2,3,5-Trisubstituted pyrazolo[1,5-a]pyrimidine compounds

Abstract

Described herein are compounds that inhibit PI3Kγ, compositions comprising such compound(s), and methods for synthesizing such compounds, as well as the use of such compounds and compositions for the treatment of a wide variety of diseases, disorders, and conditions, such as cancer and immune-related disorders, that are mediated at least in part by PI3Kγ.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 62 / 857,148, filed June 4, 2019, the entire contents of which are incorporated herein by reference.

[0002] STATEMENT OF RIGHTS TO INVENTIONS UNDER FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT Not applicable

[0003] Reference to a "Sequence Listing," table, or computer program listing appendix submitted on a compact disc Not applicable [Background technology]

[0004] Phosphatidylinositol 3-kinases (PI3Ks) belong to a family of lipid kinases and phosphorylate the 3-OH of the inositol ring of phosphoinositides. These enzymes play a central role in important cellular processes, such as cell growth, proliferation, differentiation, motility, and intracellular trafficking. Deregulation of the PI3K pathway has been implicated in numerous pathologies, including cancer, diabetes, thrombosis, rheumatoid arthritis, and asthma. To date, eight known family members have been subdivided into three classes: I, II, and III. Class I has been further subdivided into IA (PI3Kα, β, and δ) and IB (PI3Kγ) based on their regulatory proteins and signaling pathways [J. Med. Chem. 2019, 62, 10, 4815-4850]. Although the four isoforms differ in terms of function and tissue distribution, class I PI3Ks play an important role in immune regulation. The expression of PI3Kα and PI3Kβ isoforms is ubiquitous, whereas the PI3Kδ and PI3Kγ isoforms are primarily expressed in leukocytes [J.Med.Chem.2012,55,20,8559-8581]. PI3Kα is essential for angiogenesis and insulin signaling, while inhibition of PI3Kδ and PI3Kγ is known to enhance the immune response against cancer.

[0005] The expression profile of PI3Kγ has expanded to include structural populations such as cardiomyocytes, fibroblasts, and smooth muscle cells. Cardiac PI3Kγ is known to regulate sarcoplasmic reticulum phosphodiesterase, a potential protective mechanism against catecholamine-induced ventricular arrhythmias. Increased PI3Kγ expression in fibroblasts and basal cells is associated with idiopathic pulmonary fibrosis. Unlike hematopoietic cells, PI3Kγ activity in nonhematopoietic cells plays an important role in the development of obesity and insulin resistance, as observed in knockout mice. Summary of the Invention [Problem to be solved by the invention]

[0006] In view of the significant correlation between PI3Kγ in cancer, inflammation, and immunomodulatory conditions, there is a need in the art for PI3Kγ inhibitors. The present invention addresses this need and also provides related advantages. [Means for solving the problem]

[0007] The present invention relates to compounds that inhibit the activity of phosphoinositide 3-kinase (γ isoform), which compounds have the formula (I): [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X, R 1a , R 1b , R 3 , R 4a and R 4b is defined as follows:

[0008] In a related aspect, provided herein are methods of treating or preventing cancer in a subject (e.g., a human), comprising administering to the subject a therapeutically effective amount of at least one PI3Kγ inhibitor described herein. In some embodiments, provided herein are methods of treating or preventing cancer in a subject by administering to the subject at least one of the compounds described herein in an amount effective to reverse, slow, or halt the progression of PI3Kγ-mediated dysregulation.

[0009] Examples of cancers that can be treated using the compounds and compositions described herein include, but are not limited to, cancers of the prostate, colon, pancreas, cervix, stomach, endometrium, brain, liver, bladder, ovary, testis, head, neck, skin (such as melanoma and basal carcinoma), mesothelial lining, white blood cells (such as lymphoma and leukemia), esophagus, breast, muscle, connective tissue, intestine, lung (such as small cell lung cancer and non-small cell lung cancer), adrenal gland, thyroid, kidney, or bone; glioblastoma, mesothelioma, renal cell carcinoma, gastric cancer, sarcoma, choriocarcinoma, basal cell carcinoma of the skin, and testicular seminoma. In some embodiments of the present invention, the cancer is melanoma, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, leukemia, brain tumor, lymphoma, sarcoma, ovarian cancer, head and neck cancer, cervical cancer, or Kaposi's sarcoma. Potential cancers to be treated with the compounds and compositions of the present invention are further described below.

[0010] In certain embodiments, provided herein are methods for treating or preventing an infectious disorder (e.g., a viral infection) in a subject (e.g., a human), comprising administering to the subject a therapeutically effective amount of at least one PI3Kγ inhibitor (e.g., a novel inhibitor of the present invention). In some embodiments, the infectious disorder is a viral infection (e.g., a chronic viral infection), a bacterial infection, a fungal infection, or a parasitic infection. In certain embodiments, the viral infection is human immunodeficiency virus or cytomegalovirus.

[0011] In yet another embodiment, provided herein are methods for treating or preventing an immune-related disease, disorder, or condition in a subject (e.g., a human), comprising administering to the subject a therapeutically effective amount of at least one PI3Kγ inhibitor described herein. Exemplary immune-related diseases, disorders, and conditions are described below.

[0012] In yet another embodiment, provided herein are methods for treating or preventing inflammation in a subject (e.g., a human), comprising administering to the subject a therapeutically effective amount of at least one PI3Kγ inhibitor described herein. Exemplary inflammatory diseases, disorders, and conditions are described below.

[0013] Other diseases, disorders and conditions that can be treated or prevented, in whole or in part, by modulating PI3Kγ activity are candidate indications for the PI3Kγ inhibitor compounds provided herein.

[0014] Also provided herein is the use of one or more additional agents in combination with the described PI3Kγ inhibitors. The one or more additional agents may have some PI3Kγ modulating activity; alternatively, they may function through different mechanisms of action. In some embodiments, such agents include radiation (e.g., local or systemic radiation therapy) and / or other non-pharmacological treatments. When combined therapy is utilized, the compound(s) described herein and one or more additional agents may be in the form of a single composition or multiple compositions, and the treatments may be administered simultaneously, sequentially, or through some other regimen. For example, the present invention contemplates a treatment regimen in which a radiation step is followed by a chemotherapy step. This combined therapy may result in additive or synergistic effects. Other advantages of combined therapy are described below.

[0015] In certain embodiments, methods are provided herein for using the PI3Kγ inhibitors described herein in combination with immune checkpoint inhibitors. Blockade of immune checkpoints that amplify antigen-specific T cell responses is known to be a promising approach in human cancer treatment. Immune checkpoints (ligands and receptors), some of which are selectively upregulated in various types of tumor cells, include PD-1 (programmed cell death protein 1); PD-L1 (PD-1 ligand); BTLA (B and T lymphocyte attenuator); CTLA-4 (cytotoxic T lymphocyte-associated antigen 4); TIM-3 (T cell membrane protein 3); LAG-3 (lymphocyte activation gene 3); TIGIT (T cell immunoreceptor with Ig and ITIM domains); and killer inhibitory receptors. Immune checkpoint inhibitors and combination therapies therewith are described in detail elsewhere herein.

[0016] In other embodiments, provided herein are methods of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of at least one PI3K gamma inhibitor and at least one chemotherapeutic agent, including alkylating agents (e.g., nitrogen mustards, e.g., chlorambucil, cyclophosphamide, isofamide, mechlorethamine, melphalan, and uracil mustard); aziridines such as thiotepa; methanesulfonate esters such as busulfan; nucleoside analogs (e.g., gemcitabine); nitrososurics (e.g., nitrososurics); platinum complexes, such as cisplatin, carboplatin, and oxaliplatin; bioreductive alkylating agents, such as mitomycin, procarbazine, dacarbazine, and altretamine; anthracycline (e.g., doxorubicin, daunorubicin, epirubicin, and idarubicin)-based therapies; DNA strand breakers (e.g., bleomycin); topoisomerase II inhibitors (e.g., amsacrine , dactinomycin, daunorubicin, idarubicin, mitoxantrone, doxorubicin, etoposide, and teniposide); DNA minor groove binders (e.g., plicamycin); antimetabolites (e.g., folate antagonists, e.g., methotrexate and trimetrexate; pyrimidine antagonists, e.g., fluorouracil, fluorodeoxyuridine, CB3717, azacitidine, cytarabine, and floxuridine; purine antagonists, e.g., mercaptopurine, 6-thioguanine, fludarabine, pentostatin asparaginase; and ribonucleotide reductase inhibitors such as hydroxyurea; tubulin-interacting agents (e.g., vincristine, estramustine, vinblastine, docetaxol, epothilone derivatives, and paclitaxel); hormonal agents (e.g., estrogens; conjugated estrogens; ethinyl estradiol; diethylstilbestrol; chlortrianisene; idenestrol; progestins such as hydroxyprogesterone caproate, medroxyprogesterone, and megestrol);and androgens, e.g., testosterone, testosterone propionate, fluoxymesterone, and methyltestosterone; adrenal corticosteroids (e.g., prednisone, dexamethasone, methylprednisolone, and prednisolone); luteinizing hormone-releasing agents or gonadotropin-releasing hormone antagonists (e.g., leuprolide acetate and goserelin acetate); and antihormonal agents (e.g., antiandrogens, such as tamoxifen and flutamide; and antiadrenal agents, e.g., mitotane and aminoglutethimide). The present invention also contemplates the use of phosphoinositide 3-kinase (γ isoform) (PI3Kγ) inhibitors in combination with other agents known in the art (e.g., arsenic trioxide) and other chemotherapeutic agents developed in the future.

[0017] In some embodiments, provided herein are methods of treating cancer, wherein a therapeutically effective amount of a PI3K gamma inhibitor described herein is administered in combination with at least one chemotherapeutic agent to result in a cancer survival rate that is greater than the cancer survival rate observed when either agent is administered alone. In further embodiments of the methods of treating cancer, administering a therapeutically effective amount of a PI3K gamma inhibitor described herein in combination with at least one chemotherapeutic agent results in a reduction in tumor size or a slowing of tumor growth compared to the tumor size or tumor growth inhibition observed when either agent is administered alone.

[0018] In a further embodiment, the present invention contemplates a method for treating or preventing cancer in a subject, comprising administering to the subject a therapeutically effective amount of at least one PI3K gamma inhibitor described herein and a therapeutically effective amount of at least one signal transduction inhibitor (STI). In certain embodiments, the at least one STI is selected from the group consisting of a bcr / abl kinase inhibitor, an epidermal growth factor (EGF) receptor inhibitor, a her-2 / neu receptor inhibitor, and a farnesyltransferase inhibitor (FTI). Other candidate STI agents are described elsewhere herein.

[0019] The present invention also contemplates a method for enhancing the rejection of tumor cells in a subject, comprising using at least one chemotherapeutic agent and / or radiation therapy in combination with a PI3Kγ inhibitor, such that the rejection of tumor cells is greater than that achieved by using either the PI3Kγ inhibitor, the chemotherapeutic agent, or radiation therapy alone.

[0020] In a further embodiment, the present invention provides a method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of at least one PI3K gamma inhibitor and a therapeutically effective amount of at least one immunomodulatory agent other than a PI3K gamma inhibitor. In certain embodiments, the at least one immunomodulatory agent is selected from the group consisting of CD40L, B7, B7RP1, anti-CD40, anti-CD38, anti-ICOS, 4-IBB ligand, dendritic cell cancer vaccine, IL2, IL12, ELC / CCL19, SLC / CCL21, MCP-1, IL-4, IL-18, TNF, IL-15, MDC, IFN-α / -13, M-CSF, IL-3, GM-CSF, IL-13, anti-IL-10, and indoleamine 2,3-dioxygenase 1 (IDO1). Other candidate immunomodulatory agents are described elsewhere herein.

[0021] The present invention contemplates embodiments that include a method of treating or preventing an infectious disorder (e.g., a viral infection) in a subject (e.g., a human), comprising administering to the subject a therapeutically effective amount of at least one PI3Kγ inhibitor described herein and a therapeutically effective amount of an anti-infective agent(s).

[0022] In some embodiments of the present invention, the additional therapeutic agent is a cytokine, such as granulocyte-macrophage colony-stimulating factor (GM-CSF) or flt3-ligand. The present invention also contemplates methods of treating or preventing viral infections (e.g., chronic viral infections), including, but not limited to, hepatitis C virus (HCV), human papillomavirus (HPV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella-zoster virus, coxsackievirus, and human immunodeficiency virus (HIV). The use of the compounds described herein (alone or as components of combination therapies) to treat infectious diseases is further described below.

[0023] In further embodiments, treatment of infectious disorders is effective by administering a vaccine in combination with a therapeutically effective amount of a PI3Kγ inhibitor of the present invention. In some embodiments, the vaccine is an antiviral vaccine, such as an anti-HIV vaccine. In other embodiments, the vaccine is effective against tuberculosis or malaria. In yet another embodiment, the vaccine is a tumor vaccine (e.g., a vaccine effective against melanoma); the tumor vaccine may comprise genetically modified tumor cells or cell lines, for example, genetically modified tumor cells or cell lines transfected to express granulocyte-macrophage stimulating factor (GM-CSF). In certain embodiments, the vaccine comprises one or more immunogenic peptides and / or dendritic cells.

[0024] In certain embodiments of treating an infection by administering a PI3K gamma inhibitor and at least one additional therapeutic agent, the symptoms of the infection observed after administration of both the PI3K gamma inhibitor and the additional therapeutic agent are improved compared to the same symptoms of the infection observed after administration of either agent alone. In some embodiments, the symptoms of the infection are measured by a reduction in viral load, CD4 counts, or a decrease in the number of infected individuals. + This may be an increase in T cell numbers, suppression of opportunistic infections, prolonged survival, eradication of chronic infections, or a combination thereof. [Brief explanation of the drawings]

[0025] Not applicable DETAILED DESCRIPTION OF THE INVENTION

[0026] Before the present invention is further described, it is to be understood that the invention is not limited to particular embodiments described herein, and that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0027] When a numerical range is provided, it is understood that the invention includes each intervening value between the upper and lower limits of that range, to the nearest tenth of the lower limit, and any other numerical or intervening value in that range, unless expressly stated otherwise. The upper and lower limits of smaller ranges are independently inclusive, and the invention also includes any specifically excluded limit in the stated range. When a stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0028] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. Accordingly, this statement is intended to serve as a premise for the use of exclusive terminology, such as "solely," "solely," and the like, in connection with the recitation of elements or the use of a "negative" limitation in the claims.

[0029] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Further, the dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed.

[0030] Overview For example, provided herein are compounds and compositions that inhibit phosphoinositide 3-kinase (γ isoform) (PI3Kγ), and pharmaceutical compositions containing them. Also provided herein are methods for treating or preventing, for example, diseases, disorders, or conditions, or symptoms thereof, mediated by inhibition of phosphoinositide 3-kinase (γ isoform) (PI3Kγ).

[0031] definition Unless otherwise stated, the following terms are intended to have the meanings indicated: Other terms are defined elsewhere throughout the specification.

[0032] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical having the specified number of carbon atoms (i.e., C 1-8 means 1 to 8 carbons). Alkyl is C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 1-7 , C 1-8 , C 1-9 , C 1-10 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 , and C 5-6 Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0033] The term "alkylene" refers to a straight-chain or branched-chain saturated aliphatic radical, i.e., a divalent hydrocarbon radical, having the specified number of carbon atoms and linking at least two other groups. When two moieties are linked to an alkylene, they can be attached to the same atom or different atoms of the alkylene group. For example, a straight-chain alkylene is -(CH2) n -, where n is 1, 2, 3, 4, 5, or 6. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, and hexylene. 1 or X 2 Alkylene groups, often referred to as groups, can be substituted or unsubstituted. X 1 or X 2 If a group, including a group, is optionally substituted, it is understood that the optional substitution may be on the alkylene portion of that moiety. Similarly, as used herein, the term alkylene includes substitution unless otherwise specified.

[0034] The term "cycloalkyl" refers to a hydrocarbon ring having the indicated number of ring atoms (e.g., C 3-6 "Cycloalkyl" refers to a cycloalkyl group that is fully saturated or does not have more than one double bond between ring vertices. "Cycloalkyl" is also meant to refer to bicyclic and polycyclic hydrocarbon rings, such as, for example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and the like. In some embodiments, the cycloalkyl compounds of the present disclosure include monocyclic C 3-6 It is a cycloalkyl moiety.

[0035] The term "heterocycloalkyl" refers to a cycloalkyl ring having the indicated number of ring vertices (or members) and having from 1 to 5 heteroatoms selected from N, O, and S, which replace from 1 to 5 of the carbon vertices, and in which the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom(s) are optionally quaternized. Cycloheteroalkyls can be monocyclic, bicyclic, or polycyclic ring systems and can have one or two double bonds connecting the ring vertices. Examples of cycloheteroalkyl groups include, but are not limited to, pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, etc. Heterocycloalkyl groups can be attached to the remainder of the molecule through a ring carbon or heteroatom.

[0036] The term "haloalkyl" refers to an alkyl group having the indicated number of carbon atoms substituted with one to five halogen atoms, and includes groups substituted with various halogens such as fluorine or chlorine, e.g., -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2.

[0037] The term "alkoxy" refers to the -OR radical, where R is an alkyl group having the indicated number of carbon atoms as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy.

[0038] The term "alkoxyalkyl" refers to a linear or branched monovalent hydrocarbon radical having the indicated number of carbon atoms, which is substituted with one alkoxy group, as defined above, e.g., 2-methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like.

[0039] The term "haloalkoxy" refers to an -OR radical where R is haloalkyl as defined above, e.g., -OCF3, -OCHF2, and the like.

[0040] The term "haloalkoxyalkyl" refers to an alkyl radical substituted with a haloalkoxy, each of which is as defined above, for example, trifluoromethoxyethyl.

[0041] The term "hydroxyalkyl" refers to a linear or branched monovalent hydrocarbon radical having the indicated number of carbon atoms substituted with one to three hydroxy groups, provided that if two hydroxy groups are present, they are not on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl.

[0042] The term "hydroxyalkoxy" refers to the -OR radical, where R is hydroxyalkyl as defined above, e.g., hydroxyethyloxy, hydroxypropyloxy, and the like.

[0043] As used herein, wavy lines: TIFF0007665534000002.tif6137 crosses a single, double, or triple bond in any chemical structure described herein and represents the point of attachment of the single, double, or triple bond to the remainder of the molecule. Additionally, bonds extending through the center of a ring (e.g., a phenyl ring) are meant to indicate attachment at any available ring vertex. One of ordinary skill in the art will understand that multiple substituents shown attached to a ring will provide a stable compound and will otherwise occupy any sterically compatible ring vertex. For divalent moieties, the designation is meant to include either orientation (forward or reverse). For example, the group "-C(O)NH-" includes either orientation of the bond: -C(O)NH-, or -NHC(O)-; similarly, "-O-CHCH-" includes both -O-CHCH- and -CHCH-O-.

[0044] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "C 1-4 "Haloalkyl" is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0045] The term "aryl," unless otherwise specified, refers to a polyunsaturated hydrocarbon group, typically an aromatic hydrocarbon group, which can be monocyclic or polycyclic (up to three rings) that are fused or covalently linked to each other. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and biphenyl. The term is also meant to include fused cycloalkylphenyl and heterocycloalkylphenyl ring systems, such as, for example, indane, tetrahydronaphthalene, chroman, and isochroman rings. As a substituent, the point of attachment to the remainder of the molecule can be through a carbon atom of the aromatic portion, a carbon atom of the cycloalkyl portion, or an atom of the heterocycloalkyl portion for fused ring systems.

[0046] The term "heteroaryl" refers to an aryl group (or ring) containing 1 to 5 heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiazolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl, and the like. Substituents for the heteroaryl ring can be selected from the group of acceptable substituents described below.

[0047] The above terms (e.g., "alkyl," "aryl," and "heteroaryl") are, in some embodiments, optionally substituted. Selected substituents for each type of radical are provided below.

[0048] Optional substituents on alkyl radicals (such as those groups often referred to as alkylene, alkenyl, and alkynyl) include: halogen, -OR', -NR'R'', -SR', -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R'''', -NR''C(O)2R', -NH-C(NH2) =NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NR'S(O)2R'', -CN(cyano), -NO2, aryl, aryloxy, oxo, cycloalkyl, and heterocycloalkyl, in a number ranging from 0 to (2m'+1), where m' is the total number of carbon atoms in such radical. R', R'' and R''' can each independently be hydrogen, unsubstituted C 1-8 Alkyl, unsubstituted aryl, 1-3 halogens, C 1-8 Alkoxy, or C 1-8 Thioalkoxy-substituted or unsubstituted aryl-C 1-4 refers to an alkyl group. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to which they are attached to form a 3-, 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" is meant to include 1-pyrrolidinyl and 4-morpholinyl.

[0049] Optional substituents on the cycloalkyl and heterocycloalkyl radicals can be a variety of groups selected from: C(O)OR′, halogen, —OR′, —NR′R″, —SR′, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —COR′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)R′, —NH—C(NH)═NH, —NR′C(NH)═NH, —NH—C(NH)═NR′, —S(O)R′, —S(O)R′, —S(O)NR′R″, —NR′S(O)R″, —CN (cyano), —NO, aryl, aryloxy, and alkyl optionally substituted with oxo. R', R'' and R''' are each independently hydrogen, unsubstituted C 1-8 Alkyl, unsubstituted aryl, 1-3 halogens, C 1-8 Alkoxy, or C 1-8 Thioalkoxy-substituted or unsubstituted aryl-C 1-4 It refers to an alkyl group.

[0050] Similarly, optional substituents on the aryl and heteroaryl groups vary and generally include: -halogen, -OR', -OC(O)R', -NR'R'', -SR', -R', -CN, -NO2, -CO2R', -CONR'R'', -C(O)R', -OC(O)NR'R'', -NR''C(O)R', -NR''C(O)2R', -NR'-C(O)NR''R'''', -NH-C(NH2) =NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NR'S(O)2R'', -N3, perfluoro(C1-C4)alkoxy, and perfluoro(C1-C4)alkyl, the number of which ranges from 0 to the total number of open valences on the aromatic ring system; and R', R'' and R''' are independently selected from hydrogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 3-6 Cycloalkyl, C 2-8 Alkenyl, and C 2-8Other suitable substituents include each of the above aryl substituents attached to a ring atom by an alkylene tether of 1 to 6 carbon atoms.

[0051] Two substituents on adjacent atoms of an aryl or heteroaryl ring have the formula -TC(O)-(CH2) q -U-, where T and U are independently -NH-, -O-, -CH2-, or a single bond, and q is an integer from 0 to 2. Alternatively, two substituents on adjacent atoms of an aryl or heteroaryl ring may be optionally replaced by a substituent of the same formula -A-(CR f R g ) r -B-, wherein A and B are independently -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or a single bond; r is an integer of 1 to 3; and R f and R g may each be optionally replaced with a substituent of the same formula, which is independently H or halogen. One of the single bonds in the new ring so formed may optionally be replaced with a double bond. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may be replaced with a group of the formula -(CH) s -X-(CH2) t -, where s and t are independently integers from 0 to 3, and X can be optionally replaced with a substituent of the same formula, which is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituent R' in -NR'- and -S(O)2NR'- is hydrogen or an unsubstituted C 1-6 Select from alkyl.

[0052] As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si).

[0053] The term "pharmaceutically acceptable salts" is intended to include salts of active compounds, which are prepared using relatively non-toxic acids or bases, depending on the specific substituents found on the compounds described herein. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either pure or in a suitable inert solvent containing the desired base. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, such as substituted amines, cyclic amines, and naturally occurring amines, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either pure, or with the desired acid in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as those derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like.Also included are salts of amino acids such as arginate, and salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge, SM, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds of the present invention contain both basic and acid functional groups, thereby allowing the compounds to be converted into either base or acid addition salts.

[0054] The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to the parent form of the compound for purposes of this invention.

[0055] In addition to salt forms, the present invention provides compounds in prodrug form. Prodrugs of the compounds described herein are compounds that easily undergo chemical changes under physiological conditions to provide the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0056] Certain compounds of the present invention can exist in unsolvated forms and solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are intended to be within the scope of the present invention. Certain compounds of the present invention can exist in polycrystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0057] Certain compounds of the present invention may exist as polymorphs under certain conditions. Polymorphism refers to the ability of a solid material to exist in multiple crystalline structural forms or phases, and the molecules within the crystal lattice have different arrangements or conformations. These types of differences, which exist due to packing, are called "packing polymorphs," and those due to conformational differences, are called "conformational polymorphs." Different polymorphs of the same compound often exhibit different physical properties, such as packing characteristics, spectroscopic properties, thermodynamic properties, solubility, melting point, etc.; kinetic properties, such as dissolution rate and stability; and mechanical properties, such as hardness and tensile strength.

[0058] Polymorphs can be classified into one of two types depending on their stability over a range of temperatures and pressures: In a monotropic system, only one polymorph (i.e., the monotrope) is stable and exhibits low free energy content and solubility at all temperatures and pressures below the melting point; in an enantiotropic system, one polymorph is stable at a specific temperature and pressure, and the other polymorph(s) are stable over a range of temperatures and pressures.

[0059] Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; racemic mixtures, diastereomers, geometric isomers, positional isomers, and individual isomers (e.g., separated enantiomers) are all intended to be included within the scope of the present invention.

[0060] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. Unnatural proportions of an isotope may be defined as a range from the amount found in nature to the amount that constitutes 100% of the atom in question. For example, if a compound contains an isotope containing, for example, tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 Radioactive isotopes such as C, or deuterium ( 2 H), or carbon-13 ( 13Non-radioactive isotopes such as C) may be incorporated. Such isotopic variations may provide additional utilities to those described elsewhere in this application. For example, but not limited to, isotopic variants of the compounds of the present invention may find additional uses as diagnostic and / or imaging reagents or cytotoxic / radiotoxic therapeutic agents. In addition, isotopic variants of the compounds of the present invention may have modified pharmacokinetic and pharmacodynamic properties that can contribute to improved safety, tolerability, or efficacy during treatment. All isotopic variants of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

[0061] The terms "patient" and "subject" are used interchangeably to refer to a human or non-human animal (eg, a mammal).

[0062] The terms "administration," "administering," and the like, when used with respect to, for example, a subject, cell, tissue, organ, or biological fluid, refer to contacting, for example, an inhibitor of PI3Kγ, a pharmaceutical composition containing same, or a diagnostic agent with the subject, cell, tissue, organ, or biological fluid. In the context of cells, administration includes contacting a reagent with the cell (e.g., in vitro or ex vivo) as well as contacting a fluid with the reagent, where the fluid is in contact with the cell.

[0063] The terms "treat," "treating," "treatment," and the like refer to a course of action (such as administering an inhibitor of PI3Kγ, or a pharmaceutical composition comprising same) initiated after a disease, disorder, or condition, or a symptom thereof, has been diagnosed, recognized, or the like, to eliminate, reduce, suppress, alleviate, or ameliorate, either temporarily or permanently, at least one underlying cause of the disease, disorder, or condition afflicting the subject, or at least one symptom associated with the disease, disorder, or condition afflicting the subject. Thus, treatment includes inhibiting active disease (e.g., preventing the onset or further development of the disease, disorder, or condition, or clinical symptoms associated therewith).

[0064] As used herein, the term "in need of treatment" refers to a determination by a physician or other caregiver that a subject is in need of or would benefit from treatment. This determination is made based on a variety of factors within the physician's or caregiver's expertise.

[0065] The terms "prevent," "preventing," "prevention," and the like refer to initiating a course of action (e.g., before a disease, disorder, condition, or symptoms thereof are observed) (e.g., administering a PI3Kγ inhibitor, or a pharmaceutical composition comprising the same) to temporarily or permanently prevent, suppress, inhibit, or reduce a subject's risk of developing a disease, disorder, condition, or the like (e.g., as determined by the absence of clinical symptoms), or, generally, for a subject predisposed to having a particular disease, disorder, or condition, to delay its onset. In certain instances, these terms also refer to slowing the progression of a disease, disorder, or condition, or inhibiting its progression to an adverse or unwanted condition.

[0066] As used herein, the term "in need of prevention" refers to a judgment by a physician or other caregiver indicating that a subject needs or would benefit from preventative care. This judgment is made based on a variety of factors within the physician's or caregiver's expertise.

[0067] The phrase "therapeutically effective amount" refers to an amount of an agent administered to a subject, either alone or as part of a pharmaceutical composition, and either in a single dose or as part of a series of doses, that is capable of producing any detectable positive effect on any symptom, condition, or characteristic of a disease, disorder, or condition when administered to a subject. A therapeutically effective amount can be ascertained by measuring the relevant physiological effect and can be adjusted in conjunction with dosing regimens, diagnostic assays for the subject's condition, and the like. By way of example, measuring serum levels of a PI3Kγ inhibitor (or, e.g., a metabolite thereof) at a particular time after administration can be an indication of whether a therapeutically effective amount has been used.

[0068] The phrase "in an amount sufficient to effect a change" means that there is a detectable difference between the level of an indicator measured before administration of a particular therapy (e.g., baseline level) and after administration, whether the indicator is an objective parameter (e.g., serum concentration) or a subjective parameter (e.g., a subject's sense of well-being).

[0069] The term "small molecule" refers to a compound having a molecular weight of less than about 10 kDa, less than about 2 kDa, or less than about 1 kDa. Small molecules include, but are not limited to, inorganic molecules, organic molecules, organic molecules containing inorganic components, molecules containing radioactive atoms, and synthetic molecules. Therapeutically, small molecules tend to be more cell permeable, less susceptible to degradation, and less likely to elicit an immune response than larger molecules.

[0070] The term "ligand" refers to, for example, a peptide, polypeptide, membrane-associated molecule, or membrane-bound molecule, or complex thereof, that can act as an agonist or antagonist of a receptor. Ligands include natural and synthetic ligands, such as cytokines, cytokine variants, analogs, muteins, and antibody-derived binding compositions, as well as small molecules. The term also includes agents that are neither agonists nor antagonists but can bind to a receptor without significantly affecting its biological properties, such as signal transduction or adhesion. Furthermore, the term includes membrane-bound ligands that have been converted into soluble forms of the membrane-bound ligand, for example, by chemical or recombinant methods. Ligands or receptors can be entirely contained intracellularly, i.e., located in the cytosol, nucleus, or some other intracellular compartment. A complex of a ligand and a receptor is referred to as a "ligand-receptor complex."

[0071] The terms "inhibitor" and "antagonist" or "activator" and "agonist" refer to inhibitory or activating molecules, respectively, with respect to the activation of, for example, a ligand, receptor, cofactor, gene, cell, tissue, or organ. An inhibitor is a molecule that reduces, blocks, prevents, delays activation, inactivates, desensitizes, or downregulates, for example, a gene, protein, ligand, receptor, or cell. An activator is a molecule that increases, activates, promotes, enhances activation, sensitizes, or upregulates, for example, a gene, protein, ligand, receptor, or cell. An inhibitor can also be defined as a molecule that suppresses, blocks, or inactivates constitutive activity. An "agonist" is a molecule that interacts with a target to increase or promote activation of the target. An "antagonist" is a molecule that prevents the action(s) of an agonist. An antagonist prevents, suppresses, inhibits, or neutralizes the activity of an agonist, and an antagonist can also prevent, inhibit, or suppress the constitutive activity of a target, e.g., a target receptor, even in the absence of an identified agonist.

[0072] The terms "modulate," "modulation," and the like refer to the ability of a molecule (e.g., an activator or inhibitor) to enhance or suppress, either directly or indirectly, the function or activity of PI3Kγ. Modulators can act alone or can use cofactors, such as proteins, metal ions, or small molecules. Examples of modulators include small molecule compounds and other bioorganic molecules. Numerous libraries of small molecule compounds (e.g., combinatorial libraries) are commercially available and can serve as a starting point for identifying modulators. One skilled in the art can develop one or more assays (e.g., biochemical or cell-based assays) that can screen such compound libraries to identify one or more compounds with desired properties; one skilled in the art of medicinal chemistry can then optimize such one or more compounds, for example, by synthesizing and evaluating analogs and derivatives thereof. Synthesis and / or molecular modeling studies can also be used to identify activators.

[0073] The "activity" of a molecule may describe or refer to the binding of the molecule to a ligand or receptor; catalytic activity; the ability to stimulate gene expression or cell signaling, differentiation or maturation; antigenic activity; modulation of the activity of other molecules; etc. The term "proliferative activity" includes, for example, activity that promotes, requires, or is specifically associated with normal cell division, as well as cancer, tumors, metaplasia, cell transformation, metastasis, and angiogenesis.

[0074] As used herein, "comparable," "equivalent activity," "equivalent activity," "equivalent effect," "equivalent effect," and the like are relative terms that can be quantitatively and / or qualitatively recognized. The meaning of the terms varies depending on the context in which they are used. For example, if two receptor-activating agents are recognized as having comparable effects from a qualitative perspective, but one agent achieves only 20% of the activity of the other agent as determined by an art-recognized assay (e.g., a dose-response assay) or an art-recognized animal model, the two agents are not recognized as having comparable effects from a quantitative perspective. When comparing one result to another (e.g., comparing one result to a reference standard), "comparable" often (although not always) means that the one result deviates from the reference standard by less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 7%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%. In certain embodiments, a result is comparable to a reference standard if it deviates from the reference standard by less than 15%, less than 10%, or less than 5%. By way of example, activity or effect can refer to, but is not limited to, efficacy, stability, solubility, or immunogenicity.

[0075] "Substantially pure" indicates that a component constitutes greater than about 50% of the total content of the composition, and typically greater than about 60% of the total polypeptide content. More commonly, "substantially pure" refers to a composition in which the component of interest constitutes at least 75%, at least 85%, at least 90%, or more of the total composition. In some cases, the polypeptide constitutes greater than about 90%, or greater than about 95%, of the total content of the composition.

[0076] Selective compounds may be particularly useful in treating certain disorders or may reduce the potential for undesirable side effects. In certain embodiments, compounds of the present disclosure are selective over other PI3K isoforms. In yet other embodiments, compounds of the present disclosure are selective over other kinases and targets in the PI3K / mTOR / Akt pathway. Specific examples include PI3Kα, PI3Kβ, and PI3Kδ, as well as mTOR, Ak5, PIP5K, and PDPK1. Selectivity may be determined, for example, by comparing the inhibition of a compound described herein against PI3Kγ to the inhibition of a compound described herein against another target. In certain embodiments, selective inhibition of PI3Kγ is at least 1000-fold, 500-fold, 100-fold, or 20-fold greater than inhibition of another target or isoform.

[0077] The term "response," e.g., of a cell, tissue, organ, or organism, includes a change in biochemical or physiological behavior, e.g., a change in concentration, density, adhesion, or migration within a biological compartment, the rate of gene expression, or the state of differentiation, which is correlated with an internal mechanism, such as activation, stimulation, or treatment, or genetic programming. In certain contexts, the terms "activation," "stimulation," etc., refer to cellular activation regulated by internal mechanisms and external or environmental factors; whereas, the terms "inhibition," "downregulation," etc., refer to the opposite effect.

[0078] The terms "polypeptide," "peptide," and "protein," as used interchangeably herein, refer to polymeric forms of amino acids of any length, including genetically encoded and non-genetically encoded amino acids, chemically or biochemically modified or derivatized amino acids, and polypeptides with modified polypeptide backbones. These terms also encompass fusion proteins, including, but not limited to, fusion proteins with heterologous amino acid sequences, fusion proteins with heterologous and homologous leader sequences, with or without an N-terminal methionine residue, and immunologically labeled proteins.

[0079] Phosphoinositide-3-kinase gamma and its inhibition As noted above, the practice of the present invention does not require a precise understanding of the underlying mechanism by which the compounds of the present invention affect their activity, but it is believed that the effects of the compounds (or a subset thereof) are mediated through the inhibition of phosphoinositide 3-kinase (γ isoform).

[0080] Compounds of the Invention In certain embodiments, the compounds of formula (I) [ka] or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: X is C(R 2 ) or N; R 1a and R 1b are H and C, respectively. 1-6 Alkyl, C 3-6 Alkenyl, C 3-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -Y 1 , -X 1 -C(O)2R a , -X 1 -OR a , -X 1 -NR a R b , -X 1 -CONR a R b , -X 1 -N(R a )SO2R a , -X 1 -SO2R a , -X 1 -SO2R a R b , -X 1 -SO3R a , -X 1 -CN, -X 1 -Y 1 , and -X1 -Y 1 -Y 1a wherein each X is a member independently selected from the group consisting of 1 is a bond or C 1-6 Alkylene, and OH, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 and each Y is optionally further substituted with 1 to 3 substituents independently selected from the group consisting of alkyl, and COH. 1 and Y 1a C 3-10 independently selected from the group consisting of cycloalkyl, 4- to 8-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and aryl, each heterocycloalkyl and heteroaryl having 1 to 3 heteroatom ring vertices selected from O, N, and S; and each Y 1 and Y 1a Halogen, oxo, CN, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkoxy, NH2, NH(C 1-4 alkyl), N(C 1-4 alkyl)2, SO2NH2, CONH2, C(O)NHOH, PO3H2, CO-C 1-8 Alkyl, COO-C 1-8 further substituted with 1 to 4 substituents independently selected from the group consisting of alkyl, and COH; Or, R 1a and R 1b may be bonded to each other to form a 4- to 8-membered ring or a spiro ring, and may contain halogen, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkoxy, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8optionally substituted with 1 to 4 members independently selected from the group consisting of alkyl, and COH; R 2 are halogens, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -Y 2 , -X 2 -C(O)2R a , -X 2 -OR a , -X 2 -NR a R b , -X 2 -CONR a R b , -X 2 -SO2R a , -X 2 -N(R a )SO2R a , -X 2 -SO2NR a R b , -X 2 -SO3R a , -OX 2 -Y 2 , and -X 2 -Y 2 wherein each X 2 is a bond or C 1-6 Alkylene, and OH, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 and each Y is optionally further substituted with 1 to 3 substituents independently selected from the group consisting of alkyl, and COH. 2 C 3-6 independently selected from the group consisting of cycloalkyl, 4- to 8-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, each heterocycloalkyl and heteroaryl having 1 to 3 heteroatom ring vertices selected from O, N, and S; and each Y 2 halogen, oxo, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkoxy, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 further substituted with 1 to 4 substituents independently selected from the group consisting of alkyl, and COH; R 3 is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, and -X 3 -Y 3 wherein each X 3 is a bond, C 1-6 Alkylene, or C 1-6 Haloalkylene, and OH, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 and each Y is optionally further substituted with alkyl, or COH. 3 C 3-6 is selected from the group consisting of cycloalkyl, 4- to 8-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, and each heterocycloalkyl and heteroaryl has 1 to 3 heteroatom ring vertices selected from O, N, and S; and each Y 3 halogen, oxo, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkoxy, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 further substituted with 1 to 4 substituents independently selected from the group consisting of alkyl, and COH; R 4a and R 4b are H, halogen, and C, respectively.1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, and C 1-6 is a member independently selected from the group consisting of hydroxyalkyl; Each R a A, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkylene-COH, C 1-6 Alkylene-SO3H, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, C 1-3 Alkyl C 3-6 cycloalkyl, phenyl, and 3- to 7-membered heterocycloalkyl having 1 to 3 heteroatom ring vertices selected from O, N, and S; and each R a halogens, OH, C 1-4 Alkoxy, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 further substituted with one or two members independently selected from the group consisting of alkyl, and COH; Each R b A, H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkylene-COH, and C 1-6 alkylene-SO3H, each of which is independently selected from the group consisting of OH, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 optionally further substituted with one or two members independently selected from alkyl, and COH; and R a and R bare bonded to the same nitrogen atom, they may be bonded to each other to form a 4- to 8-membered ring or a spiro ring, and may be bonded to halogens, OH, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 Optionally substituted with 1 to 4 members independently selected from the group consisting of alkyl, and CO2H.

[0081] In some embodiments, there is provided a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein: X is C(R 2 ) or N; R 1a and R 1b are H and C, respectively. 1-6 Alkyl, C 3-6 Alkenyl, C 3-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -Y 1 , -X 1 -C(O)2R a , -X 1 -OR a , -X 1 -NR a R b , -X 1 -CONR a R b , -X 1 -N(R a )SO2R a , -X 1 -SO2R a , -X 1 -SO2R a R b , -X 1 -SO3R a , -X 1 -CN, -X 1 -Y 1 , and X 1 -Y 1 -Y 1a wherein each X is a member independently selected from the group consisting of 1 is a bond or C 1-6 Alkylene, and OH, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C1-8 and each Y is optionally further substituted with alkyl, or COH. 1 and Y 1a C 3-10 independently selected from the group consisting of cycloalkyl, 4- to 8-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and aryl, each of which is selected from halogen, oxo, CN, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkoxy, NH2, NH(C 1-4 alkyl), N(C 1-4 alkyl)2, SO2NH2, CONH2, C(O)NHOH, PO3H2, CO-C 1-8 Alkyl, COO-C 1-8 further substituted with 1 to 4 substituents independently selected from the group consisting of alkyl, and COH; Or, R 1a and R 1b may be bonded to each other to form a 4- to 8-membered ring or a spiro ring, and may contain halogen, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkoxy, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 optionally substituted with 1 to 4 members independently selected from the group consisting of alkyl, and COH; R 2 are halogens, CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, -Y 2 , -X 2 -C(O)2R a , -X 2 -OR a , -X2 -NR a R b , -X 2 -CONR a R b , -X 2 -SO2R a , -X 2 -N(R a )SO2R a , -X 2 -SO2NR a R b , -X 2 -SO3R a , -OX 2 -Y 2 , and -X 2 -Y 2 wherein each X 2 is a bond or C 1-6 Alkylene, and OH, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 and each Y is optionally further substituted with an alkyl or COH substituent. 2 C 3-6 cycloalkyl, 4- to 8-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, each of which is selected from the group consisting of halogen, oxo, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkoxy, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 further substituted with 1 to 4 substituents independently selected from the group consisting of alkyl, and COH; R 3 is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, and -X 3 -Y 3wherein each X 3 is a bond, C 1-6 Alkylene, or C 1-6 Haloalkylene, and OH, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 and each Y is optionally further substituted with alkyl, or COH. 3 C 3-6 cycloalkyl, 4- to 8-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, each of which is selected from the group consisting of halogen, oxo, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkoxy, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 further substituted with 1 to 4 substituents independently selected from the group consisting of alkyl, and COH; R 4a and R 4b are H, halogen, and C, respectively. 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, and C 1-6 is a member independently selected from the group consisting of hydroxyalkyl; Each R a A, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkylene-COH, C 1-6 Alkylene-SO3H, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 1-3 independently selected from the group consisting of alkyl, phenyl, and 3- to 7-membered heterocycloalkyl, each of which is selected from OH, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8further substituted with one or two members independently selected from alkyl, and COH; Each R b A, H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkylene-COH, and C 1-6 alkylene-SO3H, each of which is independently selected from the group consisting of OH, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 optionally further substituted with one or two members independently selected from alkyl, and COH; and R a and R b are bonded to the same nitrogen atom, they may be bonded to each other to form a 4- to 8-membered ring or a spiro ring, and may be bonded to halogens, OH, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 Optionally substituted with 1 to 4 members independently selected from the group consisting of alkyl, and CO2H.

[0082] In some selected embodiments, compounds of Formula (I) are those in which X is C(R 2 ) is a compound.

[0083] In some selected embodiments, the compounds of Formula (I) are those in which X is N.

[0084] In some selected embodiments, the compound of Formula (I) has the formula (Ia): [ka] or a pharmaceutically acceptable salt, hydrate, or solvate of the same.

[0085] In some selected embodiments, the compound of Formula (I) has the formula (Ib): [ka] or a pharmaceutically acceptable salt, hydrate, or solvate of the same.

[0086] In some selected embodiments, the compound of Formula (I) has the formula (Ic): [ka] or a pharmaceutically acceptable salt, hydrate, or solvate of the same.

[0087] In some selected embodiments, the compound of Formula (I) has the formula (Id): [ka] or a pharmaceutically acceptable salt, hydrate, or solvate of the same.

[0088] In some selected embodiments, the compound of Formula (I) has the formula (Ie): [ka] or a pharmaceutically acceptable salt, hydrate, or solvate of the same.

[0089] In some selected embodiments, the compound of formula (I) has the formula (If): [ka] or a pharmaceutically acceptable salt, hydrate, or solvate of the same.

[0090] In some selected embodiments, the compound of formula (I) has formula (Ig): [ka] or a pharmaceutically acceptable salt, hydrate, or solvate of the same.

[0091] In some selected embodiments, the compound of Formula (I) has the formula (Ih): [ka] or a pharmaceutically acceptable salt, hydrate, or solvate of the same.

[0092] In some selected embodiments, the compound of Formula (I) has the formula (Ii): [ka] or a pharmaceutically acceptable salt, hydrate, or solvate of the same.

[0093] In selected embodiments, compounds of formula (I), (Ia), and (Ib) are provided, wherein —N(R 1a )(R 1b )teeth: [ka] and stereoisomers thereof.

[0094] In some selected embodiments, the compounds provided herein are: [ka] [ka] is selected from the group consisting of:

[0095] In selected embodiments, compounds of formula (I), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), and (Ii) are provided, wherein R 1a and R 1b are H and C, respectively. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, -Y 1 , -X 1 -C(O)2R a, -X 1 -OR a , -X 1 -NR a R b , -X 1 -CONR a R b , -X 1 -N(R a )SO2R a , -X 1 -SO2R a , -X 1 -SO2NR a R b , -X 1 -SO3R a , -X 1 -CN, -X 1 -Y 1 , and -X 1 -Y 1 -Y 1a and each X is a member independently selected from the group consisting of 1 is a bond or C 1-3 Alkylene, and OH, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 and each Y is optionally further substituted with alkyl, or COH. 1 and Y 1a is C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and aryl, and each Y 1 and Y 1a is halogen, oxo, CN, OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkoxy, NH2, NH(C 1-4 alkyl), N(C 1-4 alkyl)2, SO2NH2, CONH2, C(O)NHOH, PO3H2, CO-C 1-8 Alkyl, COO-C 1-8It is optionally further substituted with 1 to 4 substituents independently selected from the group consisting of alkyl, and CO2H.

[0096] In selected embodiments, compounds of formula (I), (Ia), (Ib), (Ih), and (Ii) are provided, wherein R 2 is a member selected from Cl, CH, CHCH, CH(CH)OH, OCH, and NHSOCH. 2 is a member selected from OCF3 or OCF2H.

[0097] In selected embodiments, compounds of formula (I), (Ia), (Ic), (Id), and (Ie) are provided, wherein R 3 teeth: [ka] is a member selected from the group consisting of:

[0098] In selected embodiments, compounds of formula (I) are provided, wherein R 4a and R 4b are H, halogen, and C, respectively. 1-3 Alkyl, C 1-3 Haloalkyl, and C 1-3 and hydroxyalkyl.

[0099] In still other embodiments, including any of the above selected embodiments, each R a is H, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkylene-COH, C 1-3 Alkylene-SO3H, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 1-3independently selected from the group consisting of alkyl, phenyl, and 3- to 7-membered heterocycloalkyl, each of which is selected from OH, SO2NH2, CONH2, C(O)NHOH, PO3H2, COO-C 1-8 and optionally further substituted with one or two members independently selected from alkyl, COH, and COH; and b A, H, C 1-3 Alkyl, C 3-6 Cycloalkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkylene-COH, and C 1-3 alkylene-SO3H.

[0100] In some selected embodiments, a compound from any one of Tables 1-7 is provided.

[0101] Identification of PI3Kγ inhibitors with desirable properties Part of the present invention relates to the identification of PI3Kγ inhibitors that have at least one therapeutically relevant property or characteristic. Candidate inhibitors can be identified, for example, using art-accepted assays or models, examples of which are described herein.

[0102] Once identified, candidate inhibitors can be further evaluated using techniques that provide data on the inhibitor's properties (e.g., means of determining pharmacokinetic parameters, solubility, or stability). Comparison of candidate inhibitors with a reference standard (which may be a "best in class" of current inhibitors) provides an indication of the potential utility of such candidates.

[0103] Synthesis method General Methods for Preparing the Claimed Compounds Those skilled in the art will recognize that there are a variety of methods available for preparing the claimed molecules. Generally, a useful method for constructing the claimed compounds consists of three parts, which can be performed in any order: modification of functional groups present on fragments a-c, connection of fragments a and b, and connection of fragments b and c. The retrosynthetic cleavage of compounds of the invention into fragments a-c useful for constructing the compounds is shown below: [ka]

[0104] Several methods for preparing the claimed compounds are illustrated (Schemes 1-4). Scheme 1 shows one method for synthesizing an appropriately functionalized fragment c. In the case of Scheme 1, readily available 4-halo-2-methylbenzoic acid methyl ester is converted to an isoindolinone via radical benzylic bromination (e.g., using NBS), followed by cyclization with an appropriately functionalized primary amine. In the case of Scheme 1, X can be selected from a suitable group such as Cl, Br, or I. [ka]

[0105] Alternatively, a wide variety of methods for the formation of isoindolinones are known in the art (see, for example, "Synthesis of Isoindolinones" at https: / / www.organic-chemistry.org / synthesis / heterocycles / benzo-fused / isoindolinones.shtm).

[0106] Equation 2 shows one method of forming a bond between fragments b and c via a Suzuki reaction. In the case of Equation 2, Z can be selected from a suitable group such as Cl or Br, -B(OR)2 is a boronic acid or ester, and the coupling is mediated by a transition metal catalyst, preferably palladium with a suitable ligand. [ka]

[0107] Coupling can be assisted using organic or inorganic bases, and a wide variety of conditions for facilitating Suzuki coupling are known in the art. Functionalization of the coupling partners can also be reversed, as illustrated in Scheme 3. Those skilled in the art will recognize that there are other combinations that will also lead to the desired product. Formation of the bond between the b and c fragments can occur before or after forming the connection between the a and b fragments, and these groups can be further modified before or after connecting the b and c fragments. [ka]

[0108] Equation 4 illustrates one method for forming a bond between fragments a and b. In the case of Equation 4, a readily available primary amine is coupled with a carboxylic acid derivative (or an activated analog thereof) of fragment b in the presence of a suitable amide coupling reagent, such as EDC, HOBt, HATU, or a variety of other reagents (see "Synthesis of amides" at https: / / www.organic-chemistry.org / synthesis / ClN / amides.shtm). One of skill in the art will appreciate that there are a wide variety of methods available to accomplish this transformation. [ka]

[0109] In order to most effectively prepare any particular compound of the present invention, one of skill in the art will recognize that the timing and order of attachment of fragments, as well as the functional modifications present in any fragment, may vary in the preparation of any given compound. The compounds of the present invention have been prepared using a variety of methods described above, some of which are illustrated in the Examples.

[0110] Prodrugs and other means of drug delivery and / or half-life extension In some aspects of the present invention, the compounds described herein are administered in prodrug form.

[0111] To effectively extend therapeutic activity, drug molecules can be engineered to utilize carriers for delivery, either in a non-covalent manner, where the drug moiety is formulated physicochemically into a solvent-carrier mixture, or by permanently covalently attaching a carrier reagent to one of the functional groups of the drug moiety (see generally WO 2015 / 0202317).

[0112] Several non-covalent approaches are favored, including, but not limited to, depot formulations that, in certain embodiments, involve non-covalently bound drugs encapsulated in a polymeric carrier, in which drug molecules are combined with a carrier material and processed to distribute the drug molecules within the bulk carrier. Examples include microparticulate polymer-drug aggregates administered as injectable suspensions (e.g., Degradex® Microspheres (Phosphorex, Inc.)); polymer-drug molecule aggregates formulated as gels administered in a single bolus injection (e.g., Lupron Depot® (AbbVie Inc.)); and liposomal formulations (e.g., DepoCyt® (Pacira Pharmaceuticals)), which may utilize polymeric or non-polymeric substances capable of solubilizing the drug in the carrier. In these formulations, release of the drug molecules can occur when the carrier swells or physically degrades. In other cases, chemical degradation allows the drug to diffuse into the biological environment; the chemical degradation process may be autohydrolytic or enzyme-catalyzed. Another limitation is that noncovalent drug encapsulation requires prevention of uncontrolled drug release, and drug release mechanisms that rely on biodegradation can lead to patient-to-patient variability.

[0113] In certain embodiments, drug molecules, including both small and large molecules, are conjugated to the carrier by a permanent covalent bond. Certain small molecule therapeutic agents that exhibit low solubility in aqueous fluids can be solubilized by conjugation with hydrophilic polymers, examples of which are described elsewhere herein. For large protein molecules, extended half-life can be achieved by permanent covalent modification, for example, with a palmitoyl moiety and another protein (e.g., Albuferon®) that itself has an extended half-life. Generally, when a carrier is covalently conjugated to a drug, the drug molecule exhibits reduced biological activity.

[0114] In certain cases, limitations associated with drug molecules containing either non-covalent polymer mixtures or permanent covalent bonds can be successfully addressed by using a prodrug approach to chemically conjugate drugs to polymeric carriers. In this regard, therapeutic agents that are inactive or less active than the drug moiety itself are predictably transformed into active molecular entities. The reduced biological activity of the prodrug compared to the released drug is advantageous when sustained or controlled release of the drug is desired. In such cases, drug release occurs over time, thereby reducing the need for repeated and frequent drug administration. The prodrug approach can also be advantageous when the drug moiety itself is not absorbed or exhibits suboptimal absorption in the gastrointestinal tract; in these cases, the prodrug facilitates absorption of the drug moiety and is then cleaved after a period of time (e.g., via first-pass metabolism). Biologically active drug molecules are typically attached to polymeric carrier moieties via temporary bonds formed between the carrier moiety and a hydroxy, amino, or carboxy group on the drug molecule.

[0115] The above-mentioned approaches are associated with several limitations. Activation of prodrugs can occur by enzymatic or non-enzymatic cleavage of temporary bonds between carrier and drug molecules, or by a sequential combination of both (e.g., an enzymatic step followed by a non-enzymatic modification). In enzyme-free in vitro environments (e.g., aqueous buffer solutions), temporary bonds such as esters or amides can undergo hydrolysis, but the corresponding hydrolysis rates are outside the therapeutically useful range. In contrast, in vivo environments typically involve esterases or amidases, which can cause significant catalytic acceleration of hydrolysis kinetics by two to several orders of magnitude (see, e.g., Greenwald et al., (1999) J Med Chem 42(18): 3857-67).

[0116] As described herein, prodrugs can be classified into i) bioprecursors and ii) carrier-linked prodrugs. Bioprecursors do not contain a carrier group and are activated by metabolic generation of a functional group. In contrast, in carrier-linked prodrugs, the active substance is conjugated to the carrier moiety via a temporary bond at a functional group on the biologically active substance. Preferred functional groups are hydroxyl or amino groups. Both the attachment characteristics and hydrolysis conditions depend on the type of functional group used. The carrier can be biologically inert (e.g., PEG) or can have targeting properties (e.g., antibodies). Cleavage of the carrier moiety of a carrier-linked prodrug yields the desired biologically active substance, and the nature of the deprotected functional group on the biologically active substance often contributes to its biological activity.

[0117] The patent and scientific literature describes numerous polymeric prodrugs in which the temporary linkage is a labile ester bond. In these cases, the functional group of the biologically active substance is either a hydroxyl group or a carboxylic acid (see, e.g., Cheng et al. (2003) Bioconjugate Chem 14:1007-17). In addition, for biopolymers and certain small molecule drugs, it is often advantageous to conjugate the carrier to the amino group(s) of the biologically active substance (e.g., the N-terminus of a protein or a lysine amino group). During prodrug preparation, amino groups can be manipulated more chemoselectively due to their greater nucleophilicity compared to hydroxyl or phenol groups. This is particularly relevant for proteins and peptides, which contain a wide variety of different reactive functional groups; non-selective conjugation reactions result in undesirable product mixtures that require extensive characterization or purification, thereby reducing the reaction yield and therapeutic efficacy of the active ingredient.

[0118] Amide bonds are generally more hydrolytically stable than ester bonds, and the cleavage rate of the amide bond may be too slow for therapeutic utility in carrier-linked prodrugs. As a result, it may be advantageous to add structural chemical moieties to control the likelihood of prodrug amide bond cleavage. Additional chemical moieties that control this cleavage, not provided by the carrier substance or the drug, are generally referred to as "linkers." Prodrug linkers can significantly affect the hydrolysis rate of the temporary bond, and changes in the chemical nature of the linker often result in specific properties. Prodrug activation of amine-containing biologically active moieties by specific enzymes for targeted release requires that the linker structure exhibit a structural motif that the corresponding endogenous enzyme recognizes as a substrate. In these cases, temporary bond cleavage occurs in a single-step process catalyzed by the enzyme. For example, the enzymatic release of cytarabine is influenced by the protease plasmin, the concentration of which is relatively high in various types of tumor masses.

[0119] Inter-patient variability is a major drawback of predominantly enzyme cleavage. Enzyme levels can vary significantly between subjects, resulting in biological variability in prodrug activation by enzymatic cleavage. Enzyme levels can also vary depending on the site of administration (e.g., in the case of subcutaneous injection, some areas of the body produce more predictable therapeutic effects than others). In addition, it is difficult to establish in vivo-in vitro correlations of pharmacokinetic properties for prodrugs conjugated to enzyme-dependent carriers.

[0120] Other carrier prodrugs that use temporary bonds to the amino group of the drug moiety are based on a cascade mechanism. Cascade cleavage is made possible by linker compounds that consist of the structural combination of a masking group and an activating group. The masking group is attached to the activating group through a first temporary bond, such as an ester or carbamate. The activating group is attached to the amino group of the drug molecule through a second temporary bond (e.g., a carbamate). The stability or susceptibility to hydrolysis of the second temporary bond depends on the presence or absence of the masking group. In the presence of the masking group, the second temporary bond is very stable and unlikely to release the drug molecule at a therapeutically useful kinetic, whereas in the absence of the masking group, this bond is very unstable, resulting in rapid cleavage and release of the drug moiety.

[0121] Cleavage of the first temporary bond is the rate-limiting step in the cascade mechanism. The first step can induce molecular rearrangement of the activating group (e.g., 1,6-elimination as described in Greenwald et al. (1999) J Med Chem 42:3657-67), which then renders the second temporary bond even more unstable, thereby triggering its cleavage. Ideally, the cleavage rate of the first temporary bond is identical to the desired release rate of the drug molecule in a given therapeutic scenario. Furthermore, it is desirable for the cleavage of the second temporary bond to occur substantially instantaneously after its instability induces cleavage of the first temporary bond.

[0122] Another embodiment includes polymeric amino-containing prodrugs based on trimethyl lock lactonization (see, e.g., Greenwald et al. (2000) J Med Chem 43(3):457-87). In this prodrug system, a substituted o-hydroxyphenyl-dimethylpropionic acid is attached to PEG via an ester, carbonate, or carbamate group as a first temporary bond and to an amino group on a drug molecule via an amide bond as a second temporary bond. The rate-limiting step in drug release is enzymatic cleavage of the first bond, followed by rapid amide cleavage via lactonization, releasing an aromatic lactone by-product. A major drawback of the prodrug system described by Greenwald et al. is the release of reactive and potentially toxic small aromatic molecule by-products, such as quinone methides or aromatic lactones, after cleavage of the temporary bond. The potentially toxic substances are released in a 1:1 stoichiometry with the drug, which is expected to result in high in vivo concentrations.

[0123] In certain embodiments of cascade prodrugs containing aromatic activating groups based on 1,6-elimination, the masking group is structurally spaced from the carrier. This can be achieved by using a stable bond between the polymer carrier and the activating group, which is not involved in the cascade cleavage mechanism. This avoids the release of potentially toxic by-products (such as the activating group) when the carrier does not function as a masking group and the activating group is attached to the carrier by means of a stable bond. The stable bond between the activating group and the polymer also suppresses the release of pharmacologically undefined drug-linker intermediates.

[0124] A first example of the approach described in the previous paragraph involves a polymer prodrug system based on a mandelic acid activating group (see, e.g., Shabat et al. (2004) Chem Eur J 10:2626-34). In this approach, a masking group is attached to an activating group via a carbamate bond. The activating group is permanently conjugated to a polyacrylamide polymer via an amide bond. After enzymatic activation of the masking group with a catalytic antibody, the masking group undergoes cyclization and cleavage, releasing the drug; the activating group remains attached to the polyacrylamide polymer after drug release. A similar prodrug system is based on a mandelic acid activating group and an enzymatically cleavable ester-linked masking group (see, e.g., Lee et al. (2004) Angew Chem 116:1707-10).

[0125] When using the linkers described above, the 1,6-elimination step still generates highly reactive aromatic intermediates. Even if the aromatic moiety remains permanently attached to the polymeric carrier, it can lead to side reactions with potentially toxic by-products and immunogenic effects. Therefore, it is advantageous to develop linker technology for forming polymeric prodrugs of amine-containing active agents using aliphatic prodrug linkers that are not enzyme-dependent and do not generate reactive aromatic intermediates during cleavage. One such example uses PEG5000-maleic anhydride for the reversible modification of amino groups in tissue-type plasminogen activator and urokinase (see, e.g., (1987) Garman et al. FEBS Lett 223(2):361-65). Cleavage of the maleamic acid bond and regeneration of functional enzyme from the PEG-uPA conjugate by incubation in pH 7.4 buffer follows first-order kinetics with a half-life of approximately 6 hours. A drawback of the maleamic acid bond is that the conjugate becomes less stable at lower pH values.

[0126] A further approach involves the PEG cascade prodrug system based on an N,N-bis-(2-hydroxyethyl)glycinamide (bicine) linker (see, e.g., (2004) J Med Chem 47:726-34). In this system, two PEG carrier molecules are attached via temporary bonds to a bicine molecule coupled to an amino group on a drug molecule. The first step of prodrug activation involves enzymatic cleavage of the first temporary bond linking both PEG carrier molecules to the hydroxy group of the bicine activating group. Different linkages between PEG and bicine result in different prodrug activation kinetics. The second step of prodrug activation involves cleavage of the second temporary bond linking the bicine activating group to the amino group on the drug molecule. A drawback of this system is the slow hydrolysis rate of this second temporary bicine amide bond, resulting in the release of a bicine-modified prodrug intermediate that exhibits different pharmacokinetic, immunogenic, toxic, and pharmacodynamic properties compared to the original parent drug molecule.

[0127] In certain embodiments, dipeptides are utilized for the development of prodrugs for targeting or targeted delivery because they are substrates for enzymes or biotransport systems. Nonenzymatic pathways for the formation of dipeptide prodrugs, i.e., their ability to undergo intramolecular cyclization to form the corresponding diketopiperazine (DKP) and release the active drug, are not well defined.

[0128] In some embodiments, the dipeptide is attached to the drug moiety via an ester bond, as described for the dipeptide ester of the drug paracetamol (Gomes et al. (2005) Bio & Med Chem Lett. In this case, the cyclization reaction consists of forming a tetrahedral intermediate that nucleophilically attacks the ester carbon atom of the N-terminal amine of the peptide, followed by proton transfer from the amine to the leaving group oxyanion, concomitantly forming a peptide bond to provide the cyclic DKP product and the free drug. Although this method can be applied to hydroxyl-containing drugs in vitro, it was found to compete with enzymatic hydrolysis of the ester bond in vivo, as the corresponding dipeptide ester released paracetamol at a much faster rate than with buffering (Gomes et al. (Molecules 12 (2007) 2484-2506)). The susceptibility of dipeptide-based prodrugs to peptidases can be addressed by incorporating at least one unnatural amino acid into the dipeptide moiety. However, endogenous enzymes capable of cleaving the ester bond are not limited to peptidases, and the enzyme-dependence of the prodrug cleavage still leads to unpredictable in vivo performance.

[0129] In some embodiments, enzyme dependency is intentionally engineered into DKP prodrugs; for example, a dipeptide ester prodrug is formylated at the amino terminus of the dipeptide, and enzymatic deformylation is used to initiate diketopiperazine formation, followed by cleavage of the ester dipeptide bond and subsequent release of the drug molecule (see, e.g., USP 7,163,923). As a further example, an octapeptide is linked to the 4-hydroxyl group of vinblastine via an ester bond, and after removal of the N-terminal hexapeptide with a specific enzyme, the ester bond is cleaved by DKP formation (see, Brady et al. (2002) J Med Chem 45:4706-15).

[0130] The scope of DKP formation reactions also extends to amide prodrugs. For example, US Pat. No. 5,952,294 describes prodrug activation using diketopiperazine formation for a dipeptidyl amide prodrug of cytarabine. In this case, a temporary bond is formed between the carbonyl of the dipeptide and the aromatic amino group of cytarabine. However, for conjugates in the absence of a carrier or other half-life-extending moiety or functional group, it is unlikely that a sustained-release effect can be achieved.

[0131] Dipeptide prodrugs containing bioactive peptides such as GLP-1 have also been described, which can release the peptide via diketopiperazine formation of the dipeptide extension (see, for example, WO 2009 / 099763). The bioactive peptide moiety contains an additional PEG chain at one of its amino acid side chain residues, thereby achieving extended circulation of the bioactive peptide. However, this approach is associated with several significant drawbacks. First, the PEG chain must be attached to the peptide without impairing its bioactivity, which is difficult to achieve for many peptide-based bioactive agents. Second, because the PEGylated peptide itself is bioactive, the dipeptide promoiety can affect the peptide's bioactivity and adversely affect its receptor binding properties.

[0132] Specific exemplary technologies that may be used with the compounds of the present invention include those developed by ProLynx (San Francisco, CA) and Ascendis Pharma (Palo Alto, CA). The ProLynx technology platform utilizes a series of novel linkers preprogrammed to cleave at different rates, enabling controlled and predictable sustained release of small molecules and peptides from circulating semi-solid polymeric conjugates. This technology allows for the maintenance of desired steady-state serum levels of therapeutic agents over periods of weeks to months.

[0133] The Ascendis technology platform combines the benefits of prodrug and sustained-release technologies to enhance the properties of small molecules and peptides. While in circulation, the unique prodrugs release the unmodified active parent therapeutic at a predetermined rate defined by physiological pH and temperature conditions. Because the therapeutic is released in its unmodified form, it retains its original mechanism of action.

[0134] Modifications to enhance inhibitor properties It is often beneficial, and sometimes necessary, to improve one or more physical properties of the therapeutics disclosed herein and / or the method of administration thereof, for example, to increase water solubility, bioavailability, serum half-life, and / or therapeutic half-life, and / or to modulate biological activity.

[0135] Modifications known in the art include PEGylation, Fc fusion, and albumin fusion. While typically associated with large molecule agents (e.g., polypeptides), such modifications have recently been evaluated with certain small molecules. For example, Chiang, M. et al. (J. Am. Chem. Soc., 2014, 136(9):3370-73) described a small molecule agonist of the adenosine 2a receptor conjugated to an immunoglobulin Fc domain. The small molecule Fc conjugate retained potent Fc receptor and adenosine 2a receptor interactions and exhibited superior properties compared to the unconjugated small molecule. Covalent attachment of PEG molecules to small molecule therapeutics has also been described (Li, W. et al., Progress in Polymer Science, 2013, 38:421-44).

[0136] Another known modification is deuteration to improve pharmacokinetics, pharmacodynamics, and toxicity profiles. Due to the large atomic weight of deuterium, breaking a carbon-deuterium bond requires more energy than breaking a carbon-hydrogen bond. Because such strong bonds are very difficult to break, the rate of drug metabolism is slower than that of the non-deuterated form, which can allow for less frequent dosing and further reduce toxicity. (Charles Schmidt, Nature Biotechnology, 2017, 35(6):493-494; Harbeson, S. and Tung, R., Medchem News, 2014(2):8-22).

[0137] Therapeutic and prophylactic uses The present invention contemplates the use of the PI3Kγ inhibitors described herein in the treatment or prevention of a wide range of diseases, disorders, and / or conditions, and / or their symptoms. While details regarding specific uses are set forth below, it should be understood that the present invention is not limited thereto. Additionally, while general categories of certain diseases, disorders, and conditions are set forth below, some diseases, disorders, and conditions may be members of more than one category, and others may not be members of any of the disclosed categories.

[0138] In some embodiments, the diseases, disorders, and / or conditions described herein are mediated, at least in part, by PI3Kγ.

[0139] In some embodiments, the PI3Kγ inhibitors described herein are administered in an amount effective to reverse or halt the progression of PI3Kγ-mediated dysregulation.

[0140] Tumor-associated disorders. Studies investigating immune responses to tumors have identified PI3Kγ as a central node in the signaling cascade. PI3Kγ inhibitors can stimulate anti-cancer immune responses through modulation of myeloid cells, for example, by inhibiting suppressive myeloid cells, suppressing immunosuppressive tumor-infiltrating macrophages, or by stimulating macrophages and dendritic cells to produce cytokines that contribute to effective T cell responses leading to the suppression of cancer development and spread.

[0141] Without being bound by any particular theory, PI3Kγ inhibitors can be used to treat or prevent proliferative conditions or disorders, such as cancers of the uterus, cervix, breast, prostate, testis, gastrointestinal tract (e.g., esophagus, oropharynx, stomach, small or large intestine, colon or rectum), kidney, kidney cells, bladder, bone, bone marrow, skin, head and neck, liver, gallbladder, heart, lung, pancreas, salivary gland, adrenal gland, thyroid, brain (e.g., glioma), ganglion, central nervous system (CNS) and peripheral nervous system (PNS), and cancers of the hematopoietic and immune systems (e.g., spleen or thymus). The present invention also provides methods for treating or preventing other cancer-related diseases, disorders, or conditions, such as, for example, immunogenic tumors, non-immunogenic tumors, dormant tumors, virus-induced cancers (e.g., epithelial cell carcinoma, endothelial cell carcinoma, squamous cell carcinoma, and papillomavirus), adenocarcinoma, lymphoma, carcinoma, melanoma, leukemia, myeloma, sarcoma, teratocarcinoma, chemically induced cancer, metastasis, and angiogenesis. In certain embodiments, the tumor or cancer is colon cancer, ovarian cancer, breast cancer, melanoma, lung cancer, glioblastoma, or leukemia. The use of the term(s) cancer-related disease, disorder, and condition is meant to refer broadly to conditions directly or indirectly related to cancer, and includes precancerous conditions such as, for example, angiogenesis and dysplasia.

[0142] In certain embodiments, the cancer is metastatic, or at risk of becoming metastatic, or may be present in diffuse tissues, including cancers of the blood or bone marrow (e.g., leukemia).

[0143] In some embodiments, the present invention provides methods of treating a proliferative condition, cancer, tumor, or precancerous condition using a PI3Kγ inhibitor and at least one additional therapeutic or diagnostic agent, examples of which are described elsewhere herein.

[0144] Immune and Inflammatory Disorders. Dysregulated immune responses lead to autoimmune, inflammatory, and allergic conditions. Autoimmune diseases result from a breakdown in tolerance that leads to immune responses against host cells, resulting in conditions such as multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, psoriasis, and autoimmune (type 1) diabetes. Chronic inflammatory conditions such as chronic obstructive pulmonary disease (COPD), atherosclerosis, and inflammatory bowel disease result from an ongoing dysregulated immune response. Uncontrolled inflammation is also a risk factor for cancer development and is known to contribute to tumor growth and metastasis. Allergic conditions such as asthma and anaphylaxis are usually caused by inappropriate immune responses to harmless antigens [Curr Opin Pharmacol. 2015 Aug;23:82-91.] Accordingly, the terms "immune disease," "immune condition," "immune disorder," "inflammatory disease," "inflammatory condition," "inflammatory disorder," and the like, as used herein, are intended to broadly encompass immune-related conditions that can be treated with the PI3Kγ inhibitors described herein, thereby providing some degree of therapeutic benefit.

[0145] A list of immune- and inflammation-related diseases, disorders, and conditions that can be treated or prevented with the compounds and compositions of the present invention includes, but is not limited to, arthritis (e.g., rheumatoid arthritis), renal failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergies, fibrosis, surgical complications (e.g., cases where inflammatory cytokines interfere with healing), anemia, and fibromyalgia. Other diseases and disorders that may be associated with chronic inflammation include Alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infectious diseases, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), allergic contact dermatitis and other eczemas, systemic sclerosis, transplantation, and multiple sclerosis.

[0146] In certain embodiments of the present disclosure, PI3K gamma inhibitors are used to provide adjuvant activity to increase or enhance the immune response to an antigen. In certain embodiments, at least one antigen or vaccine is administered to a subject in combination with at least one PI3K gamma inhibitor of the present invention to prolong the immune response to the antigen or vaccine. Therapeutic compositions comprising at least one antigenic agent or vaccine component, including, but not limited to, viruses, bacteria, and fungi, or portions thereof, proteins, peptides, tumor-specific antigens, and nucleic acid vaccines, in combination with at least one PI3K gamma inhibitor of the present invention are also provided.

[0147] In some embodiments, the PI3Kγ inhibitors described herein can be combined with immunosuppressants to reduce the number of immune effector cells.

[0148] Some of the diseases, disorders, and conditions described above for which PI3Kγ inhibitors may be particularly effective (eg, due to limitations in current treatments) are described in further detail below.

[0149] Rheumatoid arthritis (RA) is typically characterized by chronic inflammation in the membranous lining of joints (synovium) and affects approximately 1% of the U.S. population (approximately 2.1 million people). A growing understanding of the role of cytokines such as TNF-α and IL-1 in the inflammatory process has enabled the development and introduction of a novel class of disease-modifying antirheumatic drugs (DMARDs). Agents, some of which overlap with RA treatments, include ENBREL® (etanercept), REMICADE® (infliximab), HUMIRA® (adalimumab), and KINERET® (anakinra). While some of these agents alleviate symptoms, inhibit the progression of structural damage, and improve physical function, particularly in patient populations, alternative medications with improved efficacy, complementary mechanisms of action, and fewer or no serious side effects remain desirable.

[0150] Psoriasis is a common group of immune-mediated chronic skin diseases affecting more than 4.5 million people in the United States, with 1.5 million of those patients considered to have moderate to severe disease. Furthermore, more than 10% of psoriasis patients develop psoriatic arthritis, which damages the bone and connective tissue around the joints. A better understanding of the essential physiology of psoriasis has led to the introduction of agents that target the activity of T lymphocytes and cytokines responsible for the inflammatory nature of the disease. These agents include TNF-α inhibitors, such as ENBREL® (etanercept), REMICADE® (infliximab), and HUMIRA® (adalimumab), which are also used to treat rheumatoid arthritis (RA), and T-cell inhibitors, such as AMEVIVE® (alefate) and RAPTIVA® (efalizumab). While some of these agents are somewhat effective in certain patient populations, they do not effectively treat all patients.

[0151] Other Disorders. Embodiments of the present invention contemplate administering a PI3Kγ inhibitor as described herein to a subject for the treatment or prevention of any other disorder that may benefit from at least some level of PI3Kγ inhibition. Such diseases, disorders, and conditions include, for example, cardiovascular (e.g., cardiac ischemia) and metabolic (e.g., diabetes, insulin resistance, obesity) disorders.

[0152] Pharmaceutical Composition The PI3K gamma inhibitors of the present invention may be in the form of compositions suitable for administration to a subject. Generally, such compositions are "pharmaceutical compositions" comprising a PI3K gamma inhibitor(s) and one or more pharmaceutically or physiologically acceptable diluents, carriers, or excipients. In certain embodiments, the PI3K gamma inhibitor is present in a therapeutically acceptable amount. Pharmaceutical compositions may be used in the methods of the present invention; thus, for example, pharmaceutical compositions can be administered to a subject ex vivo or in vivo to carry out the treatment and prevention methods and uses described herein.

[0153] Pharmaceutical compositions of the invention can be formulated to be compatible with the intended method or route of administration; exemplary routes of administration are described herein. Additionally, pharmaceutical compositions may be used in combination with other therapeutically active agents or compounds described herein to treat or prevent the diseases, disorders, and conditions contemplated by the invention.

[0154] Pharmaceutical compositions containing an active ingredient (e.g., an inhibitor of PI3Kγ function) may be in a form suitable for oral use, such as tablets, capsules, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, solutions, microbeads, or elixirs. Pharmaceutical compositions intended for oral use can be prepared according to any method for preparing pharmaceutical compositions known in the art, and the compositions may contain one or more additives, such as sweeteners, flavoring agents, coloring agents, and preservatives, to provide a pharmaceutically elegant and palatable formulation. Tablets, capsules, etc. contain the active ingredient in admixture with pharmaceutically acceptable, non-toxic excipients that are suitable for the manufacture of tablets. These excipients may be, for example, diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as, for example, corn starch or alginic acid; binding agents such as, for example, starch, gelatin, or acacia; and lubricating agents such as, for example, magnesium stearate, stearic acid, or talc.

[0155] Tablets, capsules, and the like suitable for oral administration can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate can be used. These can also be coated by techniques known in the art to form osmotic therapeutic tablets for controlled release. Additional additives include biodegradable or biocompatible particles or polymeric materials for controlling delivery of the administered composition, such as polyesters, polyamic acids, hydrogels, polyvinylpyrrolidone, polyanhydrides, polyglycolic acid, ethylene-vinyl acetate, methylcellulose, carboxymethylcellulose, protamine sulfate, or lactide / glycolide copolymers, polylactide / glycolide copolymers, or ethylene-vinyl acetate copolymers. For example, oral agents can be encapsulated in microcapsules, which are prepared by coacervation techniques or interfacial polymerization using hydroxymethylcellulose, gelatin-microcapsules, or poly(methyl methacrylate) microcapsules, respectively, or in colloidal drug delivery systems. Colloidal dispersion systems include macromolecule complexes, nanocapsules, microspheres, microbeads, and lipid-based systems, such as oil-in-water emulsions, micelles, mixed micelles, and liposomes. Methods for preparing the above-mentioned formulations are readily apparent to those skilled in the art.

[0156] Formulations for oral use may be provided as hard or soft gelatin capsules, i.e., by mixing the active ingredient with an inert solid diluent such as calcium carbonate, calcium phosphate, kaolin, or microcrystalline cellulose, or by mixing the active ingredient with water or an oil medium such as peanut oil, liquid paraffin, or olive oil.

[0157] Aqueous suspensions contain the active ingredient in admixture with excipients suitable for the manufacture of such suspensions. Such excipients may be suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents, such as naturally occurring phosphatides (e.g., lecithin), or condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), or condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives.

[0158] Oily suspensions may be prepared by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, such as beeswax, hard paraffin, or cetyl alcohol. Sweetening and flavoring agents, such as those mentioned above, may be added to provide a palatable oral preparation.

[0159] Dispersible powders and granules suitable for preparation of an aqueous suspension are provided by the addition of water to the active ingredient in admixture with a dispersing or wetting agent, suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified herein.

[0160] The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may include naturally occurring gums, such as acacia gum or tragacanth gum; naturally occurring phosphatides, such as soybean, lecithin, and esters or partial esters derived from fatty acids; hexitol anhydrides, such as sorbitan monooleate; and condensation products of partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.

[0161] Pharmaceutical compositions generally contain a therapeutically effective amount of a PI3Kγ inhibitor contemplated by the present invention and one or more pharmaceutically and physiologically acceptable formulation components. Suitable pharmaceutically or physiologically acceptable diluents, carriers, or excipients include, but are not limited to, antioxidants (e.g., ascorbic acid and sodium bisulfate), preservatives (e.g., benzyl alcohol, methylparaben, ethyl or n-propyl p-hydroxybenzoate), emulsifiers, suspending agents, dispersing agents, solvents, fillers, extenders, detergents, buffers, vehicles, diluents, and / or adjuvants. For example, a suitable vehicle can be saline or citrate-buffered saline, and can be supplemented with other materials commonly used in pharmaceutical compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles. Those skilled in the art will readily recognize various buffers that can be used in the pharmaceutical compositions and dosage forms contemplated herein. Common buffers include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof. For example, buffer components can be water-soluble materials such as phosphoric acid, tartaric acid, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and salts thereof. Acceptable buffers include, for example, Tris buffer, N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES), 2-(N-morpholino)ethanesulfonic acid (MES), 2-(N-morpholino)ethanesulfonic acid sodium salt (MES), 3-(N-morpholino)propanesulfonic acid (MOPS), and N-tris[hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS).

[0162] After the pharmaceutical composition is formulated, it can be stored in a sterile vial as a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. Such formulations can be stored in a ready-to-use form, a lyophilized form that must be reconstituted before use, a liquid form that must be diluted before use, or any other acceptable form. In some embodiments, the pharmaceutical composition is provided in a single-use container (e.g., a single-use vial, an ampoule, a syringe, or an autoinjector (e.g., similar to an EpiPen®)), while in other embodiments, a multi-use container (e.g., a multi-use vial) is provided.

[0163] The formulation can also include a carrier to protect the composition from rapid degradation or disappearance in the body, such as controlled-release formulations, such as liposomes, hydrogels, prodrugs, and microencapsulated delivery systems. For example, a time-delay material such as glyceryl monostearate or glyceryl stearate can be used alone or in combination with a wax. Any drug delivery device can be used to deliver the PI3Kγ inhibitor, including implants (e.g., implantable pumps) and catheter systems, slow infusion pumps and devices, all of which are well known to those skilled in the art.

[0164] Depot injections, generally administered subcutaneously or intramuscularly, can also be used to release the PI3K gamma inhibitors disclosed herein over a period of time. Depot injections are usually based on either solid or oil and generally contain at least one of the formulation components described herein. Those skilled in the art are familiar with the formulations available for depot injections and their use.

[0165] Pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. These suspensions may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents described herein. Sterile injectable preparations may be parenterally acceptable non-toxic diluents or solvents, including sterile injectable solutions or suspensions, such as solutions containing 1,3-butanediol. Acceptable diluents, solvents, and dispersion media that may be used include water, Ringer's solution, isotonic sodium chloride solution, Cremophor EL™ (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS), ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. In addition, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any sterile, fixed oil, such as synthetic mono- or diglycerides, may be used. Additionally, fatty acids, such as oleic acid, have found use in the preparation of injectables. Prolonged absorption of certain injectable formulations can be achieved by including an agent that delays absorption, for example, aluminum monostearate or gelatin.

[0166] The present invention contemplates administering a PI3Kγ inhibitor in the form of a suppository for rectal administration. Suppositories can be prepared by mixing a drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and melts in the rectum to release the drug. Such materials include, but are not limited to, cocoa butter and polyethylene glycol.

[0167] The PI3Kγ inhibitors contemplated by the present invention may be in the form of any other suitable pharmaceutical composition (eg, a spray for nasal or inhaled use) now known or later developed.

[0168] Route of administration The present invention contemplates administering PI3K gamma inhibitors and compositions thereof in any suitable manner. Suitable routes of administration include oral, parenteral (e.g., intramuscular, intravenous, subcutaneous (e.g., injection or implant), intraperitoneal, intracapsular, intraarticular, intracerebral (intraparenchymal) and intracerebroventricular, nasal, vaginal, sublingual, intraocular, rectal, topical (e.g., transdermal), buccal, and inhalation. Depot injections, generally administered subcutaneously or intramuscularly, may also be utilized to release the PI3K gamma inhibitors disclosed herein over a predetermined period of time.

[0169] Certain embodiments of the present invention contemplate oral administration.

[0170] Combination therapy The present invention contemplates the use of PI3Kγ inhibitors alone or in combination with one or more active therapeutic agents. The additional active therapeutic agent can be a small chemical molecule; a macromolecule such as a protein, antibody, peptibody, peptide, DNA, RNA, or fragment of such a macromolecule; or cell therapy or gene therapy. In such combination therapy, various active agents often exhibit different and complementary mechanisms of action. Such combination therapy can be particularly advantageous by allowing for a reduction in the dose of one or more active agents, thereby suppressing or eliminating the adverse effects associated with one or more active agents. Furthermore, such combination therapy can have a synergistic therapeutic or preventive effect on the underlying disease, disorder, or condition.

[0171] As used herein, the term "combined" refers to therapies that are administered separately, e.g., formulated and administered separately for separate administration (e.g., as may be provided in a kit), as well as therapies that are administered together in a single formulation (i.e., a "co-formulation").

[0172] In certain embodiments, the PI3K gamma inhibitors are administered or applied sequentially, e.g., one agent is administered before one or more other agents. In other embodiments, the PI3K gamma inhibitors are administered simultaneously, e.g., two or more agents are administered simultaneously or nearly simultaneously; two or more agents can be present in two or more separate formulations or combined in a single formulation (i.e., co-formulation). Whether two or more agents are administered sequentially or simultaneously, they are considered to be administered in combination for the purposes of the present invention.

[0173] The PI3K gamma inhibitors of the present invention may be used in combination with at least one other (active) agent in any manner appropriate to the situation. In one embodiment, treatment with at least one active agent and at least one PI3K gamma inhibitor of the present invention is maintained for a period of time. In another embodiment, treatment with at least one active agent is reduced or discontinued (e.g., if the subject is stable) while treatment with a PI3K gamma inhibitor of the present invention is maintained at a constant dosage regimen. In a further embodiment, treatment with at least one active agent is reduced or discontinued (e.g., if the subject is stable) while treatment with a PI3K gamma inhibitor of the present invention is reduced (e.g., to a lower dose, less frequent administration, or a shorter treatment regimen). In yet another embodiment, treatment with at least one active agent is reduced or discontinued (e.g., if the subject is stable) and treatment with a PI3K gamma inhibitor of the present invention is intensified (e.g., to a higher dose, more frequent administration, or a longer treatment regimen). In yet another embodiment, treatment with at least one active agent is maintained and treatment with a PI3K gamma inhibitor of the present invention is reduced or discontinued (e.g., to a lower dose, less frequent administration, or a shortened treatment regimen). In yet another embodiment, treatment with at least one active agent and treatment with a PI3K gamma inhibitor of the present invention are reduced or discontinued (e.g., to a lower dose, less frequent administration, or a shortened treatment regimen).

[0174] Tumor-related disorders. The present invention provides methods for treating and / or preventing a proliferative condition, cancer, tumor, or precancerous disease, disorder, or condition using a PI3Kγ inhibitor and at least one additional therapeutic or diagnostic agent. In some embodiments, the additional therapeutic or diagnostic agent is radiation, an immunomodulatory or chemotherapeutic agent, or a diagnostic agent. Suitable immunomodulatory agents that may be used in the present invention include activating monoclonal antibodies (mAbs) against stimulatory receptors such as CD40L, B7, and B7RP1; anti-CD40, anti-CD38, anti-ICOS, and 4-1BB ligand; dendritic cell antigen loading (in vitro or in vivo); anti-cancer vaccines such as dendritic cell cancer vaccines; cytokines / chemokines such as IL1, IL2, IL12, IL18, ELC / CCL19, SLC / CCL21, MCP-1, IL-4, IL-18, TNF, IL-15, MDC, IFNa / b, M-CSF, IL-3, GM-CSF, IL-13, and anti-IL-10; bacterial lipopolysaccharide (LPS); indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors, and immunostimulatory oligonucleotides.

[0175] In certain embodiments, the present invention provides a method for tumor inhibition of tumor growth, comprising administering a PI3Kγ inhibitor described herein in combination with a signal transduction inhibitor (STI) to achieve additive or synergistic inhibition of tumor growth. As used herein, the term "signal transduction inhibitor" refers to an agent that selectively inhibits one or more steps in a signal transduction pathway. Signal transduction inhibitors (STIs) of the present invention include: (i) bcr / abl kinase inhibitors (e.g., GLEEVEC®); (ii) epidermal growth factor (EGF) receptor inhibitors, including kinase inhibitors and antibodies; (iii) her-2 / neu receptor inhibitors (e.g., HERCEPTIN®); (iv) inhibitors of Akt family kinases or the Akt pathway (e.g., rapamycin); (v) cell cycle kinase inhibitors (e.g., flavopiridol); and (vi) phosphatidylinositol kinase inhibitors. Agents involved in immune modulation can also be used in combination with the PI3Kγ inhibitors described herein to inhibit tumor growth in cancer patients.

[0176] Examples of chemotherapeutic agents include alkylating agents, such as thiotepa and cyclophosphamide; alkylsulfonates, such as busulfan, improsulfan, and piposulfan; aziridines, such as benzodopa, carboquone, metoledopa, and uredopa; ethyleneimines and methylameramines, such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; nitrogen mustards, such as chlorambucil, chlornaphazine, cyclophosphamide, estramustine, Ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembitine, phenesterine, prednistine, troposfamide, uracil mustard; nitrosoureas, e.g., carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics, e.g., aclacinomycin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, caminomycin, carzinophilin, chromomycin, dactinomycin, da unorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, pomalidomide, potfilomycin, puromycin, chelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); denopterin, methotrexate ... Folic acid analogues such as lexate, pteropterin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone; antiadrenal drugs such as aminoglutethimide, mitotane, trilostane;Folic acid supplements such as folinic acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; amsacrine; Bestravcil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformitine; elliptinium acetate; etoglucide; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; fenameth; pirarubicin; podophyllic acid; 2-ethylhydrazide; procarbazine; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobromo Man; Gacitosine; Arabinoside (Ara-C); Cyclophosphamide; Thiotepa; Taxoids, such as paclitaxel and docetaxel; Chlorambucil; Gemcitabine; 6-Thioguanine; Mercaptopurine; Methotrexate; Platinum and platinum coordination complexes, such as cisplatin, carboplatin, and oxaliplatin; Vinblastine; Etoposide (VP-16); Ifosfamide; Mitomycin C; Mitoxantrone; Vincristine; Vinorelbine; Navelbine; Novantrone; Teniposide; Daunomycin; Aminopterin; Xeloda; Ibandronate; CPT11; Topoisomerase inhibitors; Difluoromethylornithine (DMFO); Retinoic acid; Esperamicin; Capecitabine; Anthracyclines; Arginase inhibitors (WO 2019 / 173188A1, and PCT / US2019 / 061657), and pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing;

[0177] Chemotherapeutic agents include antihormonal agents that act to regulate or inhibit hormone action on tumors, such as antiestrogens such as tamoxifen, raloxifene, aromatase-inhibiting 4(5)-imidazole, 4-hydroxytamoxifen, trioxoxifene, ketoxifene, onapristone, and toremifene; and antiandrogens such as abiraterone, enzalutamide, flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids, or derivatives of any of the above. In certain embodiments, the combination therapy includes a chemotherapy regimen containing one or more chemotherapeutic agents. In certain embodiments, the combination therapy includes the administration of a hormone or related hormonal agent.

[0178] Additional therapies that may be used in combination with PI3Kγ inhibitors include radiation therapy, monoclonal antibodies against tumor antigens, monoclonal antibody-toxin conjugates, T-cell adjuvants, bone marrow transplants, or antigen-presenting cells (e.g., dendritic cell therapy), including TLR agonists used to stimulate such antigen-presenting cells.

[0179] In certain embodiments, the present invention contemplates the use of the compounds described herein in combination with an agent that modulates adenosine levels. Such therapeutic agents may act on ectonucleotides, catalyzing the conversion of ATP to adenosine, such as ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1, ​​also known as CD39 or cluster of differentiation 39), which hydrolyzes ATP to ADP and ADP to AMP, and 5'-nucleotidase ecto(NT5E or 5NT, also known as CD73 or cluster of differentiation 73), which converts AMP to adenosine. The enzymatic activities of CD39 and CD73 play strategic roles in calibrating the duration, magnitude, and chemistry of the purinergic signals delivered to various cells (e.g., immune cells). In certain embodiments, the present invention contemplates combination with CD73 inhibitors described in WO 2017 / 120508, WO 2018 / 094148, WO 2018 / 067424, and WO 2020 / 046813.

[0180] Alternatively, such a therapeutic agent can be an adenosine 2 receptor (A2R) antagonist. Adenosine binds to four different G protein-coupled receptors: A1R, A2R, and A3R. 2a R.A. 2b It can bind to and activate A3R and A3R, which are expressed on myeloid cells such as T cells, natural killer cells, and dendritic cells. 2a The binding of adenosine to the R receptor increases the intracellular level of cyclic AMP, impairing the maturation and / or activation of such cells. This process significantly impairs the activation of the immune system against cancer cells. In addition, A 2AAdenosine receptor agonists are involved in selectively enhancing anti-inflammatory cytokines, promoting upregulation of PD-1 and CTLA-4, promoting the generation of LAG-3 and Foxp3+ regulatory T cells, and mediating the inhibition of regulatory T cells. PD-1, CTLA-4, and other immune checkpoints are further described herein. In some embodiments, the adenosine receptor agonist may be a dual adenosine receptor. Exemplary adenosine receptor agonists are described in WO / 2018 / 136700, WO 2018 / 204661, or WO 2020 / 023846.

[0181] In certain embodiments, the present invention contemplates the use of the compounds described herein in combination with adoptive cell therapy, a novel and promising form of personalized immunotherapy in which immune cells with anti-tumor activity are administered to cancer patients. Adoptive cell therapy has been investigated using tumor-infiltrating lymphocytes (TILs) and T cells genetically engineered to express, for example, chimeric antigen receptors (CARs) or T cell receptors (TCRs). Generally, adoptive cell therapy involves collecting T cells from an individual, genetically modifying them to target specific antigens or enhance anti-tumor effects, expanding them to sufficient numbers, and then infusing the genetically engineered T cells into a cancer patient. T cells can be collected from the patient (e.g., autologous) for later reinfusion of the expanded cells, or from a donor patient (e.g., allogeneic).

[0182] In certain embodiments, the present invention contemplates the use of the compounds described herein in combination with RNA interference-based therapy for silencing gene expression.RNAi begins by cleaving long double-stranded RNA into small interfering RNA (siRNA).One strand of siRNA is incorporated into ribonucleoprotein complex, also known as RNA-induced silencing complex (RISC), and then used to identify the mRNA molecule that is at least partially complementary to the incorporated siRNA strand.RISC can bind to mRNA or cleave it, both of which inhibit translation.

[0183] Immune Checkpoint Inhibitors The present invention contemplates the use of inhibitors of PI3Kγ function described herein in combination with immune checkpoint inhibitors.

[0184] The vast array of genetic and epigenetic alterations characteristic of all cancers provides a diverse array of antigens that the immune system can use to distinguish tumor cells from their normal counterparts. In the case of T cells, the ultimate amplitude (e.g., level of cytokine production or proliferation) and quality (e.g., type of immune response, including the pattern of cytokine production) of the response initiated by the T cell receptor (TCR) upon antigen recognition are regulated by the balance between costimulatory and inhibitory signals (immune checkpoints). Under normal physiological conditions, immune checkpoints are important for preventing autoimmunity (i.e., maintaining self-tolerance) when the immune system responds to pathogen infection and for protecting against tissue damage. The expression of immune checkpoint proteins, a key immune resistance mechanism, is dysregulated by tumors.

[0185] Efforts have been directed toward therapeutic manipulation of endogenous antitumor immunity due to T cells' i) ability for selective recognition of peptides derived from proteins in all cellular compartments; ii) ability to directly recognize and kill antigen-expressing cells (by CD8+ effector T cells, also known as cytotoxic T lymphocytes (CTLs)); and iii) ability to orchestrate diverse immune responses exerted by CD4+ helper T cells that integrate adaptive and innate effector mechanisms.

[0186] In clinical settings, blockade of immune checkpoints leading to the amplification of antigen-specific T cell responses has been shown to be a promising approach for the treatment of human cancers.

[0187] T cell-mediated immunity involves multiple sequential steps, each of which involves counteracting and modulating stimulatory and inhibitory signals to optimize the response. Nearly all inhibitory signals in an immune response ultimately regulate intracellular signaling pathways, many of which are initiated through membrane receptors, whose ligands are either membrane-bound or soluble (cytokine). Costimulatory and inhibitory receptors and ligands that regulate T cell activation are less frequently overexpressed in cancer compared with normal tissues, whereas inhibitory ligands and receptors that regulate T cell effector function within tissues are typically overexpressed in tumor cells or in non-transformed cells associated with the tumor microenvironment. The function of soluble and membrane-bound receptor-ligand immune checkpoints can be modulated, for example, using agonist antibodies (for costimulatory pathways) or antagonist antibodies (for inhibitory pathways). Thus, in contrast to most currently approved antibodies for cancer therapy, immune checkpoint-blocking antibodies do not directly target tumor cells, but rather target lymphocyte receptors or their ligands to enhance intrinsic antitumor activity [see Pardoll, (April 2012) Nature Rev. Cancer 12: 252-64].

[0188] Examples of immune checkpoints (ligands and receptors), some of which are selectively upregulated in various types of tumor cells, making them candidates for blockade, include PD-1 (programmed cell death protein 1); PD-L1 (PD1 ligand); BTLA (B- and T-lymphocyte attenuator); CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4); TIM-3 (T-cell membrane protein 3); LAG-3 (lymphocyte-activation gene 3); TIGIT (T-cell immunoreceptor with Ig and ITIM domains); and killer inhibitory receptors, which can be divided into two classes based on structural features: i) killer cell immunoglobulin-like receptors (KIRs) and ii) C-type lectin receptors (members of the type II transmembrane receptor family). Other less well-defined immune checkpoints have been described in the literature and include both receptors (e.g., the 2B4 (also known as CD244) receptor) and ligands (e.g., certain B7 family inhibitory ligands such as B7-H3 (also known as CD276) and B7-H4 (also known as B7-S1, B7x, and VCTN1)) [see Pardoll, (April 2012) Nature Rev. Cancer 12: 252-64].

[0189] The present invention contemplates the use of inhibitors of PI3Kγ function described herein in combination with inhibitors of the immune checkpoint receptors and ligands described above, as well as immune checkpoint receptors and ligands yet to be described. Certain modulators of immune checkpoints are currently approved, and many others are in development. In 2011, the fully humanized CTLA-4 monoclonal antibody ipilimumab (YERVOY®; Bristol-Myers Squibb) became the first immune checkpoint inhibitor to receive regulatory approval in the United States when it was approved for the treatment of melanoma. Fusion proteins containing CTLA-4 and antibodies (CTLA-4-Ig; abatacept (ORENCIA®; Bristol-Myers Squibb)) have been used to treat rheumatoid arthritis, and other fusion proteins have shown efficacy in kidney transplant patients susceptible to Epstein-Barr virus. The next class of immune checkpoint inhibitors to receive regulatory approval were directed against PD-1 and its ligands, PD-L1 and PD-L2. Approved anti-PD1 antibodies include nivolumab (OPDIVO; Bristol-Myers Squibb) and pembrolizumab (KEYTRUDA®; Merck), which are used for a variety of cancers, including squamous cell carcinoma, classical Hodgkin lymphoma, and urothelial carcinoma. Approved anti-PD-L1 antibodies include avelumab (BAVENCIO®, EMD Serono & Pfizer), atezolizumab (TECENTRIQ®; Roche / Genentech), and durvalumab (IMFINZI®; AstraZeneca), which are used for certain cancers, including urothelial carcinoma. There are no approved therapies targeting TIGIT or its ligands CD155 and CD112, but several in development include BMS-986207 (Bristol-Myers Squibb), MTIG7192A / RG6058 (Roche / Genentech), and OMP-31M32 (OncoMed).

[0190] In one aspect of the present invention, the claimed PI3Kγ inhibitors are combined with a cancer immunotherapeutic agent that is either (i) an agonist of a stimulatory (e.g., costimulatory) receptor or (ii) an antagonist of an inhibitory (e.g., co-inhibitory) signal in T cells, both of which amplify antigen-specific T cell responses. Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to costimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), B7-H6, and B7-H7 (HHLA2). Another family of membrane-bound ligands that bind to costimulatory or co-inhibitory receptors is the TNF family of molecules that bind to cognate TNF receptor family members, including CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LT13R, LIGHT, D cR3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin a / TNF13, TNFR2, TNFa, LT13R, lymphotoxin a 1132, FAS, FASL, RELT, DR6, TROY, NGFR.

[0191] In another aspect, the cancer immunotherapeutic is a cytokine that inhibits T cell activation (e.g., IL-6, IL-10, TGF-B, VEGF, and other immunosuppressive cytokines) or that stimulates T cell activation to stimulate an immune response.

[0192] In certain aspects, T cell responses can be stimulated by combining a disclosed PI3Kγ inhibitor with one or more of (i) an antagonist of a protein that inhibits T cell activation (e.g., an immune checkpoint inhibitor), such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin-9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, and / or (ii) an agonist of a protein that stimulates T cell activation, such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD2. Other agents that can be combined with the PI3Kγ inhibitors of the present invention for cancer treatment include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells. For example, the compounds herein can be combined with antagonists of KIR, such as lirilumab.

[0193] Yet another agent for combination therapy is an agent that inhibits or depletes macrophages or monocytes, such as, but not limited to, a CSF-1R antagonist, e.g., RG7155 (WO11 / 70024, WO11 / 107553, WO / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044), or a CSF-1R antagonist antibody such as FPA-008 (WO11 / 140249; WO13169264; WO14 / 036357).

[0194] In another aspect, the disclosed PI3Kγ inhibitors can be used in conjunction with one or more agonist agents that bind positive costimulatory receptors, blocking agents that attenuate signaling via inhibitory receptors, antagonists, and one or more agents that systemically enhance the frequency of anti-tumor T cells, ablate distinct immunosuppressive pathways in the tumor microenvironment (e.g., by blocking inhibitory receptor engagement (e.g., PD-L1 / PD-1 interaction)), deplete or inhibit Tregs (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or ex vivo anti-CD25 bead depletion), or reverse / prevent T cell anergy or complete exhaustion, and agents that cause innate immune activation and / or inflammation at the tumor site.

[0195] In some embodiments, the cancer immunotherapeutic is a CTLA-4 antagonist, e.g., an antagonistic CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, YERVOY® (ipilimumab) or tremelimumab.

[0196] In another embodiment, the cancer immunotherapeutic agent is a PD-L1 antagonist, e.g., a PD-L1 antagonistic antibody. Suitable PD-L1 antibodies include, for example, OPDIVO® (nivolumab), KEYTRUDA® (pembrolizumab), MEDI-0680 (AMP-514; WO2012 / 145493), or zimberelimab. Another cancer immunotherapeutic agent is pidilizumab (CT-011). Another approach to targeting the PD-1 receptor is a recombinant protein called AMP-224, which consists of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1.

[0197] In another embodiment, the cancer immunotherapeutic agent is a PD-L1 antagonist, e.g., an antagonistic PD-L1 antibody. Suitable PD-L1 antibodies include, for example, TECENTRIC® (atezolizumab; MPDL3280A; WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO2007 / 005874), and MSB0010718C (WO2013 / 79174).

[0198] In another embodiment, the cancer immunotherapeutic agent is a LAG-3 antagonist, for example, a LAG-3 antagonistic antibody. Suitable LAG3 antibodies include, for example, BMS-986016 (WO10 / 19570, WO14 / 08218), or IMP-731 or IMP-321 (WO08 / 132601, WO09 / 44273).

[0199] In another embodiment, the cancer immunotherapeutic is a CD137 (4-1BB) agonist, e.g., an agonistic CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (W012 / 32433).

[0200] In another embodiment, the cancer immunotherapeutic is a GITR agonist, e.g., an agonistic GITR antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO06 / 105021, WO09 / 009116), and MK-4166 (WO11 / 028683).

[0201] In another embodiment, the cancer immunotherapeutic is an OX40 agonist, e.g., an agonistic OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469.

[0202] In another embodiment, the cancer immunotherapeutic is an OX40L antagonist, e.g., an antagonistic OX40 antibody. Suitable OX40L antagonists include, for example, RG-7888 (WO06 / 029879).

[0203] In another aspect, the cancer immunotherapeutic agent is a CD40 agonist, e.g., an agonistic CD40 antibody. In yet another embodiment, the cancer immunotherapeutic agent is a CD40 antagonist, e.g., an antagonistic CD40 antibody. Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab.

[0204] In another embodiment, the cancer immunotherapeutic is a CD27 agonist, e.g., an agonistic CD27 antibody. A suitable CD27 antibody is, for example, varlilumab.

[0205] In another embodiment, the cancer immunotherapeutic is MGA271 (directed against B7H3) (WO11 / 109400).

[0206] The present invention includes pharmaceutically acceptable salts, acids or derivatives of any of the above.

[0207] Metabolic and Cardiovascular Diseases. The present invention provides methods for treating and / or preventing certain cardiovascular and / or metabolic-related diseases, disorders and conditions, and disorders related thereto, using a PI3Kγ inhibitor and at least one additional therapeutic or diagnostic agent.

[0208] Examples of therapeutic agents useful in combination therapy for the treatment of hypercholesterolemia (and atherosclerosis) include statins, which inhibit the enzymatic synthesis of cholesterol (e.g., CRESTOR®, LESCOL®, LIPITOR®, MEVACOR®, PRAVACOL®, and ZOCOR®); bile acid resins, which sequester cholesterol and prevent its absorption (e.g., COLESTID®, LO-CHOLEST®, PREVALITE®, QUESTRAN®, and WELCHOL®). fibric acids (e.g., TRICOR®), which reduce triglycerides and modestly increase HDL; niacin (e.g., NIACOR®), which modestly reduce LDL cholesterol and triglycerides; and / or combinations of the above (e.g., VYTORIN® (simvastatin and ezetimibe)). Alternative cholesterol treatments that may be candidates for use in combination with the PI3Kγ inhibitors described herein include various adjuvants and herbs (e.g., garlic, policosanol, and guggul).

[0209] The present invention includes pharmaceutically acceptable salts, acids or derivatives of any of the above.

[0210] Immune and Inflammation-Related Disorders. The present invention provides methods for treating and / or preventing immune-related diseases, disorders and conditions; and diseases, disorders and conditions with an inflammatory manifestation, using a PI3Kγ inhibitor and at least one additional therapeutic or diagnostic agent.

[0211] Examples of therapeutic agents useful in combination therapy include: nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, and other propionic acid derivatives (alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaclofen), acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid ... These include, but are not limited to, enthiazac, filofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac, fenamic acid derivatives (flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid, and tolfenamic acid), biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicams (isooxicam, piroxicam, sudoxicam, and tenoxicam), salicylates (acetylsalicylic acid, sulfasalazine), and pyrazolones (apazone, bezupiperylone, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone). Others use cyclooxygenase-2 (COX-2) inhibitors in combination.

[0212] Other active agents used in combination include steroids such as prednisolone, prednisone, methylprednisolone, betamethasone, dexamethasone, or hydrocortisone. Such combinations can be particularly advantageous because they can reduce or even eliminate one or more of the adverse effects of steroids by gradually reducing the required dose of steroids.

[0213] Further examples of active agents that may be used in combination, for example in the treatment of rheumatoid arthritis, include cytokine suppressive anti-inflammatory drug(s) (CSAIDs); antibodies or antagonists to other human cytokines or growth factors, such as TNF, LT, IL-10, IL-2, IL-6, IL-7, IL-8, IL-15, IL-16, IL-18, EMAP-II, GM-CSF, FGF, or PDGF.

[0214] Specific combinations of active agents can interfere at various points in the autoimmune and subsequent inflammatory cascade, including TNF antagonists, such as chimeric, humanized, or human TNF antibodies, REMICADE®, anti-TNF antibody fragments (e.g., CDP870), and soluble p55 or p75 TNF receptors, their derivatives, p75TNFRIgG (ENBREL®) or p55TNFR1gG (LENERCEPT®), soluble IL-13 receptors (sIL-13), and even TNFα-converting enzyme (TACE) inhibitors; IL-1 inhibitors (e.g., interleukin-1 converting enzyme inhibitors) can also be effective. Another combination is interleukin-11, anti-P7, and P-selectin glycoprotein ligand (PSGL). Other examples of agents useful in combination with the PI3Kγ inhibitors described herein include interferon-131a (AVONEX®), interferon-131b (BETASERON); copaxone; hyperbaric oxygen; intravenous immunoglobulin; clavulivin; and antibodies to or antagonists of other human cytokines or growth factors (e.g., antibodies to CD40 ligand and CD80).

[0215] dosage The PI3Kγ inhibitors of the present invention can be administered to a subject in an amount determined, for example, by the goal of administration (e.g., desired degree of achievement); the age, weight, sex, and health and physical condition of the subject to whom the formulation is administered; the route of administration; and the nature of the disease, disorder, condition, or symptom. The dosing regimen can also take into account the existence, nature, and extent of any adverse effects associated with the administered agent(s). Effective dosages and dosing regimens can be readily determined, for example, from safety and dose escalation studies, in vivo studies (e.g., animal models), and other methods known to those skilled in the art.

[0216] Generally, dosage parameters indicate that the dosage is below the amount that is irreversibly toxic to the subject (maximum tolerated dose (MTD)) and at least the amount necessary to have a measurable effect on the subject, determined, for example, by ADME-related pharmacokinetic and pharmacodynamic parameters, taking into account the route of administration and other factors.

[0217] The effective dose (ED) is the dose or amount of an agent that produces a therapeutic response or desired effect in a proportion of subjects receiving the agent. The "median effective dose" or ED50 of an agent is the dose or amount of an agent that produces a therapeutic response or desired effect in 50% of the population receiving the agent. The ED50 is generally used as a measure of the reasonable expectation of the effect of an agent, but it is not necessarily the dose that a physician considers appropriate after considering all relevant factors. Thus, in some situations, the effective amount exceeds the calculated ED50, in other situations, the effective amount is below the calculated ED50, and in still other situations, the effective amount is the same as the calculated ED50.

[0218] Additionally, an effective amount of a PI3K gamma inhibitor of the present invention can be an amount that, when administered one or more times to a subject, produces a desired result compared to a healthy subject. For example, in a subject with a particular disorder, an effective dose can be an amount that improves a diagnostic parameter, measurement, marker, etc. of the disorder by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or a greater than 90% improvement, where 100% is defined as the diagnostic parameter, measurement, marker, etc., exhibited by a normal subject.

[0219] In certain embodiments, PI3Kγ inhibitors contemplated by the present invention are administered (e.g., orally) at a dosage level of about 0.01 mg / kg to about 50 mg / kg, or about 1 mg / kg to about 25 mg / kg of subject body weight / day, one or more times per day to achieve the desired therapeutic effect.

[0220] For oral administration, the compositions may be provided in the form of tablets, capsules, and the like containing 1.0 to 1000 mg of the active ingredient, particularly 1.0, 3.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 mg of the active ingredient.

[0221] In certain embodiments, the desired dose of PI3K gamma inhibitor is contained in a "unit dosage form." The phrase "unit dosage form" refers to a physically discrete unit containing a predetermined quantity of a PI3K gamma inhibitor, alone or in combination with one or more additional active agents, sufficient to provide a desired effect. It is understood that the parameters of the unit dosage form depend on the particular active agent and the effect to be achieved.

[0222] kit The present invention also contemplates kits comprising the compounds described herein, and pharmaceutical compositions thereof. Generally, the kits are in the form of a physical structure housing various components, as described below, and can be used, for example, in practicing the methods described above.

[0223] The kits can include one or more compounds disclosed herein (e.g., in a sterile container) and can be in the form of a pharmaceutical composition suitable for administration to a subject. The compounds described herein can be provided in a ready-to-use form (e.g., a tablet or capsule) or in a form that requires, for example, reconstitution or dilution (e.g., a powder) before administration. When the compounds described herein are in a form that requires reconstitution or dilution by the user, the kit can also include a diluent (e.g., sterile water), buffer, pharmaceutically acceptable excipient, etc., packaged together with or separately from the compounds described herein. When combination therapy is contemplated, the kit can contain several agents separately or prepackaged in the kit. Each component of the kit can be enclosed in an individual container, and all of the various containers can be contained in a single container. The kits of the present invention can be designed for conditions (e.g., refrigeration or freezing) necessary to properly maintain the components contained in the kit.

[0224] The kit may include a label or package insert that describes the identity of the components contained therein and instructions for their use (e.g., dosing parameters of the active ingredient(s), clinical pharmacology, e.g., mechanism of action, pharmacokinetics and pharmacodynamics, adverse effects, contraindications, etc.). The label or package insert may include manufacturer information, such as a lot number or expiration date. The label or package insert may, for example, be integral to the physical structure that contains the component, may be contained separately within the physical structure, or may be affixed to a component of the kit (e.g., an ampoule, tube, or vial).

[0225] The label or package insert may further comprise or be incorporated into a computer readable medium, such as a disk (e.g., hard disk, card, memory disk), optical disk, e.g., CD- or DVD-ROM / RAM, DVD, MP3, magnetic tape, or electronic storage medium, e.g., RAM and ROM, or hybrids thereof, e.g., magnetic / optical storage medium, FLASH media, or memory type cards. In some embodiments, the actual instructions are not included in the kit, but rather a means is provided for obtaining the instructions from a remote source, e.g., via the internet.

[0226] experiment The following examples are presented to provide those of ordinary skill in the art with a complete disclosure and description of how to reproduce and use the invention, but are not intended to limit the scope of what the inventors regard as their invention, and are not intended to imply that the experiments described below were performed or that they are all experiments that may be performed. It should be understood that exemplary descriptions written in the present tense have not necessarily been performed, but rather that the data, features, etc. described herein may be revealed by performing the descriptions. Efforts have been made to ensure accuracy with respect to numerical values ​​used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for.

[0227] Unless otherwise indicated, parts are parts by weight, molecular weight is weight average molecular weight, temperature is degrees Celsius (°C), and pressure is at or near atmospheric. The following standard abbreviations are used: wt = wild type; bp = base pair(s); kb = kilobase(s); nt = nucleotide(s); aa = amino acid(s); s or sec = second(s); min = minute(s); h or hr = hour(s); ng = nanogram; μg = microgram; mg = milligram; g = gram; kg = kilogram; dl or dL = deciliter; μl or μL = microliter; ml or mL = milliliter; l or L = liter. mol; μM = micromolar; mM = millimolar; M = molar; rt = room temperature; kDa = kilodaltons; im = intramuscular; ip = intraperitoneal; SC or SQ = subcutaneous; QD = daily; BID = twice daily; QW = weekly; QM = monthly; HPLC = high performance liquid chromatography; BW = body weight; U = unit; ns = not statistically significant; PBS = phosphate buffered saline; IHC = immunohistochemistry; DMEM = Dulbecco's modified Eagle's medium; EDTA = ethylenediaminetetraacetic acid.

[0228] Materials and Methods The following general materials and methods were used where indicated or may be used in the examples below.

[0229] Standard methods in molecular biology are described in the scientific literature (see, e.g., Sambrook and Russell (2001) Molecular Cloning, 3rd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; and Ausubel et al. (2001) Current Protocols in Molecular Biology, Vols. 1-4, John Wiley and Sons, Inc., New York, NY, which describe cloning and DNA mutagenesis in bacterial cells (Vol. 1), cloning in mammalian cells and yeast (Vol. 2), expression of glycoconjugates and proteins (Vol. 3), and bioinformatics (Vol. 4)).

[0230] The scientific literature describes methods for protein purification, such as immunoprecipitation, chromatography, electrophoresis, centrifugation, and crystallization, as well as chemical analysis, chemical modification, post-translational modification, production of fusion proteins, and protein glycosylation (see, e.g., Coligan et al. (2000) Current Protocols in Protein Science, Vols. 1-2, John Wiley and Sons, Inc., NY).

[0231] For example, software packages and databases are available for determining antigenic fragments, leader sequences, protein folding, functional domains, glycosylation sites, and sequence alignments (see, e.g., GCG Wisconsin Package (Accelrys, Inc., San Diego, CA); and DeCypher™ (TimeLogic Corp., Crystal Bay, NV)).

[0232] The literature is replete with assays and other laboratory techniques that can be used as a basis for evaluating the compounds described herein. [Example]

[0233] Example 1: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-[trans-3-hydroxycyclobutyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0234] Step a: To a mixture of methyl cyanoacetate (44.1 mL, 500 mmol), KOAc (85.9 g, 875 mmol), and i-PrOH (500 mL) was added trichloroacetonitrile (50.1 mL, 500 mmol). The reaction mixture was stirred at room temperature for 14 h. HO (675 mL) was added, and the solid that formed was collected by filtration, washed with HO (500 mL), and dried under vacuum to give the desired product as a white solid (93.8 g; 77%).

[0235] Step b: To a mixture of the product of step a (93.8 g, 385 mmol), KOAc (56.7 g, 578 mmol), and DMF (385 mL) was added hydrazine monohydrate (28.0 mL, 578 mmol) dropwise at 0 °C. The mixture was stirred at room temperature for 1 h and then at 110 °C for 15 h. The mixture was cooled, and the solid was filtered off. The cake was washed with DMF (100 mL). The filtrate was concentrated to give a thick film. The residue was recrystallized with HO (720 mL), and the collected solid was washed with HO (500 mL). The solid was dried under vacuum to give the desired product (37.6 g, 63%) as a light brown solid.

[0236] Step c: To a mixture of the product of step b (31.2 g, 200 mmol), 1,3-dimethyluracil (28.0 g, 200 mmol), and EtOH (700 mL) was added NaOEt (299 mL, 800 mmol, 21 wt% EtOH) at room temperature. The reaction mixture was stirred at reflux for 14 hours and then allowed to cool. The solid was collected by filtration, washed with EtOH, and dried under vacuum to give the sodium salt of the desired product as a brown solid (44.8 g; 92%; approximately 9:1 mixture of ethyl ester:methyl ester). To a mixture of the sodium salt of the desired product (37.5 g, 154 mmol) and HO (375 mL) was added 2 M HCl at room temperature. (水溶液) (76.8 mL, 154 mL) was added at a rate of 60 mL / min. The mixture was stirred at room temperature for 15 min. (The pH of the aqueous phase should be about 4.) The precipitated solid was collected by filtration, washed with HO, and dried under vacuum to give the desired product in neutral form as a brown solid (28.2 g; 83%).

[0237] Step d: To a mixture of the product of step c (26.0 g, 117 mmol), benzyltriethylammonium chloride (26.6 g, 117 mmol), and dioxane (234 mL) was added POCl (32.7 mL, 351 mmol) at room temperature. The reaction mixture was stirred at 40 °C for 14 h and then allowed to cool. The mixture was poured into H O (1.17 L) with stirring at room temperature. Solid NaHCO (147 g) was carefully added until the pH was neutral. EtOAc (1 L) was added, and the mixture was filtered to remove any suspended solids. The phases were separated, and the aqueous phase was extracted with EtOAc (1 L). The combined organic phases were dried over Na2SO4 and concentrated to give the desired product (2-amino-5-chloropyrazolo[1,5-α]pyrimidine-3-carboxylic acid ethyl ester) as a pale brown solid (24.9 g; 89%).

[0238] Step e: A mixture of methyl 4-bromo-2,6-dimethylbenzoate (24.7 g, 102 mmol), NBS (20.8 g, 117 mmol), BPO (3.28 g, 10.2 mmol, 75 wt% HO), and CCl (406 mL) was stirred at reflux for 20 h. Upon cooling, HO (100 mL) and saturated brine (100 mL) were added. The organic phase was dried over NaSO and concentrated, and the resulting crude product was used in the next step.

[0239] Step f: A mixture of the crude product from Step e (102 mmol), (S)-1-cyclopropylethylamine (13.0 g, 153 mmol), B(OH) (6.30 g, 102 mmol), KCO (42.3 g, 306 mmol), and CHCN (406 mL) was stirred at 60 °C for 2 h. The mixture was cooled, the solids were removed by filtration, and the organic phase was concentrated. The crude product was purified by column chromatography (SiO, 0–20% EtOAc in hexanes) to give the desired product as an off-white solid (15.8 g; 53%).

[0240] Step g: To a mixture of the product from step f (15.8 g, 53.8 mmol), B2pin2 (13.7 g, 53.8 mmol), PdCl2(dppf) (1.97 g, 2.69 mmol), and KOAc (10.6 g, 108 mmol) was added degassed dioxane (269 mL) under N2. The reaction mixture was stirred at 100 °C for 2 h. Upon cooling, MTBE (250 mL) was added, the solids were filtered off, and the organic phase was concentrated. The crude product was purified by column chromatography (SiO2, 0–30% EtOAc in hexanes) to give the desired product as an off-white solid (15.8 g; 86%).

[0241] Step h: To a mixture of the product from step g (4.80 g, 20.0 mmol), the product from step d (6.83 g, 20.0 mmol), PdCl(dppf) (732 mg, 1.00 mmol), and KCO (5.53 g, 40.0 mmol) was added a degassed mixture of 4:1 dioxane:HO (100 mL) under N. The reaction mixture was stirred at 100 °C for 1 h. Upon cooling, saturated brine (20 mL) and 19:1 CHCl:MeOH (500 mL) were added. The organic phase was dried over NaSO, concentrated, and purified twice by column chromatography (SiO, 0–10% MeOH in CHCl) and (0–50% acetone in CHCl) to give the desired product as a yellow solid (4.02 g; 48%).

[0242] Step i: To a mixture of the product of step h (4.02 g, 9.58 mmol) and EtOH (48 mL) at room temperature was added LiOH (9.58 mL, 28.8 mmol, 3 M in HO). The reaction mixture was stirred at 80 °C for 1 h. The mixture was cooled and EtOH was removed under reduced pressure. HO (200 mL) was added and the mixture was diluted with 2 M HCl. (水溶液) (approximately 14 mL) to acidify the solution to a pH of 2-3. The solid was collected by filtration, washed with HO, and dried under vacuum to give the desired product as a yellow solid (3.49 g; 93%).

[0243] Step j: To a mixture of the product from step i (78 mg, 0.20 mmol), trans-3-aminocyclobutanol hydrochloride (27 mg, 0.22 mmol), HOBt hydrate (34 mg, 0.22 mmol), EtN (138 μL, 1.00 mmol), and DMF (1 mL) was added EDCI·HCl (58 mg, 0.30 mmol) at room temperature. The reaction mixture was stirred at 40 °C for 2 h, and HO (20 mL) was added. The solid that formed was collected by filtration and washed with HO. The crude product was purified by column chromatography (SiO, 0–10% MeOH in CHCl) to give the desired product as a yellow solid (70 mg; 76%). 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (d, J = 7.1 Hz, 1H), 8.20 (s, 1H), 8.12 (d, J = 6.9 Hz, 1H), 8.10 (s, 1H), 7.64 (d, J= 7.2 Hz, 1H), 6.54 (s, 2H), 5.18 (d, J = 5.4 Hz, 1H), 4.59 (s, 2H), 4.50 - 4.39 (m, 2H), 3.59 (dq, J = 9.3, 6.8 Hz, 1H), 2.72 (s, 3H), 2.37 - 2.23 (m, 4H), 1.31 (d, J= 6.8 Hz, 3H), 1.23-1.11 (m, 1H), 0.64 - 0.54 (m, 1H), 0.48-0.34 (m, 2H), 0.30 - 0.22 (m, 1H). + C 25 H 29 Calculated for N6O3: 461.2; Found: 461.1.

[0244] Example 2: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-[cis-4-hydroxy-4-methylcyclohexyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0245] The title compound was prepared in a similar manner to Example 1. 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (d, J = 7.1 Hz, 1H), 8.18 (s, 1H), 8.08 (s, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.63 (d, J = 7.2 Hz, 1H), 6.55 (s, 2H), 4.58 (s, 2H), 4.20 (s, 1H), 3.86 - 3.74 (m, 1H), 3.59 (dq, J = 8.6, 6.8 Hz, 1H), 2.72 (s, 3H), 1.86 - 1.69 (m, 4H), 1.69 - 1.58 (m, 2H), 1.51 - 1.40 ESI MS [M+H] + C 28 H 35 Calculated for N6O3: 503.3; Found: 503.2.

[0246] Example 3: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-[(1S,3S)-3-hydroxycyclopentyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0247] The title compound was prepared in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-d6) δ 9.00 (d, J = 7.1 Hz, 1H), 8.16 (s, 1H), 8.06 (s, 1H), 7.94 (d, J= 7.4 Hz, 1H), 7.62(d, J = 7.2 Hz, 1H), 6.55 (s, 2H), 4.65 (d, J = 3.8 Hz, 1H), 4.58 (s, 2H), 4.46 (h, J = 6.9 Hz, 1H), 4.37 - 4.30 (m, 1H), 3.59 (dq, J = 9.1, 6.8 Hz, 1H),2.71 (s, 3H), 2.27 - 2.15 (m, 1H),2.07 - 1.95(m, 2H), 1.75 (dt, J = 12.9, 6.2 Hz, 1H), 1.64 - 1.48 (m, 2H), 1.31 (d, J = 6.8 Hz, 3H), 1.22 - 1.12 (m, 1H), 0.63 - 0.55 (m, 1H), 0.47 - 0.35 (m, 2H), 0.30 - 0.22 (m, 1H). ESI MS [M+H] + C 26 H 31 Calculated for N6O3: 475.2; Found: 475.1.

[0248] Example 4: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-{trans-3-hydroxycyclobutyl]methyl}pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0249] The title compound was prepared in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-d6) δ 9.00 (d, J = 7.1 Hz, 1H), 8.20 (s, 1H), 8.07 (s, 1H), 7.90 (t, J = 5.7 Hz, 1H),7.62 (d, J = 7.2 Hz, 1H), 6.57 (s, 2H), 5.01 (d, J = 6.3 Hz, 1H), 4.58 (s, 2H), 4.30 (h, J = 6.8 Hz,1H), 3.59 (dq, J = 9.4,6.8 Hz, 1H), 3.46 (dd, J = 7.4, 5.7 Hz, 2H), 2.72 (s, 3H), 2.45 - 2.32 (m, 1H), 2.19 - 2.09 (m, 2H), 2.07 - 1.97 (m, 2H), 1.31 (d, J = 6.8 Hz, 3H), 1.22 - 1.11 (m, 1H),0.63 - 0.55 (m, 1H), 0.47 - 0.35 (m, 2H), 0.30 - 0.22 (m, 1H). ESI MS [M+H] + C 26 H 31 Calculated for N6O3: 475.2; Found: 475.2.

[0250] Example 5: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-[(1R,3R)-3-hydroxycyclopentyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0251] The title compound was prepared in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-d6) δ 9.00 (d, J = 7.1 Hz, 1H), 8.17 (s, 1H), 8.06 (s, 1H), 7.94 (d, J = 7.4 Hz, 1H), 7.62(d, J = 7.2 Hz, 1H), 6.55 (s, 2H), 4.65 (d, J = 3.8 Hz, 1H), 4.59 (s, 2H), 4.46 (h, J = 6.9 Hz, 1H), 4.33 (tq, J = 6.9, 3.5 Hz, 1H), 3.59 (dq, J = 9.1, 6.8 Hz, 1H), 2.72 (s, 3H), 2.27 - 2.15 (m, 1H), 2.07 - 1.95 (m, 2H), 1.75 (dt, J = 12.9, 6.2 Hz, 1H), 1.64 - 1.49 (m, 2H), 1.31 (d,J = 6.8 Hz, 3H), 1.23 - 1.12 (m, 1H), 0.63 - 0.54 (m, 1H), 0.47 - 0.35 (m, 2H), 0.30 - 0.21 (m, 1H). ESI MS [M+H] + C 26 H 31 Calculated for N6O3: 475.2; Found: 475.1.

[0252] Example 6: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-[trans-3-hydroxy-3-methylcyclobutyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0253] The title compound was prepared in a similar manner to Example 1. 1H NMR(400 MHz,DMSO-d6)δ 9.01 (d, J = 7.1 Hz,1H), 8.20 (s, 1H), 8.12 (s, 1H), 8.11 (s, 1H), 7.63 (d, J = 7.2 Hz, 1H), 6.55 (s, 2H), 5.01 (s, 1H), 4.58 (s, 2H), 4.54 - 4.43 (m, 1H), 3.60 (dq, J = 9.1, 6.8 Hz, 1H), 2.73 (s, 3H), 2.50 - 2.45 (m, 2H), 2.06 - 1.98 (m, 2H), 1.39 (s, 3H), 1.31 (d, J = ESI MS [M+H] + C 26 H 31 Calculated for N6O3: 475.2; Found: 475.2.

[0254] Example 7: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-[trans-4-hydroxy-4-methylcyclohexyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0255] The title compound was prepared in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-d6) δ 9.01 (d, J = 7.1 Hz, 1H), 8.14 (s, 1H), 8.02 (s, 1H), 7.99 (d, J = 7.5 Hz, 1H), 7.58 (d, J = 7.1 Hz, 1H), 6.58 (s, 2H), 4.57 (s, 2H), 4.25 (s, 1H), 4.08 - 3.98 (m, 1H), 3.60 (dq, J = 9.3, 6.8 Hz, 1H), 2.71 (s, 3H), 2.03 - 1.89 (m, 2H), 1.65 - 1.46 (m, 6H), 1.30 (d, J = ESI MS [M+H] + C 28 H 35 Calculated for N6O3: 503.3; Found: 503.2.

[0256] Example 8: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-[(1R,2R)-2-hydroxycyclopentyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0257] The title compound was prepared in a similar manner to Example 1. 1H NMR (400MHz,CDCl3)δ 8.54 (d, J = 7.1 Hz,1H),8.18 (d, J = 3.9 Hz, 1H), 7.88 (s, 2H), 7.29 (d, J = 7.1 Hz, 1H), 5.77 (s, 2H), 4.64 - 4.41 (m, 2H), 4.21 - 4.02 (m, 2H), 3.83 - 3.72 (m, 1H), 2.82 (s, 3H), 2.42 - 2.27 (m, 1H), 2.24 - 2.10 (m, 1H),2.04 - 1.62 (m, 4H), 1.39 (d, J = 6.8Hz, 3H), 1.12 - 0.97 (m, 1H), 0.73 - 0.60 (m, 1H), 0.53 - 0.32 (m, 3H). ESI MS [M+H] + C 26 H 31 Calculated for N6O3: 475.2; Found: 475.2.

[0258] Example 9: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-[(1S,3R)-3-hydroxycyclohexyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0259] The title compound was prepared in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-d6) δ 8.97 (d, J = 7.1 Hz, 1H), 8.21 (s, 1H), 8.11 - 8.08 (m, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 7.2 Hz, 1H), 4.56 (s, 2H), 3.89 (m, 1H), 3.64 - 3.52 (m, 2H), 2.69 (s, 3H),2.14 (d, J = 11.9 Hz, 1H), 1.90 (d, J = 11.7 Hz, 1H), 1.82 - 1.72 (s, 2H), 1.37 - 1.18 (m, 8H), 1.14 (m, 1H), 0.56 (m, 1H), 0.44 - 0.33 (m, 2H), 0.23 (m, 1H). ESI MS [M+H] + C 27 H 33 Calculated for N6O3: 489.2; Found: 489.2.

[0260] Example 10: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-[(3R)-5-oxopyrrolidin-3-yl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0261] The title compound was prepared in a similar manner to Example 1. 1H NMR(400 MHz,DMSO-d6) δ 8.99 (d, 7 = 7.1 Hz, 1H), 8.24 (d, J = 7.3 Hz, 1H), 8.16 (m ,1H), 8.04 (m, 1H), 7.77 (s, 1H), 7.64 (d, J = 7.2 Hz, 1H), 6.53 (s, 2H), 4.66 - 4.57 (m, 3H), 3.65 (dd, J = 10.1, 6.1 Hz,1H), 3.56 (m, 1H), 3.22 (m, 1H), 2.74 - 2.65 (m, 4H), 2.18 (dd, J = 16.7, 3.7 Hz, 1H), 1.28 (d, J = 6.8Hz, 3H), 1.11 (m, 1H), 0.56 (m, 1H), 0.44 - 0.34 (m, 2H), 0.22 (m, 1H). ESI MS [M+H] + C 25 H 28 Calculated for N7O3: 474.2; Found: 474.2.

[0262] Example 11: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-[(1R,3R)-3-hydroxycyclohexyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0263] The title compound was prepared in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-d6) δ 8.99 (d, J = 7.1 Hz, 1H), 8.12 (s, 1H), 8.01 (m, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H), 4.57 (s, 2H), 4.31 (s, 1H), 3.85 (s, 1H), 3.56 (m, 2H), 2.69 (s, 3H), 1.83 - 1.60 (m, 5H), 1.59 - 1.47 (m, 2H), 1.35 (m, 1H), 1.28 (d, J = 6.8 Hz, 3H), 1.13 (m, 1H), 0.56 (m, 1H), 0.45 - 0.33 (m, 2H), 0.23 (m, 1H). ESI MS [M+H] + C 27 H 33 Calculated for N6O3: 489.2; Found: 489.2.

[0264] Example 12: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-[trans-3-(hydroxymethyl)cyclobutyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0265] The title compound was prepared in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-d6) δ 9.01 (d, J = 7.1 Hz, 1H), 8.22 (s, 1H), 8.15 (d, J = 7.5 Hz, 1H), 8.12 (s, 1H), 7.65 (d, J = 7.1 Hz, 1H), 6.55 (s, 2H), 4.66 (t, J = 5.3 Hz, 1H), 4.60 (s, 2H), 4.54 - 4.42 (m, 1H), 3.64 - 3.54 (m, 1H), 3.51 (dd, J = 6.8, 5.3 Hz, 2H), 2.73 (s, 3H), 2.47 - 2.34 (m, 1H), 2.30 - 2.18 (m, 2H), 2.16 - 2.02 (m, 2H), 1.31 (d, J = 6.8 Hz, 3H), 1.26 - 1.09 (m, 1H), 0.66 - 0.53 (m, 1H), 0.50 - 0.32 (m, 2H), 0.30 - 0.19 (m, 1H). ESI MS [M+H] + C 26 H 31 Calculated for N6O3: 475.2; Found: 475.2.

[0266] Example 13: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-[trans-3-hydroxy-1-methylcyclobutyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0267] The title compound was prepared in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-d6) δ 9.01 (d, J = 7.1, 0.7 Hz, 1H), 8.19 (s, 1H), 8.09 (s, 1H), 8.00 (s, 1H), 7.64 (d, J = 7.2, 0.8 Hz, 1H), 6.56 (s, 2H), 5.09 (d, J = 5.9 Hz, 1H), 4.59 (s, 2H), 4.29 (q, J = 6.6 Hz, 1H), 3.65 - 3.53 (m, 1H), 2.76 - 2.64 (m, 5H), 2.05 - 1.94 (m, 2H), 1.58 (s, 3H), 1.31 (d, J = 6.8 Hz, 3H), 1.23 - 1.09 (m, 1H), 0.65 - 0.52 (m, 1H), 0.51 - 0.33 (m, 2H), 0.31 - 0.18 (m, 1H). ESI MS [M+H] + C 26 H 31 Calculated for N6O3: 475.2; Found: 475.2.

[0268] Example 14: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-[trans-3-(2-hydroxypropan-2-yl)cyclobutyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0269] The title compound was prepared in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 7.2 Hz, 1H), 8.27 - 8.16 (m, 2H), 8.12 (s, 1H), 7.65 (d, J = 7.2 Hz, 1H), 6.55 (s, 2H), 4.59 (s, 2H), 4.29 (s, 2H), 3.71 - 3.51 (m, 1H), 2.72 (d, J = 0.7 Hz, 3H), 2.49 - 2.36 (m, 3H), 2.00 - 1.84 (m, 2H), 1.30 (d, J = 6.8 Hz, 3H), 1.21 - 1.10 (m, 1H), 1.07 (s, 6H), 0.67 - 0.52 (m, 1H), 0.49 - 0.32 (m, 2H), 0.29 - 0.17 (m, 1H). ESI MS [M+H] + C 28 H 35 Calculated for N6O3: 503.3; Found: 503.2.

[0270] Example 15: m-[(5-{2-[(S)-1-cyclopropylethyl]-7-methyl-5-isoindolinolyl}-2-amino-1,4,7a-triaza-3-indenyl)carbonylamino]benzoic acid [ka]

[0271] The title compound was prepared in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-d6) δ 13.07 (s, 1H), 10.21 (s, 1H), 9.08 (d, J = 7.1 Hz, 1H), 8.30 (s, 1H), 8.17 (dq, J = 1.3, 10.2 Hz, 2H), 7.72 (d, J = 7.2 Hz, 1H), 7.66 (dt, J = 1.3, 7.7 Hz, 1H), 7.55 - 7.48 (m, 1H), 6.69 (s, 2H), 4.62 (s, 2H), 3.58 (dd, J = 6.8, 9.2 Hz, 1H), 2.76 (s, 3H), 1.31 (d, J = ESI MS [M+H] + C 28 H 26 Calculated for N6O4: 511.2; Found: 511.2.

[0272] Example 16: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0273] The title compound was prepared in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 9.05 (d, J = 7.1 Hz, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 8.10 (d, J = 0.6 Hz, 1H), 7.69 (d, J = 7.2 Hz, 1H), 7.65 (d, J = 0.7 Hz, 1H), 6.64 (s, 2H), 4.94 - 4.90 (m, 1H),4.64 (s, 2H), 4.15 (t, J = 5.6 Hz, 2H), 3.75 (q, J = 5.5 Hz, 2H), 3.60 (dq, J = 9.2, 6.8 Hz, ESI MS [M+H] + C 26 H 29 Calculated for N8O3: 501.2; Found: 501.1.

[0274] Example 17: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]pyrazolo]1,5-α]pyrimidine-3-carboxamide [ka]

[0275] The title compound was prepared in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 9.05 (d, J = 7.1 Hz, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 8.11 (d, J = 0.7 Hz, 1H), 7.69 (d, J = 7.2 Hz, 1H), 7.63 (d, J = 0.7 Hz, 1H), 6.64 (s, 2H), 4.72 (s, 1H), 4.64 (s, 2H), 4.02 (s, 2H), 3.60 (dq, J = 9.4, 6.8 Hz, 1H), 2.75 (s, 3H), 1.32 (d, J = 6.8 Hz, ESI MS [M+H] + C 28 H 33 Calculated for N8O3: 529.3; Found: 529.2.

[0276] Example 18: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0277] The title compound was prepared in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 9.05 (d, J = 7.1 Hz, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 8.06 (s, 1H), 7.69 (d, J = 7.2 Hz, 1H), 7.63 (s, 1H), 6.65 (s, 2H), 4.65 (s, 2H), 3.85 (s, 3H), 3.60 (dq, J = 9.3, 6.8 Hz, 1H), 2.75 (s, 3H), 1.32 (d, J = 6.8 Hz, 3H), 1.22 - 1.13 (m, 1H), 0.64 - 0.55 (m, 1H), 0.48 - 0.36 (m, 2H), 0.30 - 0.22 (m, 1H). ESI MS [M+H] + C 25 H 27 Calculated for N8O2: 471.2; Found: 471.2.

[0278] Example 19: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-(1,5-dimethyl-1H-pyrazol-4-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0279] The title compound was prepared in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 9.07 (d, J = 7.1 Hz, 1H), 8.23 ​​(s, 1H), 8.12 (s, 1H), 7.80 (s, 1H), 7.65 (d, J = 7.1 Hz, 1H), 6.66 (s, 2H), 4.58 (s, 2H), 3.76 (s, 3H), 3.64 - 3.51 (m, 1H), 2.72 (s, 3H), 2.36 (s, 3H), 1.31 (d, J = 6.8 Hz, 3H), 1.21 - 1.11 (m, 1H), 0.63 - 0.52 (m, 1H), 0.47 - 0.34 (m, 2H), 0.30 - 0.20 (m, 1H). ESI MS [M+H] + C 26 H 29 Calculated for N8O2: 485.2; Found: 485.2.

[0280] Example 20: 2-Amino-N-cyclopropyl-5-{2-[(1S)-1-cyclopropylethyl]-1-oxo-7-(trifluoromethoxy)-2,3-dihydro-1H-isoindol-5-yl}pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0281] Step a: A solution of 4-chloro-2-(trifluoromethoxy)aniline (25.0 g, 118 mmol) and NBS (21.0 g, 118 mmol) in CHCN (600 mL) was stirred at 50 °C for 1.5 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure to a volume of 50 mL. The residue was dissolved in EtOAc (400 mL) and washed successively with saturated aqueous NaSO (200 mL) and saturated brine (200 mL). The organic phase was separated and dried over NaSO. The solvent was then removed under reduced pressure, and the residue was purified by column chromatography (SiO, hexane / EtOAc gradient) to give 2-bromo-4-chloro-6-(trifluoromethoxy)aniline as a yellowish liquid (30.8 g, 94% yield). 1 H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 2.2 Hz, 1H), 7.13 (dq, J = 2.9, 1.5 Hz, 1H), 4.30 (br.s, 2H).

[0282] Step b: 2-Bromo-4-chloro-6-(trifluoromethoxy)aniline (30.8 g, 106 mmol), trimethylboroxine (14.9 mL, 106 mmol), and K2CO3 (44 g, 318 mmol) were mixed with dioxane (500 mL) and HO (50 mL). The resulting mixture was degassed under vacuum and refilled with N2. PdCl2(dppf) (2.6 g, 3.2 mmol) was then added, and the reaction mixture was maintained at 90 °C overnight. After complete conversion of the starting material was confirmed by TLC, the mixture was cooled to room temperature and concentrated to a volume of 100 mL. The residue was partitioned between EtOAc (500 mL) and HO (300 mL), the organic phase was separated, and the aqueous solution was extracted with EtOAc (2 × 150 mL). The combined organic phase was washed with saturated brine, dried over Na2SO4, and concentrated to dryness. The residue was purified by column chromatography (SiO2, hexane / EtOAc gradient) to give 20.7 g of an inseparable mixture of 4-chloro-2-methyl-6-(trifluoromethoxy)aniline and an unknown impurity (2:1 ratio, respectively). This material was used in the next step without further purification.

[0283] Step c: A solution of HBF (aq) (40 mL, 48 wt%) was added to a mixture of the product of step b (28.8 g) and HO (100 mL) in a round-bottom flask equipped with a mechanical stirrer at room temperature. The resulting suspension was cooled to 0 °C, and solid NaNO (9.7 g, 140 mmol) was added portionwise while maintaining the temperature below 5 °C. After the addition was complete, the mixture was stirred at 0 °C for 0.5 h, and the precipitate was then collected by filtration. (Note: Because the product is partially soluble in HO, further washing with HO should be avoided.) The precipitated diazonium salt was washed with MTBE (5 × 100 mL) and dried under vacuum for 0.5 h. The solid thus obtained was dissolved in CH3CN (500 mL), and then TMSCN (32.0 mL, 255 mmol) and Cu2O (4.4 g, 102 mmol) were added successively. After complete cessation of N2 production and complete consumption of starting material, 1The reaction mixture was stirred at 60 °C until confirmed by H NMR. The reaction mixture was filtered, and the filtrate was concentrated to dryness. The resulting crude product was dissolved in EtOAc, and the solution was passed through a plug of SiO. The solvent was removed under reduced pressure to give 4-chloro-2-methyl-6-(trifluoromethoxy)benzonitrile as a red oil (15.1 g, 49% yield). 1 H NMR (400 MHz, CDCl3) δ 7.31 - 7.25 (m, 1H), 7.26 - 7.19 (m, 1H), 2.57 (t, J = 0.7 Hz,3H).

[0284] Step d: A 1:1 solution of 4-chloro-2-methyl-6-(trifluoromethoxy)benzonitrile (3.25 g, 13.8 mmol) and NaOH (2.2 g, 55.2 mmol) in 50 mL of EtOH / HO was refluxed for 4 h. The solution was then cooled to room temperature and neutralized to acidic pH with 1 M aqueous HCl. The product was extracted with 3 × 70 mL of EtOAc. The combined organic phases were washed with saturated brine (150 mL), dried over NaSO, and concentrated to dryness under reduced pressure. The crude product was purified by column chromatography (SiO, hexane / EtOAc gradient) to afford 4-chloro-2-methyl-6-(trifluoromethoxy)benzamide (2.67 g, 76% yield) as a beige solid. 1H NMR (400 MHz, CDCl) δ 7.31-7.25 (m, 1H), 7.26-7.19 (m, 1H), 2.57 (t, J = 0.7 Hz, 3H). The solid thus obtained was suspended in 1:1 HSO / HO (80 mL) and cooled to 0 °C. A solution of NaNO (2.7 g, 39.4 mmol) in HO (10 mL) was then added portionwise over 10 min. After the addition was complete, the mixture was stirred at 100 °C for 1.5 h. Upon complete consumption of the starting material, the mixture was cooled to room temperature and diluted with CHCl (70 mL). The organic phase was separated, and the aqueous solution was further extracted with CHCl (2 × 70 mL). The combined organic solution was washed with HO, dried (NaSO), and concentrated to dryness under reduced pressure to give crude 4-chloro-2-methyl-6-(trifluoromethoxy)benzoic acid. This material was dissolved in acetone. KCO (11.0 g, 80 mmol) and MeI (3.5 mL, 56 mmol) were then added at room temperature, and the heterogeneous mixture was stirred at 55 °C for 2 h. Upon completion (monitored by TLC), the mixture was cooled to room temperature and concentrated to dryness. The residue was partitioned between EtOAc (60 mL) and HO (60 mL), the organic phase was separated, and the aqueous solution was further extracted with EtOAc (2 × 50 mL). The combined organic extracts were dried (NaSO) and concentrated to dryness. The crude product was purified by column chromatography to give methyl 4-chloro-2-methyl-6-(trifluoromethoxy)benzoate as a yellowish oil (3.73 g, 88% yield). 1 H NMR (400 MHz, CDCl3) δ 7.20 - 7.14 (m, 1H), 7.18 - 7.12 (m, 1H), 3.92 (s, 3H), 2.35 (t, J = 0.6 Hz,3H).

[0285] Step e. A mixture of methyl 4-chloro-2-methyl-6-(trifluoromethoxy)benzoate (3.7 g, 13.8 mmol), NBS (2.8 g, 15.8 mmol), and BPO (0.45 g, 0.14 mmol, containing 25 wt% HO) in CCl (55 mL) was refluxed overnight under N. The mixture was then cooled to room temperature and concentrated to dryness. The residue was dissolved in EtOAc (70 mL) and washed with HO (2 x 50 mL). The organic phase was dried over NaSO and concentrated to dryness to yield a mixture of starting material, desired product, and dibrominated by-product in a 1:3:1 ratio, respectively ( 1 1 H NMR analysis. This mixture was carried on to the next step without further purification.

[0286] Step f. The crude product from step e was dissolved in CHCN (55 mL), followed by the addition of (S)-1-cyclopropylethylamine (1.4 g, 16.5 mmol), KCO (5.7 g, 41.4 mmol), and B(OH) (0.85 g, 13.8 mmol). The mixture was stirred at 55 °C for 2 h. The mixture was cooled to room temperature and diluted with EtOAc (150 mL) and HO (150 mL). The organic phase was separated, and the aqueous solution was extracted with EtOAc (2 × 70 mL). The combined organic extracts were dried over NaSO and concentrated to dryness. The residue was purified by column chromatography to give (S)-5-chloro-2-(1-cyclopropylethyl)-7-(trifluoromethoxy)isoindolin-1-one as a white solid (2.45 g, 56% yield).

[0287] Step g. A mixture of the product of step f (1.0 g, 3.1 mmol), B2pin2 (0.87 g, 3.4 mmol), and KOAc (1.07 g, 10.9 mmol) in dioxane (16 mL) was degassed under vacuum and re-infused with N2. P(Cy)3PdG2 (185.0 mg, 0.31 mmol) was then added, and the reaction mixture was heated to 90 °C and maintained at that temperature for 1 h. Upon complete consumption of the starting material as determined by LCMS analysis, the mixture was cooled and concentrated under reduced pressure. The residue was partitioned between EtOAc (50 mL) and H2O (30 mL), the organic phase was separated, and the aqueous phase was extracted with EtOAc (2 × 35 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure to give the desired boronic acid pinacol ester, which was carried on to the next step without further purification. ESI MS [M+H] + C 14 H 14 Calculated value for F3NO2: 285.1; Measured value: 285.2.

[0288] Step h. The product of step g was dissolved in dioxane (31 mL). To this solution was added 2-amino-5-chloropyrazolo[1,5-α]pyrimidine-3-carboxylic acid ethyl ester (0.75 g, 3.1 mmol), followed by 12.4 mL of 1 M aqueous Na2CO3 and PdCl2(dppf) (227 mg, 0.31 mmol). The resulting mixture was refluxed for 1 h, then cooled to room temperature and diluted with EtOAc (150 mL) and H2O (100 mL). The organic phase was separated, and the aqueous phase was extracted with EtOAc (3 × 50 mL). The combined organic phases were dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified using column chromatography (SiO2, EtOAc) to give the desired product as a dark brown solid (1.2 g, 82% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.97 (d, J = 7.1 Hz,1H), 8.43 (s, 1H), 8.31 (s, 1H), 7.72 (d,J = 7.2 Hz,1H), 6.53 (s, 2H), 4.65 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 3.66 - 3.49 (m, 1H), 1.35 (t, J = 7.1 Hz,3H), 1.29 (d, J = 6.8 Hz,3H), 1.21 - 1.07 (m, 1H), 0.60 - 0.50 (m, 1H), 0.47 - 0.31 (m, 2H), 0.31 - 0.20 (m, 1H).

[0289] Step i. A mixture of the product from the previous step (1.0 g, 2.0 mmol) and TMSI (2.3 mL, 16.0 mmol) in DCE (10 mL) was placed in a sealed vial under N2 and stirred overnight at 80 °C in the dark. The mixture was then cooled to room temperature, diluted with DCE, and poured into 100 mL of 5% aqueous NaHSO3. The organic phase was separated, and the aqueous phase was further extracted with 10% i-PrOH in CHCl2 (4 × 70 mL). The combined organic phases were dried over NaSO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (SiO2, CHCl2 / MeOH gradient) to afford the desired carboxylic acid as a yellow solid (0.94 g, 67% yield). 1 H NMR (400 MHz, DMSO-d6) δ 12.15 (br. s, 1H), 8.98 (d ,J = 7.1 Hz,1H), 8.47 (s, 1H), 8.25 (s, 1H), 7.73 (d, J = 7.1 Hz, 1H), 6.53 (br. s, 2H), 4.68 (s, 2H), 3.74 - 3.27 (m, 1H), 1.28 (d, J = 6.8 Hz,3H), 1.18 - 1.10 (m, 1H), 0.64 - 0.50 (m, 1H), 0.46 - 0.31 (m, 2H), 0.30 - 0.18 (m, 1H).

[0290] Step j. was carried out in the same manner as in Example 1. 1 H NMR (400 MHz, DMSO-d6) δ 9.06 (d, J = 7.1 Hz, 1H), 8.43 (d, J = 1.3 Hz, 1H), 8.20 - 8.17 (m, 1H), 7.77 (d, J = 3.8 Hz, 1H), 7.69 (d, J = 7.1 Hz, 1H), 6.64 (s, 2H), 4.70 (s, 2H), 3.59 (dq, J = 9.3, 6.8 Hz, 1H), 2.87 (tt, J = 7.5, 3.8 Hz,1H), 1.32 (d, J = 6.9 Hz, 3H), 1.24 - 1.13 (m, 1H), 0.83 - 0.77 (m, 2H), 0.65 - 0.54 (m, 3H), 0.49 - 0.36 (m, 2H), 0.31 - 0.23 (m, 1H). ESI MS [M+H] + C 24 H 24 Calculated for F3N6O3: 501.2; Found: 501.1.

[0291] Example 21: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-1-oxo-7-(trifluoromethoxy)-2,3-dihydro-1H-isoindol-5-yl}-N-(oxetan-3-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0292] The title compound was prepared in a similar manner to Example 20. 1H NMR (400 MHz, DMSO-d6) δ 9.09 (d, J = 7.1 Hz, 1H), 8.51 (d, J = 1.2 Hz, 1H), 8.32 (t, J = 1.4 Hz, 1H), 8.24 (d, J = 6.6 Hz, 1H), 7.73 (d, J = 7.1 Hz, 1H), 6.63 (s, 2H), 5.07 (dt, J = 7.1, 6.3 Hz, 1H), 4.86 (dd, J = 7.4, 6.7 Hz, 2H), 4.71 (s, 2H), 4.59 (t, J = 6.6 Hz, 2H), 3.59 (dq, J = 9.3, 6.9 Hz, ESI MS [M+H] + C 24 H 24 Calculated for F3N6O4: 517.2; Found: 517.1.

[0293] Example 22: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-1-oxo-7-(trifluoromethoxy)-2,3-dihydro-1H-isoindol-5-yl}-N-[(2R)-1-hydroxypropan-2-yl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0294] The title compound was prepared in a similar manner to Example 20. 1H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 7.1 Hz, 1H), 8.58 (s, 1H), 8.23 ​​(s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 7.2 Hz, 1H), 6.60 (s, 2H), 4.66 (s, 2H), 4.06 (m, 1H), 3.60 - 3.47 (m, 4H), 1.30 (d, J = 6.8 Hz, 3H), 1.20 (d, J = 6.1 Hz, 3H), 1.14 (m, 1H), 0.57 (m, 1H), 0.45 - 0.33 (m, 2H), 0.24 (m, 1H). ESI MS [M+H] + C 24 H 26 Calculated for F3N6O4: 519.2; Found: 519.2.

[0295] Example 23: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-1-oxo-7-(trifluoromethoxy)-2,3-dihydro-1H-isoindol-5-yl}-N-[cis-3-hydroxy-3-methylcyclobutyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0296] The title compound was prepared in a similar manner to Example 20. 1H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 7.1 Hz, 1H), 8.45 (m, 1H), 8.20 (s, 1H), 7.84 (d, J = 7.2 Hz, 1H), 7.69 (d, J = 7.2 Hz, 1H), 6.60 (s, 2H), 4.68 (s, 2H), 4.07 - 3.97 (m, 2H), 3.57 (dd, J = 9.3, 6.8 Hz, 1H), 2.46 - 2.38 (m, 2H), 2.00 (t, J = 9.9 Hz, 2H), 1.33 - 1.24 (m, 6H), 1.15 (m, 1H), 0.57 (m, 1H), 0.45 - 0.34 (m, 2H), 0.25 (m, 1H). ESI MS [M+H] + C 24 H 28 Calculated for F3N6O4: 545.2; Found: 545.2.

[0297] Example 24: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-1-oxo-7-(trifluoromethoxy)-2,3-dihydro-1H-isoindol-5-yl}-N-[cis-4-hydroxy-4-methylcyclohexyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0298] The title compound was prepared in a similar manner to Example 20. 1H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 7.1 Hz, 1H), 8.44 (d, J = 1.2 Hz, 1H), 8.16 (t, J = 1.4 Hz, 1H), 7.69 (d, J = 7.2 Hz, 1H), 7.65 (d, J = 7.4 Hz, 1H), 6.64 (s, 2H), 4.69 (s, 2H), 4.10 (s, 1H), 3.82 - 3.70 (m, 1H), 3.59 (dq, J = 9.1, 6.7 Hz, 1H), 1.82 - 1.72 (m, 2H), 1.72 - 1.66 (m, 2H), 1.66 - 1.56 (m, 2H), 1.43 (td, J = 12.8, 4.2 Hz, 2H), 1.32 (d, J = 6.9 Hz, 3H), 1.23 - 1.16 (m, 1H), 1.15 (s, 3H), 0.64 - 0.55 (m, 1H), 0.49 - 0.35 (m, 2H), 0.31 - 0.23 (m, 1H). ESI MS [M+H] + C 28 H 32 Calculated for F3N6O4: 573.2; Found: 573.1.

[0299] Example 25: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-1-oxo-7-(trifluoromethoxy)-2,3-dihydro-1H-isoindol-5-yl}-N-[(2R)-1-hydroxy-3-methylbutan-2-yl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0300] The title compound was prepared in a similar manner to Example 20. 1H NMR (400 MHz, DMSO-d6) δ 9.04 (d, J = 7.1 Hz, 1H), 8.52 (d, J = 1.3 Hz, 1H), 8.23 ​​- 8.15 (m, 1H), 7.97 (d, J = 9.3 Hz, 1H), 7.69 (d, J = 7.1 Hz, 1H), 6.61 (s, 2H), 4.60 (s, 2H), 3.86 (dq, J = 10.2, 4.9 Hz, 1H), 3.63 (d, J = 6.6 Hz, 1H), 3.58 - 3.54 (m, 1H), 3.48 (dd, J = 10.9, 5.0Hz, 1H), 2.00 (h, J = 6.8 Hz, 1H), 1.30 (d, J = 6.8 Hz, 3H), 1.19 - 1.06 (m, 1H), 0.94 (dd, J = 6.8, 0.9 Hz, 6H), 0.62 - 0.50 (m, 1H), 0.47 - 0.33 (m, 2H), 0.30 - 0.16 (m, 1H). ESI MS [M+H] + C 26 H 30 Calculated for F3N6O4: 547.2; Found: 547.2.

[0301] Example 26: 2-amino-N-[(1R)-1-cyclopropyl-2-hydroxyethyl]-5-{2-[(1S)-1-cyclopropylethyl]-1-oxo-7-(trifluoromethoxy)-2,3-dihydro-1H-isoindol-5-yl}pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0302] The title compound was prepared in a similar manner to Example 20. 1H NMR (400 MHz, DMSO-d6) δ 9.04 (d, J = 7.1 Hz, 1H), 8.61 (d, J = 1.3 Hz, 1H), 8.26 - 8.21 (m, 2H), 7.72 (d, J = 7.2 Hz, 1H), 6.59 (s, 2H), 4.66 (s, 2H), 3.68 (dd, J = 10.5, 3.5 Hz, 1H), 3.62 - 3.52 (m, 2H), 3.52 - 3.44 (m, 1H), 1.30 (d, J = 6.8 Hz, 3H), 1.19 - 1.09 (m, 2H), 0.60 - 0.53 (m, 1H), 0.46 - 0.34 (m, 5H), 0.30 - 0.21 (m, 2H). ESI MS [M+H] + C 26 H 28 Calculated for F3N6O4: 545.2; Found: 545.2.

[0303] Example 27: 2-amino-N-[(2R)-1-hydroxypropan-2-yl]-5-[1-oxo-7-(trifluoromethoxy)-2-[(2S)-1,1,1-trifluoropropan-2-yl]-2,3-dihydro-1H-isoindol-5-yl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0304] Steps a and b: Step a was carried out in the same manner as step e of Example 1. The product of step a (500 mg, 1.44 mmol, 1.0 equiv.) was dissolved in CH3CN (5.8 mL), and (S)-trifluoro-2-propylamine (179 mg, 1.58 mmol, 1.1 equiv.) and K2CO3 (597 mg, 4.32 mmol, 3.0 equiv.) were added sequentially. The reaction mixture was stirred at 80 °C for 16 h and then partitioned between HO and EtOAc. The organic layer was separated and washed with saturated aqueous NaHCO3, dried over Na2SO4, and concentrated. The residue was then heated at 120 °C for 4 h without water. Purification by column chromatography (12% EtOAc gradient in hexane) afforded the desired compound as a yellow solid (152 mg, 30%).

[0305] Steps c, d, e, and f. The same procedure as in Example 20 was carried out to give the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 7.1 Hz, 1H), 8.61 (d, J = 1.3 Hz, 1H), 8.28 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 7.2 Hz, 1H), 6.61 (s, 2H), 5.04 (p, J = 7.6 Hz, 1H), 4.76 (d, J = 17.8 Hz, 1H), 4.55 (d, J = 17.7 Hz, 1H), 4.10 - 4.01 (m, 1H), 3.54 - 3.50 (m, 2H), 1.51 (d, J = 7.1 Hz, 3H), 1.20 (d, J = 6.6 Hz, 3H). ESI MS [M+H] + C 22 H 21 Calculated for F6N6O4: 547.2; Found: 547.2.

[0306] Example 28: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-1-oxo-7-(trifluoromethoxy)-2,3-dihydro-1H-isoindol-5-yl}-N-[(3R)-5-oxopyrrolidin-3-yl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0307] The title compound was prepared in a similar manner to Example 20. 1 H NMR (400 MHz, DMSO-d6) δ 9.04 (d, J = 7.1 Hz, 1H), 8.39 (m, 1H), 8.20 (m, 1H), 8.06 (d, J = 7.4 Hz, 1H), 7.76 (s, 1H), 7.70 (d, J = 7.2 Hz, 1H), 4.70 (d, J = 2.0 Hz, 2H), 4.63 (m, 1H), 3.69 - 3.50 (m, 2H), 3.19 (dd, J = 9.8, 4.4 Hz, 1H), 2.63 (dd, J = 16.6, 7.9 Hz, 1H), 2.21 (dd, J = 16.5, 5.3 Hz, 1H), 1.30 (d, J = 6.8 Hz, 3H), 1.13 (m, 1H), 0.58 (m, 1H), 0.45 - 0.33 (m, 2H), 0.25 (m, 1H). + C 25 H 25 Calculated for F3N7O4: 544.2; Found: 544.2.

[0308] Example 29: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-1-oxo-7-(trifluoromethoxy)-2,3-dihydro-1H-isoindol-5-yl}-N-[(1S,3R)-3-hydroxycyclohexyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0309] The title compound was prepared in a similar manner to Example 20. 1 HNMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 7.1 Hz, 1H), 8.47 (d, J = 1.3 Hz, 1H), 8.19 (t, J = 1.5 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 7.2 Hz, 1H), 6.61 (s, 2H), 4.66 (s, 2H), 3.98 - 3.84 (m, 1H), 3.62 - 3.52 (m, 2H), 2.14 - 2.06 (m, 1H), 1.87 - 1.70 (m, 3H), 1.35 - 1.27 (m, 1H), 1.29 (d, J ESI MS [M+H] + C 27 H 30 Calculated for F3N6O4: 559.2; Found: 559.2.

[0310] Example 30: 2-amino-5-(2-((S)-1-cyclopropylethyl)-1-oxo-7-(trifluoromethoxy)isoindolin-5-yl)-N-(trans-4-(1-hydroxycyclopropyl)cyclohexyl)pyrazolo[1,5-α]pyrimidine-3-carboxamide. [ka]

[0311] The title compound was prepared in a similar manner to Example 20. 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 7.1 HZ, 1H), 8.04 (s, 1H), 7.92 (s, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.19 (d, J = 7.1 Hz, 1H), 5.77 (br. s, 2H), 4.64 (d, J = 17.5 Hz, 1H), 4.53 (d, J = 17.5 Hz, 1H), 4.07 - 3.87 (m, 1H), 3.84 - 3.64 (m, 1H), 2.32 - 2.17 (m, 2H), 1.96 - 1.82 (m, 2H), 1.61 - 1.43 (m, 2H), 1.38 (d, J = 6.8 Hz, 3H), 1.37 - 1.22 (m, 2H), 1.12 - 0.97 (m, 2H), 0.78 - 0.71 (m, 2H), 0.70 - 0.61 (m, 1H), 0.52 - 0.38 (m, 5H). 19 F NMR (376 MHz, CDCl3) δ - 57.34. ESI MS [M+H] + C 30 H 34 Calculated for F3N6O4: 599.3; Found: 599.1.

[0312] Example 31: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-1-oxo-7-(trifluoromethoxy)-2,3-dihydro-1H-isoindol-5-yl}-N-[trans-4-aminocyclohexyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0313] The title compound was prepared in a similar manner to Example 20. 1HNMR (400 MHz, DMSO-d6) δ 9.06 (d, J = 7.1 Hz, 1H), 8.41 (s, 1H), 8.15 (m, 1H), 7.83 (d, J = 4.7 Hz, 2H), 7.67 (d, J = 7.2 Hz, 1H), 7.62 (d, J = 7.5 Hz, 1H), 6.61 (s, 2H), 4.65 (s, 2H), 3.73 (m, 1H), 3.55 (m, 1H), 2.99 (m, 1H), 2.10 (d, J = 11.4 Hz, 2H), 1.98 (d, J = 11.7 Hz, 2H), 1.52 - 1.32 (m, ESI MS [M+H] + C 27 H 31 Calculated for F3N7O3: 558.2; Found: 558.2.

[0314] Example 32: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-1-oxo-7-(trifluoromethoxy)-2,3-dihydro-1H-isoindol-5-yl}-N-[(3S)-2-oxopyrrolidin-3-yl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0315] The title compound was prepared in a similar manner to Example 20. 1H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 7.1 Hz, 1H), 8.63 (s, 1H), 8.29 (s, 1H), 8.26 (d, J = 5.2 Hz, 1H), 8.05 (m, 1H), 7.73 (d, J = 7.2 Hz, 1H), 6.60 (s, 2H), 4.65 (s, 2H), 4.37 (ddd, J = 10.9, 8.1, 5.2 Hz, 1H), 3.57 (m, 1H), 3.29 - 3.22 (m, 2H), 2.63 (m, 1H), 1.90 (m, 1H), 1.29 (d, J = 6.8 Hz, 3H), 1.13 (m, 1H), 0.57 (m, 1H), 0.45 - 0.34 (m, 2H), 0.24 (m, 1H). ESI MS [M+H] + C 25 H 25 Calculated for F3N7O4: 544.2; Found: 544.2.

[0316] Example 33: 2-amino-N-[(1R,3S)-3-aminocyclohexyl]-5-{2-[(1S)-1-cyclopropylethyl]-1-oxo-7-(trifluoromethoxy)-2,3-dihydro-1H-isoindol-5-yl}pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0317] The title compound was prepared in a similar manner to Example 20. 1H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 7.1 Hz, 1H), 8.39 (m, 1H), 8.20 - 8.14 (m, 3H), 7.68 (dd, J = 7.4, 5.3 Hz, 2H), 4.73 (s, 2H), 3.85 (m, 1H), 3.55 (m, 1H), 3.14 (s, 1H), 2.39 (d, J = 11.6 Hz, 1H), 2.02 - 1.91 (m, 2H), 1.80 (d, J = 12.9 Hz, 1H), 1.51 - 1.10 (m, 8H), 0.56 (m, 1H), 0.44 - 0.34 (m, 2H), 0.23 (m, 1H). ESI MS [M+H] + C 27 H 31 Calculated for F3N7O3: 558.2; Found: 558.2.

[0318] Example 34: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-1-oxo-7-(trifluoromethoxy)-2,3-dihydro-1H-isoindol-5-yl}-N-[(1R,3S)-3-(dimethylamino)cyclohexyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0319] The title compound was prepared in a similar manner to Example 20. 1H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 9.06 (d, J = 7.1 Hz, 1H), 8.43 (s, 1H), 8.18 (s, 1H), 7.76 - 7.67 (m, 2H), 4.71 (s, 1H), 3.90 (m, 1H), 3.55 (m, 1H), 3.33 (t, J = 11.5 Hz, 1H), 2.69 (d, J = 5.0 Hz, 6H), 2.06 (m, 1H), 1.99 (d, J = 12.4 Hz, 1H), 1.87 (m, 1H), 1.55 - 1.32 (m, 4H), 1.29 (d, ESI MS [M+H] + C 29 H 35 Calculated for F3N7O3: 586.3; Found: 586.2.

[0320] Example 35: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-1-oxo-7-(trifluoromethoxy)-2,3-dihydro-1H-isoindol-5-yl}-N-[(1R,2R)-2-hydroxycyclopentyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0321] The title compound was prepared in a similar manner to Example 20. 1H NMR (400 MHz, DMSO-d6) δ 9.08 (d, J = 7.1 Hz, 1H), 8.43 (d, J = 1.3 Hz, 1H), 8.17 - 8.12 (m, 1H), 7.74 - 7.68 (m, 2H), 6.64 (s, 2H), 4.69 (s, 2H), 4.11 - 4.02 (m, 1H), 4.00 - 3.95 (m, 1H), 3.63 - 3.53 (m, 1H), 2.20 - 2.10 (m, 1H), 1.94 - 1.83 (m, 1H), 1.84 - 1.65 (m, 2H), 1.62 - 1.45 (m, ESI MS [M+H] + C 26 H 28 Calculated for F3N6O4: 545.2; Found: 545.2.

[0322] Example 36: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-1-oxo-7-(trifluoromethoxy)-2,3-dihydro-1H-isoindol-5-yl}-N-[(1S,3S)-3-hydroxycyclopentyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0323] The title compound was prepared in a similar manner to Example 20. 1H NMR (400 MHz, DMSO-d6) δ 9.06 (d, J = 7.1 Hz, 1H), 8.43 (d, J = 1.3 Hz, 1H), 8.18 - 8.14 (m, 1H), 7.72 (d, J = 7.5 Hz, 1H), 7.68 (d, J = 7.2 Hz, 1H), 6.63 (s, 2H), 4.69 (s, 2H), 4.48 (h, J = 7.4 Hz, 1H), 4.29 - 4.24 (m, 1H), 3.62 - 3.55 (m, 1H), 2.24 - 2.11 (m, 1H), 2.02 - 1.90 (m, 2H), 1.66 (ddd, J = 13.4, 7.6, 5.8 Hz, 1H), 1.60 - 1.41 (m, 2H), 1.32 (d, J = 6.8 Hz, 3H), 1.24 - 1.09 (m, 1H), 0.63 - 0.54 (m, 1H), 0.47 - 0.35 (m, 2H), 0.30 - 0.23 (m, 1H). ESI MS [M+H] + C 26 H 28 Calculated for F3N6O4: 545.2; Found: 545.2.

[0324] Example 37: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-1-oxo-7-(trifluoromethoxy)-2,3-dihydro-1H-isoindol-5-yl}-N-[(1R,3R)-3-hydroxycyclopentyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0325] The title compound was prepared in a similar manner to Example 20. 1H NMR (400 MHz, DMSO-d6) δ 9.06 (d, J = 7.1 Hz, 1H), 8.43 (d, J = 1.2 Hz, 1H), 8.16 (t, J = 1.4 Hz, 1H), 7.72 (d, J = 7.5 Hz, 1H), 7.68 (d, J = 7.2 Hz, 1H), 6.62 (s, 2H), 4.69 (s, 2H), 4.48 (h, J = 7.4 Hz, 1H), 4.28 - 4.23 (m, 1H), 3.63 - 3.53 (m, 1H), 2.27 - 2.13 (m, 1H), 2.04 - 1.90 (m, 2H), 1.66 (ddd, J = 13.3, 7.7, 5.9 Hz, 1H), 1.61 - 1.41 (m, 2H), 1.32 (d, J = 6.8 Hz, 3H), 1.24 - 1.13 (m, 1H), 0.63 - 0.55 (m, 1H), 0.48 - 0.36 (m, 2H), 0.30 - 0.23 (m, 1H). ESI MS [M+H] + C 26 H 28 Calculated for F3N6O4: 545.2; Found: 545.2.

[0326] Example 38: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-1-oxo-7-(trifluoromethoxy)-2,3-dihydro-1H-isoindol-5-yl}-N-[(3R,4S)-4-hydroxyoxolan-3-yl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0327] The title compound was prepared in a similar manner to Example 20. 1H NMR (400 MHz, DMSO-d6) δ 9.08 (d, J = 7.1 Hz, 1H), 8.46 (d, J = 1.3 Hz, 1H), 8.20 - 8.16 (m, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.72 (d, J = 7.2 Hz, 1H), 6.63 (s, 2H), 4.68 (s, 2H), 4.33 - 4.27 (m, 1H), 4.23 - 4.19 (m, 1H), 4.01 (td, J = 9.2, 4.6 Hz, 2H), 3.71 (dd, J = 9.0, 1.9 Hz, 1H), 3.63 - 3.56 ESI MS [M+H] + C 25 H 26 Calculated for F3N6O5: 547.2; Found: 547.2.

[0328] Example 39: 5-{2-[(S)-1-cyclopropylethyl]-7-trifluoromethoxy-5-isoindolinoyl}-2-amino-1,4,7α-triaza-3-indenecarboxamide [ka]

[0329] Step a: A solution of the carboxylic acid (55 mg, 0.12 mmol) and CDI (29.2 mg, 1.8 mmol, 1.5 equiv) in NMP (1.2 mL) was heated at 40 °C for 2 h. Upon complete consumption of the starting material, NHOAc (74 mg, 0.96 mmol, 8 equiv) and EtN (88 μL, 0.72 mmol, 6 equiv) were added, and the reaction was heated at 80 °C overnight. The reaction mixture was cooled to room temperature, and 30 mL of HO was added, causing the yellow product to precipitate from solution. The solid was further purified by flash chromatography (SiO, 0% to 10% MeOH / CHCl gradient). Yield: 41.3 mg (75%). 1 H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 7.1 Hz, 1H), 8.51 (s, 1H), 8.19 (s, 1H), 7.68 (d, J = 7.2 Hz, 1H), 7.41 (s, 1H), 7.31 (s, 1H), 6.63 (s, 2H), 4.68 (s, 2H), 3.64 - 3.48 (m, 1H), 1.28 (d, J = 6.8 Hz, 3H), 1.21 - 1.07 (m, 1H), 0.60 - 0.54 (m, 1H), 0.45 - 0.32 (m, 2H), 0.29 - 0.19 (m, 1H). ESI MS [M+H] + C 21 H 19 Calculated for F3N6O3: 461.1; Found: 461.1.

[0330] Example 40: (S)-2-amino-5-(2-(1-cyclopropylethyl)-1-oxo-7-(trifluoromethoxy)isoindolin-5-yl)-N-(pyridin-4-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide. [ka]

[0331] The title compound was prepared in a similar manner to Examples 20 and 99 (see below). 1H NMR (400 MHz, CD3OD) δ 8.84 (d, J = 7.1 Hz, 1H), 8.61 (d, J = 6.6 Hz, 2H), 8.36 (s, 1H), 8.25 (s, 1H), 8.19 (d, J = 6.6 Hz, 2H), 7.66 (d, J = 7.1 Hz, 1H), 4.81 (d, J = 18.5 Hz, 1H), 4.75 (d, J = 18.5 Hz, 1H), 3.76 - 3.60 (m, 1H), 1.44 (d, J = 6.9 Hz, 3H), 1.25 - 1.14 (m, 1H), 0.79 - 0.61 (m, 1H), 0.59 - 0.49 (m, 1H), 0.48 - 0.41 (m, 1H), 0.42 - 0.33 (m, 1H). 19 F NMR (376 MHz, CD3OD) δ - 58.93. ESI MS [M+H] + C 26 H 23 Calculated for F3N7O3: 538.2; Found: 538.1.

[0332] Example 41: (S)-2-amino-5-(2-(1-cyclopropylethyl)-1-oxo-7-(trifluoromethoxy)isoindolin-5-yl)-N-(pyridin-3-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide. [ka]

[0333] The title compound was prepared in a similar manner to Example 40. 1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 9.14 (d, J = 7.1 Hz, 1H), 8.86 (dd, J = 2.7, 0.7 Hz, 1H), 8.53 (s, 1H), 8.37 (s, 1H), 8.30 (dd, J = 4.7, 1.5 Hz, 1H), 8.21 (ddd, J = 8.4, 2.6, 1.5 Hz, 1H), 7.78 (d, J = 7.2 Hz, 1H), 7.40 (ddd, J = 8.3, 4.7, 0.7 Hz, 1H), 6.77 (br. s, 2H), 4.72 (s, 2H), 3.65 - 3.51 (m, 1H), 1.33 (d, J = 6.8 Hz, 3H), 1.27 - 1.10 (m, 1H), 0.66 - 0.53 (m, 1H), 0.48 - 0.35 (m, 2H), 0.32 - 0.22 (m, 1H). 19 F NMR (376 MHz, DMSO-d6) δ - 56.75. ESI MS [M+H] + C 26 H 23 Calculated for F3N7O3: 538.2; Found: 538.2.

[0334] Example 42: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-1-oxo-7-(trifluoromethoxy)-2,3-dihydro-1H-isoindol-5-yl}-N-(5-fluoropyridin-3-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0335] The title compound was synthesized using a procedure similar to that described in Example 40. 1H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 9.12 (d, J = 7.1 Hz, 1H), 8.66 (t, J = 1.8 Hz, 1H), 8.50 (d, J = 1.3 Hz, 1H), 8.37 (s, 1H), 8.28 (dd, J = 2.6, 0.5 Hz, 1H), 8.18 (ddd, J = 11.4, 2.7, 2.1 Hz, 1H), 7.77 (d, J = 7.2 Hz, 1H), 6.75 (s, 2H), 4.69 (s, 2H), 3.71 - 3.47 (m, 1H), 1.30 (d, J = 6.9 Hz, ESI MS [M+H] + C 26 H 21 Calculated for F4N7O3: 556.2; Found: 556.1.

[0336] Example 43: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-1-oxo-7-(trifluoromethoxy)-2,3-dihydro-1H-isoindol-5-yl}-N-(5-methoxypyridin-3-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0337] The title compound was synthesized using a procedure similar to that described in Example 40. 1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 9.11 (d, J = 7.1 Hz, 1H), 8.51 (d, J = 1.3 Hz, 1H), 8.42 (d, J = 2.0 Hz, 1H), 8.33 (t, J = 1.4 Hz, 1H), 8.01 (d, J = 2.6 Hz, 1H), 7.90 (dd, J = 2.6, 2.1 Hz, 1H), 7.76 (d, J = 7.2 Hz, 1H), 6.75 (s, 2H), 4.68 (s, 2H), 3.85 (s, 3H), 3.64 - 3.52 (m, 1H), 1.30 (d, J ESI MS [MH] - C 27 H 24 Calculated for F3N7O4: 568.2; Found: 568.1.

[0338] Example 44: 2-[(S)-1-Cyclopropylethyl]-5-{2-amino-3-[(2-methyl-3-pyridylamino)carbonyl]-1,4,7α-triaza-5-indenyl}-7-trifluoromethoxy-1-isoindolinone [ka]

[0339] The title compound was prepared in a similar manner to Example 40. 1H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 9.16 (d, J = 7.1 Hz, 1H), 8.89 (d, J = 8.3 Hz, 1H), 8.49 (d, J = 1.3 Hz, 1H), 8.39 (dd, J = 1.4, 5.3 Hz, 1H), 8.21 (t, J = 1.3 Hz, 1H), 7.72 (d, J = 7.1 Hz, 1H), 7.68 - 7.60 (m, 1H), 6.81 (br., 2H), 4.66 (s, 2H), 3.64 - 3.51 (m, 1H), 2.69 (s, 3H), 1.30 (d, J = ESI MS [M+H] + C 27 H 24 Calculated for F3N7O3: 552.2; Found: 552.2.

[0340] Example 45: 2-[(S)-1-Cyclopropylethyl]-5-{2-amino-3-[(6-methyl-3-pyridylamino)carbonyl]-1,4,7α-triaza-5-indenyl}-7-trifluoromethoxy-1-isoindolinone [ka]

[0341] The title compound was prepared in a similar manner to Example 40. 1H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 9.14 (d, J = 7.1 Hz, 1H), 9.02 (s, 1H), 8.53 (d, J = 1.3 Hz, 1H), 8.39 (s, 1H), 8.30 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 7.1 Hz, 1H), 7.62 (d, J = 8.3 Hz, 1H), 6.77 (br, 2H), 4.70 (s, 2H), 3.32 - 3.23 (m, 1H), 2.57 (s, 3H), 1.31 (d, J = 6.8 Hz, 3H), 1.22 - 1.10 (m, 1H), 0.57 (dq, J = 3.4, 3.8, 8.6 Hz, 1H), 0.40 (ddq, J = 5.2, 9.3, 14.3 Hz, 2H), 0.30 - 0.20 (m, 1H). ESI MS [M+H] + C 27 H 24 Calculated for F3N7O3: 552.2; Found: 552.2.

[0342] Example 46: 2-[(S)-1-Cyclopropylthyl]-5-{2-amino-3-[(6-amino-3-pyridylamino)carbonyl]-1,4,7α-triaza-5-indenyl}-7-trifluoromethoxy-1-isoindolinone [ka]

[0343] The title compound was prepared in a similar manner to Example 40. 1H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 9.13 (d, J = 7.1 Hz, 1H), 8.51 (dd, J = 1.8, 10.7 Hz, 2H), 8.36 (s, 1H), 7.99 (dd, J = 2.5, 9.4 Hz, 1H), 7.77 (d, J = 7.2 Hz, 1H), 6.96 (d, J = 9.5 Hz, 1H), 6.71 (br., 2H), 4.69 (s, 2H), 3.64 - 3.51 (m, 1H), 1.30 (d, J = 6.8 Hz, 3H), 1.14 (ddt, J = 4.4, 8.5, 13.0 Hz, 1H), 0.62 - 0.52 (m, 1H), 0.47 - 0.33 (m, 2H), 0.30 - 0.20 (m, 1H). + C 26 H 23 Calculated for F3N8O3: 553.2; Found: 553.2.

[0344] Example 47: (S)-2-amino-5-(2-(1-cyclopropylethyl)-1-oxo-7-(trifluoromethoxy)isoindolin-5-yl)-N-(4-methylpyridin-3-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide. [ka]

[0345] The title compound was prepared in a similar manner to Example 40. 1H NMR (400 MHz, CDCl3) δ 9.35 (s, 1H), 9.26 (s, 1H), 8.59 (d, J = 7.0 Hz, 1H), 8.30 (d, J = 4.9 Hz, 1H), 8.00 (s, 1H), 7.88 (s, 1H), 7.23 (d, J = 7.0 Hz, 1H), 7.17 (d, J = 4.9 Hz, 1H), 5.86 (br. s, 2H), 4.62 (d, J = 17.6 Hz, 1H), 4.51 (d, J = 17.7 Hz, 1H), 3.85 - 3.65 (m, 1H), 2.38 (s, 3H), 1.37 (d, J = 6.8 Hz, 3H), 1.08 - 0.93 (m, 1H), 0.76 - 0.57 (m, 1H), 0.52 - 0.30 (m, 3H). 19 F NMR (376 MHz, CDCl3) δ - 57.51. ESI MS [M+H] + C 27 H 25 Calculated for F3N7O3: 552.2; Found: 552.2.

[0346] Example 48: (S)-2-amino-5-(2-(1-cyclopropylethyl)-1-oxo-7-(trifluoromethoxy)isoindolin-5-yl)-N-(4-methoxypyridin-3-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0347] The title compound was prepared in a similar manner to Example 40. 1H NMR (400 MHz, CDCl3) δ 9.85 (s, 1H), 9.65 (s, 1H), 8.55 (d, J = 7.1 Hz, 1H), 8.29 (d, J = 5.5 Hz, 1H), 8.15 (s, 1H), 8.06 (s, 1H), 7.26 (d, J = 7.1 Hz, 1H), 6.88 (d, J = 5.5 Hz, 1H), 5.86 (s, 2H), 4.65 (d, J = 17.5 Hz, 1H), 4.54 (d, J = 17.5 Hz, 1H), 3.90 (s, 3H), 3.85 - 3.65 (m, 1H), 1.38 (d, J = 6.8 Hz, 3H), 1.09 - 0.97 (m, 1H), 0.72 - 0.62 (m, 1H), 0.55 - 0.36 (m, 3H). 19 F NMR (376 MHz, CDCl3) δ - 57.66. ESI MS [M+H] + C 27 H 25 Calculated for F3N7O4: 568.2; Found: 568.2.

[0348] Example 49: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-1-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-isoindol-5-yl}-N-[(3S)-2-oxopyrrolidin-3-yl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0349] Step a: A mixture of 4-chloro-2-(trifluoromethyl)benzoic acid (20.0 g, 89 mmol), (S)-1-cyclopropylethan-1-amine (9.32 g, 107 mmol, 1.2 equiv), HATU (40.7 g, 107 mmol, 1.2 equiv), and DIPEA (48 mL, 267 mmol, 3 equiv) in anhydrous DMF (297 mL) was stirred for 2 h at 23 °C. The reaction mixture was quenched with saturated NH4Cl, extracted with EtOAc, evaporated, and the crude product was purified by column chromatography (0–40% EtOAc gradient in hexanes) to give the product as a white solid in 98% yield (25.5 g).

[0350] Step b: The product of step a (8.20 g, 28 mmol) was dissolved in THF (140 mL) and cooled to −78°C, followed by the dropwise addition of sec-butyllithium (1.4 M in cyclohexane, 50 mL, 70 mmol, 2.5 equiv.). After 20 min at −78°C, DMF (10.8 mL, 140 mmol, 5.0 equiv.) was added dropwise. The reaction mixture was stirred at −78°C for 1 h, then carefully quenched with saturated NH4Cl and extracted with EtOAc. The crude product was then dissolved in CHCl (90 mL), EtSiH (4.5 mL), and TFA (45 mL) at 0°C, and the reaction mixture was stirred at 23°C for 20 min. The reaction mixture was evaporated, quenched with saturated NaHCO3, and extracted with CHCl. The crude mixture was purified by column chromatography (0-30% gradient of EtOAc in hexanes) to give the product as a white solid in 84% yield (7.15 g).

[0351] Step c: A mixture of the product from step b (6.64 g, 21.9 mmol), B2pin2 (6.11 g, 24.0 mmol, 1.1 equiv), KOAc (7.52 g, 76.7 mmol, 3.5 equiv), and PCy3Pd G2 (1.29 g, 2.19 mmol, 0.1 equiv) in anhydrous dioxane (109 mL) was stirred at 100 °C for 1 h. The reaction mixture was filtered and evaporated, and the crude product was purified by column chromatography (0–30% gradient of EtOAc in hexanes) to give the product as a brown solid in 94% yield (8.80 g).

[0352] Step d: A mixture of the product from step c (7.10 g, 18 mmol), 2-amino-5-chloropyrazolo[1,5-α]pyrimidine-3-carboxylic acid ethyl ester (4.31 g, 18 mmol, 1 equiv), 1 M NaCO (72 mL, 72 mmol, 4 equiv), and PdCl(dppf) (658 mg, 0.90 mmol, 0.05 equiv) in anhydrous dioxane (90 mL) was stirred at 100 °C for 1 h. The reaction mixture was quenched with saturated NaCl, extracted with EtOAc, evaporated, and the crude product was purified by column chromatography (30–100% gradient of EtOAc in hexanes) to give the product as a brown solid (5.77 g) in 68% yield.

[0353] Step e: A mixture of the product from step d (5.77 g, 12.2 mmol) and TMSI (12.2 mL, 85.4 mmol, 7 equiv.) in anhydrous CHCN (61 mL) was stirred at 80 °C for 15 h. The reaction mixture was quenched with saturated sodium bisulfite, extracted with CHCl:MeOH (9:1), and evaporated. The crude product was triturated with MTBE and filtered to give the product as a yellow solid in 59% yield (3.23 g).

[0354] Step f: A mixture of the product from step e (60 mg, 0.13 mmol), amine (0.20 mmol, 1.5 equiv), EDCI·HCl (38 mg, 0.20 mmol, 1.5 equiv), HOBt (31 mg, 0.20 mmol, 1.5 equiv), and DIPEA (70 μL, 0.39 mmol, 3 equiv) in anhydrous DMF (1.3 mL) was stirred for 2 h at 23 °C. The reaction mixture was quenched with saturated aqueous NaCl, extracted with EtOAc, evaporated, and the crude product was purified by reverse-phase HPLC (C18 column, 10–90% gradient of CH3CN and HO with 0.1% TFA) to give the product as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 7.1 Hz, 1H), 8.90 (s, 1H), 8.58 (s, 1H), 8.27 (d, J = 5.3 Hz, 1H), 8.06 (s, 1H), 7.81 (d, J = 7.2 Hz, 1H), 6.61 (s, 2H), 4.69 (s, 2H), 4.37 (ddd, J = 10.8, 8.1, 5.3 Hz, 1H), 3.58 (m, 1H), 3.29 - 3.23 (m, 2H), 2.71 - 2.60 (m, 1H), 1.92 (m, 1H), 1.31 (d, J = 6.8 Hz, 3H), 1.15 (m, 1H), 0.58 (m, 1H), 0.47 - 0.34 (m, 2H), 0.26 (m, 1H). + C 25 H 25 Calculated for F3N7O3: 528.2; Found: 528.2.

[0355] Example 50: 5-(3-{[(R)-2-hydroxy-1-methylethylamino]carbonyl}-2-amino-1,4,7α-triaza-5-indenyl)-2-[(S)-1-cyclopropylethyl]-7-(trifluoromethyl)-1-isoindolinone [ka]

[0356] The title compound was prepared in a similar manner to Example 49. 1 H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 7.1 Hz, 1H), 8.83 (s, 1H), 8.59 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 7.1 Hz, 1H), 6.61 (s, 2H), 5.02 (t, J = 5.2 Hz, 1H), 4.70 (s, 2H), 4.12 - 4.00 (m, 1H), 3.65 - 3.45 (m, 3H), 1.31 (d, J = 6.8 Hz, 3H), 1.22 (d, J = 6.6 Hz, 3H), 1.20 - 1.13 (m, 1H), 0.63 - 0.53 (m, 1H), 0.48 - 0.36 (m, 2H), 0.32 - 0.18 (m, 1H). ESI MS [M+H] + C 24 H 25 Calculated for F3N6O3: 503.2; Found: 503.1.

[0357] Example 51: 2-[(S)-1-cyclopropylethyl]-5-{2-amino-3-[(2-hydroxyethylamino)carbonyl]-1,4,7α-triaza-5-indenyl}-7-(trifluoromethyl)-1-isoindolinone [ka]

[0358] The title compound was prepared in a similar manner to Example 49. 1H NMR (400 MHz, DMSO-d6) δ 9.04 (d, J = 7.1 Hz, 1H), 8.86 (s, 1H), 8.57 (s, 1H), 8.22 (t, J = 5.3 Hz, 1H), 7.80 (d, J = 7.1 Hz, 1H), 6.61 (s, 2H), 5.01 (br s, 1H), 4.69 (s, 2H), 3.66 - 3.55 (m, 3H), 3.46 (dd, J = 5.4, 5.4 Hz, 2H), 1.30 (d, J = 6.8 Hz, 3H), 1.20 - 1.10 (m, 1H), 0.62 - 0.53 (m, 1H), 0.46 - 0.34 (m, 2H), 0.28 - 0.20 (m, 1H). ESI MS [M+H] + C 23 H 23 Calculated for F3N6O3: 489.2; Found: 489.2.

[0359] Example 52: 2-[(S)-1-cyclopropylethyl]-5-{2-amino-3-[(3-hydroxypropylamino)carbonyl]-1,4,7α-triaza-5-indenyl}-7-(trifluoromethyl)-1-isoindolinone [ka]

[0360] The title compound was prepared in a similar manner to Example 49. 1H NMR (400 MHz, DMSO-d6) δ 9.04 (d, J = 7.1 Hz, 1H), 8.76 (s, 1H), 8.56 (s, 1H), 7.87 (t, J = 5.6 Hz, 1H), 7.75 (d, J = 7.1 Hz, 1H), 6.62 (s, 2H), 4.70 (s, 2H), 4.60 (t, J = 5.1 Hz, 1H), 3.65 - 3.51 (m, 3H), 3.45 (dt, J = 6.4, 6.4 Hz, 2H), 1.73 (tt, J = 1.73 Hz, 2H), 1.30 (d, J = 6.8 Hz, 3H), 1.24 - 1.09 (m, 1H), 0.62 - 0.52 (m, 1H), 0.46 - 0.33 (m, 2H), 0.30 - 0.21 (m, 1H). ESI MS [M+H] + C 24 H 25 Calculated for F3N6O3: 503.2; Found: 503.1.

[0361] Example 53: 2-[(S)-1-Cyclopropylethyl]-5-{2-amino-3-[(3-oxetanylamino)carbonyl]-1,4,7α-triaza-5-indenyl}-7-(trifluoromethyl)-1-isoindolinone [ka]

[0362] The title compound was prepared in a similar manner to Example 49. 1H NMR (400 MHz, DMSO-d6) δ 9.09 (d, J = 7.2 Hz, 1H), 8.77 (s, 1H), 8.71 (s, 1H), 8.31 (d, J = 6.6 Hz, 1H), 7.80 (d, J = 7.2 Hz, 1H), 6.60 (s, 2H), 5.08 - 5.01 (m, 1H), 4.85 (dd, J = 6.9, 6.9 Hz, 2H), 4.73 (s, 2H), 4.58 (dd, J = 6.4 Hz, 2H), 3.60 (dt, J = 9.2, 6.8 Hz, 1H), 1.32 (d, J = 6.8 Hz, 3H), 1.23 - 1.09 (m, 1H), 0.62 - 0.55 (m, 1H), 0.47 - 0.34 (m, 2H), 0.29 - 0.27 (m, 1H). ESI MS [M+H] + C 24 H 23 Calculated for F3N6O3: 501.2; Found: 501.1.

[0363] Example 54: 2-[(S)-1-Cyclopropylethyl]-5-{2-amino-3-[(cis-4-hydroxy-4-methylcyclohexylamino)carbonyl]-1,4,7α-triaza-5-indenyl}-7-(trifluoromethyl)-1-isoindolinone [ka]

[0364] The title compound was prepared in a similar manner to Example 49. 1H NMR (400 MHz, DMSO-d6) δ 9.06 (d, J = 7.1 Hz, 1H), 8.69 (s, 1H), 8.59 (s, 1H), 7.73 (d, J = 7.1 Hz, 1H), 7.69 (d, J = 7.3 Hz, 1H), 6.61 (s, 2H), 4.70 (s, 2H), 4.09 (s, 2H), 3.77 - 3.66 (m, 1H), 3.59 (dq, J = 9.2, 6.6 Hz, 1H), 1.82 - 1.52 (m, 6H), 1.46 - 1.36 (m, 2H), 1.31 (d, J = 6.6 Hz, 3H), 1.20 - 1.12 (m, 4H), 0.60 - 0.54 (m, 1H), 0.48 - 0.34 (m, 2H), 0.30 - 0.23 (m, 1H). ESI MS [M+H] + C 28 H 23 Calculated for F3N6O3: 557.2; Found: 557.1.

[0365] Example 55: 2-[(S)-1-Cyclopropylethyl]-5-(2-amino-3-{[cis-4-hydroxy-4-(trifluoromethyl)cyclohexylamino]carbonyl}-1,4,7α-triaza-5-indenyl)-7-(trifluoromethyl)-1-isoindolinone [ka]

[0366] The title compound was prepared in a similar manner to Example 49. 1H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 7.1 Hz, 1H), 8.69 (s, 1H), 8.61 (s, 1H), 7.74 (d, J = 7.1 Hz, 1H), 7.68 (d, J = 7.2 Hz, 1H), 6.61 (s, 2H), 4.70 (s, 2H), 3.78 (br s, 1H), 3.64 - 3.54 (m, 1H), 1.99 - 1.91 (m, 2H), 1.82 - 1.74 (m, 2H), 1.69 - 1.59 (m, 4H), 1.31 (d, J = 6.8 Hz, 3H), 1.26 - 1.08 (m, 1H), 0.61 - 0.52 (m, 1H), 0.48 - 0.35 (m, 2H), 0.30 - 0.21 (m, 1H). ESI MS [M+H] + C 28 H 28 Calculated for F6N6O3: 611.2; Found: 611.1.

[0367] Example 56: 2-[(S)-1-Cyclopropylethyl]-5-{2-amino-3-[(3-methyl-3-oxetanylamino)carbonyl]-1,4,7α-triaza-5-indenyl}-7-(trifluoromethyl)-1-isoindolinone [ka]

[0368] The title compound was prepared in a similar manner to Example 49. 1H NMR (400 MHz, DMSO-d6) δ 9.06 (d, J = 7.1 Hz, 1H), 8.73 (s, 1H) 8.64 (s, 1H), 8.14 (s, 1H), 7.77 (d, J = 7.1 Hz, 1H), 6.61 (s, 2H), 4.81 (d, J = 6.1 Hz, 2H), 4.70 (s, 2H), 4.44 (d, J = 6.1 Hz, 2H), 3.64 - 3.54 (m, 1H), 1.69 (s, 3H), 1.30 (d, J = 6.8 Hz, 3H), 1.23 - 1.14 (m, 1H), 061 - 0.53 (m, 1H), 0.47 - 0.34 (m, 2H), 0.29 - 0.20 (m, 1H). ESI MS [M+H] + C 25 H 25 Calculated for F3N6O3: 515.2; Found: 515.1.

[0369] Example 57: 5-(3-{[(R)-3-hydroxy-1-methylpropylamino]carbonyl}-2-amino-1,4,7α-triaza-5-indenyl)-2-[(S)-1-cyclopropylethyl]-7-(trifluoromethyl)-1-isoindolinone [ka]

[0370] The title compound was prepared in a similar manner to Example 49. 1H NMR (400 MHz, DMSO-d6) δ 9.06 (d, J = 7.1 Hz, 1H), 8.71 (s, 1H), 8.60 (s, 1H), 7.78 - 7.73 (m, 2H), 6.61 (s, 2H), 4.71 (s, 2H), 4.51 (t, J = 5.0 Hz, 1H), 4.19 - 4.12 (m, 1H), 3.67 - 3.42 (m, 3H), 1.71 (dd, J = 6.5, 6.5 Hz, 2H), 1.30 (d, J = 6.8 Hz, 3H), 1.24 (d, J = 6.6 Hz, 3H), 1.22 - 1.12 (m, 1H), 0.62 - 0.53 (m, 1H), 0.45 - 0.36 (m, 2H), 0.28 - 0.22 (m, 1H). ESI MS [M+H] + C 25 H 27 Calculated for F3N6O3: 517.2; Found: 517.1.

[0371] Example 58: 2-[(S)-1-Cyclopropylethyl]-5-{2-amino-3-[(4-hydroxybutylamino)carbonyl]-1,4,7α-triaza-5-indenyl}-7-(trifluoromethyl)-1-isoindolinone [ka]

[0372] The title compound was prepared in a similar manner to Example 49. 1H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 7.1 Hz, 1H), 8.71 (s, 1H), 8.55 (s, 1H), 7.81 - 7.71 (m, 2H), 6.61 (s, 2H), 4.72 (s, 2H), 4.43 (t, J = 5.1 Hz, 1H), 3.66 - 3.53 (m, 1H), 3.46 - 3.35 (m, 5H), 1.67 - 1.50 (m, 4H), 1.30 (d, J = 6.8 Hz, 3H), 1.22 - 1.12 (m, 1H), 0.63 - 0.52 (m, 1H), 0.48 - 0.34 (m, 2H), 0.28 - 0.24 (m, 1H). ESI MS [M+H] + C 25 H 27 Calculated for F3N6O3: 517.2; Found: 517.1.

[0373] Example 59: 2-[(S)-1-cyclopropylethyl]-5-{2-amino-3-[(3-hydroxy-3-methylbutylamino)carbonyl]-1,4,7α-triaza-5-indenyl}-7-(trifluoromethyl)-1-isomadolinone [ka]

[0374] The title compound was prepared in a similar manner to Example 49. 1H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 7.1 Hz, 1H), 8.85 (s, 1H), 8.57 (s, 1H), 7.98 (t, J = 5.1 Hz, 1H), 7.75 (d, J = 7.1 Hz, 1H), 6.62 (s, 2H), 4.71 (s, 2H), 4.45 (s, 1H), 3.69 - 3.51 (m, 1H), 3.49 - 3.45 (m, 2H), 1.71 (dd, J = 7.1, 7.1 Hz, 2H), 1.29 (d, J = 6.8 Hz, 3H), 1.23 - 1.04 (m, 7H), 0.61 - 0.51 (m, 1H), 0.50 - 0.29 (m, 2H), 0.32 - 0.19 (m, 1H). ESI MS [M+H] + C 26 H 29 Calculated for F3N6O3: 531.2; Found: 531.1.

[0375] Example 60: 2-amino-5-(2-((S)-1-cyclopropylethyl)-1-oxo-7-(trifluoromethyl)isoindolin-5-yl)-N-(trans-4-(hydroxymethyl)cyclohexyl)pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0376] The title compound was prepared in a similar manner to Example 49. 1H NMR (400 MHz, CDCl3) δ 8.61 - 8.46 (m, 2H), 8.26 - 8.15 (m, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.28 (d, J = 7.0 Hz, 1H), 5.28 (br. s, 2H), 4.69 (d, J = 17.7 Hz, 1H), 4.57 (d, J = 17.6 Hz, 1H), 3.99 - 3.87 (m, 1H), 3.86 - 3.75 (m, 1H), 3.53 (d, J = 6.4 Hz, 2H), 2.30 - 2.18 (m, 2H), 1.97 - 1.88 (m, 2H), 1.64 - 1.50 (m, 1H), 1.39 (d, J = 6.9, 3H), 1.37 - 1.22 (m, 4H), 1.10 - 1.01 (m, 1H), 0.71 - 0.63 (m, 1H), 0.53 - 0.38 (m, 3H). 19 F NMR (376 MHz, CDCl3) δ - 59.95. ESI MS [M+H] + C 28 H 32 Calculated for F3N6O3: 557.3; Found: 557.2.

[0377] Example 61: 2-amino-5-(2-((S)-1-cyclopropylethyl)-1-oxo-7-(trifluoromethyl)isoindolin-5-yl)-N-(trans-4-(2-hydroxypropan-2-yl)cyclohexyl)pyrazolo[1,5-α]pyrimidine-3-carboxamide. [ka]

[0378] The title compound was prepared in a similar manner to Example 49. 1H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 7.1 Hz, 1H), 8.69 (s, 1H), 8.61 (s, 1H), 7.73 (d, J = 7.1 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 6.60 (s, 2H), 4.71 (s, 2H), 4.10 (s, 1H), 3.79 - 3.52 (m, 2H), 2.14 - 2.05 (m, 2H), 1.88 - 1.79 (m, 2H), 1.31 (d, J = 6.8 Hz, 3H), 1.27 - 1.08 (m, 6H), 1.04 (s, 6H), 0.68 - 0.51 (m, 1H), 0.51 - 0.34 (m, 2H), 0.30 - 0.22 (m, 1H). 19 F NMR (376 MHz, DMSO-d6) δ - 58.46. ESI MS [M+H] + C 30 H 36 Calculated for F3N6O3: 585.3; Found: 585.1.

[0379] Example 62: 2-amino-5-(2-((S)-1-cyclopropylethyl)-1-oxo-7-(trifluoromethyl)isoindolin-5-yl)-N-(trans-4-(1-hydroxycyclopropyl)cyclohexyl)pyrazolo[1,5-α]pyrimidine-3-carboxamide. [ka]

[0380] The title compound was prepared in a similar manner to Example 49. 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.53 (d, J = 7.1 Hz, 1H), 8.19 (s, 1H), 7.68 (d, J = 7.1 Hz, 1H), 5.77 (br. s, 2H), 4.68 (d, J = 17.3 Hz, 1H), 4.56 (d, J = 17.3 Hz, 1H), 4.01 - 3.88 (m, 1H), 3.87 - 3.76 (m, 1H), 2.34 - 2.20 (m, 2H), 1.96 - 1.86 (m, 2H), 1.59 - 1.44 (m, 2H), 1.42 - 1.26 (m, 5H), 1.12 - 0.99 (m, 2H), 0.77 - 0.71 (m, 2H), 0.70 - 0.63 (m, 1H), 0.54 - 0.47 (m, 3H), 0.46 - 0.37 (m, 2H). 19 F NMR (376 MHz, CDCl3) δ - 59.98. ESI MS [M+H] + C 30 H 34 Calculated for F3N6O3: 583.3; Found: 583.1.

[0381] Example 63: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-1-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-isoindol-5-yl}-N-[(1S,3R)-3-hydroxycyclohexyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0382] The title compound was prepared in a similar manner to Example 49. 1H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 7.1 Hz, 1H), 8.74 (m, 1H), 8.60 (m, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.74 (d, J = 7.2 Hz, 1H), 4.68 (s, 2H), 3.88 (m, 1H), 3.65 - 3.52 (m, 2H), 2.13 (m, 1H), 1.86 (m, 1H), 1.82 - 1.71 (m, 2H), 1.30 (d, J = 6.8 Hz, 3H), 1.27 - 1.10 (m, 5H), 0.57 (m, 1H), 0.46 - 0.35 (m, 2H), 0.26 (m, 1H). ESI MS [M+H] + C 27 H 30 Calculated for F3N6O3: 543.2; Found: 543.2.

[0383] Example 64: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-1-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-isoindol-5-yl}-N-[(3R)-5-oxopyrrolidin-3-yl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0384] The title compound was prepared in a similar manner to Example 49. 1H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 7.1 Hz, 1H), 8.65 (s, 1H), 8.57 (s, 1H), 8.10 (d, J = 7.1 Hz, 1H), 7.78 (d, J = 7.2 Hz, 1H), 7.75 (s, 1H), 6.59 (s, 2H), 4.74 (d, J = 2.5 Hz, 2H), 4.63 (m, 1H), 3.68 - 3.56 (m, 2H), 3.21 (dd, J = 9.9, 4.5 Hz, 1H), 2.64 (dd, J = 16.5, 7.9 Hz, 1H), 2.22 (dd, J = ESI MS [M+H] + C 25 H 25 Calculated for F3N7O3: 528.2; Found: 528.2.

[0385] Example 65: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-1-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-isoindol-5-yl}-N-[trans-3-hydroxycyclobutyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0386] The title compound was prepared in a similar manner to Example 49. 1H NMR (400 MHz, DMSO-d6) δ 9.09 (d, J = 7.1 Hz, 1H), 8.73 (s, 1H), 8.67 (s, 1H), 7.99 (d, J = 6.8 Hz, 1H), 7.77 (d, J = 7.1 Hz, 1H), 6.62 (s, 2H), 5.13 (d, J = 5.4 Hz, 1H), 4.74 (s, 2H), 4.48 (h, J = 6.7 Hz, 1H), 4.44 - 4.32 (m, 1H), 3.62 (dq, J = 9.3, 6.8 Hz, 1H), 2.34 - 2.22 (m, 4H), 1.34 (d, J = ESI MS [M+H] + C 25 H 26 Calculated for F3N6O3: 515.2; Found: 515.1.

[0387] Example 66: 5-{2-[(S)-1-cyclopropylethyl]-7-(trifluoromethyl)-5-isoindolinoyl}-2-amino-1,4,7α-triaza-3-indenecarboxamide [ka]

[0388] The title compound was prepared in a similar manner to Examples 39 and 49. 1H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 7.1 Hz, 1H), 8.77 (s, 1H), 8.50 (s, 1H), 7.75 (d, J = 7.1 Hz, 1H), 7.42 (s, 1H), 7.32 (s, 1H), 6.63 (s, 2H), 4.72 (s, 2H), 3.64 - 3.54 (m, 1H), 1.29 (d, J = 6.8 Hz, 3H), 1.20 - 1.10 (m, 1H), 0.61 - 0.54 (m, 1H), 0.46 - 0.35 (m, 2H), 0.29 - 0.22 (m, 1H). ESI MS [M+H] + C 21 H 19 Calculated for F3N6O2: 445.2; Found: 445.0.

[0389] Example 67: 2-[(S)-1-Cyclopropylethyl]-5-[2-amino-3-(methylamino)carbonyl-1,4,7α-triaza-5-indenyl]-7-(trifluoromethyl)-1-isoindolinone [ka]

[0390] The title compound was prepared in a similar manner to Example 49. 1 H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 7.1 Hz, 1H), 8.81 (s, 1H), 8.54 (s, 1H), 7.75 (d, J = 7.1 Hz, 1H), 7.68 (q, J = 4.7 Hz, 1H), 6.63 (s, 2H), 4.72 (s, 2H), 3.66 - 3.54 (m, 1H), 2.91 (d, J = 4.7 Hz, 3H), 1.30 (d, J = 6.8 Hz, 3H), 1.24 - 1.09 (m, 1H), 0.63 - 0.53 (m, 1H), 0.48 - 0.34 (m, 2H), 0.29 - 0.21 (m, 1H). ESI MS [M+H] + C22 H 21 Calculated for F3N6O2: 459.2; Found: 459.1.

[0391] Example 68: 2-[(S)-1-Cyclopropylethyl]-5-[2-amino-3-(ethylamino)carbonyl-1,4,7α-triaza-5-indenyl]-7-(trifluoromethyl)-1-isoindolinone [ka]

[0392] The title compound was prepared in a similar manner to Example 49. 1 H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 7.1 Hz, 1H), 8.73 (s, 1H), 8.60 (s, 1H), 7.77 - 7.69 (m, 2H), 6.61 (s, 2H), 4.72 (s, 2H), 3.65 - 3.54 (m, 1H), 3.44 - 3.34 (m, 2H), 1.30 (d, J = 6.8 Hz, 3H), 1.25 - 1.10 (m, 4H), 0.62 - 0.55 (m, 1H), 0.45 - 0.35 (m, 2H), 0.30 - 0.21 (m, 1H). ESI MS [M+H] + C 23 H 23 Calculated for F3N6O2: 473.2; Found: 473.1.

[0393] Example 69: (S)-2-amino-5-(2-(1-cyclopropylethyl)-1-oxo-7-(trifluoromethyl)isoindolin-5-yl)-N-(pyridin-4-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide. [ka]

[0394] The title compound was prepared in a similar manner to Examples 49 and 99 (see below). 1H NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 8.63 - 8.59 (m, 2H), 8.55 (d, J = 6.0 Hz, 2H), 8.28 (s, 1H), 7.64 (d, J = 6.0 Hz, 2H), 7.37 (d, J = 7.1 Hz, 1H), 5.83 (s, 2H), 4.72 (d, J = 17.6 Hz, 1H), 4.60 (d, J = 17.6 Hz, 1H), 3.92 - 3.78 (m, 1H), 1.41 (d, J = 6.8 Hz, 3H), 1.12 - 1.03 (m, 1H), 0.80 - 0.63 (m, 1H), 0.58 - 0.38 (m, 3H). 19 F NMR (376 MHz, CDCl3) δ - 59.81. ESI MS [M+H] + C 26 H 23 Calculated for F3N7O2: 522.2; Found: 522.1.

[0395] Example 70: (S)-2-amino-5-(2-(1-cyclopropylethyl)-1-oxo-7-(trifluoromethyl)isoindolin-5-yl)-N-(pyridin-3-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide. [ka]

[0396] The title compound was prepared in a similar manner to Examples 49 and 99 (see below). 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.15 (d, J = 7.1 Hz, 1H), 8.87 (dd, J = 2.6, 0.7 Hz, 1H), 8.79 (d, J = 9.0 Hz, 2H), 8.30 (dd, J = 4.7, 1.5 Hz, 1H), 8.23 ​​(ddd, J = 8.3, 2.6, 1.5 Hz, 1H), 7.86 (d, J = 7.2 Hz, 1H), 7.41 (ddd, J = 8.3, 4.7, 0.7 Hz, 1H), 6.76 (br. s, 2H), 4.75 (s, 2H), 3.69 - 3.56 (m, 1H), 1.34 (d, J = 6.8 Hz, 3H), 1.27 - 1.13 (m, 1H), 0.66 - 0.55 (m, 1H), 0.50 - 0.36 (m, 2H), 0.33 - 0.24 (m, 1H). 19 F NMR (376 MHz, DMSO-d6) δ - 58.23. ESI MS [M+H] + C 26 H 23 Calculated for F3N7O2: 522.2; Found: 522.2.

[0397] Example 71: 6-[(S)-1-Cyclopropylethyl]-19-amino-10,13-dioxa-6,16,20,21,24-pentaazapentacyclo[16,5,2,12,9,04,8,021,25]hexacosa-1(24),2,4(8),9(26),18(25),19,22-heptaene-7,17-dione [ka]

[0398] Step a: To a solution of 4-bromo-2-fluoro-6-methylbenzoic acid methyl ester (45.0 g, 182 mmol, 1.0 equiv) in CCl4 (1.14 L) was added NBS (35.7 g, 200 mmol, 1.1 equiv) and BPO (80 wt%, 5.51 g, 18.2 mmol, 0.1 equiv). The resulting mixture was stirred at reflux for 3 h. Upon completion, the reaction mixture was cooled to room temperature and filtered to remove the precipitate. The filtrate was concentrated in vacuo to give the crude benzyl bromide, which was used directly in step b.

[0399] Step b: In a round-bottom flask equipped with a reflux condenser and a balloon of N2, the product from step a (45.0 g, 138 mmol, 1.0 equiv.) was combined with (αS)-α-methyl-cyclopropanemethanamine hydrochloride (33.6 g, 276 mmol, 2.0 equiv.), K2CO3 (57.2 g, 414 mmol, 3.0 equiv.), and B(OH)3 (1.71 g, 27.6 mmol, 0.2 equiv.) in CH3CN (552 mL). The resulting mixture was stirred at 50 °C for 72 h. Upon completion, the reaction mixture was allowed to cool to room temperature, and approximately 75% of the solvent was removed under vacuum. The mixture was partitioned between EtOAc (300 mL) and HO (200 mL). The organic phase was separated, and the aqueous phase was again extracted with EtOAc. The combined organic extracts were washed with HO and brine, then dried (NaSO), filtered, and concentrated in vacuo. Purification by column chromatography (SiO, 0–30% EtOAc / hexanes) afforded the product as an off-white solid (35.0 g, 58% yield over two steps).

[0400] Step c: Sodium hydride (60% in mineral oil, 600 mg, 15 mmol, 3.0 equiv.) was added portionwise to a solution of 2-(2-tert-butoxycarbonylaminoethoxy)ethanol (1.03 g, 5.0 mmol, 1.0 equiv.) in DMF (25 mL) at 0 °C. After stirring for 15 min, 2-[(S)-1-cyclopropylethyl]-5-bromo-7-fluoro-1-isoindolinone (1.5 g, 5.0 mmol, 1.0 equiv.) was dissolved in DMF (5.0 mL) and added to the solution. The reaction was stirred at 0 °C for 10 min before being quenched with saturated NH4Cl and extracted with EtOAc. The collected organics were purified by flash chromatography (SiO2, 10% to 50% EtOAc / hexane gradient) to give the aryl ether product (1.18 g, 49%).

[0401] Step d: The product of step c (1.18 g, 2.44 mmol, 1.0 equiv) was combined with Pd(dppf)Cl (175 mg, 0.24 mmol, 0.1 equiv), B2pin2 (813 mg, 3.2 mmol, 1.3 equiv), and KOAc (530 mg, 5.2 mmol, 2.2 equiv) in dioxane (24.4 mL). The resulting solution was heated to 100 °C for 2 h, cooled to room temperature, filtered through Celite (washed with EtOAc), and concentrated. The resulting residue was used directly in the next step without purification.

[0402] Step e: The product of step d (2.44 mmol, 1.0 equiv) was combined with 2-amino-5-chloropyrazolo[1,5-α]pyrimidine-3-carboxylic acid ethyl ester (587 mg, 2.44 mmol, 1.0 equiv), PCyPd G2 (142 mg, 0.24 mmol, 0.1 equiv), and Na2CO3 (2 M aqueous solution, 7.32 mmol, 3.66 mL) in dioxane (25 mL). The resulting solution was heated to 100 °C for 1 h, concentrated, and purified by flash chromatography (SiO2, 80% EtOAc in hexanes, followed by 10% MeOH in CHCl2) to give the cross-coupled ethyl ester (0.92 g, 62% over two steps).

[0403] Step f: The ethyl ester product from step e (225 mg, 0.41 mmol, 1.0 equiv) was dissolved in EtOH (2.0 mL). HO (1.39 mL) and 2 N aqueous LiOH (615 μL, 1.23 mmol, 3 equiv) were added, followed by dioxane (2.0 mL) to improve solubility. The resulting solution was heated to 60 °C overnight and then acidified to pH 3 with 2 N HCl. The solution was extracted with EtOAc, dried (NaSO), and concentrated (238 mg, 100%). A portion of the resulting material (90 mg, 0.15 mmol) was dissolved in CHCl (2.0 mL). TFA (0.2 mL) was added, and the solution was stirred at room temperature for 20 minutes. Upon completion, the reaction mixture was diluted with toluene (2.0 mL) and concentrated to the TFA salt. This material was used without purification.

[0404] Step g: The TFA salt from step f (0.15 mmol) was dissolved in DMF (7.5 mL, 0.02 M). HOBT (25.2 mg, 0.165 mmol, 1.1 equiv), EtN (105 μL, 0.75 mmol, 5.0 equiv), and EDC·HCl (43.1 mg, 0.225 mmol, 1.5 equiv) were added sequentially, and the solution was heated to 40 °C. After 2 h, the reaction solution was diluted with HO (60 mL) and extracted with EtOAc (×2) followed by 2:1 CHCl:iPrOH (×1). The combined organics were concentrated and purified by flash chromatography (SiO, MeOH / CHCl gradient 0% to 5%) to give the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 8.99 (d, J = 7.1 Hz, 1H), 8.79 (t, J = 4.2 Hz, 1H), 8.43 (s, 1H), 7.97 (s, 1H), 7.65 (d, J = 7.3 Hz, 1H), 6.47 (s, 2H), 4.53 (s, 2H), 4.49 (t, J = 4.4 Hz, 2H), 3.89 (br s, 2H), 3.68 (t, J = 5.0 Hz, 2H), 3.55 - 3.44 (m, 3H), 1.25 (d, J = 6.8 Hz, 3H), 1.16 - 1.05 (m, 1H), 0.60 - 0.49 (m, 1H), 0.43 - 0.31 (m, 2H), 0.24 - 0.15 (m, 1H). ESI MS [M+H] + C 24 H 26 Calculated for N6O4: 463.2; Found: 463.2.

[0405] Example 72: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methanesulfonamido-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-[(1R,2R)-2-hydroxycyclopentyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0406] Step a: C7-F-isoindolinone (3.00 g, 10.0 mmol, 1.0 equiv) was combined with neat PMBNH2 (4 mL) and heated to 100 °C for 14 h. The reaction mixture was cooled and partitioned between 10% aqueous citric acid and EtOAc. The aqueous layer was separated and back-extracted with more EtOAc. The organic layers were combined and then washed with more 10% aqueous citric acid, saturated brine, and dried over MgSO4. Concentration under reduced pressure gave the PMB amine adduct, which was used crude in the next step.

[0407] Step b: The product of step a was combined with TFA (15 mL) and stirred at 40° C. for 3 h. The reaction mixture was concentrated under reduced pressure, quenched with saturated aqueous NaHCO and diluted with EtOAc. The organic layers were combined, washed with brine, and dried over MgSO. Concentration under reduced pressure and purification by column chromatography (SiO, hexanes to 50% EtOAc gradient) afforded the aniline product as a white solid (2.89 g, ca. 98%, with a small amount of co-eluting impurity, which was used in the next step).

[0408] Step c: The product of step b (1.00 g, 3.38 mmol, 1.0 equiv) was dissolved in CHCl (10 mL), and the mixture was cooled to 0 °C. To this solution were added DMAP (40 mg, 0.34 mmol, 10 mol%), DIPEA (1.6 mL, 10.1 mmol, 3.0 equiv), and MsCl (0.7 mL, 8.5 mmol, 2.5 equiv). The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction was quenched with 1 M aqueous HCl and diluted with EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layers were combined, washed with brine, and dried over MgSO. Concentration under reduced pressure gave the bis-sulfonylated product, which was used crude in the next step.

[0409] Step d: The product of step c was dissolved in THF (5 mL) and TBAF (1 M in THF, 5.4 mL, 5.4 mmol, 1.6 equiv.) was added. After 15 min, the remaining portion of TBAF (1 M in THF, 3.0 mL, 0.9 equiv.) was added, followed 2 h later by the remaining portion of TBAF (1 M in THF, 3.0 mL, 0.9 equiv.). The reaction mixture was stirred for an additional 1 h, then quenched with 1 M aqueous HCl and diluted with EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layers were combined, washed with brine, and dried over MgSO. Concentration under reduced pressure and purification by flash column chromatography (SiO, hexanes to 50% EtOAc gradient) afforded the reverse sulfonamide as a yellow solid (0.766 g, 2.1 mmol, 60% over two steps).

[0410] Step e: The product of step d (2.00 g, 5.36 mmol, 1.0 equiv) was combined with Pd(dppf)Cl (390 mg, 0.54 mmol, 0.1 equiv), B2pin2 (1.80 g, 7.10 mmol, 1.3 equiv), and KOAc (1.15 g, 11.8 mmol, 2.20 equiv) in dioxane (30 mL). The resulting mixture was heated to 100 °C and stirred for 1 h. A second portion of Pd(dppf)Cl (100 mg, 0.137 mmol, 0.03 equiv) was then added. The reaction mixture was stirred for an additional 1 h, then cooled to room temperature, filtered through Celite (washed with EtOAc), and concentrated under reduced pressure. The resulting residue was used directly in the next step without purification.

[0411] Step f: The crude pinacol boronic ester was combined with Pd(dppf)Cl (390 mg, 0.54 mmol, 0.1 equiv.), 1 M aqueous NaCO (16 mmol, 16 mL, 3.0 equiv.), ethyl 2-amino-5-chloro-1,4,7α-triaza-3-indenecarboxylate (1.29 g, 5.36 mmol, 1.0 equiv.), and dioxane (20 mL). The resulting mixture was heated to 100 °C and stirred for 40 min. The reaction mixture was cooled to room temperature and diluted with CHCl and HO. The aqueous phase was separated and back-extracted with additional CHCl, then extracted once with EtOAc. The organic layers were combined and dried over MgSO. Concentration under reduced pressure and purification by column chromatography (SiO, CHCl to 5% MeOH gradient) afforded the cross-coupled ester product as a golden yellow solid (2.48 g, 92% over two steps).

[0412] Step g: The ethyl ester product from step f (500 mg, 1.00 mmol, 1.0 equiv) was dissolved in EtOH (2 mL), THF (4 mL), and HO (2 mL). LiOH·HO (250 mg, 6.00 mmol, 6.0 equiv) was added, and the reaction mixture was heated to 70 °C for 15 h. The resulting mixture was cooled to room temperature, and the solvent was removed in vacuo. The mixture was diluted with HO and acidified to pH 3 with 2 N HCl. The resulting precipitate was collected by vacuum filtration and dried under vacuum at 40 °C for 2 h to give the carboxylic acid product (369 mg, 78%), which was used in the next step without purification.

[0413] Step h: The product of step g (50 mg, 0.106 mmol) was dissolved in DMF (1.0 mL) and HOBt (20 mg, 0.127 mmol, 1.2 equiv, 20 wt% HO). EtN (50 μL, 0.32 mmol, 3.0 equiv), (1R,2R)-2-aminocyclopentanol hydrochloride (22 mg, 0.159 mmol, 1.5 equiv), and EDC·HCl (31 mg, 0.159 mmol, 1.5 equiv) were added sequentially, and the solution was heated to 40 °C. After 0.5 h, the reaction mixture was directly purified by reverse-phase HPLC (20–80% gradient of CHCN and HO with 0.1% TFA) to give the title compound as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 9.00 (d, J = 7.1 Hz, 1H), 8.21 - 8.11 (m, 1H), 8.05 - 7.93 (m, 1H), 7.67 (d, J = 7.4 Hz, 1H), 7.53 (d, J = 7.2 Hz, 1H), 6.60 (s, 2H), 4.66 (s, 2H), 4.09 - 3.93 (m, 2H), 3.60 - 3.48 (m, 1H), 3.26 (s, 3H), 2.12 - 1.97 (m, 1H), 1.95 - 1.82 (m, 1H), 1.77 - 1.62 (m, 2H), 1.60 - 1.40 (m, 2H), 1.31 (d, J = 6.8 Hz, 3H), 1.24 - 1.10 (m, 1H), 0.63 - 0.51 (m, 1H), 0.49 - 0.33 (m, 2H), 0.29 - 0.20 (m, 1H). ESI MS [M+H] + C 26 H 32 Calculated for N7O5S: 554.2; Found: 554.2.

[0414] Example 73: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methanesulfonamido-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-methylpyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0415] The title compound was synthesized using a procedure similar to that described in Example 72. 1 H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.99 (d, J = 7.1 Hz, 1H), 8.34 (d, J = 1.2 Hz, 1H), 8.13 (d, J = 1.2 Hz, 1H), 7.74 (q, J = 4.8 Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H), 4.67 (s, 2H), 3.61 - 3.45 (m, 1H), 3.32 (s, 3H), 2.90 (d, J = 4.8 Hz, 3H), 1.31 (d, J = 6.8 Hz, 3H), 1.23 - 1.09 (m, 1H), 0.57 (m, 1H), 0.41 (m, 2H), 0.30 - 0.21 (m, 1H). ESI MS [M+H] + C 22 H 25 Calculated for N7O4S: 484.2; Found: 484.1.

[0416] Example 74: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methanesulfonamido-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-ethylpyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0417] The title compound was synthesized using a procedure similar to that described in Example 72. 1H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.00 (d, J = 7.1 Hz, 1H), 8.32 (d, J = 1.2 Hz, 1H), 8.08 (d, J = 1.2 Hz, 1H), 7.80 (t, J = 5.9 Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H), 4.67 (s, 2H), 3.58 - 3.48 (m, 1H), 3.46 - 3.34 (m, 2H), 3.29 (s, 3H), 1.31 (d, J = 6.8 Hz, 3H), 1.19 (m, 4H), 0.62 - 0.53 (m, 1H), 0.46 - 0.35 (m, 2H), 0.30 - 0.21 (m, 1H). ESI MS [M+H] + C 23 H 27 Calculated for N7O4S: 498.2; Found: 498.1.

[0418] Example 75: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methanesulfonamido-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-(propan-2-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0419] The title compound was synthesized using a procedure similar to that described in Example 72. 1H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 9.00 (d, J = 7.1 Hz, 1H), 8.23 ​​(d, J = 1.2 Hz, 1H), 8.03 (d, J = 1.2 Hz, 1H), 7.55 (dd, J = 7.6, 3.6 Hz, 2H), 4.67 (s, 2H), 4.24 - 4.04 (m, 1H), 3.62 - 3.45 (m, 1H), 1.31 (d, J = 6.8 Hz, 3H), 1.24 (d, J = 6.6 Hz, 6H), 1.20 - 1.09 (m, 1H), 0.63 - 0.51 (m, 1H), 0.47 - 0.33 (m, 2H), 0.30 - 0.19 (m, 1H). ESI MS [M+H] + C 24 H 29 Calculated for N7O4S: 512.2; Found: 512.1.

[0420] Example 76: 5-{2-[(S)-1-cyclopropylethyl]-7-(methylsulfonylamino)-5-isoindolinonyl}-2-amino-1,4,7α-triaza-3-indenecarboxamide [ka]

[0421] The title compound was prepared in a similar manner to Examples 39 and 72. 1H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.99 (d, J = 7.1 Hz, 1H), 8.4 (s, 1H), 8.10 (s, 1H), 7.53 (d, J = 7.1 Hz, 1H), 7.44 (s, 1H), 7.31 (s, 1H), 6.59 (s, 2H), 4.67 (s, 2H), 3.58 - 3.49 (m, 1H), 1.30 (d, J = 6.8 Hz, 3H), 1.22 - 1.10 (m, 1H), 0.61 - 0.52 (m, 1H), 0.45 - 0.34 (m, 2H), 0.28 - 0.21 (m, 1H). ESI MS [M+H] + C 21 H 23 Calculated for N7O4S: 470.2; Found: 470.0.

[0422] Example 77: 2-[(S)-1-Cyclopropylethyl]-5-(2-amino-3-{(1-spiro[2.2]pentylamino)carbonyl}-1,4,7α-triaza-5-indenyl)-7-(methylsulfonylamino)-1-isoindolinone [ka]

[0423] The title compound was prepared in a similar manner to Example 72. 1H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.99 (d, J = 7.1 Hz, 1H), 8.11 (d,J = 1.2 Hz, 1H), 8.02 (dd, J = 0.7, 1.3 Hz, 1H), 7.80 (d, J = 4.4 Hz, 1H), 7.51 (d, J = 7.2 Hz, 1H), 6.59 (br, 2H), 4.67 (s, 2H), 3.60 - 3.48 (m, 1H), 3.26 (s, 3H), 3.19 (dt, J = 3.8, 7.2 Hz, 1H), 1.30 (m, 4H), 1.17 (ddt, J = ESI MS [M+H] + C 26 H 29 Calculated for N7O4S: 536.2; Found: 536.1.

[0424] Example 78: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methanesulfonamido-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-(oxetan-3-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0425] The title compound was prepared in a similar manner to Example 72. 1H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 1H), 9.02 (d, J = 7.1, 0.6 Hz, 1H), 8.27 (s, 1H), 8.16 - 8.05 (m, 2H), 7.60 (d, J = 7.2 Hz, 1H), 6.60 (s, 2H), 5.10 (q, J = 7.2 Hz, 1H), 4.79 (t, J = 7.1 Hz, 2H), 4.70 - 4.62 (m, 4H), 3.62 - 3.46 (m, 1H), 3.31 (s, 3H), 1.32 (d, J = 6.8 Hz, 3H), 1.24 - 1.14 (m, 1H), 0.66 - 0.51 (m, 1H), 0.48 - 0.33 (m, 2H), 0.31 - 0.19 (m, 1H). ESI MS [M+H] + C 24 H 28 Calculated for N7O5S: 526.2; Found: 526.2.

[0426] Example 79: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methanesulfonamido-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-(3-methyloxetan-3-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0427] The title compound was prepared in a similar manner to Example 72. 1H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 9.04 (d, J = 7.1 Hz, 1H), 8.27 (s, 1H), 8.10 (s, 1H), 8.05 (s, 1H), 7.61 (d, J = 7.2 Hz, 1H), 6.62 (s, 2H), 4.80 (d, J = 6.3 Hz, 2H), 4.69 (s, 2H), 4.45 (d, J = 6.4 Hz, 2H), 3.65 - 3.46 (m, 1H), 3.31 (s, 3H), 1.69 (s, 3H), 1.34 (d, J = 6.8 Hz, 3H), 1.29 - 1.12 (m, 1H), 0.69 - 0.52 (m, 1H), 0.51 - 0.34 (m, 2H), 0.33 - 0.19 (m, 1H). ESI MS [M+H] + C 25 H 30 Calculated for N7O5S: 540.2; Found: 540.2.

[0428] Example 80: 2-amino-N-(3-cyanooxetan-3-yl)-5-{2-[(1S)-1-cyclopropyl]-7-methanesulfonamido-1-oxo-2,3-dihydro-1H-isoindol-5-yl}pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0429] The title compound was prepared in a similar manner to Example 72. 1H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 1H), 9.04 (d, J = 7.1 Hz, 1H), 8.65 (s, 1H), 8.27 (s, 1H), 8.19 (s, 1H), 7.66 (d, J = 7.2 Hz, 1H), 6.65 (s, 2H), 4.97 (d, J = 7.5 Hz, 2H), 4.84 (d, 2H), 4.67 (s, 2H), 3.59 - 3.47 (m, 1H), 3.36 (s, 3H), 1.32 (d, J = 6.8 Hz, 3H), 1.26 - 1.09 (m, 1H), 0.66 - 0.51 (m, 1H), 0.50 - 0.32 (m, 2H), 0.32 - 0.14 (m, 1H). ESI MS [M+H] + C 25 H 27 Calculated for N8O5S: 551.2; Found: 551.2.

[0430] Example 81: 2-amino-N-(1-cyanocyclobutyl)-5-{2-[(1S)-1-cyclopropylethyl]-7-methanesulfonamido-1-oxo-2,3-dihydro-1H-isoindol-5-yl}pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0431] The title compound was prepared in a similar manner to Example 72. 1H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 9.07 (d, J = 7.1 Hz, 1H), 8.23 ​​(s, 1H), 8.20 (s, 1H), 8.13 (s, 1H), 7.63 (d, J = 7.2 Hz, 1H), 6.66 (s, 2H), 4.69 (s, 2H), 3.61 - 3.48 (m, 1H), 3.32 (s, 3H), 2.82 - 2.71 (m, 2H), 2.60 - 2.48 (m, 2H), 2.17 - 2.03 (m, 2H), 1.34 (d, J = 6.8 Hz, 3H), 1.27 - 1.13 (m, 1H), 0.64 - 0.54 (m, 1H), 0.51 - 0.36 (m, 2H), 0.34 - 0.21 (m, 1H). ESI MS [M+H] + C 26 H 29 Calculated for N8O4S: 549.2; Found: 549.2.

[0432] Example 82: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methanesulfonamido-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-[trans-3-hydroxy-3-methylcyclobutyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0433] The title compound was prepared in a similar manner to Example 72. 1H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 9.03 (d, J = 7.1 Hz, 1H), 8.19 (s, 1H), 8.07 (s, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 7.2 Hz, 1H), 6.63 (s, 2H), 4.95 (s, 1H), 4.70 (s, 2H), 4.09 (q, J = 7.9 Hz, 1H), 3.56 (dd, J = 9.2, 6.7 Hz, 1H), 3.37 (s, 3H), 2.45 - 2.36 (m, 2H), 2.14 - 2.04 (m, 2H), 1.34 (d, J = 6.8 Hz, 3H), 1.29 (s, 3H), 1.25 - 1.12 (m, 1H), 0.64 - 0.55 (m, 1H), 0.49 - 0.38 (m, 2H), 0.32 - 0.23 (m, 1H). ESI MS [M+H] + C 26 H 32 Calculated for N7O5S: 554.2; Found: 554.1.

[0434] Example 83: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methanesulfonamido-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-[trans-3-hydroxy-1-methylcyclobutyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0435] The title compound was prepared in a similar manner to Example 72. 1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 9.02 (d, J = 7.1 Hz, 1H), 8.15 (s, 1H), 8.03 (s, 1H), 7.76 (s, 1H), 7.53 (d, J = 7.2 Hz, 1H), 6.61 (s, 2H), 5.01 (d, J = 5.8 Hz, 1H), 4.69 (s, 2H), 4.21 (q, J = 6.6 Hz, 1H), 3.56 (dd, J = 9.2, 6.8 Hz, 1H), 3.28 (s, 3H), 2.75 - 2.65 (m, 2H), 1.99 - 1.87 (m, 2H), 1.54 (s, 3H), 1.34 (d, J = 6.8 Hz, 3H), 1.26 - 1.13 (m, 1H), 0.64 - 0.53 (m, 1H), 0.50 - 0.34 (m, 2H), 0.32 - 0.22 (m, 1H). ESI MS [M+H] + C 26 H 32 Calculated for N7O5S: 554.2; Found: 554.1.

[0436] Example 84: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methanesulfonamido-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-[trans-3-methoxycyclobutyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0437] The title compound was prepared in a similar manner to Example 72. 1H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 9.03 (d, J = 7.1 Hz, 1H), 8.30 (s, 1H), 8.09 (s, 1H), 7.89 (s, 1H), 7.59 (d, J = 7.2 Hz, 1H), 6.62 (s, 2H), 4.70 (s, 2H), 4.59 (q, J = 7.4 Hz, 1H), 4.07 - 3.99 (m, 1H), 3.64 - 3.51 (m, 1H), 3.30 (s, 3H), 3.18 (s, 3H), 2.32 (dd, J = 7.4, 4.9 Hz, 4H), 1.34 (d, J = 6.8 Hz, 3H), 1.28 - 1.13 (m, 1H), 0.68 - 0.55 (m, 1H), 0.54 - 0.34 (m, 2H), 0.31 - 0.22 (m, 1H). ESI MS [M+H] + C 26 H 32 Calculated for N7O5S: 554.2; Found: 554.2.

[0438] Example 85: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methanesulfonamido-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-{[trans-3-hydroxycyclobutyl]methyl}pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0439] The title compound was prepared in a similar manner to Example 72. 1H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 9.03 (d, J = 7.1 Hz, 1H), 8.30 (s, 1H), 8.10 (s, 1H), 7.92 (t, J = 6.0 Hz, 1H), 7.60 (d, J = 7.2 Hz, 1H), 6.61 (s, 2H), 4.99 - 4.93 (m, 1H), 4.69 (s, 2H), 4.30 - 4.22 (m, 1H), 3.61 - 3.50 (m, 1H), 3.46 - 3.39 (m, 2H), 3.31 (s, 3H), 2.47 - 2.34 (m, 1H), 2.10 - 2.00 (m, 2H), 1.97 - 1.85 (m, 2H), 1.34 (d, J = 6.8 Hz, 3H), 1.26 - 1.12 (m, 1H), 0.64 - 0.55 (m, 1H), 0.50 - 0.37 (m, 2H), 0.31 - 0.23 (m, 1H). ESI MS [M+H] + C 26 H 32 Calculated for N7O5S: 554.2; Found: 554.1.

[0440] Example 86: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methanesulfonamido-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-[(1R,3R)-3-hydroxycyclopentyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0441] The title compound was prepared in a similar manner to Example 72. 1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 9.02 (d, J = 7.1 Hz, 1H), 8.21 (d, J = 1.2 Hz, 1H), 8.04 (d, J = 1.2 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 7.2 Hz, 1H), 6.62 (s, 2H), 4.69 (s, 2H), 4.53 (h, J = 7.6 Hz, 1H), 4.28 - 4.23 (m, 1H), 3.61 - 3.51 (m, 1H), 3.27 (s, 3H), 2.18 - 1.89 (m, 3H), 1.72 (ddd, J = 13.0, 8.6, 5.9 Hz, 1H), 1.57 - 1.46 (m, 2H), 1.34 (d, J = 6.8 Hz, 3H), 1.24 - 1.13 (m, 1H), 0.65 - 0.53 (m, 1H), 0.48 - 0.35 (m, 2H), 0.31 - 0.24 (m, 1H). ESI MS [M+H] + C 26 H 32 Calculated for N7O5S: 554.2; Found: 554.2.

[0442] Example 87: 2-Amino-N-cyclopropyl-5-{2-[(1S)-1-cyclopropylethyl]-7-methanesulfonamido-1-oxo-2,3-dihydro-1H-isoindol-5-yl}pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0443] The title compound was prepared in a similar manner to Example 72. 1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 9.02 (d, J = 7.1 Hz, 1H), 8.22 - 8.18 (m, 1H), 8.07 - 8.01 (m, 1H), 7.71 (d, J = 3.6 Hz, 1H), 7.57 (d, J = 7.2 Hz, 1H), 6.64 (s, 2H), 4.70 (s, 2H), 3.56 (dt, J = 9.3, 6.8 Hz, 1H), 3.33 (s, 3H), 2.90 - 2.76 (m, 1H), 1.34 (d, J = 6.8 Hz, 3H), 1.28 - 1.13 (m, ESI MS [M+H] + C 24 H 28 Calculated for N7O4S: 510.2; Found: 510.2.

[0444] Example 88: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methanesulfonamido-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-[(3R,4S)-4-hydroxyoxolan-3-yl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0445] The title compound was prepared in a similar manner to Example 72. 1H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 9.03 (d, J = 7.1 Hz, 1H), 8.07 (dd, J = 19.5, 1.2 Hz, 2H), 7.86 (d, J = 7.4 Hz, 1H), 7.54 (d, J = 7.2 Hz, 1H), 6.62 (s, 2H), 4.67 (s, 2H), 4.32 - 4.24 (m, 2H), 3.99 (ddd, J = 13.1, 9.3, 4.8 Hz, 2H), 3.73 - 3.70 (m, 1H), 3.60 - 3.55 (m, 2H), 3.31 (s, 3H), 1.34 (d, J = 6.8 Hz, 3H), 1.24 - 1.14 (m, 1H), 0.64 - 0.54 (m, 1H), 0.49 - 0.37 (m, 2H), 0.31 - 0.23 (m, 1H). ESI MS [M+H] + C 25 H 30 Calculated for N7O6S: 556.2; Found: 556.2.

[0446] Example 89: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methanesulfonamido-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-[cis-4-hydroxy-4-methylcyclohexyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0447] The title compound was prepared in a similar manner to Example 72. 1H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 9.02 (d, J = 7.1 Hz, 1H), 8.20 - 8.13 (m, 1H), 8.07 - 7.99 (m, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.54 (d, J = 7.1 Hz, 1H), 6.63 (s, 2H), 4.67 (s, 2H), 3.94 (s, 1H), 3.66 - 3.52 (m, 1H), 3.27 (s, 3H), 1.95 - 1.81 (m, 2H), 1.67 - 1.42 (m, 6H), 1.33 (d, J = 6.8 ESI MS [M+H] + C 28 H 36 Calculated for N7O5S: 582.2; Found: 582.2.

[0448] Example 90: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methanesulfonamido-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-[cis-4-hydroxy-4-(trifluoromethyl)cyclohexyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0449] The title compound was synthesized in a similar manner to 72. 1H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 1H), 9.00 (d, J = 7.1 Hz, 1H), 8.15 (d, J = 1.2 Hz, 1H), 7.98 (d, J = 1.2 Hz, 1H), 7.52 (dd, J = 7.5, 3.4 Hz, 2H), 4.66 (s, 2H), 3.92 - 3.76 (m, 1H), 3.64 - 3.48 (m, 1H), 3.32 (s, 3H), 1.87 (d, J = 10.9 Hz, 2H), 1.79 (d, J = 10.5 Hz, 2H), 1.73 - 1.57 (m, 4H), 1.32 (d, J = 6.8 Hz, 3H), 1.21 - 1.11 (m, 1H), 0.57 (m, 1H), 0.41 (m, 2H), 0.31 - 0.18 (m, 1H). ESI MS [MH] - C 28 H 32 Calculated for F3N7O5S: 636.2; Found: 636.1.

[0450] Example 91: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methanesulfonamido-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-[trans-4-(2-hydroxypropan-2-yl)cyclohexyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0451] The title compound was prepared in a similar manner to Example 72. 1H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 9.02 (d, J = 7.1 Hz, 1H), 8.25 (s, 1H), 8.05 (s, 1H), 7.61 - 7.50 (m, 2H), 6.63 (s, 2H), 4.69 (s, 2H), 4.09 (s, 1H), 3.83 - 3.69 (m, 1H), 3.61 - 3.49 (m, 1H), 3.28 (s, 3H), 2.53 - 2.49 (m, 1H), 2.03 - 1.94 (m, 2H), 1.90 - 1.80 (m, 2H), 1.48 - 0.99 (m, 13H), 0.64 - 0.55 (m, 1H), 0.50 - 0.36 (m, 2H), 0.33 - 0.22 (m, 1H). ESI MS [M+H] + C 30 H 40 Calculated for N7O5S: 610.3; Found: 610.2.

[0452] Example 92: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methanesulfonamido-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-[trans-4-(1-hydroxycyclopropyl)cyclohexyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0453] The title compound was prepared in a similar manner to Example 72. 1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 9.02 (d, J = 7.1 Hz, 1H), 8.24 (s, 1H), 8.05 (s, 1H), 7.61 - 7.48 (m, 2H), 6.62 (s, 2H), 4.91 (s, 1H), 4.69 (s, 2H), 3.84 - 3.69 (m, 1H), 3.61 - 3.50 (m, 1H), 3.25 (s, 3H), 2.03 - 1.92 (m, 2H), 1.80 - 1.69 (m, 2H), 1.49 - 1.26 (m, 7H), 1.26 - 1.13 (m, 1H), 1.07 - 0.93 (m, 1H), 0.63 - 0.54 (m, 1H), 0.53 - 0.47 (m, 2H), 0.47 - 0.37 (m, 1H), 0.37 - 0.32 (m, 2H), 0.32 - 0.23 (m, 1H). ESI MS [M+H] + C 30 H 38 Calculated for N7O5S: 608.3; Found: 608.2.

[0454] Example 93: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methanesulfonamido-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-[(2R)-1-hydroxypropan-2-yl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0455] The title compound was prepared in a similar manner to Example 72. 1H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 1H), 9.01 (d, J = 7.1 Hz, 1H), 8.21 (s, 1H), 8.13 (s, 1H), 7.95 (d,J = 8.3 Hz, 1H), 7.56 (d, J = 7.2 Hz, 1H), 6.62 (s, 2H), 4.68 (s, 2H), 4.16 - 4.05 (m, 1H), 3.60 - 3.46 (m, 3H), 3.32 (s, 3H), 1.34 (d, J = 6.8 Hz, 3H), 1.23 (d, J = 6.7 Hz, 3H), 1.21 - 1.09 (m, 1H), 0.67 - 0.54 (m, 1H), 0.50 - 0.35 (m, 2H), 0.33 - 0.22 (m, 1H). ESI MS [M+H] + C 24 H 30 Calculated for N7O5S: 528.2; Found: 528.2.

[0456] Example 94: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methanesulfonamido-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-(1-hydroxy-2-methylpropan-2-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0457] The title compound was prepared in a similar manner to Example 72. 1H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 9.00 (d, J = 7.1 Hz, 1H), 8.25 (s, 1H), 8.03 (s, 1H), 8.01 (s, 1H), 7.50 (d, J = 7.2 Hz, 1H), 6.60 (s, 2H), 4.68 (s, 2H), 3.61 - 3.49 (m, 3H), 3.31 (s, 3H), 1.41 (s, 6H), 1.34 (d, J = 6.8 Hz, 3H), 1.25 - 1.12 (m, 1H), 0.67 - 0.55 (m, 1H), 0.51 - 0.36 (m, 2H), 0.34 - 0.24 (m, 1H). ESI MS [M+H] + C 25 H 32 Calculated for N7O5S: 542.2; Found: 542.2.

[0458] Example 95: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methanesulfonamido-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-(3-hydroxy-3-methylbutyl)pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0459] The title compound was prepared in a similar manner to Example 72. 1H NMR (400 MHz, CDCl3) δ 9.64 (s, 1H), 8.49 (d, J = 7.1 Hz, 1H), 8.41 (s, 1H), 8.13 - 8.04 (m, 1H), 7.80 (s, 1H), 7.20 (d, J = 7.1 Hz, 1H), 5.77 (s, 2H), 4.74 - 4.42 (m, 2H), 3.78 - 3.58 (m, 3H), 3.13 (s, 3H), 2.42 (s, 1H), 1.90 (t, J = 6.8 Hz, 2H), 1.40 (d, J = 6.8 Hz, 3H), 1.32 (s, 6H), 1.11 - 0.98 (m, 1H), 0.74 - 0.64 (m, 1H), 0.55 - 0.33 (m, 3H). ESI MS [M+H] + C 26 H 34 Calculated for N7O5S: 556.2; Found: 556.2.

[0460] Example 96: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methanesulfonamido-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-[(2R)-1-hydroxy-3-methylbutan-2-yl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0461] The title compound was prepared in a similar manner to Example 72. 1H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 9.02 (d, J = 7.1 Hz, 1H), 8.16 (s, 1H), 8.06 (s, 1H), 7.97 (d, J = 9.4 Hz, 1H), 7.53 (d, J = 7.2 Hz, 1H), 6.62 (s, 2H), 4.83 (t, J = 5.1 Hz, 1H), 4.66 (s, 2H), 3.95 - 3.83 (m, 1H), 3.72 - 3.61 (m, 1H), 3.60 - 3.47 (m, 2H), 3.30 (s, 3H), 2.12 - 1.94 (m, 1H), 1.34 (d, J = 6.8 Hz, 3H), 1.25 - 1.09 (m, 1H), 0.95 (dd, J = 6.8, 2.5 Hz, 6H), 0.70 - 0.52 (m, 1H), 0.49 - 0.36 (m, 2H), 0.32 - 0.22 (m, 1H). ESI MS [M+H] + C 26 H 34 Calculated for N7O5S: 556.2; Found: 556.2.

[0462] Example 97: 2-amino-N-((R)-1-cyclopropyl-2-hydroxyethyl)-5-(2-((S)-1-cyclopropylethyl)-7-(methylsulfonamido)-1-oxoisoindolin-5-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide. [ka]

[0463] The title compound was prepared in a similar manner to Example 72. 1H NMR (400 MHz,CDCl3) δ 9.64 (s, 1H), 8.46 (d, J = 7.1 Hz, 1H), 8.27 (d, J = 1.2 Hz, 1H), 8.18 (d, J = 7.4 Hz, 1H), 7.80 (d, J = 1.2 Hz, 1H), 7.21 (d, J = 7.1 Hz, 1H), 5.70 (s, 2H), 4.60 (d, J = 17.5 Hz, 1H), 4.51 (d, J = 17.5 Hz, 1H), 3.94 - 3.88 (m, 2H), 3.74 - 3.62 (m, 2H), 3.59 - 3.48 (m, 1H), 3.09 (s, 3H), 1.39 (d, J = 6.8 Hz, 3H), 1.28 - 1.17 (m, 1H), 1.12 - 0.98 (m, 1H), 0.71 - 0.44 (m, 4H), 0.45 - 0.33 (m, 3H). ESI MS [M+H] + C 26 H 32 Calculated for N7O5S: 554.2; Found: 554.2.

[0464] Example 98: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methanesulfonamido-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-[(1R)-1-(1-methyl-1H-pyrazol-4-yl)ethyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0465] The title compound was prepared in a similar manner to Example 72. 1H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 9.02 (d, J = 7.1 Hz, 1H), 8.10 (s, 1H), 7.94 (s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.68 (s, 1H), 7.54 (d, J = 7.1 Hz, 1H), 7.49 (s, 1H), 6.63 (s, 2H), 5.23 - 5.11 (m, 1H), 4.69 (s, 2H), 3.78 (s, 3H), 3.63 - 3.50 (m, 1H), 3.21 (s, 3H), 1.56 (d, J = 6.8 Hz, ESI MS [M+H] + C 27 H 32 Calculated for N9O4S: 578.2; Found: 578.2.

[0466] Example 99: (S)-2-amino-5-(2-(1-cyclopropylethyl)-7-(methylsulfonamido)-1-oxoisoindolin-5-yl)-N-(pyridin-3-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide. [ka]

[0467] Step a: EDC·HCl (0.32 g, 1.68 mmol, 1.5 equiv.) and HOBt hydrate (0.33 g, 1.68 mmol, 1.5 equiv., 20 wt% HO) were added to a solution of carboxylic acid (0.50 g, 1.12 mmol, 1.0 equiv.) in DMF (5.5 mL). The reaction mixture was stirred at 40 °C for 1 h. The resulting solution was then cooled to room temperature. 50 mL of HO was added, and the product precipitated from the mixture and was collected by filtration. The precipitate was thoroughly washed with HO and dried under high vacuum until a constant weight was observed. The prepared hydroxybenzotriazole ester was used in the next step without further purification. Yield: 0.56 g (85%).

[0468] Step b: A mixture of hydroxybenzotriazole ester (80 mg, 0.14 mmol, 1 equiv.), 3-aminopyridine (64 mg, 0.68 mmol, 5 equiv.), and NMP (0.7 mL) was stirred in a sealed vial at 110 °C for 2 h. Upon complete consumption of the hydroxybenzotriazole ester, the reaction was cooled to room temperature and diluted with HO. The product precipitate was collected by filtration and washed twice with HO. Purification by reverse-phase HPLC (10–90% gradient of CHCN and HO with 0.1% TFA) afforded the title compound as a pale yellow solid. Yield: 32 mg (43%). 1H NMR (400 MHz, DMSO-d6) δ 9.81 (s, 1H), 9.68 (s, 1H), 9.06 (d, J = 7.1 Hz, 1H), 8.99 (s, 1H), 8.39 - 8.23 ​​(m, 3H), 8.10 (s, 1H), 7.63 (d, J = 7.1 Hz, 1H), 7.50 (dd, J = 8.4, 4.8 Hz, 1H), 6.73 (br. s, 2H), 4.67 (s, 2H), 3.61 - 3.47 (m, 1H), 3.32 (s, 3H), 1.32 (d, J = 6.8 Hz, 3H), 1.23 - 1.08 (m, 1H), 0.62 - 0.54 (m, 1H), 0.49 - 0.34 (m, 2H), 0.32 - 0.20 (m, 1H). ESI MS [M+H] + C 26 H 27 Calculated for N8O4S: 547.2; Found: 547.1.

[0469] Example 100: (S)-2-amino-5-(2-(1-cyclopropylethyl)-7-(methylsulfonamido)-1-oxoisoindolin-5-yl)-N-(pyridin-4-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide. [ka]

[0470] The title compound was prepared in a similar manner to Example 99. 1H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 9.73 (s, 1H), 9.13 (d, J = 7.1 Hz, 1H), 8.71 (d, J = 6.5 Hz, 2H), 8.27 (s, 1H), 8.18 (d, J = 6.5 Hz, 2H), 8.14 (s, 1H), 7.74 (d, J = 7.1 Hz, 1H), 6.84 (br. s, 2H), 4.70 (s, 2H), 3.65 - 3.47 (m, 1H), 3.37 (s, 3H), 1.33 (d, J = 6.8 Hz, 3H), 1.25 - 1.08 (m, 1H), 0.64 - 0.51 (m, 1H), 0.50 - 0.34 (m, 2H), 0.34 - 0.21 (m, 1H). ESI MS[M+H] + C 26 H 27 Calculated for N8O4S: 547.2; Found: 547.1.

[0471] Example 101: (S)-2-amino-5-(2-(1-cyclopropylethyl)-7-(methylsulfonamido)-1-oxoisoindolin-5-yl)-N-(2-methylpyridin-4-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide. [ka]

[0472] The title compound was prepared in a similar manner to Example 99. 1H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 9.72 (s, 1H), 9.11 (d, J = 7.1 Hz, 1H), 8.33 (d, J = 5.6 Hz, 1H), 8.26 (d, J = 1.2 Hz, 1H), 8.13 (d, J = 1.2 Hz, 1H), 7.71 - 7.61 (m, 2H), 7.53 (d, J = 2.2 Hz, 1H), 6.78 (s, 2H), 4.72 (s, 2H), 3.66 - 3.49 (m, 1H), 3.31 (s, 3H), 2.46 (s, 3H), 1.35 (d, J = 6.8 ESI MS [M+H] + C 27 H 29 Calculated for N8O4S: 561.2; Found: 561.2.

[0473] Example 102: (S)-2-amino-5-(2-(1-cyclopropylethyl)-7-(methylsulfonamido)-1-oxoisoindolin-5-yl)-N-(2,6-dimethylpyridin-4-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide. [ka]

[0474] The title compound was prepared in a similar manner to Example 99. 1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 9.72 (s, 1H), 9.14 (d, J = 7.1 Hz, 1H), 8.31 (d, J = 1.2 Hz, 1H), 8.12 (d, J = 1.2 Hz, 1H), 7.89 (s, 2H), 7.74 (d, J = 7.1 Hz, 1H), 6.84 (br. s, 2H), 4.69 (s, 2H), 3.75 - 3.42 (m, 1H), 3.28 (s, 3H), 2.61 (s, 6H), 1.32 (d, J = 6.8 Hz, 3H), 1.24 - 1.06 (m, 1H), 0.65 - 0.53 (m, 1H), 0.50 - 0.35 (m, 2H), 0.33 - 0.21 (m, 1H). ESI MS[M+H] + C 28 H 31 Calculated for N8O4S: 575.2; Found: 575.2.

[0475] Example 103: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methanesulfonamido-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-[6-(2-hydroxypropan-2-yl)pyridin-3-yl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0476] The title compound was prepared in a similar manner to Example 99. 1H NMR (400 MHz, CDCl3) δ 10.02 (s, 1H), 9.74 (s, 1H), 9.45 (s, 1H), 8.75 (d, J = 8.7 Hz, 1H), 8.58 (s, 1H), 8.40 (s, 1H), 7.79 (s, 1H), 7.73 (d, J = 8.7 Hz, 1H), 7.42 - 7.31 (m, 1H), 4.78 - 4.55 (m, 2H), 3.69 (q, J = 7.4, 6.9 Hz, 2H), 3.15 (s, 3H), 1.74 (s, 6H), 1.42 (d, J = 6.8 Hz, 3H), 1.16 - 0.97 (m, 1H), 0.77 - 0.62 (m, 1H), 0.59 - 0.28 (m, 3H). ESI MS [M+H] + C 29 H 33 Calculated for N8O5S: 605.2; Found: 605.2.

[0477] Example 104: (S)-2-Amino-5-(2-(1-cyclopropylethyl)-7-(methylsulfonamido)-1-oxoisoindolin-5-yl)-N-phenylpyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0478] The title compound was prepared in a similar manner to Example 99. 1H NMR (400 MHz, CDCl3) δ 9.68(s, 1H), 9.62 (s, 1H), 8.52 (d, J = 7.0 Hz, 1H), 8.25 (s, 1H), 7.80 (s, 1H), 7.72 (d, J = 7.9 Hz, 2H), 7.37 (t, J = 7.7 Hz, 2H), 7.27 - 7.22 (m, 1H), 7.12 (t, J = 7.4 Hz, 1H), 4.63 (d, J = 17.6 Hz, 1H), 4.53 (d, J = 17.6 Hz, 1H), 3.77 - 3.61 (m, 1H), 3.10 (s, 3H), 1.40 (d, J = 6.8 Hz, 3H), 1.13 - 0.98 (m, 1H), 0.73 - 0.66 (m, 1H), 0.58 - 0.30 (m, 3H). ESI MS [M+H] + C 27 H 28 Calculated for N7O4S: 546.2; Found: 546.1.

[0479] Example 105: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methanesulfonamido-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-[4-(hydroxymethyl)phenyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0480] The title compound was prepared in a similar manner to example 99 (amide coupling in step b was carried out at 150° C. for 1 hour). 1H NMR (400 MHz, CDCl3) δ 9.71 (s, 1H), 9.70 (s, 1H), 8.54 (d, J = 7.1 Hz, 1H), 8.31 (s, 1H), 7.85 (s, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.29 - 7.26 (m, 1H), 4.72 - 4.50 (m, 4H), 3.76 - 3.66 (m, 1H), 3.12 (s, 3H), 1.41 (d, J = 6.8 Hz, 3H), 1.15 - 0.97 (m, 1H), 0.76 - 0.61 (m, 1H), 0.58 - 0.33 (m, 3H). ESI MS [M+H] + C 28 H 30 Calculated for N7O5S: 576.2; Found: 576.3.

[0481] Example 106: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methanesulfonamido-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0482] The title compound was prepared in a similar manner to Example 99. 1H NMR (400 MHz, CDCl3) δ 9.68 (s, 1H), 9.41 (s, 1H), 8.49 (d, J = 7.1 Hz, 1H), 8.32 (d, J = 1.2 Hz, 1H), 8.25 (s, 1H), 7.94 (s, 1H), 7.76 (s, 1H), 7.24 (d, J = 7.1 Hz, 1H), 4.78 - 4.49 (m, 4H), 3.78 - 3.62 (m, 1H), 3.11 (s, 3H), 1.42 (d, J = 6.9 Hz, 3H), 1.07 (ddt, J = 13.2, 9.1, 4.4 Hz, 1H), 0.77 - 0.64 (m, 1H), 0.61 - 0.30 (m, 3H). 19 F NMR (376 MHz, CDCl3) δ - 71.65 (t). ESI MS [M+H] + C 26 H 27 Calculated for F3N9O4S: 618.2; Found: 618.1.

[0483] Example 107: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methanesulfonamido-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-(1,3-dimethyl-1H-pyrazol-4-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0484] The title compound was prepared in a similar manner to Example 99. 1H NMR (400 MHz, CDCl3) δ 9.66 (s, 1H), 9.46 (s, 1H), 8.59 (d, J = 7.1 Hz, 1H), 8.20 (d, J = 1.2 Hz, 1H), 8.09 (s, 1H), 7.93 (d, J = 1.1 Hz, 1H), 7.32 (d, J = 7.1 Hz, 1H), 4.67 - 4.45 (m, 2H), 3.96 (s, 3H), 3.75 - 3.64 (m, 1H), 3.11 (s, 3H), 2.44 (s, 3H), 1.41 (d, J = 6.8 Hz, 3H), 1.13 - 1.01 (m, 1H), 0.76 - 0.65 (m, 1H), 0.58 - 0.31 (m, 3H). ESI MS [M+H] + C 26 H 30 Calculated for N9O4S: 564.2; Found: 564.3.

[0485] Example 108: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methanesulfonamido-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-(1,5-dimethyl-1H-pyrazol-4-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0486] The title compound was prepared in a similar manner to Example 99. 1H NMR (400 MHz, CDCl3) δ 9.60 (s, 1H), 9.22 (s, 1H), 8.61 (d, J = 7.0 Hz, 1H), 8.32 (d, J = 1.1 Hz, 1H), 7.95 (s, 1H), 7.77 (d, J = 1.2 Hz, 1H), 7.31 (d, J = 7.0 Hz, 1H), 4.70 - 4.48 (m, 2H), 3.94 (s, 3H), 3.75 - 3.63 (m, 1H), 3.08 (s, 3H), 2.36 (s, 3H), 1.39 (d, J = 6.8 Hz, 3H), 1.11 - 0.98 (m, 1H), 0.76 - 0.63 (m, 1H), 0.57 - 0.30 (m, 3H). ESI MS [M+H] + C 26 H 30 Calculated for N9O4S: 564.2; Found: 564.2.

[0487] Example 109: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methanesulfonamido-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-(1-methyl-1H-1,2,4-triazol-3-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0488] The title compound was prepared in a similar manner to Example 99. 1H NMR (400 MHz, CDCl3) δ 10.21 (s, 1H), 9.65 (s, 1H), 8.53 (d, J = 7.0 Hz, 1H), 8.33 (s, 1H), 8.13 (s, 1H), 7.91 (s, 1H), 7.31 (d, J = 7.1 Hz, 1H), 4.71 - 4.48 (m, 2H), 3.98 (s, 3H), 3.76 - 3.62 (m, 1H), 3.16 (s, 3H), 1.39 (d, J = 6.8 Hz, 3H), 1.11 - 0.99 (m, 1H), 0.75 - 0.61 (m, 1H), 0.57 - 0.30 (m, 3H). ESI MS [M+H] + C 24 H 27 N 10 Calculated for O4S: 551.2; Found: 551.2.

[0489] Example 110: 2-Amino-N-cyclopropyl-5-{2-[(1S)-1-cyclopropylethyl]-7-ethanesulfonamido-1-oxo-2,3-dihydro-1H-isoindol-5-yl}pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0490] This molecule was prepared in a similar manner to Example 113 (see below), substituting ethanesulfonyl chloride for 2-methoxy-ethanesulfonyl chloride in step a, and the final compound was obtained via the same chemical steps using cyclopropylamine for the final amide coupling. 1H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 1H), 9.00 (d, J = 7.2 Hz, 1H), 8.21 (s, 1H), 8.04 (s, 1H), 7.67 (d, J = 3.7 Hz, 1H), 7.54 (d, J = 7.2 Hz, 1H), 4.68 (s, 2H), 3.61 - 3.51 (m, 1H), 3.39 (q, J = 7.3 Hz, 2H), 2.92 - 2.75 (m, 1H), 1.32 (d, J = 6.9 Hz, 3H), 1.23 (t, J = 7.3 Hz, 3H), 1.20 - 1.10 (m, ESI MS [M+H] + C 25 H 30 Calculated for N7O4S: 524.1; Found: 524.1.

[0491] Example 111: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-ethanesulfonamido-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-[trans-3-hydroxy-3-methylcyclobutyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0492] The title compound was prepared in a similar manner to Example 72. 1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 9.02 (d, J = 7.1 Hz, 1H), 8.28 (s, 1H), 8.07 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 7.2 Hz, 1H), 6.63 (s, 2H), 4.88 (s, 1H), 4.69 (s, 2H), 4.58 (q, J = 7.8 Hz, 1H), 3.57 (dd, J = 9.2, 6.7 Hz, 1H), 3.40 - 3.32 (m, 2H), 2.39 - 2.30 (m, 2H), 2.14 - 2.02 (m, 2H), 1.37 - 1.28 (m, 6H), 1.27 - 1.12 (m, 4H), 0.64 - 0.52 (m, 1H), 0.51 - 0.34 (m, 2H), 0.32 - 0.19 (m, 1H). ESI MS [M+H] + C 27 H 34 Calculated for N7O5S: 568.2; Found: 568.2.

[0493] Example 112: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-ethanesulfonamido-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-(pyridin-3-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0494] The title compound was prepared in a similar manner to Example 99. 1H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H), 9.72 (s, 1H), 9.11 (d, J = 7.1 Hz, 1H), 8.94 (dd, J = 2.6, 0.7 Hz, 1H), 8.32 - 8.29 (m, 2H), 8.21 (ddd, J = 8.3, 2.6, 1.5 Hz, 1H), 8.15 (d,J = 1.2 Hz, 1H), 7.65 (d, J = 7.1 Hz, 1H), 7.40 (ddd, J = 8.3, 4.7, 0.7 Hz, 1H), 6.76 (s, 2H), 4.72 (s, 2H), 3.63 - 3.52 (m, 1H), 3.43 (q, J = 7.3 Hz, 2H), 1.35 (d, J = 6.8 Hz, 3H), 1.27 - 1.15 (m, 4H), 0.63 - 0.54 (m, 1H), 0.49 - 0.37 (m, 2H), 0.32 - 0.25 (m, 1H). ESI MS [M+H] + C 27 H 29 Calculated for N8O4S: 561.2; Found: 561.2.

[0495] Example 113: 2-Amino-N-cyclopropyl-5-{2-[(1S)-1-cyclopropylethyl]-7-(2-methoxyethanesulfonamido)-1-oxo-2,3-dihydro-1H-isoindol-5-yl}pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0496] Step a: The aniline product from step b of Example 72 (500 mg, 1.69 mmol, 1.0 equiv) was dissolved in CHCl (6 mL), and the mixture was cooled to 0 °C. To this solution were added DMAP (21 mg, 0.169 mmol, 10 mol%), DIPEA (0.90 mL, 5.07 mmol, 3.0 equiv), and 2-methoxyethanesulfonyl chloride (670 mg, 4.23 mmol, 2.5 equiv). The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction was quenched with 1 M aqueous HCl and diluted with EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layers were combined, washed with brine, and dried over MgSO. Concentration under reduced pressure gave the bis-sulfonylated product, which was carried on crude to the next step.

[0497] Step b: The product of step a was dissolved in THF (5 mL) and TBAF (1.0 M in THF, 2.70 mL, 2.70 mmol, 1.6 equiv) was added. The reaction mixture was stirred for 1 h, then quenched with 1 M aqueous HCl and diluted with EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layers were combined, washed with brine, and dried over MgSO. Concentration under reduced pressure and purification by flash column chromatography (SiO, hexane to 50% EtOAc gradient) afforded the reverse sulfonamide as a white solid (318 mg, 0.763 mmol, 45% over two steps).

[0498] Step c: The product of step b (215 mg, 0.515 mmol, 1.0 equiv) was combined with Pd(dppf)Cl (38 mg, 0.052 mmol, 0.1 equiv), B2pin2 (170 mg, 0.670 mmol, 1.3 equiv), and KOAc (111 mg, 1.13 mmol, 2.2 equiv) in dioxane (3 mL). The resulting mixture was heated to 100 °C and stirred for 1 h. The mixture was cooled to room temperature, filtered through Celite (washed with EtOAc), and concentrated under reduced pressure. The resulting residue was used directly in the next step without purification.

[0499] Step d: The crude pinacol boronic ester obtained in step c was combined with Pd(dppf)Cl (38 mg, 0.052 mmol, 0.1 equiv.), 1 M aqueous NaCO (1.5 mmol, 1.5 mL, 3.0 equiv.), 2-amino-5-chloropyrazolo[1,5-α]pyrimidine-3-carboxylic acid ethyl ester (124 mg, 0.515 mmol, 1.0 equiv.), and dioxane (2 mL). The resulting mixture was heated to 100 °C and stirred for 1 h. The reaction mixture was cooled to room temperature and diluted with CHCl and HO. The aqueous phase was separated and back-extracted with additional CHCl, then extracted once with EtOAc. The organic layers were combined and dried over MgSO. Concentration under reduced pressure and purification by column chromatography (SiO2, gradient from 100% CH2Cl2 to 100% EtOAc) afforded the cross-coupled ester product (95 mg, 34% over two steps).

[0500] Step e: The ethyl ester product of step d (95 mg, 0.175 mmol, 1.0 equiv) was dissolved in EtOH (0.2 mL), THF (1 mL), and HO (0.2 mL). · HO (88 mg, 2.1 mmol, 12.0 equiv) was added and the reaction mixture was heated to 80° C. for 4 h. The resulting mixture was cooled to room temperature and the solvent was removed in vacuo. The mixture was diluted with HO and acidified to pH 3 with 2 N HCl. The resulting precipitate was collected by vacuum filtration and dried under vacuum at 40° C. for 2 h to give the carboxylic acid product (65 mg, 72%), which was used in the next step without purification.

[0501] Step f: The product of step e (65 mg, 0.126 mmol) was dissolved in DMF (1.0 mL) and cyclopropylamine (20 μL, 0.35 mmol, 2.0 equiv.), EtN (50 μL, 0.38 mmol, 3.0 equiv.), and HATU (96 mg, 0.252 mmol, 2.0 equiv.) were added sequentially, and the solution was stirred at room temperature. After 0.5 h, the reaction mixture was quenched with 2 M aqueous HCl and diluted with EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layers were combined, washed with brine, and dried over MgSO. Concentration under reduced pressure and purification by flash column chromatography (SiO2, gradient series of 100% DCM - 100% EtOAc - 100% CH2Cl2 - 10% MeOH) afforded the title compound as a yellow solid (26.8 mg, 38%). 1 H NMR (400 MHz, CDCl3) δ 9.74 (s, 1H), 8.48 (d, J = 7.1 Hz, 1H), 8.33 (s, 1H), 7.82 (s, 1H), 7.73 (s, 1H), 7.20 (d, J = 7.1 Hz, 1H), 5.80 (s, 2H), 4.67 - 4.49 (m, 2H), 3.82 (t, J = 5.9 Hz, 2H), 3.77 - 3.63 (m, 1H), 3.45 (t, J = 5.9 Hz, 2H), 3.27 (s, 3H), 3.05 - 2.86 (m, 1H), 1.40 (d, J = 6.8 Hz, ESI MS [M+H] + C 26 H 32 Calculated for N7O5S: 554.2; Found: 554.2.

[0502] Example 114: 2-Amino-N-cyclopropyl-5-{2-[(1S)-1-cyclopropylethyl]-7-(N-methylmethanesulfonamido)-1-oxo-2,3-dihydro-1H-isoindol-5-yl}pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0503] Step a: To a solution of the aryl bromide (800 mg, 2.14 mmol, 1.0 equiv) in DMF (7 mL) was added K2CO3 (590 mg, 4.28 mmol, 2.0 equiv) and Mel (0.45 mL, 4.28 mmol, 2.0 equiv). The resulting mixture was stirred at room temperature for 3 h. The reaction was quenched with 2 M aqueous HCl and diluted with EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layers were combined, washed with HO, brine, and dried over MgSO4. Concentration under reduced pressure gave the crude methylated reverse sulfonamide, which was used directly in the next step.

[0504] Step b: The product of step a (approximately 2.14 mmol, 1.0 equiv.) was combined with Pd(dppf)Cl (150 mg, 0.21 mmol, 0.1 equiv.), B2pin2 (700 mg, 2.78 mmol, 1.3 equiv.), and KOAc (460 mg, 4.70 mmol, 2.2 equiv.) in dioxane (10 mL). The resulting mixture was heated to 100 °C and stirred for 2 h. The mixture was cooled to room temperature, filtered through Celite (washed with EtOAc), and concentrated under reduced pressure. The resulting residue was used directly in the next step without purification.

[0505] Step c: The crude pinacol boronic ester obtained in step b was combined with Pd(dppf)Cl (150 mg, 0.21 mmol, 0.1 equiv.), 1 M aqueous NaCO (6.5 mmol, 6.5 mL, 3.0 equiv.), 2-amino-5-chloropyrazolo[1,5-α]pyrimidine-3-carboxylic acid ethyl ester (513 mg, 0.515 mmol, 1.0 equiv.), and dioxane (6.5 mL). The resulting mixture was heated to 100 °C and stirred for 1.5 h. The reaction mixture was cooled to room temperature and diluted with CHCl and HO. The aqueous phase was separated and back-extracted with additional CHCl, then extracted once with EtOAc. The organic layers were combined and dried over MgSO. Concentration under reduced pressure and purification by column chromatography (SiO2, gradient from 100% DCM to 100% EtOAc) afforded the cross-coupled ester product (550 mg, 50% over three steps).

[0506] Step d: The ethyl ester product from step c (300 mg, 0.586 mmol, 1.0 equiv) was dissolved in EtOH (1 mL), THF (2 mL), and HO (1 mL). LiOH·HO (147 mg, 3.52 mmol, 6.0 equiv) was added, and the reaction mixture was heated to 70 °C for 15 h. The resulting mixture was cooled to room temperature, and the solvent was removed in vacuo. The mixture was diluted with HO and acidified to pH 3 with 2 N HCl. The resulting precipitate was collected by vacuum filtration and dried under vacuum at 40 °C for 2 h to give the carboxylic acid product (130 mg, 46%), which was used in the next step without purification.

[0507] Step e: The product of step d (50 mg, 0.103 mmol) was dissolved in DMF (1.0 mL) and HOBt (24 mg, 0.134 mmol, 1.3 equiv, 20 wt% HO), EtN (50 μL, 0.31 mmol, 3.0 equiv), cyclopropylamine (10 mg, 0.165 mmol, 1.6 equiv), and EDC·HCl (31 mg, 0.162 mmol, 1.6 equiv) were added sequentially, and the solution was heated to 40 °C. After 2 days, the reaction mixture was directly purified by reverse-phase HPLC (20–80% gradient of CHCN and HO with 0.1% TFA) to give the title compound as a yellow solid. 1 H NMR (400 MHz, DMSO―d6) δ 9.04 (d, J = 7.1 Hz, 1H), 8.35 (s, 1H), 8.14 (s, 1H), 7.82 (d, J = 4.0 Hz, 1H), 7.65 (d, J = 7.2 Hz, 1H), 6.62 (s, 2H), 4.67 (s, 2H), 3.69 - 3.57 (m, 1H), 3.38 (s, 3H), 3.12 (s, 3H), 2.92 - 2.83 (m, 1H), 1.32 (d, J = 6.8 Hz, 3H), 1.23 - 1.11 (m, 1H), 0.84 - 0.73 (m, 2H), 0.68 - 0.53 (m, 3H), 0.50 - 0.34 (m, 2H), 0.34 - 0.23 (m, 1H). ESI MS [M+H] + C 25 H 30 Calculated for N7O4S: 524.2; Found: 524.2.

[0508] Example 115: 2-amino-N-cyclopropyl-5-{7-methanesulfonamido-1-oxo-2-[(2S)-1,1,1-trifluoropropan-2-yl]-2,3-dihydro-1H-isoindol-5-yl}pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0509] The title compound was prepared in a similar manner to Examples 27 and 72. 1 H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 9.01 (d, J = 7.1 Hz, 1H), 8.21 (s, 1H), 8.04 (s, 1H), 7.67 (d, J = 3.6 Hz, 1H), 7.54 (d, J = 7.1 Hz, 1H), 6.63 (s, 2H), 5.03 (p, J = 7.6 Hz, 1H), 4.77 (d, J = 17.7 Hz, 1H), 4.54 (d, J = 17.7 Hz, 1H), 3.31 (s, 3H), 2.81 (tq, J = 7.4, 3.8 Hz, 1H), 1.51 (d, J = 7.1 Hz, 3H), 0.85 - 0.70 (m, 2H), 0.70 - 0.55 (m, 2H). ESI MS [M+H] + C 22 H 22 Calculated for F3N7O4S: 538.1; Found: 538.0.

[0510] Example 116: 2-amino-5-{7-methanesulfonamido-1-oxo-2-[(2S)-1,1,1-trifluoropropan-2-yl]-2,3-dihydro-1H-isoindol-5-yl}-N-(oxetan-3-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0511] The title compound was prepared in a similar manner to Example 123 (see below). 1H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H), 9.04 (d, J = 7.1 Hz, 1H), 8.30 (s, 1H), 8.14 - 8.02 (m, 2H), 7.58 (d, J = 7.2 Hz, 1H), 6.61 (s, 2H), 5.18 - 4.94 (m, 2H), 4.84 - 4.73 (m, 3H), 4.66 (t, J = 6.6 Hz, 2H), 4.55 (d, J = 17.6 Hz, 1H), 3.31 (s, 3H), 1.51 (d, J = 7.1 Hz, 3H). ESI MS [M+H] + C 22 H 22 Calculated for F3N7O5S: 554.1; Found: 554.1.

[0512] Example 117: (S)-2-Amino-N-(3-cyanooxetan-3-yl)-5-(7-(methylsulfonamido)-1-oxo-2-(1,1,1-trifluoropropan-2-yl)isoindolin-5-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0513] The title compound was prepared in a similar manner to Example 123 (see below). 1H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H), 9.06 (d, J = 7.1 Hz, 1H), 8.65 (s, 1H), 8.30 (d, J = 1.2 Hz, 1H), 8.20 (d, J = 1.2 Hz, 1H), 7.65 (d, J = 7.1 Hz, 1H), 6.67 (br. s, 2H), 5.10 - 4.99 (m, 1H), 4.97 (d, J = 7.4 Hz, 2H), 4.84 (dd, J = 7.6, 1.9 Hz, 2H), 4.77 (d, J = 17.7 Hz, 1H), 4.54 (d, J = 17.7 Hz, 1H), 3.39 (s, 3H), 1.51 (d, J = 7.1 Hz, 3H). 19 F NMR (376 MHz, DMSO-d6) δ - 73.53 (d, J = 8.2 Hz). ESI MS [M+H] + C 23 H 22 Calculated for F3N8O5S: 579.1; Found: 579.1.

[0514] Example 118: 2-amino-N-[(2R)-1-hydroxypropan-2-yl]-5-{7-methanesulfonamido-1-oxo-2-[(2S)-1,1,1-trifluoropropan-2-yl]-2,3-dihydro-1H-isoindol-5-yl}pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0515] The title compound was prepared in a similar manner to Example 123 (see below). 1H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 9.00 (d, J = 7.1 Hz, 1H), 8.19 (s, 1H), 8.12 (s, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.52 (d, J = 7.1 Hz, 1H), 6.60 (s, 2H), 5.18 - 4.88 (m, 2H), 4.74 (d, J = 17.7 Hz, 1H), 4.53 (d, J = 17.6 Hz, 1H), 4.15 - 4.00 (m, 1H), 3.62 - 3.41 (m, 2H), 3.31 (s, 3H), 1.51 (d, J = 7.1 Hz, 3H), 1.20 (d, J = 6.7 Hz, 3H). ESI MS [M+H] + C 22 H 24 Calculated for F3N7O5S: 556.2; Found: 556.0.

[0516] Example 119: 2-amino-N-[(2R)-1-hydroxybutan-2-yl]-5-{7-methanesulfonamido-1-oxo-2-[(2S)-1,1,1-trifluoropropan-2-yl]-2,3-dihydro-1H-isoindol-5-yl}pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0517] The title compound was prepared in a similar manner to Example 123 (see below). 1H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 9.00 (d, J = 7.1 Hz, 1H), 8.19 (s, 1H), 8.10 (s, 1H), 7.94 (d, J = 8.7 Hz, 1H), 7.52 (d, J = 7.1 Hz, 1H), 6.61 (s, 2H), 5.03 (p, J = 7.6 Hz, 1H), 4.91 (t, J = 5.0 Hz, 1H), 4.73 (d, J = 17.7 Hz, 1H), 4.52 (d, J = 17.6 Hz, 1H), 3.96 - 3.83 (m, 1H), 3.67 - 3.55 ESI MS [M+H] + C 23 H 26 Calculated for F3N7O5S: 570.2; Found: 570.0.

[0518] Example 120: 2-amino-N-((R)-1-cyclopropyl-2-hydroxyethyl)-5-(7-(methylsulfonamido)-1-oxo-2-((S)-1,1,1-trifluoropropan-2-yl)isoindolin-5-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0519] The title compound was prepared in a similar manner to Example 123 (see below). 1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 9.01 (d, J = 7.1 Hz, 1H), 8.27 (s, 1H), 8.16 (d, J = 8.8 Hz, 1H), 8.12 (s, 1H), 7.54 (d, J = 7.1 Hz, 1H), 6.59 (br. s, 2H), 5.12 - 4.94 (m, 1H), 4.74 (d, J = 17.8 Hz, 1H), 4.53 (d, J = 17.8 Hz, 1H), 3.69 (dd, J = 10.6, 4.2 Hz, 1H), 3.60 (dd, J = 10.6, 4.2 Hz, 1H), 3.50 - 3.42 (m, 1H), 3.31 (s, 3H), 1.51 (d, J = 7.1 Hz, 3H), 1.23 - 1.06 (m, 1H), 0.55 - 0.33 (m, 3H), 0.31 - 0.21 (m, 1H). ESI MS [M+H] + C 24 H 27 Calculated for F3N7O5S: 582.2; Found: 582.2.

[0520] Example 121: 2-amino-5-{7-methanesulfonamido-1-oxo-2-[(2S)-1,1,1-trifluoropropan-2-yl]-2,3-dihydro-1H-isoindol-5-yl}-N-[trans-3-hydroxycyclobutyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0521] The title compound was prepared in a similar manner to Example 123 (see below). 1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 9.02 (d, J = 7.1 Hz, 1H), 8.25 (s, 1H), 8.06 (s, 1H), 7.80 (d, J = 7.4 Hz, 1H), 7.54 (d, J = 7.1 Hz, 1H), 6.61 (s, 2H), 5.14 - 4.92 (m, 1H), 4.83 - 4.69 (m, 1H), 4.62 - 4.48 (m, 2H), 4.32 - 4.25 (m, 1H), 3.30 (s, 3H), 2.37 - 2.27 (m, 2H), 2.24 - 2.13 (m, 2H), 1.51 (d, J = 7.0 Hz, 4H). ESI MS [M+H] + C 23 H 24 Calculated for F3N7O5S: 568.2; Found: 568.1.

[0522] Example 122: 2-amino-5-{7-methanesulfonamido-1-oxo-2-[(2S)-1,1,1-trifluoropropan-2-yl]-2,3-dihydro-1H-isoindol-5-yl}-N-[cis-4-hydroxy-4-methylcyclohexyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0523] The title compound was prepared in a similar manner to Example 123 (see below). 1H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H), 9.01 (d, J = 7.1 Hz, 1H), 8.15 (s, 1H), 8.00 (s, 1H), 7.57 - 7.46 (m, 2H), 6.70 - 6.56 (m, 2H), 5.03 (p, J = 7.6 Hz, 1H), 4.75 (d, J = 17.8 Hz, 1H), 4.53 (d, J = 17.7 Hz, 1H), 3.81 (q, J = 7.3 Hz, 1H), 3.36 (s, 3H), 1.74 - 1.62 (m, 4H), 1.64 - 1.54 (m, 2H), 1.51 (d, J = 7.1 Hz, 3H), 1.46 - 1.33 (m, 2H), 1.12 (s, 3H). ESI MS [M+H] + C 26 H 30 Calculated for F3N7O5S: 610.2; Found: 610.1.

[0524] Example 123: 2-amino-5-{7-methanesulfonamido-1-oxo-2-[(2S)-1,1,1-trifluorobutan-2-yl]-2,3-dihydro-1H-isoindol-5-yl}-N-(oxetan-3-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0525] Step a: The crude benzyl bromide starting material (6.40 g, 19.6 mmol, 1.0 equiv.) was combined with CHCN (150 mL), (2S)-1,1,1-trifluoro-2-butanamine (2.5 mL, 19.6 mmol, 1.0 equiv.), and KCO (8.11 g, 58.8 mmol, 3.0 equiv.). The resulting mixture was stirred at 80 °C for 14 h and then cooled to room temperature. The mixture was filtered and concentrated onto Celite. Purification by column chromatography (SiO, hexane to 20% EtOAc gradient) afforded the displacement product as a pale yellow oil (4.62 g, 63%), which was carried on directly to the next step.

[0526] Step b: The amine product from step a (4.62 g) was heated without water at 120° C. for 4 h. Purification by column chromatography (SiO, hexane to 20% EtOAc gradient) afforded the isoindolinone product as a white solid (1.4 g, 33%).

[0527] Step c: The product of step b (1.1 g, 3.24 mmol, 1.0 equiv) was mixed with neat PMBNH (3.5 mL) and heated at 100 °C for 14 h. The reaction mixture was cooled and partitioned with 10% aqueous citric acid and EtOAc. The aqueous layer was separated and back-extracted with more EtOAc. The organic layers were combined and washed with more 10% aqueous citric acid, saturated brine, and dried over MgSO. Concentration under reduced pressure gave the PMB amine adduct, which was used crude in the next step.

[0528] Step d: The product of step c was mixed with TFA (6 mL) and stirred at 50° C. for 4 h. The reaction mixture was concentrated under reduced pressure, then quenched with saturated aqueous NaHCO and diluted with EtOAc. The organic layers were combined, washed with brine, and dried over MgSO. Concentration under reduced pressure and purification by column chromatography (SiO, hexane to 20% EtOAc gradient) afforded the aniline product as a white solid (630 mg, 58% over two steps).

[0529] Step e: The product of step d (630 mg, 1.87 mmol, 1.0 equiv) was dissolved in CHCl (10 mL) and the mixture was cooled to 0 °C. To this solution were added DMAP (22 mg, 0.19 mmol, 10 mol%), DIPEA (1.0 mL, 5.60 mmol, 3.0 equiv), and MsCl (0.40 mL, 4.70 mmol, 2.5 equiv). The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction was quenched with 1 M aqueous HCl and diluted with EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layers were combined, washed with brine, and dried over MgSO. Concentration under reduced pressure gave the bis-sulfonylated product, which was used crude in the next step.

[0530] Step f: The product of step e was combined with THF (4 mL), HO (2 mL), and NaOH (150 mg, 3.75 mmol, 2.0 equiv). The mixture was stirred at room temperature for 3 h. The reaction was quenched with 1 M aqueous HCl and diluted with EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layers were combined, washed with brine, and dried over MgSO. Concentration under reduced pressure gave the crude reverse sulfonamide material (810 mg), which was used directly in the next step.

[0531] Step g: The product of step f (810 mg, 1.95 mmol, 1.0 equiv) was combined with Pd(dppf)Cl (142 mg, 0.19 mmol, 0.1 equiv), B2pin2 (642 mg, 2.54 mmol, 1.3 equiv), and KOAc (420 mg, 4.30 mmol, 2.2 equiv) in dioxane (13 mL). The resulting mixture was heated to 100 °C and stirred for 3 h. The reaction was cooled to room temperature, filtered through Celite (washed with EtOAc), and concentrated under reduced pressure. The resulting residue was used directly in the next step without purification.

[0532] Step h: The crude pinacol boronic ester obtained in step g was combined with Pd(dppf)Cl (142 mg, 0.19 mmol, 0.1 equiv.), 1 M aqueous NaCO (6.0 mmol, 6.0 mL, 3.0 equiv.), 2-amino-5-chloropyrazolo[1,5-α]pyrimidine-3-carboxylic acid ethyl ester (470 mg, 1.95 mmol, 1.0 equiv.), and dioxane (6 mL). The resulting mixture was heated to 100 °C and stirred for 1 h. The reaction mixture was cooled to room temperature and diluted with CHCl and HO. The aqueous phase was separated and back-extracted with additional CHCl, then extracted once with EtOAc. The organic layers were combined and dried over MgSO. Concentration under reduced pressure and purification by column chromatography (SiO2, CH2Cl2 to 5% MeOH gradient) afforded the cross-coupled ester product (970 mg, 92% over two steps).

[0533] Step i: The ethyl ester product from step h (970 mg, 1.80 mmol, 1.0 equiv) was dissolved in EtOH (5 mL), THF (10 mL), and HO (5 mL). LiOH·HO (460 mg, 10.8 mmol, 6.0 equiv) was added, and the reaction mixture was heated to 80 °C for 15 h. The resulting mixture was cooled to room temperature, and the solvent was removed in vacuo. The mixture was diluted with HO and acidified to pH 3 with 2 N HCl. The resulting precipitate was collected by vacuum filtration and dried under vacuum at 40 °C for 2 h to give the carboxylic acid product (479 mg, 52%), which was used in the next step without purification.

[0534] Step j: The product of step i (55 mg, 0.107 mmol) was dissolved in DMF (1.0 mL) and HOBt (21 mg, 0.139 mmol, 1.3 equiv, 20 wt% HO), EtN (50 μL, 0.32 mmol, 3.0 equiv), 3-oxetanamine (13 mg, 0.171 mmol, 1.6 equiv), and EDC·HCl (33 mg, 0.171 mmol, 1.6 equiv) were added sequentially, and the solution was heated to 40 °C. After 2 h, the reaction mixture was diluted with HO and EtOAc. The aqueous layer was separated and back-extracted with additional EtOAc. The organic layers were combined, washed with HO, and dried over MgSO. Concentration under reduced pressure and purification by column chromatography (SiO2, DCM to 5% MeOH gradient) afforded the title compound as a yellow solid (23 mg, 38%). 1H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 9.07 (d, J = 7.1 Hz, 1H), 8.32 (s, 1H), 8.18 - 8.06 (m, 2H), 7.61 (d, J = 7.2 Hz, 1H), 6.64 (s, 2H), 5.23 - 5.05 (m, 1H), 4.95 - 4.72 (m, 4H), 4.68 (t, J = 6.7 Hz, 2H), 4.57 (d, J = 17.9 Hz, 1H), 3.38 (s, 3H), 2.05 - 1.91 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H). ESI MS [M+H] + C 23 H 25 Calculated for F3N7O5S: 568.2; Found: 568.2.

[0535] Example 124: 2-amino-N-cyclopropyl-5-{7-methanesulfonamido-1-oxo-2-[(2S)-1,1,1-trifluorobutan-2-yl]-2,3-dihydro-1H-isoindol-5-yl}pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0536] The title compound was prepared in a similar manner to Example 123. 1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 9.04 (d, J = 7.1 Hz, 1H), 8.23 ​​(s, 1H), 8.05 (s, 1H), 7.70 (d, J = 3.6 Hz, 1H), 7.56 (d, J = 7.2 Hz, 1H), 6.66 (s, 2H), 4.94 - 4.80 (m, 1H), 4.75 (d, J = 17.9 Hz, 1H), 4.56 (d, J = 17.8 Hz, 1H), 3.35 (s, 3H), 2.84 (td, J = 7.1, 3.6 Hz, 1H), 1.97 (dq, J = 0.89 (t, J = 7.3 Hz, 3H), 0.81 - 0.73 (m, 2H), 0.69 - 0.62 (m, 2H). ESI MS [M+H] + C 23 H 25 Calculated for F3N7O4S: 552.2; Found: 552.2.

[0537] Example 125: 2-amino-5-{7-methanesulfonamido-1-oxo-2-[(2S)-1,1,1-trifluorobutan-2-yl]-2,3-dihydro-1H-isoindol-5-yl}-N-(3-methyloxetan-3-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0538] The title compound was prepared in a similar manner to Example 123. 1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 9.03 (d, J = 7.1 Hz, 1H), 8.36 - 8.21 (m, 1H), 8.11 - 8.05 (m, 1H), 8.02 (s, 1H), 7.57 (d, J = 7.2 Hz, 1H), 6.61 (s, 2H), 4.90 - 4.79 (m, 1H), 4.77 (d, J = 6.4 Hz, 2H), 4.72 (d, J = 18.0 Hz, 1H), 4.53 (d, J = 17.8 Hz, 1H), 4.42 (d, J = 6.4 Hz, 2H), 3.32 (s, 3H), 2.01 - 1.84 (m, 2H), 1.66 (s, 3H), 0.86 (t, J = 7.3 Hz, 3H). ESI MS [M+H] + C 24 H 27 Calculated for F3N7O5S: 582.2; Found: 582.2.

[0539] Example 126: 2-amino-5-{7-methanesulfonamido-1-oxo-2-[(2S)-1,1,1-trifluorobutan-2-yl]-2,3-dihydro-1H-isoindol-5-yl}-N-[trans-3-(2-hydroxypropan-2-yl)cyclobutyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0540] The title compound was prepared in a similar manner to Example 123. 1H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 9.05 (d, J = 7.1 Hz, 1H), 8.31 (d, J = 1.3 Hz, 1H), 8.09 (d, J = 1.2 Hz, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.56 (d, J = 7.2 Hz, 1H), 6.64 (s, 2H), 4.86 (p, J = 7.9 Hz, 1H), 4.75 (d, J = 17.9 Hz, 1H), 4.55 (d, J = 17.8 Hz, 1H), 4.49 - 4.39 (m, 1H), 4.25 (s, 1H), 3.33 (s, 3H), 2.40 - 2.24 (m, 3H), 2.11 - 1.91 (m, 4H), 1.07 (s, 6H), 0.89 (t, J = 7.3 Hz, 3H). ESI MS [M+H] + C 27 H 33 Calculated for F3N7O5S: 624.2; Found: 624.2.

[0541] Example 127: 2-amino-5-{7-methanesulfonamido-1-oxo-2-[(2S)-1,1,1-trifluorobutan-2-yl]-2,3-dihydro-1H-isoindol-5-yl}-N-[trans-4-hydroxy-4-methylcyclohexyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0542] The title compound was prepared in a similar manner to Example 123. 1H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 9.04 (d, J = 7.1 Hz, 1H), 8.18 (s, 1H), 8.03 (d, J = 1.2 Hz, 1H), 7.72 (d, J = 7.9 Hz, 1H), 7.52 (d, J = 7.1 Hz, 1H), 6.64 (br. s, 2H), 4.87 (q, J = 8.0 Hz, 1H), 4.72 (d, J = 18.0 Hz, 1H), 4.53 (d, J = 17.7 Hz, 1H), 3.95 - 3.90 (m, 1H), 3.31 (s, 3H), 1.96 (p, J ESI MS [M+H] + C 27 H 33 Calculated for F3N7O5S: 624.2; Found: 624.2.

[0543] Example 128: 2-amino-N-cyclopropyl-5-{2-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]-7-methanesulfonamido-1-oxo-2,3-dihydro-1H-isoindol-5-yl}pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0544] This molecule was prepared in a similar manner to Example 123, except that (αS)-α-(trifluoromethyl)cyclopropanemethanamine was used instead of (2S)-1,1,1-trifluoro-2-butanamine in step a, and cyclopropylamine was used for the final amide coupling. 1H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 9.04 (d, J = 7.1 Hz, 1H), 8.24 (s, 1H), 8.08 (s, 1H), 7.70 (d, J = 3.6 Hz, 1H), 7.57 (d, J = 7.2 Hz, 1H), 6.65 (s, 2H), 4.92 (d, J = 17.9 Hz, 1H), 4.70 (d,J = 17.9 Hz, 1H), 4.26 - 4.11 (m, 1H), 3.35 (s, 3H), 2.88 - 2.79 (m, 1H), 1.57 - 1.43 (m, 1H), 0.91 - 0.57 (m, 7H), 0.33 - 0.18 (m, 1H). ESI MS [M+H] + C 24 H 25 Calculated for F3N7O4S: 564.2; Found: 564.2.

[0545] Example 129: 2-amino-N-cyclopropyl-5-{2-[(1R)-1-cyclopropyl-2,2,2-trifluoroethyl]-7-methanesulfonamido-1-oxo-2,3-dihydro-1H-isoindol-5-yl}pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0546] This molecule was prepared using a procedure similar to that of Example 123, except that (2S)-1,1,1-trifluoro-2-butanamine was replaced with (αR)-α-(trifluoromethyl)cyclopropanemethanamine in step a, and cyclopropylamine was used for the final amide coupling. 1H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 9.04 (d, J = 7.1 Hz, 1H), 8.24 (s, 1H), 8.08 (s, 1H), 7.70 (d, J = 3.6 Hz, 1H), 7.57 (d, J = 7.2 Hz, 1H), 6.65 (s, 2H), 4.92 (d, J = 17.9 Hz, 1H), 4.70 (d, J = 17.9 Hz, 1H), 4.26 - 4.11 (m, 1H), 3.35 (s, 3H), 2.88 - 2.79 (m, 1H), 1.57 - 1.43 (m, 1H), 0.91 - 0.57 (m, 7H), 0.33 - 0.18 (m, 1H). ESI MS [M+H] + C 24 H 25 Calculated for F3N7O4S: 564.2; Found: 564.2.

[0547] Example 130: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methanesulfonyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0548] Step a: Carried out in the same manner as in step h of Example 1.

[0549] Step b: To a mixture of the product from step a (1.00 g, 2.35 mmol) and NMP (7.8 mL) at room temperature, sodium methanethiolate (165 mg, 2.35 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 3 h. EtOAc (100 mL) was added, and the organic phase was washed with 1:1 HO:brine (4 × 100 mL). The organic phase was dried over NaSO and concentrated. The crude product was purified by column chromatography (SiO, 0–10% MeOH in CHCl) to give the desired product as an orange solid (968 mg; 91%).

[0550] Step c: The reaction was carried out in a similar manner as in Example 1, step i, to give the desired product as a yellow solid (906 mg, 85%).

[0551] Step d: The reaction was carried out in a similar manner as in step j of Example 1 to give the desired product as a yellow solid (91 mg, 60%).

[0552] Step e: To a mixture of the product from step c (91 mg, 0.182 mmol) in 9:1 CHCl:MeOH (3.6 mL) was added m-CPBA (125 mg, 0.543 mmol, 75 wt% HO) in one portion. The reaction mixture was stirred at room temperature for 3 h and then concentrated under reduced pressure. The crude product was purified by column chromatography (SiO, 0–15% MeOH in CHCl) followed by reverse-phase HPLC (5–95% CHCN and HO with 0.1% TFA) to afford the desired product as a yellow solid (10 mg; 10%). 1H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 9.14 (d, J = 7.1 Hz, 1H), 9.05 (d, J = 1.5 Hz, 1H), 8.85 (d, J = 1.5 Hz, 1H), 8.12 (s, 1H), 7.81 (d, J = 7.2 Hz, 1H), 7.79 (s, 1H), 6.72 (s, 2H), 4.80 (s, 2H), 3.85 (s, 3H), 3.72 (s, 3H), 3.70 - 3.62 (m, 1H), 1.36 (d, J = 6.8 Hz, 3H), 1.28 - 1.17 (m, 1H), 0.67 - 0.57 (m, 1H), 0.51 - 0.39 (m, 2H), 0.36 - 0.27 (m, 1H). ESI MS [M+H] + C 25 H 27 Calculated for N8O4S: 535.2; Found: 535.1.

[0553] Example 131: 2-amino-5-{2-[(1S)-1-cyclopropylethyl]-7-methanesulfonyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl}-N-[cis-4-hydroxy-4-methylcyclohexyl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0554] The title compound was prepared in a similar manner to Example 130. 1H NMR (400 MHz, DMSO-d6) δ 9.08 (d, J = 7.1 Hz, 1H), 8.79 (d, J = 1.5 Hz, 1H), 8.71 (d, J = 1.5 Hz, 1H), 7.71 (d, J = 7.3 Hz, 1H), 7.68 (d, J = 7.2 Hz, 1H), 6.65 (s, 2H), 4.77 (s, 2H), 4.06 (s, 1H), 3.83 - 3.70 (m, 1H), 3.70 - 3.60 (m, 4H), 1.85 - 1.67 (m, 4H), 1.65 - 1.56 (m, 2H), 1.49 - 1.38 (m, 2H), 1.35 (d, J = 6.8 Hz, 3H), 1.27 - 1.17 (m, 1H), 1.14 (s, 3H), 0.66 - 0.57 (m, 1H), 0.51 - 0.39 (m, 2H), 0.34 - 0.27 (m, 1H). ESI MS [M+H] + C 28 H 35 Calculated for N6O5S: 567.2; Found: 567.1.

[0555] Example 132: 2-amino-N-cyclopropyl-5-{2-[(1S)-1-cyclopropylethyl]-7-methanesulfonyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl}pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0556] The title compound was prepared in a similar manner to Example 130. 1H NMR (400 MHz, DMSO-d6) δ 9.08 (d, J = 7.1 Hz, 1H), 8.87 (d, J = 1.5 Hz, 1H), 8.76 (d, J = 1.5 Hz, 1H), 7.75 (d, J = 4.2 Hz, 1H), 7.73 (d, J = 7.2 Hz, 1H), 6.66 (s, 2H), 4.77 (s, 2H), 3.69 (s, 4H), 3.68 - 3.60 (m, 1H), 2.96 - 2.87 (m, 1H), 1.35 (d, J = 6.8 Hz, 3H), 1.27 - 1.15 (m, 1H), 0.83 - 0.75 (m, 2H), 0.76 - 0.69 (m, 2H), 0.65 - 0.57 (m, 1H), 0.50 - 0.40 (m, 2H), 0.34 - 0.27 (m, 1H). ESI MS [M+H] + C 24 H 27 Calculated for N6O4S: 495.2; Found: 495.0.

[0557] Example 133: 2-amino-N-cyclopropyl-5-{2-[(1S)-1-cyclopropylethyl]-7-(ethanesulfonyl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl}pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0558] The title compound was prepared in a similar manner to Example 130. 1H NMR (400 MHz, DMSO-d6) δ 9.09 (d, J = 7.1 Hz, 1H), 8.85 (d, J = 1.6 Hz, 1H), 8.76 (d, J = 1.6 Hz, 1H), 7.78 (d, J = 4.2 Hz, 1H), 7.72 (d, J = 7.2 Hz, 1H), 6.66 (s, 2H), 4.77 (s, 2H), 3.98 - 3.87 (m, 2H), 3.64 (dq, J = 8.9, 6.8 Hz, 1H), 2.96 - 2.88 (m, 1H), 1.34 (d, J = 6.8 Hz, 3H), 1.26 - 1.13 (m, ESI MS [M+H] + C 25 H 29 Calculated for N6O4S: 509.2; Found: 509.1.

[0559] Example 134: 2-amino-N-cyclopropyl-5-{2-[(1S)-1-cyclopropylethyl]-1-oxo-7-(propane-2-sulfonyl)-2,3-dihydro-1H-isoindol-5-yl}pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0560] The title compound was prepared in a similar manner to Example 130. 1H NMR (400 MHz, DMSO-d6) δ 9.09 (d, J = 7.1 Hz, 1H), 8.82 (d, J = 1.6 Hz, 1H), 8.74 (d, J = 1.5 Hz, 1H), 7.79 (d, J = 4.3 Hz, 1H), 7.71 (d, J = 7.2 Hz, 1H), 6.66 (s, 2H), 4.77 (s, 2H), 4.58 (h, J = 6.8 Hz, 1H), 3.63 (dq, J = 9.0, 6.8 Hz, 1H), 2.97 - 2.87 (m, 1H), 1.34 (d, J = 6.8Hz, 3H), 1.28 - 1.16 ESI MS [M+H] + C 26 H 31 Calculated for N6O4S: 523.2; Found: 523.1.

[0561] Example 135: 2-amino-N-cyclopropyl-5-{2-[(1S)-1-cyclopropylethyl]-7-cyclopropylmethanesulfonyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl}pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0562] The title compound was prepared in a similar manner to Example 130. 1H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 7.1 Hz, 1H), 8.86 (d, J = 1.6 Hz, 1H), 8.72 (d, J = 1.5 Hz, 1H), 7.75 (d, J = 4.3 Hz, 1H), 7.69 (d, J = 7.3 Hz, 1H), 4.76 (s, 2H), 3.88 (d, J = 7.2 Hz, 2H), 3.66 - 3.56 (m, 1H), 2.94 - 2.87 (m, 1H), 1.31 (d, J = 6.8 Hz, 3H), 1.17 (m, 1H), 0.88 (m, 1H), 0.79 - 0.73 (m, 2H), 0.73 - 0.66 (m, 2H), 0.61 - 0.55 (m, 1H), 0.47 - 0.36 (m, 4H), 0.28 - 0.16 (m, 3H).ESI MS [M+H] + C 27 H 31 Calculated for N6O4S: 535.2; Found: 535.2.

[0563] Example 136: 2-amino-5-[7-(cyclobutanesulfonyl)-2-[(1S)-1-cyclopropylethyl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-N-cyclopropylpyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0564] The title compound was prepared in a similar manner to Example 130. 1H NMR (400 MHz, DMSO-d6) δ 9.06 (d, J = 7.1 Hz, 1H), 8.83 (d, J = 1.6 Hz, 1H), 8.70 (d, J = 1.6 Hz, 1H), 7.79 (d, J = 4.2 Hz, 1H), 7.68 (d, J = 7.3 Hz, 1H), 5.15 (p, J = 8.1 Hz, 1H), 4.75 (s, 2H), 3.61 (m, 1H), 2.91 (td, J = 7.2, 3.8 Hz, 1H), 2.39 - 2.26 (m, 2H), 2.22 - 2.10 (m, 2H), 2.03 - 1.93 (m, 2H), 1.31 (d, J = 6.8 Hz, 3H), 1.17 (m, 1H), 0.81 - 0.76 (m, 2H), 0.71 - 0.66 (m, 2H), 0.57 (m, 1H), 0.47 - 0.35 (m, 2H), 0.27 (m, 1H). ESI MS [M+H] + C 27 H 31 Calculated for N6O4S: 535.2; Found: 535.2.

[0565] Example 137: 2-amino-5-[7-(cyclopentanesulfonyl)-2-[(1S)-1-cyclopropylethyl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-N-cyclopropylpyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0566] The title compound was prepared in a similar manner to Example 130. 1H NMR (400 MHz, DMSO-d6) δ 9.09 (d, J = 7.1 Hz, 1H), 8.84 (d, J = 1.5 Hz, 1H), 8.73 (d, J = 1.5 Hz, 1H), 7.79 (d, J = 4.3 Hz, 1H), 7.71 (d, J = 7.2 Hz, 1H), 6.66 (s, 2H), 4.93 (tt, J = 9.1, 6.0 Hz, 1H), 4.77 (s, 2H), 3.64 (dq, J = 8.9, 6.8 Hz, 1H), 2.98 - 2.88 (m, 1H), 1.99 - 1.80 (m, 4H), 1.79 - 1.67 (m, 2H), 1.67 - 1.54 (m, 2H), 1.34 (d, J = 6.8 Hz, 3H), 1.26 - 1.15 (m, 1H), 0.82 - 0.74 (m, 2H), 0.71 - 0.64 (m, 2H), 0.64 - 0.57 (m, 1H), 0.50 - 0.37 (m, 2H), 0.34 - 0.25 (m, 1H). ESI MS [M+H] + C 28 H 33 Calculated for N6O4S: 549.2; Found: 549.1.

[0567] Example 138: 2-amino-5-[7-(cyclohexanesulfonyl)-2-[(1S)-1-cyclopropylethyl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-N-cyclopropylpyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0568] The title compound was prepared in a similar manner to Example 130. 1H NMR (400 MHz, DMSO-d6) δ 9.09 (d, J = 7.1 Hz, 1H), 8.80 (d, J = 1.6 Hz, 1H), 8.74 (d, J = 1.5 Hz, 1H), 7.79 (d, J = 4.2 Hz, 1H), 7.71 (d, J = 7.2 Hz, 1H), 6.66 (s, 2H), 4.77 (s, 2H), 4.37 (tt, J = 12.0, 3.4 Hz, 1H), 3.66 (dq, J = 9.0, 6.9 Hz, 1H), 2.96 - 2.88 (m, 1H), 1.93 - 1.76 (m, 5H), 1.70 - 1.58 (m, 1H), 1.55 - 1.40 (m, 2H), 1.34 (d, J = 6.8 Hz, 3H), 1.26 - 1.14 (m, 5H), 0.83 - 0.76 (m, 2H), 0.72 - 0.66 (m, 2H), 0.65 - 0.57 (m, 1H), 0.49 - 0.39 (m, 2H), 0.34 - 0.27 (m, 1H). ESI MS [M+H] + C 29 H 35 Calculated for N6O4S: 563.2; Found: 563.1.

[0569] Example 139: 2-amino-N-cyclopropyl-5-[7-(methylsulfamoyl)-1-oxo-2-[(2S)-1,1,1-trifluoropropan-2-yl]-2,3-dihydro-1H-isoindol-5-yl]pyrazolo[1,5-α]pyrimidine-3-carboxamide [ka]

[0570] Step a: To a solution of methyl 4-bromo-2-(bromomethyl)-6-fluorobenzoate (23.4 g, 71.8 mmol, 1.0 equiv.) and (2S)-1,1,1-trifluoro-2-propanamine (7.41 mL, 75.4 mmol, 1.05 equiv.) in CHCN (360 mL, 0.2 M) was added KCO (29.8 g, 215.4 mmol, 3.0 equiv.). The mixture was heated to 60 °C overnight. The mixture was filtered, concentrated to dryness, and purified by flash chromatography (SiO, 0→20% EtOAc / hexanes) to give the desired product as a colorless oil (15.9 g, 62%). ESI MS [M+H] + C 12 H 12 Calculated for BrF4NO2: 358.0; Found: 358.0.

[0571] Step b: A flask containing the product of step a (5.0 g, 15.3 mmol) was heated to 130 °C under N2 overnight. The desired product was used without further purification. ESI MS [M+H] + C 11 Calculated for H8BrF4NO3: 326.0; Found: 326.0.

[0572] Step c: The product of step b (661 mg, 0.2.03 mmol, 1.0 equiv) was combined with Pd(dppf)Cl (146 mg, 0.20 mmol, 0.1 equiv), B2pin2 (618 mg, 2.43 mmol, 1.2 equiv), and KOAc (497 mg, 5.08 mmol, 2.5 equiv) in dioxane (6.8 mL). The resulting solution was heated to 100 °C for 2 h, cooled to room temperature, filtered through Celite (washed with EtOAc), and concentrated. The resulting residue was used directly in the next step without purification.

[0573] Step d: The product residue from step c (511 mg, 1.37 mmol, 1.0 equiv) was combined with 2-amino-5-chloropyrazolo[1,5-α]pyrimidine-3-carboxylic acid ethyl ester (330 mg, 1.37 mmol, 1.0 equiv), Pd(dppf)Cl (102 mg, 0.14 mmol, 0.1 equiv), and NaCO (1 M aqueous solution, 5.5 mL) in dioxane (13.7 mL). The resulting solution was heated to 100 °C for 1 h, concentrated, and purified by flash chromatography (SiO, 0→10% MeOH / CHCl) to give the cross-coupled ethyl ester (340 mg, 37% over two steps). ESI MS [M+H] + C 20 H 17 Calculated for F4N5O3: 452.1; Found: 452.1.

[0574] Step e: To a solution of the product from step d (500 mg, 1.11 mmol, 1.0 equiv) and benzyl mercaptan (143 μL, 1.22 mmol, 1.1 equiv) in DMF (3.7 mL, 0.3 M) was added K2CO3 (460 mg, 3.33 mmol, 3.0 equiv). The mixture was heated to 55 °C for 4 h. After cooling to room temperature, the mixture was partitioned between EtOAc and H2O. The organic layer was washed with H2O (2x) and brine, dried over MgSO4, and concentrated to dryness. Flash chromatography (SiO2, 0→10% MeOH / CH2Cl2) afforded the desired product (494 mg, 84%). ESI MS [M+H] + C 27 H 24 Calculated for F3N5O3S: 556.2; Found: 556.1.

[0575] Step f: To a suspension of the product of step e (494 mg, 0.936 mmol, 1.0 equiv) in EtOH (4.7 mL, 0.2 M) was added LiOH (3 M aqueous solution, 0.94 mL, 2.81 mmol). The mixture was heated to 80° C. for 1 h. After cooling to room temperature, the EtOH was removed under reduced pressure. The product was precipitated by the addition of 2 M HCl and filtered. The desired product was used without further purification. ESI MS [M+H] + C 25 H 20 Calculated for F3N5O3S: 528.1; Found: 528.1.

[0576] Step g: To a solution of the product from step f, cyclopropylamine (70 μL, 1.03 mmol, 1.1 equiv), HOBt (158 mg, 1.03 mmol, 1.1 equiv), and EtN (652 μL, 4.68 mmol, 5 equiv) in DMF (9.4 mL, 0.1 M) was added at room temperature in the presence of EDC (269 mg, 1.40 mmol, 1.5 equiv). The reaction mixture was heated to 40 °C for 4 h. The mixture was diluted with EtOAc and washed sequentially with 10% citric acid, H2O, and saturated brine. The organics were dried over MgSO4, filtered, and concentrated under reduced pressure. Flash chromatography (SiO2, 0→10% MeOH / CH2Cl2) afforded the desired product (230 mg, 44% over two steps). ESI MS [M+H] + C 28 H 25 Calculated for F3N6O2S: 567.2; Found: 567.1.

[0577] Step h: To a solution of the product of step g (230 mg, 0.41 mmol, 1.0 equiv) in AcOH (2.41 mL) and HO (266 pL) was added NCS (163 mg, 1.22 mol). The reaction was stirred at room temperature for 3 h and then partitioned between EtOAc and HO. The organic layer was washed with HO and brine, dried over MgSO, and concentrated to dryness. The crude sulfonyl chloride was reconstituted in CHCl (3.3 mL, 0.13 M) and cooled to 0 °C in an ice bath. Pyridine (547 μL, 0.75 M) and methylamine (40 wt% in water, 177 μL, 2.05 mmol, 5 equiv) were added simultaneously. After 1 h, the reaction mixture was partitioned between EtOAc and 1 M HCl. The organic layer was washed with HO and brine, dried over MgSO, and concen...

Claims

1. Formula (I) 【Chemistry 1】 or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, wherein X is C(R ２ ) or N; R １ａ and R １ｂ are H and C, respectively. １－６ Alkyl, C ３－６ Alkenyl, C ３－６ Alkynyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, -Y １ , -X １ -C(O) ２ R ａ , -X １ -OR ａ , -X １ -NR ａ R ｂ , -X １ -CONR ａ R ｂ , -X １ -N(R ａ ) S.O. ２ R ａ , -X １ -SO ２ R ａ , -X １ -SO ２ R ａ R ｂ , -X １ -SO ３ R ａ , -X １ -CN, -X １ -Y １ , and -X １ -Y １ -Y １ａ wherein each X is a member independently selected from the group consisting of １ is a bond or C １－６ alkylene, and OH, SO ２ N.H. ２ , C.O.N.H. ２ ,C(O)NHOH,PO ３ H ２ , COO-C １－８ Alkyl, and CO ２ H, and each Y １ and Y １ａ , C ３－１０ independently selected from the group consisting of cycloalkyl, 4- to 8-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and aryl, each heterocycloalkyl and heteroaryl having 1 to 3 heteroatom ring vertices selected from O, N, and S; and each Y １ and Y １ａ Halogen, oxo, CN, OH, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Alkoxy, C １－４ Haloalkoxy, C １－４ Hydroxyalkoxy, NH ２ , NH(C １－４ Alkyl), N(C １－４ Alkyl) ２ , S.O. ２ N.H. ２ , C.O.N.H. ２ ,C(O)NHOH,PO ３ H ２ , C.O.C. １－８ Alkyl, COO-C １－８ Alkyl, and CO ２ H; Or, R １ａ and R １ｂ may be bonded together to form a 4- to 8-membered ring or a spiro ring, and may include halogen, OH, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Alkoxy, C １－４ Haloalkoxy, C １－４ Hydroxyalkoxy, SO ２ N.H. ２ , C.O.N.H. ２ ,C(O)NHOH,PO ３ H ２ , COO-C １－８ Alkyl, and CO ２ H; R ２ is halogen, CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, -Y ２ , -X ２ -C(O) ２ R ａ , -X ２ -OR ａ , -X ２ -NR ａ R ｂ , -X ２ -CONR ａ R ｂ , -X ２ -SO ２ R ａ , -X ２ -N(R ａ ) S.O. ２ R ａ , -X ２ -SO ２ N.R. ａ R ｂ , -X ２ -SO ３ R ａ , -O-X ２ -Y ２ , and -X ２ -Y ２ wherein each X is a member selected from the group consisting of ２ is a bond or C １－６ Alkylene, and OH, SO ２ N.H. ２ , C.O.N.H. ２ ,C(O)NHOH,PO ３ H ２ , COO-C １－８ Alkyl, and CO ２ H, and each Y ２ , C ３－６ cycloalkyl, 4- to 8-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, each of which has 1 to 3 heteroatom ring vertices selected from O, N, and S; and each of Y ２ halogen, oxo, OH, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Alkoxy, C １－４ Haloalkoxy, C １－４ Hydroxyalkoxy, SO ２ N.H. ２ , C.O.N.H. ２ ,C(O)NHOH,PO ３ H ２ , COO-C １－８ Alkyl, and CO ２ H; R ３ is C １－６ Alkyl, C ３－６ Cycloalkyl, C ３－６ Cycloalkyl C １－３ Alkyl, C １－６ Hydroxyalkyl, C １－６ Haloalkyl and -X ３ -Y ３ wherein each X is a member selected from the group consisting of ３ is a bond, C １－６ Alkylene, or C １－６ haloalkylene, and OH, SO ２ N.H. ２ , C.O.N.H. ２ ,C(O)NHOH,PO ３ H ２ , COO-C １－８ Alkyl, or CO ２ and each Y ３ , C ３－６ cycloalkyl, 4- to 8-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, each of which has 1 to 3 heteroatom ring vertices selected from O, N, and S; and each of Y ３ halogen, oxo, OH, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Alkoxy, C １－４ Haloalkoxy, C １－４ Hydroxyalkoxy, SO ２ N.H. ２ , C.O.N.H. ２ ,C(O)NHOH,PO ３ H ２ , COO-C １－８ Alkyl, and CO ２ H; R ４ａ and R ４ｂ are H, halogen, and C, respectively. １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, and C １－６ is a member independently selected from the group consisting of hydroxyalkyl; Each R ａ , H, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Alkylene-CO ２ H.C. １－６ Alkylene-SO ３ H.C. ３－６ Cycloalkyl, C ３－６ Cycloalkyl C １－３ Alkyl, C １－３ Alkyl C ３－６ cycloalkyl, phenyl, and 3- to 7-membered heterocycloalkyl having 1 to 3 heteroatom ring vertices selected from O, N, and S; and ａ halogen, OH, C １－４ Alkoxy, SO ２ N.H. ２ , C.O.N.H. ２ ,C(O)NHOH,PO ３ H ２ , COO-C １－８ Alkyl, and CO ２ is further substituted with one or two members independently optionally selected from H; Each R ｂ , H, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Alkylene-CO ２ H and C １－６ Alkylene-SO ３ H, each of which is independently selected from the group consisting of OH, SO ２ N.H. ２ , C.O.N.H. ２ ,C(O)NHOH,PO ３ H ２ , COO-C １－８ Alkyl, and CO ２ H; and ａ and R ｂ are bonded to the same nitrogen atom, they may be bonded to each other to form a 4- to 8-membered ring or a spiro ring, and may contain halogen, OH, SO ２ N.H. ２ , C.O.N.H. ２ ,C(O)NHOH,PO ３ H ２ , COO-C １－８ Alkyl, and CO ２ H.

2. X is C(R ２ ) or N; R １ａ and R １ｂ are H and C, respectively. １－６ Alkyl, C ３－６ Alkenyl, C ３－６ Alkynyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, -Y １ , -X １ -C(O) ２ R ａ , -X １ -OR ａ , -X １ -NR ａ R ｂ , -X １ -CONR ａ R ｂ , -X １ -N(R ａ ) S.O. ２ R ａ , -X １ -SO ２ R ａ , -X １ -SO ２ N.R. ａ R ｂ , -X １ -SO ３ R ａ , -X １ -CN, -X １ -Y １ , and -X １ -Y １ -Y １ａ wherein each X is a member independently selected from the group consisting of １ is a bond or C １－６ alkylene, and OH, SO ２ N.H. ２ , C.O.N.H. ２ ,C(O)NHOH,PO ３ H ２ , COO-C １－８ Alkyl, or CO ２ and each Y １ and Y １ａ , C ３－１０ Independently selected from the group consisting of cycloalkyl, 4- to 8-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and aryl, each of which is selected from halogen, oxo, CN, OH, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Alkoxy, C １－４ Haloalkoxy, C １－４ Hydroxyalkoxy, NH ２ , NH(C １－４ Alkyl), N(C １－４ Alkyl) ２ , S.O. ２ N.H. ２ , C.O.N.H. ２ ,C(O)NHOH,PO ３ H ２ , C.O.C. １－８ Alkyl, COO-C １－８ Alkyl, and CO ２ H; Or, R １ａ and R １ｂ may be bonded together to form a 4- to 8-membered ring or a spiro ring, and may include halogen, OH, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Alkoxy, C １－４ Haloalkoxy, C １－４ Hydroxyalkoxy, SO ２ N.H. ２ , C.O.N.H. ２ ,C(O)NHOH,PO ３ H ２ , COO-C １－８ Alkyl, and CO ２ H; R ２ is halogen, CN, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, -Y ２ , -X ２ -C(O) ２ R ａ , -X ２ -OR ａ , -X ２ -NR ａ R ｂ , -X ２ -CONR ａ R ｂ , -X ２ -SO ２ R ａ , -X ２ -N(R ａ ) S.O. ２ R ａ , -X ２ -SO ２ N.R. ａ R ｂ , -X ２ -SO ３ R ａ , -O-X ２ -Y ２ , and -X ２ -Y ２ wherein each X is a member selected from the group consisting of ２ is a bond or C １－６ Alkylene, and OH, SO ２ N.H. ２ , C.O.N.H. ２ ,C(O)NHOH,PO ３ H ２ , COO-C １－８ Alkyl, or CO ２ and each Y ２ , C ３－６ cycloalkyl, 4- to 8-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, each of which is selected from the group consisting of halogen, oxo, OH, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Alkoxy, C １－４ Haloalkoxy, C １－４ Hydroxyalkoxy, SO ２ N.H. ２ , C.O.N.H. ２ ,C(O)NHOH,PO ３ H ２ , COO-C １－８ Alkyl, and CO ２ H; R ３ is C １－６ Alkyl, C ３－６ Cycloalkyl, C ３－６ Cycloalkyl C １－３ Alkyl, C １－６ Hydroxyalkyl, C １－６ Haloalkyl and -X ３ -Y ３ wherein each X is a member selected from the group consisting of ３ is a bond, C １－６ Alkylene, or C １－６ haloalkylene, and OH, SO ２ N.H. ２ , C.O.N.H. ２ ,C(O)NHOH,PO ３ H ２ , COO-C １－８ Alkyl, or CO ２ and each Y ３ , C ３－６ cycloalkyl, 4- to 8-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, each of which is selected from the group consisting of halogen, oxo, OH, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Hydroxyalkyl, C １－４ Alkoxy, C １－４ Haloalkoxy, C １－４ Hydroxyalkoxy, SO ２ N.H. ２ , C.O.N.H. ２ ,C(O)NHOH,PO ３ H ２ , COO-C １－８ Alkyl, and CO ２ H; R ４ａ and R ４ｂ are H, halogen, and C, respectively. １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Haloalkyl and C １－６ Hydroxyalkyl is a member independently selected from the group consisting of: Each R ａ , H, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Alkylene-CO ２ H.C. １－６ Alkylene-SO ３ H.C. ３－６ Cycloalkyl, C ３－６ Cycloalkyl C １－３ alkyl, phenyl, and 3- to 7-membered heterocycloalkyl, each of which is independently selected from the group consisting of OH, SO ２ N.H. ２ , C.O.N.H. ２ ,C(O)NHOH,PO ３ H ２ , COO-C １－８ Alkyl, and CO ２ H; Each R ｂ , H, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Alkylene-CO ２ H and C １－６ Alkylene-SO ３ H, each of which is independently selected from the group consisting of OH, SO ２ N.H. ２ , C.O.N.H. ２ ,C(O)NHOH,PO ３ H ２ , COO-C １－８ Alkyl, and CO ２ H; and ａ and R ｂ are bonded to the same nitrogen atom, they may be bonded to each other to form a 4- to 8-membered ring or a spiro ring, and may contain halogen, OH, SO ２ N.H. ２ , C.O.N.H. ２ ,C(O)NHOH,PO ３ H ２ , COO-C １－８ Alkyl, and CO ２ H, 2. A compound according to claim 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

3. X is C(R ２ 2. The compound of claim 1, wherein:

4. 2. The compound of claim 1, wherein X is N, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

5. Formula (Ia): 【Chemistry 2】 2. The compound of claim 1 having the formula: or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

6. Formula (Ib): 【Chemistry 3】 2. The compound of claim 1 having the formula: or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

7. Formula (Ic): 【Chemistry 4】 2. The compound of claim 1 having the formula: or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

8. Formula (Id): 【Chemistry 5】 2. The compound of claim 1 having the formula: or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

9. Formula (Ie): 【Chemistry 6】 2. The compound of claim 1 having the formula: or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

10. Formula (If): 【Chemistry 7】 2. The compound of claim 1 having the formula: or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

11. Formula (Ig): 【Chemistry 8】 2. The compound of claim 1 having the formula: or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

12. Formula (Ih): 【Chemistry 9】 2. The compound of claim 1 having the formula: or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

13. Formula (Ii): 【Chemistry 10】 2. The compound of claim 1 having the formula: or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

14. -N(R １ａ ) (R １ｂ )of: 【Chemistry 11】 and stereoisomers thereof, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

15. -N(R １ａ ) (R １ｂ )of: 【Chemistry 12】 2. The compound of claim 1 selected from the group consisting of: or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

16. -NH(R １ａ )of: 【Chemistry 13】 and stereoisomers thereof, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

17. -NH(R １ａ )of: 【Chemistry 14】 14. The compound according to any one of claims 6 to 13, selected from the group consisting of: or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

18. 【Chemical 15-1】 【Chemistry 15-2】 2. The compound of claim 1 selected from the group consisting of: or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

19. A compound selected from the group consisting of the following compound numbers 1 to 455, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof: 。

20. 20. The compound of claim 19, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, which is the following compound: 【Chemistry 16】 。

21. 20. The compound of claim 19, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, selected from the group consisting of the following compounds: 【Chemistry 17】 。

22. 22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, and a pharma- ceutically acceptable excipient.

23. 22. A pharmaceutical composition for the treatment of a disease, disorder or condition mediated at least in part by PI3Kγ, comprising a compound according to any one of claims 1 to 21, or a pharma- ceutical acceptable salt, hydrate or solvate thereof.

24. 24. The pharmaceutical composition of claim 23, wherein the compound is administered in an amount effective to reverse, slow, or stop the progression of PI3Kγ-mediated dysregulation.

25. 25. The pharmaceutical composition of claim 23 or 24, wherein the disease, disorder, or condition is cancer.

26. 26. The pharmaceutical composition of claim 25, wherein the cancer is cancer of the prostate, colon, rectum, pancreas, cervix, stomach, endometrium, uterus, brain, liver, bladder, ovary, testis, head, neck, skin (such as melanoma or basal carcinoma), mesothelium, white blood cells (such as lymphoma or leukemia), esophagus, breast, muscle, connective tissue, intestine, lung (such as small cell lung carcinoma or non-small cell lung carcinoma), adrenal gland, thyroid, kidney, or bone; or glioblastoma, mesothelioma, renal cell carcinoma, gastric carcinoma, sarcoma (such as Kaposi's sarcoma), choriocarcinoma, basal cell carcinoma of the skin, or testicular seminoma.

27. 26. The pharmaceutical composition of claim 25, wherein the cancer is selected from the group consisting of melanoma, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, leukemia, brain cancer, lymphoma, ovarian cancer, Kaposi's sarcoma, renal cell carcinoma, head and neck cancer, esophageal cancer, and urothelial cancer.

28. 25. The pharmaceutical composition of claim 23 or 24, wherein the disease, disorder, or condition is an immune-related disease, disorder, or condition.

29. 29. The pharmaceutical composition of claim 28, wherein the immune-related disease, disorder, or condition is selected from the group consisting of rheumatoid arthritis, renal failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergy, fibrosis, fibromyalgia anemia, Alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infectious diseases, Crohn's disease, ulcerative colitis, allergic contact dermatitis and other eczema, systemic sclerosis, and multiple sclerosis.

30. 24. The pharmaceutical composition of claim 23, further comprising at least one additional therapeutic agent.

31. 31. The pharmaceutical composition of claim 30, wherein the at least one further therapeutic agent is a chemotherapeutic agent, an immunomodulatory agent, and / or an inflammation modulating agent, or radiation.

32. The at least one additional therapeutic agent is an immune checkpoint inhibitor, a chemotherapeutic agent, ２ 31. The pharmaceutical composition of claim 30, which is an R antagonist or a CD73 inhibitor.

33. 33. The pharmaceutical composition of claim 32, wherein the immune checkpoint inhibitor blocks at least one activity of PD-1, PD-L1, BTLA, LAG-3, a B7 family member, TIM-3, TIGIT, or CTLA-4.

34. The pharmaceutical composition of claim 33, wherein the immune checkpoint inhibitor blocks the activity of PD-1 or PD-L1.

35. 35. The pharmaceutical composition of claim 34, wherein the immune checkpoint inhibitor is selected from the group consisting of zimberelimab, nivolumab, pembrolizumab, avelumab, atezolizumab, durvalumab, and cemiplimab.

36. The pharmaceutical composition of any one of claims 33 to 35, further comprising a chemotherapeutic agent.

37. A ２ The pharmaceutical composition according to any one of claims 33 to 36, further comprising an R antagonist.

38. The pharmaceutical composition of any one of claims 33 to 37, further comprising a CD73 inhibitor.

39. The pharmaceutical composition according to any one of claims 33 to 38, which is used in combination with radiation.

40. 20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, for use in combination with at least one further therapeutic agent.

41. 41. The pharmaceutical composition of claim 40, wherein the at least one further therapeutic agent is a chemotherapeutic agent, an immunomodulatory agent, and / or an inflammation modulating agent, or radiation.

42. The at least one additional therapeutic agent is an immune checkpoint inhibitor, a chemotherapeutic agent, ２ 41. The pharmaceutical composition of claim 40, which is an R antagonist or a CD73 inhibitor.

43. 43. The pharmaceutical composition of claim 42, wherein the immune checkpoint inhibitor blocks at least one activity of PD-1, PD-L1, BTLA, LAG-3, a B7 family member, TIM-3, TIGIT, or CTLA-4.

44. The pharmaceutical composition of claim 43, wherein the immune checkpoint inhibitor blocks the activity of PD-1 or PD-L1.

45. 45. The pharmaceutical composition of claim 44, further comprising a chemotherapeutic agent.

46. 46. ​​The pharmaceutical composition of claim 45, wherein the chemotherapeutic agent comprises a platinum-based chemotherapeutic agent or an anthracycline-based chemotherapeutic agent.

47. 47. The pharmaceutical composition of claim 46, wherein the chemotherapeutic agent is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, doxorubicin, and paclitaxel.

48. A ２ The pharmaceutical composition according to any one of claims 44 to 47, which is used in further combination with an R antagonist.

49. The pharmaceutical composition according to any one of claims 44 to 48, which is used in further combination with a CD73 inhibitor.

50. The pharmaceutical composition according to any one of claims 44 to 49, which is used in combination with radiation.

51. 42. The pharmaceutical composition of claim 41, wherein the at least one additional therapeutic agent is a chemotherapeutic agent.

52. 52. The pharmaceutical composition of claim 51, wherein the chemotherapeutic agent is a platinum-based chemotherapeutic agent or an anthracycline-based chemotherapeutic agent.

53. 53. The pharmaceutical composition of claim 52, wherein the chemotherapeutic agent is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, doxorubicin, and paclitaxel.

54. 54. The pharmaceutical composition of claim 53, further used in combination with an agent that targets the extracellular production of adenosine.

55. The pharmaceutical composition according to claims 52 to 54, which is used in combination with radiation.

56. The pharmaceutical composition according to any one of claims 40 to 55, adapted to be administered in combination with said compound and at least one further said therapeutic agent.

57. 56. The pharmaceutical composition of any one of claims 40 to 55, wherein said compound and at least one further said therapeutic agent are administered sequentially.

58. 56. The pharmaceutical composition of any one of claims 40 to 55, wherein a treatment period during which said compound is administered overlaps with a treatment period during which at least one further said therapeutic agent is administered.

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