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WO2023078398A1 - Composés utillisés en tant qu'inhibiteurs de bcl-2 - Google Patents

Composés utillisés en tant qu'inhibiteurs de bcl-2 Download PDF

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Publication number
WO2023078398A1
WO2023078398A1 PCT/CN2022/129903 CN2022129903W WO2023078398A1 WO 2023078398 A1 WO2023078398 A1 WO 2023078398A1 CN 2022129903 W CN2022129903 W CN 2022129903W WO 2023078398 A1 WO2023078398 A1 WO 2023078398A1
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Prior art keywords
alkyl
cycloalkyl
independently selected
heterocyclyl
heteroaryl
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Inventor
Rui Tan
Hongbin Liu
Weipeng Zhang
Jinhua Yu
Zhuo HUANG
Zuwen ZHOU
Qihong Liu
Xiaodong Jia
Haohan TAN
Yue RONG
Lihua Jiang
Shu Lin
Xingdong ZHAO
Weibo Wang
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Fochon Pharmaceuticals Ltd
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Fochon Pharmaceuticals Ltd
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Priority to CN202280073843.7A priority Critical patent/CN118215661A/zh
Publication of WO2023078398A1 publication Critical patent/WO2023078398A1/fr
Anticipated expiration legal-status Critical
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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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D471/12—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 three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • BCL-2 BCL-2 family proteins and their drug-resistant mutations, and may be useful for the treatment of hyper-proliferative diseases like cancer and inflammation, or immune and autoimmune diseases.
  • 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 that drive the disease initiation and progression.
  • PPIs Protein-protein interactions
  • the BCL-2 family of proteins are central to the regulation of apoptosis, which are vital for proper tissue development and cellular homeostasis. Apoptosis occurs via activation of two different pathways. The extrinsic pathway, triggered by activation of the intrinsic pathway involves members of the BCL-2 family of proteins.
  • the BCL-2 family proteins include anti-apoptotic proteins, such as BCL-2, BCL-X L and Mcl-1, and pro-apoptotic proteins, including Bid, Bim, Bad, Bak and Bax.
  • BCL-2 proteins are under investigation as potential therapeutic drug targets which include, for example, BCL-2 and BCL-X L .
  • Expression of BCL-2 proteins is an independent indicator of poor prognosis in tumors including chronic lymphocytic leukemia (CLL) , prostate cancer, and small cell lung cancer (SCLC) .
  • CLL chronic lymphocytic leukemia
  • SCLC small cell lung cancer
  • BCL-X L expression is linked to grade and stage, and in hepatocellular cancer, BCL-X L expression is an independent marker of poorer overall and disease-free survival.
  • Venetolax as a potent first-generation BCL-2 inhibitor, selectively inhibits BCL-2 by binding its key hydrophobic groove, which is the same site that sequesters its physiological ligands (BH3 domain-containing pro-apoptotic proteins) , thus attenuating the tumor progression.
  • BCL-2 the mutations in the drug-binding sites of BCL-2, such as G101V, D103Y, F104L, F104C, etc., is one of the key mechanisms driving drug resistance.
  • BCL-2 inhibitors were disclosed in the arts, e.g. WO 2011149492, many suffer from short half-life or toxicity. Therefore, there is a need for new BCL-2 inhibitors that have at least one advantageous property selected from solubility, drug-drug interactions, potency, stability, selectivity, toxicity, drug resistance, pharmacokinetics, and pharmacodynamics properties as an alternative for the treatment of hyper-proliferative diseases.
  • a novel class of BCL-2 inhibitors is provided herein.
  • Q is selected from aryl, heteroaryl and heterocyclyl
  • X is selected from N and CH;
  • Y 1 , Y 2 and Y 3 are independently selected from CH and N;
  • Z 1 , Z 2 and Z 3 are independently selected from C, CH and N;
  • a and B are independently selected from CH and N;
  • L 1 and L 2 are independently selected from a bond, - (CR C0 R D0 ) u -, - (CR C0 R D0 ) u O (CR C0 R D0 ) t -, - (CR C0 R D0 ) u NR A0 (CR C0 R D0 ) t -and - (CR C0 R D0 ) u S (O) r (CR C0 R D0 ) t -;
  • R 3 is selected from aryl, heteroaryl and heterocyclyl, wherein aryl, heteroaryl and heterocyclyl are each unsubstituted or substituted with at least one substituent, independently selected from R X3 ;
  • R 4 is selected from aryl, heteroaryl and heterocyclyl, wherein aryl, heteroaryl and heterocyclyl are each unsubstituted or substituted with at least one substituent, independently selected from R X4 ;
  • R 5 together with the atoms to which they are attached form a C 3-10 cycloalkyl or heterocyclic ring of 4 to 12 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R X5 groups;
  • R 6 together with the carbon atoms to which they are attached form a C 3-10 cycloalkyl or heterocyclic ring of 4 to 12 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R X6 groups;
  • R 7 together with the carbon atoms to which they are attached form a C 3-10 cycloalkyl or heterocyclic ring of 4 to 12 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R X7 groups;
  • R A0 is 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, 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, independently selected from R X0 ;
  • each R A1 and R B1 are independently selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, 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, independently selected from R X1 ;
  • each R A2 and 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, 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, independently selected from R X2 ;
  • each R A5 and R B5 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, 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, independently selected from R X5 ;
  • each R A6 and R B6 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, 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, independently selected from R X6 ;
  • each R A7 and R B7 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, 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, independently selected from R X7 ;
  • each R A8 and R B8 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, 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, independently selected from R X8 ;
  • each R A9 and R B9 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, 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, independently selected from R X9 ;
  • each R C0 and R D0 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, 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, independently selected from R X0 ;
  • R C0 and R D0 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 X0 groups;
  • each R E1 , R E2 , R E5 , R E6 , R E7 , R E8 and R E9 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 , wherein alkyl is unsubstituted or substituted with at least one substituent, independently selected from R X1 ;
  • each R X0 , R X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 , R X8 and R X9 is 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, 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 C (O) R a1 , - (CR c1 R
  • 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, 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, 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 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
  • 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 u is independently selected from 0, 1, 2, 3 and 4.
  • a method to treat, ameliorate or prevent a condition which responds to inhibition of BCL-2 comprising administering to a system or subject in need of such treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or pharmaceutical compositions thereof, and optionally in combination with a second therapeutic agent, thereby treating said condition.
  • R 1 when there are two or more variables (e.g. R 1 ) occur at the structure of a compound at the same time, each is selected independently. As a non-limiting example, there are two R 1 occur at the structure of a compound at the same time, one R 1 is methyl and the other R 1 is F.
  • bridged cycloalkyl ring systems include, but are not limited to, bicyclo [1.1.1] pentane, 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 cycloalkyl can be attached to the parent molecular moiety through any substitutable atom contained within the ring system.
  • 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 removing “-yl” and adding “-idene” to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene.
  • a 11-to 14-membered tricyclic aromatic ring system containing one or more, for example, from 1 to 8, or, in some embodiments, from 1 to 6, or, in some embodiments, 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.
  • 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, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyrazin-2-yl, pyrazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, pyridazinyl, triazinyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, thienyl, furyl.
  • heteroaryl groups include but are not limited to indolyl, benzothienyl, benzofuryl, benzoimidazolyl, benzotriazolyl, quinoxalinyl, quinolinyl, and isoquinolinyl.
  • Heteroaryl is also understood to include the N-oxide derivative of any nitrogen-containing heteroaryl.
  • Suitable heterocycles include, for example, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-3-yl, imidazolidin-4-yl, imidazolidin-5-yl, pyrazolidin-1-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, pyrazolidin-4-yl, pyrazolidin-5-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, hexahydropyridazin-1-yl, hexahydropyridazin-3-yl, hexahydropyridazin-4-yl and tetrahydropyridy
  • aryl-alkyl refers to an alkyl moiety as defined above substituted by an aryl group as defined above.
  • exemplary aryl-alkyl groups include but are not limited to benzyl, phenethyl and naphthylmethyl groups. In some embodiments, aryl-alkyl groups have 7-20 or 7-11 carbon atoms.
  • 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 as defined above substituted by heterocyclyl as defined above.
  • 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.
  • 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 is aryl-C l-4 alkyl and may be unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R X , it should be understood that 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 crystalline forms, or polymorphs, and may also be in the form of solvates, such as hydrates.
  • 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.
  • 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.
  • 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
  • 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, oxygen, 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 of the invention may be used as standards to determine the effectiveness of ALK inhibitors in binding assays.
  • Isotope containing compounds have been used in pharmaceutical research to investigate the in vivo metabolic fate of the compounds by evaluation of the mechanism of action and metabolic pathway of the nonisotope-labeled parent compound (Blake et al. J. Pharm. Sci. 64, 3, 367-391 (1975) ) .
  • Such metabolic studies are important in the design of safe, effective therapeutic drugs, either because the in vivo active compound administered to the patient or because the metabolites produced from the parent compound prove to be toxic or carcinogenic (Foster et al., Advances in Drug Research Vol. 14, pp.
  • non-radioactive isotope containing drugs such as deuterated drugs called “heavy drugs” can be used for the treatment of diseases and conditions related to ALK activity.
  • Increasing the amount of an isotope present in a compound above its natural abundance is called enrichment.
  • Examples of the amount of enrichment include but are not limited to 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 to a compound of formula (I) ,
  • Z 1 , Z 2 and Z 3 are independently selected from C, CH and N;
  • Aand B are independently selected from CH and N;
  • L 1 and L 2 are independently selected from a bond, - (CR C0 R D0 ) u -, - (CR C0 R D0 ) u O (CR C0 R D0 ) t -, - (CR C0 R D0 ) u NR A0 (CR C0 R D0 ) t -and - (CR C0 R D0 ) u S (O) r (CR C0 R D0 ) t -;
  • R 3 is selected from aryl, heteroaryl and heterocyclyl, wherein aryl, heteroaryl and heterocyclyl are each unsubstituted or substituted with at least one substituent, independently selected from R X3 ;
  • R 5 together with the atoms to which they are attached form a C 3-10 cycloalkyl or heterocyclic ring of 4 to 12 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R X5 groups;
  • R A0 is 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, 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, independently selected from R X0 ;
  • each R A1 and R B1 are independently selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 1-10 alkoxy, 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, independently selected from R X1 ;
  • each R A2 and 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, 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, independently selected from R X2 ;
  • each R A5 and R B5 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, 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, independently selected from R X5 ;
  • each R A6 and R B6 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, 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, independently selected from R X6 ;
  • each R A7 and R B7 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, 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, independently selected from R X7 ;
  • each R A8 and R B8 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, 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, independently selected from R X8 ;
  • each R C0 and R D0 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, 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, independently selected from R X0 ;
  • R C0 and R D0 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 X0 groups;
  • each R E1 , R E2 , R E5 , R E6 , R E7 , R E8 and R E9 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 , wherein alkyl is unsubstituted or substituted with at least one substituent, independently selected from R X1 ;
  • each R X0 , R X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 , R X8 and R X9 is 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, 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 C (O) R a1 , - (CR c1 R
  • 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, 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, 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 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 N (C 1-4 alkyl) 2 and -S (O) 2 N (C 3-10 cycloalkyl) 2 ;
  • n, n1, n2, p, p1, p2, q, q1 and q2 are independently selected from 0, 1, 2 and 3;
  • each r is independently selected from 0, 1 and 2;
  • each t is independently selected from 0, 1, 2, 3 and 4;
  • each u is independently selected from 0, 1, 2, 3 and 4.
  • the invention provides a compound of Embodiments (1) or a pharmaceutically acceptable salt thereof, wherein Q is selected from heteroaryl and heterocyclyl.
  • the invention provides a compound of Embodiments (2) or a pharmaceutically acceptable salt thereof, wherein Q is selected from and wherein the symbol indicates the point of attachment to the rest of the molecule. In another Embodiment, Q is selected from and wherein the symbol indicates the point of attachment to the rest of the molecule.
  • the invention provides a compound of any one of Embodiments (1) - (3) or a pharmaceutically acceptable salt thereof, wherein L 1 is selected from a bond, - (CR C0 R D0 ) u -, - (CR C0 R D0 ) u O (CR C0 R D0 ) t -and - (CR C0 R D0 ) u NR A0 (CR C0 R D0 ) t -.
  • the invention provides a compound of Embodiments (4) or a pharmaceutically acceptable salt thereof, wherein L 1 is selected from - (CR C0 R D0 ) u -, -O-and -NR A0 (CR C0 R D0 ) t -.
  • the invention provides a compound of Embodiments (5) or a pharmaceutically acceptable salt thereof, wherein L 1 is selected from -CH 2 -, -O-, -NH-and -NHCH 2 -. In an embodiment, L 1 is selected from -O-, -NH-and -NHCH 2 -. In an embodiment, L 1 is selected from -NH-and -NHCH 2 -.
  • the invention provides a compound of any one of Embodiments (1) - (6) or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-10 alkyl, 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, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R X1 .
  • the invention provides a compound of Embodiments (7) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, heterocyclyl and heterocyclyl-C 1-4 alkyl, wherein alkyl, cycloalkyl and heterocyclyl are each unsubstituted or substituted with at least one substituent, independently selected from R X1 .
  • the invention provides a compound of Embodiments (8) or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from and which are unsubstituted or substituted with at least one substituent, independently selected from R X1 . In another Embodiment, wherein R 1 is selected from and which are unsubstituted or substituted with at least one substituent, independently selected from R X1 . In another Embodiment, wherein R 1 is selected from and which are unsubstituted or substituted with at least one substituent, independently selected from R X1 . In another Embodiment, wherein R 1 is selected from and which are unsubstituted or substituted with at least one substituent, independently selected from R X1 .
  • the invention provides a compound of Embodiments (10) or a pharmaceutically acceptable salt thereof, wherein each R a1 and each R b1 are independently selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl and C 2-10 alkynyl, wherein alkyl, alkenyl and alkynyl are each unsubstituted or substituted with at least one substituent, 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 8 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 X1 is independently selected from CN, OH, F, Cl, Br, methyl, difluoromethyl, trifluoromethyl, ethyl, isopropyl, ethynyl, hydroxymethyl, -C (O) CH 3 , -S (O) 2 CH 3 , and
  • each R X1 is independently selected from CN, OH, F, methyl, trifluoromethyl, isopropyl, ethynyl, hydroxymethyl, -C (O) CH 3 , -S (O) 2 CH 3
  • each R X1 is independently selected from OH, CN, halogen, C 1-10 alkyl
  • each R X1 is independently selected from OH, F and methyl.
  • the invention provides a compound of Embodiments (12) or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from and In another Embodiment, R 1 is selected from and In another Embodiment, wherein R 1 is selected from and In another Embodiment, R 1 is selected from and
  • the invention provides a compound of any one of Embodiments (1) - (13) or a pharmaceutically acceptable salt thereof, wherein m is selected from 0, 1 and 2.
  • the invention provides a compound of any one of Embodiments (1) - (14) or a pharmaceutically acceptable salt thereof, wherein each R 2 , at each occurrence, is independently selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, CN, NO 2 , -NR A2 R B2 and -OR A2 , wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R X2 .
  • the invention provides a compound of Embodiments (15) or a pharmaceutically acceptable salt thereof, wherein each R 2 , at each occurrence, is independently selected from F, Cl, Br, CN, -OH, NO 2 , NH 2 , methyl, ethyl and cyclopropyl, wherein methyl, ethyl and cyclopropyl are each unsubstituted or substituted with at least one substituent, independently selected from R X2 .
  • each R 2 at each occurrence, is independently selected from F and methyl.
  • the invention provides a compound of any one of Embodiments (1) - (16) or a pharmaceutically acceptable salt thereof, wherein the moiety in Formula (I) is selected from and wherein the symbol indicates the point of attachment to the rest of the molecule.
  • the invention provides a compound of any one of Embodiments (1) - (17) or a pharmaceutically acceptable salt thereof, wherein m1 and m2 are independently selected from 0, 1 and 2.
  • the invention provides a compound of any one of Embodiments (1) - (18) or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from aryl and heteroaryl, wherein aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R X4 .
  • the invention provides a compound of Embodiments (19) or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from phenyl and pyridinyl, wherein phenyl and pyridinyl is unsubstituted or substituted with at least one substituent, independently selected from R X4 .
  • each R X4 is independently selected from halogen, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, wherein alkyl, alkenyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R Y .
  • the invention provides a compound of Embodiments (21) or a pharmaceutically acceptable salt thereof, wherein each R X4 is independently selected from halogen, methyl, ethyl, isopropyl, tert-butyl, propenyl, ethynyl and cyclopropyl, wherein methyl, ethyl, isopropyl, tert-butyl, propenyl and cyclopropyl are each unsubstituted or substituted with at least one substituent, independently selected from halogen, C 1-10 alkyl, CN, NO 2 , -NH 2 and -OH.
  • each R X4 is independently selected from halogen, methyl, ethyl, isopropyl, tert-butyl, propenyl and cyclopropyl, wherein methyl, ethyl, isopropyl, tert-butyl, propenyl and cyclopropyl are each unsubstituted or substituted with at least one substituent, independently selected from halogen, C 1-10 alkyl, CN, NO 2 , -NH 2 and -OH.
  • each R X4 is selected from halogen, methyl, ethyl, isopropyl, propenyl and cyclopropyl, wherein methyl, ethyl, isopropyl, propenyl and cyclopropyl are each unsubstituted or substituted with at least one substituent, independently selected from halogen.
  • the invention provides a compound of Embodiments (22) or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from and In another embodiment R 4 is selected from and In another embodiment, R 4 is
  • the invention provides a compound of any one of Embodiments (1) - (23) or a pharmaceutically acceptable salt thereof, wherein each R 5 , at each occurrence, is independently selected from hydrogen, halogen, C 1-10 alkyl, 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 A5 R B5 , -OR A5 , -C (O) R A5 , -C (O) OR A5 , -OC (O) R A5 , -C (O) NR A5 R B5 and -S (O) r R A5 , wherein alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubsti
  • each R 5 at each occurrence
  • any two of R 5 together with the atoms to which they are attached form a C 3-8 cycloalkyl or heterocyclic ring of 4 to 8 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R X5 groups.
  • the invention provides a compound of Embodiments (24) or a pharmaceutically acceptable salt thereof, wherein each R 5 , at each occurrence, is independently selected from hydrogen, halogen, -OH, methyl, ethyl, isopropyl and cyclopropyl, wherein methyl, ethyl, isopropyl and cyclopropyl are each unsubstituted or substituted with at least one substituent, independently selected from R X5 ;
  • R 5 together with the atoms to which they are attached form a heterocyclic ring of 4 to 8 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R X5 groups.
  • the invention provides a compound of any one of Embodiments (1) - (25) or a pharmaceutically acceptable salt thereof, wherein the moiety in Formula (I) is selected from and wherein the symbol indicates the point of attachment to the rest of the molecule.
  • the invention provides a compound of Embodiments (27) or a pharmaceutically acceptable salt thereof, W is selected from -O-, -CR 9’ R 9 -and -NR 9 -. In another Embodiment, W is selected from -O-, -CR 9 and -NR 9 -.
  • R 9’ is selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, CN, NO 2 , -NR A9 R B9 and -OR A9 , wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R X9 .
  • W is selected from -O-, -CHR 9 and -NR 9 -.
  • the invention provides a compound of Embodiments (1) or a pharmaceutically acceptable salt thereof, W is -P (O) R 9 -.
  • the invention provides a compound of any one of Embodiments (27) - (29) or a pharmaceutically acceptable salt thereof, wherein each R 9 , at each occurrence, is independently selected from hydrogen, C 1-10 alkyl, 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, -C (O) R A9 , -C (O) NR A9 R B9 , -C (O) OR A9 , -S (O) r R A9 and -S (O) r NR A9 R B9 , wherein alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R X9
  • each R 9 is independently selected from hydrogen, C 1-10 alkyl, C 3-10 cycloalkyl, heterocyclyl, heterocyclyl-C 1-4 alkyl, aryl, aryl-C 1-4 alkyl, heteroaryl, heteroaryl-C 1-4 alkyl, -C (O) R A9 , -C (O) NR A9 R B9 , -C (O) OR A9 , -S (O) r R A9 and -S (O) r NR A9 R B9 , wherein alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R X9 .
  • each R 9 is independently selected from hydrogen, C 1-10 alkyl, C 3-10 cycloalkyl, aryl-C 1-4 alkyl, heteroaryl-C 1-4 alkyl, -C (O) R A9 , -C (O) OR A9 and -S (O) r R A9 , wherein alkyl, cycloalkyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R X9 .
  • the invention provides a compound of Embodiments (30) or a pharmaceutically acceptable salt thereof, wherein each R 9 is independently selected from hydrogen, methyl, ethyl, cyclopropyl, -C (O) CH 3 , -C (O) OCH 3 , -S (O) 2 CH 3 , and wherein methyl, ethyl, cyclopropyl, and are each unsubstituted or substituted with at least one substituent, independently selected from R X9 .
  • the invention provides a compound of any one of Embodiments (30) - (31) or a pharmaceutically acceptable salt thereof, wherein each R X9 is independently selected from halogen, CN, NO 2 , -NH 2 , C 1-10 alkyl, C 3-10 cycloalkyl, aryl, heteroaryl, - (CR c1 R d1 ) t OR b1 , and - (CR c1 R d1 ) t S (O) r R b1 , wherein alkyl, cycloalkyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R Y .
  • each R X9 is independently selected from F, Cl, Br, -CN, -OH, -NH 2 , methyl, ethyl, difluoroethyl, isopropyl, cyclopropyl, methoxy, difluoromethoxy, methoxy-d3, ethoxy, trifluoroethoxy, methylthio, methoxyphenyl and
  • each R X9 is independently selected from F, Cl, Br, -CN, -OH, -NH 2 , methyl, ethyl, isopropyl, cyclopropyl, methoxy, difluoromethoxy, methoxy-d3, ethoxy, trifluoroethoxy, methylthio, methoxyphenyl and
  • each R 9 is independently selected from hydrogen, methyl, ethyl, cyclopropyl, -C (O) CH 3 , -C (O) OCH 3 , -S (O) 2 CH 3 , and wherein methyl, ethyl, cyclopropyl, and are each unsubstituted or substituted with at least one substituent, independently selected from R X9 .
  • each R X9 is independently selected from halogen, CN, NO 2 , -NH 2 , C 1-10 alkyl, C 3-10 cycloalkyl and - (CR c1 R d1 ) t OR b1 .
  • each R X9 is independently selected from F, Cl, Br, methyl, ethyl, isopropyl, cyclopropyl, methoxy and ethoxy.
  • each R 9 is independently selected from hydrogen, methyl, ethyl, cyclopropyl, -C (O) CH 3 , -C (O) OCH 3 , -S (O) 2 CH 3 , and In another Embodiment, each R 9 is independently selected from hydrogen, methyl, ethyl, cyclopropyl, -C (O) CH 3 , -C (O) OCH 3 , -S (O) 2 CH 3 , and In another embodiment, each R 9 is independently selected from hydrogen, and
  • the moiety in Formula (I) is selected from and wherein the symbol indicates the point of attachment to the rest of the molecule. In an Embodiment, wherein the moiety in Formula (I) is selected from and
  • the invention provides a compound of any one of Embodiments (1) - (32) or a pharmaceutically acceptable salt thereof, wherein L 2 is selected from a bond, - (CR C0 R D0 ) u O (CR C0 R D0 ) t -and - (CR C0 R D0 ) u S (O) r (CR C0 R D0 ) t -.
  • the invention provides a compound of Embodiments (33) or a pharmaceutically acceptable salt thereof, wherein L 2 is selected from a bond and -O-.
  • the invention provides a compound of any one of Embodiments (1) - (34) or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from heteroaryl and heterocyclyl, wherein heteroaryl and heterocyclyl are each unsubstituted or substituted with at least one substituent, independently selected from R X3 .
  • R 3 is a heteroaryl or heterocyclyl comprising a pyridyl condensed pyrrole structure, which are each unsubstituted or substituted with at least one substituent, independently selected from R X3 .
  • the invention provides a compound of Embodiments (35) or a pharmaceutically acceptable salt thereof, R 3 is selected from and which are unsubstituted or substituted with at least one substituent, independently selected from R X3 . In another Embodiment, R 3 is selected from and which are unsubstituted or substituted with at least one substituent, independently selected from R X3 .
  • the invention provides a compound of any one of Embodiments (1) - (36) or a pharmaceutically acceptable salt thereof, wherein each R X3 is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, heterocyclyl, heterocyclyl-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 C (O) OR b1 , - (CR c1 R d1 ) t C (O) OR b1 , - (CR c1 R d1 ) t C (O) NR a1 R b1 , - (CR c1 R d1 ) t NR a1 C (O) R
  • each R X3 is independently selected from C 1-10 alkyl, C 3- 10 cycloalkyl, halogen, CN, NO 2 , - (CR c1 R d1 ) t NR a1 R b1 and - (CR c1 R d1 ) t OR b1 , wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R Y .
  • each R X3 is independently selected from F, Cl, Br, -CN, -OH, -NH 2 , methyl, trifluoromethyl, cycloprpyl, methoxy, ethoxy, methoxyethoxy, difluoromethoxy and methoxypropoxy.
  • each R X3 is selected from halogen, -CN, -NH 2 , methyl, trifluoromethyl, cycloprpyl, methoxy, ethoxy, methoxyethoxy, difluoromethoxy and methoxypropoxy.
  • each R X3 is independently selected from F, Cl, Br, methyl, methoxy, ethoxy and methoxypropoxy.
  • the invention provides a compound of any one of Embodiments (1) - (38) or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from and In another embodiment, wherein R 3 is selected from and In another embodiment, wherein R 3 is selected from and
  • the invention provides a compound of any one of Embodiments (1) - (39) or a pharmaceutically acceptable salt thereof, wherein each R 8 , at each occurrence, is independently selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, CN, NO 2 , -NR A8 R B8 , -OR A8 and -C (O) R A8 , wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R X8 , preferably, each R 8 , at each occurrence, is independently selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, CN, NO 2 , -NH 2 and -OH, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R X8 ;
  • each R 8 at each occurrence, is independently selected from hydrogen, halogen
  • the invention provides a compound of any one of Embodiments (1) - (41) or a pharmaceutically acceptable salt thereof, wherein the moiety in Formula (I) is selected from and wherein the symbol indicates the point of attachment to the rest of the molecule. In another Embodiment, wherein the moiety in Formula (I) is selected from and wherein the symbol indicates the point of attachment to the rest of the molecule.
  • the invention provides a compound of any one of Embodiments (1) - (42) or a pharmaceutically acceptable salt thereof, wherein each R 7 , at each occurrence, is independently selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, CN, NO 2 , -NR A7 R B7 , -OR A7 and -C (O) R A7 , wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R X7 , preferably, each R 7 , at each occurrence, is independently selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, CN, NO 2 , -NH 2 and -OH, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R X7 .
  • R 7 is independently selected from hydrogen, halogen, C 1-10 alky
  • the invention provides a compound selected from and pharmaceutically acceptable salts thereof.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of any one of Embodiments (1) - (44) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.
  • the invention provides a method of treating, ameliorating or preventing a condition, which responds to inhibition of Bcl-2, comprising administering to a subject in need of such treatment an effective amount of a compound of any one of Embodiments (1) -(44) , 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) - (44) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a cell-proliferative disorder or autoimmune disease.
  • the invention provides the use of Embodiment (47) , wherein the cell-proliferative disorder is selected from breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, testicular cancer, lung cancer (for example, NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma) , esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer (for example, RCC) , liver cancer (for example, HCC) , pancreatic cancer, stomach (i.e., gastric) cancer, thyroid cancer, chronic lymphocytic leukemia (CLL) , lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia and myeloma.
  • lung cancer for example, NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma
  • esophageal cancer
  • the invention provides the use of Embodiment (47) , wherein the autoimmune disease is selected from allergy, Alzheimer's disease, acute disseminated encephalomyelitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome, asthma, atherosclerosis, autoimmune hemolytic anemia, autoimmune hemolytic and thrombocytopenic states, autoimmune hepatitis, autoimmune inner ear disease, bullous pemphigoid, coeliac disease, chagas disease, chronic obstructive pulmonary disease, chronic Idiopathic thrombocytopenic purpura (ITP) , churg-strauss syndrome, Crohn's disease, dermatomyositis, diabetes mellitus type 1, endometriosis, Goodpasture's syndrome (and associated glomerulonephritis and pulmonary hemorrhage) , graves'disease, guillainbarre syndrome, hashimoto
  • kits comprising a compound disclosed herein, or a pharmaceutically acceptable salt 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 salt 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 salt thereof.
  • a method of inhibiting a BCL-2 comprising contacting the BCL-2 with a compound disclosed herein, or a pharmaceutically acceptable salt thereof.
  • a method of inhibiting a BCL-2 comprising causing a compound disclosed herein, or a pharmaceutically acceptable salt thereof to be present in a subject in order to inhibit the BCL-2 in vivo.
  • a method of inhibiting BCL-2 comprising administering a first compound to a subject that is converted in vivo to a second compound wherein the second compound inhibits the BCL-2 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 BCL-2 possesses activity that contributes to the pathology and/or symptomology of the disease state comprising causing a compound disclosed herein, or a pharmaceutically acceptable salt 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 BCL-2 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 BCL-2 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, eczema, and
  • a method of treating a disease state for which a mutation in the BCL-2 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 BCL-2.
  • 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 BCL-2 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 monooleate) .
  • viscosity-increasing agents including but not limited to, sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone, gelatins, or solubilizers, e.g. Tween 80 (polyoxyethylene (20) sorbitan monooleate) .
  • 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 but are not limited to liquid fatty acid esters that contain as the acid component a long-chained fatty acid having 8-22 carbon atoms, or in some embodiments, 12-22 carbon atoms.
  • Suitable liquid fatty acid esters include but are not limited to lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid or corresponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, brassidic acid and linoleic acid, and if desired, may contain antioxidants, for example vitamin E, 3-carotene or 3, 5-di-tert-butyl-hydroxytoluene.
  • the alcohol component of these fatty acid esters may have six carbon atoms and may be monovalent or polyvalent, for example a mono-, di-or trivalent, alcohol. Suitable alcohol components include but are not limited to methanol, ethanol, propanol, butanol or pentanol or isomers thereof; glycol and glycerol.
  • Suitable fatty acid esters include but are not limited ethyl-oleate, isopropyl myristate, isopropyl palmitate, M 2375, (polyoxyethylene glycerol) , M 1944 CS (unsaturated polyglycolized glycerides prepared by alcoholysis of apricot kernel oil and comprising glycerides and polyethylene glycol ester) , LABRASOL TM (saturated polyglycolized glycerides prepared by alcoholysis of TCM and comprising glycerides and polyethylene glycol ester; all available from GaKefosse, France) , and/or 812 (triglyceride of saturated fatty acids of chain length C8 to C12 from Hüls AG, Germany) , and vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil, or groundnut oil.
  • vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, ses
  • compositions for oral administration may be obtained, for example, by combining the active ingredient with one or more solid carriers, and if desired, granulating a resulting mixture, and processing the mixture or granules by the inclusion of additional excipients, to form tablets or tablet cores.
  • Suitable carriers include but are not limited to fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starches, for example corn, wheat, rice or potato starch, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, carboxymethyl starch, crosslinked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate.
  • 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
  • binders such as starches, for example
  • Additional excipients include but are not limited to 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.
  • 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 cellulose acetate phthalate or hydroxypropyl methylcellulose 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 cellulose acetate phthalate or hydroxypropyl methylcellulose phthalate.
  • Dyes or pigments may be added to the tablets or tablet coatings,
  • compositions for oral administration may also include hard capsules comprising gelatin or soft-sealed capsules comprising gelatin and a plasticizer, such as glycerol or sorbitol.
  • the hard capsules may contain the active ingredient in the form of granules, for example in admixture with fillers, such as corn starch, binders, and/or glidants, such as talc or magnesium stearate, and optionally stabilizers.
  • the active ingredient may be dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilizers and detergents, for example of the polyoxyethylene sorbitan fatty acid ester type, may also be added.
  • suitable liquid excipients such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilizers and detergents, for example of the polyoxyethylene sorbitan fatty acid ester type, may also be added.
  • compositions suitable for rectal administration are, for example, suppositories comprising a combination of the active ingredient and a suppository base.
  • Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
  • compositions suitable for parenteral administration may comprise aqueous solutions of an active ingredient in water-soluble form, for example of a water-soluble salt, or aqueous injection suspensions that contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if desired, stabilizers.
  • the active ingredient optionally together with excipients, can also be in the form of a lyophilizate and can be made into a solution before parenteral administration by the addition of suitable solvents. Solutions such as are used, for example, for parenteral administration can also be employed as infusion solutions.
  • the manufacture of injectable preparations is usually carried out under sterile conditions, as is the filling, for example, into ampoules or vials, and the sealing of the containers.
  • the disclosure also provides for a pharmaceutical combination, 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.
  • a pharmaceutical combination 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.
  • 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.
  • a compound of formula (I) 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) 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) are set forth in the definitions section of this Application.
  • the salt forms of the compounds of formula (I) can be prepared using salts of the starting materials or intermediates.
  • the free acid or free base forms of the compounds of formula (I) can be prepared from the corresponding base addition salt or acid addition salt form.
  • a compound of formula (I) in an acid addition salt form can be converted to the corresponding free base thereof by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like) .
  • a compound of formula (I) in a base addition salt form can be converted to the corresponding free acid thereof by, for example, treating with a suitable acid (e.g., hydrochloric acid, etc) .
  • N-oxides of a compound of formula (I) or a pharmaceutically acceptable salt thereof can be prepared by methods known to those of ordinary skill in the art.
  • N-oxides can be prepared by treating an unoxidized form of the compound of formula (I) with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at approximately 0 to 80°C.
  • an oxidizing agent e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or the like
  • a suitable inert organic solvent e.g., a halogenated hydrocarbon such as dichloromethane
  • the N-oxides of the compounds of formula (I) can
  • Compounds of formula (I) in an unoxidized form can be prepared from N-oxides of compounds of formula (I) by, for example, treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, and the like) in an suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, and the like) at 0 to 80°C.
  • a reducing agent e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, and the like
  • an inert organic solvent e.g., acetonitrile, ethanol, aqueous dioxane, and the like
  • Protected derivatives of the compounds of formula (I) can be made by methods known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley &Sons, Inc. 1999.
  • references to ether or Et 2 O are to diethyl ether; brine refers to a saturated aqueous solution of NaCl. Unless otherwise indicated, all temperatures are expressed in °C (degrees Centigrade) . All reactions were conducted under an inert atmosphere at RT unless otherwise noted.
  • MS mass spectra
  • ESI electrospray ionization
  • UV detector (220 and 254 nm)
  • ELSD evaporative light scattering detector
  • Thin-layer chromatography was performed on 0.25 mm Superchemgroup silica gel plates (60F-254) , visualized with UV light, 5%ethanolic phosphomolybdic acid, ninhydrin, or p-anisaldehyde solution. Flash column chromatography was performed on silica gel (200-300 mesh, Branch of Qingdao Haiyang Chemical Co., Ltd) .
  • a compound of formula I 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 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.
  • Benzyl bromide (5.1 g, 29.9 mmol) was added to a solution of 3- (2-isopropylphenyl) -4-methoxypyridine (C-1) (6.8 g, 29.9 mmol) in acetone (68 mL) and the mixture was heated under reflux for 10 hours. The mixture was cooled and concentrated in vacuo. The residue was dissolved in EtOH (100 mL) and cooled to -10°C. Sodium borohydride (1.7 g, 44.9 mmol) was added in portions. The mixture was stirred at RT for 1 hour. The mixture was evaporated under reduced pressure. Dichloromethane (300 mL) and water (200 mL) were added and the layers were separated.
  • C-1 3- (2-isopropylphenyl) -4-methoxypyridine
  • the mixture was extracted by DCM (150 mL ⁇ 2) , the extracts were washed with 1N HCl (100 mL ⁇ 2) , brine (50 mL ⁇ 2) , dried over Na 2 SO 4 and concentrated.
  • Examples 4 ⁇ 422 listed in Table 1 were/can be prepared using appropriate intermediates, which can be readily synthesized by methods known in the art, and sequential modifications as necessary. The structures and names of Examples 4 ⁇ 422 are given in table 1.
  • MTS testing kit was purchased from Promega (Madison, WI, USA) .
  • the RPMI-1640, Fetal bovine serum and Penicillin-Streptomycin were purchased from BI (Biological Industries, Beit Haemek, Israel) .
  • Dimethyl sulfoxide (DMSO) was purchased from Sigma (St. Louis., MO, USA) .
  • Toledo (ATCC catalog#: CRL-2631) cells were cultured in RPMI-1640 supplemented with Penicillin-Streptomycin and 10%FBS.
  • MTS testing kit was purchased from Promega (Madison, WI, USA) .
  • the RPMI-1640, Fetal bovine serum and Penicillin-Streptomycin were purchased from BI (Biological Industries, Beit Haemek, Israel) .
  • Puromycin was purchased from Beyotime (shanghai, China) .
  • Dimethyl sulfoxide (DMSO) was purchased from Sigma (St. Louis., MO, USA) .
  • RS4; 11-BCL-2 G101V Cobioer Lot. #: CBD2021063013P4) , RS4; 11-BCL-2 D103E (Cobioer Lot. #: CBD2021063013P4) , RS4; 11-BCL-2 D103Y (Cobioer Lot.
  • CBD2022012101P4 and RS4; 11-BCL-2 F104L (Cobioer Lot. #: CBD2021063014P4) cells were cultured in RPMI1640 supplemented with 1ug/mL puromycin, 100U/mL Penicillin-Streptomycin and 10%FBS.
  • a mechanism-based assay using engineered cell lines stably overexpressing BCL-2 mutation (RS4; 11-BCL-2 G101V, RS4; 11-BCL-2 D103E, RS4; 11-BCL-2 D103Y, and RS4; 11-BCL-2 F104L) was developed.
  • the inhibition of BCL-2 mutation was reflected by the inhibition of cell proliferation of engineered RS4; 11 cells.
  • Cells were plated into 96-well plates at optimized cell density (RS4; 11-BCL-2 G101V: 5000 cells/well; RS4; 11-BCL-2 D103E: 7500 cells/well; RS4; 11-BCL-2 D103Y: 7500 cells/well; RS4; 11-BCL-2 F104L: 5000 cells/well) . Plates were incubated at 37°C, with 5%CO 2 for 4h (RS4; 11-BCL-2 G101V, RS4; 11-BCL-2 F104L) and 24 h (RS4; 11-BCL-2 D103E, RS4; 11-BCL-2 D103Y) , respectively.
  • RS4; 11-BCL-2 G101V 5000 cells/well
  • RS4; 11-BCL-2 D103E 7500 cells/well
  • RS4; 11-BCL-2 D103Y 7500 cells/well
  • RS4; 11-BCL-2 F104L 5000 cells/well

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Abstract

L'invention concerne certains inhibiteurs de BCL-2, des compositions pharmaceutiques de ceux-ci, et des procédés d'utilisation de ceux-ci.
PCT/CN2022/129903 2021-11-05 2022-11-04 Composés utillisés en tant qu'inhibiteurs de bcl-2 Ceased WO2023078398A1 (fr)

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WO2021083135A1 (fr) * 2019-10-28 2021-05-06 Beigene, Ltd. Inhibiteurs de bcl-2
WO2021133817A1 (fr) * 2019-12-27 2021-07-01 Guangzhou Lupeng Pharmaceutical Company Ltd. Dérivés de 1h-pyrrolo[2,3-b]pyridine comme inhibiteurs bcl-2 pour le traitement des maladies néoplasiques et auto-immunes
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