WO2023078401A1 - Compounds as protein kinase inhibitors - Google Patents

Compounds as protein kinase inhibitors Download PDF

Info

Publication number
WO2023078401A1
WO2023078401A1 PCT/CN2022/129918 CN2022129918W WO2023078401A1 WO 2023078401 A1 WO2023078401 A1 WO 2023078401A1 CN 2022129918 W CN2022129918 W CN 2022129918W WO 2023078401 A1 WO2023078401 A1 WO 2023078401A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
cycloalkyl
independently selected
heteroaryl
aryl
Prior art date
Application number
PCT/CN2022/129918
Other languages
French (fr)
Inventor
Haohan TAN
Zhifu Li
Bin Liu
Yunling Wang
Chengxi HE
Qihong Liu
Hua Xu
Yangli QI
Yanxin Liu
Shu Lin
Xingdong ZHAO
Weibo Wang
Original Assignee
Fochon Biosciences, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fochon Biosciences, Ltd. filed Critical Fochon Biosciences, Ltd.
Publication of WO2023078401A1 publication Critical patent/WO2023078401A1/en

Links

Classifications

    • 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
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • 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
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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

  • Certain compounds or pharmaceutically acceptable salts thereof which can inhibit kinase activity of PI3K and may be useful for the treatment of hyper-proliferative diseases like cancer and inflammation, or immune and autoimmune diseases.
  • Phosphoinositide 3-kinase belongs to a large family of lipid signaling kinase that plays key role in cellular processes, including cell growth, differentiation, migration and apoptosis.
  • PI3K family is divided to three classes, I, II and III, based on sequence homology and lipid substrate specificity. Among them, Class I PI3K, which includes PI3K ⁇ , PI3K ⁇ , PI3K ⁇ , and PI3K ⁇ , is mostly studied.
  • Class I PI3K is a heterodimer formed by two subunits, a catalytic subunit (p110) and a regulatory subunit (p85) .
  • the catalytic subunit, p110 has four isotypes, ⁇ , ⁇ , ⁇ , and ⁇ .
  • p110 ⁇ has a role in insulin-dependent signaling
  • p110 ⁇ functions in platelet aggregation
  • p110 ⁇ and p110 ⁇ are expressed mainly in leukocytes and have roles in lymphocyte activation, mast cell degranulation, and chemotaxis.
  • the catalytic p110 subunit associates with p85 regulatory subunit.
  • the p85 regulatory subunit Upon reception of upstream activation signals, the p85 regulatory subunit releases its inhibition of p110, such that p110 can interact with the lipid membranes to phosphorylate phosphatidylinositol-4, 5-bisphosphate (PIP2) at the 3’-OH position of the inositol ring to generate phosphatidylinositol-3, 4, 5-trisphosphate (PIP3) , which then activates downstream signals, resulting in dysregulation of metabolism and protein synthesis, and cell growth, proliferation and survival.
  • PIP2 5-bisphosphate
  • PIP3 5-trisphosphate
  • All four class I catalytic PI3K isoforms show a characteristic expression pattern in vivo.
  • p110 ⁇ and p110 ⁇ are expressed ubiquitously in mammalian tissue, while p110 ⁇ and p110 ⁇ appear to be more selectively expressed in leukocyte, endothelial cells, and smooth muscle cells. Deletion of the p110 ⁇ or p110 ⁇ induces embryonic lethality.
  • p110 ⁇ -deficient mice develop and reproduce normally, although they have suboptimal immune responses because of defects in T-cell activation as well as in neutrophil and macrophage migration.
  • p110 ⁇ -deficient mice are also viable and fertile but exhibit significant defects in T, B cell activation.
  • the PI3K pathway is one of the most commonly activated pathways in human cancers and involves in roughly half of the malignancies (Vanhaesebroeck et al., Nat Rev Drug Discov 20, 741–769 (2021) ; Zhang et al., Chem. Sci., 2020, 11, 5855) .
  • PI3KCA gene coding for PI3K ⁇
  • cancers such as endometrial cancers (24-46%) , breast cancers (20-32%) , bladder cancers (20-27%) , cervical cancers (14-23%) , colorectal cancers (13-28%) , and head-and-neck cancers (12-15%) (Arafeh & Samuels, Seminars in Cancer Biology (2019) ) .
  • PI3K ⁇ mutations are missense mutations that concentrate on hot spots located on the helical domain and the catalytical domain of p110 ⁇ , such as E542K, E545K and H1047R (Arafeh & Samuels, 2019; Vanhaesebroeck et al., 2021; Zhang et al., 2020) .
  • E542K, E545K and H1047R Arafeh & Samuels, 2019; Vanhaesebroeck et al., 2021; Zhang et al., 2020
  • PI3K is widely involved in important normal physiological functions; for example, PI3K ⁇ is involved in regulation of metabolic processes (activation of anabolic processes and inhibition of catabolic processes leads to cell growth and survival) , cell cytoskeleton function (such as cell migration) , and insulin signaling (such as regulating glucose homeostasis) (Vanhaesebroeck et al., 2021) .
  • PI3K ⁇ inhibitors target the ATP pocket of PI3K ⁇ , a region that is highly conserved among PI3K isoforms, resulting in low selectivity among PI3K isoforms caused off-target toxicities; later designs such as inavolisib and BLY-719 utilize specific interactions on PI3K ⁇ , resulting in better selectivity against other isoforms, but their inhibition against wild-type PI3K ⁇ often exhibit on-target toxicities such as hyperglycemia, hyperinsulinemia and glucose intolerance (Vanhaesebroeck et al., 2021; Arafeh & Samuels, 2019) .
  • PI3K inhibitors were disclosed in the arts, e.g. WO 2012146666, WO 2003035075 and US 20110015212, many suffer from short half-life or toxicity. Therefore, there is an urgent need for novel PI3K 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.
  • PI3K ⁇ inhibitors For instance, oncogenic mutations on PI3K ⁇ create binding pockets that can be exploited to create novel PI3K ⁇ inhibitors with improved selectivity over wild-type PI3K isoforms and safety profiles (Zhang et al., 2020; Wang et al., Acta Pharmacol Sin (2016) 39: 1816-182) .
  • a novel class of PI3K inhibitors is provided herein.
  • X is selected from C and N
  • Y is selected from C (O) , CR 9 and N,
  • Z is selected from CR 10 and N,
  • W is selected from C and N,
  • Q is selected from C 3-10 cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 2 together with the atoms to which they are attached form selected from a C 3-10 cycloalkyl, aryl, heteroaryl and heterocyclic ring of 4 to 12 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein cycloalkyl, aryl, heteroaryl and heterocyclic ring are each unsubstituted or substituted with at least one substituent, independently selected from R X2 ;
  • R 3 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, CN, NO 2 , -NR A3 R B3 , -OR A3 and -C (O) R A3 , wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are each unsubstituted or substituted with at least one substituent, independently selected from R X3 ;
  • 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, CN, NO 2 , -NR A4 R B4 , -OR A4 , -C (O) R A4 , wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are each unsubstituted or substituted with at least one substituent, independently selected from R X4 ;
  • R 3 and R 4 together with the atoms to which they are attached form selected from a C 3-10 cycloalkyl, aryl, heteroaryl and heterocyclic ring of 4 to 12 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein cycloalkyl, aryl, heteroaryl and heterocyclic ring 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 selected from a C 3-10 cycloalkyl, aryl, heteroaryl and heterocyclic ring of 4 to 12 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein cycloalkyl, aryl, heteroaryl and heterocyclic ring are each unsubstituted or substituted with at least one substituent, independently selected from R X5 ;
  • 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 A3 and R B3 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 X3 ;
  • each R A4 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, 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 X4 ;
  • 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 A10 and R B10 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 X10 ;
  • each R E1 , R E2 , R E5 , R E6 , R E7 , R E8 , R E9 and R E10 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 X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 , R X8 , R X9 and R X10 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, 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
  • R X2 together with the atoms to which they are attached form selected from selected from a C 3-10 cycloalkyl, aryl, heteroaryl and heterocyclic ring of 4 to 12 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein cycloalkyl, aryl, heteroaryl and heterocyclic are each unsubstituted or substituted with at least one substituent, independently selected from R Y ;
  • 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 is selected from 0, 1, 2, 3 and 4;
  • n is selected from 0, 1, 2, 3 and 4;
  • p is selected from 0, 1, 2, 3 and 4;
  • 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.
  • compositions comprising a compound of formula (I) or at least one pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • the disclosure provides methods for modulating PI3K, comprising administering to a system or a subject in need thereof, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or pharmaceutical compositions thereof, thereby modulating said PI3K.
  • a method to treat, ameliorate or prevent a condition which responds to inhibition of PI3K 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.
  • the present disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a condition mediated by PI3K.
  • the compounds of the disclosure may be used alone or in combination with a second therapeutic agent to treat a condition mediated by PI3K.
  • the condition herein includes but not limited to, an autoimmune disease, a heteroimmune disease, an infectious disease or a cell proliferative disorder.
  • the disclosure provides methods for treating a cell proliferative disorder, comprising administering to a system or subject in need of such treatment an effective amount of a compound 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.
  • the condition herein includes but not limited to, is an autoimmune disease, a heteroimmune disease, an allergic disease, an inflammatory disease or a cell proliferative disorder.
  • the cell-proliferative disorder is selected from breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, testicular cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma) , esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer (including RCC) , liver cancer (including 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 including NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma
  • esophageal cancer head and neck cancer
  • colorectal cancer kidney cancer (including RCC)
  • liver cancer including H
  • the condition is cell proliferative disorder.
  • the cell proliferative disorder is B-cell proliferative disorder, which includes but not limited to, B-cell malignancies, B-cell chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, multiple sclerosis, small lymphocytic lymphoma, mantle cell lymphoma, B-cell non-Hodgkin’s lymphoma, activated B-cell like diffuse large B-cell lymphoma, multiple myeloma, diffuse large B-cell lymphoma, follicular lymphoma, primary effusion lymphoma, burkitt lymphoma/leukemia, lymphomatoid granulomatosis, and plasmacytoma.
  • the condition is autoimmune disease, which includes but not limited to, rheumatoid arthritis, psoriatic arthritis, psoriasis, osteoarthritis, juvenile arthritis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, myasthenia gravis, Hashimoto's thyroiditis, multiple sclerosis, acute disseminated encephalomyelitis, Addison’s disease, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, coeliac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, scleroderma, primary biliary cirrhosis, Reiter's syndrome, psoriasis, dysautonomia, neuromyotonia, interstitial cystitis, lupus, systemic lupus erythematosus, and lupus nephritis.
  • autoimmune disease includes but
  • the condition is heteroimmune disease, which includes but not limited to, graft versus host disease, transplantation, transfusion, anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.
  • the condition is inflammatory disease, which includes but not limited to, athma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered to a system comprising cells or tissues, or to a subject including a mammalian subject such as a human or animal subject.
  • 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 .
  • substituted means that a hydrogen atom is replaced by a substituent. It is to be understood that substitution at a given atom is limited by valency. If a bond to a substituent is shown to cross the bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound, then such substituent may be bonded via any atom in such substituent. Generally, when any substituent or group occurs more than one time in any constituent or compound, its definition on each occurrence is independent of its definition at every other occurrence. Such combinations of substituents and/or variables, however, are permissible only if such combinations result in stable compounds.
  • 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.
  • C i-j or “i-j membered” used herein means that the moiety has i-j carbon atoms or i-j atoms.
  • C 1-6 alkyl means said alkyl has 1-6 carbon atoms.
  • C 3-10 cycloalkyl means said cycloalkyl has 3-10 carbon atoms.
  • hydrogen refers to 1 H, 2 H and 3 H.
  • each R n or each R Xn is selected independently.
  • any variable e.g. R
  • R any variable
  • the group may be optionally substituted by at most two R and R has independent option at each case.
  • a combination of substituents and/or the variants thereof are allowed only if such a combination will result in a stable compound.
  • hetero means heteroatom or heteroatom radical (i.e. a radical containing heteroatom) , i.e. the atoms beyond carbon and hydrogen atoms or the radical containing such atoms.
  • the heteroatom (s) is independently selected from the group consisting of O, N, S, P and the like.
  • the two or more heteroatoms may be the same, or part or all of the two or more heteroatoms may be different.
  • alkyl refers to branched or 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 saturated monocyclic or multicyclic (e.g. bicyclic or tricyclic) hydrocarbon ring system, usually with 3 to 16 ring atoms.
  • the ring atoms of cycloalkyl are all carbon and the cycloalkyl contains zero heteroatoms and zero double bonds.
  • two or more rings can be fused or bridged or spiro together.
  • monocyclic ring systems include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • the bridged cycloalkyl is a polycyclic ring system containing 3-10 carbon atoms, which contains one or two alkylene bridges, each alkylene bridge consisting of one, two, or three carbon atoms, each linking two non-adjacent carbon atoms of the ring system.
  • Cycloalkyl can be fused with aryl or heteroaryl group. In some embodiments, cycloalkyl is benzocondensed.
  • 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.
  • alkenyl refers to a non-aromatic hydrocarbon radical, straight, branched or cyclic, containing 2-10 carbon atoms and at least one carbon to carbon double bond.
  • the cyclic refers to monocyclic or multicyclic. In a multicyclic alkenyl, two or more rings can be fused or bridged or spiro together. 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 2-6 carbon atoms.
  • Alkenyl groups include but are not limited to ethenyl, propenyl, butenyl, 2-methylbutenyl, cyclopentenyl 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.
  • cycloalkenyl refers to a non-aromatic hydrocarbon ring system having 3 to 30 carbons (e.g., C 3 -C 10 ) and one or more double bonds. Examples include cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl etc.
  • alkynyl refers to a hydrocarbon radical, straight, branched or cyclic, containing 2-10 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 2-6 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 as defined above, which 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 1-10 carbon atoms, having straight or branched moieties. Alkoxy group includes but is not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, and the like.
  • cycloalkoxy refers to cycloalkyl as defined above, which 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 3-10 carbon atoms. Cycloalkoxy can be fused with aryl or heteroaryl group. In some embodiments, cycloalkoxy is benzocondensed. Cycloalkoxy group includes but is not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • alkylthio refers to an alkyl radical as defined above, which 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 1-10 carbon atoms, having straight or branched moieties.
  • Alkylthio group includes but is not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, hexylthio, and the like.
  • cycloalkylthio employed alone or in combination with other terms, refers to cycloalkyl as defined above, which 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 3-10 carbon atoms. Cycloalkylthio can be fused with aryl or heteroaryl group. In some embodiments, cycloalkylthio is benzocondensed. Cycloalkylthio group includes but is not limited to, cyclopropylthio, cyclobutylthio, cyclohexylthio, and the like.
  • alkylamino refers to an alkyl as defined above, which 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 1-10 carbon atoms, having straight or branched moieties.
  • Alkylamino group includes but is not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, hexylamoino, and the like.
  • cycloalkylamino employed alone or in combination with other terms, refers to cycloalkyl as defined above, which 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 3-10 carbon atoms.
  • Cycloalkylamino can be fused with aryl or heteroaryl group. In some embodiments, cycloalkylamino is benzocondensed. Cycloalkylamino group includes but is not limited to, cyclopropylamino, cyclobutylamino, cyclohexylamino, and the like.
  • di (alkyl) amino refers to two alkyl as defined above, which 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 1-10 carbon atoms, having straight or branched moieties.
  • aryl refers to a monovalent, monocyclic-, bicyclic-or tricyclic aromatic hydrocarbon ring system having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms (a “C 6-14 aryl” group) , particularly a ring having 6 carbon atoms (a“C 6 aryl” group) , e.g. a phenyl group; or a ring having 10 carbon atoms (a “C 10 aryl” group) , e.g. a naphthyl group; or a ring having 14 carbon atoms, (a “C 14 aryl” group) , e.g. an anthranyl group.
  • Aryl can be fused with cycloalkyl or heterocycle group.
  • 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.
  • heteroaryl refers to a monovalent, monocyclic-, bicyclic-or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms (a “5-to 14-membered heteroaryl” group) , particularly 5 or 6 or 9 or 10 atoms, and which contains at least one heteroatom which may be identical or different, said heteroatom selected from N, O and S.
  • Heteroaryl can be fused with cycloalkyl or heterocycle group.
  • “heteroaryl” refers to
  • a 5-to 8-membered monocyclic aromatic ring 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; or
  • a 8-to 12-membered bicyclic aromatic ring system containing one or more, for example, 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; or
  • 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.
  • 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.
  • heterocycle employed alone or in combination with other terms, (and variations thereof such as “heterocyclic” , or “heterocyclyl” ) broadly refers to a saturated or unsaturated mono-or multicyclic (e.g. bicyclic or tricyclic) aliphatic ring system, usually with 3 to 16 ring atoms, wherein at least one (e.g. 2, 3 or 4) ring atom is heteroatom independently selected from O, S, N and P (preferably O, S, N) .
  • two or more rings can be fused or bridged or spiro together.
  • Heterocycle can be fused with aryl or heteroaryl group.
  • heterocycle is benzocondensed.
  • Heterocycle also includes ring systems substituted with one or more oxo or imino moieties.
  • the C, N, S and P atoms in the heterocycle ring are optionally substituted by oxo.
  • the C, S and P atoms in the heterocycle ring are optionally substituted by imino, and imino can be unsubstituted or substituted.
  • the point of the attachment may be carbon atom or heteroatom in the heterocyclic ring, provided that attachment results in the creation of a stable structure.
  • 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 result.
  • 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
  • Morpholinyl groups are also contemplated, such as morpholin-1-yl, morpholin-2-yl, morpholin-3-yl and morpholin-4-yl.
  • heterocycle with one or more oxo moieties include but are not limited to, piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-thiomorpholinyl and 1, 1-dioxo-thiomorpholinyl.
  • Bicyclic heterocycles include, for example:
  • 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.
  • cycloalkyl-alkyl refers to alkyl as defined above substituted by cycloalkyl as defined above.
  • C 3-10 cycloalkyl-C l-4 alkyl 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 as defined above substituted by heteroaryl as defined above.
  • 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 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.
  • 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.
  • basic ion exchange resins
  • 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.
  • the asymmetric center is S configured carbon atom, enriched S configured carbon atom or racemic carbon atom.
  • the asymmetric center is R configured carbon atom, enriched R configured carbon atom or racemic carbon atom.
  • 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 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 PI3K 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 PI3K activity.
  • deuterated drugs called “heavy drugs”
  • enrichment ve its natural abundance is called enrichment.
  • 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) :
  • X is selected from C and N
  • Y is selected from C (O) , CR 9 and N,
  • Z is selected from CR 10 and N,
  • W is selected from C and N,
  • Q is selected from C 3-10 cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 2 together with the atoms to which they are attached form selected from a C 3-10 cycloalkyl, aryl, heteroaryl and heterocyclic ring of 4 to 12 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein cycloalkyl, aryl, heteroaryl and heterocyclic ring are each unsubstituted or substituted with at least one substituent, independently selected from R X2 ;
  • R 3 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, CN, NO 2 , -NR A3 R B3 , -OR A3 and -C (O) R A3 , wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are each unsubstituted or substituted with at least one substituent, independently selected from R X3 ;
  • 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, CN, NO 2 , -NR A4 R B4 , -OR A4 , -C (O) R A4 , wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are each unsubstituted or substituted with at least one substituent, independently selected from R X4 ;
  • R 3 and R 4 together with the atoms to which they are attached form selected from a C 3-10 cycloalkyl, aryl, heteroaryl and heterocyclic ring of 4 to 12 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein cycloalkyl, aryl, heteroaryl and heterocyclic ring 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 selected from a C 3-10 cycloalkyl, aryl, heteroaryl and heterocyclic ring of 4 to 12 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein cycloalkyl, aryl, heteroaryl and heterocyclic ring are each unsubstituted or substituted with at least one substituent, independently selected from R X5 ;
  • 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 A3 and R B3 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 X3 ;
  • each R A4 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, 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 X4 ;
  • 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 A10 and R B10 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 X10 ;
  • each R E1 , R E2 , R E5 , R E6 , R E7 , R E8 , R E9 and R E10 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 X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 , R X8 , R X9 and R X10 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, 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
  • R X2 together with the atoms to which they are attached form selected from selected from a C 3-10 cycloalkyl, aryl, heteroaryl and heterocyclic ring of 4 to 12 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein cycloalkyl, aryl, heteroaryl and heterocyclic are each unsubstituted or substituted with at least one substituent, independently selected from R Y ;
  • 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 is selected from 0, 1, 2, 3 and 4;
  • n is selected from 0, 1, 2, 3 and 4;
  • p is selected from 0, 1, 2, 3 and 4;
  • 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.
  • Embodiment (2) the invention provides a compound of Embodiment (1) or a pharmaceutically acceptable salt thereof, wherein:
  • the invention provides a compound of any one of Embodiment (1) - (2) or a pharmaceutically acceptable salt thereof, wherein W is C, shown as formula (II) ,
  • the invention provides a compound of Embodiment (3) or a pharmaceutically acceptable salt thereof, wherein X is N, Y is C (O) and Z is N.
  • the invention provides a compound of Embodiment (3) or a pharmaceutically acceptable salt thereof, wherein X is N, Y is C (O) and Z is CR 10 .
  • the invention provides a compound of Embodiment (3) or a pharmaceutically acceptable salt thereof, wherein X is C, Y is CR 9 and Z is N.
  • the invention provides a compound of Embodiment (3) or a pharmaceutically acceptable salt thereof, wherein X is C, Y is N and Z is N.
  • the invention provides a compound of any one of Embodiment (1) - (2) or a pharmaceutically acceptable salt thereof, wherein W is N.
  • the invention provides a compound of Embodiment (8) or a pharmaceutically acceptable salt thereof, wherein X is C, Y is C (O) and Z is N.
  • the invention provides a compound of Embodiment (8) or a pharmaceutically acceptable salt thereof, wherein X is C, Y is C (O) and Z is CR 10 .
  • the invention provides a compound of any one of Embodiment (1) - (3) , (5) and (10) , or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, CN, NO 2 , -NR A10 R B10 and -OR A10 , wherein alkyl, alkenyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R X10 .
  • the invention provides a compound of Embodiment (11) or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from hydrogen, F, Cl, Br, CN, NO 2 , NH 2 , 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 X10 .
  • R 10 is hydrogen.
  • the invention provides a compound of any one of Embodiment (1) - (3) and (6) , or a pharmaceutically acceptable salt thereof, wherein R 9 is selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, CN, NO 2 , -NR A9 R B9 and -OR A9 , wherein alkyl, alkenyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R X9 .
  • the invention provides a compound of Embodiment (13) or a pharmaceutically acceptable salt thereof, wherein R 9 is selected from hydrogen, F, Cl, Br, CN, NO 2 , NH 2 , 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 X9 .
  • R 9 is selected from hydrogen, CN and F.
  • R 9 is selected from hydrogen and F.
  • the invention provides a compound of any one of Embodiments (1) - (14) or a pharmaceutically acceptable salt thereof, wherein n is selected from 0, 1, 2 and 3. In another Embodiment, n is selected from 0, 1 and 2.
  • the invention provides a compound of any one of Embodiment (1) - (15) or a pharmaceutically acceptable salt thereof, wherein each R 2 , at each occurrence, is independently selected from hydrogen, deuterium, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, CN, NO 2 , -NR A2 R B2 and -OR A2 , wherein alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R X2 ;
  • R 2 together with the atoms to which they are attached form selected from a C 3-10 cycloalkyl, aryl, heteroaryl and heterocyclic ring of 4 to 8 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein cycloalkyl, aryl, heteroaryl and heterocyclic are each unsubstituted or substituted with at least one substituent, independently selected from R X2 .
  • each R 2 is independently selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, CN, NO 2 , -NR A2 R B2 and -OR A2 , wherein alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R X2 ;
  • R 2 together with the atoms to which they are attached form selected from a C 3-10 cycloalkyl, aryl, heteroaryl and heterocyclic ring of 4 to 8 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein cycloalkyl, aryl, heteroaryl and heterocyclic are each unsubstituted or substituted with at least one substituent, independently selected from R X2 .
  • the invention provides a compound of Embodiment (16) or a pharmaceutically acceptable salt thereof, wherein each R 2 , at each occurrence, is independently selected from hydrogen, deuterium, F, Cl, Br, CN, NO 2 , NH 2 , OH, methyl, ethyl, isopropyl, cyclopropyl and phenyl, wherein methyl, ethyl, isopropyl, cyclopropyl and phenyl are each unsubstituted or substituted with at least one substituent, independently selected from R X2 .
  • each R 2 is independently selected from deuterium, F, CN, methyl and phenyl, wherein methyl and phenyl are each unsubstituted or substituted with at least one substituent, independently selected from R X2 .
  • each R 2 is independently selected from hydrogen, F, Cl, Br, CN, NO 2 , NH 2 , OH, methyl, ethyl, isopropyl, cyclopropyl and phenyl, wherein methyl, ethyl, isopropyl, cyclopropyl and phenyl are each unsubstituted or substituted with at least one substituent, independently selected from R X2 .
  • each R 2 is independently selected from F, CN, methyl and phenyl, wherein methyl and phenyl are each unsubstituted or substituted with at least one substituent, independently selected from R X2 .
  • the invention provides a compound of Embodiment (16) or a pharmaceutically acceptable salt thereof, wherein any two of R 2 together with the atoms to which they are attached form selected from a C 3-8 cycloalkyl, aryl, heteroaryl and heterocyclic ring of 4 to 8 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein cycloalkyl, aryl, heteroaryl and heterocyclic are each unsubstituted or substituted with at least one substituent, independently selected from R X2 .
  • any two of R 2 together with the atoms to which they are attached form selected from a cyclopropyl, cyclobutyl, phenyl, pyridinyl and which are each unsubstituted or substituted with at least one substituent, independently selected from R X2 .
  • the invention provides a compound of any one of Embodiments (16) - (18) or a pharmaceutically acceptable salt thereof, wherein each R X2 , at each occurrence, is independently selected from C 1-10 alkyl, C 3-10 cycloalkyl, heterocyclyl, 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 d1 ) t C (O) OR b1 , - (CR c1 R d1 ) t OC (O) R b1 , - (CR c1 R d1 ) t C (O) NR a1 R b1 , - (CR c1 R d1
  • the invention provides a compound of Embodiment (19) or a pharmaceutically acceptable salt thereof, wherein each R X2 , at each occurrence, is independently selected from F, Cl, Br, CN, NO 2 , NH 2 , 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 Y .
  • each R X2 is independently selected from F, Cl, Br, CN, NO 2 , NH 2 , OH, methyl and ethyl.
  • each R X2 is independently selected from F, Cl, Br and methyl.
  • the invention provides a compound of any one of Embodiments (1) - (18) or a pharmaceutically acceptable salt thereof, wherein any two of R X2 together with the atoms to which they are attached form a C 3-10 cycloalkyl or heterocyclic ring of 4 to 10 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R Y groups.
  • the invention provides a compound of Embodiment (21) or a pharmaceutically acceptable salt thereof, wherein any two of R X2 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 Y groups.
  • any two of R X2 together with the atoms to which they are attached form a 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) - (22) or a pharmaceutically acceptable salt thereof, wherein the moiety in Formula (I) and Formula (II) is selected from wherein the symbol indicates the point of attachment to the rest of the molecule. In another Embodiment, the moiety in Formula (I) and Formula (II) is selected from 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) - (23) or a pharmaceutically acceptable salt thereof, wherein Q is selected from aryl and heteroaryl.
  • the invention provides a compound of Embodiment (24) or a pharmaceutically acceptable salt thereof, wherein Q is selected from phenyl and pyridinyl.
  • Q is selected from phenyl and pyridin-3-yl.
  • the invention provides a compound of any one of Embodiments (1) - (25) or a pharmaceutically acceptable salt thereof, wherein each R 5 , at each occurrence, is independently selected from halogen, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-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 , -NR A5 C (O) R B5 , -OC (O) NR A5 R B5 , -NR A5 C (O) OR B5 , -NR A5 C (O) NR A5 R B5 , -S (O) r R A5 , -S (O) 2 OR A5 , -NR A5 C
  • R 5 together with the atoms to which they are attached form selected from a C 3-8 cycloalkyl and heterocyclic ring of 4 to 10 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein cycloalkyl, aryl, heteroaryl and heterocyclic are each unsubstituted or substituted with at least one substituent, independently selected from R X5 .
  • the invention provides a compound of Embodiment (26) or a pharmaceutically acceptable salt thereof, wherein each R 5 , at each occurrence, is independently selected from halogen, C 1-10 alkyl, C 3-10 cycloalkyl, CN, NO 2 , -NR A5 R B5 , -OR A5 , -C (O) R A5 and -C (O) OR A5 , wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R X5 .
  • the invention provides a compound of Embodiment (27) or a pharmaceutically acceptable salt thereof, wherein each R 5 , at each occurrence, is independently selected from F, Cl, Br, CN, NO 2 , NH 2 , OH, -C (O) OH, methyl, ethyl, isopropyl, methoxy and cyclopropyl, wherein methyl, ethyl, isopropyl, methoxy and cyclopropyl are each unsubstituted or substituted with at least one substituent, independently selected from R X5 .
  • each R 5 is independently selected from methyl, methoxy, OH, NO 2 , F, Cl and -C (O) OH.
  • each R 5 is independently selected from F, Cl, Br, CN, NO 2 , NH 2 , OH, -C (O) 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 .
  • each R 5 is independently selected from F, Cl and -C (O) OH.
  • the invention provides a compound of any one of Embodiments (1) - (28) or a pharmaceutically acceptable salt thereof, wherein the moiety in Formula (I) and Formula (II) is selected from wherein the symbol indicates the point of attachment to the rest of the molecule.
  • the moiety in Formula (I) and Formula (II) is selected from wherein the symbol indicates the point of attachment to the rest of the molecule.
  • the moiety in Formula (I) and Formula (II) is selected from wherein the symbol indicates the point of attachment to the rest of the molecule.
  • the moiety in Formula (I) is selected from 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) - (29) or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, 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 , -C (O) R A1 , -C (O) OR A1 , -OC (O) R A1 , -C (O) NR A1 R B1 , -NR A1 C (O) R B1 , -OC (O) NR A1 R B1 , -NR A1 C (O) OR B1 ,
  • the invention provides a compound of Embodiment (30) or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, heterocyclyl-C 1-4 alkyl, CN, NO 2 , -NR A1 R B1 , -OR A1 and -C (O) R A1 , wherein alkyl, alkenyl, cycloalkyl and heterocyclyl are each unsubstituted or substituted with at least one substituent, independently selected from R X1 .
  • R 1 is selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, heterocyclyl-C 1-4 alkyl, CN, NO 2 , -NR A1 R B1 , -OR A1 and -C (O) R A1 , wherein alkyl, alkenyl, cycloal
  • R 1 is selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, CN, NO 2 , -NR A1 R B1 and -OR A1 , wherein alkyl, alkenyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R X1 .
  • the invention provides a compound of Embodiment (31) or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from hydrogen, F, Cl, Br, CN, NO 2 , NH 2 , OH, methyl, ethyl, isopropyl, cyclopropyl, -C (O) CH 3 and wherein methyl, ethyl, isopropyl, cyclopropyl and are each unsubstituted or substituted with at least one substituent, independently selected from R X1 .
  • R 1 is selected from hydrogen, F, Cl, Br, CN, NO 2 , NH 2 , OH, methyl, ethyl, isopropyl, cyclopropyl, -C (O) CH 3 and wherein methyl, ethyl, isopropyl, cyclopropyl and are each unsubstituted or substituted with at least one substituent, independently selected from R X1 .
  • R 1 is selected from hydrogen, F, Cl, Br, CN, methyl, trifluoromethyl, ethyl, isopropyl, cyclopropyl, -C (O) CH 3 and In another Embodiment, R 1 is selected from hydrogen, F, Cl, Br, CN, methyl, trifluoromethyl, ethyl and cyclopropyl.
  • the invention provides a compound of any one of Embodiments (1) - (32) or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, CN, NO 2 , -NR A6 R B6 and -OR A6 , wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R X6 .
  • the invention provides a compound of Embodiment (33) or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from hydrogen, F, Cl, Br, CN, NO 2 , NH 2 , 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 X6 .
  • R 6 is hydrogen.
  • the invention provides a compound of any one of Embodiments (1) - (34) or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, CN, NO 2 , -NR A7 R B7 and -OR A7 , wherein alkyl, and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R X7 .
  • the invention provides a compound of Embodiment (35) or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from hydrogen, F, Cl, Br, CN, NO 2 , NH 2 , OH, methyl, ethyl, isopropyl, cyclopropyl and methoxy, wherein methyl, ethyl, isopropyl, cyclopropyl and methoxy are each unsubstituted or substituted with at least one substituent, independently selected from R X7 .
  • R 7 is selected from hydrogen, F, Cl, Br, CN, methyl, trifluoromethyl, methoxy, hydroxymethyl and cyclopropy.
  • R 7 is selected from hydrogen, F, Cl, Br, CN, methyl, trifluoromethyl and methoxy.
  • the invention provides a compound of any one of Embodiments (1) - (36) or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, CN, NO 2 , -NR A8 R B8 and -OR A8 , wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R X8 .
  • the invention provides a compound of Embodiment (37) or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from hydrogen, F, Cl, Br, CN, NO 2 , NH 2 , 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 X8 .
  • R 8 is hydrogen.
  • the invention provides a compound of any one of Embodiments (1) - (38) or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, CN, NO 2 , -NR A3 R B3 , -OR A3 and -C (O) R A3 , wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R X3 .
  • the invention provides a compound of Embodiment (39) or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from hydrogen, F, Cl, Br, CN, NO 2 , NH 2 , 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 X3 .
  • R 3 is selected from hydrogen and methyl.
  • the invention provides a compound of any one of Embodiments (1) - (40) or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, CN, NO 2 , -NR A4 R B4 , -OR A4 and -C (O) R A4 , wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R X4 .
  • the invention provides a compound of Embodiment (41) or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from hydrogen, F, Cl, Br, CN, NO 2 , NH 2 , 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 X4 .
  • R 4 is selected from hydrogen and methyl.
  • the invention provides a compound of any one of Embodiments (1) - (38) or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 together with the atoms to which they are attached form selected from a C 3-10 cycloalkyl or heterocyclic ring of 4 to 10 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein cycloalkyl and heterocyclic are each unsubstituted or substituted with at least one substituent, independently selected from R X3 .
  • the invention provides a compound of Embodiment (43) or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 together with the atoms to which they are attached form a cyclopropyl, which are each unsubstituted or substituted with at least one substituent, independently selected from R X3 .
  • R 3 and R 4 together with the atoms to which they are attached form selected from a cyclopropyl.
  • the invention provides a compound selected from
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of any one of Embodiments (1) - (45) 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 PI3K, comprising administering to a subject in need of such treatment an effective amount of a compound of any one of Embodiments (1) - (45) , 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) - (45) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a cell-proliferative disorder.
  • the invention provides a compound of Embodiment (48) or a pharmaceutically acceptable salt thereof, 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
  • 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 PI3K comprising contacting the PI3K with a compound disclosed herein, or a pharmaceutically acceptable salt thereof.
  • a method of inhibiting a PI3K comprising causing a compound disclosed herein, or a pharmaceutically acceptable salt thereof to be present in a subject in order to inhibit the PI3K in vivo.
  • a method of inhibiting PI3K comprising administering a first compound to a subject that is converted in vivo to a second compound wherein the second compound inhibits the PI3K 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 PI3K 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 PI3K 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 PI3K 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 PI3K 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 PI3K.
  • 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 PI3K 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 acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments may be added to the tablets or tablet coatings, for example for identification purposes or to indicate different doses of active ingredient.
  • concentrated sugar solutions which may comprise gum arable, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate.
  • Dyes or pigments may be added to the tablets or tablet coatings,
  • compositions for oral administration may also include hard capsules comprising gelatin or soft-sealed capsules comprising gelatin and a plasticizer, such as glycerol or sorbitol.
  • the hard capsules may contain the active ingredient in the form of granules, for example in admixture with fillers, such as corn starch, binders, and/or glidants, such as talc or magnesium stearate, and optionally stabilizers.
  • the active ingredient may be dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilizers and detergents, for example of the polyoxyethylene sorbitan fatty acid ester type, may also be added.
  • suitable liquid excipients such as fatty oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, to which stabilizers and detergents, for example of the polyoxyethylene sorbitan fatty acid ester type, may also be added.
  • compositions suitable for rectal administration are, for example, suppositories comprising a combination of the active ingredient and a suppository base.
  • Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
  • compositions suitable for parenteral administration may comprise aqueous solutions of an active ingredient in water-soluble form, for example of a water-soluble salt, or aqueous injection suspensions that contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if desired, stabilizers.
  • the active ingredient optionally together with excipients, can also be in the form of a lyophilizate and can be made into a solution before parenteral administration by the addition of suitable solvents. Solutions such as are used, for example, for parenteral administration can also be employed as infusion solutions.
  • the manufacture of injectable preparations is usually carried out under sterile conditions, as is the filling, for example, into ampoules or vials, and the sealing of the containers.
  • the 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 and/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 compounds of formula I can be synthesized from halide II & amine III or amine IV & aryl /heteroaryl halide V, 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 the amine with halide in the presence of a base such as DIPEA or under other coupling conditions known in the literature provide compounds of formula I.
  • a preparation of compound IVa is shown in Scheme 2.
  • heteroaryl halide IVa-A which is either commercially available or known in the literature. Cyclization of IVa-A results in IVa-B.
  • the hydroxy group of IVa-B can be converted into a leaving group by reacting with reagents such as MsCl or POCl 3 to give IVa-C.
  • reagents such as MsCl or POCl 3
  • IVa-C Displacement of leaving group in IVa-C by nucleophilic reagents IVa-D leads to IVa-E.
  • IVa-G is prepared by treating IVa-E with tributyl (1-ethoxyvinyl) stannane followed by hydrolysis in HCl/dioxane solution.
  • reaction flask A a mixture of 2- (3-bromo-5-methylpyridin-2-yl) acetic acid (1b) (55 mg, 0.24 mmol) and CDI (58 mg, 0.36 mmol) in THF (1 mL) was stirred at RT for 1 h.
  • reaction flask B another mixture of A potassium 3-ethoxy-3-oxopropanoate (122 mg, 0.72 mmol) , MgCl 2 (68 mg, 0.72 mmol) and Et 3 N (173 mg, 1.24 mmol) in THF (1 ml) was stirred at RT for 1 h.
  • the mixture of reaction flask A was added to reaction flask B dropwise.
  • Examples 2-416 listed in Table 1 were/can be prepared from the appropriate starting materials which are commercially available or known in the literature.
  • the structures and names of Examples 2-416 are given in Table 1.
  • MTS testing kit was purchased from Promega (Madison, WI, USA) .
  • the RPMI-1640, DMEM, Penicillin-Streptomycin and Trypsin-EDTA (0.25%) were purchased from BI (Biological Industries, Beit Haemek, Israel) .
  • Fetal bovine serum was purchased from GIBCO (Grand Island, NY, USA) .
  • Dimethyl sulfoxide (DMSO) was purchased from Sigma (St. Louis., MO, USA) .
  • T47D (ATCC, Cat. No: HTB-133) cells were cultured in RPMI-1640 supplemented with 10%FBS and MDA-MB-453 (Cobioer, Cat. No: CBP60386) cells were cultured in DMEM supplemented with 10%FBS.
  • T47D PI3K ⁇ H1047R
  • MDA-MB-453 PI3K ⁇ H1047R

Abstract

Provided are certain PI3K inhibitors, pharmaceutical compositions thereof, and methods of use thereof.

Description

COMPOUNDS AS PROTEIN KINASE INHIBITORS
This application claims the priority to the U.S. provisional application No. 63/276,093, 63/288,597, 63/311,458 and 63/332,923, each of which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
Provided are certain compounds or pharmaceutically acceptable salts thereof which can inhibit kinase activity of PI3K and may be useful for the treatment of hyper-proliferative diseases like cancer and inflammation, or immune and autoimmune diseases.
BACKGROUND OF THE INVENTION
Phosphoinositide 3-kinase (PI3K) belongs to a large family of lipid signaling kinase that plays key role in cellular processes, including cell growth, differentiation, migration and apoptosis. PI3K family is divided to three classes, I, II and III, based on sequence homology and lipid substrate specificity. Among them, Class I PI3K, which includes PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ, is mostly studied.
Class I PI3K is a heterodimer formed by two subunits, a catalytic subunit (p110) and a regulatory subunit (p85) . The catalytic subunit, p110, has four isotypes, α, β, γ, and δ. p110α has a role in insulin-dependent signaling, p110β functions in platelet aggregation, thrombosis and insulin signaling, and p110γ and p110δ are expressed mainly in leukocytes and have roles in lymphocyte activation, mast cell degranulation, and chemotaxis. The catalytic p110 subunit associates with p85 regulatory subunit. Upon reception of upstream activation signals, the p85 regulatory subunit releases its inhibition of p110, such that p110 can interact with the lipid membranes to phosphorylate phosphatidylinositol-4, 5-bisphosphate (PIP2) at the 3’-OH position of the inositol ring to generate phosphatidylinositol-3, 4, 5-trisphosphate (PIP3) , which then activates downstream signals, resulting in dysregulation of metabolism and protein synthesis, and cell growth, proliferation and survival.
All four class I catalytic PI3K isoforms show a characteristic expression pattern in vivo. p110α and p110β are expressed ubiquitously in mammalian tissue, while p110γ and p110δappear to be more selectively expressed in leukocyte, endothelial cells, and smooth muscle cells. Deletion of the p110α or p110β induces embryonic lethality. p110γ-deficient mice develop and reproduce normally, although they have suboptimal immune responses because of defects in T-cell activation as well as in neutrophil and macrophage migration. p110δ-deficient mice are also viable and fertile but exhibit significant defects in T, B cell activation.
The PI3K pathway is one of the most commonly activated pathways in human cancers and involves in roughly half of the malignancies (Vanhaesebroeck et al., Nat Rev Drug Discov 20, 741–769 (2021) ; Zhang et al., Chem. Sci., 2020, 11, 5855) . For example, activating (oncogenic) mutations in PI3KCA (gene coding for PI3Kα) is frequently identified in cancers such as endometrial cancers (24-46%) , breast cancers (20-32%) , bladder cancers (20-27%) , cervical cancers (14-23%) , colorectal cancers (13-28%) , and head-and-neck cancers (12-15%) (Arafeh & Samuels, Seminars in Cancer Biology (2019) ) . Most PI3Kα mutations are missense mutations that concentrate on hot spots located on the helical domain and the catalytical domain of p110α, such as E542K, E545K and H1047R (Arafeh & Samuels, 2019; Vanhaesebroeck et al., 2021; Zhang et al., 2020) . The high frequency of PIK3CA mutations in cancers suggest this pathway is a promising therapeutic target.
PI3K is widely involved in important normal physiological functions; for example, PI3Kα is involved in regulation of metabolic processes (activation of anabolic processes and inhibition of catabolic processes leads to cell growth and survival) , cell cytoskeleton function (such as cell migration) , and insulin signaling (such as regulating glucose homeostasis) (Vanhaesebroeck et al., 2021) . Early PI3Kα inhibitors target the ATP pocket of PI3Kα, a region that is highly conserved among PI3K isoforms, resulting in low selectivity among PI3K isoforms caused off-target toxicities; later designs such as inavolisib and BLY-719 utilize specific interactions on PI3Kα, resulting in better  selectivity against other isoforms, but their inhibition against wild-type PI3Kα often exhibit on-target toxicities such as hyperglycemia, hyperinsulinemia and glucose intolerance (Vanhaesebroeck et al., 2021; Arafeh & Samuels, 2019) .
Therefore, a compound having an inhibitory activity on PI3K will be useful for the prevention or treatment of cancer. Although PI3K inhibitors were disclosed in the arts, e.g. WO 2012146666, WO 2003035075 and US 20110015212, many suffer from short half-life or toxicity. Therefore, there is an urgent need for novel PI3K 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. For instance, oncogenic mutations on PI3Kα create binding pockets that can be exploited to create novel PI3Kα inhibitors with improved selectivity over wild-type PI3K isoforms and safety profiles (Zhang et al., 2020; Wang et al., Acta Pharmacol Sin (2018) 39: 1816-182) . In this regard, a novel class of PI3K inhibitors is provided herein.
DISCLOSURE OF THE INVENTION
Disclosed herein are certain novel compounds, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, and their use as pharmaceuticals.
In one aspect, disclosed herein is a compound of formula (I) :
Figure PCTCN2022129918-appb-000001
or a pharmaceutically acceptable salt thereof, wherein:
X is selected from C and N,
Y is selected from C (O) , CR 9 and N,
Z is selected from CR 10 and N,
W is selected from C and N,
wherein:
when X is C and Y is C (O) , W is N;
Q is selected from C 3-10 cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 1 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 A1R B1, -OR A1, -C (O) R A1, -C (=NR E1) R A1, -C (=N-OR B1) R A1, -C (O) OR A1, -OC (O) R A1, -C (O) NR A1R B1, -NR A1C (O) R B1, -C (=NR E1) NR A1R B1, -NR A1C (=NR E1) R B1, -OC (O) NR A1R B1, -NR A1C (O) OR B1, -NR A1C (O) NR A1R B1, -NR A1C (S) NR A1R B1, -NR A1C (=NR E1) NR A1R B1, -S (O)  rR A1, -S (O) (=NR E1) R B1, -N=S (O) R A1R B1, -S (O)  2OR A1, -OS (O)  2R A1, -NR A1S (O)  rR B1, -NR A1S (O) (=NR E1) R B1, -S (O)  rNR A1R B1, -S (O) (=NR E1) NR A1R B1, -NR A1S (O)  2NR A1R B1, -NR A1S (O) (=NR E1) NR A1R B1, -P (O) R A1R B1 and -P (O) (OR A1) (OR B1) , 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 2, at each occurrence, 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 A2R B2, -OR A2, -C (O) R A2, -C (=NR E2) R A2, -C (=N-OR B2) R A2, -C (O) OR A2, -OC (O) R A2, -C (O) NR A2R B2, -NR A2C (O) R B2, -C (=NR E2) NR A2R B2, -NR A2C (=NR E2) R B2, -OC (O) NR A2R B2, -NR A2C (O) OR B2, -NR A2C (O) NR A2R B2, -NR A2C (S) NR A2R B2, -NR A2C (=NR E2) NR A2R B2, -S (O)  rR A2, -S (O) (=NR E2) R B2, -N=S (O) R A2R B2, - S (O)  2OR A2, -OS (O)  2R A2, -NR A2S (O)  rR B2, -NR A2S (O) (=NR E2) R B2, -S (O)  rNR A2R B2, -S (O) (=NR E2) NR A2R B2, -NR A2S (O)  2NR A2R B2, -NR A2S (O) (=NR E2) NR A2R B2, -P (O) R A2R B2 and -P (O) (OR A2) (OR B2) , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R X2;
or any two of R 2 together with the atoms to which they are attached form selected from a C 3-10 cycloalkyl, aryl, heteroaryl and heterocyclic ring of 4 to 12 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein cycloalkyl, aryl, heteroaryl and heterocyclic ring are each unsubstituted or substituted with at least one substituent, independently selected from R X2;
R 3 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, CN, NO 2, -NR A3R B3, -OR A3 and -C (O) R A3, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are each unsubstituted or substituted with at least one substituent, independently selected from R X3;
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, CN, NO 2, -NR A4R B4, -OR A4, -C (O) R A4, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are each unsubstituted or substituted with at least one substituent, independently selected from R X4;
or R 3 and R 4 together with the atoms to which they are attached form selected from a C 3-10 cycloalkyl, aryl, heteroaryl and heterocyclic ring of 4 to 12 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein cycloalkyl, aryl, heteroaryl and heterocyclic ring are each unsubstituted or substituted with at least one substituent, independently selected from R X3;
each R 5, at each occurrence, 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 A5R B5, -OR A5, -C (O) R A5, -C (=NR E5) R A5, -C (=N-OR B5) R A5, -C (O) OR A5, -OC (O) R A5, -C (O) NR A5R B5, -NR A5C (O) R B5, -C (=NR E5) NR A5R B5, -NR A5C (=NR E5) R B5, -OC (O) NR A5R B5, -NR A5C (O) OR B5, -NR A5C (O) NR A5R B5, -NR A5C (S) NR A5R B5, -NR A5C (=NR E5) NR A5R B5, -S (O)  rR A5, -S (O) (=NR E5) R B5, -N=S (O) R A5R B5, -S (O)  2OR A5, -OS (O)  2R A5, -NR A5S (O)  rR B5, -NR A5S (O) (=NR E5) R B5, -S (O)  rNR A5R B5, -S (O) (=NR E5) NR A5R B5, -NR A5S (O)  2NR A5R B5, -NR A5S (O) (=NR E5) NR A5R B5, -P (O) R A5R B5 and -P (O) (OR A5) (OR B5) , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R X5;
or any two of R 5 together with the atoms to which they are attached form selected from a C 3-10 cycloalkyl, aryl, heteroaryl and heterocyclic ring of 4 to 12 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein cycloalkyl, aryl, heteroaryl and heterocyclic ring are each unsubstituted or substituted with at least one substituent, independently selected from R X5;
R 6 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 A6R B6, -OR A6, -C (O) R A6, -C (=NR E6) R A6, -C (=N-OR B6) R A6, -C (O) OR A6, -OC (O) R A6, -C (O) NR A6R B6, -NR A6C (O) R B6, -C (=NR E6) NR A6R B6, -NR A6C (=NR E6) R B6, -OC (O) NR A6R B6, -NR A6C (O) OR B6, -NR A6C (O) NR A6R B6, -NR A6C (S) NR A6R B6, -NR A6C (=NR E6) NR A6R B6, -S (O)  rR A6, -S (O) (=NR E6) R B6, -N=S (O) R A6R B6, -S (O)  2OR A6, -OS (O)  2R A6, -NR A6S (O)  rR B6, -NR A6S (O) (=NR E6) R B6, -S (O)  rNR A6R B6, -S (O) (=NR E6) NR A6R B6, -NR A6S (O)  2NR A6R B6, -NR A6S (O) (=NR E6) NR A6R B6, -P (O) R A6R B6 and -P (O) (OR A6) (OR B6) , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R X6;
R 7 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 A7R B7, -OR A7, -C (O) R A7, -C (=NR E7) R A7, -C (=N-OR B7) R A7, -C (O) OR A7, -OC (O) R A7, -C (O) NR A7R B7, -NR A7C (O) R B7, -C (=NR E7) NR A7R B7, -NR A7C (=NR E7) R B7, - OC (O) NR A7R B7, -NR A7C (O) OR B7, -NR A7C (O) NR A7R B7, -NR A7C (S) NR A7R B7, -NR A7C (=NR E7) NR A7R B7, -S (O)  rR A7, -S (O) (=NR E7) R B7, -N=S (O) R A7R B7, -S (O)  2OR A7, -OS (O)  2R A7, -NR A7S (O)  rR B7, -NR A7S (O) (=NR E7) R B7, -S (O)  rNR A7R B7, -S (O) (=NR E7) NR A7R B7, -NR A7S (O)  2NR A7R B7, -NR A7S (O) (=NR E7) NR A7R B7, -P (O) R A7R B7 and -P (O) (OR A7) (OR B7) , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R X7;
R 8 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 A8R B8, -OR A8, -C (O) R A8, -C (=NR E8) R A8, -C (=N-OR B8) R A8, -C (O) OR A8, -OC (O) R A8, -C (O) NR A8R B8, -NR A8C (O) R B8, -C (=NR E8) NR A8R B8, -NR A8C (=NR E8) R B8, -OC (O) NR A8R B8, -NR A8C (O) OR B8, -NR A8C (O) NR A8R B8, -NR A8C (S) NR A8R B8, -NR A8C (=NR E8) NR A8R B8, -S (O)  rR A8, -S (O) (=NR E8) R B8, -N=S (O) R A8R B8, -S (O)  2OR A8, -OS (O)  2R A8, -NR A8S (O)  rR B8, -NR A8S (O) (=NR E8) R B8, -S (O)  rNR A8R B8, -S (O) (=NR E8) NR A8R B8, -NR A8S (O)  2NR A8R B8, -NR A8S (O) (=NR E8) NR A8R B8, -P (O) R A8R B8 and -P (O) (OR A8) (OR B8) , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R X8;
R 9 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 A9R B9, -OR A9, -C (O) R A9, -C (=NR E9) R A9, -C (=N-OR B9) R A9, -C (O) OR A9, -OC (O) R A9, -C (O) NR A9R B9, -NR A9C (O) R B9, -C (=NR E9) NR A9R B9, -NR A9C (=NR E9) R B9, -OC (O) NR A9R B9, -NR A9C (O) OR B9, -NR A9C (O) NR A9R B9, -NR A9C (S) NR A9R B9, -NR A9C (=NR E9) NR A9R B9, -S (O)  rR A9, -S (O) (=NR E9) R B9, -N=S (O) R A9R B9, -S (O)  2OR A9, -OS (O)  2R A9, -NR A9S (O)  rR B9, -NR A9S (O) (=NR E9) R B9, -S (O)  rNR A9R B9, -S (O) (=NR E9) NR A9R B9, -NR A9S (O)  2NR A9R B9, -NR A9S (O) (=NR E9) NR A9R B9, -P (O) R A9R B9 and -P (O) (OR A9) (OR B9) , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R X9;
R 10 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 A10R B10, -OR A10, -C (O) R A10, -C (=NR E10) R A10, -C (=N-OR B10) R A10, -C (O) OR A10, -OC (O) R A10, -C (O) NR A10R B10, -NR A10C (O) R B10, -C (=NR E10) NR A10R B10, -NR A10C (=NR E10) R B10, -OC (O) NR A10R B10, -NR A10C (O) OR B10, -NR A10C (O) NR A10R B10, -NR A10C (S) NR A10R B10, -NR A10C (=NR E10) NR A10R B10, -S (O)  rR A10, -S (O) (=NR E10) R B10, -N=S (O) R A10R B10, -S (O)  2OR A10, -OS (O)  2R A10, -NR A10S (O)  rR B10, -NR A10S (O) (=NR E10) R B10, -S (O)  rNR A10R B10, -S (O) (=NR E10) NR A10R B10, -NR A10S (O)  2NR A10R B10, -NR A10S (O) (=NR E10) NR A10R B10, -P (O) R A10R B10 and -P (O) (OR A10) (OR B10) , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R X10;
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;
or each “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 X1 groups;
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;
or each “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, 2 or 3 R X2 groups;
each R A3 and R B3 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 X3;
or each “R A3 and R B3” 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 X3 groups;
each R A4 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, 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 X4;
or each “R A4 and R B4” 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 X4 groups;
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;
or each “R A5 and R B5” 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 X5 groups;
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;
or each “R A6 and R B6” 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 X6 groups;
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;
or each “R A7 and R B7” 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 X7 groups;
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;
or each “R A8 and R B8” 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 X8 groups;
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;
or each “R A9 and R B9” 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 X9 groups;
each R A10 and R B10 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 X10;
or each “R A10 and R B10” 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 X10 groups;
each R E1, R E2, R E5, R E6, R E7, R E8, R E9 and R E10 are independently selected from hydrogen, C 1- 10 alkyl, CN, NO 2, -OR a1, -SR a1, -S (O)  rR a1, -C (O) R a1, -C (O) OR a1, -C (O) NR a1R b1 and -S (O)  rNR a1R b1, wherein alkyl is unsubstituted or substituted with at least one substituent, independently selected from R X1;
each R X1, R X2, R X3, R X4, R X5, R X6, R X7, R X8, R X9 and R X10 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, heteroaryl-C 1-4 alkyl, halogen, CN, NO 2, - (CR c1R d1)  tNR a1R b1, - (CR c1R d1)  tOR b1, - (CR c1R d1)  tC (O) R a1, - (CR c1R d1)  tC (=NR e1) R a1, - (CR c1R d1)  tC (=N-OR b1) R a1, - (CR c1R d1)  tC (O) OR b1, - (CR c1R d1)  tOC (O) R b1, - (CR c1R d1)  tC (O) NR a1R b1, - (CR c1R d1)  tNR a1C (O) R b1, - (CR c1R d1)  tC (=NR e1) NR a1R b1, - (CR c1R d1)  tNR a1C (=NR e1) R b1, - (CR c1R d1)  tOC (O) NR a1R b1, - (CR c1R d1)  tNR a1C (O) OR b1, - (CR c1R d1)  tNR a1C (O) NR a1R b1, - (CR c1R d1)  tNR a1C (S) NR a1R b1, - (CR c1R d1)  tNR a1C (=NR e1) NR a1R b1, - (CR c1R d1)  tS (O)  rR b1, - (CR c1R d1)  tS (O) (=NR e1) R b1, - (CR c1R d1)  tN=S (O) R a1R b1, - (CR c1R d1)  tS (O)  2OR b1, - (CR c1R d1)  tOS (O)  2R b1, - (CR c1R d1)  tNR a1S (O)  rR b1, - (CR c1R d1)  tNR a1S (O) (=NR e1) R b1, - (CR c1R d1)  tS (O)  rNR a1R b1, - (CR c1R d1)  tS (O) (=NR e1) NR a1R b1, - (CR c1R d1)  tNR a1S (O)  2NR a1R b1, - (CR c1R d1)  tNR a1S (O) (=NR e1) NR a1R b1, - (CR c1R d1)  tP (O) R a1R b1 and - (CR c1R d1)  tP (O) (OR a1) (OR b1) , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R Y;
or any two of R X2 together with the atoms to which they are attached form selected from selected from a C 3-10 cycloalkyl, aryl, heteroaryl and heterocyclic ring of 4 to 12 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein cycloalkyl, aryl, heteroaryl and heterocyclic are each unsubstituted or substituted with at least one substituent, independently selected from R Y;
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;
or 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;
or 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)  rR a2, -C (O) R a2, -C (O) OR a2, -S (O)  rNR a2R b2 and -C (O) NR a2R 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 c2R d2)  tNR a2R b2, - (CR c2R d2)  tOR b2, - (CR c2R d2)  tC (O) R a2, - (CR c2R d2)  tC (=NR e2) R a2, - (CR c2R d2)  tC (=N-OR b2) R a2, - (CR c2R d2)  tC (O) OR b2, - (CR c2R d2)  tOC (O) R b2, - (CR c2R d2)  tC (O) NR a2R b2, - (CR c2R d2)  tNR a2C (O) R b2, - (CR c2R d2)  tC (=NR e2) NR a2R b2, - (CR c2R d2)  tNR a2C (=NR e2) R b2, - (CR c2R d2)  tOC (O) NR a2R b2, - (CR c2R d2)  tNR a2C (O) OR b2, - (CR c2R d2)  tNR a2C (O) NR a2R b2, - (CR c2R d2)  tNR a2C (S) NR a2R b2, - (CR c2R d2)  tNR a2C (=NR e2) NR a2R b2, - (CR c2R d2)  tS (O)  rR b2, - (CR c2R d2)  tS (O) (=NR e2) R b2, - (CR c2R d2)  tN=S (O) R a2R b2, - (CR c2R d2)  tS (O)  2OR b2, - (CR c2R d2)  tOS (O)  2R b2, - (CR c2R d2)  tNR a2S (O)  rR b2, - (CR c2R d2)  tNR a2S (O) (=NR e2) R b2, - (CR c2R d2)  tS (O)  rNR a2R b2, - (CR c2R d2)  tS (O) (=NR e2) NR a2R b2, - (CR c2R d2)  tNR a2S (O)  2NR a2R b2, - (CR c2R d2)  tNR a2S (O) (=NR e2) NR a2R b2, - (CR c2R d2)  tP (O) R a2R b2 and - (CR c2R d2)  tP (O) (OR a2) (OR b2) , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from OH, CN, amino, halogen, C 1- 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, C 1-10 alkylamino, C 3-10 cycloalkylamino and di (C 1-10 alkyl) amino;
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, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, 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;
or 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, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, 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;
or 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)  2C 1- 4 alkyl, -S (O)  2C 3-10 cycloalkyl, -S (O)  2N (C 1-4 alkyl)  2 and -S (O)  2N (C 3-10 cycloalkyl)  2;
m is selected from 0, 1, 2, 3 and 4;
n is selected from 0, 1, 2, 3 and 4;
p is selected from 0, 1, 2, 3 and 4;
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.
In yet another aspect, the present disclosure provides pharmaceutical compositions comprising a compound of formula (I) or at least one pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
In yet another aspect, the disclosure provides methods for modulating PI3K, comprising administering to a system or a subject in need thereof, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or pharmaceutical compositions thereof, thereby modulating said PI3K.
In yet another aspect, disclosed is a method to treat, ameliorate or prevent a condition which responds to inhibition of PI3K comprising administering to a system or subject in need of such treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or pharmaceutical compositions thereof, and optionally in combination with a second therapeutic agent, thereby treating said condition.
Alternatively, the present disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a condition mediated by PI3K. 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 PI3K.
Alternatively, disclosed is a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating a condition mediated by PI3K, especially a condition mediated by PI3KαH1047R mutations.
Specifically, the condition herein includes but not limited to, an autoimmune disease, a heteroimmune disease, an infectious disease or a cell proliferative disorder.
Furthermore, the disclosure provides methods for treating a cell proliferative disorder, comprising administering to a system or subject in need of such treatment an effective amount of a compound 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.
Specifically, the condition herein includes but not limited to, is an autoimmune disease, a heteroimmune disease, an allergic disease, an inflammatory disease or a cell proliferative disorder.
In certain embodiments, the cell-proliferative disorder is selected from breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, testicular cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma) , esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer (including RCC) , liver cancer (including 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.
In certain embodiments, the condition is cell proliferative disorder. In one embodiment, the cell proliferative disorder is B-cell proliferative disorder, which includes but not limited to, B-cell malignancies, B-cell chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, multiple sclerosis, small lymphocytic lymphoma, mantle cell lymphoma, B-cell non-Hodgkin’s lymphoma, activated B-cell like diffuse large B-cell lymphoma, multiple myeloma, diffuse large B-cell lymphoma, follicular lymphoma, primary effusion lymphoma, burkitt lymphoma/leukemia, lymphomatoid granulomatosis, and plasmacytoma.
In certain embodiments, the condition is autoimmune disease, which includes but not limited to, rheumatoid arthritis, psoriatic arthritis, psoriasis, osteoarthritis, juvenile arthritis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, myasthenia gravis, Hashimoto's thyroiditis, multiple sclerosis, acute disseminated encephalomyelitis, Addison’s disease, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, coeliac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, scleroderma, primary biliary cirrhosis, Reiter's syndrome, psoriasis, dysautonomia, neuromyotonia, interstitial cystitis, lupus, systemic lupus erythematosus, and lupus nephritis.
In certain embodiments, the condition is heteroimmune disease, which includes but not limited to, graft versus host disease, transplantation, transfusion, anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.
In certain embodiments, the condition is inflammatory disease, which includes but not limited to, athma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritic, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, endonitis, tonsillitis, uveitis, vaginitis, vasculitis, and vulvitis.
In the above methods for using the compounds of the disclosure, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered to a system comprising cells or tissues, or to a subject including a mammalian subject such as a human or animal subject.
Certain Terminology
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. All patents, patent applications, published materials referred to throughout the entire disclosure herein, unless noted otherwise, are incorporated by reference in their entirety. In the event that there is a plurality of definitions for terms herein, those in this section prevail.
It is to be understood that the foregoing general description and the following detailed description are 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.
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, CH 2O is equivalent to OCH 2.
The term “substituted” means that a hydrogen atom is replaced by a substituent. It is to be understood that substitution at a given atom is limited by valency. If a bond to a substituent is shown to cross the bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound, then such substituent may be bonded via any atom in such substituent. Generally, when any substituent or group occurs more than one time in any constituent or compound, its definition on each occurrence is independent of its definition at every other occurrence. Such combinations of substituents and/or variables, however, are permissible only if such combinations result in stable compounds.
The
Figure PCTCN2022129918-appb-000002
symbol indicates the point of attachment to the rest of the molecule.
It is to be understood that 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.
The term “optional” or “optionally” means the event described subsequent thereto may or may not happen. This term encompasses the cases that the event may or may not happen.
The term “C i-j” or “i-j membered” used herein means that the moiety has i-j carbon atoms or i-j atoms. For example, “C 1-6 alkyl” means said alkyl has 1-6 carbon atoms. Likewise, C 3-10 cycloalkyl means said cycloalkyl has 3-10 carbon atoms.
The term “hydrogen” refers to  1H,  2H and  3H.
It is to be understood that when there are two or more R n or R Xn (n being 1, 2, 3, 4, 5, 6, 7, etc. ) , each R n or each R Xn is selected independently.
When any variable (e.g. R) occurs at the structure of a compound over one time, it is defined independently at each case. Therefore, for example, if a group is substituted by 0-2 R, the group may be optionally substituted by at most two R and R has independent option at each case. Additionally, a combination of substituents and/or the variants thereof are allowed only if such a combination will result in a stable compound.
The expression “one or more” or “at least one” refers to one, two, three, four, five, six, seven, eight, nine or more.
Unless stated otherwise, the term “hetero” means heteroatom or heteroatom radical (i.e. a radical containing heteroatom) , i.e. the atoms beyond carbon and hydrogen atoms or the radical containing such atoms. Preferably, the heteroatom (s) is independently selected from the group consisting of O, N, S, P and the like. In an embodiment wherein two or more heteroatoms are involved, the two or more heteroatoms may be the same, or part or all of the two or more heteroatoms may be different.
The term “alkyl” , employed alone or in combination with other terms, refers to branched or 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. For example, “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.
The term “cycloalkyl” , employed alone or in combination with other terms, refers to a saturated monocyclic or multicyclic (e.g. bicyclic or tricyclic) hydrocarbon ring system, usually with 3 to 16 ring atoms. The ring atoms of cycloalkyl are all carbon and the cycloalkyl contains zero heteroatoms and zero double bonds. In a multicyclic cycloalkyl, two or more rings can be fused or bridged or spiro together. Examples of monocyclic ring systems include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The bridged cycloalkyl is a polycyclic ring system containing 3-10 carbon atoms, which contains one or two  alkylene bridges, each alkylene bridge consisting of one, two, or three carbon atoms, each linking two non-adjacent carbon atoms of the ring system. Cycloalkyl can be fused with aryl or heteroaryl group. In some embodiments, cycloalkyl is benzocondensed. Representative examples of such 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.
The term “alkenyl” , employed alone or in combination with other terms, refers to a non-aromatic hydrocarbon radical, straight, branched or cyclic, containing 2-10 carbon atoms and at least one carbon to carbon double bond. In some embodiments, the cyclic refers to monocyclic or multicyclic. In a multicyclic alkenyl, two or more rings can be fused or bridged or spiro together. 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, “C 2-6 alkenyl” means an alkenyl radical having 2-6 carbon atoms. Alkenyl groups include but are not limited to ethenyl, propenyl, butenyl, 2-methylbutenyl, cyclopentenyl 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 “cycloalkenyl” refers to a non-aromatic hydrocarbon ring system having 3 to 30 carbons (e.g., C 3-C 10) and one or more double bonds. Examples include cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl etc.
The term “alkynyl” , employed alone or in combination with other terms, refers to a hydrocarbon radical, straight, branched or cyclic, containing 2-10 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, “C 2-6 alkynyl” means an alkynyl radical having 2-6 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 as defined above, which 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 “C 1-10 alkoxy” refers to an alkoxy radical containing 1-10 carbon atoms, having straight or branched moieties. Alkoxy group includes but is not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, and the like.
The term “cycloalkoxy” , employed alone or in combination with other terms, refers to cycloalkyl as defined above, which 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 3-10 carbon atoms. Cycloalkoxy can be fused with aryl or heteroaryl group. In some embodiments, cycloalkoxy is benzocondensed. Cycloalkoxy group includes but is not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
The term “alkylthio” , employed alone or in combination with other terms, refers to an alkyl radical as defined above, which 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 “C 1-10 alkylthio” refers to an alkylthio radical containing 1-10 carbon atoms, having straight or branched moieties. Alkylthio group 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 as defined above, which 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 3-10  carbon atoms. Cycloalkylthio can be fused with aryl or heteroaryl group. In some embodiments, cycloalkylthio is benzocondensed. Cycloalkylthio group 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 as defined above, which 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 “C 1-10 alkylamino” refers to an alkylamino radical containing 1-10 carbon atoms, having straight or branched moieties. Alkylamino group 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 as defined above, which 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 3-10 carbon atoms. Cycloalkylamino can be fused with aryl or heteroaryl group. In some embodiments, cycloalkylamino is benzocondensed. Cycloalkylamino group 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 as defined above, which 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 (C 1-10 alkyl) amino” refers to a di (C 1-10 alkyl) amino radical wherein the alkyl radicals each independently contains 1-10 carbon atoms, having straight or branched moieties.
The term “aryl” , employed alone or in combination with other terms, refers to a monovalent, monocyclic-, bicyclic-or tricyclic aromatic hydrocarbon ring system having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms (a “C 6-14 aryl” group) , particularly a ring having 6 carbon atoms (a“C 6 aryl” group) , e.g. a phenyl group; or a ring having 10 carbon atoms (a “C 10 aryl” group) , e.g. a naphthyl group; or a ring having 14 carbon atoms, (a “C 14 aryl” group) , e.g. an anthranyl group. Aryl can be fused with cycloalkyl or heterocycle group.
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.
The term “heteroaryl” , employed alone or in combination with other terms, refers to a monovalent, monocyclic-, bicyclic-or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms (a “5-to 14-membered heteroaryl” group) , particularly 5 or 6 or 9 or 10 atoms, and which contains at least one heteroatom which may be identical or different, said heteroatom selected from N, O and S. Heteroaryl can be fused with cycloalkyl or heterocycle group. In some embodiments, “heteroaryl” refers to
a 5-to 8-membered monocyclic aromatic ring 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; or
a 8-to 12-membered bicyclic aromatic ring system containing one or more, for example, 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; or
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.
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, 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.
Further 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.
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.
The term “heterocycle” , employed alone or in combination with other terms, (and variations thereof such as “heterocyclic” , or “heterocyclyl” ) broadly refers to a saturated or unsaturated mono-or multicyclic (e.g. bicyclic or tricyclic) aliphatic ring system, usually with 3 to 16 ring atoms, wherein at least one (e.g. 2, 3 or 4) ring atom is heteroatom independently selected from O, S, N and P (preferably O, S, N) . In a multicyclic heterocycle, two or more rings can be fused or bridged or spiro together. Heterocycle can be fused with aryl or heteroaryl group. In some embodiments, heterocycle is benzocondensed. Heterocycle also includes ring systems substituted with one or more oxo or imino moieties. In some embodiments, the C, N, S and P atoms in the heterocycle ring are optionally substituted by oxo. In some embodiments, the C, S and P atoms in the heterocycle ring are optionally substituted by imino, and imino can be unsubstituted or substituted. The point of the attachment may be carbon atom 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 result.
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 tetrahydropyridyl. Morpholinyl groups are also contemplated, such as morpholin-1-yl, morpholin-2-yl, morpholin-3-yl and morpholin-4-yl. Examples of heterocycle with one or more oxo moieties include but are not limited to, piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-thiomorpholinyl and 1, 1-dioxo-thiomorpholinyl. Bicyclic heterocycles include, for example:
Figure PCTCN2022129918-appb-000003
Figure PCTCN2022129918-appb-000004
As used herein, “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. When used in the phrase “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.
As used herein, “heterocyclyl-alkyl” refers to alkyl as defined above substituted by heterocyclyl as defined above. When used in the phrase “heterocyclyl-C 1-4 alkyl” , the term “C 1-4” refers to the alkyl portion of the moiety and does not describe the number of atoms in the heterocyclyl portion of the moiety.
As used herein, “cycloalkyl-alkyl” refers to alkyl as defined above substituted by cycloalkyl as defined above. When used in the phrase “C 3-10 cycloalkyl-C l-4 alkyl” , 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, and the term “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.
As used herein, “heteroaryl-alkyl” refers to alkyl as defined above substituted by heteroaryl as defined above. When used in the phrase “heteroaryl-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 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 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.
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 crystalline forms, or polymorphs, and may also be in the form of solvates, such as 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 -CH 2CH 2SO 2Ph, 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-1, 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. When the carbon marked with * is asymmetric center. In an embodiment, the asymmetric center is S configured carbon atom, enriched S configured carbon atom or racemic carbon atom. In an embodiment, the asymmetric center is R configured carbon atom, enriched R configured carbon atom or racemic carbon atom.
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, oxygen, 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 D 2SO 4/D 2O.
The isotope-labeled compounds of the invention may be used as standards to determine the effectiveness of PI3K 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 Compounds. Radiopharmaceuticals, 36 (10) , 927-932 (1995) ; Kushner et al., Can. J. Physiol. Pharmacology, 77, 79-88 (1999) .
In addition, non-radioactive isotope containing drugs, such as deuterated drugs called "heavy drugs" can be used for the treatment of diseases and conditions related to PI3K activity. Increasing the amount of an isotope present in a compound abo
ve 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.
In an Embodiment (1) , this invention provides to a compound of formula (I) :
Figure PCTCN2022129918-appb-000005
or a pharmaceutically acceptable salt thereof, wherein:
X is selected from C and N,
Y is selected from C (O) , CR 9 and N,
Z is selected from CR 10 and N,
W is selected from C and N,
wherein:
when X is C and Y is C (O) , W is N;
Q is selected from C 3-10 cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 1 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 A1R B1, -OR A1, -C (O) R A1, -C (=NR E1) R A1, -C (=N-OR B1) R A1, -C (O) OR A1, -OC (O) R A1, -C (O) NR A1R B1, -NR A1C (O) R B1, -C (=NR E1) NR A1R B1, -NR A1C (=NR E1) R B1, -OC (O) NR A1R B1, -NR A1C (O) OR B1, -NR A1C (O) NR A1R B1, -NR A1C (S) NR A1R B1, -NR A1C (=NR E1) NR A1R B1, -S (O)  rR A1, -S (O) (=NR E1) R B1, -N=S (O) R A1R B1, -S (O)  2OR A1, -OS (O)  2R A1, -NR A1S (O)  rR B1, -NR A1S (O) (=NR E1) R B1, -S (O)  rNR A1R B1, -S (O) (=NR E1) NR A1R B1, -NR A1S (O)  2NR A1R B1, -NR A1S (O) (=NR E1) NR A1R B1, -P (O) R A1R B1 and -P (O) (OR A1) (OR B1) , 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 2, at each occurrence, 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 A2R B2, -OR A2, -C (O) R A2, -C (=NR E2) R A2, -C (=N-OR B2) R A2, -C (O) OR A2, -OC (O) R A2, -C (O) NR A2R B2, -NR A2C (O) R B2, -C (=NR E2) NR A2R B2, -NR A2C (=NR E2) R B2, -OC (O) NR A2R B2, -NR A2C (O) OR B2, -NR A2C (O) NR A2R B2, - NR A2C (S) NR A2R B2, -NR A2C (=NR E2) NR A2R B2, -S (O)  rR A2, -S (O) (=NR E2) R B2, -N=S (O) R A2R B2, -S (O)  2OR A2, -OS (O)  2R A2, -NR A2S (O)  rR B2, -NR A2S (O) (=NR E2) R B2, -S (O)  rNR A2R B2, -S (O) (=NR E2) NR A2R B2, -NR A2S (O)  2NR A2R B2, -NR A2S (O) (=NR E2) NR A2R B2, -P (O) R A2R B2 and -P (O) (OR A2) (OR B2) , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R X2;
or any two of R 2 together with the atoms to which they are attached form selected from a C 3-10 cycloalkyl, aryl, heteroaryl and heterocyclic ring of 4 to 12 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein cycloalkyl, aryl, heteroaryl and heterocyclic ring are each unsubstituted or substituted with at least one substituent, independently selected from R X2;
R 3 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, CN, NO 2, -NR A3R B3, -OR A3 and -C (O) R A3, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are each unsubstituted or substituted with at least one substituent, independently selected from R X3;
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, CN, NO 2, -NR A4R B4, -OR A4, -C (O) R A4, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are each unsubstituted or substituted with at least one substituent, independently selected from R X4;
or R 3 and R 4 together with the atoms to which they are attached form selected from a C 3-10 cycloalkyl, aryl, heteroaryl and heterocyclic ring of 4 to 12 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein cycloalkyl, aryl, heteroaryl and heterocyclic ring are each unsubstituted or substituted with at least one substituent, independently selected from R X3;
each R 5, at each occurrence, 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 A5R B5, -OR A5, -C (O) R A5, -C (=NR E5) R A5, -C (=N-OR B5) R A5, -C (O) OR A5, -OC (O) R A5, -C (O) NR A5R B5, -NR A5C (O) R B5, -C (=NR E5) NR A5R B5, -NR A5C (=NR E5) R B5, -OC (O) NR A5R B5, -NR A5C (O) OR B5, -NR A5C (O) NR A5R B5, -NR A5C (S) NR A5R B5, -NR A5C (=NR E5) NR A5R B5, -S (O)  rR A5, -S (O) (=NR E5) R B5, -N=S (O) R A5R B5, -S (O)  2OR A5, -OS (O)  2R A5, -NR A5S (O)  rR B5, -NR A5S (O) (=NR E5) R B5, -S (O)  rNR A5R B5, -S (O) (=NR E5) NR A5R B5, -NR A5S (O)  2NR A5R B5, -NR A5S (O) (=NR E5) NR A5R B5, -P (O) R A5R B5 and -P (O) (OR A5) (OR B5) , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R X5;
or any two of R 5 together with the atoms to which they are attached form selected from a C 3-10 cycloalkyl, aryl, heteroaryl and heterocyclic ring of 4 to 12 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein cycloalkyl, aryl, heteroaryl and heterocyclic ring are each unsubstituted or substituted with at least one substituent, independently selected from R X5;
R 6 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 A6R B6, -OR A6, -C (O) R A6, -C (=NR E6) R A6, -C (=N-OR B6) R A6, -C (O) OR A6, -OC (O) R A6, -C (O) NR A6R B6, -NR A6C (O) R B6, -C (=NR E6) NR A6R B6, -NR A6C (=NR E6) R B6, -OC (O) NR A6R B6, -NR A6C (O) OR B6, -NR A6C (O) NR A6R B6, -NR A6C (S) NR A6R B6, -NR A6C (=NR E6) NR A6R B6, -S (O)  rR A6, -S (O) (=NR E6) R B6, -N=S (O) R A6R B6, -S (O)  2OR A6, -OS (O)  2R A6, -NR A6S (O)  rR B6, -NR A6S (O) (=NR E6) R B6, -S (O)  rNR A6R B6, -S (O) (=NR E6) NR A6R B6, -NR A6S (O)  2NR A6R B6, -NR A6S (O) (=NR E6) NR A6R B6, -P (O) R A6R B6 and -P (O) (OR A6) (OR B6) , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R X6;
R 7 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 A7R B7, -OR A7, -C (O) R A7, -C (=NR E7) R A7, -C (=N-OR B7) R A7, - C (O) OR A7, -OC (O) R A7, -C (O) NR A7R B7, -NR A7C (O) R B7, -C (=NR E7) NR A7R B7, -NR A7C (=NR E7) R B7, -OC (O) NR A7R B7, -NR A7C (O) OR B7, -NR A7C (O) NR A7R B7, -NR A7C (S) NR A7R B7, -NR A7C (=NR E7) NR A7R B7, -S (O)  rR A7, -S (O) (=NR E7) R B7, -N=S (O) R A7R B7, -S (O)  2OR A7, -OS (O)  2R A7, -NR A7S (O)  rR B7, -NR A7S (O) (=NR E7) R B7, -S (O)  rNR A7R B7, -S (O) (=NR E7) NR A7R B7, -NR A7S (O)  2NR A7R B7, -NR A7S (O) (=NR E7) NR A7R B7, -P (O) R A7R B7 and -P (O) (OR A7) (OR B7) , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R X7;
R 8 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 A8R B8, -OR A8, -C (O) R A8, -C (=NR E8) R A8, -C (=N-OR B8) R A8, -C (O) OR A8, -OC (O) R A8, -C (O) NR A8R B8, -NR A8C (O) R B8, -C (=NR E8) NR A8R B8, -NR A8C (=NR E8) R B8, -OC (O) NR A8R B8, -NR A8C (O) OR B8, -NR A8C (O) NR A8R B8, -NR A8C (S) NR A8R B8, -NR A8C (=NR E8) NR A8R B8, -S (O)  rR A8, -S (O) (=NR E8) R B8, -N=S (O) R A8R B8, -S (O)  2OR A8, -OS (O)  2R A8, -NR A8S (O)  rR B8, -NR A8S (O) (=NR E8) R B8, -S (O)  rNR A8R B8, -S (O) (=NR E8) NR A8R B8, -NR A8S (O)  2NR A8R B8, -NR A8S (O) (=NR E8) NR A8R B8, -P (O) R A8R B8 and -P (O) (OR A8) (OR B8) , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R X8;
R 9 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 A9R B9, -OR A9, -C (O) R A9, -C (=NR E9) R A9, -C (=N-OR B9) R A9, -C (O) OR A9, -OC (O) R A9, -C (O) NR A9R B9, -NR A9C (O) R B9, -C (=NR E9) NR A9R B9, -NR A9C (=NR E9) R B9, -OC (O) NR A9R B9, -NR A9C (O) OR B9, -NR A9C (O) NR A9R B9, -NR A9C (S) NR A9R B9, -NR A9C (=NR E9) NR A9R B9, -S (O)  rR A9, -S (O) (=NR E9) R B9, -N=S (O) R A9R B9, -S (O)  2OR A9, -OS (O)  2R A9, -NR A9S (O)  rR B9, -NR A9S (O) (=NR E9) R B9, -S (O)  rNR A9R B9, -S (O) (=NR E9) NR A9R B9, -NR A9S (O)  2NR A9R B9, -NR A9S (O) (=NR E9) NR A9R B9, -P (O) R A9R B9 and -P (O) (OR A9) (OR B9) , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R X9;
R 10 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 A10R B10, -OR A10, -C (O) R A10, -C (=NR E10) R A10, -C (=N-OR B10) R A10, -C (O) OR A10, -OC (O) R A10, -C (O) NR A10R B10, -NR A10C (O) R B10, -C (=NR E10) NR A10R B10, -NR A10C (=NR E10) R B10, -OC (O) NR A10R B10, -NR A10C (O) OR B10, -NR A10C (O) NR A10R B10, -NR A10C (S) NR A10R B10, -NR A10C (=NR E10) NR A10R B10, -S (O)  rR A10, -S (O) (=NR E10) R B10, -N=S (O) R A10R B10, -S (O)  2OR A10, -OS (O)  2R A10, -NR A10S (O)  rR B10, -NR A10S (O) (=NR E10) R B10, -S (O)  rNR A10R B10, -S (O) (=NR E10) NR A10R B10, -NR A10S (O)  2NR A10R B10, -NR A10S (O) (=NR E10) NR A10R B10, -P (O) R A10R B10 and -P (O) (OR A10) (OR B10) , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R X10;
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;
or each “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 X1 groups;
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;
or each “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, 2 or 3 R X2 groups;
each R A3 and R B3 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 X3;
or each “R A3 and R B3” 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 X3 groups;
each R A4 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, 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 X4;
or each “R A4 and R B4” 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 X4 groups;
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;
or each “R A5 and R B5” 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 X5 groups;
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;
or each “R A6 and R B6” 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 X6 groups;
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;
or each “R A7 and R B7” 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 X7 groups;
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;
or each “R A8 and R B8” 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 X8 groups;
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;
or each “R A9 and R B9” 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 X9 groups;
each R A10 and R B10 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 X10;
or each “R A10 and R B10” 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 X10 groups;
each R E1, R E2, R E5, R E6, R E7, R E8, R E9 and R E10 are independently selected from hydrogen, C 1- 10 alkyl, CN, NO 2, -OR a1, -SR a1, -S (O)  rR a1, -C (O) R a1, -C (O) OR a1, -C (O) NR a1R b1 and -S (O)  rNR a1R b1, wherein alkyl is unsubstituted or substituted with at least one substituent, independently selected from R X1;
each R X1, R X2, R X3, R X4, R X5, R X6, R X7, R X8, R X9 and R X10 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, heteroaryl-C 1-4 alkyl, halogen, CN, NO 2, - (CR c1R d1)  tNR a1R b1, - (CR c1R d1)  tOR b1, - (CR c1R d1)  tC (O) R a1, - (CR c1R d1)  tC (=NR e1) R a1, - (CR c1R d1)  tC (=N-OR b1) R a1, - (CR c1R d1)  tC (O) OR b1, - (CR c1R d1)  tOC (O) R b1, - (CR c1R d1)  tC (O) NR a1R b1, - (CR c1R d1)  tNR a1C (O) R b1, - (CR c1R d1)  tC (=NR e1) NR a1R b1, - (CR c1R d1)  tNR a1C (=NR e1) R b1, - (CR c1R d1)  tOC (O) NR a1R b1, - (CR c1R d1)  tNR a1C (O) OR b1, - (CR c1R d1)  tNR a1C (O) NR a1R b1, - (CR c1R d1)  tNR a1C (S) NR a1R b1, - (CR c1R d1)  tNR a1C (=NR e1) NR a1R b1, - (CR c1R d1)  tS (O)  rR b1, - (CR c1R d1)  tS (O) (=NR e1) R b1, - (CR c1R d1)  tN=S (O) R a1R b1, - (CR c1R d1)  tS (O)  2OR b1, - (CR c1R d1)  tOS (O)  2R b1, - (CR c1R d1)  tNR a1S (O)  rR b1, - (CR c1R d1)  tNR a1S (O) (=NR e1) R b1, - (CR c1R d1)  tS (O)  rNR a1R b1, - (CR c1R d1)  tS (O) (=NR e1) NR a1R b1, - (CR c1R d1)  tNR a1S (O)  2NR a1R b1, - (CR c1R d1)  tNR a1S (O) (=NR e1) NR a1R b1, - (CR c1R d1)  tP (O) R a1R b1 and - (CR c1R d1)  tP (O) (OR a1) (OR b1) , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R Y;
or any two of R X2 together with the atoms to which they are attached form selected from selected from a C 3-10 cycloalkyl, aryl, heteroaryl and heterocyclic ring of 4 to 12 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein cycloalkyl, aryl, heteroaryl and heterocyclic are each unsubstituted or substituted with at least one substituent, independently selected from R Y;
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;
or 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;
or 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)  rR a2, -C (O) R a2, -C (O) OR a2, -S (O)  rNR a2R b2 and -C (O) NR a2R 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 c2R d2)  tNR a2R b2, - (CR c2R d2)  tOR b2, - (CR c2R d2)  tC (O) R a2, - (CR c2R d2)  tC (=NR e2) R a2, - (CR c2R d2)  tC (=N-OR b2) R a2, - (CR c2R d2)  tC (O) OR b2, - (CR c2R d2)  tOC (O) R b2, - (CR c2R d2)  tC (O) NR a2R b2, - (CR c2R d2)  tNR a2C (O) R b2, - (CR c2R d2)  tC (=NR e2) NR a2R b2, - (CR c2R d2)  tNR a2C (=NR e2) R b2, - (CR c2R d2)  tOC (O) NR a2R b2, - (CR c2R d2)  tNR a2C (O) OR b2, - (CR c2R d2)  tNR a2C (O) NR a2R b2, - (CR c2R d2)  tNR a2C (S) NR a2R b2, - (CR c2R d2)  tNR a2C (=NR e2) NR a2R b2, - (CR c2R d2)  tS (O)  rR b2, - (CR c2R d2)  tS (O) (=NR e2) R b2, - (CR c2R d2)  tN=S (O) R a2R b2, - (CR c2R d2)  tS (O)  2OR b2, - (CR c2R d2)  tOS (O)  2R b2, - (CR c2R d2)  tNR a2S (O)  rR b2, - (CR c2R d2)  tNR a2S (O) (=NR e2) R b2, - (CR c2R d2)  tS (O)  rNR a2R b2, - (CR c2R d2)  tS (O) (=NR e2) NR a2R b2, - (CR c2R d2)  tNR a2S (O)  2NR a2R b2, - (CR c2R d2)  tNR a2S (O) (=NR e2) NR a2R b2, - (CR c2R d2)  tP (O) R a2R b2 and - (CR c2R d2)  tP (O) (OR a2) (OR b2) , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from OH, CN, amino, halogen, C 1- 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, C 1-10 alkylamino, C 3-10 cycloalkylamino and di (C 1-10 alkyl) amino;
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, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, 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;
or 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, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, 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;
or 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)  2C 1- 4 alkyl, -S (O)  2C 3-10 cycloalkyl, -S (O)  2N (C 1-4 alkyl)  2 and -S (O)  2N (C 3-10 cycloalkyl)  2;
m is selected from 0, 1, 2, 3 and 4;
n is selected from 0, 1, 2, 3 and 4;
p is selected from 0, 1, 2, 3 and 4;
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.
In another Embodiment (2) , the invention provides a compound of Embodiment (1) or a pharmaceutically acceptable salt thereof, wherein:
when X is C and Y is CR 9 or N, Z is N;
when X is N and Y is C (O) , Z is CR 10 or N.
In another Embodiment (3) , the invention provides a compound of any one of Embodiment (1) - (2) or a pharmaceutically acceptable salt thereof, wherein W is C, shown as formula (II) ,
Figure PCTCN2022129918-appb-000006
or a pharmaceutically acceptable salt thereof, wherein X, Y, Z, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, m, n and p are as defined in formula (I) .
In another Embodiment (4) , the invention provides a compound of Embodiment (3) or a pharmaceutically acceptable salt thereof, wherein X is N, Y is C (O) and Z is N.
In another Embodiment (5) , the invention provides a compound of Embodiment (3) or a pharmaceutically acceptable salt thereof, wherein X is N, Y is C (O) and Z is CR 10.
In another Embodiment (6) , the invention provides a compound of Embodiment (3) or a pharmaceutically acceptable salt thereof, wherein X is C, Y is CR 9 and Z is N.
In another Embodiment (7) , the invention provides a compound of Embodiment (3) or a pharmaceutically acceptable salt thereof, wherein X is C, Y is N and Z is N.
In another Embodiment (8) , the invention provides a compound of any one of Embodiment (1) - (2) or a pharmaceutically acceptable salt thereof, wherein W is N.
In another Embodiment (9) , the invention provides a compound of Embodiment (8) or a pharmaceutically acceptable salt thereof, wherein X is C, Y is C (O) and Z is N.
In another Embodiment (10) , the invention provides a compound of Embodiment (8) or a pharmaceutically acceptable salt thereof, wherein X is C, Y is C (O) and Z is CR 10.
In another Embodiment (11) , the invention provides a compound of any one of Embodiment (1) - (3) , (5) and (10) , or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, CN, NO 2, -NR A10R B10 and -OR A10, wherein alkyl, alkenyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R X10.
In another Embodiment (12) , the invention provides a compound of Embodiment (11) or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from hydrogen, F, Cl, Br, CN, NO 2, NH 2, 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 X10. In another Embodiment, R 10 is hydrogen.
In another Embodiment (13) , the invention provides a compound of any one of Embodiment (1) - (3) and (6) , or a pharmaceutically acceptable salt thereof, wherein R 9 is selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, CN, NO 2, -NR A9R B9 and -OR A9, wherein alkyl, alkenyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R X9.
In another Embodiment (14) , the invention provides a compound of Embodiment (13) or a pharmaceutically acceptable salt thereof, wherein R 9 is selected from hydrogen, F, Cl, Br, CN, NO 2, NH 2, 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 X9. In another Embodiment, R 9 is selected from hydrogen, CN and F. In another Embodiment, R 9 is selected from hydrogen and F.
In another Embodiment (15) , the invention provides a compound of any one of Embodiments (1) - (14) or a pharmaceutically acceptable salt thereof, wherein n is selected from 0, 1, 2 and 3. In another Embodiment, n is selected from 0, 1 and 2.
In another Embodiment (16) , the invention provides a compound of any one of Embodiment (1) - (15) or a pharmaceutically acceptable salt thereof, wherein each R 2, at each occurrence, is independently selected from hydrogen, deuterium, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, CN, NO 2, -NR A2R B2 and -OR A2, wherein alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R X2;
or any two of R 2 together with the atoms to which they are attached form selected from a C 3-10 cycloalkyl, aryl, heteroaryl and heterocyclic ring of 4 to 8 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein cycloalkyl, aryl, heteroaryl and heterocyclic are each unsubstituted or substituted with at least one substituent, independently selected from R X2. In another Embodiment, each R 2, at each occurrence, is independently selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, CN, NO 2, -NR A2R B2 and -OR A2, wherein alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R X2;
or any two of R 2 together with the atoms to which they are attached form selected from a C 3-10 cycloalkyl, aryl, heteroaryl and heterocyclic ring of 4 to 8 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein cycloalkyl, aryl, heteroaryl and heterocyclic are each unsubstituted or substituted with at least one substituent, independently selected from R X2.
In another Embodiment (17) , the invention provides a compound of Embodiment (16) or a pharmaceutically acceptable salt thereof, wherein each R 2, at each occurrence, is independently selected from hydrogen, deuterium, F, Cl, Br, CN, NO 2, NH 2, OH, methyl, ethyl, isopropyl, cyclopropyl and phenyl, wherein methyl, ethyl, isopropyl, cyclopropyl and phenyl are each unsubstituted or substituted with at least one substituent, independently selected from R X2. In another Embodiment, each R 2 is independently selected from deuterium, F, CN, methyl and phenyl, wherein methyl and phenyl are each unsubstituted or substituted with at least one substituent, independently selected from R X2. In another Embodiment, each R 2, at each occurrence, is independently selected from hydrogen, F, Cl, Br, CN, NO 2, NH 2, OH, methyl, ethyl, isopropyl, cyclopropyl and phenyl, wherein methyl, ethyl, isopropyl, cyclopropyl and phenyl are each unsubstituted or substituted with at least one substituent, independently selected from R X2. In another Embodiment, each R 2 is independently selected from F, CN, methyl and phenyl, wherein methyl and phenyl are each unsubstituted or substituted with at least one substituent, independently selected from R X2.
In another Embodiment (18) , the invention provides a compound of Embodiment (16) or a pharmaceutically acceptable salt thereof, wherein any two of R 2 together with the atoms to which they are attached form selected from a C 3-8 cycloalkyl, aryl, heteroaryl and heterocyclic ring of 4 to 8 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein cycloalkyl, aryl, heteroaryl and heterocyclic are each unsubstituted or  substituted with at least one substituent, independently selected from R X2. In another Embodiment, wherein any two of R 2 together with the atoms to which they are attached form selected from a cyclopropyl, cyclobutyl, phenyl, pyridinyl and
Figure PCTCN2022129918-appb-000007
which are each unsubstituted or substituted with at least one substituent, independently selected from R X2.
In another Embodiment (19) , the invention provides a compound of any one of Embodiments (16) - (18) or a pharmaceutically acceptable salt thereof, wherein each R X2, at each occurrence, is independently selected from C 1-10 alkyl, C 3-10 cycloalkyl, heterocyclyl, halogen, CN, NO 2, - (CR c1R d1)  tNR a1R b1, - (CR c1R d1)  tOR b1, - (CR c1R d1)  tC (O) R a1, - (CR c1R d1)  tC (O) OR b1, - (CR c1R d1)  tOC (O) R b1, - (CR c1R d1)  tC (O) NR a1R b1, - (CR c1R d1)  tNR a1C (O) R b1, - (CR c1R d1)  tS (O)  rR b1, - (CR c1R d1)  tS (O)  2OR b1 and - (CR c1R d1)  tNR a1S (O)  rR b1, wherein alkyl, cycloalkyl and heterocyclyl are each unsubstituted or substituted with at least one substituent, independently selected from R Y.
In another Embodiment (20) , the invention provides a compound of Embodiment (19) or a pharmaceutically acceptable salt thereof, wherein each R X2, at each occurrence, is independently selected from F, Cl, Br, CN, NO 2, NH 2, 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 Y. In another Embodiment, wherein each R X2, at each occurrence, is independently selected from F, Cl, Br, CN, NO 2, NH 2, OH, methyl and ethyl. In another Embodiment, each R X2, at each occurrence, is independently selected from F, Cl, Br and methyl.
In another Embodiment (21) , the invention provides a compound of any one of Embodiments (1) - (18) or a pharmaceutically acceptable salt thereof, wherein any two of R X2 together with the atoms to which they are attached form a C 3-10 cycloalkyl or heterocyclic ring of 4 to 10 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R Y groups.
In another Embodiment (22) , the invention provides a compound of Embodiment (21) or a pharmaceutically acceptable salt thereof, wherein any two of R X2 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 Y groups. In another Embodiment, wherein any two of R X2 together with the atoms to which they are attached form a
Figure PCTCN2022129918-appb-000008
wherein the
Figure PCTCN2022129918-appb-000009
symbol indicates the point of attachment to the rest of the molecule.
In another Embodiment (23) , the invention provides a compound of any one of Embodiments (1) - (22) or a pharmaceutically acceptable salt thereof, wherein the moiety
Figure PCTCN2022129918-appb-000010
in Formula (I) and Formula (II) is selected from
Figure PCTCN2022129918-appb-000011
Figure PCTCN2022129918-appb-000012
Figure PCTCN2022129918-appb-000013
wherein the
Figure PCTCN2022129918-appb-000014
symbol indicates the point of attachment to the rest of the molecule. In  another Embodiment, the moiety
Figure PCTCN2022129918-appb-000015
in Formula (I) and Formula (II) is selected from 
Figure PCTCN2022129918-appb-000016
Figure PCTCN2022129918-appb-000017
wherein the
Figure PCTCN2022129918-appb-000018
symbol indicates the point of attachment to the rest of the molecule.
In another Embodiment (24) , the invention provides a compound of any one of Embodiments (1) - (23) or a pharmaceutically acceptable salt thereof, wherein Q is selected from aryl and heteroaryl.
In another Embodiment (25) , the invention provides a compound of Embodiment (24) or a pharmaceutically acceptable salt thereof, wherein Q is selected from phenyl and pyridinyl. In another Embodiment, Q is selected from phenyl and pyridin-3-yl.
In another Embodiment (26) , the invention provides a compound of any one of Embodiments (1) - (25) or a pharmaceutically acceptable salt thereof, wherein each R 5, at each occurrence, is independently selected from halogen, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, CN, NO 2, -NR A5R B5, -OR A5, -C (O) R A5, -C (O) OR A5, -OC (O) R A5, -C (O) NR A5R B5, -NR A5C (O) R B5, -OC (O) NR A5R B5, -NR A5C (O) OR B5, -NR A5C (O) NR A5R B5, -S (O)  rR A5, -S (O)  2OR A5, -OS (O)  2R A5, -NR A5S (O)  rR B5 and -S (O)  rNR A5R B5, wherein alkyl, alkenyl and cycloalkyl, are each unsubstituted or substituted with at least one substituent, independently selected from R X5;
or any two of R 5 together with the atoms to which they are attached form selected from a C 3-8 cycloalkyl and heterocyclic ring of 4 to 10 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein cycloalkyl, aryl, heteroaryl and heterocyclic are each unsubstituted or substituted with at least one substituent, independently selected from R X5.
In another Embodiment (27) , the invention provides a compound of Embodiment (26) or a pharmaceutically acceptable salt thereof, wherein each R 5, at each occurrence, is independently selected from halogen, C 1-10 alkyl, C 3-10 cycloalkyl, CN, NO 2, -NR A5R B5, -OR A5, -C (O) R A5 and -C (O) OR A5, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R X5.
In another Embodiment (28) , the invention provides a compound of Embodiment (27) or a pharmaceutically acceptable salt thereof, wherein each R 5, at each occurrence, is independently selected from F, Cl, Br, CN, NO 2, NH 2, OH, -C (O) OH, methyl, ethyl, isopropyl, methoxy and cyclopropyl, wherein methyl, ethyl, isopropyl, methoxy and cyclopropyl are each unsubstituted or substituted with at least one substituent, independently selected from R X5. In another Embodiment, wherein each R 5, at each occurrence, is independently selected from methyl, methoxy, OH, NO 2, F, Cl and -C (O) OH. In another Embodiment, each R 5, at each occurrence, is independently selected from F, Cl, Br, CN, NO 2, NH 2, OH, -C (O) 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. In another Embodiment, wherein each R 5, at each occurrence, is independently selected from F, Cl and -C (O) OH.
In another Embodiment (29) , the invention provides a compound of any one of Embodiments (1) - (28) or a pharmaceutically acceptable salt thereof, wherein the moiety 
Figure PCTCN2022129918-appb-000019
in Formula (I) and Formula (II) is selected from
Figure PCTCN2022129918-appb-000020
Figure PCTCN2022129918-appb-000021
Figure PCTCN2022129918-appb-000022
wherein the
Figure PCTCN2022129918-appb-000023
symbol indicates the point of attachment to the rest of the molecule. In another Embodiment, wherein the moiety
Figure PCTCN2022129918-appb-000024
in Formula (I) and Formula (II) is selected from
Figure PCTCN2022129918-appb-000025
Figure PCTCN2022129918-appb-000026
wherein the
Figure PCTCN2022129918-appb-000027
symbol indicates the point of attachment to the rest of the molecule. In another Embodiment, the moiety
Figure PCTCN2022129918-appb-000028
in Formula (I) and Formula (II) is selected from
Figure PCTCN2022129918-appb-000029
wherein the
Figure PCTCN2022129918-appb-000030
symbol indicates the point of attachment to the rest of the molecule. In another Embodiment, wherein the moiety
Figure PCTCN2022129918-appb-000031
in Formula (I) is selected from
Figure PCTCN2022129918-appb-000032
wherein the 
Figure PCTCN2022129918-appb-000033
symbol indicates the point of attachment to the rest of the molecule.
In another Embodiment (30) , the invention provides a compound of any one of Embodiments (1) - (29) or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, 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 A1R B1, -OR A1, -C (O) R A1, -C (O) OR A1, -OC (O) R A1, -C (O) NR A1R B1, -NR A1C (O) R B1, -OC (O) NR A1R B1, -NR A1C (O) OR B1, -NR A1C (O) NR A1R B1, -NR A1C (S) NR A1R B1, -S (O)  rR A1, -S (O)  2OR A1, -OS (O)  2R A1, -NR A1S (O)  rR B1, -S (O)  rNR A1R B1 and -NR A1S (O)  2NR A1R B1, wherein alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R X1.
In another Embodiment (31) , the invention provides a compound of Embodiment (30) or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, heterocyclyl-C 1-4 alkyl, CN, NO 2, -NR A1R B1, -OR A1 and -C (O) R A1, wherein alkyl, alkenyl, cycloalkyl and heterocyclyl are each unsubstituted or substituted with at least one substituent, independently selected from R X1. In another Embodiment, R 1 is selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, CN, NO 2, -NR A1R B1 and -OR A1, wherein alkyl, alkenyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R X1.
In another Embodiment (32) , the invention provides a compound of Embodiment (31) or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from hydrogen, F, Cl, Br, CN, NO 2, NH 2, OH, methyl, ethyl, isopropyl, cyclopropyl, -C (O) CH 3 and
Figure PCTCN2022129918-appb-000034
wherein methyl, ethyl,  isopropyl, cyclopropyl and
Figure PCTCN2022129918-appb-000035
are each unsubstituted or substituted with at least one substituent, independently selected from R X1. In another Embodiment, R 1 is selected from hydrogen, F, Cl, Br, CN, methyl, trifluoromethyl, ethyl, isopropyl, cyclopropyl, -C (O) CH 3 and
Figure PCTCN2022129918-appb-000036
In another Embodiment, R 1 is selected from hydrogen, F, Cl, Br, CN, methyl, trifluoromethyl, ethyl and cyclopropyl.
In another Embodiment (33) , the invention provides a compound of any one of Embodiments (1) - (32) or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, CN, NO 2, -NR A6R B6 and -OR A6, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R X6.
In another Embodiment (34) , the invention provides a compound of Embodiment (33) or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from hydrogen, F, Cl, Br, CN, NO 2, NH 2, 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 X6. In another Embodiment, R 6 is hydrogen.
In another Embodiment (35) , the invention provides a compound of any one of Embodiments (1) - (34) or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, CN, NO 2, -NR A7R B7 and -OR A7, wherein alkyl, and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R X7.
In another Embodiment (36) , the invention provides a compound of Embodiment (35) or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from hydrogen, F, Cl, Br, CN, NO 2, NH 2, OH, methyl, ethyl, isopropyl, cyclopropyl and methoxy, wherein methyl, ethyl, isopropyl, cyclopropyl and methoxy are each unsubstituted or substituted with at least one substituent, independently selected from R X7. In another Embodiment, R 7 is selected from hydrogen, F, Cl, Br, CN, methyl, trifluoromethyl, methoxy, hydroxymethyl and cyclopropy. In another Embodiment, R 7 is selected from hydrogen, F, Cl, Br, CN, methyl, trifluoromethyl and methoxy.
In another Embodiment (37) , the invention provides a compound of any one of Embodiments (1) - (36) or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, CN, NO 2, -NR A8R B8 and -OR A8, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R X8.
In another Embodiment (38) , the invention provides a compound of Embodiment (37) or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from hydrogen, F, Cl, Br, CN, NO 2, NH 2, 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 X8. In another Embodiment, R 8 is hydrogen.
In another Embodiment (39) , the invention provides a compound of any one of Embodiments (1) - (38) or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, CN, NO 2, -NR A3R B3, -OR A3 and -C (O) R A3, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R X3.
In another Embodiment (40) , the invention provides a compound of Embodiment (39) or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from hydrogen, F, Cl, Br, CN, NO 2, NH 2, 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 X3. In another Embodiment, wherein R 3 is selected from hydrogen and methyl.
In another Embodiment (41) , the invention provides a compound of any one of Embodiments (1) - (40) or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, CN, NO 2, -NR A4R B4, -OR A4 and -C (O) R A4, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R X4.
In another Embodiment (42) , the invention provides a compound of Embodiment (41) or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from hydrogen, F, Cl, Br, CN, NO 2, NH 2, 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 X4. In another Embodiment, wherein R 4 is selected from hydrogen and methyl.
In another Embodiment (43) , the invention provides a compound of any one of Embodiments (1) - (38) or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 together with the atoms to which they are attached form selected from a C 3-10 cycloalkyl or heterocyclic ring of 4 to 10 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein cycloalkyl and heterocyclic are each unsubstituted or substituted with at least one substituent, independently selected from R X3.
In another Embodiment (44) , the invention provides a compound of Embodiment (43) or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 together with the atoms to which they are attached form a cyclopropyl, which are each unsubstituted or substituted with at least one substituent, independently selected from R X3. In another Embodiment, wherein R 3 and R 4 together with the atoms to which they are attached form selected from a cyclopropyl.
In another Embodiment (45) , the invention provides a compound selected from
Figure PCTCN2022129918-appb-000037
Figure PCTCN2022129918-appb-000038
Figure PCTCN2022129918-appb-000039
Figure PCTCN2022129918-appb-000040
Figure PCTCN2022129918-appb-000041
Figure PCTCN2022129918-appb-000042
Figure PCTCN2022129918-appb-000043
Figure PCTCN2022129918-appb-000044
Figure PCTCN2022129918-appb-000045
Figure PCTCN2022129918-appb-000046
and pharmaceutically acceptable salts thereof.
In another Embodiment (46) , the invention provides a pharmaceutical composition comprising a compound of any one of Embodiments (1) - (45) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.
In another Embodiment (47) , the invention provides a method of treating, ameliorating or preventing a condition, which responds to inhibition of PI3K, comprising administering to a subject in need of such treatment an effective amount of a compound of any one of Embodiments (1) - (45) , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent.
In another Embodiment (48) , the invention provides a use of a compound of any one of Embodiments (1) - (45) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a cell-proliferative disorder.
In another Embodiment (49) , the invention provides a compound of Embodiment (48) or a pharmaceutically acceptable salt thereof, 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.
In yet another of its aspects, there is provided a kit 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. 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 salt 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 salt thereof.
In another of its aspects, there is provided a method of inhibiting a PI3K comprising contacting the PI3K with a compound disclosed herein, or a pharmaceutically acceptable salt thereof.
In yet another of its aspects, there is provided a method of inhibiting a PI3K comprising causing a compound disclosed herein, or a pharmaceutically acceptable salt thereof to be present in a subject in order to inhibit the PI3K in vivo.
In a further of its aspects, there is provided a method of inhibiting PI3K comprising administering a first compound to a subject that is converted in vivo to a second compound wherein the second compound inhibits the PI3K 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 PI3K 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 salt 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 PI3K 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 PI3K 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, eczema, 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 PI3K 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 PI3K.
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 PI3K 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 monooleate) .
Suspensions in oil may comprise as the oil component the vegetable, synthetic, or semi-synthetic 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.
Other suitable fatty acid esters include but are not limited ethyl-oleate, isopropyl myristate, isopropyl palmitate, 
Figure PCTCN2022129918-appb-000047
M 2375, (polyoxyethylene glycerol) , 
Figure PCTCN2022129918-appb-000048
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 
Figure PCTCN2022129918-appb-000049
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 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.
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 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.
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.
EXAMPLES
Various methods may be developed for synthesizing a compound of formula (I) or a pharmaceutically acceptable salt thereof. Representative methods for synthesizing a compound of formula (I) or a pharmaceutically acceptable salt thereof are provided in the Examples. It is noted, however, that a compound of formula (I) or a pharmaceutically acceptable salt thereof may also be synthesized by other synthetic routes that others may devise.
It will be readily recognized that certain compounds of formula (I) have atoms with linkages to other atoms that confer a particular stereochemistry to the compound (e.g., chiral centers) . It is recognized that synthesis of a compound of formula (I) or a pharmaceutically acceptable salt thereof may result in the creation of mixtures of different stereoisomers (enantiomers, diastereomers) . Unless a particular stereochemistry is specified, recitation of a compound is intended to encompass all of the different possible stereoisomers.
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. Alternatively, 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. Alternatively, the salt forms of the compounds of formula (I) can be prepared using salts of the starting materials or intermediates.
The free acid or free base forms of the compounds of formula (I) can be prepared from the corresponding base addition salt or acid addition salt form. For example, a compound of formula (I) in an acid addition salt form can be converted to the corresponding free base thereof by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like) . A compound of formula (I) in a base addition salt form can be converted to the corresponding free acid thereof by, for example, treating with a suitable acid (e.g., hydrochloric acid, etc) .
The N-oxides of a compound of formula (I) or a pharmaceutically acceptable salt thereof can be prepared by methods known to those of ordinary skill in the art. For example, N-oxides can be prepared by treating an unoxidized form of the compound of formula (I) with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at approximately 0 to 80℃. Alternatively, the N-oxides of the compounds of formula (I) can be prepared from the N-oxide of an appropriate starting material.
Compounds of formula (I) in an unoxidized form can be prepared from N-oxides of compounds of formula (I) by, for example, treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, and the like) in an suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, and the like) at 0 to 80℃.
Protected derivatives of the compounds of formula (I) can be made by methods known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protecting groups and their removal can be found in T.W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.
As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Standard single-letter or three-letter abbreviations are generally used to designate amino acid residues, which are  assumed to be in the L-configuration unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. For example, the following abbreviations may be used in the examples and throughout the specification: g (grams) ; mg (milligrams) ; L (liters) ; mL (milliliters) ; μL (microliters) ; psi (pounds per square inch) ; M (molar) ; mM (millimolar) ; i. v. (intravenous) ; Hz (Hertz) ; MHz (megahertz) ; mol (moles) ; mmol (millimoles) ; RT (room temperature) ; min (minutes) ; h (hours) ; mp (melting point) ; TLC (thin layer chromatography) ; Rt (retention time) ; RP (reverse phase) ; MeOH (methanol) ; i-PrOH (isopropanol) ; TEA (triethylamine) ; TFA (trifluoroacetic acid) ; TFAA (trifluoroacetic anhydride) ; THF (tetrahydrofuran) ; DMSO (dimethyl sulfoxide) ; EtOAc (ethyl acetate) ; DME (1, 2-dimethoxyethane) ; DCM (dichloromethane) ; DCE (dichloroethane) ; DMF (N, N-dimethylformamide) ; DMPU (N, N'-dimethylpropyleneurea) ; CDI (1, 1-carbonyldiimidazole) ; IBCF (isobutyl chloroformate) ; HOAc (acetic acid) ; HOSu (N-hydroxysuccinimide) ; HOBT (1-hydroxybenzotriazole) ; Et 2O (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 chromatography) ; BOP (bis (2-oxo-3-oxazolidinyl) phosphinic chloride) ; TBAF (tetra-n-butylammonium fluoride) ; m-CPBA (meta-chloroperbenzoic acid) .
For example, the following abbreviations in table 1 may be used in the examples and throughout the specification.
References to ether or Et 2O 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 quadrupole 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 and/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 shown in Scheme 1, the compounds of formula I can be synthesized from halide II & amine III or amine IV & aryl /heteroaryl halide V, 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 the amine with halide in the presence of a base such as DIPEA or under other coupling conditions known in the literature provide compounds of formula I.
Figure PCTCN2022129918-appb-000050
Scheme 1
As an illustration of the preparation of intermediates of formula IV, a preparation of compound IVa is shown in Scheme 2. Starting from heteroaryl halide IVa-A, which is either commercially available or known in the literature. Cyclization of IVa-A results in IVa-B. The hydroxy group of IVa-B can be converted into a leaving group by reacting with reagents such as MsCl or POCl 3 to give IVa-C. Displacement of leaving group in IVa-C by nucleophilic reagents IVa-D leads to IVa-E. IVa-G is prepared by treating IVa-E with tributyl (1-ethoxyvinyl) stannane followed by hydrolysis in HCl/dioxane solution. Condensation of IVa-G with Ellman reagent (R) or (S) -tert-butansulfinamide provides immine IVa-H. Reduction of IVa-H with a reducing reagent such as NaBH 4 gives IVa-I which can be converted to intermediate IVa by treatment with aqueous HCl.
Figure PCTCN2022129918-appb-000051
Scheme 2
As a further illustration of the synthesis of compounds of formula IV, one synthetic approach of intermediate IVb is outlined in Scheme 3. Starting from the compounds of formula IVb-A, which is either commercially available or known in the literature. Coupling of carboxylic acid IVb-A with amine via a condensation reaction leads to compounds of formula IVb-B. Cyclization of IVb-B with reagents such as triphosgene provides IVb-C. Intermediates of formula IVb can be prepared from IVb-C following similar manipulations described in the preparation of IVa.
Figure PCTCN2022129918-appb-000052
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.
Example 1
2- ( (1- (2- (4, 4-dimethylpiperidin-1-yl) -7-methyl-4-oxo-4H-quinolizin-9- yl) ethyl) amino) benzoic acid (1)
Figure PCTCN2022129918-appb-000053
diethyl 2- (3-bromo-5-methylpyridin-2-yl) malonate (1a)
The title compound diethyl 2- (3-bromo-5-methylpyridin-2-yl) malonate (1a) was prepared according to the method described in Bioorganic & Medicinal Chemistry, 2020, 28 (11) , 115524. MS-ESI (m/z) : 330 [M + 1]  +
2- (3-bromo-5-methylpyridin-2-yl) acetic acid (1b)
A mixture diethyl 2- (3-bromo-5-methylpyridin-2-yl) malonate (1a) (10 g, 30.4 mmol) in hydrochloric acid (6 M, 300 mL) was stirred at 100℃ for 5 hours. When cooled to below 10℃ the mixture was added NaOH solution (50 wt%) slowly to neutralize to pH = 5 ～ 6. The mixture was extracted with EtOAc (300 mL × 5) , the combined organic layer was washed with brine, dried over Na 2SO 4, and concentrated. The residue was suspended in saturated NaHCO 3 solution (50 mL) and stirred at RT for 15 minutes. Filtered and washed with water, the filtrate was adjusted to pH = 5 with citric acid solution (10 wt%) , extracted with DCM (300 mL × 5) , the combined organic layers were washed with brine, dried over Na 2SO 4, and concentrated to give the title compound 2- (3-bromo-5-methylpyridin-2-yl) acetic acid (1b) . MS-ESI (m/z) : 230, 232 [M + 1]  +.
ethyl 4- (3-bromo-5-methylpyridin-2-yl) -3-oxobutanoate (1c)
In a reaction flask A, a mixture of 2- (3-bromo-5-methylpyridin-2-yl) acetic acid (1b) (55 mg, 0.24 mmol) and CDI (58 mg, 0.36 mmol) in THF (1 mL) was stirred at RT for 1 h. In a reaction flask B, another mixture of A potassium 3-ethoxy-3-oxopropanoate (122 mg, 0.72 mmol) , MgCl 2 (68 mg, 0.72 mmol) and Et 3N (173 mg, 1.24 mmol) in THF (1 ml) was stirred at RT for 1 h. The mixture of reaction flask A was added to reaction flask B dropwise. The resulting mixture was stirred at 70℃ for 5 h. The mixture was quenched with H 2O, and extracted with EtOAc. The combined organic phase was washed with Citric acid solution (5 wt%) and brine, dried over Na 2SO 4. and concentrated to give the title compound ethyl 4- (3-bromo-5-methylpyridin-2-yl) -3-oxobutanoate (1c) . MS-ESI (m/z) : 300, 302 [M + 1]  +.
9-bromo-2-hydroxy-7-methyl-4H-quinolizin-4-one (1d)
A mixture of ethyl 4- (3-bromo-5-methylpyridin-2-yl) -3-oxobutanoate (1c) (2.3 g, 7.7 mmol) in polyphosphoric acid (20 g) was stirred at 100℃ for 1 h. The mixture was cooled to RT and poured into water. The mixture was extracted with DCM, the organic layer was washed with brine, dried over Na 2SO 4, and concentrated. The residue was purified by column chromatography on silica gel eluting with PE/EtOAc to give the title compound 9-bromo-2-hydroxy-7-methyl-4H-quinolizin-4-one (1d) . MS-ESI (m/z) : 254, 256 [M + 1]  +.
9-bromo-7-methyl-4-oxo-4H-quinolizin-2-yl trifluoromethanesulfonate (1e)
To a solution of 9-bromo-2-hydroxy-7-methyl-4H-quinolizin-4-one (1d) (500 mg, 1.97 mmol) in DCM (20 mL) was added Et 3N (0.8 mL, 5.74 mmol) and Tf 2O (0.6 mL, 3.57 mmol) at 0-5℃, the mixture was stirred at 0-5℃ for 5-10 min. The reaction was quenched by ice water and extracted by DCM, the DCM phase was washed with brine, dried over Na 2SO 4, and evaporated. The residue was used directly for next step. MS-ESI (m/z) : 386, 388 [M + 1]  +.
9-bromo-2- (4, 4-dimethylpiperidin-1-yl) -7-methyl-4H-quinolizin-4-one (1f)
A mixture of 9-bromo-7-methyl-4-oxo-4H-quinolizin-2-yl trifluoromethanesulfonate (1e) (382 mg, 0.984 mmol) , 4, 4-dimethylpiperidine hydrochloride (368 mg, 2.46 mmol) and Et 3N (0.68 mL, 4.92 mmol) in MeCN (5 mL) was stirred at 85℃ for 2 h. The mixture was cooled to RT and poured into water. The mixture was extracted with EtOAc, the organic layer was washed with brine, dried over Na 2SO 4, and concentrated. The residue was purified by column chromatography on silica gel eluting with PE/EtOAc (4: 1 ～ 1: 1) to give the title compound 9-bromo-2- (4, 4-dimethylpiperidin-1-yl) -7-methyl-4H-quinolizin-4-one (1f) . MS-ESI (m/z) : 349, 351 [M + 1]  +.
9-acetyl-2- (4, 4-dimethylpiperidin-1-yl) -7-methyl-4H-quinolizin-4-one (1g)
A mixture of 9-bromo-2- (4, 4-dimethylpiperidin-1-yl) -7-methyl-4H-quinolizin-4-one (1f) (20 mg, 0.057 mmol) , Pd (PPh 3)  2Cl 2 (10 mg, 11.46 mmol) and tributyl (1-ethoxyvinyl) stannane (42 mg, 0.12 mmol) in dioxane (1.3 mL) was stirred at 100℃ under N 2 atmosphere for 16 h. HCl (0.1 mL, 2 M) was added into the mixture and stirred at 50℃ for 0.5 h. The mixture was added sat. KF (1 mL) and stirred at RT for 0.5 h. The gray suspension was filtered. The filter cake was washed with EtOAc. The aqueous phase was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na 2SO 4, and concentrated. The residue was purified by column chromatography on silica gel eluting with PE/EtOAc to give the title compound 9-acetyl-2- (4, 4-dimethylpiperidin-1-yl) -7-methyl-4H-quinolizin-4-one (1g) . MS-ESI (m/z) : 313 [M + 1]  +.
2- (4, 4-dimethylpiperidin-1-yl) -9- (1-hydroxyethyl) -7-methyl-4H-quinolizin-4-one  (1h)
To a solution of 9-acetyl-2- (4, 4-dimethylpiperidin-1-yl) -7-methyl-4H-quinolizin-4-one (1g) (30 mg, 0.10 mmol) in DCM (1 mL) and MeOH (1 mL) was added NaBH 4 (7.3 mg, 0.20 mmol) in portions at 0℃, then stirred at RT for 0.5 h. The mixture was quenched with water and extracted with EtOAc. The combined extract was washed with brine, dried over Na 2SO 4, and concentrated. The residue was purified by column chromatography on silica gel eluting with PE/EtOAc to give the title compound 2- (4, 4-dimethylpiperidin-1-yl) -9- (1-hydroxyethyl) -7-methyl-4H-quinolizin-4-one (1h) . MS-ESI (m/z) : 315 [M + 1]  +.
2- ( (1- (2- (4, 4-dimethylpiperidin-1-yl) -7-methyl-4-oxo-4H-quinolizin-9- yl) ethyl) amino) benzoic acid (1)
To a solution of 2- (4, 4-dimethylpiperidin-1-yl) -9- (1-hydroxyethyl) -7-methyl-4H-quinolizin-4-one (1h) (24 mg, 0.076 mmol) in DCM (3 mL) was added a solution of PBr 3 (31 mg, 0.11 mmol) in DCM (0.2 mL) at 0-5℃, then stirred at 0-5℃ for 10-20 min. Then a solution of 2-aminobenzoic acid (32 mg, 0.23 mmol) in DMF (2 mL) was added, followed by DIPEA (0.1 mL, 1.04 mmol) and stirred at 80℃ for 3 h. When cooled to RT, the mixture was quenched with cold water and extracted with EtOAc, dried over Na 2SO 4, concentrated and purified by PTLC EtOAc/PE (2: 1) to give the title compound 2- ( (1- (2- (4, 4-dimethylpiperidin-1-yl) -7-methyl-4-oxo-4H-quinolizin-9-yl) ethyl) amino) benzoic acid (1) . MS-ESI (m/z) : 434 [M + 1]  +.
Following essentially the same procedures described for Examples 1, Examples 2-416 listed in Table 1 were/can be prepared from the appropriate starting materials which are commercially available or known in the literature. The structures and names of Examples 2-416 are given in Table 1.
Table 1
Figure PCTCN2022129918-appb-000054
Figure PCTCN2022129918-appb-000055
Figure PCTCN2022129918-appb-000056
Figure PCTCN2022129918-appb-000057
Figure PCTCN2022129918-appb-000058
Figure PCTCN2022129918-appb-000059
Figure PCTCN2022129918-appb-000060
Figure PCTCN2022129918-appb-000061
Figure PCTCN2022129918-appb-000062
Figure PCTCN2022129918-appb-000063
Figure PCTCN2022129918-appb-000064
Figure PCTCN2022129918-appb-000065
Figure PCTCN2022129918-appb-000066
Figure PCTCN2022129918-appb-000067
Figure PCTCN2022129918-appb-000068
Figure PCTCN2022129918-appb-000069
Figure PCTCN2022129918-appb-000070
Figure PCTCN2022129918-appb-000071
Figure PCTCN2022129918-appb-000072
Figure PCTCN2022129918-appb-000073
Figure PCTCN2022129918-appb-000074
Figure PCTCN2022129918-appb-000075
Figure PCTCN2022129918-appb-000076
Figure PCTCN2022129918-appb-000077
Figure PCTCN2022129918-appb-000078
Figure PCTCN2022129918-appb-000079
Figure PCTCN2022129918-appb-000080
Figure PCTCN2022129918-appb-000081
Figure PCTCN2022129918-appb-000082
Figure PCTCN2022129918-appb-000083
Figure PCTCN2022129918-appb-000084
Figure PCTCN2022129918-appb-000085
Figure PCTCN2022129918-appb-000086
Figure PCTCN2022129918-appb-000087
Figure PCTCN2022129918-appb-000088
Figure PCTCN2022129918-appb-000089
Figure PCTCN2022129918-appb-000090
Figure PCTCN2022129918-appb-000091
*:LC/MS data for the prepared compounds is obtained using the above indicated method.
The symbol "//" indicates the example can be prepared using appropriate intermediates, which can be readily synthesized by methods known in the art, and sequential modifications as necessary.
Cell Proliferation Assays
MTS testing kit was purchased from Promega (Madison, WI, USA) . The RPMI-1640, DMEM, Penicillin-Streptomycin and Trypsin-EDTA (0.25%) were purchased from BI (Biological Industries, Beit Haemek, Israel) . Fetal bovine serum was purchased from GIBCO (Grand Island, NY, USA) . Dimethyl sulfoxide (DMSO) was purchased from Sigma (St. Louis., MO, USA) . T47D (ATCC, Cat. No: HTB-133) cells were cultured in RPMI-1640 supplemented with 10%FBS and MDA-MB-453 (Cobioer, Cat. No: CBP60386) cells were cultured in DMEM supplemented with 10%FBS.
To investigate whether a compound is able to inhibit the activity of PI3Kα H1047R in cells, a mechanism-based assay using T47D (PI3Kα H1047R) and MDA-MB-453 (PI3Kα H1047R) cell lines was developed. In this assay, the inhibition of PI3KΑ H1047R was reflected by the inhibition of cell proliferation of T47D and MDA-MB-453 cells. Cells were plated into 96-well plates  at the optimized cell density (T47D: 3000 cells/well; MDA-MB-453: 1000 cells/well) . Plates were incubated at 37℃, with 5%CO 2 for 24 h. Compounds were serially diluted and added to the plates with the final concentrations of 10000, 3333.3, 1111.1, 370.4, 123.5, 41.2, 13.7, 4.6 and 1.5 nM. Plates were incubated at 37℃, with 5%CO 2 for 7 days (T47D) and 5 days (MDA-MB-453) , respectively. 20 μL MTS was added into each well and the plates were incubated at 37℃, with 5%CO 2 for 2 h. The absorbance was measured by a microplate reader at 490 nm. IC 50 was calculated using GraphPad Prism 8.0 software.
Selected compounds prepared as described above were assayed according to the biological procedures described herein. The results are shown in the table below:
Table 2
Example T47D IC 50 (nM) MB-453 IC 50 (nM)
5a 12 /
6 11 /
11 6 /
23 19 /
26 3 10
31 1 /
29a or 29b 5 52
45 15 /
47 11 /
131 6 29
133 26 10
212 1 4
213 17 18
230 25 18
276 9 23
277 18 35

Claims (48)

  1. A compound of formula (I) :
    Figure PCTCN2022129918-appb-100001
    or a pharmaceutically acceptable salt thereof, wherein:
    X is selected from C and N,
    Y is selected from C (O) , CR 9 and N,
    Z is selected from CR 10 and N,
    W is selected from C and N,
    wherein:
    when X is C and Y is C (O) , W is N;
    Q is selected from C 3-10 cycloalkyl, heterocyclyl, aryl and heteroaryl;
    R 1 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 A1R B1, -OR A1, -C (O) R A1, -C (=NR E1) R A1, -C (=N-OR B1) R A1, -C (O) OR A1, -OC (O) R A1, -C (O) NR A1R B1, -NR A1C (O) R B1, -C (=NR E1) NR A1R B1, -NR A1C (=NR E1) R B1, -OC (O) NR A1R B1, -NR A1C (O) OR B1, -NR A1C (O) NR A1R B1, -NR A1C (S) NR A1R B1, -NR A1C (=NR E1) NR A1R B1, -S (O)  rR A1, -S (O) (=NR E1) R B1, -N=S (O) R A1R B1, -S (O)  2OR A1, -OS (O)  2R A1, -NR A1S (O)  rR B1, -NR A1S (O) (=NR E1) R B1, -S (O)  rNR A1R B1, -S (O) (=NR E1) NR A1R B1, -NR A1S (O)  2NR A1R B1, -NR A1S (O) (=NR E1) NR A1R B1, -P (O) R A1R B1 and -P (O) (OR A1) (OR B1) , 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 2, at each occurrence, 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 A2R B2, -OR A2, -C (O) R A2, -C (=NR E2) R A2, -C (=N-OR B2) R A2, -C (O) OR A2, -OC (O) R A2, -C (O) NR A2R B2, -NR A2C (O) R B2, -C (=NR E2) NR A2R B2, -NR A2C (=NR E2) R B2, -OC (O) NR A2R B2, -NR A2C (O) OR B2, -NR A2C (O) NR A2R B2, -NR A2C (S) NR A2R B2, -NR A2C (=NR E2) NR A2R B2, -S (O)  rR A2, -S (O) (=NR E2) R B2, -N=S (O) R A2R B2, -S (O)  2OR A2, -OS (O)  2R A2, -NR A2S (O)  rR B2, -NR A2S (O) (=NR E2) R B2, -S (O)  rNR A2R B2, -S (O) (=NR E2) NR A2R B2, -NR A2S (O)  2NR A2R B2, -NR A2S (O) (=NR E2) NR A2R B2, -P (O) R A2R B2 and -P (O) (OR A2) (OR B2) , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R X2;
    or any two of R 2 together with the atoms to which they are attached form selected from a C 3-10 cycloalkyl, aryl, heteroaryl and heterocyclic ring of 4 to 12 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein cycloalkyl, aryl, heteroaryl and heterocyclic ring are each unsubstituted or substituted with at least one substituent, independently selected from R X2;
    R 3 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, CN, NO 2, -NR A3R B3, -OR A3 and -C (O) R A3, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are each unsubstituted or substituted with at least one substituent, independently selected from R X3;
    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, CN, NO 2, -NR A4R B4, -OR A4, - C (O) R A4, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are each unsubstituted or substituted with at least one substituent, independently selected from R X4;
    or R 3 and R 4 together with the atoms to which they are attached form selected from a C 3-10 cycloalkyl, aryl, heteroaryl and heterocyclic ring of 4 to 12 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein cycloalkyl, aryl, heteroaryl and heterocyclic ring are each unsubstituted or substituted with at least one substituent, independently selected from R X3;
    each R 5, at each occurrence, 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 A5R B5, -OR A5, -C (O) R A5, -C (=NR E5) R A5, -C (=N-OR B5) R A5, -C (O) OR A5, -OC (O) R A5, -C (O) NR A5R B5, -NR A5C (O) R B5, -C (=NR E5) NR A5R B5, -NR A5C (=NR E5) R B5, -OC (O) NR A5R B5, -NR A5C (O) OR B5, -NR A5C (O) NR A5R B5, -NR A5C (S) NR A5R B5, -NR A5C (=NR E5) NR A5R B5, -S (O)  rR A5, -S (O) (=NR E5) R B5, -N=S (O) R A5R B5, -S (O)  2OR A5, -OS (O)  2R A5, -NR A5S (O)  rR B5, -NR A5S (O) (=NR E5) R B5, -S (O)  rNR A5R B5, -S (O) (=NR E5) NR A5R B5, -NR A5S (O)  2NR A5R B5, -NR A5S (O) (=NR E5) NR A5R B5, -P (O) R A5R B5 and -P (O) (OR A5) (OR B5) , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R X5;
    or any two of R 5 together with the atoms to which they are attached form selected from a C 3-10 cycloalkyl, aryl, heteroaryl and heterocyclic ring of 4 to 12 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein cycloalkyl, aryl, heteroaryl and heterocyclic ring are each unsubstituted or substituted with at least one substituent, independently selected from R X5;
    R 6 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 A6R B6, -OR A6, -C (O) R A6, -C (=NR E6) R A6, -C (=N-OR B6) R A6, -C (O) OR A6, -OC (O) R A6, -C (O) NR A6R B6, -NR A6C (O) R B6, -C (=NR E6) NR A6R B6, -NR A6C (=NR E6) R B6, -OC (O) NR A6R B6, -NR A6C (O) OR B6, -NR A6C (O) NR A6R B6, -NR A6C (S) NR A6R B6, -NR A6C (=NR E6) NR A6R B6, -S (O)  rR A6, -S (O) (=NR E6) R B6, -N=S (O) R A6R B6, -S (O)  2OR A6, -OS (O)  2R A6, -NR A6S (O)  rR B6, -NR A6S (O) (=NR E6) R B6, -S (O)  rNR A6R B6, -S (O) (=NR E6) NR A6R B6, -NR A6S (O)  2NR A6R B6, -NR A6S (O) (=NR E6) NR A6R B6, -P (O) R A6R B6 and -P (O) (OR A6) (OR B6) , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R X6;
    R 7 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 A7R B7, -OR A7, -C (O) R A7, -C (=NR E7) R A7, -C (=N-OR B7) R A7, -C (O) OR A7, -OC (O) R A7, -C (O) NR A7R B7, -NR A7C (O) R B7, -C (=NR E7) NR A7R B7, -NR A7C (=NR E7) R B7, -OC (O) NR A7R B7, -NR A7C (O) OR B7, -NR A7C (O) NR A7R B7, -NR A7C (S) NR A7R B7, -NR A7C (=NR E7) NR A7R B7, -S (O)  rR A7, -S (O) (=NR E7) R B7, -N=S (O) R A7R B7, -S (O)  2OR A7, -OS (O)  2R A7, -NR A7S (O)  rR B7, -NR A7S (O) (=NR E7) R B7, -S (O)  rNR A7R B7, -S (O) (=NR E7) NR A7R B7, -NR A7S (O)  2NR A7R B7, -NR A7S (O) (=NR E7) NR A7R B7, -P (O) R A7R B7 and -P (O) (OR A7) (OR B7) , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R X7;
    R 8 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 A8R B8, -OR A8, -C (O) R A8, -C (=NR E8) R A8, -C (=N-OR B8) R A8, -C (O) OR A8, -OC (O) R A8, -C (O) NR A8R B8, -NR A8C (O) R B8, -C (=NR E8) NR A8R B8, -NR A8C (=NR E8) R B8, -OC (O) NR A8R B8, -NR A8C (O) OR B8, -NR A8C (O) NR A8R B8, -NR A8C (S) NR A8R B8, -NR A8C (=NR E8) NR A8R B8, -S (O)  rR A8, -S (O) (=NR E8) R B8, -N=S (O) R A8R B8, -S (O)  2OR A8, -OS (O)  2R A8, -NR A8S (O)  rR B8, -NR A8S (O) (=NR E8) R B8, -S (O)  rNR A8R B8, -S (O) (=NR E8) NR A8R B8, -NR A8S (O)  2NR A8R B8, -NR A8S (O) (=NR E8) NR A8R B8, -P (O) R A8R B8 and -P (O) (OR A8) (OR B8) , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R X8;
    R 9 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 A9R B9, -OR A9, -C (O) R A9, -C (=NR E9) R A9, -C (=N-OR B9) R A9, -C (O) OR A9, -OC (O) R A9, -C (O) NR A9R B9, -NR A9C (O) R B9, -C (=NR E9) NR A9R B9, -NR A9C (=NR E9) R B9, -OC (O) NR A9R B9, -NR A9C (O) OR B9, -NR A9C (O) NR A9R B9, -NR A9C (S) NR A9R B9, -NR A9C (=NR E9) NR A9R B9, -S (O)  rR A9, -S (O) (=NR E9) R B9, -N=S (O) R A9R B9, -S (O)  2OR A9, -OS (O)  2R A9, -NR A9S (O)  rR B9, -NR A9S (O) (=NR E9) R B9, -S (O)  rNR A9R B9, -S (O) (=NR E9) NR A9R B9, -NR A9S (O)  2NR A9R B9, -NR A9S (O) (=NR E9) NR A9R B9, -P (O) R A9R B9 and -P (O) (OR A9) (OR B9) , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R X9;
    R 10 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 A10R B10, -OR A10, -C (O) R A10, -C (=NR E10) R A10, -C (=N-OR B10) R A10, -C (O) OR A10, -OC (O) R A10, -C (O) NR A10R B10, -NR A10C (O) R B10, -C (=NR E10) NR A10R B10, -NR A10C (=NR E10) R B10, -OC (O) NR A10R B10, -NR A10C (O) OR B10, -NR A10C (O) NR A10R B10, -NR A10C (S) NR A10R B10, -NR A10C (=NR E10) NR A10R B10, -S (O)  rR A10, -S (O) (=NR E10) R B10, -N=S (O) R A10R B10, -S (O)  2OR A10, -OS (O)  2R A10, -NR A10S (O)  rR B10, -NR A10S (O) (=NR E10) R B10, -S (O)  rNR A10R B10, -S (O) (=NR E10) NR A10R B10, -NR A10S (O)  2NR A10R B10, -NR A10S (O) (=NR E10) NR A10R B10, -P (O) R A10R B10 and -P (O) (OR A10) (OR B10) , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R X10;
    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;
    or each “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 X1 groups;
    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;
    or each “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, 2 or 3 R X2 groups;
    each R A3 and R B3 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 X3;
    or each “R A3 and R B3” 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 X3 groups;
    each R A4 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, 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 X4;
    or each “R A4 and R B4” 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 X4 groups;
    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;
    or each “R A5 and R B5” 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 X5 groups;
    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;
    or each “R A6 and R B6” 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 X6 groups;
    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;
    or each “R A7 and R B7” 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 X7 groups;
    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;
    or each “R A8 and R B8” 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 X8 groups;
    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;
    or each “R A9 and R B9” 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 X9 groups;
    each R A10 and R B10 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 X10;
    or each “R A10 and R B10” 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 X10 groups;
    each R E1, R E2, R E5, R E6, R E7, R E8, R E9 and R E10 are independently selected from hydrogen, C 1- 10 alkyl, CN, NO 2, -OR a1, -SR a1, -S (O)  rR a1, -C (O) R a1, -C (O) OR a1, -C (O) NR a1R b1 and -S (O)  rNR a1R b1, wherein alkyl is unsubstituted or substituted with at least one substituent, independently selected from R X1;
    each R X1, R X2, R X3, R X4, R X5, R X6, R X7, R X8, R X9 and R X10 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, heteroaryl-C 1-4 alkyl, halogen, CN, NO 2, - (CR c1R d1)  tNR a1R b1, - (CR c1R d1)  tOR b1, - (CR c1R d1)  tC (O) R a1, - (CR c1R d1)  tC (=NR e1) R a1, - (CR c1R d1)  tC (=N-OR b1) R a1, - (CR c1R d1)  tC (O) OR b1, - (CR c1R d1)  tOC (O) R b1, - (CR c1R d1)  tC (O) NR a1R b1, - (CR c1R d1)  tNR a1C (O) R b1, - (CR c1R d1)  tC (=NR e1) NR a1R b1, - (CR c1R d1)  tNR a1C (=NR e1) R b1, - (CR c1R d1)  tOC (O) NR a1R b1, - (CR c1R d1)  tNR a1C (O) OR b1, - (CR c1R d1)  tNR a1C (O) NR a1R b1, - (CR c1R d1)  tNR a1C (S) NR a1R b1, - (CR c1R d1)  tNR a1C (=NR e1) NR a1R b1, - (CR c1R d1)  tS (O)  rR b1, - (CR c1R d1)  tS (O) (=NR e1) R b1, - (CR c1R d1)  tN=S (O) R a1R b1, - (CR c1R d1)  tS (O)  2OR b1, - (CR c1R d1)  tOS (O)  2R b1, -(CR c1R d1)  tNR a1S (O)  rR b1, - (CR c1R d1)  tNR a1S (O) (=NR e1) R b1, - (CR c1R d1)  tS (O)  rNR a1R b1, - (CR c1R d1)  tS (O) (=NR e1) NR a1R b1, - (CR c1R d1)  tNR a1S (O)  2NR a1R b1, - (CR c1R d1)  tNR a1S (O) (=NR e1) NR a1R b1, - (CR c1R d1)  tP (O) R a1R b1 and - (CR c1R d1)  tP (O) (OR a1) (OR b1) , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R Y;
    or any two of R X2 together with the atoms to which they are attached form selected from selected from a C 3-10 cycloalkyl, aryl, heteroaryl and heterocyclic ring of 4 to 12 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein cycloalkyl, aryl, heteroaryl and heterocyclic are each unsubstituted or substituted with at least one substituent, independently selected from R Y;
    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;
    or 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;
    or 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)  rR a2, -C (O) R a2, -C (O) OR a2, -S (O)  rNR a2R b2 and -C (O) NR a2R 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 c2R d2)  tNR a2R b2, - (CR c2R d2)  tOR b2, - (CR c2R d2)  tC (O) R a2, - (CR c2R d2)  tC (=NR e2) R a2, - (CR c2R d2)  tC (=N-OR b2) R a2, - (CR c2R d2)  tC (O) OR b2, - (CR c2R d2)  tOC (O) R b2, -(CR c2R d2)  tC (O) NR a2R b2, - (CR c2R d2)  tNR a2C (O) R b2, - (CR c2R d2)  tC (=NR e2) NR a2R b2, - (CR c2R d2)  tNR a2C (=NR e2) R b2, - (CR c2R d2)  tOC (O) NR a2R b2, - (CR c2R d2)  tNR a2C (O) OR b2, - (CR c2R d2)  tNR a2C (O) NR a2R b2, - (CR c2R d2)  tNR a2C (S) NR a2R b2, - (CR c2R d2)  tNR a2C (=NR e2) NR a2R b2, - (CR c2R d2)  tS (O)  rR b2, - (CR c2R d2)  tS (O) (=NR e2) R b2, - (CR c2R d2)  tN=S (O) R a2R b2, - (CR c2R d2)  tS (O)  2OR b2, - (CR c2R d2)  tOS (O)  2R b2, - (CR c2R d2)  tNR a2S (O)  rR b2, - (CR c2R d2)  tNR a2S (O) (=NR e2) R b2, - (CR c2R d2)  tS (O)  rNR a2R b2, - (CR c2R d2)  tS (O) (=NR e2) NR a2R b2, - (CR c2R d2)  tNR a2S (O)  2NR a2R b2, -  (CR c2R d2)  tNR a2S (O) (=NR e2) NR a2R b2, - (CR c2R d2)  tP (O) R a2R b2 and - (CR c2R d2)  tP (O) (OR a2) (OR b2) , wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from OH, CN, amino, halogen, C 1- 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 1-10 alkoxy, C 3-10 cycloalkoxy, C 1-10 alkylthio, C 3-10 cycloalkylthio, C 1-10 alkylamino, C 3-10 cycloalkylamino and di (C 1-10 alkyl) amino;
    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, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, 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;
    or 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, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, 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;
    or 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)  2C 1- 4 alkyl, -S (O)  2C 3-10 cycloalkyl, -S (O)  2N (C 1-4 alkyl)  2 and -S (O)  2N (C 3-10 cycloalkyl)  2;
    m is selected from 0, 1, 2, 3 and 4;
    n is selected from 0, 1, 2, 3 and 4;
    p is selected from 0, 1, 2, 3 and 4;
    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.
  2. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
    when X is C and Y is CR 9 or N, Z is N;
    when X is N and Y is C (O) , Z is CR 10 or N.
  3. A compound of any one of claim 1-2 or a pharmaceutically acceptable salt thereof, wherein W is C, shown as formula (II) ,
    Figure PCTCN2022129918-appb-100002
    or a pharmaceutically acceptable salt thereof, wherein X, Y, Z, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, m, n and p are as defined in formula (I) .
  4. A compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein X is N, Y is C (O) and Z is N.
  5. A compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein X is N, Y is C (O) and Z is CR 10.
  6. A compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein X is C, Y is CR 9 and Z is N.
  7. A compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein X is C, Y is N and Z is N.
  8. A compound of any one of claim 1-2 or a pharmaceutically acceptable salt thereof, wherein W is N.
  9. A compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein X is C, Y is C (O) and Z is N.
  10. A compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein X is C, Y is C (O) and Z is CR 10.
  11. A compound of any one of claim 1-3, 5 and 10 or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, CN, NO 2, -NR A10R B10 and -OR A10, wherein alkyl, alkenyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R X10.
  12. A compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from hydrogen, F, Cl, Br, CN, NO 2, NH 2, 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 X10.
  13. A compound of any one of claim 1-3 and 6 or a pharmaceutically acceptable salt thereof, wherein R 9 is selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, CN, NO 2, -NR A9R B9 and -OR A9, wherein alkyl, alkenyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R X9.
  14. A compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein R 9 is selected from hydrogen, F, Cl, Br, CN, NO 2, NH 2, 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 X9.
  15. A compound of any one of claim 1-14 or a pharmaceutically acceptable salt thereof, wherein n is selected from 0, 1, 2 and 3.
  16. A compound of any one of claim 1-15 or a pharmaceutically acceptable salt thereof, wherein each R 2, at each occurrence, is independently selected from hydrogen, deuterium, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, CN, NO 2, -NR A2R B2 and -OR A2, wherein alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R X2;
    or any two of R 2 together with the atoms to which they are attached form selected from a C 3-10 cycloalkyl, aryl, heteroaryl and heterocyclic ring of 4 to 8 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein cycloalkyl, aryl,  heteroaryl and heterocyclic are each unsubstituted or substituted with at least one substituent, independently selected from R X2.
  17. A compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein each R 2, at each occurrence, is independently selected from hydrogen, deuterium, F, Cl, Br, CN, NO 2, NH 2, OH, methyl, ethyl, isopropyl, cyclopropyl and phenyl, wherein methyl, ethyl, isopropyl, cyclopropyl and phenyl are each unsubstituted or substituted with at least one substituent, independently selected from R X2.
  18. A compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein any two of R 2 together with the atoms to which they are attached form selected from a C 3-8 cycloalkyl, aryl, heteroaryl and heterocyclic ring of 4 to 8 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein cycloalkyl, aryl, heteroaryl and heterocyclic are each unsubstituted or substituted with at least one substituent, independently selected from R X2, preferably, any two of R 2 together with the atoms to which they are attached form selected from a cyclopropyl, cyclobutyl, phenyl, pyridinyl and
    Figure PCTCN2022129918-appb-100003
    which are each unsubstituted or substituted with at least one substituent, independently selected from R X2.
  19. A compound of any one of claim 16-18 or a pharmaceutically acceptable salt thereof, wherein each R X2, at each occurrence, is independently selected from C 1-10 alkyl, C 3-10 cycloalkyl, heterocyclyl, halogen, CN, NO 2, - (CR c1R d1)  tNR a1R b1, - (CR c1R d1)  tOR b1, - (CR c1R d1)  tC (O) R a1, - (CR c1R d1)  tC (O) OR b1, - (CR c1R d1)  tOC (O) R b1, - (CR c1R d1)  tC (O) NR a1R b1, - (CR c1R d1)  tNR a1C (O) R b1, - (CR c1R d1)  tS (O)  rR b1, - (CR c1R d1)  tS (O)  2OR b1 and - (CR c1R d1)  tNR a1S (O)  rR b1, wherein alkyl, cycloalkyl and heterocyclyl are each unsubstituted or substituted with at least one substituent, independently selected from R Y.
  20. A compound of claim 19 or a pharmaceutically acceptable salt thereof, wherein each R X2, at each occurrence, is independently selected from F, Cl, Br, CN, NO 2, NH 2, 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 Y, preferably, each R X2 is independently selected from F, Cl, Br, CN, NO 2, NH 2, OH, methyl and ethyl.
  21. A compound of any one of claim 1-18 or a pharmaceutically acceptable salt thereof, wherein any two of R X2 together with the atoms to which they are attached form a C 3-10 cycloalkyl or heterocyclic ring of 4 to 10 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, and optionally substituted with 1, 2 or 3 R Y groups.
  22. A compound of claim 21 or a pharmaceutically acceptable salt thereof, wherein any two of R X2 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 Y groups.
  23. A compound of any one of claim 1-22 or a pharmaceutically acceptable salt thereof, wherein the moiety
    Figure PCTCN2022129918-appb-100004
    in Formula (I) and Formula (II) is selected from
    Figure PCTCN2022129918-appb-100005
    Figure PCTCN2022129918-appb-100006
    Figure PCTCN2022129918-appb-100007
    wherein the
    Figure PCTCN2022129918-appb-100008
    symbol indicates the point of attachment to the rest of the molecule.
  24. A compound of any one of claim 1-23 or a pharmaceutically acceptable salt thereof, wherein Q is selected from aryl and heteroaryl.
  25. A compound of claim 21 or a pharmaceutically acceptable salt thereof, wherein Q is selected from phenyl and pyridinyl.
  26. A compound of any one of claim 1-25 or a pharmaceutically acceptable salt thereof, wherein each R 5, at each occurrence, is independently selected from halogen, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, CN, NO 2, -NR A5R B5, -OR A5, -C (O) R A5, -C (O) OR A5, -OC (O) R A5, -C (O) NR A5R B5, -NR A5C (O) R B5, -OC (O) NR A5R B5, -NR A5C (O) OR B5, -NR A5C (O) NR A5R B5, -S (O)  rR A5, -S (O)  2OR A5, -OS (O)  2R A5, -NR A5S (O)  rR B5 and -S (O)  rNR A5R B5, wherein alkyl, alkenyl and cycloalkyl, are each unsubstituted or substituted with at least one substituent, independently selected from R X5;
    or any two of R 5 together with the atoms to which they are attached form selected from a C 3-8 cycloalkyl and heterocyclic ring of 4 to 10 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein cycloalkyl, aryl, heteroaryl and heterocyclic are each unsubstituted or substituted with at least one substituent, independently selected from R X5.
  27. A compound of claim 26 or a pharmaceutically acceptable salt thereof, wherein each R 5, at each occurrence, is independently selected from halogen, C 1-10 alkyl, C 3-10 cycloalkyl, CN, NO 2, -NR A5R B5, -OR A5, -C (O) R A5 and -C (O) OR A5, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R X5.
  28. A compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein each R 5, at each occurrence, is independently selected from F, Cl, Br, CN, NO 2, NH 2, OH, -C (O) OH, methyl, ethyl, isopropyl, methoxy and cyclopropyl, wherein methyl, ethyl, isopropyl, methoxy and cyclopropyl are each unsubstituted or substituted with at least one substituent, independently selected from R X5.
  29. A compound of any one of claim 1-28 or a pharmaceutically acceptable salt thereof, wherein wherein the moiety
    Figure PCTCN2022129918-appb-100009
    in Formula (I) and Formula (II) is selected from
    Figure PCTCN2022129918-appb-100010
    Figure PCTCN2022129918-appb-100011
    Figure PCTCN2022129918-appb-100012
    wherein the
    Figure PCTCN2022129918-appb-100013
    symbol indicates the point of attachment to the rest of the molecule.
  30. A compound of any one of claim 1-29 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from hydrogen, halogen, C 1-10 alkyl, C 2-10 alkenyl, 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 A1R B1, -OR A1, -C (O) R A1, -C (O) OR A1, -OC (O) R A1, -C (O) NR A1R B1, -NR A1C (O) R B1, -OC (O) NR A1R B1, -NR A1C (O) OR B1, -NR A1C (O) NR A1R B1, -NR A1C (S) NR A1R B1, -S (O)  rR A1, -S (O)  2OR A1, -OS (O)  2R A1, -NR A1S (O)  rR B1, -S (O)  rNR A1R B1 and -NR A1S (O)  2NR A1R B1, wherein alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, independently selected from R X1.
  31. A compound of claim 30 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from hydrogen, F, Cl, Br, CN, NO 2, NH 2, OH, methyl, ethyl, isopropyl, cyclopropyl, - C (O) CH 3 and
    Figure PCTCN2022129918-appb-100014
    wherein methyl, ethyl, isopropyl, cyclopropyl and
    Figure PCTCN2022129918-appb-100015
    are each unsubstituted or substituted with at least one substituent, independently selected from R X1.
  32. A compound of any one of claim 1-31 or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, CN, NO 2, -NR A6R B6 and -OR A6, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R X6.
  33. A compound of claim 32 or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from hydrogen, F, Cl, Br, CN, NO 2, NH 2, 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 X6.
  34. A compound of any one of claim 1-33 or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, CN, NO 2, -NR A7R B7 and -OR A7, wherein alkyl, and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R X7.
  35. A compound of claim 34 or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from hydrogen, F, Cl, Br, CN, NO 2, NH 2, OH, methyl, ethyl, isopropyl, cyclopropyl and methoxy, wherein methyl, ethyl, isopropyl, cyclopropyl and methoxy are each unsubstituted or substituted with at least one substituent, independently selected from R X7.
  36. A compound of any one of claim 1-35 or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, CN, NO 2, -NR A8R B8 and -OR A8, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R X8.
  37. A compound of claim 36 or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from hydrogen, F, Cl, Br, CN, NO 2, NH 2, 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 X8.
  38. A compound of any one of claim 1-37 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, CN, NO 2, -NR A3R B3, -OR A3 and -C (O) R A3, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R X3.
  39. A compound of claim 36 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from hydrogen, F, Cl, Br, CN, NO 2, NH 2, 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 X3.
  40. A compound of any one of claim 1-39 or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, CN, NO 2, -NR A4R B4, -OR A4 and -C (O) R A4, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent, independently selected from R X4.
  41. A compound of claim 40 or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from hydrogen, F, Cl, Br, CN, NO 2, NH 2, 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 X4.
  42. A compound of any one of claim 1-37 or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 together with the atoms to which they are attached form selected from a C 3-10 cycloalkyl or heterocyclic ring of 4 to 10 members containing 1, 2 or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, wherein cycloalkyl and heterocyclic are each unsubstituted or substituted with at least one substituent, independently selected from R X3.
  43. A compound of claim 42 or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 together with the atoms to which they are attached form a cyclopropyl, which are each unsubstituted or substituted with at least one substituent, independently selected from R X3.
  44. A compound selected from
    Figure PCTCN2022129918-appb-100016
    Figure PCTCN2022129918-appb-100017
    Figure PCTCN2022129918-appb-100018
    Figure PCTCN2022129918-appb-100019
    Figure PCTCN2022129918-appb-100020
    Figure PCTCN2022129918-appb-100021
    Figure PCTCN2022129918-appb-100022
    Figure PCTCN2022129918-appb-100023
    Figure PCTCN2022129918-appb-100024
    Figure PCTCN2022129918-appb-100025
    and pharmaceutically acceptable salts thereof.
  45. A pharmaceutical composition, comprising a compound of any one of claims 1-44 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.
  46. A method of treating, ameliorating or preventing a condition, which responds to inhibition of PI3K, comprising administering to a subject in need of such treatment an effective amount of a compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent.
  47. Use of a compound of any one of claims 1-44 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a cell-proliferative disorder.
  48. A use according to claim 47, wherein the cell-proliferative disorder is selected from breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, testicular cancer, lung cancer, esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer, thyroid cancer, chronic lymphocytic leukemia, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia and myeloma.
PCT/CN2022/129918 2021-11-05 2022-11-04 Compounds as protein kinase inhibitors WO2023078401A1 (en)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US202163276093P 2021-11-05 2021-11-05
US63/276,093 2021-11-05
US202163288597P 2021-12-11 2021-12-11
US63/288,597 2021-12-11
US202263311458P 2022-02-18 2022-02-18
US63/311,458 2022-02-18
US202263332923P 2022-04-20 2022-04-20
US63/332,923 2022-04-20

Publications (1)

Publication Number Publication Date
WO2023078401A1 true WO2023078401A1 (en) 2023-05-11

Family

ID=86240651

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/129918 WO2023078401A1 (en) 2021-11-05 2022-11-04 Compounds as protein kinase inhibitors

Country Status (1)

Country Link
WO (1) WO2023078401A1 (en)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023192416A1 (en) * 2022-03-29 2023-10-05 Prelude Therapeutics, Incorporated Mutant pi3k-alpha inhibitors and their use as pharmaceuticals
WO2023239710A1 (en) 2022-06-08 2023-12-14 Onkure, Inc. Benzopyrimidin-4(3h)-ones as pi3k inhibitors
WO2024008122A1 (en) * 2022-07-07 2024-01-11 海创药业股份有限公司 Pi3k inhibitor, preparation method therefor, and use thereof
US11873295B2 (en) 2021-05-03 2024-01-16 Petra Pharma Corporation Allosteric chromenone inhibitors of phosphoinositide 3-kinase (PI3K) for the treatment of disease
US11878970B2 (en) 2021-05-27 2024-01-23 Petra Pharma Corporation Allosteric chromenone inhibitors of phosphoinositide 3-kinase (PI3K) for the treatment of disease
WO2024026424A1 (en) * 2022-07-27 2024-02-01 Black Diamond Therapeutics, Inc. Quinazolinone derivatives as and related uses
WO2024026423A1 (en) * 2022-07-27 2024-02-01 Black Diamond Therapeutics, Inc. Substituted quinoline derivatives as pi3k inhibitors
WO2024026419A1 (en) * 2022-07-27 2024-02-01 Black Diamond Therapeutics, Inc. Quinoxaline derivatives as pik3 alpha modulators
WO2024044769A1 (en) * 2022-08-26 2024-02-29 Mirati Therapeutics, Inc. Substituted pyridopyrimidinones
WO2024054469A1 (en) 2022-09-08 2024-03-14 Onkure, Inc. Isoquinolones as pi3k inhibitors
WO2024064024A1 (en) 2022-09-19 2024-03-28 Onkure, Inc. ((4-oxo-3,4-dihydroquinazolin-8-yl)methyl)amine derivatives as p13k inhibitors for the treatment of cancer
WO2024081345A1 (en) 2022-10-14 2024-04-18 Onkure, Inc. Benzopyrimidin-4(3h)-ones as pi3k inhibitors

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013130660A1 (en) * 2012-02-28 2013-09-06 Amgen Inc. Amides as pim inhibitors
CN107207441A (en) * 2014-11-01 2017-09-26 上海复尚慧创医药研究有限公司 Kinases inhibitor
CN111205281A (en) * 2018-04-07 2020-05-29 阮富强 Heterocyclic compounds and their use
WO2022140456A1 (en) * 2020-12-22 2022-06-30 Mekanistic Therapeutics Llc Substituted aminobenzyl heteroaryl compounds as egfr and/or pi3k inhibitors
WO2022143629A1 (en) * 2020-12-29 2022-07-07 上海岸阔医药科技有限公司 Reagent and method for treating skin diseases or conditions associated with anti-tumor agent

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013130660A1 (en) * 2012-02-28 2013-09-06 Amgen Inc. Amides as pim inhibitors
CN107207441A (en) * 2014-11-01 2017-09-26 上海复尚慧创医药研究有限公司 Kinases inhibitor
CN111205281A (en) * 2018-04-07 2020-05-29 阮富强 Heterocyclic compounds and their use
WO2022140456A1 (en) * 2020-12-22 2022-06-30 Mekanistic Therapeutics Llc Substituted aminobenzyl heteroaryl compounds as egfr and/or pi3k inhibitors
WO2022143629A1 (en) * 2020-12-29 2022-07-07 上海岸阔医药科技有限公司 Reagent and method for treating skin diseases or conditions associated with anti-tumor agent

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LIPING H. PETTUS, KRISTIN L. ANDREWS, SHON K. BOOKER, JIE CHEN, VICTOR J. CEE, FRANK CHAVEZ, YUPING CHEN, HEATHER EASTWOOD, NADIA : "Discovery and Optimization of Quinazolinone-pyrrolopyrrolones as Potent and Orally Bioavailable Pan-Pim Kinase Inhibitors", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 59, no. 13, 14 July 2016 (2016-07-14), US , pages 6407 - 6430, XP055761979, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.6b00610 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11873295B2 (en) 2021-05-03 2024-01-16 Petra Pharma Corporation Allosteric chromenone inhibitors of phosphoinositide 3-kinase (PI3K) for the treatment of disease
US11878970B2 (en) 2021-05-27 2024-01-23 Petra Pharma Corporation Allosteric chromenone inhibitors of phosphoinositide 3-kinase (PI3K) for the treatment of disease
WO2023192416A1 (en) * 2022-03-29 2023-10-05 Prelude Therapeutics, Incorporated Mutant pi3k-alpha inhibitors and their use as pharmaceuticals
WO2023239710A1 (en) 2022-06-08 2023-12-14 Onkure, Inc. Benzopyrimidin-4(3h)-ones as pi3k inhibitors
WO2024008122A1 (en) * 2022-07-07 2024-01-11 海创药业股份有限公司 Pi3k inhibitor, preparation method therefor, and use thereof
WO2024026424A1 (en) * 2022-07-27 2024-02-01 Black Diamond Therapeutics, Inc. Quinazolinone derivatives as and related uses
WO2024026423A1 (en) * 2022-07-27 2024-02-01 Black Diamond Therapeutics, Inc. Substituted quinoline derivatives as pi3k inhibitors
WO2024026419A1 (en) * 2022-07-27 2024-02-01 Black Diamond Therapeutics, Inc. Quinoxaline derivatives as pik3 alpha modulators
WO2024044769A1 (en) * 2022-08-26 2024-02-29 Mirati Therapeutics, Inc. Substituted pyridopyrimidinones
WO2024054469A1 (en) 2022-09-08 2024-03-14 Onkure, Inc. Isoquinolones as pi3k inhibitors
WO2024064024A1 (en) 2022-09-19 2024-03-28 Onkure, Inc. ((4-oxo-3,4-dihydroquinazolin-8-yl)methyl)amine derivatives as p13k inhibitors for the treatment of cancer
WO2024081345A1 (en) 2022-10-14 2024-04-18 Onkure, Inc. Benzopyrimidin-4(3h)-ones as pi3k inhibitors

Similar Documents

Publication Publication Date Title
WO2023078401A1 (en) Compounds as protein kinase inhibitors
WO2022228387A1 (en) Compounds as parp inhibitors
CN114008042B (en) Substituted pyrrolo [2,3-b ] pyridine and pyrazolo [3,4-b ] pyridine derivatives as protein kinase inhibitors
EP4110782A1 (en) Compounds as cdk2/4/6 inhibitors
EP4146649A1 (en) Compounds as bcl-2 inhibitors
WO2021180107A1 (en) Compounds useful as kinase inhibitors
WO2020063751A1 (en) Substituted imidazo [1, 2-a] pyridine and [1, 2, 4] triazolo [1, 5-a] pyridine compounds as ret kinase inhibitors
WO2017193872A1 (en) Certain protein kinase inhibitors
AU2017280412B2 (en) Substituted pyrrolo (2, 3-D) pyridazin-4-ones and pyrazolo (3, 4-D) pyridazin-4-ones as protein kinase inhibitors
WO2023078398A1 (en) Compounds as bcl-2 inhibitors
WO2022268065A1 (en) Compounds as erk inhibitors
WO2020063659A1 (en) Substituted [1, 2, 4] triazolo [1, 5-a] pyridine compounds as ret kinase inhibitors
WO2021233227A1 (en) Compounds as protein kinase inhibitors
AU2021383227A1 (en) SUBSTITUTED PYRROLO [2, 3-b] PYRIDINE AND PYRAZOLO [3, 4-b] PYRIDINE DERIVATIVES AS PROTEIN KINASE INHIBITORS
WO2023231777A1 (en) Compounds as bcl-2 inhibitors
WO2024032755A1 (en) Compounds as bcl-2 inhibitors
WO2024032776A1 (en) Compounds as bcl-2 inhibitors
WO2021047584A1 (en) SUBSTITUTED (2-AZABICYCLO [3.1.0] HEXAN-2-YL) PYRAZOLO [1, 5-a] PYRIMIDINE AND IMIDAZO [1, 2-b] PYRIDAZINE COMPOUNDS AS TRK KINASES INHIBITORS
WO2023088167A1 (en) Compounds as bcl-2 inhibitors
WO2020063860A1 (en) Naphthyridinone and pyridopyrimidinone compounds useful as kinases inhibitors

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22889422

Country of ref document: EP

Kind code of ref document: A1