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WO2023109870A1 - 吡唑并嘧啶类化合物及其用途 - Google Patents

吡唑并嘧啶类化合物及其用途 Download PDF

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WO2023109870A1
WO2023109870A1 PCT/CN2022/139044 CN2022139044W WO2023109870A1 WO 2023109870 A1 WO2023109870 A1 WO 2023109870A1 CN 2022139044 W CN2022139044 W CN 2022139044W WO 2023109870 A1 WO2023109870 A1 WO 2023109870A1
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alkyl
heteroaryl
ring
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叶斌
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上海壹迪生物技术有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—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

  • Phosphoinositides serve as second messengers that play key roles in a variety of cellular functions, including cell survival, signal transduction, and regulation of membrane traffic and transport (Di Paolo, G. et al Nature, 2006, 443, 651-657; Schaeffer, E.M. et al Curr. Opin. Immunol., 2000, 12, 282-288). Dysregulation of various phosphoinositides has been linked to a variety of diseases, including cancer, autoimmune diseases, and inflammation. Phosphoinositides are lipids that contain two layers of fatty acids that can be linked to cytosolic 1-inositol through glycerophosphate linkages.
  • Lipid kinase PI3K converts PI phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate (PIP3) by phosphorylating the 3-OH of the inositol ring moiety through ATP ( Parker, P. J. Biochem. Soc. Trans., 2004, 32, 893-898).
  • PIP3 acts as an anchor site for protein kinases containing a highly conserved pleckstrin homology (PH) domain (Hawkins, P.T. et al. Biochem. Soc.
  • class I The most studied of PI3Ks is class I, which can be divided into two subclasses (class 1A and class 1B). Among them, class 1A (PI3K ⁇ , PI3K ⁇ , and PI3K ⁇ ) is located downstream of receptor tyrosine kinases (RTKs), while class 1B (PI3K ⁇ ) is located downstream of G protein-coupled receptors (GPCRs). These four homologous kinases exist as heterodimers of regulatory and catalytic subunits. Regulatory subunits contain domains that allow anchoring to cell surface receptors and other regulatory proteins. The catalytic subunits (p110 ⁇ , p110 ⁇ , p110 ⁇ , p110 ⁇ ) contain an ATP-binding domain.
  • RTKs receptor tyrosine kinases
  • GPCRs G protein-coupled receptors
  • the catalytic subunit is currently the focus of research on small molecule inhibitors of PI3K.
  • Small molecular compounds can block the phosphorylation of PIP2 and the formation of PIP3 by competitively inhibiting the ATP binding site. Therefore important regulatory proteins such as AKT will not be able to be anchored to the cell membrane and their function will be inhibited.
  • PI3K ⁇ and PI3K ⁇ are ubiquitously expressed in vivo, PI3K ⁇ and PI3K ⁇ are mainly present in leukocytes, and PI3K ⁇ is almost restricted to spleen, thymus and peripheral blood leukocytes (Eicholt, B.J. et al PLoS One, 2007, 9, e869).
  • the dysregulation of PI3K ⁇ and PI3K ⁇ is associated with the occurrence and development of solid tumor diseases; while the dysregulation of PI3K ⁇ and PI3K ⁇ is associated with inflammatory and immune system diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), pulmonary Diseases such as chronic obstructive pulmonary disease lung disease COPD and asthma, hematological malignancies.
  • RA rheumatoid arthritis
  • SLE systemic lupus erythematosus
  • pulmonary Diseases such as chronic obstructive pulmonary disease lung disease COPD and asthma
  • COPD chronic obstructive pulmonary disease lung disease
  • PI3K ⁇ has a unique role in B cell maturation and function (Vallerskog, T. et al Clin. Immunol., 2007, 122, 62-74), inhibition of PI3K should have similar effects to these two biologics.
  • PI3K ⁇ plays a role in T cell activation (Soond, R. et al; Blood, 2010, 115, 2203-3313) and neutrophil trafficking (Ali, K.
  • PI3K ⁇ in leukocyte function is supported by two recent papers. These two papers describe several major gain-of-function PI3K ⁇ mutations from several different families in Europe. PI3K ⁇ mutants display lymphoproliferative and immunodeficiency that predispose them to lung and ear infections (Angulo, I. et al Science 2013, 342, 866-871).
  • COPD chronic obstructive pulmonary disease
  • continuous exposure to cigarette smoke is associated with high levels of PI3K ⁇ and phosphorylated AKT in the lung (To, Y. et al, Am. J. Respir. Crit. Care Med. 2010, 182, 897 -904).
  • COPD patients are more susceptible to recurrent bacterial respiratory infections, including Haemophilus influenzae and Streptococcus pneumoniae.
  • Similar immunodeficiency in patients with gain-of-function gene mutations may be related to persistently activated PI3K ⁇ signaling in COPD.
  • Leukocyte deficiency in patients with gain-of-function mutations improves with rapamycin treatment.
  • Rapamycin is an inhibitor of mTOR, a downstream protein of PI3K ⁇ . Therefore, it is speculated that inhibition of PI3K ⁇ is also a potentially feasible therapeutic option for diseases related to PI3K ⁇ signaling pathway, not only for complex autoimmune diseases such as APDS (activated PI3K syndrome), SLE, RA, but also for PI3K ⁇ Pathological diseases caused by driven activity of B cells and other leukocyte subsets (Palanki, M. et al, J. Med. Chem. 2007, 50, 4279-4294; Pei, Z. et al, ACS Med. Chem.
  • PI3K ⁇ inhibitors can be used clinically, especially for first-line lymphoma, solid tumors, and non-cancer fields such as inflammatory diseases.
  • the flat structure usually has many aromatic groups conjugated to each other, and the structure has high planarity, and there are problems of poor solubility and poor selectivity.
  • the inventors of the present application and their team expected to select a propeller type skeleton, designed and synthesized a class of new compounds with pyrazolopyrimidine as the core, in order to obtain , A more selective PI3K ⁇ inhibitor.
  • the first aspect of the present invention provides a compound represented by formula (I) and/or a pharmaceutically acceptable salt thereof,
  • R is independently selected from hydrogen, halogen, -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 alkoxy, wherein said alkyl can be optionally replaced by one Or a plurality of R 1a is substituted, and R 1a is selected from halogen;
  • R 2 is selected from hydrogen, halogen, deuterium, hydroxyl, cyano, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-6 cycloalkyl, -C 3-6 heterocycloalkyl, -C 3-6 cycloalkoxy, -C 3-6 heterocycloalkoxy, -COOH, -C(O)NH 2 , -C(O)NH(C 1- 6 alkyl), -C(O)NH(C 1-6 alkyl) 2 , -S(O)2NH 2 , -S(O)(NH)NH 2 , -C(O)OR 2a , -C (O)NH 2 , aryl, heteroaryl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocycloalkoxy, aryl, heteroary
  • R 2a is selected from hydrogen, deuterium, halogen, cyano, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocycloalkoxy, aryl, aryloxy radical, heteroaryl, heteroaryloxy, -COOH, -C(O)NH 2 , -C(O)NH(C 1-6 alkyl), -C(O)N(C 1-6 alk group) (C 1-6 alkyl), -S(O)2NH 2 , -S(O)(NH)NH 2 , -C(O)OR a ; wherein the alkyl, alkenyl, alkynyl , cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocycloalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, -C(O)NH 2 , -S( O)
  • R is selected from hydrogen, halogen, cyano, -C 1-6 alkyl, -C 3-6 cycloalkyl;
  • R 1 and R 2 selectively form 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered heterocyclic Alkenyl, aryl, heteroaryl, and optionally substituted by one or more R 1a or R 2a ; and the carbon atoms in the above-mentioned cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl or The sulfur atom can be selectively oxo-substituted to form a part of the ring carbonyl, amide, ester, sulfone (-S(O)2-), sulfonamide (-S(O)2NH-);
  • R 1 and R 2 selectively form a 3-6 membered cycloalkyl group, a 3-6 membered heterocycloalkyl group, and the above-mentioned cycloalkyl group, heterocycloalkyl group,
  • the carbon atoms in can be selectively oxo-substituted to form part of the carbonyl and ester groups in the ring.
  • R 3 is selected from hydrogen, deuterium, C 1-6 alkyl, deuterated alkyl, halogenated C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, cyanoalkyl, -C 3-6 ring Alkyl, -C 3-6 heterocycloalkyl, alkoxyalkyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl;
  • R 3 is selected from C 1-6 alkyl, deuterated alkyl, halogenated C 1-6 alkyl, -C 3-6 cycloalkyl.
  • R is independently selected from heteroaryl, which is a monocyclic aromatic hydrocarbon group with 5, 6 or 7 ring atoms, which contains 1 or 2 N ring heteroatoms in the ring, and the remaining ring atoms is a carbon atom, or is a bicyclic aromatic hydrocarbon group having 9 or 10 ring atoms, which contains 1, 2, 3, or 4 N ring heteroatoms in the ring, the remaining ring atoms being carbon atoms, at least one of which is aromatic ring, and said heteroaryl groups include those in which the N-ring heteroatoms are in the form of N-oxides, and said heteroaryl groups are optionally substituted with one or more substituents selected from : Halogen, deuterium, cyano, hydroxyl, mercapto, C 1-6 alkyl, haloalkyl, cycloalkyl, cycloalkoxy, heterocyclyl, heteroepoxy, -NH 2 , -NH(C 1- 6 alkyl), -N(C
  • R is independently selected from hydrogen, C 1-6 alkyl, hydroxy-substituted alkyl, deuterated alkyl, hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, cycloalkylalkane A group or a cycloalkoxyalkyl group, wherein the alkyl group is optionally substituted by one or more R 5a ;
  • R 5a is selected from deuterium, halogen, CN, alkyl, alkenyl, alkynyl, cycloalkyl , heterocycloalkyl, aryl, heteroaryl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl can be replaced by halogen, CN, -OR a , -SR a , -NR b R c , alkyl, alkenyl, alkynyl, cyclo
  • R 4 and R 5 selectively form a nitrogen-containing heterocyclic group or a heteroaryl group with the N atom jointly connected to the two, wherein the nitrogen-containing heterocyclic group and heteroaryl group can be substituted by one or more Optional substitution with radicals, including but not limited to halogen, deuterium, amino, hydroxyl, mercapto, cyano, alkyl, deuterated alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy radical, heterocycloalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, -COOH, -C(O)NH 2 , -C(O)NH(C 1-6 alkyl ), -C(O)N(C 1-6 alkyl)(C 1-6 alkyl), -S(O)2NH 2 , -S(O)(NH)NH 2 , -C(O)OR
  • R a , R b and R c are independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, -C 2-6 Alkenyl, -C 2-6 alkynyl, -C 3-6 cycloalkyl, -C 3-6 heterocycloalkyl, C 1-6 alkyl substituted by hydroxyl, -C 1-6 alkyl (O) C 1-6 alkyl, aryl, heteroaryl;
  • R b and R c form a 4 to 7-membered heterocycloalkyl group together with the nitrogen atom jointly connected to them or are substituted by 1 to 3 R a .
  • the Ar is selected from aryl or heteroaryl:
  • the aryl group is a carbocyclic hydrocarbon group containing 6-12 ring carbon atoms composed of one or more rings condensed, wherein at least one ring is an aromatic ring and the other rings are not heteroaryl;
  • the aryl and heteroaryl groups are optionally substituted by one or more of the following substituents: hydrogen, deuterium, halogen, cyano, hydroxyl, mercapto, -C 1-6 alkyl, haloalkyl, alkane Oxy, haloalkoxy, haloalkoxyalkyl, cycloalkyl, halocycloalkyl, -(C 1-6 alkyl)OH and -SO2(C 1-6 alkyl), alkenyl, alkynyl .
  • the Ar is selected from aryl or heteroaryl, and the aryl or heteroaryl is selected from aryl and heteroaryl with 6 ring atoms, heteroaryl with 5 ring atoms, Bicyclic heteroaryl or aromatic groups having 9 or 10 ring atoms;
  • aryl and/or the heteroaryl include phenyl, deuterated phenyl, naphthyl, pyridyl, pyrimidine, pyridazine, piperazine, pyrazolyl, imidazolyl, quinolinyl, thienyl, Benzothienyl, indolyl, optionally substituted by one or more of the following substituents: deuterium, halogen, cyano, hydroxyl, -C 1-6 alkyl, -(C 1-6 alkane group) OH, C 1-6 haloalkyl and -SO2(C 1-6 alkyl).
  • the Ar is selected from the following groups:
  • the above groups are optionally substituted by one or more substituents selected from the group consisting of hydrogen, halogen, deuterium, cyano, hydroxyl, amino, C 1-3 alkyl, C 1-3 alkoxy, C 1 -3 haloalkyl, -O - , -S(O) 2 (C 1-3 alkyl).
  • R4 is selected from heteroaryl, or R4 and R5 form a heteroaryl
  • said heteroaryl is a monocyclic aromatic hydrocarbon group with 6 ring atoms, which contains 1 or 2 N ring heteroatoms in the ring, and the remaining ring atoms are carbon atoms, or a bicyclic aromatic hydrocarbon group with 9 ring atoms An aromatic hydrocarbon group containing 3 or 4 N ring heteroatoms in the ring, the remaining ring atoms being carbon atoms, wherein at least one ring is an aromatic ring and the heteroaryl group is optionally selected from one of the following substituents or Multiple substitutions: halogen, cyano, hydroxyl, mercapto, C 1-6 alkyl, haloalkyl, cycloalkyl, -O(C 1-6 alkyl) and -O(C 1-6 haloalkyl), - NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl)(C 1-6 alkyl), -CO 2 H, -C(O)NH 2 ,
  • R 4 is selected from heteroaryl, or R 4 and R 5 form a heteroaryl
  • heteroaryl is a monocyclic aromatic hydrocarbon group with 6 ring atoms, which contains 1 or 2 N ring heteroatoms in the ring, and the remaining ring atoms are carbon atoms, or a bicyclic aromatic hydrocarbon group with 9 ring atoms
  • An aromatic hydrocarbon group comprising 3 or 4 N ring heteroatoms in the ring, the remaining ring atoms being carbon atoms, wherein at least one ring is an aromatic ring and the heteroaryl group is optionally selected from one or more of Substituent substitution: fluorine, chlorine, bromine, cyano, hydroxyl, mercapto, haloalkyl, C 1-6 alkyl, -NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl) (C 1-6 alkyl), -CO 2 H, -C(O)NH 2 , -C(O)NH(C 1-6 alkyl), phenyl, pyridyl, pyrimidin
  • the phenyl, pyridyl, pyrazolyl, imidazolyl, triazolyl and tetrazolyl in the R are optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, mercapto , amino, C 1-6 alkyl, haloalkyl, cycloalkyl, -O(C 1-6 alkyl) and -O(C 1-6 haloalkyl).
  • aryl group in the heteroaryl group is selected from pyrimidine, purinyl, pyrazolopyrimidine and pyrrolopyrimidine.
  • R 4 or the heteroaryl group formed by R 4 and R 5 is selected from the substituents shown below
  • the substituents are optionally substituted by one or more of the following substituents: fluorine, chlorine, bromine, cyano, hydroxyl, mercapto, haloalkyl, C 1-6 alkyl, -NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl)(C 1-6 alkyl), -CO 2 H, -CONH 2 , -C(O)NH(C 1-6 alkyl ), phenyl, pyridyl, pyrazolyl, imidazolyl, oxazolyl, triazolyl and tetrazolyl, wherein the phenyl, pyridyl, pyrimidinyl, piperazinyl, pyridazinyl as R substituent , pyrazolyl, imidazolyl, triazolyl and tetrazolyl are optionally substituted by one or more of the following substituents: halogen, hydroxyl,
  • R4 is selected from Any of the substituents, R4 is optionally substituted by one or more of the following substituents: fluorine, chlorine, bromine, cyano, haloalkyl, C 1-6 alkyl, -NH 2 , NH(C 1-6 alkyl), -CO2H, -CONH 2 , phenyl, pyridyl, pyrazolyl, triazolyl and tetrazolyl,
  • R substituents are optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, C 1- 6 alkyl and -O(C 1-6 alkyl).
  • R 3 is C 1-4 alkyl and C 1-4 haloalkyl.
  • R 3 is methyl, ethyl and trifluoromethyl.
  • PI3K-mediated related diseases include diseases responsive to inhibition of PI3K, including autoinflammatory diseases, respiratory diseases, infectious diseases, autoimmune diseases and cancers.
  • PI3K PI3K ⁇ .
  • the disease is selected from cancer, inflammation, respiratory disease, infectious disease, bone marrow related disease and autoimmune disease.
  • cancers are solid tumors, leukemia, lymphoma and multiple myeloma.
  • Leukemia may be selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and chronic myelogenous leukemia (CML); said lymphoma is selected from Hodgkin's lymphoma, non-Hodgkin's lymphoma Nodular lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, B-cell lymphoma, -cell lymphoma, and diffuse large B-cell lymphoma; the autoimmune disease, inflammatory Disease, respiratory disease, bone marrow related disease and infectious disease may be selected from skin inflammation, rheumatoid arthritis, allergic rhinitis, asthma, Klinefelter's disease, chronic obstructive pulmonary disease (COPD), systemic lupus erythematosus,
  • the cancer is a solid tumor, including breast cancer, melanoma, head and neck cancer, lung cancer, thymus cancer and hematological malignancies.
  • the third aspect of the present invention provides a pharmaceutical composition, which comprises any compound of the above formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition is used in combination with small molecule compounds and/or macromolecular antibodies to treat cancer, inflammation, bone marrow-related diseases and autoimmune diseases.
  • small molecule compounds include BTK inhibitors and Bcl2 inhibitors.
  • macromolecular antibodies include anti-CD20, anti-CTLA4, anti-PD-1, anti-PD-L1 antibodies.
  • the fourth aspect of the present invention provides the use of any of the above-mentioned pharmaceutical compositions in the treatment of related diseases mediated by PI3K, wherein the diseases are selected from cancer, inflammation, respiratory diseases, infectious diseases, bone marrow-related diseases and autoimmunity disease.
  • a solvate, a racemic mixture, an enantiomer, a diastereomer, a tautomer or a racemic mixture of any of the above-mentioned compounds of formula (I) A mixture thereof in any proportion, wherein each substituent of R 1 , R 2 , R 3 , R 4 and R 5 is as defined above.
  • the seventh aspect of the present invention provides a method for inhibiting PI3K activity in vivo or in vitro by any compound of formula (I) above, which comprises making an effective dose of any compound of formula (I) above and/or a pharmaceutically acceptable salt thereof Contact with PI3K kinases.
  • the PI3K kinase is any one or more of PI3K ⁇ , PI3K ⁇ , PI3K ⁇ , and PI3K ⁇ . Further, the PI3K kinase is PI3K ⁇ .
  • the compounds of the invention may be asymmetric, for example having one or more stereocenters. Unless otherwise specified, all stereoisomers, for example, are enantiomers and diastereomers. Containing asymmetrically substituted carbon atoms.
  • the compounds of the invention may be isolated in optically pure or racemic forms. Optically pure forms can be prepared by resolution of racemates, or by use of chiral synthons or chiral reagents.
  • the compounds of the present invention may also include tautomeric forms.
  • New forms of tautomers result from the interchange of a single bond with an adjacent double bond together with migration of a proton.
  • the compounds of the invention may also include all isotopic forms of atoms present in intermediates or final compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium.
  • the present invention also includes pharmaceutically acceptable salts of compounds of formula (I).
  • Pharmaceutically acceptable salts are derivatives of compounds of formula (I) wherein the parent compound is modified by the presence of a base moiety into its salt form, or wherein the parent compound is converted into its salt form by the presence of an acid moiety and modified derivatives of compounds of formula (I).
  • examples of pharmaceutically acceptable salts include, but are not limited to: salts of inorganic or organic acids with basic groups such as amines, or salts of inorganic or organic bases with acidic groups such as carboxylic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compounds of formula (I) by reacting the free base forms of these compounds with 1-4 equivalents of the appropriate acid in a solvent system. Suitable salts are listed in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977).
  • the compounds of the present invention and their pharmaceutically acceptable salts also include solvated or hydrated forms.
  • solvated or hydrated forms are equivalent to unsolvated or nonhydrated forms and are included within the scope of the present invention.
  • Some of the compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms of the compounds are included within the scope of the present invention.
  • the present invention is further illustrated by the examples below, and the examples are only used to more specifically illustrate preferred embodiments of the present invention, and are not intended to limit the technical solution of the present invention.
  • the above-mentioned solutions of the present invention are all technical solutions that can realize the object of the present invention.
  • the temperature and reagents used in the following examples can be replaced by the above-mentioned corresponding temperatures and reagents to achieve the purpose of the present invention.
  • a dash ("-") between two letters or symbols indicates the point of attachment of a substituent.
  • -O(C 1-4 alkyl) refers to a C 1-4 alkyl group attached to the rest of the molecule through an oxygen atom.
  • "-" can be omitted.
  • alkyl refers to a straight or branched chain containing 1-18 carbon atoms, such as 1-12 carbon atoms, another example 1-6 carbon atoms, another example 1-4 carbon atoms Saturated hydrocarbon group.
  • C1-6 alkyl within the scope of “alkyl” means the said alkyl group having 1-6 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (“Me”), ethyl (“Et”), n-propyl (“n-Pr”), isopropyl (“i-Pr”), n-butyl ( “n-Bu”), isobutyl (“i-Bu”), sec-butyl (“sBu”) and tert-butyl (“t-Bu”).
  • C2-6 alkenyl within the scope of “alkenyl” means the said alkenyl group having 2-6 carbon atoms.
  • alkenyl groups include, but are not limited to, ethenyl, 2-propenyl, and 2-butenyl.
  • alkynyl refers to a group containing one or more, such as 1, 2 or 3 carbon-carbon triple bonds (C ⁇ C), containing 2-10 carbon atoms, such as 2-6 carbon atoms, Another example is a straight chain or branched chain hydrocarbon group with 2-4 carbon atoms.
  • C 2-6 alkynyl means said alkynyl group containing 1 carbon-carbon triple bond (C ⁇ C) and having 2-6 carbon atoms.
  • alkynyl include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl.
  • alkoxy refers to the group -O-alkyl, wherein alkyl is as defined above.
  • alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, and hexyloxy, including their isomers.
  • Heterocyclyl or “heterocyclic” also refers to a single ring containing at least one heteroatom selected from O, S and N; or a fused ring wherein at least one ring contains at least one heteroatom selected from O, S and N and the other ring is not heteroaryl or aryl, the point of attachment can be on the heterocycle or on the other ring.
  • cycloalkoxy refers to the group -O-cycloalkyl, wherein cycloalkyl is as defined above.
  • examples of cycloalkoxy include, but are not limited to, cyclopropyloxy, cyclobutyloxy, including isomers thereof.
  • heterocycloalkoxy refers to the group -O-heterocycloalkyl, wherein heterocycloalkyl is as defined above.
  • examples of cycloalkoxy include, but are not limited to, aziridinyloxy, epoxypropyleneoxy, azetidinyloxy, oxetanyloxy, including isomers thereof.
  • cycloalkenyl refers to one or more, such as 1, 2 or 3 carbon-carbon double bonds, containing 3-12 ring carbon atoms, preferably 3-8 ring carbon atoms, more preferably A non-aromatic cyclic hydroxyl group of 3-6 ring carbon atoms, which may have one or more rings, preferably one or two rings.
  • C 3-8 ring carbon atoms and cycloalkenyl preferably "C 3-6 cycloalkenyl", that is, the cycloalkenyl with 3-6 ring carbon atoms.
  • cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • aryl refers to a carbocyclic hydrocarbon group consisting of one or more fused rings containing 6-14 ring carbon atoms, for example 6-12 ring carbon atoms, wherein Where at least one ring is aromatic and the other ring is not heteroaryl as defined below, the point of attachment may be on the aromatic ring or on the other ring.
  • aryl groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indenyl, indanyl, azulenyl, preferably phenyl and naphthyl.
  • aryl or “aromatic” follows Hückel's rule, where the number of pi electrons is equal to 4n+2, and n is zero or any positive integer up to six.
  • heterocyclyl refers to a ring selected from 4 to 12 membered monocyclic, bicyclic and tricyclic, saturated and partially unsaturated rings, which, in addition to containing at least one, such as In addition to 1-4, further such as 1-3 or further such as 1 or 2 heteroatoms selected from O, S and N, it also contains at least one carbon atom.
  • the point of attachment of a heterocyclyl group can be at a heteroatom or at a carbon.
  • Heterocyclyl or “heterocyclic” also refers to a single ring containing at least one heteroatom selected from O, S and N; or a fused ring wherein at least one ring contains at least one heteroatom selected from O, S and N and the other ring is not heteroaryl or aryl, the point of attachment can be on the heterocycle or on the other ring.
  • heteroaryl refers to a monocyclic aromatic hydrocarbon group having 5, 6 or 7 ring atoms, for example 6 ring atoms, which contains one or more one, such as 1, 2 or 3, such as 1 or 2 ring heteroatoms independently selected from N, O and S (such as N), the remaining ring atoms being carbon atoms; and having 8-12 ring atoms, such as A bicyclic aromatic hydrocarbon group having 9 or 10 ring atoms, which contains one or more, such as 1, 2, 3 or 4, such as 1 or 2, independently selected from N, O and S (such as N) ring heteroatoms, the remaining ring atoms are carbon atoms, at least one of which is an aromatic ring.
  • a bicyclic heteroaryl includes a 5-6 membered heteroaryl ring fused to a 5-6 membered cycloalkyl ring, heterocyclyl ring, or aryl ring, where the point of attachment can be at the heteroaryl ring or at On cycloalkyl ring/heterocyclyl ring/aryl ring.
  • the total number of S and O atoms in the heteroaryl exceeds 1, these S and O heteroatoms are not adjacent to each other.
  • Heteroaryl also includes those in which the N-ring heteroatom is in the form of an N-oxide, eg, N-oxypyrimidinyl.
  • the ring heteroatoms in the above-mentioned heteroaryl groups are N atoms, and such heteroaryl groups are referred to as "nitrogen-containing heteroaryl groups".
  • Nitrogen-containing heteroaryl groups also include those in which the N-ring heteroatom is in the form of an N-oxide, such as pyridinyl N-oxide.
  • heteroaryl groups include, but are not limited to: pyridyl, pyridyl N-oxide; pyrazinyl; pyrimidinyl; pyrazolyl; imidazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; Diazolyl; tetrazolyl; triazolyl; thienyl; furyl; pyryl; pyrrolyl; pyridazinyl; benzo[d]thiazolyl; benzodioxolyl, e.g.
  • nitrogen-containing heteroaryl groups include, but are not limited to: pyrrolyl; pyrazolyl; imidazolyl; pyridyl; pyrazinyl; pyrimidinyl, N-oxypyrimidinyl; pyridazinyl; [3,4-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl; purinyl, such as 9H-purinyl and 7H-purinyl; quinolinyl; indolyl; and indazolyl .
  • hydroxyl refers to the -OH group.
  • mercapto refers to a -SH group.
  • cyano refers to a -CN group.
  • amino refers to a -NH2 group.
  • group and “radical” are synonymous terms used to denote functional groups or molecular fragments that can be attached to other molecular fragments.
  • a structural formula herein contains an asterisk "*"
  • the compound represented by the structural formula is a chiral compound, that is, the compound is in R-configuration or S-configuration.
  • the configuration of a compound can be determined by one skilled in the art using a variety of analytical techniques, such as single crystal X-ray crystallography and/or optical polarimetry, and according to routine protocols.
  • substitution pattern As used herein, the terms “optional”, “selective”, “optionally”, “optionally”, “optionally” or “optionally” mean that the subsequently described substitution pattern, event or circumstance can occur One or more times, or may not occur, and the description includes instances where the substitution pattern occurs and instances where the substitution pattern does not occur.
  • “optionally substituted alkyl” includes “unsubstituted alkyl” and “substituted alkyl” as defined herein.
  • substituted or “substituted by” as used herein means that one or more hydrogen atoms on a given atom or group are replaced by one or more substituents selected from a given group of substituents, Provided that the normal valence for that given atom is not exceeded.
  • two hydrogen atoms on a single atom are replaced by oxygen.
  • substituents and/or variables are permissible only if such combinations result in chemically correct and stable compounds.
  • a chemically correct and stable compound means that the compound is sufficiently stable that it can be isolated from a reaction mixture and the chemical structure of the compound can be determined, and subsequently formulated into a preparation that is at least practical.
  • substituents are named into the core structure.
  • (cycloalkyl)alkyl is listed as a possible substituent, it means that the point of attachment of the substituent to the core structure is at the alkyl moiety.
  • substituted with one or more substituents means that one or more hydrogen atoms on a given atom or group are independently replaced by one or more substituents selected from the given group.
  • substituted with one or more substituents means that a given atom or group is substituted with 1, 2, 3 or 4 substituents independently selected from the given group.
  • some compounds of formula (I) may contain one or more chiral centers and thus exist as two or more stereoisomers. Racemic mixtures of these isomers, individual isomers and one enantiomerically enriched mixture, as well as diastereomers and specific diastereomers when there are two chiral centers Constructively partially enriched mixtures are within the scope of the present invention. Those skilled in the art will also understand that the present invention includes all individual stereoisomers (such as enantiomers), racemic mixtures or partially resolved mixtures of compounds of formula (I), and where appropriate In this case, the individual tautomers thereof are included.
  • the invention provides compounds that contain multiple stereoisomeric purities, ie, diastereomeric or enantiomeric purities expressed as different "ee” or “de” values.
  • the compound of formula (I) eg, as described herein
  • has at least 60% ee eg, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% ee, or any value between these recited values) enantiomeric purity).
  • compounds of formula (I) have an enantiomeric purity of greater than 99.9% ee, up to 100% ee.
  • the compound of formula (I) eg, as described herein
  • has at least 60% de eg, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%de, or any value between these recited values) of diastereomeric purity.
  • compounds of Formula (I), such as described herein have a diastereomeric purity of greater than 99.9% de.
  • enantiomeric excess or "ee” means the amount of one enantiomer relative to the other.
  • the percentage of enantiomeric excess is defined as ([a]obs/[a]max)*100, where [a]obs is the optical rotation of the mixture of enantiomers, [ a]max is the optical rotation of the pure enantiomer.
  • diastereomeric excess indicates the amount of one diastereoisomer relative to the other and is defined by analogy in terms of enantiomeric excess.
  • Diastereomers and/or enantiomeric excess can be determined using a variety of analytical techniques, including nuclear magnetic resonance spectroscopy, chiral column chromatography and/or optical polarimetry, and according to routine protocols familiar to those skilled in the art To be done.
  • diastereoisomeric salts to obtain individual isomers from the mixture by chemical separation, fractional crystallization of said salts, followed by freeing one or both of the resolved bases, optionally repeating the process, Thereby obtaining one or both isomers substantially free of the other isomer, i.e. having an optical purity of, for example, at least 91%, 92%, 93%, 94%, 95%, 96%, 97% by weight , 98%, 99%, or 99.5% of the desired stereoisomer.
  • the racemate can be covalently attached to a chiral compound (auxiliary) to give diastereoisomers, which can be separated by chromatography or fractional crystallization, followed by Chemical removal of the chiral auxiliary affords the pure enantiomer.
  • the "pharmaceutically acceptable salt” of the present invention refers to the free acid or base of the compound of formula (I) that is non-toxic, biologically tolerable or other biologically suitable for administering to an individual for treatment. Salt. .
  • “Pharmaceutically acceptable salts” include, but are not limited to: acid addition salts formed by compounds of formula (I) and inorganic acids, such as hydrochloride, hydrobromide, carbonate, bicarbonate, phosphate, Sulfates, sulfites, nitrates, etc.; and acid addition salts of compounds of formula (I) with organic acids, such as formate, acetate, malate, maleate, fumarate , tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, benzoate, salicylate, stearate and Salts with alkanedicarboxylic acids of formula HOOC-(CH2)n-COOH wherein n is 0-4, and the like.
  • “Pharmaceutically acceptable salts” also include base addition salts of compounds of formula (I) bearing acidic groups with pharmaceutically acceptable cations such as sodium, potassium, calcium, aluminum, lithium and ammonium.
  • the molar ratio of the compound of formula (I) to the acid or cation in the resulting pharmaceutically acceptable salt includes but is not limited to 1:1, 1:2, 1:3 and 1:4.
  • prodrug in the present invention refers to a pharmacological substance (ie drug) derived from a parent drug, which is metabolized into the parent drug in vivo after administration.
  • Prodrugs can be prepared by substituting one or more functional groups present on a compound, wherein the substituents in the prodrug are removed in vivo in such a way as to convert them to the parent compound.
  • the preparation and use of prodrugs can be found in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol.14 of the A.C.S. Symposium Series and Bioreversible.
  • Prodrugs include, but are not limited to: esters of compounds of formula (I) such as phosphates, formates, carbamates; amides such as formamide and acetamide.
  • a compound described herein is obtained in the form of an acid addition salt, its free base form can be obtained by basifying a solution of the acid addition salt.
  • its acid addition salts especially pharmaceutically acceptable acid addition salts, may be prepared by dissolving the free base in a suitable solvent and treating the solution with acid.
  • solvate means a solvent addition form comprising stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to recruit a fixed molar ratio of solvent molecules in the solid state, thereby forming solvates. If the solvent is water, the solvate formed is a hydrate, and when the solvent is ethanol, the solvate formed is an ethanolate. Hydrates are formed by one or more molecules of water and one molecule of said substance, wherein the water retains its molecular state of H2O, such combination can form one or more hydrates, such as hemihydrate, monohydrate and dihydrates, and variable hydrates.
  • group and “radical” are synonymous and are used to denote functional groups or molecular fragments that can be linked to other molecular fragments.
  • active ingredient is used to denote a chemical substance that has biological activity.
  • an “active ingredient” is a chemical substance that has pharmaceutical use.
  • actual drug activity may be determined by appropriate preclinical testing, either in vitro or in vivo.
  • drug activity that is sufficient to be accepted by regulatory agencies (such as the FDA in the United States) requires a higher standard than preclinical trials. The success of such a higher standard of drug activity cannot generally be reasonably expected from preclinical test results, but can be obtained through appropriate and effective randomized, double-blind, controlled clinical trials in humans to establish.
  • treating means giving the disease or disorder, or symptoms of, or predisposition to, the disease or disorder.
  • the disease or disorder is cancer.
  • treating when referring to a chemical reaction mean adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or desired product. It should be understood that the reaction leading to the shown and/or desired product may not necessarily result directly from the combination of the two reagents initially added, i.e. there may be one or more intermediates formed in the mixture which forms ultimately lead to the formation of the shown and/or desired products.
  • the term "effective amount” refers to an amount or dose of a PI3K inhibitor generally sufficient to produce a beneficial therapeutic effect on a patient in need of treatment of a disease or disorder mediated by PI3K activity. It can be done by conventional methods (such as modeling, dose escalation studies or clinical trials) in combination with conventional influencing factors (such as the mode or route of administration or administration, pharmacokinetics of the pharmaceutical ingredients, the severity and course of the disease or disorder, individual).
  • the effective amount or dosage of the active ingredients in the present invention is determined based on previous or ongoing treatment, the individual's health status and response to the drugs, and the judgment of the attending physician. In the United States, the determination of effective doses is generally difficult to predict from preclinical trials. In fact, dosing is completely unpredictable, and new unpredictable dosing regimens are developed after the original dose was used in a randomized, double-blind, controlled clinical trial.
  • Typical dosage ranges are from about 0.0001 to about 200 mg active ingredient per kg body weight of the subject per day, for example from about 0.001 to 100 mg/kg/day, or from about 0.01 to 35 mg/kg/day, or from about 0.1 to 10 mg/kg once daily or in divided dosage units (eg, twice daily, three times daily, four times daily).
  • suitable dosages may range from about 0.05 to about 7 grams per day, or from about 0.2 to about 5 grams per day.
  • inhibitor refers to a reduction in the baseline activity of a biological activity or process.
  • inhibitor PI3K activity is the actual pharmaceutical activity used for the purpose of the present invention, and refers to the effect on the presence of the formula (I) described herein relative to the PI3K activity in the absence of the compound of formula (I) and/or its pharmaceutically acceptable salt.
  • the reduction of PI3K activity caused by the direct or indirect response of the compound and/or its pharmaceutically acceptable salt.
  • the decrease in activity may be caused by the direct interaction between the compound of formula (I) described herein and/or its pharmaceutically acceptable salt and PI3K, or by the compound of formula (I) described herein and/or its pharmaceutical
  • the above-acceptable salt interacts with one or more other factors to affect the activity of PI3K.
  • the presence of a compound of formula (I) described herein and/or a pharmaceutically acceptable salt thereof can reduce the activity of PI3K by directly binding to PI3K, and can reduce the activity of PI3K by directly or indirectly affecting another factor. activity, or reduce the activity of PI3K by directly or indirectly reducing the amount of PI3K present in cells or organisms.
  • the palladium-catalyzed carbon-carbon coupling reaction can be carried out under suitable conditions: such as in a suitable polar solvent such as DMF, ACN, THF or DMSO, etc.; in a suitable base such as TEA, DIEPA, Cs 2 CO 3 , KOAc etc.; use catalysts such as Pd(OAc) 2 , Pd(dppf) 2 Cl 2 , Pd(PPh 3 ) 4 or Pd 2 (dba) 3 and so on.
  • a suitable polar solvent such as DMF, ACN, THF or DMSO, etc.
  • a suitable base such as TEA, DIEPA, Cs 2 CO 3 , KOAc etc.
  • catalysts such as Pd(OAc) 2 , Pd(dppf) 2 Cl 2 , Pd(PPh 3 ) 4 or Pd 2 (dba) 3 and so on.
  • the next reaction can be carried out as follows:
  • the compound of formula i-4 is reacted with ester hydrolysis to obtain the compound acid of formula i-5.
  • the compound acid of formula i-5 is reacted with N,O-dimethylhydroxylamine to obtain the amide compound of formula i-6.
  • the compound of formula i-6 is reacted with Grignard reagent (alkylmagnesium halide) under appropriate conditions to generate the compound of formula i-7.
  • the compound of formula i-8 is obtained by introducing halogen into the compound of formula i-7 under appropriate conditions, or the compound of formula i-8 is obtained by further modifying the obtained halide.
  • the compound of formula i-4 can be synthesized from another route.
  • the compound of formula i-12 is reacted with ethyl acetate under basic conditions to obtain the compound of formula i-13.
  • the compound of formula i-13 and DMF-DMA are refluxed in toluene, and then the concentrated reaction is further reacted with the compound of formula i-1 under acidic conditions to generate the compound of formula i-4.
  • a compound of formula (I) described herein (eg, any compound herein) and/or a pharmaceutically acceptable salt thereof may be formulated into a pharmaceutical composition alone or in combination with one or more additional active ingredients.
  • the pharmaceutical composition comprises: (a) an effective amount of a compound of formula (I) described herein and/or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable excipient (eg, a pharmaceutically acceptable carrier).
  • a pharmaceutically acceptable carrier is one that is compatible with (and, in some embodiments, stabilizes) the active ingredients in the composition and not deleterious to the individual being treated.
  • solubilizers such as cyclodextrins, which are capable of forming specific, more soluble complexes with compounds of formula (I) described herein and/or pharmaceutically acceptable salts thereof, can be used as pharmaceutical excipients agent to deliver the active ingredient.
  • examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and colors such as D&C Yellow #10. Suitable pharmaceutically acceptable carriers are disclosed in a standard reference text in the field (Remington's Pharmaceutical Sciences, A. Osol).
  • compositions comprising a compound of formula (I) described herein (e.g., any compound herein) and/or a pharmaceutically acceptable salt thereof may be administered in various known ways, for example, orally, topically, rectally, gastrointestinally Administered externally, inhaled or implanted.
  • parenteral as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intraspinal, intralesional and intracranial injection or infusion.
  • the pharmaceutical composition described herein can be prepared in the form of tablets, capsules, bagged granules, sugar-coated pills, powders, granules, buccal tablets, powder injections, liquid preparations or suppositories.
  • the pharmaceutical composition comprising the compound of formula (I) and/or a pharmaceutically acceptable salt thereof can be formulated for intravenous infusion, topical administration or oral administration.
  • Compositions for oral administration may be in any orally acceptable dosage form including, but not limited to, tablets, capsules, emulsions, and aqueous suspensions, dispersions, and solutions.
  • Common tablet carriers include lactose and corn starch.
  • Lubricants such as magnesium stearate are also often added to tablets.
  • useful diluents include lactose and dried cornstarch.
  • the active ingredient When administered orally in the form of an aqueous suspension or emulsion, the active ingredient can be suspended or dissolved in the oily phase with emulsifying or suspending agents. Certain sweetening, flavoring or coloring agents can also be added, if desired.
  • Fatty acids such as oleic acid and its glyceride derivatives
  • natural pharmaceutically-acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated versions, are commonly employed as intermediates for injectables.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents.
  • compositions for inhalation may be prepared according to techniques well known in the art of pharmaceutical formulation, using benzyl alcohol or other suitable preservatives, using absorption enhancers to enhance bioavailability, using fluorocarbons and/or other solubilizing or dispersing agents known in the art. It can also be prepared as a solution in saline.
  • Topical compositions may be formulated as oils, creams, lotions, ointments, and the like.
  • suitable carriers for the composition include vegetable or mineral oil, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohols (ie, those having greater than 12 carbon atoms).
  • a pharmaceutically acceptable carrier is one in which the active ingredient is soluble.
  • the composition if desired, may also contain emulsifiers, stabilizers, wetting agents and antioxidants, as well as substances imparting color or flavor thereto.
  • transdermal penetration enhancers may be added to topical formulations. Examples of such accelerators can be found in US Patent Nos. 3,989,816 and 4,444,762.
  • a cream may be formulated from a mixture of mineral oil, self-emulsifying beeswax and water, into which the active ingredient is incorporated dissolved in a small amount of fat, such as almond oil.
  • An example of a cream comprises, by weight, about 40 parts water, about 20 parts beeswax, about 40 parts mineral oil, and about 1 part almond oil.
  • An ointment can be formulated by mixing a solution of the active ingredient in a vegetable oil, such as almond oil, with warm soft paraffin and cooling the mixture.
  • An example of an ointment comprises, by weight, about 30% almond oil and about 70% white soft paraffin.
  • Suitable in vitro assays can be used to evaluate the practical use of compounds of formula (I) and/or pharmaceutically acceptable salts thereof described herein in inhibiting PI3K activity. Further practical use of the compounds of formula (I) and/or pharmaceutically acceptable salts thereof described herein in the treatment of cancer or autoimmune diseases can be further tested by in vivo assays.
  • the compound of formula (I) described herein and/or a pharmaceutically acceptable salt thereof can be administered to animals (such as mouse models) suffering from cancer or autoimmune diseases, and then the therapeutic effect can be evaluated if the clinical The results of the previous tests were successful and its dosage range and route of administration in animals such as humans can also be predicted.
  • the compounds of formula (I) described herein and/or pharmaceutically acceptable salts thereof may show sufficient preclinical practical use to be worthy of clinical trials, and are expected to show beneficial therapeutic or prophylactic effects, for example, in patients with A beneficial therapeutic or prophylactic effect is shown in individuals with cancer.
  • cancer refers to a cellular disorder characterized by uncontrolled or dysregulated cell proliferation, reduced cell differentiation, inappropriate ability to invade surrounding tissues, and/or the ability to establish new growth foci elsewhere.
  • cancer includes, but is not limited to: solid tumors and hematological malignancies.
  • cancer includes cancers of the skin, tissues, organs, bones, cartilage, blood and blood vessels.
  • cancer includes both primary and metastatic cancers.
  • Non-limiting examples of hematological malignancies include acute myeloid leukemia (AML); chronic myeloid leukemia (CML), including accelerated phase CML and CML blast phase (CML-BP); acute lymphoblastic leukemia (ALL); Cellular leukemia (CLL); Hodgkin lymphoma; non-Hodgkin lymphoma (NHL), including follicular lymphoma and mantle cell lymphoma; B-cell lymphoma; T-cell lymphoma; multiple myeloma (MM ); Waldenstrom's macroglobulinemia; myelodysplastic syndrome (MDS), including refractory anemia (refractory anemia, RA), ring sideroblastic refractory anemia (refractory anemia with ringed siderblast (RARS), refractory anemia with excess blast (RAEB), and refractory anemia with excess blast in transformation (RAEB-T); and Myeloproliferative syndrome (myelop
  • typical hematological malignancies include leukemias, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML); multiple Myeloma (MM); and lymphomas such as Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, B-cell lymphoma, T-cell lymphoma and diffuse large B-cell lymphoma (DLBCL).
  • ALL acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • CML chronic myelogenous leukemia
  • MM multiple Myeloma
  • lymphomas such as Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), mant
  • inflammatory disease refers to a pathological state leading to an inflammatory response, especially due to neutrophil chemotaxis.
  • diseases include inflammatory skin diseases (including psoriasis and atopic dermatitis); systemic scleroderma and sclerosis; and inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis )-related reactions; ischemia-reperfusion injury, including surgery-induced tissue reperfusion injury, myocardial ischemia such as myocardial infarction, cardiac arrest, postcardiac reperfusion, and abnormal contractile response of coronary vessels after percutaneous coronary angioplasty , stroke and abdominal aortic aneurysm surgical tissue reperfusion injury; cerebral edema secondary to stroke; traumatic head injury; hemorrhagic shock; asphyxia; adult respiratory distress syndrome; acute lung injury; Behcet's disease; dermatomyositis; polymyositis multiple sclerosis (MS); dermatitis;
  • Preferred indications include, but are not limited to, chronic inflammation, autoimmune diabetes, rheumatoid arthritis (RA), rheumatoid spondylitis, gouty arthritis and other arthritic conditions, multiple sclerosis (MS) , asthma, systemic lupus erythematosus, adult respiratory distress syndrome, Behcet's disease, psoriasis, chronic pulmonary inflammatory disease, graft versus host reaction, Crohn's disease, ulcerative colitis, inflammatory bowel disease (IBD), Alzheimer's disease and paralysis.
  • RA rheumatoid arthritis
  • MS multiple sclerosis
  • pulmonary disease refers to pathological conditions associated with the lung organ.
  • diseases include bronchiectasis, idiopathic pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, pneumonia, acute lung injury, acute respiratory distress syndrome.
  • bone marrow-related disease refers to a pathological condition associated with the bone marrow organ.
  • diseases include myelofibrosis, polycythemia vera.
  • autoimmune disease refers to a disease or disease caused by the body's immune response to self-antigens, resulting in damage to its own tissues or organs.
  • autoimmune diseases include, but are not limited to: Chronic Obstructive Pulmonary Disease (COPD), Allergic Rhinitis, Lupus Erythematosus, Myasthenia Gravis, Multiple Sclerosis (MS), Rheumatoid Arthritis (RA), Psoriasis , inflammatory bowel disease (IBD), asthma, and idiopathic thrombocytopenic purpura, and myeloid proliferative disorders such as myelofibrosis, polycythemia vera/essential platelets Polycythemia vera/essential thrombocytosis myelofibrosis (PV/ET).
  • COPD Chronic Obstructive Pulmonary Disease
  • RA Rheumatoid Arthritis
  • IBD inflammatory bowel disease
  • myeloid proliferative disorders such as myel
  • compounds of formula (I) described herein may be administered in combination with additional active ingredients for the treatment of cancer, inflammatory or autoimmune disease.
  • the additional active ingredient may be administered separately from the compound of formula (I) described herein and/or a pharmaceutically acceptable salt thereof, or it may be included in a pharmaceutical composition according to the present disclosure, such as a fixed dose combination .
  • the additional active ingredients are those known or found to be effective in the treatment of diseases mediated by PI3K activity, such as another PI3K modulator or an agent effective to antagonize the specific Compounds for another target associated with the disease.
  • Combinations may be used to increase efficacy (for example, by including in the combination a compound that enhances the potency or effectiveness of a compound of formula (I) described herein and/or a pharmaceutically acceptable salt thereof), reducing One or more side effects, or a reduction in the required dose of a compound of formula (I) described herein and/or a pharmaceutically acceptable salt thereof.
  • Embodiment 1 the synthesis of target molecule
  • N-methoxy-N-methyl 5-phenylpyrazol[1,5-a]pyrimidine-6-carboxamide 730 mg, 2.59 mmol was dissolved in THF (10 ml ), then methyl Grignard reagent MeMgBr (1.9 mL, 3.0 M, 5.7 mmol, 2.2 eq) was added dropwise. Stir at room temperature for 4 hours, quench the reaction with saturated aqueous ammonium chloride solution (15 mL), extract with ethyl acetate (3x30 mL), combine the organic phases, dry over anhydrous Na 2 SO 4 , filter and concentrate to obtain the primary product.
  • (+)-DIPCl (3M in THF) (5.8mL, 17.5mmol) was added dropwise to a solution of 95-6 (1.6g, 7mmol) in THF (30mL). Stir at room temperature for 2 After hours, water was added and extracted with ethyl acetate. It was dried over anhydrous Na2SO4, filtered, concentrated, and purified by flash column chromatography to give yellow solid 95-7 (1 g, 58.3%).
  • NCS 625 mg, 4.68 mmol
  • ACN 20 mL
  • Water was added and extracted with ethyl acetate. It was dried over anhydrous Na2SO4, filtered, concentrated, and purified by flash column chromatography to give the product 105-7 as a yellow solid (1.16g, 3.67mmol, 94.31%).
  • Embodiment 2 Measuring PI3K enzyme activity by fluorescence method
  • PI3K kinases including PIK3CG were purchased from Invitrogen, p110 ⁇ /p85 ⁇ , p110 ⁇ /p85 ⁇ and p110 ⁇ /p85 ⁇ were purchased from BPS.
  • ADP-Glo TM Kinase Assay (ADP-Glo TM Kinase Assay Kit) (Promega, v9102) is a luminescent kinase assay kit that detects the ADP formed in the kinase reaction; ADP is converted into ATP, and then ATP is regenerated Converted to a light signal by Ultra-Glo TM luciferase. Luminescent signal correlates positively with kinase activity.
  • the kit is suitable for testing the effect of compounds on the activity of a variety of purified kinases, making it an ideal tool for primary screening and to study the selectivity of kinase action.
  • kinase reaction adds a portion of ADP-Glo TM reagent equal to the volume of the kinase reaction system to terminate the reaction and consume the remaining ATP.
  • a kinase detection reagent is added, which simultaneously converts ADP to ATP and detects newly synthesized ATP using a coupled luciferase/luciferin reaction.
  • the detection process is as follows:
  • Kinase buffer contains 50mM HEPES, pH 7.5; 3mM MgCl2; 1mM EGTA; 100mM NaCl; 0.03% CHAPS; 2mM DTT.
  • Table 2 shows some compounds of the present invention IC50 (nM) values determined in this example
  • Example 3 Inhibitor effects of compounds on PI3K ⁇ and PI3K ⁇ were evaluated in the human lymphoma cell line RAJI and the mouse macrophage-like cell Raw264.7 cell line, respectively
  • the effects of compounds on different subtypes of PI3K at the cellular level are evaluated by detecting the phosphorylation of AKT.
  • the human lymphoma cell line RAJI was conjugated to an anti-IgM antibody.
  • mouse macrophage-like cells Raw264.7 require stimulation of a G protein-coupled receptor agonist, C5a.
  • PI3K- ⁇ subtype RAW264.7 cells were resuspended in serum-free DMEM medium, and 60,000 cells/45 ⁇ L of cell suspension were added to each well of a 96-well plate. The cells were incubated overnight in a 5% CO 2 , 37°C incubator. After 18 hours of serum-free starvation, 50 ⁇ L of the compound was added and incubated in the incubator for 60 minutes. Then, 5 ⁇ L of 25 nM C5a (R&D Systems, diluted with serum medium) was added to stimulate for 5 min. Aspirate medium and add 50 ⁇ L of 1x Lysis Buffer per well. Shake at room temperature for 45 minutes.
  • PI3K- ⁇ subtype Raji cells were cultured in 96-well plates with 30 ⁇ L per well, 50,000 cells, and the cell culture medium was RPMI-1640 without serum. Cells were incubated overnight in a 5% CO2 and 37°C incubator. After 18 h of serum-free starvation, 2 s.5 ⁇ L of compound (14X) was added to the cells and incubated for 60 min in the incubator. Then add 2.5 ⁇ L (14X, diluted with serum medium), anti-human IgM (Jackson Immuno Research), put into the incubator to stimulate for 30 minutes (final concentration is 10 ⁇ g/mL). Add 11.5 ⁇ L of 4x Lysis Buffer to each well. Shake at room temperature for 45 minutes.
  • Table 3 shows some compounds of the present invention IC50 (nM) values determined in this example

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Abstract

本发明属于药物合成领域，提供一种吡唑并嘧啶类化合物及其用途，具体涉及一种如式（I）所示吡唑并嘧啶化合物和/或其要求学上可接受的盐、包含该化合物和/或其要求学上可接受的盐的药物组合物、制备该化合物的方法，以及该化合物在用于制备治疗由PI3K介导相关疾病的药物中的用途。

Description

吡唑并嘧啶类化合物及其用途 技术领域
本发明属于药物合成领域，涉及一种如式(I)所示吡唑并嘧啶化合物和/或其要求学上可接受的盐、包含该化合物和/或其要求学上可接受的盐的药物组合物、制备该化合物的方法，以及该化合物在用于制备治疗由PI3K介导相关疾病的药物中的用途。
Figure PCTCN2022139044-appb-000001
背景技术
磷酸肌醇(PI)作为第二信使在多种细胞功能中发挥关键作用，包括细胞存活、信号转导以及膜运输和转运的调节(Di Paolo,G.et al Nature,2006,443,651-657；Schaeffer,E.M.et al Curr.Opin.Immunol.,2000,12,282-288)。各种磷酸肌醇的功能失调与多种疾病有关，包括癌症、自身免疫性疾病和炎症等。磷酸肌醇是包含两层脂肪酸的脂质，其脂肪酸可通过甘油磷酸酯键连接到胞质1-肌醇。脂质激酶PI3K通过ATP磷酸化肌醇环部分的3-OH，将PI磷脂酰肌醇4,5-二磷酸(PIP2)转化为磷脂酰肌醇3,4,5-三磷酸(PIP3)(Parker,P.J.Biochem.Soc.Trans.,2004,32,893-898)。PIP3对含有高度保守的pleckstrin同源(PH)结构域的蛋白激酶起到锚定位点的作用(Hawkins,P.T.et al.Biochem.Soc.Trans.,2006,34,647-662)，可与细胞内含有PH结构域的信号蛋白如丝氨酸/苏氨酸激酶Akt和PDK1(3-磷酸肌醇依赖性蛋白激酶)结合，促使PDK1磷酸化Akt蛋白，导致Akt活化。这些激酶被激活(磷酸化或去磷酸化)后可调节大量重要的细胞功能，如可通过调节下游蛋白如mTOR、GSK3β、Foxo3a、p70S6K和NF-κB控制细胞的大部分生长、存活和增殖功能。而且钙动员和基因转录也受PH结构域的Tec家族酪氨酸激酶BTK、ETK和ITK的控制(Fruman,D.A.et al Immunol.Rev.2009,228,253-272.)。因此，磷酸肌醇代谢酶如PI3K已成为调节这些第二信使功能具有吸引力的靶点。
PI3K中研究最多的是第I类，这一类可分为两个子类(1A类和1B类)。其中，1A类(PI3Kα、PI3Kβ和PI3Kδ)位于受体酪氨酸激酶(RTK)的下游，而1B类(PI3Kγ)位于G蛋白偶联受体(GPCR)的下游。这四种同源激酶作为调节和催化亚基的异二聚体存在。调节亚基含有允许锚定到细胞表面受体和其他调节蛋白的域。催化亚基(p110α、p110β、p110γ、p110δ)含有ATP结合域。催化亚基，尤其是其ATP结合位点，是目前PI3K小分子抑制剂研究的重点。小分子化合物通过对ATP结合位点竞争性抑制，可阻断PIP2的磷酸化，阻断PIP3的形成。因此重要的调节蛋白如AKT将无法被锚定在细胞膜上，从而他们的功能会受到抑制。
PI3Kα和PI3Kβ在体内普遍表达，PI3Kγ和PI3Kδ主要存在于白细胞中，并且PI3Kδ几乎局限于脾脏、胸腺和外周血白细胞(Eicholt,B.J.et al PLoS One,2007,9,e869)。PI3Kα和PI3Kβ的失调与实体瘤疾病的发生、发展有关；而PI3Kγ和PI3Kδ的失调与炎性和免疫系统疾病有关，例如类风湿性关节炎(RA)、系统性红斑狼疮(SLE)、肺部疾病如慢性阻塞性肺疾病肺病COPD和哮喘、血液系统恶性肿瘤。从转基因小鼠以及两种成功的靶向B细胞的生物制品所获得的数据证明了PI3Kδ严格的表达模式，从而驱动本领域研究人员开发新的PI3Kδ小分子抑制剂。这些生物制品，如利妥昔单抗和贝利木单抗，已被证明分别对RA和SLE有效。由于PI3Kδ在B细胞成熟和功能中有独特的作用(Vallerskog,T.et al Clin.Immunol.,2007,122, 62-74)，所以抑制PI3K应该具有类似这两种生物制品的作用。除了B细胞的调节作用，PI3Kδ在T细胞活化(Soond,R.et al；Blood,2010,115,2203-3313)和中性粒细胞运输(Ali,K.et al Nature,2004,431,1007-1011)中也起到部分作用，并且还有助于激活其他与自身免疫疾病有关的白细胞如巨噬细胞、树突状细胞和NK T细胞(Fung-Leung,W.P.Cell.Signalling 2011,23,603-608)。PI3Kδ在白细胞功能中的作用可从最近两篇文献中获得支持。这两篇文献描述了几来自欧洲几个不同家族的主要功能获得性PI3Kδ突变。PI3Kδ突变者表现为淋巴增殖和免疫缺陷，这让他们易患肺和耳部感染(Angulo,I.et al Science 2013,342,866-871)。与这种突变相关的免疫缺陷的机制尚不是非常清楚，据文献推测过度活跃的p110δ-AKT-mTOR通路促进有氧糖酵解，限制淋巴细胞的功能和存活并促使它们过早衰老，损害对病原体合适的免疫反应(Lucas,C.L.et al,Nat.Immunol.2014,15,88-97)。慢性炎症并非自身免疫性疾病所独有，还与长期暴露于压力或身体受到的损伤有关。这些都有可能导致响应白细胞中PI3Kδ通路的持续信号传导。例如，在慢性阻塞性肺疾病(COPD)中，持续接触香烟烟雾与肺中高水平的PI3Kδ和磷酸化AKT相关(To,Y.et al,Am.J.Respir.Crit.Care Med.2010,182,897-904)。与功能获得性PI3Kδ突变个体一样，COPD患者更容易受到复发性细菌性呼吸道感染的困扰，包括流感嗜血杆菌和肺炎链球菌。如功能获得性基因突变患者，这类患者类似的免疫缺陷可能与COPD中持续活化的PI3Kδ信号传导有关。功能获得性突变患者的白细胞缺陷可通过雷帕霉素治疗改善。雷帕霉素是PI3Kδ下游蛋白mTOR的抑制剂。因此，据推测，抑制PI3Kδ也是PI3Kδ信号通路相关疾病的一种潜在的可行性治疗选择，不仅适用于APDS(活化的PI3K综合征)，SLE、RA等复杂的自身免疫性疾病，也适用于PI3Kδ驱动的B细胞和其他白细胞亚群活动而导致的病理学疾病(Palanki,M.et al,J.Med.Chem.2007,50,4279-4294；Pei,Z.et al,ACS Med.Chem.Lett.2013,4,103-107；Cushing,T.D.et al,J.Med.Chem.2012,55,8559-8581；Shukla,MR.et al J.Med.Chem.2020,63,14700-14723,Methot,J.L.,et al,J.Med.Chem.2021,64,5137-5156)，同时还适用于慢性非自身免疫性疾病，例如呼吸疾病COPD。
口服PI3Kδ抑制剂，如Idelalisib、Duvelisib和近期获批的Umbralisib，已获批用于治疗B细胞淋巴瘤，但因剂量限制性毒性限制了临床应用，仅用于二线及以后治疗患者。其中，Umbralisib相对另外两款上市药物而言，安全性相对较好，结直肠炎及免疫性肝毒性相对较小。根据最新Nature期刊综述总结，其原因之一是因为该药对PI3Kδ之外的其他PI3K亚型选择性最高(Nat Rev Drug Discov.2021Oct；20(10):741-769.)。
另外，已有PI3Kδ抑制剂在癌症领域的应用，目前仍限于血液癌，其在实体瘤中探索及研究成果有限。而研究显示PI3Kδ也可与抗-PD1抗体联合用于热肿瘤(J Mol Med(Berl).2016Jan；94(1):5-11.)。因此，虽然目前已有5个以上的PI3Kδ抑制剂上市或者在临床晚期开发中，但均是针对血液癌的研究，且均尚未在国内上市，因此，仍然需要一种选择性更高、毒性更小的PI3Kδ抑制剂，以应用于临床，尤其是，拓展用于一线淋巴瘤，或者拓展用于实体瘤，以及用于炎性疾病等非癌症领域。
值得注意的是，目前已上市药物均未在炎症性疾病中获批。除了两项小型研究外，Duvelisib没有进一步研究炎症性疾病。吸入给药已被探索靶向肺部治疗，因系统性给药可能会导致不可耐受的毒性。现有技术中，专利文献WO2005113556、US20130071212、US20140179718、WO2016045591、CN108017641、US2021046075公开了一系列选择性PI3Kδ抑制剂的化合物，以及他们在PI3Kδ基因功能获得性突变、自身免疫性疾病和慢性炎性疾病及癌症等领域的医药用途。
考虑到PI3Kδ抑制剂结构主要有两种类型，扁平型(flat type)和带有手性基团的螺旋桨类型(propeller-type)。扁平型结构通常相互共轭的芳香基团多，结构平面性高，存在溶解性差、选择性差的问题。
基于解决现有技术中的上述缺陷和不足，本发明申请的发明人及其团队期望选择螺旋桨类型骨架，设计并合成了一类以吡唑并嘧啶为母核的新的化合物，以获得溶解度高、选择性更优的PI3Kδ抑制剂。
尽管将化合物开发成盐是提高溶解度的有效方法，但本发明化合物并非与所有的有机酸或者无机酸都能成盐，其成盐性具有不可预知性，不同的盐的溶解性、稳定性以及结晶性等理化性能更无法预测。
发明内容
本发明的第一方面，提供一种式(I)所示的化合物和/或其药学上可接受的盐，
Figure PCTCN2022139044-appb-000002
其中：
R 1独立地选自氢、氘、卤素、氰基、羟基、巯基、氨基、-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基、-C 2-6炔基、-C 3-6环烷基、-C 3-6杂环烷基、-C 3-6环烷氧基、-C 3-6杂环烷氧基、-C 1-6烷基(O)C 1-6烷基、-COOH、-C(O)NH 2、-C(O)NH(C 1-6烷基)、-C(O)N(C 1-6烷基)(C 1-6烷基)、-S(O)2NH 2、-S(O)(NH)NH 2、-C(O)OR 1a、芳基、芳烷基、芳烷氧基、杂芳基、杂芳烷基、杂芳烷氧基；其中所述的巯基、氨基、烷基、烷氧基、烯基、炔基、环烷基、环烷氧基、杂环烷基、杂环烷氧基、芳基、芳烷基、-C(O)NH 2、-S(O)2NH 2、-S(O)(NH)NH 2、芳烷氧基、杂芳基、杂芳烷基、杂芳烷氧基可选择性被一个或多个R 1a取代。
R 1a选自氢、氘、卤素、氰基、羟基、巯基、氨基、烷基、烷氧基、烯基、炔基、环烷基、环烷氧基、杂环烷基、杂环烷氧基、芳基、杂芳基、-COOH、-C(O)NH 2、-C(O)NH(C 1-6烷基)、-C(O)N(C 1-6烷基)(C 1-6烷基)、-S(O)2NH 2、-S(O)(NH)NH 2、-C(O)OR a；其中所述的烷基、烯基、炔基、环烷基、杂环烷基、环烷氧基、杂环烷氧基、芳基、杂芳基、-C(O)NH 2、-S(O)2NH 2、-S(O)(NH)NH 2选择性被卤素、氰基、-OR a、-SR a、NR bR c、烷基、烯基、炔基、环烷基、杂环烷基、环烷氧基、杂环氧基中的任一个或多个取代或未取代；
优选地，R 1独立地选自氢、卤素、-C 1-6烷基、-C 3-6环烷基、-C 1-6烷氧基、，其中所述烷基可选择性被一个或多个R 1a取代，R 1a选自卤素；
R 2选自氢、卤素、氘、羟基、氰基、-C 1-6烷基、-C 2-6烯基、-C 2-6炔基、-C 3-6环烷基、-C 3-6杂环烷基、-C 3-6环烷氧基、-C 3-6杂环烷氧基、-COOH、-C(O)NH 2、-C(O)NH(C 1-6烷基)、-C(O)NH(C 1-6烷基) 2、-S(O)2NH 2、-S(O)(NH)NH 2、-C(O)OR 2a、-C(O)NH 2、芳基、杂芳基；其中所述烷基、烯基、炔基、环烷基、杂环烷基、环烷氧基、杂环烷氧基、芳基、杂芳基、-C(O)NH 2、-S(O)2NH 2、-S(O)(NH)NH 2可选择性地被一个或多个R 2a取代；
R 2a选自氢、氘、卤素、氰基、羟基、烷基、烯基、炔基、环烷基、杂环烷基、环烷氧基、杂环烷氧基、芳基、芳基氧基、杂芳基、杂芳基氧基、-COOH、-C(O)NH 2、-C(O)NH(C 1-6烷基)、-C(O)N(C 1-6烷基)(C 1-6烷基)、-S(O)2NH 2、-S(O)(NH)NH 2、-C(O)OR a；其中所述的烷基、烯基、炔基、环烷基、杂环烷基、环烷氧基、杂环烷氧基、芳基、芳基氧基、杂芳基、杂芳基氧基、-C(O)NH 2、-S(O)2NH 2、-S(O)(NH)NH 2选择性地被选自卤素、氰基、-OR a、-SR a、NR bR c、烷基、烯基、炔基、环烷基、杂环烷基、环烷氧基、杂环氧基中的一个或多个取代或未取代；
优选地，R 2选自氢、卤素、氰基、-C 1-6烷基、-C 3-6环烷基；
和/或，R 1与R 2选择性地与其各自连接的碳原子形成3-6元环烷基、3-6元杂环烷基、3-6元环烯基、3-6元杂环烯基、芳基、杂芳基，并且可选择性被一个或者多个R 1a或者R 2a取代；并且上述环烷 基、杂环烷基、环烯基、杂环烯基中的碳原子或硫原子可被选择性氧代，形成环内羰基、酰胺基、酯基、砜基(-S(O)2-)、磺酰胺基(-S(O)2NH-)的一部分；
优选地，和/或，R 1与R 2选择性地与其各自连接的碳原子形成3-6元环烷基、3-6元杂环烷基，并且上述环烷基、杂环烷基、中的碳原子可被选择性氧代，形成环内羰基、酯基的一部分。
R 3选自氢、氘、C 1-6烷基、氘代烷基、卤代C 1-6烷基、羟基取代的C 1-6烷基、氰基烷基、-C 3-6环烷基、-C 3-6杂环烷基、烷氧基烷基、环烷基烷基、杂环基烷基、环烷氧基烷基、杂环烷氧基烷基；
优选地，R 3选自C 1-6烷基、氘代烷基、卤代C 1-6烷基、-C 3-6环烷基。
R 4独立地选自杂芳基，所述的杂芳基是具有5、6或7个环原子的单环芳族烃基，其在环中包含1或2个N环杂原子，其余环原子是碳原子，或者是具有9或10个环原子的二环芳族烃基，其在环中包含1、2、3或4个N环杂原子，其余环原子是碳原子，其中至少一个环是芳族环，并且所述杂芳基包括其中的N环杂原子是N-氧化物形式的那些杂芳基，并且所述杂芳基任选地被一个或多个选自以下的取代基取代：卤素、氘、氰基、羟基、巯基、C 1-6烷基、卤代烷基、环烷基、环烷氧基、杂环基、杂环氧基、-NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基)(C 1-6烷基)、-COOH、-C(O)NH 2、-C(O)NH(C1-6烷基)、-C(O)N(C 1-6烷基)(C 1-6烷基)、-S(O)2NH 2、-S(O)(NH)NH 2、-C(O)OR a、-NHC(O)(C 1-6烷基)、-NHC(O)(C 1-6环烷基)、-NHC(O)O(C 1-6烷基)、-NHC(O)O(C 1-6环烷基)、苯基和5或6元杂芳基；其中C 1-6烷基、卤代烷基、-NH 2、-COOH、-C(O)NH 2、环烷基、杂环烷基可被一个或者多个R 1a选择性取代；其中作为R 4的取代基的5或6元杂芳基是具有5或6个环原子的单环芳族烃基，其在环中包含1、2或3个独立地选自N、O或S的环杂原子，其余环原子是碳原子，当杂芳基中的S和O原子的总数超过1时，这些S和O杂原子彼此不相邻，其中作为杂芳基的取代基的苯基或者5或6元杂芳基任选地被一个或多个选自以下的取代基取代：卤素、氨基、羟基、巯基、C1-6烷基和-O(C1-6烷基)、卤代烷基；
R 5独立地选自氢、C 1-6烷基、羟基取代烷基、氘代烷基、羟基烷基、C 3-6环烷基、C 3-6杂环烷基、环烷基烷基或环烷氧基烷基，其中所述的烷基可选择性的被一个或多个R 5a取代；R 5a选自氘、卤素、CN、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基；其中所述的烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基可被卤素、CN、-OR a、-SR a、-NR bR c、烷基、烯基、炔基、环烷基、杂环烷基取代；
和/或，R 4和R 5选择性地与两者共同连接的N原子形成含氮杂环基或者杂芳基，其中所述含氮杂环基和杂芳基可被一个或者多个取代基选择性取代，包括但不限于卤素、氘、氨基、羟基、巯基、氰基、烷基、氘代烷基、卤代烷基、烯基、炔基、环烷基、烷氧基、环烷氧基、杂环烷氧基、芳香基、芳香基氧基、杂芳香基、杂芳香基氧基、-COOH、-C(O)NH 2、-C(O)NH(C 1-6烷基)、-C(O)N(C 1-6烷基)(C 1-6烷基)、-S(O)2NH 2、-S(O)(NH)NH 2、-C(O)OR a、-OR a、-SR a、NR bR c；
其中，R a、R b和R c独立地选自氢、氘、卤素、C 1-6烷基、氘代C 1-6烷基、卤代C 1-6烷基、-C 2-6烯基、-C 2-6炔基、-C 3-6环烷基、-C 3-6杂环烷基、羟基取代的C 1-6烷基、-C 1-6烷基(O)C 1-6烷基、芳基、杂芳基；
和/或R b和R c与和两者共同连接的氮原子一起形成4至7元杂环烷基或地被1至3个R a取代。
所述Ar选自芳基或杂芳基：
所述芳基是由一个环或多个环稠合组成的含有6-12个环碳原子的碳环烃基，其中，至少一个环是芳族环并且其它环不是杂芳基；
所述杂芳基是具有5、6或7个环原子的单环芳族烃基，其在环中包含1或2个独立选自N、O和S的环杂原子，其余环原子是碳原子，或者是具有9或10个环原子的二环芳族烃基，其在环中包含1、2、 3或4个独立选自N、O和S的环杂原子，其余环原子是碳原子，其中至少一个环是芳族环，当杂环上的S和O原子的总数超过1时，所述S和O原子彼此不相邻，并且所述杂芳基包括其中的N杂原子是N-氧化物形式的那些杂芳基；
所述芳基和杂芳基任选地被选自以下取代基中的一个或多个取代：氢、氘、卤素、氰基、羟基、巯基、-C 1-6烷基、卤代烷基、烷氧基、卤代烷氧基、卤代烷氧基烷基、环烷基、卤代环烷基、-(C 1-6烷基)OH和-SO2(C 1-6烷基)、烯基、炔基。
进一步地，所述Ar选自芳基或杂芳基，所述芳基或所述杂芳基选自具有6个环原子的芳香基和杂芳基、具有5个环原子的杂芳基、具有9或10个环原子的二环杂芳基或者芳香基；
其中所述芳基和/或所述杂芳基包括苯基、氘代苯基、萘基、吡啶基、嘧啶、哒嗪、哌嗪、吡唑基、咪唑基、喹啉基、噻吩基、苯并噻吩基、吲哚基，任选地被选自以下取代基中的一个或多个取代：氘、卤素、氰基、羟基、-C 1-6烷基、-(C 1-6烷基)OH、C 1-6卤代烷基和-SO2(C 1-6烷基)。
优选地，所述Ar选自如下基团：
Figure PCTCN2022139044-appb-000003
上述基团任选地可被一个或多个选自以下的取代基取代：氢、卤素、氘、氰基、羟基、氨基、C 1-3烷基、C 1-3烷氧基、C 1-3卤代烷基、-O -、-S(O) 2(C 1-3烷基)。
进一步地，R4选自杂芳基，或者R4与R5形成杂芳基；
其中所述杂芳基是具有6环原子的单环芳族烃基，其在环中包含1或2个N环杂原子，其余环原子是碳原子，或者是具有9个环原子的二环芳族烃基，其在环中包含3或4个N环杂原子，其余环原子是碳原子，其中至少一个环是芳族环且所述杂芳基任选地被选自以下取代基中一个或多个取代：卤素、氰基、羟基、巯基、C 1-6烷基、卤代烷基、环烷基、-O(C 1-6烷基)和-O(C 1-6卤代烷基)、-NH 2、NH(C 1-6烷基)、N(C 1-6烷基)(C 1-6烷基)、-CO 2H、-C(O)NH 2、-C(O)NH(C 1-6烷基)、-C(O)N(C 1-6烷基)(C 1-6烷基)、苯基和5或6元杂芳基。
进一步地，R 4选自杂芳基，或者R 4与R 5形成杂芳基；
其中所述杂芳基是具有6环原子的单环芳族烃基，其在环中包含1或2个N环杂原子，其余环原子是碳原子，或者是具有9个环原子的二环芳族烃基，其在环中包含3或4个N环杂原子，其余环原子是碳原子，其中至少一个环是芳族环并且所述杂芳基任选地被选自以下的一个或多个取代基取代：氟、氯、溴、氰基、羟基、巯基、卤代烷基、C 1-6烷基、-NH 2、NH(C 1-6烷基)、N(C 1-6烷基)(C 1-6烷基)、-CO 2H、-C(O)NH 2、-C(O)NH(C 1-6烷基)、苯基、吡啶基、嘧啶基、哌嗪基、哒嗪基、吡唑基、咪唑基、三唑基和四唑基。
进一步地，所述R 4中的苯基、吡啶基、吡唑基、咪唑基、三唑基和四唑基任选地被一个或多个选自以下的取代基取代：卤素、羟基、巯基、氨基、C 1-6烷基、卤代烷基、环烷基、-O(C 1-6烷基)和-O(C 1-6卤代烷基)。
进一步地，所述杂芳基中的芳基选自嘧啶、嘌呤基、吡唑并嘧啶、吡咯并嘧啶。
进一步地，R 4、或者R 4与R 5形成的杂芳基选自以下所示取代基
Figure PCTCN2022139044-appb-000004
其中，所述取代基任选地被选自以下取代基中的一个或多个取代：氟、氯、溴、氰基、羟基、巯基、卤代烷基、C 1-6烷基、-NH 2、NH(C 1-6烷基)、N(C 1-6烷基)(C 1-6烷基)、-CO 2H、-CONH 2、-C(O)NH(C 1-6烷基)、苯基、吡啶基、吡唑基、咪唑基、噁唑基、三唑基和四唑基，其中作为R 4取代基的苯基、吡啶基、嘧啶基、哌嗪基、哒嗪基、吡唑基、咪唑基、三唑基和四唑基任选地被选自以下取代基中的一个或多个取代：卤素、羟基、巯基、C 1-6烷基、卤代烷基、环烷基、-O(C 1-6烷基)和-O(C 1-6卤代烷基)。
进一步地，R4选自
Figure PCTCN2022139044-appb-000005
中任一取代基，R4任选地被选自以下取代基中的一个或多个取代：氟、氯、溴、氰基、卤代烷基、C 1-6烷基，-NH 2、NH(C 1-6烷基)、-CO2H、-CONH 2、苯基、吡啶基、吡唑基、三唑基和四唑基，
其中作为R 4取代基的苯基、吡啶基、吡唑基、咪唑基、三唑基和四唑基任选地被一个或多个选自以下的取代基取代：卤素、羟基、C 1-6烷基和-O(C 1-6烷基)。
进一步地，R 3是C 1-4烷基和C 1-4卤代烷基。
进一步地，R 3是甲基、乙基和三氟甲基。
进一步地，式(I)所示化合物选自：
Figure PCTCN2022139044-appb-000006
Figure PCTCN2022139044-appb-000007
Figure PCTCN2022139044-appb-000008
Figure PCTCN2022139044-appb-000009
Figure PCTCN2022139044-appb-000010
Figure PCTCN2022139044-appb-000011
本发明的第二方面，本发明上述的任一式(I)化合物其药学上可接受的盐在制备用于治疗由PI3K介导相关疾病的药物中的用途。
进一步地，由PI3K介导相关疾病包括对抑制PI3K有响应的疾病，其包括自炎症性疾病、呼吸疾病、感染性疾病、自身免疫性疾病和癌症。
进一步地，用于治疗由PI3K介导的疾病的药物中的用途，所述PI3K为PI3Kδ。
进一步地，所述疾病选自癌症、炎症、呼吸疾病、感染性疾病、骨髓相关疾病和自身免疫性疾病。
进一步地，癌症是实体瘤、白血病、淋巴瘤和多发性骨髓瘤。白血病可选自急性淋巴细胞白血病(ALL)、急性髓性白血病(AML)、慢性淋巴细胞白血病(CLL)和慢性髓性白血病(CML)；所述淋巴瘤选自霍奇金淋巴瘤、非霍奇金淋巴瘤(NHL)、套细胞淋巴瘤(MCL)、滤泡淋巴瘤、B-细胞淋巴瘤、-细胞淋巴瘤和弥漫性大B-细胞淋巴瘤；所述自身免疫性疾病、炎性疾病、呼吸疾病、骨髓相关疾病和感染性疾病可以 是选自皮肤炎症、类风湿性关节炎、过敏性鼻炎、哮喘、克氏病、慢性阻塞性肺疾病(COPD)、系统性红斑狼疮、牛皮癣、多发性硬化症、活化的PI3K综合症、Sjogren综合症、骨髓纤维化和/或利什曼病。
进一步地，所述癌症是实体瘤，包括乳腺癌、黑色素瘤、头颈癌、肺癌、胸腺癌和血液恶性肿瘤。
本发明的第三方面，提供了一种药物组合物，其包括如上述任一式(I)化合物或其药学上可接受的盐、及至少一种药用载体或赋形剂。
进一步地，所述药物组合物还包括与小分子化合物和/或大分子抗体联合使用，以治疗癌症、炎症、骨髓相关疾病和自身免疫性疾病。
进一步地，所述小分子化合物包括BTK抑制剂、Bcl2抑制剂。
进一步地，所述大分子抗体包括抗-CD20、抗-CTLA4、抗PD-1、抗PD-L1抗体。
本发明的第四方面，提供了上述任一药物组合物在治疗由PI3K介导相关疾病中的用途，其中所述疾病选自癌症、炎症、呼吸疾病、感染性疾病、骨髓相关疾病和自身免疫性疾病。
本发明的第五方面，提供了上述任一式(I)化合物的溶剂合物、外消旋混合物、对映异构体、非对映异构体、互变异构体或包括外消旋混合物其任意比例的混合物，其中，R 1、R 2、R 3、R 4和R 5各取代基如上述任一限定。
Figure PCTCN2022139044-appb-000012
本发明的第六方面，提供了上述任一式(I)化合物的前药。
本发明的第七方面，提供了上述任一式(I)化合物在体内或体外抑制PI3K活性的方法，其包括使有效剂量的上述任一式(I)的化合物和/或其药学上可接受的盐与PI3K激酶接触。
进一步地，PI3K激酶是PI3Kα、PI3Kβ、PI3Kγ、PI3Kδ中的任意一种或多种。进一步地，PI3K激酶是PI3Kδ。
本发明的第八方面，提供了一种治疗癌症、炎症和自身免疫性疾病的联合治疗体系，其至少包括上述任一式(I)化合物或其药学上可接受的盐，以及小分子化合物或大分子抗体。
本发明的化合物可以是非对称的，例如具有一个或多个立体中心。除非有另外的限定，所有的立体异构体，例如是对映异构体和非对映异构体。含有非对称取代的碳原子的。本发明的化合物可以被分离成光学纯或外消旋形式。光学纯形式可以通过外消旋体的拆分来制备，或者通过使用手性合成子(synthon)或手性试剂来制备。
本发明的化合物也可以包括互变异构体形式。互变异构体新形式由单键和相邻的双键一起伴随质子的迁移而互换所产生的。
本发明的化合物也可以包括存在于中间体或最终化合物中的原子的所有同位素形式。同位素包括具有相同的原子序数但不同的质量数的那些原子。例如，氢的同位素包括氘和氚。
本发明还包括式(I)化合物的药用盐。药用盐是指，其中母体化合物通过所存在的碱部分转化成它的盐形式进行改性的式(I)化合物的衍生物，或者其中母体化合物通过所存在的酸部分转化成它的盐形式而进行改性的式(I)化合物化合物的衍生物。
具体地，药用盐的实例包括但不限于：碱性基团(如胺)的无机或有机酸的盐，或者酸性基团(如羧酸)的 无机或有机碱的盐。本发明的药用盐可以由式(I)的母体化合物通过在溶剂体系中使这些化合物的游离碱形式与1-4当量适当的酸反应而合成。合适的盐被在Remington’s PharmaceuticalSciences,17th ed.,Mack Publishing Company,Easton,Pa.,1985,p.1418和Journal of Pharmaceutical Science,66,2(1977)中列出。
本发明的化合物以及其药用盐还包括溶剂化物形式或水合物形式。一般而言，溶剂化物形式或水合物形式与非溶剂化物形式或非水合物形式是等同的，均包括在本发明的范围内。本发明的一些化合物可以以多种晶型或非晶型形式存在。总体而言，化合物的所有的物理形式都包括在本发明的范围内。
本发明还包括式(I)化合物的前药。前药是一种由母体药物衍生的药理学物质(即药物)一旦给药之后，前药在体内被代谢成为母体药物。前药可以通过取代在化合物中存在的一个或多个官能团来制备，其中前药中的取代基在体内以这样一种方式被去除而转化成母体化合物。关于前药的制备和使用如T.Higuchi and V.Stella,“Pro-drugs asNovel Delivery Systems”Vol.14of the A.C.S.Symposium Series和Bioreversible所记载。
具体实施方式
以下通过实施例进一步说明本发明，实施例仅用于更具体的说明本发明优选地实施方案，不用于对本发明的技术方案进行限定。上述本发明的方案均为可实现本发明目的之技术方案。以下实施例所采用温度和试剂，均可以用上述相应温度和试剂替代以实现本发明之目的。
定义
本申请中所用的下列术语、短语和符号具有如下所述的含义，其所处的上下文中另有说明的除外。
在两个字母或符号之间的短横(“-”)表示取代基的连接位点。例如，-O(C 1-4烷基)是指通过氧原子与分子的其余部分连接的C 1-4烷基。然而，当取代基的连接位点对本领域技术人员来说是显而易见的时候，例如，卤素取代基，“-”可以被省略。
除非另有明确说明，使用“一”或者“1”之类的术语是指一个或多个。
本文所用的术语“烷基”是指含有1-18个碳原子、例如1-12个碳原子、再例如1-6个碳原子、再例如1-4个碳原子的直链或支链的饱和烃基。例如，“C1-6烷基”在“烷基”的范围内，表示所述的具有1-6个碳原子的烷基。烷基的例子包括但不限于甲基(“Me”)、乙基(“Et”)、正丙基(“n-Pr”)、异丙基(“i-Pr”)、正丁基(“n-Bu”)、异丁基(“i-Bu”)、仲丁基(“sBu”)和叔丁基(“t-Bu”)。
本文所用的术语“烯基”是指含有一个或多个、例如1、2或3个碳碳双键(C＝C)的、含有2-10个碳原子、例如2-6个碳原子、再例如2-4个碳原子的直链或支链的烃基。例如，“C2-6烯基”在“烯基”的范围内，表示所述的具有2-6个碳原子的烯基。烯基的例子包括但不限于乙烯基、2-丙烯基和2-丁烯基。
本文所用的术语“炔基”是指含有一个或多个、例如1、2或3个碳碳三键(C≡C)的、含有2-10个碳原子、例如2-6个碳原子、再例如2-4个碳原子的直链或支链的烃基。例如，“C 2-6炔基”表示所述的包含1个碳碳三键(C≡C)并具有2-6个碳原子的炔基。炔基的例子包括但不限于乙炔基、2-丙炔基和2-丁炔基。
本文所用的术语“卤代”是指氟代、氯代、溴代和碘代，“卤素”是指氟、氯、溴和碘。
本文所用的术语“卤代烷基”是指其中一个或多个氢原子、例如1、2、3、4或5个氢原子被卤素原子替代的本文所定义的烷基，并且当超过一个氢原子被卤素原子替代时，所述卤素原子可以彼此相同或不同。在一个实施方案中，本文所用的术语“卤代烷基”是指其中两个或更多个氢原子、例如2、3、4或5个氢原子被卤素原子替代的本文所定义的烷基，其中所述卤素原子彼此相同。在另一个实施方案中，本文所用的术语“卤代烷基”是指其中两个或更多个氢原子、例如2、3、4或5个氢原子被卤素原子替代的本文所定义的烷基，其中所述卤素原子彼此不同。卤代烷基的例子包括但不限于-CF3、-CHF2、-CH2CF3等。
本文所用的术语“烷氧基”是指基团-O-烷基，其中烷基如上文所定义。烷氧基的例子包括但不限于甲 氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基和己氧基，包括它们的异构体。
本文所用的术语“环烷基”是指含有3-12个环碳原子、例如3-8个环碳原子、再例如3-6个环碳原子的饱和或部分不饱和的环状烃基，其可以具有一个或多个环，例如具有1个或2个环。例如，“C3-8环烷基”表示所述的具有3-8个环碳原子的环烷基。环烷基的例子包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、金刚烷基，以及类似的基团。
本文所用的术语“杂环基”或“杂环的”是指选自4至12元单环的、双环的和三环的、饱和的和部分不饱和的环，其除了包含至少一个、例如1-4个、再例如1-3个或再例如1或2个选自O、S和N的杂原子外，还包含至少一个碳原子。杂环基的连接点可以在杂原子上或在碳上。“杂环基”或“杂环的”也指单环，其包含至少一个选自O、S和N的杂原子；或者是稠环，其中至少一个环包含至少一个选自O、S和N的杂原子并且其它环不是杂芳基或芳基，其连接点可以在杂环上或在其它环上。
本文所用的术语“环烷氧基”是指基团-O-环烷基，其中环烷基如上文所定义。环烷氧基的例子包括但不限于环丙基氧基、环丁基氧基，包括它们的异构体。
本文所用的术语“杂环烷氧基”是指基团-O-杂环烷基，其中杂环烷基如上文所定义。环烷氧基的例子包括但不限于氮杂环丙基氧基、环氧丙烷氧基、氮杂环丁基氧基、氧杂环丁基氧基，包括它们的异构体。
本文所述的“环烯基”是指含有一个或多个，例如1、2或3个碳碳双键的、含有3-12个环碳原子、优选3-8个环碳原子、更优选3-6个环碳原子的非芳族的环状羟基，其可以具有一个或多个环，优选具有1个或2个环。例如，C 3-8个环碳原子和环烯基，优选“C 3-6环烯基”，即所述的具有3-6个环碳原子的环烯基。环烯基的例子包括但不限于环丙烯及、环丁烯基、环戊烯基、环戊二烯基、环己烯基、环庚烯基和环辛烯基。
本文所述的“杂环烯基”是指上述“环烯基”中的一个或者多个碳原子被N、O、S替换。例如，C 3-8个环原子的杂环烯基，优选“C 3-6杂环烯基”，即所述的具有3-6个环原子的杂环烯基。杂环烯基的例子包括但不限于氮杂环丁烯及、氧杂环丁烯基、氮杂环戊烯基、氧杂环戊烯基、氧杂环己烯基。
本文所用的术语“芳基”除非有明确定义，否则是指由一个环或多个环稠合组成的含有6-14个环碳原子，例如6-12个环碳原子的碳环烃基，其中至少一个环是芳族环并且其它环不是如下文所定义的杂芳基，其连接点可以在芳族环上或在其它环上。芳基的例子包括但不限于苯基、萘基、1,2,3,4-四氢萘基、茚基、茚满基、薁基，优选苯基和萘基。如本文所用，“芳基”或“芳族的”遵循休克尔规则(Hückel's rule)，其中π电子数等于4n+2，n为零或任何最多为6的正整数。
本文所用的术语“杂环基”或“杂环的”是指选自4至12元单环的、双环的和三环的、饱和的和部分不饱和的环，其除了包含至少一个、例如1-4个、再例如1-3个或再例如1或2个选自O、S和N的杂原子外，还包含至少一个碳原子。杂环基的连接点可以在杂原子上或在碳上。“杂环基”或“杂环的”也指单环，其包含至少一个选自O、S和N的杂原子；或者是稠环，其中至少一个环包含至少一个选自O、S和N的杂原子并且其它环不是杂芳基或芳基，其连接点可以在杂环上或在其它环上。
本文所用的术语“杂芳基”除非有明确定义，否则，是指：具有5、6或7个环原子、例如具有6个环原子的单环芳族烃基，其在环中包含一个或多个、例如1、2或3个、例如1或2个独立地选自N、O和S(例如N)的环杂原子，其余环原子是碳原子；和具有8-12个环原子、例如具有9或10个环原子的二环芳族烃基，其在环中包含一个或多个、例如1、2、3或4个、例如1或2个独立地选自N、O和S(例如N)的环杂原子，其余环原子是碳原子，其中至少一个环是芳族环。例如，二环杂芳基包括与5-6元环烷基环、杂环基环或芳基环稠合的5-6元杂芳基环，其中连接点可以在杂芳基环上或在环烷基环/杂环基环/芳基环 上。当杂芳基中的S和O原子的总数超过1时，这些S和O杂原子彼此不相邻。杂芳基也包括其中的N环杂原子是N-氧化物形式的那些杂芳基，例如N-氧化嘧啶基。在一些实施方案中，上述杂芳基中的环杂原子是N原子，这类杂芳基称为“含氮杂芳基”。含氮杂芳基也包括其中的N环杂原子是N-氧化物形式的那些杂芳基，例如N-氧化吡啶基。
杂芳基的例子包括但不限于：吡啶基、N-氧化吡啶基；吡嗪基；嘧啶基；吡唑基；咪唑基；噁唑基；异噁唑基；噻唑基；异噻唑基；噻二唑基；四唑基；三唑基；噻吩基；呋喃基；吡喃基；吡咯基；哒嗪基；苯并[d]噻唑基；苯并间二氧杂环戊烯基，例如苯并[d][1,3]间二氧杂环戊烯基；苯并噁唑基，例如苯并[d]噁唑基；咪唑并吡啶基，例如咪唑并[1,2-a]吡啶基；三唑并吡啶基，例如[1,2,4]三唑并[4,3-a]吡啶基和[1,2,4]三唑并[1,5-a]吡啶基；吲唑基；2H-吲唑基；吡咯并嘧啶基，例如吡咯并[3,4-d]嘧啶基、7H-吡咯并[2,3-d]嘧啶基；吡唑并嘧啶基，例如吡唑并[1,5-a]嘧啶基；四唑并吡啶基，例如四唑并[1,5-a]吡啶基；苯并噻吩基；苯并呋喃基；苯并咪唑啉基；吲哚基；吲哚啉基；嘌呤基，例如9H-嘌呤基和7H-嘌呤
含氮杂芳基的实例包括但不限于：吡咯基；吡唑基；咪唑基；吡啶基；吡嗪基；嘧啶基、N-氧化嘧啶基；哒嗪基；吡咯并嘧啶基，例如吡咯并[3,4-d]嘧啶基、7H-吡咯并[2,3-d]嘧啶基；嘌呤基，例如9H-嘌呤基和7H-嘌呤基；喹啉基；吲哚基；以及吲唑基。
本文所述的术语“羟基”是指–OH基团。
本文所用的术语“巯基”是指–SH基团。
本文所用的术语“氧代”是指＝O基团。
本文所用的术语“羧基”是指–C(O)-OH基团。
本文所用的术语“氰基”是指-CN基团。
本文所用的术语“氨基”是指-NH2基团。
本文所用的“基团”和“基”是同义词，用于表示可与其他分子片段连接的官能团或分子片段。
如果本文的某个结构式包含星号“*”，则该结构式所表示的化合物是手性化合物，即该化合物是R-构型或S-构型。化合物的构型可以由本领域技术人员使用多种分析技术、例如单晶X-射线晶体学和/或光学旋光测定法并根据常规方案来确定。
本文所用的术语“选择性”、“选择性的”、“选择性地”、“任选”、“任选的”或“任选地”意指随后描述的取代模式、事件或情况可以发生一次或者多次、或可以不发生，并且该描述包括所述取代模式发生的情形以及所述取代模式不发生的情形。例如，“任选被取代的烷基”包括本文定义的“未被取代的烷基”和“被取代的烷基”。本领域技术人员应当理解的是，对于含有一个或多个取代基的任意基团而言，所述基团不包括任何在空间上不切实际的、化学上不正确的、合成上不可行的和/或内在不稳定的取代模式。
本文所用的术语“包括但不限于”意指所选择的范围优先后续例举的基团，但没有被例举的基团也可以使用。
本文所用的术语“被取代的”或“被……取代”意指给定原子或基团上的一个或多个氢原子被一个或多个选自给定的取代基组的取代基替换，条件是不超过该给定原子的正常化合价。当取代基是氧代(即＝O)时，则单个原子上的两个氢原子被氧替换。只有当取代基和/或变量的组合导致化学上正确的且稳定的化合物时，这类组合才是允许的。化学上正确的且稳定的化合物意味着化合物足够稳定，以至于能从反应混合物中被分离出来并能确定化合物的化学结构，并且随后能被配制成至少具有实际效用的制剂。
除非另有说明，取代基被命名入核心结构中。例如，应当理解的是，当(环烷基)烷基被列为一种可能的取代基时，其表示该取代基与核心结构的连接点在烷基部分。
本文所用的术语“被一个或多个取代基取代”意指给定的原子或基团上的一个或多个氢原子独立地被 一个或多个选自给定基团的取代基替换。在一些实施方案中，“被一个或多个取代基取代”意指给定的原子或基团被1、2、3或4个独立地选自给定基团的取代基取代。
本领域技术人员应当理解的是，一些式(I)的化合物可以包含一个或多个手性中心，因此存在两个或更多个立体异构体。这些异构体的外消旋混合物、单个异构体和一种对映异构体富集的混合物，以及当有两个手性中心时的非对映异构体和特定的非对映异构体部分富集的混合物均在本发明的范围内。本领域技术人员还应当理解的是，本发明包括式(I)的化合物的所有单个立体异构体(例如对映异构体)、外消旋混合物或部分拆分的混合物，以及在适当的情况下，包括其单个互变异构体。
换言之，在一些实施方案中，本发明提供了含有多种立体异构体纯度的化合物，即以不同“ee”或“de”值表示的非对映体或对映体纯度。在一些实施方案中，式(I)的化合物(例如如本文所述)有至少60％ee(例如60％、65％、70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％、99.5％、99.9％ee，或任何在这些列举的数值之间的数值)的对映体纯度。在一些实施方案中，式(I)的化合物(例如如本文所述)有大于99.9％ee、达到100％ee的对映体纯度。在一些实施方案中，式(I)的化合物(例如如本文所述)有至少60％de(例如60％、65％、70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％、99.5％、99.9％de，或任何在这些列举的数值之间的数值)的非对映体纯度。在一些实施方案中，式(I)的化合物(例如本文所述)有大于99.9％de的非对映体纯度。
术语“对映体过量”或“ee”表示一种对映异构体相对于另一种对映异构体的多少。对于R和S对映异构体的混合物，对映体过量的百分数定义为│R-S│*100，其中R和S为混合物中各自对映异构体的摩尔或重量分数，R+S＝1。若已知一手性物质的旋光度，则对映体过量的百分数定义为([a]obs/[a]max)*100，其中[a]obs为对映异构体混合物的旋光度，[a]max为纯的对映异构体的旋光度。
术语“非对映体过量”或“de”表示一种非对映异构体相对于另一种非对映异构体的多少，并用类推的方法根据对映体过量来定义。因此，对于非对映异构体D1和D2的混合物，非对映体过量的百分数定义为│D1–D2│*100，其中D1和D2为混合物中各自非对映异构体的摩尔或重量分数，D1+D2＝1。
非对映体和/或对映体过量的测定可采用多种分析技术，包括核磁共振光谱法、手性柱色谱法和/或光学旋光测定法，并根据本领域技术人员所熟悉的常规方案来完成。
外消旋混合物可以以其本身的形式使用或者拆分成单个异构体使用。通过拆分可以得到立体化学上的纯的化合物或者富集一种或多种异构体的混合物。分离异构体的方法是众所周知的，包括物理方法，例如使用手性吸附剂的色谱法。可以由手性前体制备得到手性形式的单个异构体。或者，可以通过与手性酸(例如，10-樟脑磺酸、樟脑酸、α-溴樟脑酸、酒石酸、二乙酰基酒石酸、苹果酸、吡咯烷酮-5-羧酸等的单个对映异构体)形成非对映异构体盐而由混合物化学分离得到单个异构体，将所述的盐分级结晶，然后游离出拆分的碱中的一个或两个，任选地重复这一过程，从而得到一个或两个基本上不包含另一种异构体的异构体，即光学纯度以重量计为例如至少91％、92％、93％、94％、95％、96％、97％、98％、99％或99.5％的所需的立体异构体。或者，如本领域技术人员所熟知的，可以将外消旋物共价连接到手性化合物(辅助物)上，得到非对映异构体，可通过色谱法或分级结晶法将其分离，之后化学除去手性辅助物，得到纯的对映异构体。
本发明所述“药学上可接受的盐”，指的是无毒的、生物学上可耐受的或其他生物学上适合于给予治疗个体的式(I)的化合物的游离酸或碱的盐。。
“药学上可接受的盐”包括但不限于：式(I)的化合物与无机酸形成的酸加成盐，例如盐酸盐、氢溴酸盐、碳酸盐、碳酸氢盐、磷酸盐、硫酸盐、亚硫酸盐、硝酸盐等；以及式(I)的化合物与有机酸形成的酸加成盐，例如甲酸盐、乙酸盐、苹果酸盐、马来酸盐、富马酸盐、酒石酸盐、琥珀酸盐、柠檬酸盐、乳酸盐、甲磺 酸盐、对甲苯磺酸盐、2-羟基乙磺酸盐、苯甲酸盐、水杨酸盐、硬脂酸盐和与式HOOC-(CH2)n-COOH(其中n是0-4)的链烷二羧酸形成的盐等。“药学上可接受的盐”也包括带有酸性基团的式(I)的化合物与药学上可接受的阳离子例如钠、钾、钙、铝、锂和铵形成的碱加成盐。所得的药学上可接受的盐中的式(I)的化合物与酸或阳离子的摩尔比包括但不限于1:1、1:2、1:3和1:4。
本发明所述“前药”，指的是一种由母体药物衍生的药理学物质(即药物)一旦给药之后，前药在体内被代谢成为母体药物。前药可以通过取代在化合物中存在的一个或多个官能团来制备，其中前药中的取代基在体内以这样一种方式被去除而转化成母体化合物。关于前药的制备和使用可以在T.Higuchi and V.Stella,“Pro-drugs asNovel Delivery Systems,”Vol.14of the A.C.S.Symposium Series和Bioreversible。“前药”包括但不限于：式(I)的化合物的酯类如磷酸酯、甲酸酯、氨基甲酸酯；酰胺如甲酰胺、乙酰胺。
此外，如果本文所述的化合物是以酸加成盐的形式得到的，其游离碱形式可以通过碱化该酸加成盐的溶液获得。相反地，如果产物是游离碱形式，则其酸加成盐、特别是药学上可接受的酸加成盐可以按照由碱性化合物制备酸加成盐的常规操作通过将游离碱溶于合适的溶剂并且用酸处理该溶液来得到。本领域技术人员无需过多实验即可确定各种可用来制备无毒的药学上可接受的酸加成盐的合成方法。
术语“溶剂合物”意指包含化学计量的或非化学计量的溶剂的溶剂加成形式。一些化合物具有在固体状态中网罗固定摩尔比的溶剂分子的倾向，从而形成溶剂合物。如果溶剂是水，则形成的溶剂合物是水合物，当溶剂是乙醇时，则形成的溶剂合物是乙醇合物。水合物是通过一个或多个分子的水与一分子所述物质形成的，其中水保留其H2O的分子状态，这样的组合能形成一种或多种水合物，例如半水合物、一水合物和二水合物，以及可变的水合物。
本文所用的术语“基团”和“基”是同义词，用于表示可与其它分子片段连接的官能团或分子片段。
术语“活性成分”用来表示具有生物活性的化学物质。在一些实施方案中，“活性成分”是具有制药用途的化学物质。在美国，实际的药物活性可通过适当的无论是体外的或体内的临床前试验来确定。但是能够足以被监管机构(例如美国的FDA)接受的药物活性，要有比临床前试验更高的标准。这样一种更高标准的药物活性，其是否能成功获得一般不能从临床前的试验结果合理地预期到，但可以通过在人体中进行的适当并有效的随机、双盲、可控的临床试验来确立。
术语“处置”或“治疗”疾病或障碍，在达到有益治疗效果的情况下，是指给患有所述疾病或障碍、或者具有所述疾病或障碍的症状、或者具有易患所述疾病或障碍的体质的个体、例如人施用一种或多种药物物质、特别是本文所述的式(I)化合物和/或其药学上可接受的盐，用以治愈、愈合、缓解、减轻、改变、医治、改善、改进或影响所述疾病或障碍、所述疾病或障碍的症状或者易患所述疾病或障碍的体质。在一些实施方案中，所述疾病或障碍是癌症。
当涉及化学反应时，术语“处理”、“接触”和“反应”意指在适当的条件下加入或混合两种或更多种试剂，以产生所示的和/或所需的产物。应当理解的是，产生所示的和/或所需的产物的反应可能不一定直接来自最初加入的两种试剂的组合，即，在混合物中可能存在生成的一个或多个中间体，这些中间体最终导致了所示的和/或所需的产物的形成。
本文所用的术语“有效量”是指通常足以对需要治疗具有由PI3K活性介导的疾病或障碍的患者产生有益治疗效果的PI3K抑制剂的量或剂量。可以通过常规方法(例如建模、剂量递增研究或临床试验)结合常规影响因素(例如给药或施药的方式或途径、药物成分的药代动力学、疾病或障碍的严重程度和病程、个体先前的或正在进行的治疗、个体的健康状况和对药物的反应、以及主治医生的判断)来确定本发明中活性成分的有效量或剂量。在美国，有效剂量的确定一般难以从临床前试验中预知。事实上，剂量是完全不可预知的，剂量在原始用于随机的、双盲的、可控的临床试验后会发展出新的不可预知的剂量方案。
典型的剂量范围是从约0.0001至约200毫克活性成分每公斤个体体重每天，例如从约为0.001至100毫克/公斤/天，或者约为0.01至35毫克/公斤/天，或者约为0.1至10毫克/公斤，每日一次或分剂量单位服用(例如，每日两次、每日三次、每日四次)。对于一个70公斤的人而言，合适剂量范围可以是约0.05至约7克/天，或者约为0.2至约5克/天。一旦患者的疾病或障碍出现改善，可以调整剂量以维持治疗。例如，根据症状的变化可以将给药剂量或给药次数，或者将给药剂量和给药次数减少至维持所期望的治疗效果的水平。当然，如果症状减轻到了适当的水平，可以停止治疗。然而，对于症状的复发，患者可能需要间歇性长期治疗。
术语“抑制”是指生物活动或过程的基线活性的降低。术语“抑制PI3K活性”是用于本发明目的的实际药物活性，是指相对于不存在式(I)化合物和/或其药学上可接受的盐时的PI3K活性，对存在本文所述的式(I)化合物和/或其药学上可接受的盐的直接或间接响应导致的PI3K活性的降低。活性的降低可以是由本文所述的式(I)化合物和/或其药学上可接受的盐与PI3K直接相互作用引起的，或者是由本文所述的式(I)化合物和/或其药学上可接受的盐与一种或多种其它因子相互作用进而影响PI3K活性引起的。例如，本文所述的式(I)化合物和/或其药学上可接受的盐的存在可通过直接与PI3K结合而降低PI3K的活性、可通过直接或间接地影响另一种因子来降低PI3K的活性，或者通过直接或间接地减少存在于细胞或机体中的PI3K的量来降低PI3K的活性。
本文所用的术语“个体”是指哺乳动物和非哺乳动物。哺乳动物是指哺乳类的任何成员，其包括但不限于：人；非人灵长类动物，如黑猩猩及其它猿类和猴类物种；农场动物，如牛、马、绵羊、山羊和猪；家畜，如兔、狗和猫；实验室动物，包括啮齿类动物，如大鼠、小鼠和豚鼠；等。非哺乳动物的例子包括但不限于鸟等。术语“个体”并不限定特定的年龄或性别。在一些实施方案中，个体是人。
一般而言，术语“约”在本文中用于将所给出的数值调整至高于或低于该数值20％。
上述式(I)化合物通用合成方法
反应路线1
Figure PCTCN2022139044-appb-000013
如路线1所示，式i-1的化合物与乙氧甲叉基丙二酸二乙酯在碱性条件下反应得到式i-2吡唑并嘧啶的化合物。式i-2的化合物与三氯氧磷反应得到式i-3的化合物。式i-3的化合物与ArB(OH) 2(Ar如本文所定义)的化合物在适当的钯试剂催化下，通过Suzuki偶联反应得到式i-4的化合物。钯催化的碳-碳偶联反应可在合适的条件下进行：如在合适的极性溶剂如DMF,ACN,THF或DMSO等；在合适的碱中如TEA,DIEPA,Cs 2CO 3,KOAc等；使用催化剂如Pd(OAc) 2,Pd(dppf) 2Cl 2,Pd(PPh 3) 4或Pd 2(dba) 3等。接下来的反应可如下进行：
式i-4的化合物通过酯水解反应得到式i-5的化合物酸。式i-5的化合物酸与N,O-二甲基羟胺反应，得到式i-6的酰胺化合物。得到式i-6的化合物在适当的条件下与格氏试剂(烷基卤化镁)反应，生成式i-7的化合物。对式i-7的化合物在适当的条件下引进卤素得到式i-8的化合物，或对所得卤代物进一步改造而得到式i-8的化合物。式i-8的化合物与(R)-2-甲基丙烷-2-亚磺酰胺缩合，然后在适当的还原剂存在下还原，得到式i-10的化合物。式i-10的化合物脱除保护基，得到式i-11的化合物。式i-11的化合物在碱(如DIEPA等)的存在下，以及适当的条件下与R 4-Cl反应，和/或进一步衍生化(R 5-x)得到式(I)的化合物。
Figure PCTCN2022139044-appb-000014
如路线2所示，式i-4的化合物可以从另外的途径合成而得。式i-12的化合物与乙酸乙酯在碱性条件下反应得到式i-13的化合物。在甲苯中回流式i-13的化合物与DMF-DMA,然后将浓缩反应再在再酸性条件下进一步与式i-1的化合物反应生成式i-4的化合物。
药物组合物及用途
本文所述的式(I)的化合物(例如，本文中的任何化合物)和/或其药学上可接受的盐可单独或者与一种或多种另外的活性成分联合配制成药物组合物。药物组合物包括：(a)有效量的本文所述的一种式(I)的化合物和/或一种其药学上可接受的盐；和(b)一种药学上可接受的赋形剂(例如，一种药学上可接受的载体)。
药学上可接受的载体是指能与组合物中的活性成分相容(在一些实施方案中，能稳定活性成分)并且对所治疗的个体无害的载体。例如，增溶剂如环糊精(其能与本文所述的式(I)的化合物和/或其药学上可接受的盐形成特定的、溶解性更强的复合物)可用作药物赋形剂来递送活性成分。其它载体的例子包括胶态二氧化硅、硬脂酸镁、纤维素、十二烷基硫酸钠以及色素如D&C黄色10号(D&C Yellow#10)。合适的药学上可接受的载体在本领域一本标准的参考书(Remington's Pharmaceutical Sciences,A.Osol)中公开。
包含本文所述的式(I)化合物(例如，本文中的任何化合物)和/或其药学上可接受的盐的药物组合物可以以各种已知的方式、例如口服、局部、直肠、肠胃外、吸入或植入等方式施用。本文所用的术语“肠胃外”包括皮下、皮内、静脉、肌内、关节内、动脉内、滑膜内、胸骨内、脊椎内、患处内以及颅内注射或输注。
本文所述的药物组合物被制备成的形式可以是片剂、胶囊、袋装冲剂、糖衣丸、散剂、颗粒剂、含片、粉针剂、液体制剂或栓剂。在一些实施方案中，包含式(I)化合物和/或其药学上可接受的盐的药物组合物可被配制成用于静脉滴注、局部给药或口服给药的形式。
口服施用的组合物可以是任何口服可接受的剂型，包括但不限于：片剂、胶囊、乳剂以及水性的混悬剂、分散剂和溶液。常用的片剂载体包括乳糖和玉米淀粉。润滑剂如硬脂酸镁也常加入到片剂中。以胶囊形式口服施用时，有用的稀释剂包括乳糖和干燥的玉米淀粉。当以水性混悬剂或乳剂形式口服施用时，可用乳化剂或助悬剂使活性成分混悬或溶解于油相中。若有需要，还可添加某些甜味剂、矫味剂或色素。
在一些实施方案中，式(I)的化合物和/或其药学上可接受的盐在片剂中的量可以是1、5、10、15、20、25、50、75、80、85、90、95、100、125、150、200、250、300、400和500毫克。在一些实施方案中，式(I)的化合物和/或其药学上可接受的盐在胶囊中的量可以是1、5、10、15、20、25、50、75、80、85、90、95、100、125、150、200、250、300、400和500毫克。
无菌可注射组合物(如水性或油性混悬剂)可按照本领域已知的技术，使用适合的分散剂或润湿剂(例如，吐温80)以及助悬剂来配制。无菌可注射中间介质也可以是在无毒的肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液或混悬液，例如在1,3-丁二醇中的溶液。药学上可接受的载体和溶剂尤其可使用的是甘露醇、水、林格氏液和生理盐水。此外，无菌的不易挥发的油例如合成的单或二甘油酯通常用作溶剂或混悬介质。脂肪酸例如油酸及其甘油酯衍生物以及天然的药学上可接受的油例如橄榄油或蓖麻油(尤其是其聚氧乙基化形式)常用作可注射中间介质。这些油溶液或混悬液也可含有长链的醇类稀释剂或分散剂、或羧 甲基纤维素或类似的分散剂。
使用苯甲醇或其它适宜的防腐剂、使用提高生物利用度的吸收促进剂、使用碳氟化合物和/或其它本领域已知的增溶剂或分散剂，可以根据药物制剂领域众所周知的技术制备吸入组合物，也可将其制成在盐水中的溶液。
局部组合物可配制为油、乳膏剂、洗剂、软膏剂等形式。用于组合物的适合载体包括植物油或矿物油、白凡士林(白软石蜡)、支链脂肪或油、动物脂肪和高分子量的醇(即，碳原子数大于12的醇)。在一些实施方案中，药学上可接受的载体是活性成分能溶解于其中的载体。如有需要，组合物还可以包含乳化剂、稳定剂、湿润剂和抗氧化剂，以及赋予其颜色或香味的物质。此外，局部制剂中还可加入透皮渗透促进剂。这类促进剂的例子可见于美国专利US No.3,989,816和4,444,762。
乳膏剂可以由矿物油、自乳化蜂蜡和水的混合物配制，将溶解于少量油脂例如杏仁油中的活性成分混合在其中。乳膏剂的一个例子包含以重量计约40份水、约20份蜂蜡、约40份矿物油以及约1份杏仁油。软膏剂可通过将活性成分在植物油例如杏仁油中的溶液与温热的软石蜡混合并将混合物冷却来配制。软膏剂的一个例子包含以重量计约30％杏仁油和约70％白软石蜡。
合适的体外实验可用于评价本文所述的式(I)的化合物和/或其药学上可接受的盐在抑制PI3K活性中的实际用途。可进一步通过体内试验检测本文所述的式(I)的化合物和/或其药学上可接受的盐在治疗癌症或自身免疫性疾病中的另外的实际用途。例如，可将本文所述的式(I)的化合物和/或其药学上可接受的盐施用给患有癌症或自身免疫性疾病的动物(如小鼠模型)，然后评估其治疗效果如果临床前试验的结果是成功的，还可以预测其对动物例如人的剂量范围和施用途径。
本文所述的式(I)的化合物和/或其药学上可接受的盐可显示有足够的临床前的实际用途以值得进行临床试验，并期望显示有益的治疗或预防效果，例如，在患有癌症的个体中显示有益的治疗或预防效果。
本文所用的术语“癌症”是指以失控或失调的细胞增殖、减少的细胞分化、不恰当的侵入周围组织的能力和/或在其它部位建立新生长灶的能力为特征的细胞障碍。术语“癌症”包括但不限于：实体瘤和血液系统恶性肿瘤。术语“癌症”包括皮肤、组织、器官、骨骼、软骨、血液和血管的癌症。术语“癌症”既包括原发性癌症，也包括转移性癌症。
实体瘤的非限制性例子包括胰腺癌；膀胱癌；结肠直肠癌；乳腺癌，包括转移性乳腺癌；前列腺癌，包括雄性激素依赖性和非雄性激素依赖性前列腺癌；肾癌，包括例如转移性肾细胞癌；肝细胞癌；肺癌，包括例如非小细胞肺癌(NSCLC)、细支气管肺泡癌(BAC)和肺腺癌；卵巢癌，包括例如进行性上皮癌或原发性腹膜癌；宫颈癌；胃癌；食道癌；头颈癌，包括例如头颈部鳞状细胞癌；皮肤癌，包括例如恶性黑素瘤；神经内分泌癌，包括转移性神经内分泌瘤；脑瘤，包括例如神经胶质瘤、间变性少突神经胶质瘤(anaplastic oligodendroglioma)、成人多形性成胶质细胞瘤和成人间变型星形细胞瘤；骨癌；软组织肉瘤；和甲状腺癌。
血液系统恶性肿瘤的非限制性例子包括急性髓性白血病(AML)；慢性髓性白血病(CML)，包括加速期CML和CML急变期(CML-BP)；急性淋巴细胞白血病(ALL)；慢性淋巴细胞白血病(CLL)；霍奇金淋巴瘤；非霍奇金淋巴瘤(NHL)，包括滤泡型淋巴瘤和套细胞淋巴瘤；B细胞淋巴瘤；T细胞淋巴瘤；多发性骨髓瘤(MM)；瓦尔登斯特伦巨球蛋白血症(Waldenstrom'smacroglobulinemia)；骨髓增生异常综合征(myelodysplastic syndrome,MDS)，包括顽固性贫血(refractory anemia,RA)、环状铁粒幼细胞顽固性贫血(refractory anemia with ringed siderblast,RARS)、过量芽细胞顽固性贫血(refractory anemia with excess blast,RAEB)和过量芽细胞顽固性贫血合并急性转化(refractory anemia with excess blast in transformation,RAEB-T)；以及骨髓增生综合征(myeloproliferative syndrome)。
在一些实施方案中，典型的血液系统恶性肿瘤包括白血病，例如急性淋巴细胞白血病(ALL)、急性髓 性白血病(AML)、慢性淋巴细胞白血病(CLL)和慢性髓性白血病(CML)；多发性骨髓瘤(MM)；以及淋巴瘤，例如霍奇金淋巴瘤、非霍奇金淋巴瘤(NHL)、套细胞淋巴瘤(MCL)、滤泡型淋巴瘤、B细胞淋巴瘤、T细胞淋巴瘤和弥散性大B细胞淋巴瘤(DLBCL)。
术语“炎症性疾病”指的是导致炎症反应的病理状态，尤其是由于嗜中性粒细胞趋化引起的。这种疾病的例子包括炎性皮肤疾病(包括银屑病和特应性皮炎)；系统性硬皮病和硬化症；与炎性肠病(IBD)(例如克罗恩病和溃疡性结肠炎)有关的反应；缺血再灌注损伤，包括手术引起组织再灌注损伤、心肌缺血如心肌梗死、心脏骤停、心脏术后再灌注和经皮冠状动脉成形术后冠脉血管的异常收缩反应、中风和腹主动脉瘤手术组织再灌注损伤；中风继发脑水肿；颅外伤；失血性休克；窒息；成人呼吸窘迫综合征；急性肺损伤；白塞氏病；皮肌炎；多发性肌炎；多发性硬化(MS)；皮炎；脑膜炎；脑炎；葡萄膜炎；骨关节炎；狼疮性肾炎；自身免疫性疾病如类风湿性关节炎(RA)；舍格林氏综合征；脉管炎；涉及白细胞渗出的疾病；败血症或创伤继发中枢神经系统(CNS)炎症性疾病、多器官损伤综合征；酒精性肝炎；细菌性肺炎；抗原-抗体复合物介导的疾病，包括肾小球肾炎；脓血症；结节病；组织/器官移植引起的免疫病理反应；肺部炎症，包括胸膜炎、肺泡炎、脉管炎、肺炎、慢性支气管炎、支气管扩张、弥漫性泛细支气管炎、过敏性肺炎、特发性肺纤维化(IPF)以及囊性纤维化等。优选的适应症包括，但不限于，慢性炎症、自身免疫性糖尿病、类风湿性关节炎(RA)、类风湿性脊椎炎、痛风性关节炎和其他的关节炎病症、多发性硬化(MS)、哮喘、系统性红斑狼疮、成人呼吸窘迫综合征、白塞氏病、银屑病、慢性肺部炎症性疾病、移植物抗宿主反应、克罗恩病、溃疡性结肠炎、炎性肠病(IBD)、阿尔茨海默氏病和麻痹症。
术语“感染性疾病”指的病毒、细菌、寄生虫等感染导致的病理状态。这种疾病的非限制性例子包括利什曼病、新型冠状病毒感染肺炎、脓毒症。
术语“肺部疾病”指的是肺部器官相关的病理状态。这种疾病的非限制性例子包括支气管扩张、特发性肺纤维化、哮喘、慢性阻塞性肺部疾病、肺炎、急性肺损伤、急性呼吸窘迫综合征。
术语“骨髓相关疾病”指的是骨髓器官相关的病理状态。这种疾病的非限制性例子包括骨髓纤维化、真性红细胞增多症。
本文所述的式(I)的化合物和/或其药学上可接受的盐可用来达到有益的治疗或预防效果，例如，在患有自身免疫性疾病的个体中达到有益的治疗或预防效果。
术语“自身免疫性疾病”是指机体对自身抗原发生免疫反应而导致自身组织或器官损害所引起的疾病或病症。自身免疫性疾病的例子包括但不限于：慢性阻塞性肺病(COPD)、变应性鼻炎、红斑狼疮、重症肌无力、多发性硬化(MS)、类风湿性关节炎(RA)、银屑病、炎性肠病(IBD)、哮喘和特发性血小板减少性紫癜(idiopathic thrombocytopenicpurpura)以及骨髓增生性疾病(myeloid proliferative disorder)，例如骨髓纤维化(myelofibrosis)、真性红细胞增多症/原发性血小板增多症性骨髓纤维化(postpolycythemia vera/essential thrombocytosis myelofibrosis,PV/ET)。
在一些实施方案中，炎症性疾病和自身免疫性疾病包括类风湿性关节炎、慢性阻塞性肺病(COPD)、变应性鼻炎、哮喘、红斑狼疮、系统性红斑狼疮、银屑病和多发性硬化。
此外，本文所述的式(I)的化合物(例如，本文中的任何化合物)和/或其药学上可接受的盐可与另外的活性成分联合用药，用于治疗癌症、炎症性或自身免疫性疾病。另外的活性成分可以与本文所述的式(I)的化合物和/或其药学上可接受的盐分开给药，或者可以根据本公开将其包含在药物组合物中，例如固定剂量的复方药品。在一个典型的实施方案中，另外的活性成分是那些已知的或已被发现对治疗PI3K活性介导的疾病有效的成分，例如另一种PI3K调节剂或一种能有效拮抗与该特定的疾病相关的另一个靶点的化合物。联合用药可用于提高疗效(例如，通过将一种能增强本文所述的式(I)的化合物和/或其药学上可接受的盐的 效力或有效性的化合物包含入联合用药中)，降低一种或多种副作用，或者减少所需的本文所述的式(I)的化合物和/或其药学上可接受的盐的剂量。
实施例
下述实施例是对本发明的示例性说明，不以任何方式限制本发明。除非另外说明，否则所有分数均是重量分数，温度为摄氏温度。压力为大气压或接近大气压。所有数据均由安捷伦(Agilent 6120and/or 1100)测得。除了合成的中间体外，本发明所用的所有试剂均为商业渠道获得。除试剂外所有化合物的名称均由ChemDrew 20.0生成。
ACN          乙腈
Boc          叔丁氧基羰基
(Boc) 2O      焦碳酸而叔丁酯
DAST         二乙氨基三氟化硫
DCM          二氯甲烷
DEA          二乙氨
DMF          N,N-二甲基甲酰胺
DMA          二甲基乙酰胺
DIBAL-H      二异丁基氢化铝
DIEPA        N,N-二异丙基乙胺
EDCI         1-(3-二甲基胺基丙基)-3-乙基碳二亚胺盐酸盐
EtOAc/EA     乙酸乙酯
Et3N         三乙胺
HATU         2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯
HBTU         O-苯并三氮唑-四甲基脲六氟磷酸酯
HOAc         乙酸
HOBt         1-羟基苯并三唑
ee           对映异构体过量
mL           毫升
g            克
mg           毫克
ng           纳克
mol          摩尔
mmol         毫摩尔
h            小时
MeOH         甲醇
NaH          氢化钠
NCS          N-氯代琥珀酰亚胺
NMP          N-甲基-2-吡咯烷酮
PE           石油醚
Pd(dppf) 2Cl 2 [1,1'-双(二苯基膦基)二茂铁]二氯化钯
Pd 2(dba) 3    三二亚苄基丙酮二钯
Pd(PPh 3) 4    四(三苯基膦)钯
PMB          对甲氧基氰苄基
PPh 3         三苯基膦
THF          四氢呋喃
TFA          三氟乙酸
TFE          三氟乙醇
TsOH         4-甲苯磺酸
Xphos        2-二环己基膦-2’，4’，6’-三异丙基联苯
中间体的合成：
中间体25-3:
Figure PCTCN2022139044-appb-000015
a)室温氮气保护下，向25-1(10g,92.6mmol)的THF(1000mL)溶液中滴加入t-BuOK(1M in THF)(92.6mL,92.6mmol).搅拌8小时后，加入H 2SO 4(9.07g,92.6mmol)(1M).继续室温搅拌18小时后，加入饱和NH 4Cl(500mL)。乙酸乙酯萃取(500mL x 3)，水洗，无水Na 2SO 4干燥，浓缩的黄色油状产物25-2(5g,50％)。
b)室温氮气保护下，向25-2(4g,36.66mmol)的EtOH(100mL)溶液中，加入盐酸肼(2.5g,36.66mmol).反应升温至60℃，并继续搅拌12小时.冷至室温，浓缩，用NaHCO3溶液中和，乙酸乙酯萃取(200mL x 3)，水洗，无水Na 2SO 4干燥，浓缩。柱层析纯化得的黄色油状产物25-3(3g,66.5％).
中间体27-3:
Figure PCTCN2022139044-appb-000016
a)在0℃氮气保护下,向t-BuOK(1M in THF)(190mL,190mmol)的THF(100mL)溶液中，滴加27-1(20g,222mmol).搅拌10分子后，滴加入丙稀晴(10g,190mmol)的THF(100mL)溶液。室温反应3小时后，加入水，并用1N HCl(aq)调节酸碱度到pH＝1。乙酸乙酯萃取(300mL x 3)，水洗，无水Na 2SO 4干燥，浓缩的黄色固体产物27-2(10g,47％).
b)室温氮气保护下，向27-2(9g,81mmol)的EtOH(100mL)溶液中，加入盐酸肼(6.65g,97mmol).反应升温至60℃，并继续搅拌12小时.冷至室温，浓缩，用NaHCO3溶液中和，乙酸乙酯萃取(200mL x 3)，水洗，无水Na 2SO 4干燥，浓缩。柱层析纯化得的黄色固体产物27-3(4g,39.5％). 1H NMR(400MHz,MeOD-d 4)δ4.74(s,2H),4.69(s,2H).
中间体58-3:
Figure PCTCN2022139044-appb-000017
a)在-10℃氮气保护下,向t-BuOK(1M in THF)(181.72mL,181.72mmol)的THF(100mL)溶液中滴加入MeCN(7.46g,181.72mmol)。搅拌30分子后，滴加入methyl 2,2-difluoroacetate(10g,90.86mmol)的THF(100mL)溶液。继续反应1.5小时后，加入水，并用4N HCl(aq)处理至pH＝5。乙酸乙酯萃取(200mL x 3)，水洗，无水Na 2SO 4干燥，浓缩。柱层析纯化得的黄色油状产物58-2(10g,92.4％).
b)室温下，向58-2(10g,84.03mmol)的EtOH(100mL)溶液中加入盐酸肼(8.067g,117.65mmol).在90℃搅拌16后，冷至室温，加水稀释，乙酸乙酯萃取(200mL x 3)，水洗，无水Na 2SO 4干燥，浓缩黄色固体产物102-3(10g,89.5％). 1H NMR(400MHz,MeOD-d 4)δ6.69-6.41(t,J＝56Hz,1H),5.64(s,1H).
中间体60-3:
Figure PCTCN2022139044-appb-000018
a)室温下,向60-1(10g,100.92mmol)的醋酸(250mL)溶液中加入异苯并呋喃-1,3-二酮(14.95g,100.92mmol).在130℃反应2小时后，冷至0℃.过滤得固体产物，石油醚洗涤，真空干燥得棕色固体产物60-2(13g,56.72mmol,56.2％).
b)在0℃氮气保护下，向60-2(13g,56.72mmol)的THF(200mL)溶液中，依次加入MeOH(2.18g,68.06mmol),PPh 3(16.36g,62.39mmol)和DEAD(12.84g,73.74mmol).升至室温，并继续搅拌16hours。加入水合肼(30mL,60％)，并搅拌1小时。滤去固体，滤液浓缩,柱层析纯化得的棕色油状产物60-3(1g,8.84mmol,15.6％).
实施例1：目标分子的合成
化合物4：(S-2,4-二氨基-6-(1-(5-苯基吡唑[1,5-a]嘧啶-6-基)乙胺基)嘧啶-5-腈
Figure PCTCN2022139044-appb-000019
具体步骤如下：
a)将3-氨基吡唑溶解(1.43克，17.2毫摩尔)在N,N-二甲基甲酰胺(17毫升)中，依次加入乙氧甲叉基丙二酸二乙酯(4.65克,21.5毫摩尔,1.25当量)，K 2CO 3(5.94克,40.3毫摩尔,2.5当量)。氮气保护下，反应液在120-125℃搅拌8小时。冷却到室温，用冰水淬灭反应，然后用6N盐酸调节至pH 1-2，析出固体，过滤，水洗，空气干燥2天得5-羟基吡唑[1,5-a]嘧啶-6-甲酸乙酯(2.8克,收率78％).LC-MS(m/z):208.1(M ++1)。
b)室温下，将5-羟基吡唑[1,5-a]嘧啶-6-乙基酯溶解(10克，48.3毫摩尔)溶解在乙腈(50毫升)中，然后加入依次三氯氧磷(30克,193.2毫摩尔,4当量)，N,N-二异丙基乙胺(12.5克,96.6毫摩尔,2当量)。将反应液加热到120-125 o，并继续搅拌7小时。冷却到室温，并倒到冰水中(300毫升)，乙酸乙酯萃取(3x350毫升),合并有机相，无水Na 2SO 4干燥，过滤后浓缩得黄色固体5-氯吡唑[1,5-a]嘧啶-6-甲酸乙酯(6.91克,收率61％).LC-MS(m/z):226.1(M ++1)。该产品不需纯化直接用于下一步反应。
c)在封管中依次加入5-氯吡唑[1,5-a]嘧啶-6-乙基酯(1.95克,8.7毫摩尔)，苯硼酸(1.27克,10.4毫摩尔,1.2当量),Pd(dppf) 2Cl 2(318毫克,0.44毫摩尔,0.05当量),Na 2CO 3(1.1克,10.4毫摩尔,1.2当量),磁力搅拌子，dioxane(29毫升)和水(11毫升)。封管中空气通过三次真空抽气和氮气冲气排除后，将封管关闭。将封管放在90-95℃搅拌4小时。冷却到室温，加入水中(30毫升)，乙酸乙酯萃取(3x60毫升),合并有机相，无水Na2SO4干燥，过滤后浓缩得初品。初品用快速柱层析纯化得黄色固体5-苯基吡唑[1,5-a]嘧啶-6-甲酸乙酯(1.61克，收率69％)。LC-MS:268.1(M ++1)。
d)在0℃下，将5-苯基吡唑[1,5-a]嘧啶-6-乙基酯(2.41克，9.03毫摩尔)溶解在水/四氢呋喃/甲醇(20毫升/10毫升/10毫升)中，然后一次加入固体LiOH H2O(947毫克,22.6毫摩尔,2.5当量)。室温搅 拌过夜,然后用1N盐酸调节至pH 2-3,乙酸乙酯萃取,合并有机相，无水Na2SO4干燥，过滤后浓缩得白色固体5-苯基吡唑[1,5-a]嘧啶-6-甲酸(2.51克,收率>100％)。该产品不需纯化直接用于下一步反应。
e)在0℃下，将5-苯基吡唑[1,5-a]嘧啶-6-甲酸(2.16克，9.03毫摩尔)溶解在二氯甲烷(30毫升)中，然后依次加入N,O-二甲基羟胺盐酸盐(1.77克，18毫摩尔,2当量)，EDCI(2.72克,14.2毫摩尔,1.57当量)，HOBt(2.1克,13.6毫摩尔,1.5当量),和Et 3N(2.74克,27.1毫摩尔,3当量)。室温搅拌过夜,用冰水(50毫升)淬灭反应，乙酸乙酯萃取(3x60毫升),合并有机相，无水Na2SO4干燥，过滤后浓缩得初品。初品用快速柱层析纯化得黄色固体N-甲氧基-N-甲基5-苯基吡唑[1,5-a]嘧啶-6-甲酰胺(960毫克,收率38％)。LC-MS:283.1(M ++1)。
f)在0℃下，将N-甲氧基-N-甲基5-苯基吡唑[1,5-a]嘧啶-6-甲酰胺(730毫克，2.59毫摩尔)溶解THF(10毫升)中，然后滴加甲基格氏试剂MeMgBr(1.9毫升，3.0M，5.7毫摩尔，2.2当量)。室温搅拌4小时,用饱和氯化氨水溶液(15毫升)淬灭反应，乙酸乙酯萃取(3x30毫升),合并有机相，无水Na 2SO 4干燥，过滤后浓缩得初品。初品用快速柱层析纯化得黄色固体1-(5-苯基吡唑[1,5-a]嘧啶-6-基)-乙基酮(390毫克,收率63％)。LC-MS:238.1(M ++1)。
g)在室温下，将1-(5-苯基吡唑[1,5-a]嘧啶-6)-乙基酮(350毫克，1.47毫摩尔)溶解在THF(10毫升)中，然后依次加入(R)-2-甲基丙烷-2-亚磺酰(196毫克,1.62毫摩尔,1.1当量)，Ti(OEt) 4(675毫克，2.96毫摩尔，2当量)。加热回流6小时，冷却到室温，用饱和氯化氨水溶液(10毫升)淬灭反应，乙酸乙酯萃取(3x20毫升),合并有机相，无水Na 2SO 4干燥，过滤后浓缩得初品。初品用快速柱层析纯化得黄色固体(R,Z)-2-甲基-N-(1-(5-苯基吡唑[1,5-a]嘧啶-6-基)乙烯基)-2-甲基丙烷-2-亚磺酰胺(301毫克,收率62％)。LC-MS:341.1(M ++1)。
h)室温下，将(R,Z)-2-甲基-N-(1-(5-苯基吡唑[1,5-a]嘧啶-6-基)乙烯基)-2-甲基丙烷-2-亚磺酰胺(340毫克，1毫摩尔)溶解THF(8毫升)中，冷至-78℃，滴加L-selectride(2.5毫升，1.0M in THF，2.5毫摩尔,2.5当量)。在-78℃搅拌2小时后，用饱和氯化氨水溶液(15毫升)淬灭反应，乙酸乙酯萃取(2x20毫升),合并有机相，无水Na 2SO 4干燥，过滤后浓缩得初品。初品用快速柱层析纯化得黄色固体(R)-2-甲基-N-((S)-1-(5-苯基吡唑[1,5-a]嘧啶-6-基)乙基)-2-甲基丙烷-2-亚磺酰胺(197毫克,收率58％)。LC-MS:343.1(M ++1)。
i)在0℃下，将(R)-2-甲基-N-((S)-1-(5-苯基吡唑[1,5-a]嘧啶-6-基)乙基)-2-甲基丙烷-2-亚磺酰胺(200毫克，0.58毫摩尔)溶解二氯甲烷(3毫升)中，然后滴加4N HCl的dioxane(0.58毫升,2.34毫摩尔,4当量)溶液。室温搅拌2小时,浓缩得(S)-1-(5-苯基吡唑[1,5-a]嘧啶-6-基)-乙胺盐酸盐。将该盐溶解到nBuOH(3毫升)中,后依次加入2,4-二氨基-6-氯嘧啶-5-腈(149毫克,0.88毫摩尔,1.5当量)，DIEPA(302毫克,2.34毫摩尔,4当量)。加热回流16小时，冷却到室温，浓缩得初品。初品用快速柱层析纯化得黄色固体(S)-2,4-二氨基-6-(1-(5-苯基吡唑[1,5-a]嘧啶-6-基)乙胺基)嘧啶-5-腈4(59毫克,收率27％)。LC-MS:372.2(M ++1)。
化合物23，24，47，48可以按合成化合物4类似的方法合成而得到。
化合物1：(S)-2,4-二氨基-6-(1-(2-甲基-5-苯基吡唑[1,5-a]嘧啶-6-基)乙胺基)嘧啶-5-腈
Figure PCTCN2022139044-appb-000020
a)于1000毫升圆底烧瓶中，加入苯甲酰甲酸乙酯(32.9克，171毫摩尔),N,N-二甲基甲酰胺二甲基缩醛(24.5克，205.2毫摩尔，1.2当量),甲苯(350毫升)。加热回流2小时，冷却到室温，减压蒸流去除甲苯。所得剩余物溶于350毫升乙醇，依次加入5-甲基-3-氨基吡唑(16.6克，171毫摩尔，1当量)，冰乙酸(100毫升)。室温搅拌24小时，减压蒸流除去乙醇，剩余物用饱和NaHCO3调节至pH 7-8,乙酸乙酯萃取(3x200毫升),合并有机相，用饱和盐水洗涤，无水Na 2SO 4干燥，过滤后浓缩得初品。初品用快速柱层析纯化得白色固体2-甲基-5-苯基吡唑[1,5-a]嘧啶-6-甲酸乙酯(27.8克,收率58％).LC-MS:282.2(M ++1)。
b)其他反应步骤：(S)-2,4-二氨基-6-(1-(2-甲基-5-苯基吡唑[1,5-a]嘧啶-6-基)乙胺基)嘧啶-5-腈1可以按合成化合物4类似的方法得到。
化合物2(S)-N-(1-(2-甲基-5-苯基吡唑并[1,5-a]嘧啶-6-基)乙基)-9H-嘌呤-6-胺和化合物3(S)-4-氨基-6-(1-(2-甲基-5-苯基吡唑[1,5-a]嘧啶-6-基)乙胺基)嘧啶-5-腈可以按合成化合物1类似的方法从(S)-1-(2-甲基-5-苯基吡唑并[1,5-a]嘧啶-6-基)乙氨合成而得到。
Figure PCTCN2022139044-appb-000021
化合物5：(S)-2,4-二氨基-6-(1-(3-氯-2-甲基-5-苯基吡唑[1,5-a]嘧啶-6-基)乙胺基)嘧啶-5-腈
Figure PCTCN2022139044-appb-000022
a)在室温下，将1-(2-甲基-5-苯基吡唑[1,5-a]嘧啶-6)-乙基酮(3.22克，12.83毫摩尔)溶解在CHCl 3(40毫升)中，然后加入NCS(2.06克,15.4毫摩尔,1.2当量)，加热回流7小时，冷却到室温，加入硅胶，浓缩后的浓缩物用快速柱层析纯化得黄色固体1-(3-氯-2-甲基--5-苯基吡唑[1,5-a]嘧啶-6-基)乙酮(2.41克，收率64％)。
b)在室温下，将1-(3-氯-2-甲基-5-苯基吡唑[1,5-a]嘧啶-6-基)乙酮(2.45克，9.8毫摩尔)溶解在THF(40毫升)中，然后依次加入(R)-2-甲基丙烷-2-亚磺酰(1.89克，15.6毫摩尔，1.6当量)，Ti(OEt) 4(4.45克,19.5毫摩尔，2当量)，再加热回流20小时，然后冷却到室温，用饱和氯化氨水溶液(50毫升)淬灭反应，乙酸乙酯萃取(3x50毫升),合并有机相，无水Na 2SO 4干燥，过滤后浓缩得初品。初品用快速柱层析纯化得黄色固体(R,Z)-N-(1-(3-氯-2-甲基-5-苯基吡唑[1,5-a]嘧啶-6-基)乙烯基)-2-甲基丙烷-2-亚磺酰胺(2.2克,收率71％)。LC-MS:389.1(M ++1)。
c)室温下，将(R,Z)-N-(1-(3-氯-2-甲基-5-苯基吡唑[1,5-a]嘧啶-6-基)乙烯基)-2-甲基丙烷-2-亚磺酰胺(2.04克，5.76毫摩尔)溶解到THF(20毫升)中，冷至-78℃，滴加L-selectride(14.4毫升，1.0M in THF,14.4毫摩尔，2.5当量)。在-78℃搅拌2小时后，用饱和氯化氨水溶液(50毫升)淬灭反应，乙酸乙酯萃取(3x40毫升),合并有机相，用无水Na 2SO 4干燥，过滤后浓缩得初品。初品用快速柱层析纯化得 黄色固体(R)-N-((S)-1-(3氯-2-甲基-5-苯基吡唑[1,5-a]嘧啶-6-基)乙基)-2-甲基丙烷-2-亚磺酰胺(1.97克,收率96％)。LC-MS:391.1(M ++1)。
d)在0℃下，将(R)-N-((S)-1-(3氯-2-甲基-5-苯基吡唑[1,5-a]嘧啶-6-基)乙基)-2-甲基丙烷-2-亚磺酰胺(530毫克，1.41毫摩尔)溶解二氯甲烷(10毫升)中，然后滴加4N HCl的dioxane(1.41毫升,5.64毫摩尔,4当量)溶液。室温搅拌2小时,浓缩得(S)-1-(3-氯-2-甲基-5-苯基吡唑[1,5-a]嘧啶-6-基)-乙胺盐酸盐。将该盐溶于nBuOH(10毫升)，依次加入2,4-二氨基-6-氯嘧啶-5-腈(359毫克,2.12毫摩尔,1.5当量)，DIEPA(729毫克,5.64毫摩尔，4当量)。加热回流14小时，冷却到室温，用水稀释，乙酸乙酯萃取(3x40毫升),合并有机相，无水Na2SO4干燥，过滤后浓缩得粗品。初品用快速柱层析纯化得黄色固体(S)-2,4-二氨基-6-(1-(3-氯-2-甲基-5-苯基吡唑[1,5-a]嘧啶-6-基)乙胺基)嘧啶-5-腈(270毫克,收率49％)。LC-MS:420.14(M ++1)。
化合物6(S)-4-氨基-6-(1-(3-氯-2-甲基-5-苯基吡唑[1,5-a]嘧啶-6-基)乙胺基)嘧啶-5-腈和化合物7(S)-N-(1-(3-氯-2-甲基-5-苯基吡唑并[1,5-a]嘧啶-6-基)乙基)-9H-嘌呤-6-胺可以按合成化合物5类似的方法从(S)-1-(3-氯2-甲基-5-苯基吡唑并[1,5-a]嘧啶-6-基)乙
化合物8-22，25-46，49-94，96-104可以按合成化合物5类似的方法合成而得到。
化合物95:(S)-2,4-二氨基-6-((1-(3-氯-2-甲基-5-(吡啶-2-基)吡唑[1,5-a]嘧啶-6-基)乙基)氨基)嘧啶-5-甲腈
Figure PCTCN2022139044-appb-000023
a)在0℃氮气保护下，向95-1(40g,412.4mmol)的二氯甲烷(1L)溶液中，加入NCS(60.6g,453.9mmol).零度搅拌2小时后，升至室温，浓缩，加入水，并用乙酸乙酯萃取。无水Na2SO4干燥，过滤后浓缩，快速柱层析纯化得紫红色固体95-2(47g,87.01％).
b)在0℃氮气保护下，室温下，向95-2(47g,358.8mmol)和ethyl(E)-3-ethoxyacrylate(56.83g,394.7mmol)的DMF(500mL)溶液中，加入Cs 2CO 3(175.3g,538.1mmol)。在110℃氮气保护下，搅拌过夜。冷至室温，滤去固体，用乙酸乙酯洗涤。浓缩滤液，快速柱层析纯化得棕色固体95-3(34g,51.78％).
c)在0℃氮气保护下，向95-3的(34g,185.8mmol)乙晴(500mL)溶液中，加入NIS(62.7g,278.7mmol)。在70℃搅拌2天后，冷至室温，浓缩，快速柱层析纯化得棕色固体95-4(33g,57.48％)
d)向95-4(33g,106.8mmol)中加入in POCl 3(100mL)，并在100℃反应6小时.冷至室温，浓缩，快速 柱层析纯化得黄色固体95-5(4.8g,13.8％).
e)室温下，向95-5(4.8g,15mmol)的1,4-dioxane(10mL)溶液中，依次加入tributyl(1-ethoxyvinyl)stannane(22g,60mmol)和Pd(dppf)Cl 2(1.1g,1.5mmol)。去除空气，并80℃氮气保护下搅拌2小时。冷至室温，加入4N HCl，并继续搅拌30分钟。加数稀释，乙酸乙酯萃取，干燥，浓缩，快速柱层析纯化得黑色固体95-6(1.6g,43.9％)。
f)在0℃氮气保护下，向95-6(1.6g,7mmol)的THF(30mL)溶液中，滴加入(+)-DIPCl(3M in THF)(5.8mL,17.5mmol).室温搅拌2小时后，加水，并用乙酸乙酯萃取。无水Na2SO4干燥，过滤后浓缩，快速柱层析纯化得黄色固体95-7(1g,58.3％).
g)在0℃氮气保护下，向95-7(1g,4.1mmol)的THF(20mL)溶液中，加入Isoindoline-1,3-dione(1.2g,8.2mmol).然后滴人PPh 3(4.3g,16.4mmol)和DIAD(3.3g,16.4mmol)的THF(50mL)溶液。室温搅拌4小时后，加水，并用乙酸乙酯萃取。无水Na2SO4干燥，过滤后浓缩，快速柱层析纯化得浅黄色固95-8(754mg,49.2％)
h)室温下，向95-8(754mg,2.0mmol)和2-(tributylstannyl)pyridine(371mg,1mmol)的dioxane(6mL)溶液中，加入Pd(dppf)Cl 2(145.1mg,0.2mmol),xphos(190.7mg,0.4mmol)和Na 2CO 3(423.6mg,4mmol).去除空气，在80℃氮气保护下搅拌12小时。冷至室温，加水，并用乙酸乙酯萃取。无水Na2SO4干燥，过滤后浓缩，快速柱层析纯化得黄色固体95-9(120mg,14.4％).
i)室温下，向95-9(120mg,0.29mmol)的EtOH(3mL)溶液中，加入水合肼(145mg,2.9mmol).在100℃搅拌半小时后，冷至室温，加水，并用乙酸乙酯萃取。无水Na2SO4干燥，过滤后浓缩，快速柱层析纯化得棕色油状产物95-10(31mg,37.2％).
j)室温下，向95-10(31mg,0.11mmol)和2,4-diamino-6-chloropyrimidine-5-carbonitrile(37.2mg,0.22mmol)的DMSO(1mL)溶液中加入KF(9.6mg,0.17mmol)和DIEA(71.1mg,0.55mmol).The mixture在130℃搅拌12后，冷至室温，加水，并用乙酸乙酯萃取。无水Na2SO4干燥，过滤后浓缩，C18柱层析纯化得黄色固体95(11.6mg,25.1％).MS(ESI):m/z＝421.2[M+H] +；
1H NMR(400MHz,DMSO)δ9.05(s,1H),8.70–8.66(m,1H),8.06–7.98(m,1H),7.95–7.88(m,1H),7.57–7.52(m,1H),5.61(q,J＝6.8Hz,1H),2.41(s,3H),1.32(d,J＝6.8Hz,3H).
化合物105:(S)-2,4-二氨基-6-((1-(3-氯-2-环丙基-5-(5-氟吡啶-3-基)吡唑并[1,5-a]嘧啶-6-基)乙基-2,2,2-d3)氨基)嘧啶-5-甲腈
Figure PCTCN2022139044-appb-000024
a)在-10℃，向105-1(20g,129mmol)中加入t-BuOK(the solution of THF)(1M,350mL)，并继续搅拌1.5小时。然后滴加入EtOAC(31.3mg,355mmol)，搅拌1小时后，加入4N HCl至pH3-4，乙酸乙酯萃取。无水Na2SO4干燥，过滤后浓缩，快速柱层析纯化得黄色固体105-2(23g,94.79mmol,84.50％).
b)将105-2(4g,18.95mmol)和DMF-DMA(2.60g,18.95mmol)在甲苯(40mL)中的混合物，在110℃搅拌2小时。冷至室温，浓缩。然后依次加入EtOH(80mL)，5-cyclopropyl-1H-pyrazol-3-aminehydrochloride(1.84g,18.95mmol)，和and HOAc(16mL).搅拌过夜，浓缩。加水，并用乙酸乙酯萃取。无水Na2SO4干燥，过滤后浓缩，快速柱层析纯化得黄色固体产物105-3(4.8g,14.72mmol,78.06％).
c)在0℃，向105-3(4.8g,4.72mmol)的THF(30mL),MeOH(20mL)和H 2O(10mL)溶液中，加入LiOH·H 2O(3.1g,73.59mmol).室温搅拌2小时后，浓缩，并用4N HCl酸化至pH＝1-2.过滤干燥得黄的固体产物105-4(3.5g,11.74mmol,79.73％)。
d)在0℃，向105-4(3.5g,11.74mmol)的DCM(50mL)溶液中，依次加入N,O-dimethylhydroxylaminehydrochloride(4.9g,17.61mmol),DIEA(3.1g,23.48mmol)和HATU(4.9g,12.92mmol)。室温搅拌2小时后，加水，并用二氯甲烷萃取。无水Na2SO4干燥，过滤后浓缩，快速柱层析纯化得黄色固体产物105-5(3.5g,11.75mmol,87.50％).
e)在-70℃，向105-5(2.1g,6.16mmol)的THF(30mL)溶液中加日LiAlH 4(6.8mL,15.4mmol)。搅拌1小时后，加入饱和saturated NH 4Cl(aq).乙酸乙酯萃取。无水Na2SO4干燥，过滤后浓缩，柱层析纯化得黄色固体105-6(1.16g,3.9mmol,63.36％)。
f)室温下，向105-6(1.1g,3.9mmol)的ACN(20mL)溶液中加日NCS(625mg,4.68mmol).在60℃反应12小时，冷至室温，浓缩。加水，并用乙酸乙酯萃取。无水Na2SO4干燥，过滤后浓缩，快速柱层析纯化得黄色固体产物105-7(1.16g,3.67mmol,94.31％).
g)室温下，向105-7(1.16mg,3.67mmol)的THF(20mL)溶液中加入(S)-2-methylpropane-2-sulfinamide(1.34mg,11.01mmol)和Titanium ethoxide(5g,22.02mmol).在65℃搅拌12小时后，冷至室温，加入饱和NH 4Cl(aq)，乙酸乙酯萃取。无水Na2SO4干燥，过滤后浓缩，柱层析纯化得黄色固体105-8(1.1g,2.63mmol,71.52％).
h)在0℃，向105-8(500mg,1.19mmol)的THF(15mL)溶液中，加入CD 3MgI(3.6mL,3.58mmol).搅拌1小时后，加入饱和NH 4Cl(aq).乙酸乙酯萃取。无水Na2SO4干燥，过滤后浓缩，快速柱层析纯化得黄色固体产物105-9(1.1g,2.63mmol,71.52％).
i)室温下，向105-9(500mg,1.14mmol)的MeOH(5mL)溶液中，加人HCl(g)in 1,4-dioxane(4M,0.75mL).搅拌1小时后，用饱和Na 2CO 3(aq)溶液碱化至pH＝8-9.乙酸乙酯萃取。无水Na2SO4干燥，过滤后浓缩，柱层析纯化得黄色固体105-10(310mg,0.93mmol,81.36％).
j)室温下，向105-10(250mg,0.75mmol)和2,4-diamino-6-chloropyrimidine-5-carbonitrile(152mg,0.9mmol)的DMSO(5mL)溶液中，加入KF(87mg,1.5mmol)和DIEA(483mg,3.74mmol).在140℃搅拌4小时后，冷至室温，加水，乙酸乙酯萃取。无水Na2SO4干燥，过滤后浓缩，C18快速柱层析纯化得黄色固体产物(43.94mg,0.094mmol,12.55％).MS(ESI):m/z＝468.2[M+H]+；
1H NMR(400MHz,DMSO)δ8.91(s,1H),8.79(d,J＝2.8Hz,1H),8.70(s,1H),8.18–8.11(m,1H),4.88(s,1H),2.12–2.06(m,1H),1.03–0.95(m,2H),0.85–0.79(m,2H).
表1.合成实例化合物光谱数据总结
Figure PCTCN2022139044-appb-000025
Figure PCTCN2022139044-appb-000026
Figure PCTCN2022139044-appb-000027
Figure PCTCN2022139044-appb-000028
Figure PCTCN2022139044-appb-000029
Figure PCTCN2022139044-appb-000030
Figure PCTCN2022139044-appb-000031
Figure PCTCN2022139044-appb-000032
Figure PCTCN2022139044-appb-000033
Figure PCTCN2022139044-appb-000034
Figure PCTCN2022139044-appb-000035
Figure PCTCN2022139044-appb-000036
Figure PCTCN2022139044-appb-000037
Figure PCTCN2022139044-appb-000038
Figure PCTCN2022139044-appb-000039
实施例2：荧光法测定PI3K酶活性
PI3K激酶包括PIK3CG(p110gamma)购买自Invitrogen，p110α/p85α、p110β/p85α和p110δ/p85α购买自BPS。
ADP-Glo TMKinase Assay(ADP-Glo TM激酶检测试剂盒)(Promega,v9102)是一个发光法的激酶检测试剂盒，它检测激酶反应中所形成的ADP；ADP被转化成ATP，然后ATP再被Ultra-Glo TM萤光素酶转化成光信号。发光信号与激酶活性正相关。该试剂盒适合检测化合物对多种纯化激酶活性的影响，使之成为初级筛选和研究激酶作用的选择性的理想工具。该试剂盒的操作有两个步骤：首先，在激酶反应后，向其中加入一份与激酶反应体系等体积的ADP-Glo TM试剂，使反应终止，并消耗完剩余的ATP。 在第二步中，加入激酶检测试剂，它在使ADP转化成ATP的同时，还使用偶联的萤光素酶/萤光素反应来检测新合成的ATP。
检测过程如下：
激酶缓冲液包含50mM HEPES,pH 7.5；3mM MgCl2；1mM EGTA；100mM NaCl；0.03％CHAPS；2mM DTT。
1)384检测板(Corning,Cat#4512)中加入1μL化合物稀释液。(化合物检测的终浓度为1000nM、333.33nM、111.11nM、37.037nM、12.345nM、4.115nM、1.372nM、0.457nM、0.1524nM和0.0508nM共10个浓度，复孔。DMSO终浓度为1％)
2)384检测板的相应位置加入2μl激酶溶液(PI3Kα终浓度为0.25μg/ml；PI3Kβ终浓度为0.3μg/ml；PI3Kγ终浓度为1.2μg/ml；PI3Kδ终浓度为0.3μg/ml)。
3)384检测板的相应位置加入2μl底物溶液(PI3Kα:PIP2终浓度20μM,ATP终浓度10μM；PI3Kγ、β和δ:PIP2终浓度30μM,ATP终浓度20μM)。室温反应120分钟。
4)将ADP-Glo试剂平衡至室温。检测板每孔加5μl ADP-Glo试剂终止反应。离心机1000转/分钟，离心1分钟。随后在振动筛上缓慢摇匀，室温平衡40分钟。
5)每孔加入10μl激酶检测试剂，离心1分钟，平衡30分钟后使用Envision读数。
数据分析：从Envision复制检测值，将检测值数据转换为百分比抑制值。抑制率＝(Max-Sample)/(Max-Min)*100。在XLfit excel插件版本中拟合数据，得到IC50值。(Max：反应体系中含有激酶与底物；Min：反应体系中只含有底物；Sample：反应体系中含有激酶、底物和化合物)。
表2示出了本实施例中测定的一些本发明的化合物IC50(nM)值
Figure PCTCN2022139044-appb-000040
Figure PCTCN2022139044-appb-000041
Figure PCTCN2022139044-appb-000042
Figure PCTCN2022139044-appb-000043
*ND：没有测试
从上表可见本发明的一些化合物体外激酶测试中显示对PI3Kδ激酶具有nM级别的活性，且有的化合物对其他亚型选择性超200倍。
实施例3：在人类淋巴瘤细胞系RAJI和小鼠的巨噬样细胞Raw264.7细胞系中分别评估化合物对PI3Kδ和PI3Kγ的抑制剂效果
本实施例是通过检测AKT的磷酸化来评估化合物在细胞水平下对PI3K不同亚型的作用。为了评估化合物对PI3K-δ亚型的作用，人类淋巴瘤细胞系RAJI需要与anti-IgM抗体相结合。评估化合物对PI3K-γ的抑制效果，小鼠的巨噬样细胞Raw264.7需要一种G蛋白偶联受体激动剂C5a的刺激。
PI3K-γ亚型：用无血清DMEM培养基重悬RAW264.7细胞，在96孔板中每孔加入60000个/45μL的细胞悬液。细胞置于5％CO 2，37℃培养箱中孵育过夜。无血清饥饿18小时后，加入50μL化合物，在培养箱中培养60min。然后加入5μL的25nM的C5a(R&D Systems，用血清培养基稀释)刺激5min。吸出培养基每孔加入50μL 1x裂解液。室温震荡45分钟。将16μL裂解物转入384板，加入4μL Cisbio公司的Phospho-AKT(Ser473)试剂盒的预混抗体。1000rpm/min离心1分钟，22℃.孵育4小时后用Envision读数(665nm/615nm)。
PI3K-δ亚型：Raji细胞以每孔30μL，50,000个细胞种在96孔板中培养，细胞培养基是不加血清的RPMI-1640。细胞在5％CO 2和37℃培养箱中孵育过夜。无血清饥饿18小时后，在细胞中加入2s.5μL化合物(14X)，在培养箱中孵育60分钟。然后加入2.5μL(14X，用血清培养基稀释)，的anti-human IgM(Jackson Immuno Research)，放入培养箱内刺激30分钟(终浓度为10μg/mL)。每孔加入11.5μL的4x裂解液。室温震荡45分钟。将16μL裂解物加入转入384板，加入4μL Cisbio公司的Phospho-AKT(Ser473)试剂盒的预混抗体。1000rpm/min离心1分钟，22℃孵育4小时后用Envision读数(665nm/615nm)。
表3示出了本实施例中测定的一些本发明的化合物IC50(nM)值
Figure PCTCN2022139044-appb-000044
*ND：没有测试
从上表可见本发明的一些化合物体外细胞测试中显示对PI3Kδ激酶具有nM级别的活性，且有的化合物对其他亚型选择性超100倍。
应理解，在阅读了本发明的上述公开内容之后，在不脱离本发明申请的方面构思和精神的情况下，本领域普通技术人员可以对本发明的技术方案作各种改动、调整或组合等，这些等价形式同样落于本申请要求保

Claims (23)

  1. 式(I)所示的化合物和/或其药学上可接受的盐，其特征在于，
    Figure PCTCN2022139044-appb-100001
    其中：
    R 1独立地选自氢、氘、卤素、氰基、羟基、巯基、氨基、-C 1-6烷基、-C 1-6烷氧基、-C 2-6烯基、-C 2-6炔基、-C 3-6环烷基、-C 3-6杂环烷基、-C 3-6环烷氧基、-C 3-6杂环烷氧基、-C 1-6烷基(O)C 1-6烷基、-COOH、-C(O)NH 2、-C(O)NH(C 1-6烷基)、-C(O)N(C 1-6烷基)(C 1-6烷基)、-S(O)2NH 2、-S(O)(NH)NH 2、-C(O)OR 1a、芳基、芳烷基、芳烷氧基、杂芳基、杂芳烷基、杂芳烷氧基；其中所述的巯基、氨基、烷基、烷氧基、烯基、炔基、环烷基、环烷氧基、杂环烷基、杂环烷氧基、芳基、芳烷基、-C(O)NH 2、-S(O)2NH 2、-S(O)(NH)NH 2、芳烷氧基、杂芳基、杂芳烷基、杂芳烷氧基可选择性被一个或多个R 1a取代；
    R 1a选自氢、氘、卤素、氰基、羟基、巯基、氨基、烷基、烷氧基、烯基、炔基、环烷基、环烷氧基、杂环烷基、杂环烷氧基、芳基、杂芳基、-COOH、-C(O)NH 2、-C(O)NH(C 1-6烷基)、-C(O)N(C 1-6烷基)(C 1-6烷基)、-S(O)2NH 2、-S(O)(NH)NH 2、-C(O)OR a；其中所述的烷基、烯基、炔基、环烷基、杂环烷基、环烷氧基、杂环烷氧基、芳基、杂芳基、-C(O)NH 2、-S(O)2NH 2、-S(O)(NH)NH 2选择性被卤素、氰基、-OR a、-SR a、NR bR c、烷基、烯基、炔基、环烷基、杂环烷基、环烷氧基、杂环氧基中的任一个或多个取代或未取代；
    R 2选自氢、卤素、氘、羟基、氰基、-C 1-6烷基、-C 2-6烯基、-C 2-6炔基、-C 3-6环烷基、-C 3-6杂环烷基、-C 3-6环烷氧基、-C 3-6杂环烷氧基、-COOH、-C(O)NH 2、-C(O)NH(C 1-6烷基)、-C(O)NH(C 1-6烷基) 2、-S(O)2NH 2、-S(O)(NH)NH 2、-C(O)OR 2a、-C(O)NH 2、芳基、杂芳基；其中所述烷基、烯基、炔基、环烷基、杂环烷基、环烷氧基、杂环烷氧基、芳基、杂芳基、-C(O)NH 2、-S(O)2NH 2、-S(O)(NH)NH 2可选择性地被一个或多个R 2a取代；
    R 2a选自氢、氘、卤素、氰基、羟基、烷基、烯基、炔基、环烷基、杂环烷基、环烷氧基、杂环烷氧基、芳基、芳基氧基、杂芳基、杂芳基氧基、-COOH、-C(O)NH 2、-C(O)NH(C 1-6烷基)、-C(O)N(C 1-6烷基)(C 1-6烷基)、-S(O)2NH 2、-S(O)(NH)NH 2、-C(O)OR a；其中所述的烷基、烯基、炔基、环烷基、杂环烷基、环烷氧基、杂环烷氧基、芳基、芳基氧基、杂芳基、杂芳基氧基、-C(O)NH 2、-S(O)2NH 2、-S(O)(NH)NH 2选择性地被选自卤素、氰基、-OR a、-SR a、NR bR c、烷基、烯基、炔基、环烷基、杂环烷基、环烷氧基、杂环氧基中的一个或多个取代或未取代；
    和/或，R 1与R 2选择性地与其各自连接的碳原子形成3-6元环烷基、3-6元杂环烷基、3-6元环烯基、3-6元杂环烯基、芳基、杂芳基，并且可选择性被一个或者多个R 1a或者R 2a取代；并且上述环烷基、杂环烷基、环烯基、杂环烯基中的碳原子或硫原子可被选择性氧代，形成环内羰基、酰胺基、酯基、砜基(-S(O)2-)、磺酰胺基(-S(O)2NH-)的一部分；
    R 3选自氢、氘、C 1-6烷基、氘代烷基、卤代C 1-6烷基、羟基取代的C 1-6烷基、氰基烷基、-C 3-6环烷基、-C 3-6杂环烷基、烷氧基烷基、环烷基烷基、杂环基烷基、环烷氧基烷基、杂环烷氧基烷基；
    R 4独立地选自杂芳基，所述的杂芳基是具有5、6或7个环原子的单环芳族烃基，其在环中包含 1或2个N环杂原子，其余环原子是碳原子，或者是具有9或10个环原子的二环芳族烃基，其在环中包含1、2、3或4个N环杂原子，其余环原子是碳原子，其中至少一个环是芳族环，并且所述杂芳基包括其中的N环杂原子是N-氧化物形式的那些杂芳基，并且所述杂芳基任选地被一个或多个选自以下的取代基取代：卤素、氘、氰基、羟基、巯基、C 1-6烷基、卤代烷基、环烷基、环烷氧基、杂环基、杂环氧基、-NH 2、-NH(C 1-6烷基)、-N(C 1-6烷基)(C 1-6烷基)、-COOH、-C(O)NH 2、-C(O)NH(C1-6烷基)、-C(O)N(C 1-6烷基)(C 1-6烷基)、-S(O)2NH 2、-S(O)(NH)NH 2、-C(O)OR a、-NHC(O)(C 1-6烷基)、-NHC(O)(C 1-6环烷基)、-NHC(O)O(C 1-6烷基)、-NHC(O)O(C 1-6环烷基)、苯基和5或6元杂芳基；其中C 1-6烷基、卤代烷基、-NH 2、-COOH、-C(O)NH 2、环烷基、杂环烷基可被一个或者多个R 1a选择性取代；其中作为R 4的取代基的5或6元杂芳基是具有5或6个环原子的单环芳族烃基，其在环中包含1、2或3个独立地选自N、O或S的环杂原子，其余环原子是碳原子，当杂芳基中的S和O原子的总数超过1时，这些S和O杂原子彼此不相邻，其中作为杂芳基的取代基的苯基或者5或6元杂芳基任选地被一个或多个选自以下的取代基取代：卤素、氨基、羟基、巯基、C1-6烷基和-O(C1-6烷基)、卤代烷基；
    R 5独立地选自氢、C 1-6烷基、羟基取代烷基、氘代烷基、羟基烷基、C 3-6环烷基、C 3-6杂环烷基、环烷基烷基或环烷氧基烷基，其中所述的烷基可选择性的被一个或多个R 5a取代；R 5a选自氘、卤素、CN、烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基；其中所述的烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基可被卤素、CN、-OR a、-SR a、-NR bR c、烷基、烯基、炔基、环烷基、杂环烷基取代；
    和/或，R 4和R 5选择性地与两者共同连接的N原子形成含氮杂环基或者杂芳基，其中所述含氮杂环基和杂芳基可被一个或者多个取代基选择性取代，包括但不限于卤素、氘、氨基、羟基、巯基、氰基、烷基、氘代烷基、卤代烷基、烯基、炔基、环烷基、烷氧基、环烷氧基、杂环烷氧基、芳香基、芳香基氧基、杂芳香基、杂芳香基氧基、-COOH、-C(O)NH 2、-C(O)NH(C 1-6烷基)、-C(O)N(C 1-6烷基)(C 1-6烷基)、-S(O)2NH 2、-S(O)(NH)NH 2、-C(O)OR a、-OR a、-SR a、NR bR c；
    其中，R a、R b和R c独立地选自氢、氘、卤素、C 1-6烷基、氘代C 1-6烷基、卤代C 1-6烷基、-C 2-6烯基、-C 2-6炔基、-C 3-6环烷基、-C 3-6杂环烷基、羟基取代的C 1-6烷基、-C 1-6烷基(O)C 1-6烷基、芳基、杂芳基；
    和/或R b和R c与和两者共同连接的氮原子一起形成4至7元杂环烷基或地被1至3个R a取代；
    所述Ar选自芳基或杂芳基：
    所述芳基是由一个环或多个环稠合组成的含有6-12个环碳原子的碳环烃基，其中，至少一个环是芳族环并且其它环不是杂芳基；
    所述杂芳基是具有5、6或7个环原子的单环芳族烃基，其在环中包含1或2个独立选自N、O和S的环杂原子，其余环原子是碳原子，或者是具有9或10个环原子的二环芳族烃基，其在环中包含1、2、3或4个独立选自N、O和S的环杂原子，其余环原子是碳原子，其中至少一个环是芳族环，当杂环上的S和O原子的总数超过1时，所述S和O原子彼此不相邻，并且所述杂芳基包括其中的N杂原子是N-氧化物形式的那些杂芳基；
    所述芳基和杂芳基任选地被选自以下取代基中的一个或多个取代：氢、氘、卤素、氰基、羟基、巯基、-C 1-6烷基、卤代烷基、烷氧基、卤代烷氧基、卤代烷氧基烷基、环烷基、卤代环烷基、-(C 1-6烷基)OH和-SO2(C 1-6烷基)、烯基、炔基。
  2. 根据权利要求1所述式(I)的化合物和/或其药学上可接受的盐，其特征在于，所述Ar选自芳基或杂芳基：所述芳基或所述杂芳基选自具有6个环原子的芳香基和杂芳基、具有5个环原子的杂芳基、具有9或10个环原子的二环杂芳基或者芳香基；
    其中所述芳基和/或所述杂芳基包括苯基、氘代苯基、萘基、吡啶基、嘧啶、哒嗪、哌嗪、吡唑基、咪唑基、喹啉基、噻吩基、苯并噻吩基、吲哚基，任选地被选自以下取代基中的一个或多个取代：氘、卤素、氰基、羟基、-C 1-6烷基、-(C 1-6烷基)OH、C 1-6卤代烷基和-SO2(C 1-6烷基)。
  3. 根据权利要求1所述式(I)的化合物和/或其药学上可接受的盐，其特征在于，所述Ar选自如下基团：
    Figure PCTCN2022139044-appb-100002
    上述基团任选地可被一个或多个选自以下的取代基取代：氢、卤素、氘、氰基、羟基、氨基、C 1- 3烷基、C 1-3烷氧基、C 1-3卤代烷基、-O -、-S(O) 2(C 1-3烷基)。
  4. 根据权利要求1所述式(I)的化合物和/或其药学上可接受的盐，其特征在于，R4选自杂芳基，或者R4与R5形成杂芳基；
    其中所述杂芳基是具有6环原子的单环芳族烃基，其在环中包含1或2个N环杂原子，其余环原子是碳原子，或者是具有9个环原子的二环芳族烃基，其在环中包含3或4个N环杂原子，其余环原子是碳原子，其中至少一个环是芳族环且所述杂芳基任选地被选自以下取代基中一个或多个取代：卤素、氰基、羟基、巯基、C 1-6烷基、卤代烷基、环烷基、-O(C 1-6烷基)和-O(C 1-6卤代烷基)、-NH 2、NH(C 1-6烷基)、N(C 1-6烷基)(C 1-6烷基)、-CO 2H、-C(O)NH 2、-C(O)NH(C 1-6烷基)、-C(O)N(C 1-6烷基)(C 1-6烷基)、苯基和5或6元杂芳基。
  5. 根据权利要求1所述的式(I)的化合物和/或其药学上可接受的盐，其特征在于，R 4选自杂芳基，或者R 4与R 5形成杂芳基；
    其中所述杂芳基是具有6环原子的单环芳族烃基，其在环中包含1或2个N环杂原子，其余环原子是碳原子，或者是具有9个环原子的二环芳族烃基，其在环中包含3或4个N环杂原子，其余环原子是碳原子，其中至少一个环是芳族环并且所述杂芳基任选地被选自以下的一个或多个取代基取代：氟、氯、溴、氰基、羟基、巯基、卤代烷基、C 1-6烷基、-NH 2、NH(C 1-6烷基)、N(C 1-6烷基)(C 1-6烷基)、-CO 2H、-C(O)NH 2、-C(O)NH(C 1-6烷基)、苯基、吡啶基、嘧啶基、哌嗪基、哒嗪基、吡唑基、咪唑基、三唑基和四唑基。
  6. 根据权利要求5所述式(I)的化合物和/或其药学上可接受的盐，其特征在于，所述R 4中的苯基、吡啶基、吡唑基、咪唑基、三唑基和四唑基任选地被一个或多个选自以下的取代基取代：卤素、羟基、巯基、氨基、C 1-6烷基、卤代烷基、环烷基、-O(C 1-6烷基)和-O(C 1-6卤代烷基)。
  7. 根据权利要求5所述式(I)的化合物和/或其药学上可接受的盐，其特征在于，所述杂芳基选自嘧啶、嘌呤基、吡唑并嘧啶、吡咯并嘧啶。
  8. 根据权利要求4或5所述式(I)的化合物和/或其药学上可接受的盐，其特征在于，
    R 4、或者R 4与R 5形成的杂芳基选自以下所示取代基
    Figure PCTCN2022139044-appb-100003
    其中，所述取代基任选地被选自以下取代基中的一个或多个取代：氟、氯、溴、氰基、羟基、巯基、卤代烷基、C 1-6烷基、-NH 2、NH(C 1-6烷基)、N(C 1-6烷基)(C 1-6烷基)、-CO 2H、-CONH 2、-C(O)NH(C 1-6烷基)、苯基、吡啶基、吡唑基、咪唑基、噁唑基、三唑基和四唑基，其中作为R 4取代基的苯基、吡啶基、嘧啶基、哌嗪基、哒嗪基、吡唑基、咪唑基、三唑基和四唑基任选地被选自以下取代基中的一个或多个取代：卤素、羟基、巯基、C 1-6烷基、卤代烷基、环烷基、-O(C 1-6烷基)和-O(C 1-6卤代烷基)。
  9. 根据权利要求8所述式(I)的化合物和/或其药学上可接受的盐，其特征在于，R4选自
    Figure PCTCN2022139044-appb-100004
    中任一取代基，R4任选地被选自以下取代基中的一个或多个取代：氟、氯、溴、氰基、卤代烷基、C 1-6烷基，-NH 2、NH(C 1-6烷基)、-CO2H、-CONH 2、苯基、吡啶基、吡唑基、三唑基和四唑基，
    其中作为R 4取代基的苯基、吡啶基、吡唑基、咪唑基、三唑基和四唑基任选地被一个或多个选自以下的取代基取代：卤素、羟基、C 1-6烷基和-O(C 1-6烷基)。
  10. 根据权利要求1-9中任一项所述式(I)的化合物和/或其药学上可接受的盐，其特征在于，R 3是C 1-4烷基和C 1-4卤代烷基。
  11. 根据权利要求10中任一项所述式(I)的化合物和/或其药学上可接受的盐，其特征在于，R 3是甲基、乙基和三氟甲基。
  12. 根据权利要求1-10中任一项所述式(I)的化合物和/或其药学上可接受的盐，其特征在于，式(I)所示化合物选自：
    Figure PCTCN2022139044-appb-100005
    Figure PCTCN2022139044-appb-100006
    Figure PCTCN2022139044-appb-100007
    Figure PCTCN2022139044-appb-100008
    Figure PCTCN2022139044-appb-100009
    Figure PCTCN2022139044-appb-100010
  13. 根据权利要求1-12中任一项所述的式(I)化合物其药学上可接受的盐在制备用于治疗由
    PI3K介导相关疾病的药物中的用途。
  14. 根据权利要求13所述的式(I)化合物其药学上可接受的盐在制备用于治疗由PI3K介导的疾 病的药物中的用途，其特征在于，所述PI3K为PI3Kδ。
  15. 根据权利要求13所述的式(I)化合物其药学上可接受的盐在制备用于治疗由PI3K介导的疾病的药物中的用途，其特征在于，所述疾病选自癌症、炎症、呼吸疾病、感染性疾病、骨髓相关疾病和自身免疫性疾病。
  16. 根据权利要求15所述的式(I)化合物其药学上可接受的盐在制备用于治疗由PI3K介导的疾病的药物中的用途，其特征在于，所述癌症是实体瘤，包括乳腺癌、黑色素瘤、头颈癌、肺癌、胸腺癌和血液恶性肿瘤。
  17. 一种药物组合物，其包括如权利要求1-12中任一项所述式(I)化合物其药学上可接受的盐、及至少一种药用载体或赋形剂。
  18. 根据权利要求17所述的药物组合物，其特征在于，所述药物组合物还包括与小分子化合物和/或大分子抗体联合使用，以治疗癌症、炎症、骨髓相关疾病和自身免疫性疾病。
  19. 根据权利要求18所述的药物组合物，其特征在于，所述小分子化合物包括激酶抑制剂以及其他非激酶抑制剂。
  20. 根据权利要求18所述的药物组合物，其特征在于，所述小分子化合物包括BTK抑制剂、Bcl2抑制剂。
  21. 根据权利要求18所述的药物组合物，其特征在于，所述大分子抗体包括抗-CD20、抗-CTLA4、抗PD-1、抗PD-L1抗体。
  22. 根据权利要求17所述组合物在治疗由PI3K介导相关疾病中的用途，其中所述疾病选自癌症、炎症、呼吸疾病、感染性疾病、骨髓相关疾病和自身免疫性疾病。
  23. 根据权利要求1-16中任一项所述的式(I)化合物的溶剂合物、外消旋混合物、对映异构体、非对映异构体、互变异构体或包括外消旋混合物其任意比例的混合物，其特征在于，如所述权利要求1中所述R 1、R 2、R 3、R 4和R 5各取代基
    Figure PCTCN2022139044-appb-100011
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