)
A mixture of 5-Bromo-N3-isopropylpyridine-2, 3-diamine (A-1) (1.2 g, 5.2 mmol) and Ac2O (2.6 g, 26 mmol) in HOAc (10 mL) was heated at 90℃ for overnight. The solvent was removed by evaporation, the residue was diluted with DCM (50 mL) . The mixture was adjusted to pH ＝ 8 ～ 9 with 1 N NaOH aqueous solution, and the organic layer was separated. The extracts were washed with brine (50 mL) , dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with PE/EtOAc (5: 1～1: 2) to give 6-Bromo-1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridine (A-2) as yellow solid. MS-ESI (m/z) : 254, 256 [M + 1] +.
6- (tri-n-butylstannyl) -1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridine (A-3)
To a solution of -Bromo-1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridine (A-2) (0.5 g, 2 mmol) in THF (10 mL) was added (Bu3Sn) 2 (2.32 g, 4 mmol) , Pd (PPh3) (OAc) 2 (0.08 g, 0.1 mmol) and TBAF (1.044 g, 8 mmol) . The mixture was stirred at 70℃ for 4 h under N2 atmosphere. The reaction solution was concentrate and the residue was diluted with EtOAc (50 mL) , washed with water (50 mL) , dried over magnesium sulfate. The residue was filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with PE/EtOAc (9: 1～1: 1) to give 6- (tri-n-butylstannyl) -1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridine (A-3) as yellow oil. MS-ESI (m/z) : 466 [M + 1] +.
6- (2-chloro-5-fluoropyrimidin-4-yl) -1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyrid ine (Intermediate A)
To a solution of 6- (tri-n-butylstannyl) -1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridine (A-3) (0.455 g, 0.97 mmol) and 2, 4-dichloro-5-fluoropyrimidine (0.25 g, 1.49 mmol) in toluene (8 mL) was added Pd (PPh3) 4 (0.06 g, 0.05 mmol) . The mixture was stirred at 110℃for 4 h under N2 atmosphere. The reaction solution was concentrated, and the residue was  purified by flash column chromatography on silica gel eluting with EtOAc to give 6- (2-chloro-5-fluoropyrimidin-4-yl) -1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridine (Intermediate A) as yellow solid . MS-ESI (m/z) : 306 [M + 1] +.
Intermediate B
5- (2-chloro-5-fluoropyrimidin-4-yl) -7-fluoro-3-isopropyl-1-methyl-3a, 7a-dihydro- 1H-indazole (Intermediate B)
Figure PCTCN2017072958-appb-000022
5-bromo-2-chloronicotinic (isobutyl carbonic) anhydride (B-1)
To a solution of 5-bromo-2-choronicatimic acid (10.0 g, 42.3 mmol) in dried THF (440 mL) at 0℃ was added TEA (7.06 mL, 50.8 mmol) followed by isobutylchloroformate (6.64 mL, 50.76mmol) , and white precipitate formed quickly. The mixture was stirred at 0℃ for 75 min. The solid was filtered off and washed with THF (30 mL) . The solution containing 5-bromo-2-chloronicotinic (isobutyl carbonic) anhydride (B-1) was concentrated to about 200 mL, which was used in next step without further purification.
(5-bromo-2-chloropyridin-3-yl) methanol (B-2)
Water (10 mL) was added to above solution. The mixture was cooled to 0℃, NaBH4 (3.38 g, 89 mmol) was added and stirred at 0℃ for 1 h, then warmed to r. t. over 2 h. EtOAc was added, and the mixture was washed with water and brine, dried over K2CO3 and Na2SO4, and concentrated to give (5-bromo-2-chloropyridin-3-yl) methanol (B-2) as crude, which was used in next step without further purification.
5-bromo-2-chloronicotinaldehyde (B-3)
To a solution of (COCl) 2 (2.95 mL, 34.84 mmol) in dried DCM (26 mL) at -78 ℃was added a solution of DMSO (4.94 mL, 69.7mmol) in DCM (45 mL) dropwise, and stirred at -78℃ for 10 min. Then a solution of (5-bromo-2-chloropyridin-3-yl) methanol (B-2) in DCM (45 mL) was added dropwise. The mixture was stirred at -78℃ for 10 min. TEA (18.2 mL, 131 mmol) was added dropwise, and stirred for 1 h at -78℃. The mixture was warmed to r. t. and stirred for 1 h. The mixture was diluted with water (100 mL) . Layers were separated. The organic layer was washed with water and brine, dried over MgSO4, and concentrated. The residue was purified by column chromatography on silica gel eluting with 3-5％EA in hexane to give 5-bromo-2-chloronicotinaldehyde (B-3) as a white solid. MS-ESI (m/z) : 220 [M + 1] +.
1- (5-bromo-2-chloropyridin-3-yl) -2-methylpropan-1-ol (B-4)
To a solution of 5-bromo-2-chloronicotinaldehyde (B-3) (5.63 g, 25.53 mmol) in dried THF (70 mL) at -78℃ under N2 was added a solution of isopropyl magnesium chloride (2.0  M in THF 15.3 mL) dropwise. The mixture was warmed to r. t. and stirred overnight. Water was added, and layers were separated. The aqueous layer was extracted with EtOAc, The organic layers were washed with water and brine, dried over MgSO4, and concentrated. The residue was purified by column chromatography on silica gel to give 1- (5-bromo-2-chloropyridin-3-yl) -2-methylpropan-1-ol (B-4) . MS-ESI (m/z) : 264 [M + 1] +.
1- (5-bromo-2-chloropyridin-3-yl) -2-methylpropan-1-one (B-5)
A mixture of B-4 (265 mg, 1 mmol) , PCC (431 mg, 2 mmol) , SiO2 (0.5 g) in DCM (8 mL) was stirred at r. t. for 5 h. The mixture was filtered through celite, washed with DCM, and filtrate was concentrated. The residue was purified by column chromatography on silica gel to give 1- (5-bromo-2-chloropyridin-3-yl) -2-methylpropan-1-one (B-5) . MS-ESI (m/z) : 262 [M + 1] +.
5-bromo-3-isopropyl-1H-pyrazolo [3, 4-b] pyridine (B-6)
To a solution of 1- (5-bromo-2-chloropyridin-3-yl) -2-methylpropan-1-one (B-5) (177 mg, 0.674 mmol) in isopropyl alcohol (2 mL) was added hydrazine hydrate (0.5 mL) at r. t.. The mixture was heated to 80℃ overnight. The mixture was cooled to r. t., diluted with water, and extracted with EtOAc. The extracts were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane/EA (1: 1) to give 5-bromo-3-isopropyl-1H-pyrazolo [3, 4-b] pyridine (B-6) . MS-ESI (m/z) : 240 [M + 1] +.
5-bromo-3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridine (B-7)
To a solution of 5-bromo-3-isopropyl-1H-pyrazolo [3, 4-b] pyridine (B-6) (48 mg, 0.2 mmol) in THF was added NaH (10 mg, 60％in oil) at 0℃, and stirred for 5 min then MeI (25 uL, 0.4 mmol) was added dropwise. The mixture was stirred at 0℃ for 20 min. The reaction was quenched with water, and the mixture was extracted with EtOAc. The extracts were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel eluting with EA/hexane (10～100％) to give 5-bromo-3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridine (B-7) , MS-ESI (m/z) : 254 [M + 1] +, and 5-bromo-3-isopropyl-1-methyl-1H-pyrazolo [3, 4-b] pyridine (B-7b) , MS-ESI (m/z) : 254 [M +1] +.
(3-isopropyl-1-methyl-1H-pyrazolo [3, 4-b] pyridin-5-yl) boronic acid (B-8)
A mixture of 5-bromo-3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridine (B-7) (724 mg, 2.85 mmol) , Bis (pinacolato) diboron (1.09 g, 4.27 mmol) , Pd (OAc) 2 (64 mg, 0.28 mmol) , Cy3P (160 mg, 0.57 mmol) and KOAc (838 mg, 8.55 mmol) in DMSO (10 mL) was stirred at 100℃ in sealed-tube under N2 for 2 h. The reaction was quenched by water and the mixture was extracted with DCM. The extracts were dried over Na2SO4, and concentrated to give the title compound (3-isopropyl-1-methyl-1H-pyrazolo [3, 4-b] pyridin-5-yl) boronic acid (B-8) . MS-ESI (m/z) : 220 [M + 1] +.
5- (2-chloro-5-fluoropyrimidin-4-yl) -7-fluoro-3-isopropyl-1-methyl-3a, 7a-dihydro- 1H-indazole (Intermediate B)
A mixture of (3-isopropyl-1-methyl-1H-pyrazolo [3, 4-b] pyridin-5-yl) boronic acid (B-8) (624 mg, 2.85 mmol) , 2, 4-dichloro-5-fluoropyrimidine (952 mg, 5.7 mmol) , Pd (PPh3) 2Cl2 (200 mg, 0.28 mmol) and Na2CO3 (906 mg, 8.55 mmol) in DME/H2O (24 ml/10 ml) was stirred at 80℃ in sealed-tube under N2 for 2 h. The reaction was quenched by water and the mixture was extracted with DCM. The combined organic layer was dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel eluting with Hex/EtOAc (2: 1) to give title compound 5- (2-chloro-5-fluoropyrimidin-4-yl) -7-fluoro-3-isopropyl-1-methyl-3a, 7a-dihydro-1H-indazole (Intermediate B) . MS-ESI (m/z) : 306 [M + 1] +.
Intermediate C
5- (2-chloro-5-fluoropyrimidin-4-yl) -3-isopropyl-1-methyl-1H-pyrazolo [3, 4-b] pyri dine (Intermediate C)
Figure PCTCN2017072958-appb-000023
5-bromo-3-isopropyl-1-methyl-1H-pyrazolo [3, 4-b] pyridine (C-1)
To a mixture of 1- (5-bromo-2-chloropyridin-3-yl) -2-methylpropan-1-one (B-5) (38 mg, 0.15 mmol) and methylhydrazine sulfate (25 mg, 0.2 mmol) in EtOH (2 mL) was added TEA (50 mg, 5 mmol) . The mixture was stirred at r. t. for 0.5 h and then refluxed overnight. The mixture was cooled to r. t. and concentrated. The residue was diluted with DCM (20 mL) , washed sequentially with water and brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel eluting with PE/EA (100: 1～50: 1) to give 5-bromo-3-isopropyl-1-methyl-1H-pyrazolo [3, 4-b] pyridine (C-1) . MS-ESI (m/z) : 254 [M+1] +.
(3-isopropyl-1H-pyrazolo [3, 4-b] pyridin-5-yl) boronic acid (C-2)
The title compound (C-2) was prepared according to the synthetic method of B-8 by replacing 5-bromo-3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridine (B-7) with 5-bromo-3-isopropyl-1-methyl-1H-pyrazolo [3, 4-b] pyridine (C-1) . MS-ESI (m/z) : 220 [M + 1] +.
5- (2-chloro-5-fluoropyrimidin-4-yl) -3-isopropyl-1-methyl-1H-pyrazolo [3, 4-b] pyri dine (Intermediate J)
The title compound Intermediate C was prepared according to the synthetic method of Intermediate B by replacing (3-isopropyl-1-methyl-1H-pyrazolo [3, 4-b] pyridin-5-yl) boronic acid (B-8) with (3-isopropyl-1H-pyrazolo [3, 4-b] pyridin-5-yl) boronic acid (C-2) . MS-ESI (m/z) : 306 [M + 1] +.
Intermediate D
6-bromo-1-tert-butyl-2-methyl-1H-imidazo [4, 5-b] pyridine (Intermediate D)
Figure PCTCN2017072958-appb-000024
5-bromo-3-fluoropyridin-2-amine (D-1)
To a mixture of 3-fluoropyridin-2-amine (11.0 g, 98.0 mmol) in ACN (300 mL) was added NBS (8.72 g, 49.0 mmol) at 0℃, and stirred for 1 h at r. t. and then another NBS (8.72 g, 49.0 mmol) was added dropwise. The reaction mixture was concentrated and diluted with water (100 mL) . The mixture was filtered through Celite. The cake was washed with water and the filtrate was concentrated to give the title compound 5-bromo-3-fluoropyridin-2-amine (D-1) as crude. MS-ESI (m/z) : 191 [M + 1] +.
5-bromo-3-fluoro-2-nitropyridine (D-2)
To a mixture of 5-bromo-3-fluoropyridin-2-amine (D-1) (4.0 g, 21.0 mmol) in conc. H2SO4 (20 mL) was added a solution of H2O2 (33 mL, 29.1 mmol) in conc. H2SO4 (66 mL) at 0℃. The mixture was warmed to r. t. and stirred overnight. The mixture was adjusted to pH ＝ 7 with Na2CO3 aqueous solution at 0℃ and then extracted with EtOAc (3 × 30 mL) . The combined organic layer was washed sequentially with Na2S2O3 aqueous solution and brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel eluting with PE/EtOAc (40: 1) to give title compound 5-bromo-3-fluoro-2-nitropyridine (D-2) . MS-ESI (m/z) : 220 [M + 1] +.
5-bromo-N-tert-butyl-2-nitropyridin-3-amine (D-3)
A mixture of 5-bromo-3-fluoro-2-nitropyridine (D-2) (1.63 g, 7.38 mmol) , t-BuNH2 (1.08 g, 14.8 mmol) and TEA (1.49 g, 14.8 mmol) in THF (30 mL) was stirred at 45℃overnight. Water and EA were added. The aqueous layer was extracted with EtOAc (3 × 30 mL) . The combined organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel eluting with PE/EtOAc (30: 1) to give title compound 5-bromo-N-tert-butyl-2-nitropyridin-3-amine (D-3) . MS-ESI (m/z) : 274 [M+1] +.
5-bromo-N3-tert-butylpyridine-2, 3-diamine (D-4)
A mixture of 5-bromo-N-tert-butyl-2-nitropyridin-3-amine (D-3) (1.3 g, 4.7 mmol) , NH4Cl aqueous solution (16 mL) and Fe (2.6 g, 46 mmol) in EtOH (16 mL) was stirred at 75℃ for 40 min. The mixture was filtered, and filtrate was extracted with DCM (3 × 30 mL) . The combined organic layer was washed with brine, dried over Na2SO4, and concentrated to give title compound 5-bromo-N3-tert-butylpyridine-2, 3-diamine (D-4) . MS-ESI (m/z) : 244 [M+ 1] +.
6-bromo-1-tert-butyl-2-methyl-1H-imidazo [4, 5-b] pyridine (Intermediate D)
A mixture of 5-bromo-N3-tert-butylpyridine-2, 3-diamine (D-4) (50 mg, 0.205 mmol) and Ac2O (21μl, 0.225 mmol) in AcOH (1 mL) was stirred at 90℃ overnight. The  reaction mixture was concentrated. The residue was washed with NaHCO3 (50 ml) and then extracted with EtOAc (3 × 30 mL) . The extracts were washed sequentially with water (2 × 30 mL) and brine (30 mL) , dried and concentrated to give the title compound 6-bromo-1-tert-butyl-2-methyl-1H-imidazo [4, 5-b] pyridine (Intermediate D) . MS-ESI (m/z) : 268 [M + 1] +.
Intermediate E
3-tert-butyl-2-methyl-5- (tributylstannyl) -2H-pyrazolo [3, 4-b] pyridine  (Intermediate E)
Figure PCTCN2017072958-appb-000025
5-bromo-2-chloro-N-methoxy-N-methylnicotinamide (E-1)
The title compound 5-bromo-2-chloro-N-methoxy-N-methylnicotinamide (E-1) was prepared according to the synthetic method of B-1 by replacing isobutylchloroformate with N-methoxymethanamine hydrochloride. MS-ESI (m/z) : 279 [M + 1] +.
5-bromo-2-chloronicotinaldehyde (E-2)
To a solution of 5-bromo-2-chloro-N-methoxy-N-methylnicotinamide (E-1) (11.8 g, 42 mmol) in CDM (250 mL) was added DIBAl-H (70 mL, 105 mmol) at -78℃, and the mixture was stirred at 0℃ for 0.5 h. The reaction solution was concentrate and the residue was purified by column chromatography on silica gel eluting with PE/EtOAc (10: 1) to give 5-bromo-2-chloronicotinaldehyde (E-2) . MS-ESI (m/z) : 220 [M + 1] +.
1- (5-bromo-2-chloropyridin-3-yl) -2, 2-dimethylpropan-1-ol (E-3)
To a solution of 5-bromo-2-chloronicotinaldehyde (E-2) (2.1 g, 10 mmol) in THF (60 ml) was added t-BuMgCl (50 mL, 50 mmol) at 0℃. The mixture was stirred at 0 -10℃ for 2 h and the reaction was quenched by MeOH (10 mL) . The mixture was concentrated to give the title compound 1- (5-bromo-2-chloropyridin-3-yl) -2, 2-dimethylpropan-1-ol (E-3) . MS-ESI (m/z) : 278 [M + 1] +.
1- (5-bromo-2-chloropyridin-3-yl) -2, 2-dimethylpropan-1-one (E-4)
The title compound 1- (5-bromo-2-chloropyridin-3-yl) -2, 2-dimethylpropan-1-one (E-4) was prepared according to the synthetic method of B-5 by replacing 1- (5-bromo-2-chloropyridin-3-yl) -2-methylpropan-1-ol (B-4) with 1- (5-bromo-2-chloropyridin-3-yl) -2, 2-dimethylpropan-1-ol (E-3) . MS-ESI (m/z) : 276 [M + 1] +.
5-bromo-3-tert-butyl-1H-pyrazolo [3, 4-b] pyridine (E-5)
The title compound 5-bromo-3-tert-butyl-1H-pyrazolo [3, 4-b] pyridine (E-5) was prepared according to the synthetic method of B-6 by replacing 1- (5-bromo-2-chloropyridin-3-yl) -2-methylpropan-1-one (B-5) with 1- (5-bromo-2-chloropyridin-3-yl) -2, 2-dimethylpropan-1-one (E-4) . MS-ESI (m/z) : 254 [M + 1] +.
5-bromo-3-tert-butyl-2-methyl-2H-pyrazolo [3, 4-b] pyridine (E-6)
To a solution of 5-bromo-3-tert-butyl-1H-pyrazolo [3, 4-b] pyridine (E-5) (320 mg, 1.3 mmol) in THF (10 ml) was added NaH (80 mg, 60％in oil) at 0℃, and stirred for 5 min. Then MeI (370 mg, 2.6 mmol) was added dropwise. The mixture was stirred at 0℃ for 20 min. The reaction was quenched with water, and the mixture was extracted with EtOAc. The extracts were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel eluting with EtOAc/hexane (10～100％) to give 5-bromo-3-tert-butyl-2-methyl-2H-pyrazolo [3, 4-b] pyridine (E-6) , MS-ESI (m/z) : 268 [M + 1] +, and 5-bromo-3-tert-butyl-1-methyl-1H-pyrazolo [3, 4-b] pyridine (E-6b) , MS-ESI (m/z) : 268 [M +1] +.
3-tert-butyl-2-methyl-5- (tributylstannyl) -2H-pyrazolo [3, 4-b] pyridine (Intermediate E)
A mixture of 5-bromo-3-tert-butyl-2-methyl-2H-pyrazolo [3, 4-b] pyridine (E-6) (134 mg, 0.5 mmol) , (Bu3Sn) 2 (870 mg, 1.5 mmol) , Pd (PPh3) 4 (22 mg, 0.02 mmol) and TEA (150 mg, 1.5 mmol) in Dioxane (5 mL) was stirred at 80℃ overnight. The reaction mixture was concentrated. The residue was purified by column chromatography on silica gel eluting with EtOAc to give title compound 3-tert-butyl-2-methyl-5- (tributylstannyl) -2H-pyrazolo [3, 4-b] pyridine (Intermediate E) . MS-ESI (m/z) : 480 [M + 1] +.
Example 1
5-Fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- (piperazin -1-ylmethyl) pyridin-2-yl) pyrimidin-2-amine (1)
Figure PCTCN2017072958-appb-000026
Tert-butyl 4- ( (6-bromopyridin-3-yl) methyl) piperazine-1-carboxylate (1a)
To a solution of 6-bromonicotinaldehyde (11.0 g, 59.1 mmol) and tert-butyl piperazine-1-carboxylate (10.0 g, 53.7 mmol) in DCM (100 mL) was added NaBH (OAc) 3 (13.6 g, 64.1 mmol) portionwise at 0℃. After addition, the mixture was warmed to r. t. and stirred at r. t. for overnight. DCM (100 mL) was added, followed by 2 N NaOH aqueous solution (100 mL) at  0℃. The organic layer was separated, and the aqueous layer was extracted with DCM (100 mL) . The combined organic layer was washed with brine (100 mL) , dried over Na2SO4 and concentrated to give the crude product of tert-butyl 4- ( (6-bromopyridin-3-yl) methyl) piperazine-1-carboxylate (1a) (19.0 g) as yellow oil, which was used for next step without further purification. MS-ESI (m/z) : 356, 358 [M + 1] +.
tert-butyl 4- ( (6-aminopyridin-3-yl) methyl) piperazine-1-carboxylate (1b)
Nitrogen was bubbled into a mixture of tert-butyl 4- ( (6-bromopyridin-3-yl) methyl) piperazine-1-carboxylate (1a) (3.56 g, 10 mmol) , Cu2O (0.50 g, 0.3 mmol) in NH3. H2O (20 mL) and MeOH (20 mL) , and the mixture was heated at 70℃ in sealed tube for overnight. The reaction mixture was cooled to r. t., and filtered. The filtrate was concentrated, diluted with NaOH aqueous solution (2 N, 50 mL) , and extracted with DCM (2 ×100 mL) . The extracts were washed with brine (100 mL) , dried over Na2SO4, filtered, and concentrated to give crude product as yellow oil, recrystallized by MTBE to give tert-butyl 4- ( (6-aminopyridin-3-yl) methyl) piperazine-1-carboxylate (1b) . MS-ESI (m/z) : 293 [M + 1] +.
Tert-butyl  4- ( (6- ( (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-yl) amino) py ridin-3-yl) methyl) piperazine-1-carboxylate (1c)
A mixture of 6- (2-chloro-5-fluoropyrimidin-4-yl) -1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridine (Intermediate A) (0.045 g, 0.15 mmol) , tert-butyl 4- ( (6-aminopyridin-3-yl) methyl) piperazine-1-carboxylate (1b) (0.055 g, 0.18 mmol) , Pd2 (dba) 3 (0.008 g, 0.015 mmol) , Xantphos (0.01 g, 0.015 mmol) and Cs2CO3 (0.103 g, 0.3 mmol) in dioxane (3 mL) was heated at 90℃ for 1 h under nitrogen. The mixture was cooled to r. t. and diluted with DCM (10 mL) . The solution was filtered by celite, and the filtrate was concentrated. The residue was purified by preparative TLC eluting with DCM /MeOH (20: 1) to give tert-butyl 4- ( (6- ( (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-yl) amino) p yridin-3-yl) methyl) -piperazine-1-carboxylate (1c) . MS-ESI (m/z) : 562 [M + 1] +.
5-Fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- (piperazin -1-ylmethyl) pyridin-2-yl) pyrimidin-2-amine (1)
A mixture of tert-butyl 4- ( (6- ( (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-yl) amino) p yridin-3-yl) methyl) piperazine-1-carboxylate (1c) (0.03 g, 0.05 mmol) in TFA (2 mL) and DCM (4 mL) was stirred at r. t. for 2 h. The solvent was removed in vacuo, and the residue was diluted with water (10 mL) , washed with DCM (10 mL) . The aqueous layer was adjusted to pH ＝ 11 ～12 with 2 N NaOH, extracted with IPA /DCM (25％, 4 × 20 mL) . The extracts were washed with brine (40 mL) , dried over Na2SO4 and concentrated. The residue was purified by preparative TLC eluting with DCM /MeOH (10: 1) to give 5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- (piperazin-1-ylmethyl) py ridin-2-yl) pyrimidin-2-amine (1) . MS-ESI (m/z) : 462 [M + 1] +.
Example 2
5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (4- methylpiperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine (2)
Figure PCTCN2017072958-appb-000027
5- ( (4-Methylpiperazin-1-yl) methyl) pyridin-2-amine (2a)
The title compound 5- ( (4-methylpiperazin-1-yl) methyl) pyridin-2-amine (2a) was prepared according to the synthetic method of 1b by replacing tert-butyl piperazine-1-carboxylate with 1-methylpiperazine. MS-ESI (m/z) : 207 [M + 1] +.
5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (4- methylpiperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine (2)
The title compound 5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (4-methylpiperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine (2) was prepared according to the synthetic method of 1c by replacing tert-butyl 4- ( (6-aminopyridin-3-yl) methyl) piperazine-1-carboxylate (1b) with 5- ( (4-methylpiperazin-1-yl) methyl) pyridin-2-amine (2a) . MS-ESI (m/z) : 476 [M + 1] +.
Example 3
N- (5- ( (4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl -1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine (3)
Figure PCTCN2017072958-appb-000028
5- ( (4-ethylpiperazin-1-yl) methyl) pyridin-2-amine (3a)
The title compound 5- ( (4-ethylpiperazin-1-yl) methyl) pyridin-2-amine (3a) was prepared according to the synthetic method of 1b by replacing tert-butyl piperazine-1-carboxylate with 1-ethylpiperazine. MS-ESI (m/z) : 221 [M + 1] +.
N- (5- ( (4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl -1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine (3)
The title compound N- (5- ( (4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine (3) was prepared according to the synthetic method of 1c by replacing tert-butyl 4- ( (6-aminopyridin-3-yl) methyl) piperazine-1-carboxylate (1b) with 5- ( (4-ethylpiperazin-1-yl) methyl) pyridin-2-amine (3a) . MS-ESI (m/z) : 490 [M + 1] +.
Example 4
(S) -5-fluoro-N- (5- ( (hexahydropyrrolo [1, 2-a] pyrazin-2 (1H) -yl) methyl) pyridin-2-yl)  -4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine (4)
Figure PCTCN2017072958-appb-000029
(tert-butoxycarbonyl) -L-proline (4a)
The title compound (tert-butoxycarbonyl) -L-proline (4a) was prepared according to the method described in literature Tetrahedron . 2013, 10, 156.
tert-butyl (S) -2- ( (2-ethoxy-2-oxoethyl) carbamoyl) pyrrolidine-1-carboxylate (4b)
To a solution of (tert-butoxycarbonyl) -L-proline (4a) (21.5 g, 100 mmol) in THF (200 mL) was added CDI (17.8 g, 110 mmol) portionwise at 0℃. The mixture was stirred at r. t. for 0.5 h. Ethyl glycinate hydrochloride (15.3 g, 110 mmol) was added followed by TEA (15.0g, 150 mmol) at 0℃, and the mixture was stirred at r. t. overnight. The solvent was removed in vacuo, and the residue was diluted with EtOAc (250 mL) , washed sequentially with saturated NaHCO3 (200 mL) , 10％citric acid aqueous solution (2 × 200 mL ) and brine (200 mL) , dried over Na2SO4 and concentrated to give tert-butyl (S) -2- ( (2-ethoxy-2-oxoethyl) carbamoyl) pyrrolidine-1-carboxylate (4b) .
Ethyl (S) -prolylglycinate trifluoroacetic acid salt (4c)
A mixture of tert-butyl (S) -2- ( (2-ethoxy-2-oxoethyl) carbamoyl) pyrrolidine-1-carboxylate (4b) (24.8 g, 82.6 mmol) and TFA (100mL) in DCM (125 mL) was stirred at r. t. for 2 h, and concentrated to give ethyl (S) -prolylglycinate trifluoroacetic acid salt (4c) as crude, which was used for next step without further purification. MS-ESI (m/z) : 201 [M + 1] +.
(S) -hexahydropyrrolo [1, 2-a] pyrazine-1, 4-dione (4d)
A mixture of ethyl (S) -prolylglycinate trifluoroacetic acid salt (4c) (40 g, 127 mmol) in TEA (150 mL) and MeOH (800 mL) was refluxed overnight. The solvent was removed by evaporation, and the residue was diluted with IPA (100 mL) . The residue was filtered, and the  cake was washed with hexane. The residue was dried in vacuo to give (S) -hexahydropyrrolo [1, 2-a] pyrazine-1, 4-dione (4d) . MS-ESI (m/z) : 154 [M + 1] +.
Benzyl (S) -hexahydropyrrolo [1, 2-a] pyrazine-2 (1H) -carboxylate (4e)
To a suspension of LAH (5.9 g, 156 mmol) in THF (60 mL) was added a solution of (S) -hexahydropyrrolo [1, 2-a] pyrazine-1, 4-dione (4d) (4.0 g, 26 mmol) in THF (40 mL) dropwise, and the resulting mixture was refluxed for 16 h. Then the reaction mixture was cooled to 0℃, and saturated NaHCO3 (100 mL) was added dropwise, followed by benzyl carbonochloridate (6.67 g, 39 mmol) . The mixture was stirred at 0℃ for 1 h, then stirred at r. t. for another 2 h. The reaction solution was extracted with chloroform (3 × 200 mL) , and the extracts were washed with brine (400 mL) , dried over Mg2SO4 and concentrated. The residue was purified by column chromatography on silica gel eluting with DCM /MeOH (25: 1) to give benzyl (S) -hexahydropyrrolo [1, 2-a] pyrazine-2 (1H) -carboxylate (4e) . MS-ESI (m/z) : 261 [M + 1] +.
(S) -octahydropyrrolo [1, 2-a] pyrazine (4f)
A mixture of benzyl (S) -hexahydropyrrolo [1, 2-a] pyrazine-2 (1H) -carboxylate (4e) (5.0 g, 19 mmol) and Pd/C (10％, 1.0 g) in MeOH (50 mL) was stirred at r. t. for 2 h under H2 atmosphere. The residue was filtered by celite, and the filtrate was concentrated to give (S) -octahydropyrrolo [1, 2-a] pyrazine (4f) as crude. MS-ESI (m/z) : 127 [M + 1] +.
(S) -2- ( (6-Bromopyridin-3-yl) methyl) octahydropyrrolo [1, 2-a] pyrazine (4g)
The title compound (S) -2- ( (6-bromopyridin-3-yl) methyl) octahydropyrrolo [1, 2-a] pyrazine (4g) was prepared according to the synthetic method of 1a by replacing tert-butyl piperazine-1-carboxylate with (S) -octahydropyrrolo [1, 2-a] pyrazine (4f) . MS-ESI (m/z) : 296, 298 [M + 1] +.
(S) -5- ( (hexahydropyrrolo [1, 2-a] pyrazin-2 (1H) -yl) methyl) pyridin-2-amine (4h)
The title compound (S) -5- ( (hexahydropyrrolo [1, 2-a] pyrazin-2 (1H) -yl) methyl) -pyridin-2-amine (4h) was prepared according to the synthetic method of 1b by replacing tert-butyl 4- ( (6-bromopyridin-3-yl) methyl) piperazine-1-carboxylate (1a) with (S) -2- ( (6-Bromopyridin-3-yl) methyl) octahydropyrrolo [1, 2-a] pyrazine (4g) . MS-ESI (m/z) : 233 [M + 1] +.
(S) -5-fluoro-N- (5- ( (hexahydropyrrolo [1, 2-a] pyrazin-2 (1H) -yl) methyl) pyridin-2-yl)  -4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine (4)
The title compound (S) -5-fluoro-N- (5- ( (hexahydropyrrolo [1, 2-a] pyrazin-2 (1H) -yl) methyl) pyridin-2-yl) -4- (1-isopropy l-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine (4) was prepared according to the synthetic method of 1c by replacing tert-butyl 4- ( (6-aminopyridin-3-yl) methyl) piperazine-1-carboxylate (1b) with (S) -5- ( (hexahydropyrrolo [1, 2-a] pyrazin-2 (1H) -yl) methyl) pyridin-2-amine (4h) . MS-ESI (m/z) : 502 [M + 1] +.
Example 5
(R) -5-fluoro-N- (5- ( (hexahydropyrrolo [1, 2-a] pyrazin-2 (1H) -yl) methyl) pyridin-2-yl ) -4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine (5)
Figure PCTCN2017072958-appb-000030
(R) -5- ( (hexahydropyrrolo [1, 2-a] pyrazin-2 (1H) -yl) methyl) pyridin-2-amine (5a)
The title compound (R) -5- ( (hexahydropyrrolo [1, 2-a] pyrazin-2 (1H) -yl) methyl) -pyridin-2-amine (5a) was prepared according to the synthetic method of 4h started from D-proline instead of L-Proline. MS-ESI (m/z) : 233 [M + 1] +.
(R) -5-fluoro-N- (5- ( (hexahydropyrrolo [1, 2-a] pyrazin-2 (1H) -yl) methyl) pyridin-2-yl ) -4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine (5)
The title compound (R) -5-fluoro-N- (5- ( (hexahydropyrrolo [1, 2-a] pyrazin-2 (1H) -yl) methyl) pyridin-2-yl) -4- (1-isoprop yl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine (5) was prepared according to the synthetic method of 1c by replacing tert-butyl 4- ( (6-aminopyridin-3-yl) methyl) piperazine-1-carboxylate (1b) with (R) -5- ( (hexahydropyrrolo [1, 2-a] pyrazin-2 (1H) -yl) methyl) pyridin-2-amine (5a) . MS-ESI (m/z) : 502 [M + 1] +.
Example 6
N- (5- ( ( (1S, 4S) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) methyl) pyridin-2-yl) -5-fluoro-4 - (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine (6)
Figure PCTCN2017072958-appb-000031
Tert-butyl (1S, 4S) -5- ( (6-bromopyridin-3-yl) methyl) -2, 5-diazabicyclo [2.2.1] - heptane-2-carboxylate (6a)
To a mixture of tert-butyl (1S, 4S) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate (0.099 g, 0.5 mmol) , 5-bromopicolinaldehyde (0.093 g, 0.5 mmol) and AcOH (0.03 g, 0.5 mmol)  in THF (1 mL) was added Sodium triacetoxyborohydride (0.159 g, 0.75 mmol) . Then the reaction mixture was stirred at ambient temperature overnight. The reaction was quenched with saturated NaHCO3 and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give tert-butyl (1S, 4S) -5- ( (6-bromopyridin-3-yl) methyl) -2, 5-diazabicyclo [2.2.1] -heptane-2-carboxylate (6a) . MS-ESI (m/z) : 368, 390 [M + 1] +.
Tert-butyl (1S, 4S) -5- ( (6-aminopyridin-3-yl) methyl) -2, 5-diazabicyclo [2.2.1] - heptane-2-carboxylate (6b)
A mixture of tert-butyl (1S, 4S) -5- ( (6-bromopyridin-3-yl) methyl) -2, 5-diazabicyclo- [2.2.1] -heptane-2-carboxylate (6a) (180 mg, 0.49 mmol) , NH3·H2O (4.5 mL) , Cu2O (80.0 mg, 0.56 mmol) in MeOH (1.5 mL) was heated to 65℃ overnight in a sealed tube. The reaction mixture was cooled to r. t. and filtered. The filtrate was concentrated under reduced pressure. The residue was partitioned between DCM and 2 N aq. NaOH. The separated organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography eluting with DCM: MeOH ＝10: 1 to give tert-butyl (1S, 4S) -5- ( (6-aminopyridin-3-yl) methyl) -2, 5-diazabicyclo [2.2.1] -heptane-2-carboxylate (6b) . MS-ESI (m/z) : 305 [M + 1] +.
Tert-butyl  (1S, 4S) -5- ( (6- ( (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-yl) a mino) pyridin-3-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate (6c)
The title compound tert-butyl (1S, 4S) -5- ( (6- ( (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) -2, 5-diazabicyclo [2.2.1] -heptane-2-carboxylate (6c) was prepared according to the synthetic method of 1c by replacing tert-butyl 4- ( (6-aminopyridin-3-yl) methyl) piperazine-1-carboxylate (1b) with tert-butyl (1S, 4S) -5- ( (6-aminopyridin-3-yl) methyl) -2, 5-diazabicyclo [2.2.1] -heptane-2-carboxylate (6b) . MS-ESI (m/z) : 574 [M + 1] +.
N- (5- ( ( (1S, 4S) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) methyl) pyridin-2-yl) -5-fluoro-4 - (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine (6)
The title compound N- (5- ( ( (1S, 4S) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) methyl) -pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine (6) was prepared according to the synthetic method of 1 by replacing tert-butyl 4- ( (6- ( (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-yl) amino) p yridin-3-yl) methyl) piperazine-1-carboxylate (1c) with tert-butyl (1S, 4S) -5- ( (6- ( (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate (6c) . MS-ESI (m/z) : 474 [M + 1] +.
Example 7
5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( ( (1S, 4S) -5 -methyl-2, 5-diazabicyclo [2.2.1] heptan-2-yl) methyl) pyridin-2-yl) pyrimidin-2-amine (7)
Figure PCTCN2017072958-appb-000032
(1S, 4S) -2- ( (6-Bromopyridin-3-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptane (7a)
To a solution of tert-butyl (1S, 4S) -5- ( (6-bromopyridin-3-yl) methyl) -2, 5-diazabicyclo [2.2.1] -heptane-2-carboxylate (6a) (0.81 g, 2.2 mmol) in DCM (6 mL) was added TFA (4 mL) at r. t. . The mixture was stirred for 2 h. The pH was adjusted to 8 with Na2CO3 (aq) . The mixture was extracted with DCM (3 × 6 mL) . The extracts were washed sequentially with water and brine (5 mL) , dried over Na2SO4, and concentrated to give (1S, 4S) -2- ( (6-bromopyridin-3-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptane (7a) (0.534 g) . MS-ESI (m/z) : 268 [M + 1] +.
(1S, 4S) -2- ( (6-bromopyridin-3-yl) methyl) -5-methyl-2, 5-diazabicyclo [2.2.1]  heptane (7b)
To a solution of (1S, 4S) -2- ( (6-bromopyridin-3-yl) methyl) -2, 5-diazabicyclo [2.2.1] -heptane (7a) (0.15 g, 0.56 mmol) in DCM (2 mL) , formaldehyde (37％, 63 μL) was added followed by NaBH (OAc) 3 (0.273 g, 1.12 mmol) at r. t. . Then the reaction mixture was stirred vigorously for 30 min. The reaction was quenched with saturated Na2CO3. The mixture was extracted with DCM (2 × 5 mL) . The extracts were washed sequentially with water and brine (5 mL) , dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with DCM/MeOH (10: 1) to give (1S, 4S) -2- ( (6-bromopyridin-3-yl) methyl) -5-methyl-2, 5-diazabicyclo- [2.2.1] heptane (7b) . MS-ESI (m/z) : 282, 284 [M + 1] +.
5- ( ( (1S, 4S) -5-Methyl-2, 5-diazabicyclo [2.2.1] heptan-2-yl) methyl) pyridin-2-amine  (7c)
The title compound 5- ( ( (1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] heptan-2-yl) -methyl) pyridin-2-amine (7c) was prepared according to the synthetic method of 6b by replacing tert-butyl (1S, 4S) -5- ( (6-bromopyridin-3-yl) methyl) -2, 5-diazabicyclo [2.2.1] -heptane-2-carboxylate (6a) with (1S, 4S) -2- ( (6-bromopyridin-3-yl) methyl) -5-methyl-2, 5-diazabicyclo [2.2.1] heptane (7b) . MS-ESI (m/z) : 219 [M + 1] +.
5-Fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( ( (1S, 4S) - 5-methyl-2, 5-diazabicyclo [2.2.1] heptan-2-yl) methyl) pyridin-2-yl) pyrimidin-2-amine (7)
The title compound 5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( ( (1S, 4S) -5-methyl-2, 5-di azabicyclo [2.2.1] heptan-2-yl) methyl) pyridin-2-yl) pyrimidin-2-amine (7) was prepared according to the synthetic method of 1c by replacing tert-butyl 4- ( (6-aminopyridin-3-yl) methyl) piperazine-1-carboxylate (1b) with 5- ( ( (1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] heptan-2-yl) methyl) pyridin-2-amine (7c) . MS-ESI (m/z) : 488 [M + 1] +.
Example 8
N- (5- ( ( (1S, 4S) -5-Ethyl-2, 5-diazabicyclo [2.2.1] heptan-2-yl) methyl) pyridin-2-yl) -5-f luoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine (8)
Figure PCTCN2017072958-appb-000033
(1S, 4S) -2- ( (6-bromopyridin-3-yl) methyl) -5-ethyl-2, 5-diazabicyclo [2.2.1] heptane  (8a)
To a solution of (1S, 4S) -2- ( (6-bromopyridin-3-yl) methyl) -2, 5-diazabicyclo [2.2.1] heptane (7a) (0.10 g, 0.37 mmol) and TEA (60 μL, 0.41 mmol) in DMF (1 mL) was added bromoethane (27 μL, 0.33 mmol) dropwise at r. t. . Then the reaction mixture was stirred for 3.5 h. The solution was extracted with water (5 mL) and DCM (5 mL) . The organic layer was washed sequentially with water (2 mL) and brine (2 mL) , dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel eluting with DCM /MeOH (10: 1) to give (1S, 4S) -2- ( (6-bromopyridin-3-yl) methyl) -5-ethyl-2, 5-diazabicyclo [2.2.1] heptane (8a) . MS-ESI (m/z) : 296, 298 [M + 1] +.
5- ( ( (1S, 4S) -5-Ethyl-2, 5-diazabicyclo [2.2.1] heptan-2-yl) methyl) pyridin-2-amine  (8b)
The title compound 5- ( ( (1S, 4S) -5-ethyl-2, 5-diazabicyclo [2.2.1] heptan-2-yl) -methyl) pyridin-2-amine (8b) was prepared according to the synthetic method of 6b by replacing tert-butyl (1S, 4S) -5- ( (6-bromopyridin-3-yl) methyl) -2, 5-diazabicyclo [2.2.1] -heptane-2-carboxylate (6a) with (1S, 4S) -2- ( (6-bromopyridin-3-yl) methyl) -5-ethyl-2, 5-diazabicyclo [2.2.1] heptane (8a) . MS-ESI (m/z) : 233 [M + 1] +.
N- (5- ( ( (1S, 4S) -5-Ethyl-2, 5-diazabicyclo [2.2.1]heptan-2-yl) methyl) pyridin-2-yl) -5-f luoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine (8)
The title compound N- (5- ( ( (1S, 4S) -5-ethyl-2, 5-diazabicyclo [2.2.1] heptan-2-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-iso propyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine (8) was prepared according to the synthetic method of 1c by replacing tert-butyl 4- ( (6-aminopyridin-3-yl) methyl) piperazine-1-carboxylate (1b) with 5- ( ( (1S, 4S) -5-ethyl-2, 5-diazabicyclo [2.2.1] heptan-2-yl) methyl) pyridin-2-amine (8b) . MS-ESI (m/z) : 488 [M + 1] +.
Following essentially the same procedures described for Examples 1-8, or using similar synthetic strategies or methods, Examples 9-81 listed in Table 1 were prepared from appropriate starting materials which are commercially available or known in the literature and sequential modifications as necessary. The structures and names of Examples 9-81 are given in Table 1.
Table 1
Figure PCTCN2017072958-appb-000034
Figure PCTCN2017072958-appb-000035
Figure PCTCN2017072958-appb-000036
Figure PCTCN2017072958-appb-000037
Figure PCTCN2017072958-appb-000038
Figure PCTCN2017072958-appb-000039
Figure PCTCN2017072958-appb-000040
Figure PCTCN2017072958-appb-000041
Figure PCTCN2017072958-appb-000042
Figure PCTCN2017072958-appb-000043
Example 83
5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- (piperazin -1-ylmethyl) pyridin-2-yl) pyrimidin-2-amine (83)
Figure PCTCN2017072958-appb-000044
tert-butyl 4- ( (6- ( (5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl)  pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazine-1-carboxylate (83a)
The title compound tert-butyl 4- ( (6- ( (5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazine-1-carboxylate (83a) was prepared according to the synthetic method of 1c starting from 5- (2-chloro-5-fluoropyrimidin-4-yl) -7-fluoro-3-isopropyl-1-methyl-3a, 7a-dihydro-1H-indazole (Intermediate B) and tert-butyl 4- ( (6-aminopyridin-3-yl) methyl) piperazine-1-carboxylate (1b) . MS-ESI (m/z) : 562 [M + 1] +.
5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- (piperazin -1-ylmethyl) pyridin-2-yl) pyrimidin-2-amine (83)
The title compound 5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- (piperazin-1-ylmethyl) p yridin-2-yl) pyrimidin-2-amine (83) was prepared according to the synthetic method of 1 by replacing tert-butyl 4- ( (6- ( (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazine-1-carboxylate (1c) with tert-butyl 4- ( (6- ( (5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazine-1-carboxylate (83a) . MS-ESI (m/z) : 462 [M + 1] +.
Example 84
5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (4-methyl  piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine (84)
Figure PCTCN2017072958-appb-000045
To a mixture of 5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- (piperazin-1-ylmethyl) pyridin-2-yl) pyrimidin-2-amine (83) (17.8 mg, 0.0386 mmol) , NaBH (OAc) 3 (12.3 mg, 0.0579 mmol) in DCE (1 mL) was added HCHO (37％in water) (2 drops) at r. t., and then the mixture was stirred at r. t. for 4 h. The mixture was diluted with NaHCO3 aq, and extracted with DCM. The extracts were dried over Na2SO4, and concentrated. The residue was purified by PTLC to give 5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (4-methylpiperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine (84) . MS-ESI (m/z) : 476 [M + 1] +.
Example 85
N- (5- ( (4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl -2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine (85)
Figure PCTCN2017072958-appb-000046
To a mixture of 5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- (piperazin-1-ylmethyl) pyridin-2-yl) pyrimidin-2-amine (83) (17.8 mg, 0.0386 mmol) , and NaBH (OAc) 3 (12.3 mg, 0.0579 mmol) in DCE (1 mL) was added MeCHO (40％in water) (2 drops) at r. t., and the mixture was stirred at r. t. for 4 h. The mixture was diluted with NaHCO3 aq, and extracted with DCM. The extracts were dried over Na2SO4, and concentrated. The residue was purified by PTLC to give N- (5- ( (4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine (85) . MS-ESI (m/z) : 490[M+1] +
Example 86
5-fluoro-4- (3-isopropyl-1-methyl-1H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (4-methyl  piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine (86)
Figure PCTCN2017072958-appb-000047
The title compound 5-fluoro-4- (3-isopropyl-1-methyl-1H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (4-methylpiperazin-1-yl ) methyl) pyridin-2-yl) pyrimidin-2-amine (86) was prepared according to the synthetic method of 1c prepared from 5- (2-chloro-5-fluoropyrimidin-4-yl) -3-isopropyl-1-methyl-1H-pyrazolo [3, 4-b] pyridine (Intermediate C) and 5- ( (4-methylpiperazin-1-yl) methyl) pyridin-2-amine (2a) . MS-ESI (m/z) : 476 [M + 1] +.
Example 87
N- (5- ( (4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-1-methyl -1H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine (87)
Figure PCTCN2017072958-appb-000048
The title compound N- (5- ( (4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-1-methyl-1H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine (87) was prepared according to the synthetic method of 1c  prepared from 5- (2-chloro-5-fluoropyrimidin-4-yl) -3-isopropyl-1-methyl-1H-pyrazolo [3, 4-b] pyridine (Intermediate C) and 5- ( (4-ethylpiperazin-1-yl) methyl) pyridin-2-amine (3a) . MS-ESI (m/z) : 476 [M + 1] +.
Following essentially the same procedures described for Examples 83-87, Examples 88-156 listed in Table 2 were prepared from the corresponding substituted aminopyridines and sequential modifications as necessary, or using similar synthetic strategies or methods.
Table 2
Figure PCTCN2017072958-appb-000049
Figure PCTCN2017072958-appb-000050
Figure PCTCN2017072958-appb-000051
Figure PCTCN2017072958-appb-000052
Figure PCTCN2017072958-appb-000053
Figure PCTCN2017072958-appb-000054
Figure PCTCN2017072958-appb-000055
Figure PCTCN2017072958-appb-000056
Figure PCTCN2017072958-appb-000057
Figure PCTCN2017072958-appb-000058
Cell Proliferation Assays
To investigate whether a compound is able to inhibit the activity of CDK4/6 in cells, a mechanism-based assay using BE (2) -C cell was developed. In this assay, inhibition of CDK4/6 was detected by the inhibition of BE (2) -C cells proliferation. BE (2) -C Cells were plated in 96-well plates with 150 μl culture medium at cell density of 5000 cells/well. Compounds dilution: 20 mM stock solution of all compounds in DMSO. On the day of treatment, compounds were fresh diluted from the stock solution to a working solution (4× of final concentrations) in culture medium. 50 μl of compound mixtures were added to duplicate wells along with 150 μl of cells. 24 hours after BE (2) -C cells were plated, testing compounds were added. Cell proliferation was measured by MTS assay following manufacturer’s instruction after compound treatment for 72 hours.
Select compounds prepared as described above were assayed according to the biological procedures described herein. The results are given in Table 3.
Table 3
Example IC50 (nM) Example IC50 (nM) Example IC50 (nM) Example IC50 (nM)
1 857 49 728 91 574 126 192
2 343 54 58 92 124 129 464
3 204 56 740 93 96 134 323
4 19 57 456 94 68 135 418
5 49 58 279 95 768 136 46
7 583 59 37 96 51 137 28
8 811 60 435 97 55 138 18
10 82 61 217 99 176 139 26
11 60 62 251 100 74 140 38
13 546 63 91 102 74 141 102
14 392 65 58 103 99 142 26
16 751 66 51 105 640 143 20
19 396 68 58 106 177 144 31
20 272 69 31 107 178 145 16
22 840 70 148 108 456 146 37
23 514 71 38 109 297 147 535
27 91 72 25 110 165 148 51
28 15 73 901 111 253 149 27
29 85 74 182 112 954 151 121
31 364 75 22 113 243 152 99
32 273 77 624 114 61 153 51
34 473 78 59 116 228 154 13
35 53 80 911 117 157 155 22
40 460 81 365 118 463 156 35
41 332 84 64 119 42 157 30
43 662 85 19 120 46 159 44
44 440 88 994 121 489 160 22
46 420 88 85 122 433    
47 152 89 28 125 309    

Claims (23)

  1. A compound of formula (I) or (II)
    Figure PCTCN2017072958-appb-100001
    or a pharmaceutically acceptable salt thereof, wherein
    Q is selected from aryl and heteroaryl；
    each R1 is 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, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino di (alky) amino, 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, 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；
    each R3 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, -NRA2RB2, -ORA2, -S (O) rRA2, -S (O) 2ORA2, -OS (O) 2RA2, -P (O) RA2RB2, -P (O) (ORA2) (ORB2) , -C (O) RA2, -C (O) ORA2, -OC (O) RA2, -C (O) NRA2RB2, -NRA2C (O) RB2, -OC (O) NRA2RB2, -NRA2C (O) ORB2, -NRA2C (O) NRA2RB2, -NRA2C (S) NRA2RB2, -S (O) rNRA2RB2, -NRA2S (O) rRB2, -NRA2S (O) 2NRA2RB2, -S (O) (＝NRE2) RB2, -N＝S (O) RA2RB2, -NRA2S (O) (＝NRE2) RB2, -S (O) (＝NRE2) NRA2RB2, -NRA2S (O) (＝NRE2) NRA2RB2, -C (＝NRE2) RA2, -C (＝N-ORB2) RA2, -C (＝NRE2) NRA2RB2, -NRA2C (＝NRE2) RB2 and -NRA2C (＝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 RX；
    each R4 is 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, -NRA3RB3, -ORA3, -S (O) rRA3, -S (O) 2ORA3, -OS (O) 2RA3, -P (O) RA3RB3, -P (O) (ORA3) (ORB3) , -C (O) RA3, -C (O) ORA3, -OC (O) RA3, -C (O) NRA3RB3, -NRA3C (O) RB3, -OC (O) NRA3RB3, -NRA3C (O) ORB3, -NRA3C (O) NRA3RB3, -NRA3C (S) NRA3RB3, -S (O) rNRA3RB3, -NRA3S (O) rRB3, -NRA3S (O) 2NRA3RB3, -S (O) (＝NRE3) RB3, -N＝S (O) RA3RB3, -NRA3S (O) (＝NRE3) RB3, -S (O) (＝NRE3) NRA3RB3, -NRA3S (O) (＝NRE3) NRA3RB3, -C (＝NRE3) RA3, -C (＝N-ORB3) RA3, -C (＝NRE3) NRA3RB3, -NRA3C (＝NRE3) RB3 and -NRA3C (＝NRE3) NRA3RB3, 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；
    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, -NRA4RB4, - (CH2) tNRA4RB4, -ORA4, -S (O) rRA4, -S (O) 2ORA4, -OS (O) 2RA4, -P (O) RA4RB4, -P (O) (ORA4) (ORB4) , -C (O) RA4, -C (O) ORA4, -OC (O) RA4, -C (O) NRA4RB4, -NRA4C (O) RB4, -OC (O) NRA4RB4, -NRA4C (O) ORB4, -NRA4C (O) NRA4RB4, -NRA4C (S) NRA4RB4, -S (O) rNRA4RB4, -NRA4S (O) rRB4, -NRA4S (O) 2NRA4RB4, -S (O) (＝NRE4) RB4, -N＝S (O) RA4RB4, -NRA4S (O) (＝NRE4) RB4, -S (O) (＝NRE4) NRA4RB4, -NRA4S (O) (＝NRE4) NRA4RB4, -C (＝NRE4) RA4, -C (＝N-ORB4) RA4, -C (＝NRE4) NRA4RB4, -NRA4C (＝NRE4) RB4 and -NRA4C (＝NRE4) NRA4RB4, 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；
    each RA1, RA2, RA3, RA4, RB1, RB2, RB3 and RB4 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 “RA1 and RB1” , “RA2 and RB2” , “RA3 and RB3” or “RA4 and RB4” 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, RE2, RE3 and RE4 are 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 selected from 0, 1, 2, 3 and 4；
    n is selected from 0, 1 and 2；
    p is selected from 0, 1 and 2；
    each r is independently selected from 0, 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 the formula is
    Figure PCTCN2017072958-appb-100002
  3. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the formula is
    Figure PCTCN2017072958-appb-100003
  4. A compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein Q is heteroaryl.
  5. A compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein Q is independently selected from
    Figure PCTCN2017072958-appb-100004
  6. A compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof, wherein each R5 is independently selected from C1-10 alkyl, heterocycle, heterocyclyl-C1-4 alkyl, -S (O) rRA4, -C (O) RA4 and -CH2NRA4RB4, 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.
  7. A compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein each R5 is independently selected from methyl, ethyl,
    Figure PCTCN2017072958-appb-100005
    which is 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 6 or a pharmaceutically acceptable salt thereof, wherein each R5 is independently selected from -S (O) 2RA4 and -C (O) RA4, wherein each RA4 is independently selected from heterocyclyl and heterocyclyl-C1-4 alkyl, 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, and each RB4 is independently selected from C1-10 alkyl.
  9. A compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein each R5 is independently selected from -S (O) 2RA4 and -C (O) RA4, wherein each RA4 is independently selected from
    Figure PCTCN2017072958-appb-100006
    which is unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RX, and each RB4 is methyl.
  10. A compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein each R5 is independently selected from -CH2NRA4RB4, wherein each RA4 is
    Figure PCTCN2017072958-appb-100007
    which unsubstituted or substituted with at least one substituent, such as one, two, three or four substituents, independently selected from RX, and each RB4 is methyl.
  11. A compound of any one of claims 6-10 or a pharmaceutically acceptable salt thereof, wherein each RX is independently selected from methyl, ethyl, methoxymethyl, cyanoethyl and oxetan-3-yl.
  12. A compound of any one of claims 1-11 or a pharmaceutically acceptable salt thereof, wherein m is 1.
  13. A compound of any one of claims 1-12 or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen.
  14. A compound of any one of claims 1-13 or a pharmaceutically acceptable salt thereof, wherein each R2 is hydrogen.
  15. A compound of any one of claims 1-14 or a pharmaceutically acceptable salt thereof, wherein each R3 is independently selected from C1-10 alkyl.
  16. A compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein each R3 is independently selected from methyl, isopropyl and tert-butyl.
  17. A compound of any one of claims 15-16 or a pharmaceutically acceptable salt thereof, wherein p is 2.
  18. A compound of any one of claims 1-17 or a pharmaceutically acceptable salt thereof, wherein each R4 is halogen.
  19. A compound of claim 18 or a pharmaceutically acceptable salt thereof, wherein each R4 is independently selected from fluorine and chlorine.
  20. A compound selected from
    5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- (piperazin-1-ylmethyl) pyridin-2-yl) pyrimidin-2-amine,
    5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (4-methylpiperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    N- (5- ( (4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
    (S) -5-fluoro-N- (5- ( (hexahydropyrrolo [1, 2-a] pyrazin-2 (1H) -yl) methyl) pyridin-2-yl) -4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
    (R) -5-fluoro-N- (5- ( (hexahydropyrrolo [1, 2-a] pyrazin-2 (1H) -yl) methyl) pyridin-2-yl) -4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
    N- (5- ( ( (1S, 4S) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
    5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( ( (1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] heptan-2-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    N- (5- ( ( (1S, 4S) -5-ethyl-2, 5-diazabicyclo [2.2.1] heptan-2-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
    N- (5- ( (3, 8-diazabicyclo [3.2.1] octan-8-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
    5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (3-methyl-3, 8-diazabicyclo [3.2.1] octan-8-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    N- (5- ( (3-ethyl-3, 8-diazabicyclo [3.2.1] octan-8-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
    N- (5- ( (3, 8-diazabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
    5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (8-methyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    N- (5- ( (8-ethyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
    5-fluoro-N- (5- ( (hexahydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) methyl) pyridin-2-yl) -4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
    5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (5-methylhexahydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    N- (5- ( (5-ethylhexahydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
    N- (5- ( (2, 7-diazaspiro [3.5] nonan-2-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
    5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (7-methyl-2, 7-diazaspiro [3.5] nonan-2-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    N- (5- ( (7-ethyl-2, 7-diazaspiro [3.5] nonan-2-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
    N- (5- ( (2, 6-diazaspiro [3.3] heptan-2-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
    5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (6-methyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    N- (5- ( (6-ethyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
    N- (5- ( (3, 9-diazaspiro [5.5] undecan-3-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
    5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (9-methyl-3, 9-diazaspiro [5.5] undecan-3-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    N- (5- ( (9-ethyl-3, 9-diazaspiro [5.5] undecan-3-yl) methyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
    N- (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-yl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-amine,
    N- (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-yl) -6-methyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-amine,
    6-ethyl-N- (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-yl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-amine,
    (6- ( (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (piperazin-1-yl) methanone,
    (6- ( (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (4-methylpiperazin-1-yl) methanone,
    (4-ethylpiperazin-1-yl) (6- ( (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,
    (3, 8-diazabicyclo [3.2.1] octan-3-yl) (6- ( (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,
    (6- ( (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (8-methyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) methanone,
    (8-ethyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) (6- ( (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,
    (6- ( (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (2, 7-diazaspiro [3.5] nonan-2-yl) methanone,
    (6- ( (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (7-methyl-2, 7-diazaspiro [3.5] nonan-2-yl) methanone,
    (7-ethyl-2, 7-diazaspiro [3.5] nonan-2-yl) (6- ( (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4,5-b] pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,
    (6- ( (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (hexahydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) methanone,
    (6- ( (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (5-methylhexahydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) methanone,
    (5-ethylhexahydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) (6- ( (5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,
    5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- (piperazin-1-ylsulfonyl) pyridin-2-yl) pyrimidin-2-amine,
    5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (4-methylpiperazin-1-yl) sulfonyl) pyridin-2-yl) pyrimidin-2-amine,
    N- (5- ( (4-ethylpiperazin-1-yl) sulfonyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
    N- (5- ( (3, 8-diazabicyclo [3.2.1] octan-3-yl) sulfonyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
    5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (8-methyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) sulfonyl) pyridin-2-yl) pyrimidin-2-amine,
    N- (5- ( (8-ethyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) sulfonyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
    5-fluoro-N- (5- ( (hexahydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) sulfonyl) pyridin-2-yl) -4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
    5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (5-methylhexahydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) sulfonyl) pyridin-2-yl) pyrimidin-2-amine,
    N- (5- ( (5-ethylhexahydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) sulfonyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
    N- (5- ( (2, 7-diazaspiro [3.5] nonan-2-yl) sulfonyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
    5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (7-methyl-2, 7-diazaspiro [3.5] nonan-2-yl) sulfonyl) pyridin-2-yl) pyrimidin-2-amine,
    N- (5- ( (7-ethyl-2, 7-diazaspiro [3.5] nonan-2-yl) sulfonyl) pyridin-2-yl) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) pyrimidin-2-amine,
    5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    (S) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (2-methyl-4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    (R) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (2-methyl-4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    (R) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (3-methyl-4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine.
    (S) -5-fluoro-4- (1-isopropyl-2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (3-methyl-4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-fluoro-N- (5- ( (4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    (S) -4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-fluoro-N- (5- ( (2-methyl-4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    (R) -4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-fluoro-N- (5- ( (2-methyl-4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    (R) -4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-fluoro-N- (5- ( (3-methyl-4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    (S) -4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-fluoro-N- (5- ( (3-methyl-4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-fluoro-N- (5- (piperazin-1-ylmethyl) pyridin-2-yl) pyrimidin-2-amine,
    4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-fluoro-N- (5- ( (4-methylpiperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine,
    N- (5- ( (3, 8-diazabicyclo [3.2.1] octan-8-yl) methyl) pyridin-2-yl) -4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-fluoropyrimidin-2-amine,
    4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-fluoro-N- (5- ( (3-methyl-3, 8-diazabicyclo [3.2.1] octan-8-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (3-ethyl-3, 8-diazabicyclo [3.2.1] octan-8-yl) methyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine,
    (S) -4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-fluoro-N- (5- ( (3- (methoxymethyl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    (S) -4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-fluoro-N- (5- ( (3- (methoxymethyl) -4-methylpiperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    (S) -4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (4-ethyl-3- (methoxymethyl) piperazin-1-yl) methyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine,
    N- (5- ( (3, 8-diazabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) -4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-fluoropyrimidin-2-amine,
    4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-fluoro-N- (5- ( (8-methyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- ( (8-ethyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine,
    4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-fluoro-N- (5- (1- (piperazin-1-yl) ethyl) pyridin-2-yl) pyrimidin-2-amine,
    4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-fluoro-N- (5- (1- (4-methylpiperazin-1-yl) ethyl) pyridin-2-yl) pyrimidin-2-amine,
    4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -N- (5- (1- (4-ethylpiperazin-1-yl) ethyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine,
    4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-chloro-N- (5- (piperazin-1-ylmethyl) pyridin-2-yl) pyrimidin-2-amine,
    4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-chloro-N- (5- ( (4-methylpiperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    4- (1- (tert-butyl) -2-methyl-1H-imidazo [4, 5-b] pyridin-6-yl) -5-chloro-N- (5- ( (4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- (piperazin-1-ylmethyl) pyridin-2-yl) pyrimidin-2-amine,
    5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (4-methylpiperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    N- (5- ( (4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
    5-fluoro-4- (3-isopropyl-1-methyl-1H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (4-methylpiperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    N- (5- ( (4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-1-methyl-1H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
    N- (5- ( (3, 8-diazabicyclo [3.2.1] octan-8-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
    5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (3-methyl-3, 8-diazabicyclo [3.2.1] octan-8-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    N- (5- ( (3-ethyl-3, 8-diazabicyclo [3.2.1] octan-8-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
    N- (5- ( (3, 8-diazabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
    5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (8-methyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    N- (5- ( (8-ethyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
    (R) -5-fluoro-N- (5- ( (hexahydropyrrolo [1, 2-a] pyrazin-2 (1H) -yl) methyl) pyridin-2-yl) -4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
    N- (5- ( (2, 7-diazaspiro [3.5] nonan-2-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
    5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (7-methyl-2, 7-diazaspiro [3.5] nonan-2-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    N- (5- ( (7-ethyl-2, 7-diazaspiro [3.5] nonan-2-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
    5-fluoro-N- (5- ( (hexahydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) methyl) pyridin-2-yl) -4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
    5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (5-methylhexahydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    N- (5- ( (5-ethylhexahydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
    N- (5- ( (2, 7-diazaspiro [3.5] nonan-7-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
    5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (2-methyl-2, 7-diazaspiro [3.5] nonan-7-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    N- (5- ( (2-ethyl-2, 7-diazaspiro [3.5] nonan-7-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
    N- (5- ( (3, 9-diazaspiro [5.5] undecan-3-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
    5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (9-methyl-3, 9-diazaspiro [5.5] undecan-3-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    N- (5- ( (9-ethyl-3, 9-diazaspiro [5.5] undecan-3-yl) methyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
    5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    (S) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (2-methyl-4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    (R) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (2-methyl-4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    (R) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (3-methyl-4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    (S) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (3-methyl-4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    (6- ( (5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (piperazin-1-yl) methanone,
    (6- ( (5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (4-methylpiperazin-1-yl) methanone,
    (4-ethylpiperazin-1-yl) (6- ( (5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,
    (3, 8-diazabicyclo [3.2.1] octan-8-yl) (6- ( (5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,
    (6- ( (5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (3-methyl-3, 8-diazabicyclo [3.2.1] octan-8-yl) methanone,
    (3-ethyl-3, 8-diazabicyclo [3.2.1] octan-8-yl) (6- ( (5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,
    (3, 8-diazabicyclo [3.2.1] octan-3-yl) (6- ( (5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,
    (6- ( (5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (8-methyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) methanone,
    (8-ethyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) (6- ( (5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,
    (6- ( (5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (2, 7-diazaspiro [3.5] nonan-2-yl) methanone,
    (6- ( (5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (7-methyl-2, 7-diazaspiro [3.5] nonan-2-yl) methanone,
    (7-ethyl-2, 7-diazaspiro [3.5] nonan-2-yl) (6- ( (5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,
    (6- ( (5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (hexahydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) methanone,
    (6- ( (5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) (5-methylhexahydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) methanone,
    (5-ethylhexahydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) (6- ( (5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-yl) amino) pyridin-3-yl) methanone,
    N- (5- ( (3, 8-diazabicyclo [3.2.1] octan-3-yl) sulfonyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
    5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (8-methyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) sulfonyl) pyridin-2-yl) pyrimidin-2-amine,
    N- (5- ( (8-ethyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) sulfonyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
    N- (5- ( (2, 7-diazaspiro [3.5] nonan-2-yl) sulfonyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
    5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (7-methyl-2, 7-diazaspiro [3.5] nonan-2-yl) sulfonyl) pyridin-2-yl) pyrimidin-2-amine,
    N- (5- ( (7-ethyl-2, 7-diazaspiro [3.5] nonan-2-yl) sulfonyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
    5-fluoro-N- (5- ( (hexahydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) sulfonyl) pyridin-2-yl) -4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
    5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (5-methylhexahydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) sulfonyl) pyridin-2-yl) pyrimidin-2-amine,
    N- (5- ( (5-ethylhexahydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl) sulfonyl) pyridin-2-yl) -5-fluoro-4- (3-isopropyl-2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) pyrimidin-2-amine,
    4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoro-N- (5- ( (4- (oxetan-3-yl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoro-N- (5- ( (4-methylpiperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (4-ethylpiperazin-1-yl) methyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine,
    (R) -4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoro-N- (5- ( (methyl ( (1-methylpyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) pyrimidin-2-amine,
    (R) -4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoro-N- (5- ( (hexahydropyrrolo [1, 2-a] pyrazin-2 (1H) -yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    N- (5- ( (3, 8-diazabicyclo [3.2.1] octan-8-yl) methyl) pyridin-2-yl) -4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoropyrimidin-2-amine,
    4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoro-N- (5- ( (3-methyl-3, 8-diazabicyclo [3.2.1] octan-8-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (3-ethyl-3, 8-diazabicyclo [3.2.1] octan-8-yl) methyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine,
    (S) -4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoro-N- (5- ( (3- (methoxymethyl) piperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    (S) -4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoro-N- (5- ( (3- (methoxymethyl) -4-methylpiperazin-1-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    (S) -4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( (4-ethyl-3- (methoxymethyl) piperazin-1-yl) methyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine,
    N- (5- ( ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) -4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoropyrimidin-2-amine,
    4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoro-N- (5- ( ( (1R, 5S) -8-methyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) pyrimidin-2-amine,
    4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- ( ( (1R, 5S) -8-ethyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) methyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine,
    4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoro-N- (5- (1- (piperazin-1-yl) ethyl) pyridin-2-yl) pyrimidin-2-amine,
    4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoro-N- (5- (1- (4-methylpiperazin-1-yl) ethyl) pyridin-2-yl) pyrimidin-2-amine,
    4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -N- (5- (1- (4-ethylpiperazin-1-yl) ethyl) pyridin-2-yl) -5-fluoropyrimidin-2-amine,
    N- (4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoropyrimidin-2-yl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-amine,
    N- (4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoropyrimidin-2-yl) -6-methyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-amine,
    N- (4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoropyrimidin-2-yl) -6-ethyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-amine,
    4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoro-N- (5- (morpholinomethyl) pyridin-2-yl) pyrimidin-2-amine,
    3- (4- ( (6- ( (4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoropyrimidin-2-yl) amino) pyridin-3-yl) methyl) piperazin-1-yl) propanenitrile,
    N- (4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoropyrimidin-2-yl) -6- (piperidin-4-yl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-amine,
    N- (4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoropyrimidin-2-yl) -6- (1-methylpiperidin-4-yl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-amine,
    N- (4- (3- (tert-butyl) -2-methyl-2H-pyrazolo [3, 4-b] pyridin-5-yl) -5-fluoropyrimidin-2-yl) -6- (1-ethylpiperidin-4-yl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-amine,
    or pharmaceutically acceptable salt thereof.
  21. A pharmaceutical composition, comprising a compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  22. A method of treating, ameliorating or preventing a condition, which responds to inhibition of cyclin-dependent kinase 4/6, comprising administering to a subject in need of such treatment an effective amount of a compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or of at least one pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent.
  23. Use of a compound of any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a cell-proliferative disorder.
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