WO2023096850A1

WO2023096850A1 - Phosphoinositide 3 kinase gamma inhibitors and compositions and methods thereof

Info

Publication number: WO2023096850A1
Application number: PCT/US2022/050544
Authority: WO
Inventors: Jean Zhao; Qi Wang; Xiang Y. Yu; Huimin CHENG; Peiyu Zhang
Original assignee: Xtalpi Inc; Geode Therapeutics Inc
Current assignee: Xtalpi Inc; Geode Therapeutics Inc
Priority date: 2021-11-24
Filing date: 2022-11-21
Publication date: 2023-06-01
Anticipated expiration: 2024-05-24

Abstract

The invention provides novel phosphoinositide 3 kinase gamma-selective inhibitors and pharmaceutical compositions thereof, as well as methods of their preparation and use, in therapy of various diseases and conditions, such as solid tumors and hematological cancer.

Description

PHOSPHOINOSITIDE 3 KINASE GAMMA INHIBITORS AND

COMPOSITIONS AND METHODS THEREOF

Priority Claims and Related Patent Applications

[0001] This application claims the benefit of priority to U.S. Provisional Application Serial No. 63/283,104, filed November 24, 2021, the entire content of which is incorporated herein by reference.

Technical Fields of the Invention

[0002] The invention generally relates to pharmaceuticals and therapeutic methods. More particularly, the invention provides novel phosphoinositide 3 kinase gamma (PI3Ky) inhibitors and pharmaceutical compositions thereof, as well as methods of their preparation and use in therapy of various disorders related to the activity of PI3Ky, including solid cancers, selected hematological malignancies and autoimmune diseases.

Background of the Invention

[0003] Phosphoinositide 3 -kinases (PI3Ks) are a family of lipid kinases that catalyze the phosphorylation of the inositol ring of phosphoinositide and are secondary messengers to transduce signals. PI3Ks play a central role in numerous aspects of cellular homeostasis. Aberrant activation of this pathway enhances cell survival, growth, and proliferation, often leading to malignant transformation and cancer development (Thorpe LM et al., Nat Rev Cancer. 2015,15, 7-14).

[0004] PI3Ks are divided into three classes: class I, II, and III, based on their characteristics and substrate specificity. Class I PI3Ks have been extensively studied for treating cancer and immune diseases over the past two decades (Liu P et al., Nat Drug Discov . 2009,8, 627-44). This class of PI3Ks consists of a catalytic and a regulatory subunit, the nature of which determines a further subdivision into Class IA and IB. Class IA PI3Ks, activated by receptor tyrosine kinases (RTKs), G protein-coupled receptors (GPCRs), and oncoproteins, are heterodimers of a pl 10 catalytic subunit and a p85 regulatory subunit. Three highly homologous pl 10 catalytic isoforms pl 10a, pl iop, and pl 106, associate with any of five p85 regulatory isoforms, p85a (and its splicing variants p55a and p50a), p85p, and p55y. Class IB PI3Ks are heterodimers of a pl lOy catalytic subunit coupled with two regulatory isoforms plOl or p84. They are regulated exclusively by GPCRs and trigger phosphoinositide and MAPK-dependent signaling downstream of GPCRs (Engelman JA et al., Nat Rev Genet. 2006,7, 606-19). Unlike pl 10a and pl lOp are ubiquitously expressed, pl 10 y (and pl 10 6 expression) is mainly restricted to the hematopoietic system (OKKenhaug K et al., Nat Rev Immunol. 2003, 3, 317-30).

[0005] PI3Ky is expressed strongly in many myeloid lineage immune cells, including mast cells, neutrophils, and eosinophils. It sits at a key stage in pro-inflammatory, intracellular signaling pathways, suggesting its potential role in various autoimmune and inflammatory diseases. Mast cells are critical regulators of allergy and inflammation. These tissue-resident immune cells express high-affinity receptors for IgE (FcsRI) and are activated by antigen/IgE-mediated crosslinking of FcsRI. Once activated, mast cells can release a massive amount of inflammatory mediators. PI3Ky involves activating adenosine working back on A3 (As-Ars) GPCRs through an autocrine/paracrine mechanism and synergizes with the primary effects of FcsRI activation. Consequently, PI3Ky relays inflammatory signals through various Gi-coupled receptors and is central to mass cell function. (Laffargue M et al., Immunity. 2002,16: 441-51). Genetic loss or selective inhibition of PI3Ky has little effect on normal mouse development and function. But it can suppress inflammation in some mouse disease models, including anaphylaxis (Laffargue M et al., Immunity 2002, 16: 441-451), rheumatoid arthritis (Camps M et al., Nat Med. 2005, 11 : 936- 43), atherosclerosis (Fougerat A. et al., Circulation. 2008, 117: 1310-17), and glomerulonephritis (Barber DF et al., Nat Med. 2005, 11 : 933-35). It is also a promising therapeutic target for obesity, insulin resistance, and Type 2 diabetes (Wymann M et al., Ann N Y Acad Sci. 2013, 1280:44-47). Hence, targeting PI3Ky would be a helpful strategy for treating autoimmune and inflammatory diseases.

[0006] PI3Ky also seems to play essential roles in other cell types/systems that are often barely detectable under physiological conditions. For example, it suppresses cAMP signaling and contractility in the heart and may be a valuable therapeutic target in certain types of cardiac failure. PI3Ky was reported to play a crucial role in regulating cAMP, Ca (2+) cycling, beta-adrenergic signaling, and myocardial structure and function in heart disease. Loss of pl 10 y enhances cardiac excitation-contraction coupling by modulating cyclic adenosine monophosphate (cAMP) levels in subcellular domains containing the sarcoplasmic reticulum (SR), leading to increased cAMP- mediated phosphorylation of phospholamban. Deprivation of PI3Ky leads to acute decompensation and rapid progression into heart failure in response to pathological biomechanical stress. (Oudit GY and Kassiri A, Cardiovasc Hematol Discord Drug Targets. 2007, 7:295-304; Perino et al., Mol Cell. 2011 42: 84-95).

[0007] It is worth noting that PI3Ky emerged as a potential oncogene because overexpression of the catalytic subunit pl lOy or the regulatory subunit plOl causes oncogenic cellular transformation and malignancy. PI3Ky may directly affect cancer cells and support tumor growth, progression or migration in pancreatic ductal adenocarcinoma (PDAC), hepatocellular carcinoma (HCC), breast cancer cells. Immunohistochemical screening studies revealed high specific expression of the PI3Ky isoform in PDAC. Scoring indicated that 72% of the PDAC tissue stained positive for PI3Ky, whereas no stain was detected in normal pancreatic ducts. Moreover, a survey of driver mutations in pancreatic cancer, PI3Ky gene was found to contain the second-highest scoring predict driven mutation (R839C) among the set of genes not previously identified as a driver in pancreatic cancer. Overexpression of PI3Ky indeed increased cell numbers and mediated activation of Akt in PDAC cell lines (Carter et al., Cancer Biol. Ther. 2010, 10, 582-87). Loss of PI3Ky is sufficient to reduce in vivo tumor growth and metastasis. Knockdown of PI3Ky subunits, such as p84 or plOl, in a breast cancer cell line MDA- MB-231 cells, reduced in vitro migration. Knockdown of PI3Ky or plOl suppressed apoptosis, Akt phosphorylation, and lung colonization in SCID mice. Moreover, Knockdown of PI3Ky or plOl in murine epithelial carcinoma 4T1.2 cells inhibited primary tumor growth, spontaneous metastasis, and lung colonization. (Brazzatti JA e t al., Oncogene, 2012, 31 : 2350-61; Edling EE et al., Clin Cancer Res. 2010, 16: 4928-37).

[0008] The PI3K pathway plays critical roles not merely in cancer cells but also in the tumor microenvironment (TME), as PI3K signaling regulates cytokine responses and ensures the development and function of immune cells. In many cancer entities, pro-inflammatory cytokine expression is correlated with a better prognosis. High expression levels of PI3Ky that induce immunosuppression in Tumor-associated macrophages (TAMs) were reported (Kaneda MM et al., Nature. 2016, 539:437-42). Selective inhibition of PI3Ky led to downregulation of M2 markers in mouse models of melanoma and breast cancer (Tgfbl, ArgL Idol and upregulation of Ml markers (1112a and Nos2) (Henau OD et al., Nature. 2016, 539:443-7), demonstrating the influence of PI3Ky on the phenotype and polarization of TAMs. Reduced tumor growth and enhanced anti -tumoral T-cell responses by genetic or pharmacological PI3Ky inhibition were also observed (Kaneda MM et al., Nature. 2016, 539:437-42; Henau OD et al., Nature. 2016, 539:443- 7). Although most types of solid tumor cells do not express PI3Ky, anti-tumoral effects of PI3Ky inhibition might be ascribed to TAMs and TME, giving rise to increased interest in the immune microenvironment for cancer therapy. The approval of checkpoint inhibitors has been a significant breakthrough in immunotherapy. Multiple resistance mechanisms exist, however, including the presence of tumor infiltrating myeloid cells. Knockdown of PI3Ky in mice altered migration and recruitment of myeloid cell populations (Kaneda MM et al., Cancer Discovery. 2016, 6:870-85; Henau OD et al., Nature. 2016, 539:443-7), suggesting that the use of PI3Ky selective inhibitors may allow enhancement of anti -tumoral immune responses and improvement of the long-term survival rate for cancer patients.

[0009] Genetic and pharmacological experiments have confirmed the vital role of PI3Ky in cancer pathogenesis and immune responses during the last two decades. The restricted expression pattern of PI3Ky can alleviate the risk of undesirable side effects when inhibiting PI3Ky, which has motivated the development of PI3Ky-specific inhibitors. However, the development of PI3Ky-selective inhibitors remains challenging due in part to the high structural and sequence homology with other PI3K isoforms (Ruckle T et al., Nat Rev Drug Discov. 2006, 5:903-918). Many PI3Ky-selective inhibitors have been discovered, while only a few have been advanced to clinical trials (NCT02637531, NCT03719326, NCT3980041, and NCT00103350).

[0010] There is an ongoing need for novel PI3Ky inhibitors and treatment methods for solid cancers, hematological malignancies, autoimmune disorders, inflammatory and cardiac diseases, as well as other PI3Ky dependent diseases and conditions to provide patients with an improved clinical effectiveness and reduced side effects.

Summary of the Invention

[0011] The invention provides novel selective PI3Ky inhibitors that are useful for treating various of diseases including cancers and immune-related disorders.

[0012] In one aspect, the invention generally relates to a compound having the structural formula (I):

wherein

W is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -COR¹, - COOR¹, -CONR^¹, or -Si(R¹)3, wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R¹; each of R¹, R² and R³ is independently H, halogen, NH2, OH, CN, CF3, CHO, COCi- ₄alkyl, CH₂C(=O)-NR^laR^lb, C(=O)-NR^laR^lb, CH₂COOR^1C, NR^ldR^le, C_1-4 alkyl, Ci-₄ alkenyl, Ci-₄ alkynyl, O-Ci-₄ alkyl, cycloalkyl, Het, Ar, NR^lh(C=O)Rⁿ, NR¹J(C=O)NR^lkR¹¹, N(SO₂)R^lm, SO₂NR^lnR¹⁰, N(C=O)C(CN)C(OH)R^lp, P(O)MeMe, or P(O)OMeOMe; wherein each of R^la, R^lb, R^lc, R^ld, R^le, R^lh, Rⁿ, R¹-¹, R^{l k} R¹¹, R^lm, R^ln, R¹⁰ and R^lp is independently selected from the group consisting of H, Ci-₄ alkyl, C_3-8 cycloalkyl and C_3-8 heterocycloalkyl, wherein Ci-₄ alkyl is optionally substituted with one or more substituents selected from the group consisting of OH, OMe, CN, halogen, NR^3aR^3b, C_3-8 cycloalkyl and C3- 8 heterocycloalkyl; and each pair of R^la and R^lb, R^ld and R^le, R^lk and R¹¹, or R^ln and R¹⁰, optionally form a 3- to 8-membered nitrogen-containing heterocyclyl ring, wherein the heterocyclyl ring is optionally substituted with one or more R⁶;

Het represents a 3- to 8-membered saturated or partially saturated monocyclic, bridged or spiro heterocyclyl comprising one or more heteroatoms or groups each independently selected from O, S, S(=O), S(=O)₂ and N, wherein Het is optionally substituted with one or two substituents each independently selected from the group consisting of halogen, NR^laR^lb, Ci-₄ alkyl, OH, OMe and CN, wherein Ci-₄ alkyl is unsubstituted or substituted with one or more substituent selected from the group consisting of OH, halogen, NR^ldR^le; n is 0, 1, 2 or 3; p is 0, 1, 2;

Z is C or N;

R⁴ is H, CN, halogen, OH, NHR⁷, NHCOR⁷, NH(S=O)R⁷, or NHSO2R⁷;

R⁵ is H, C_1-4 alkyl, C_1-4 alkoxyl, C_1-4 alkyl-NR^ldR^le, C_1-4 alkyl-cycloalkyl, C_1-4 alkyl-O- cycloalkyl, C_1-4 alkyl-NH-cycloalkyl, C_1-4 alkyl-heterocycle, C_1-4 alkyl-O- heterocycle, or C_1-4 alkyl-NH- heterocycle;

X ring is a 5- to 6-membered aromatic or heteroaromatic ring, Y ring is a 4- to 8-membered aliphatic carbocyclic or heterocyclic ring, wherein X and Y ring are each optionally substituted with one or more R⁶;

X X Y r_ef_ers to X ring and Y ring having exactly two atoms and one bond in common; each R⁶ is independently H, halogen, C_1-4 alkyl, OH, OMe, CN, CF3, NR^laR^lb, C_3-8 cycloalkyl, or C_3-8 heterocycloalkyl; and each R⁷ is independently H, NH2, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, or cycloalkyl; or a pharmaceutically acceptable form or an isotope derivative thereof.

[0013] In another aspect, the invention generally relates to a pharmaceutical composition comprising a compound disclosed herein, effective to treat or reduce one or more diseases or disorders, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0014] In yet another aspect, the invention generally relates to a pharmaceutical composition comprising a compound having the structural formula (I):

wherein

W is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -COR¹, - COOR¹, -CONR^¹, or -Si(R¹)3, wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R¹; each of R¹, R² and R³ is independently H, halogen, NH2, OH, CN, CF3, CHO, COCi- ₄alkyl, CH₂C(=O)-NR^laR^lb, C(=O)-NR^laR^lb, CH₂COOR^1C, NR^ldR^le, C_1-4 alkyl, Ci-₄ alkenyl, Ci-₄ alkynyl, O-Ci-₄ alkyl, cycloalkyl, Het, Ar, NR^lh(C=O)Rⁿ, NR¹J(C=O)NR^lkR¹¹, N(SO₂)R^lm, SO₂NR^lnR¹⁰, N(C=O)C(CN)C(OH)R^lp, P(O)MeMe, or P(O)OMeOMe; wherein each of R^la, R^lb, R^lc, R^ld, R^le, R^lh, Rⁿ, Rb, R^lk R¹¹, R^lm, R^ln, R¹⁰ and R^lp is independently selected from the group consisting of H, Ci-₄ alkyl, C_3-8 cycloalkyl and C_3-8 heterocycloalkyl, wherein Ci-₄ alkyl is optionally substituted with one or more substituents selected from the group consisting of OH, OMe, CN, halogen, NR^3aR^3b, C_3-8 cycloalkyl and C3- 8 heterocycloalkyl; and each pair of R^la and R^lb, R^ld and R^le, R^lk and R¹¹, or R^ln and R¹⁰, optionally form a 3- to 8-membered nitrogen-containing heterocyclyl ring, wherein the heterocyclyl ring is optionally substituted with one or more R⁶;

Z is C or N;

R⁴ is H, CN, halogen, OH, NHR⁷, NHCOR⁷, NH(S=O)R⁷, or NHSO₂R⁷;

R⁵ is H, Ci-₄ alkyl, Ci-₄ alkoxyl, Ci-₄ alkyl-NR^ldR^le, Ci-₄ alkyl-cycloalkyl, Ci-₄ alkyl-O- cycloalkyl, Ci-₄ alkyl-NH-cycloalkyl, Ci-₄ alkyl-heterocycle, Ci-₄ alkyl-O- heterocycle, or Ci-₄ alkyl-NH- heterocycle;

_refers to x ring and Y ring having exactly two atoms and one bond in common; each R⁶ is independently H, halogen, C_1-4 alkyl, OH, OMe, CN, CF3, NR^laR^lb, C_3-8 cycloalkyl, or C_3-8 heterocycloalkyl; and each R⁷ is independently H, NH2, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, or cycloalkyl; or a pharmaceutically acceptable form or an isotope derivative thereof, effective to treat or reduce one or more diseases or disorders, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0015] In yet another aspect, the invention generally relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.

[0016] In yet another aspect, the invention generally relates to a method for treating or reducing cancer, or a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0017] In yet another aspect, the invention generally relates to a method for treating or reducing a disease or disorder, comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound having the structural formula (I):

wherein

W is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -COR¹, - COOR¹, -CONR^¹, or -Si(R¹)3, wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R¹; each of R¹, R² and R³ is independently H, halogen, NH2, OH, CN, CF3, CHO, COCi- ₄alkyl, CH₂C(=O)-NR^laR^lb, C(=O)-NR^laR^lb, CH₂COOR^1C, NR^ldR^le, C_1-4 alkyl, C_1-4 alkenyl, Ci-4 alkynyl, O-C_1-4 alkyl, cycloalkyl, Het, Ar, NR^lh(C=O)Rⁿ, NR¹J(C=O)NR^lkR¹¹, N(SO₂)R^lm, SO₂NR^lnR¹⁰, N(C=O)C(CN)C(OH)R^lp, P(O)MeMe, or P(O)OMeOMe; each of R^1a, R^1b, R^1c, R^ld, R^1e, R^1h, R¹ⁱ, R^1j, R^lk R^1l, R^lm, R^ln, R^1o and R^1p is independently selected from the group consisting of H, C_1-4 alkyl, C_3-8 cycloalkyl and C_3-8 heterocycloalkyl, wherein C_1-4 alkyl is optionally substituted with one or more substituents selected from the group consisting of OH, OMe, CN, halogen, NR^3aR^3b, C_3-8 cycloalkyl and C3- ₈ heterocycloalkyl; each pair of R^la and R^lb, R^ld and R^le, R^lk and R¹¹, or R^ln and R¹⁰, optionally form a 3- to 8-membered nitrogen-containing heterocyclyl ring, wherein the heterocyclyl ring is optionally substituted with one or more R⁶;

Het represents a 3- to 8-membered saturated or partially saturated monocyclic, bridged or spiro heterocyclyl comprising one or more heteroatoms or groups each independently selected from O, S, S(=O), S(=O)₂ and N, wherein Het is optionally substituted with one or two substituents each independently selected from the group consisting of halogen, NR^laR^lb, C_1-4 alkyl, OH, OMe and CN, wherein C_1-4 alkyl is unsubstituted or substituted with one or more substituent selected from the group consisting of OH, halogen, NR^ldR^le; n is 0, 1, 2 or 3; p is 0, 1, 2;

Z is C or N;

R⁴ is H, CN, halogen, OH, NHR⁷, NHCOR⁷, NH(S=O)R⁷, or NHSO₂R⁷;

X ring is a 5- to 6-membered aromatic or heteroaromatic ring, Y ring is a 4- to 8-membered aliphatic carbocyclic or heterocyclic ring, wherein X and Y ring are each optionally substituted with one or more R⁶; refers to X ring and Y ring having exactly two atoms and one bond in common; each R⁶ is independently H, halogen, C_1-4 alkyl, OH, OMe, CN, CF3, NR^laR^lb, C_3-8 cycloalkyl, or C_3-8 heterocycloalkyl; each R⁷ is independently H, NH₂, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, or cycloalkyl; or a pharmaceutically acceptable form or an isotope derivative thereof, effective to treat cancer, or a related disease or disorder, in a mammal, including a human.

Definitions

[0018] Unless defined otherwise, 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. General principles of organic chemistry, as well as specific functional moieties and reactivity, are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 2006. [0019] As used herein, “at least” a specific value is understood to be that value and all values greater than that value.

[0020] The term “comprising”, when used to define compositions and methods, is intended to mean that the compositions and methods include the recited elements, but do not exclude other elements. The term “consisting essentially of’, when used to define compositions and methods, shall mean that the compositions and methods include the recited elements and exclude other elements of any essential significance to the compositions and methods. For example, “consisting essentially of’ refers to administration of the pharmacologically active agents expressly recited and excludes pharmacologically active agents not expressly recited. The term consisting essentially of does not exclude pharmacologically inactive or inert agents, e.g., pharmaceutically acceptable excipients, carriers or diluents. The term “consisting of’, when used to define compositions and methods, shall mean excluding trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.

[0021] Unless specifically stated or obvious from context, as used herein, the term “about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from context, all numerical values provided herein can be modified by the term about.

[0022] As used herein, the term “administration” of a disclosed compound encompasses the delivery to a subject of a compound as described herein, or a prodrug or other pharmaceutically acceptable form thereof, using any suitable formulation or route of administration, as discussed herein. [0023] The terms “disease”, “disorder” and “condition” are used interchangeably unless indicated otherwise.

[0024] As used herein, the terms "effective amount" or "therapeutically effective amount" refer to that amount of a compound or pharmaceutical composition described herein that is sufficient to effect the intended application including, but not limited to, disease treatment, as illustrated below. [0025] In some embodiments, the amount is that effective for detectable killing or inhibition of the growth or spread of cancer cells; the size or number of tumors; or other measure of the level, stage, progression or severity of the cancer.

[0026] The therapeutically effective amount can vary depending upon the intended application, or the subject and disease condition being treated, e.g., the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the weight and age of the patient, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, e.g., reduction of cell migration. The specific dose will vary depending on, for example, the particular compounds chosen, the species of subject and their age/existing health conditions or risk for health conditions, the dosing regimen to be followed, the severity of the disease, whether it is administered in combination with other agents, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0027] The term “optionally substituted” is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but is not required to) be bonded other substituents (e.g., heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (i.e. a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term “optionally substituted” means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any further functional groups. Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, CN, -COOH, -CH₂CN, -OC₁-C₆ alkyl, C₁-C₆ alkyl, -OC₁-C₆ alkenyl, -OC₁-C₆ alkynyl, -Ci-C₆ alkenyl, -Ci-C₆ alkynyl, -OH, -OP(O)(OH)₂, -OC(O)Ci-C₆ alkyl, -C(O)Ci-C₆ alkyl, -OC(O)OCi-C₆ alkyl, NH₂, NH(CI-C₆ alkyl), N(CI-C₆ alkyl)₂, -NHC(O)CI-C₆ alkyl, - C(O)NHCI-C₆ alkyl, -S(O)₂-Ci-C₆ alkyl, -S(O)NHCI-C₆ alkyl, and S(O)N(CI-C₆ alkyl)₂. [0028] As used herein, a “pharmaceutically acceptable form” of a disclosed compound includes, but is not limited to, pharmaceutically acceptable salts, esters, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives of disclosed compounds. In one embodiment, a "pharmaceutically acceptable form" includes, but is not limited to, pharmaceutically acceptable salts, esters, isomers, prodrugs and isotopically labeled derivatives of disclosed compounds. In some embodiments, a "pharmaceutically acceptable form" includes, but is not limited to, pharmaceutically acceptable salts, esters, stereoisomers, prodrugs and isotopically labeled derivatives of disclosed compounds.

[0029] In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. In some embodiments, organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoracetic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0030] The salts can be prepared in situ during the isolation and purification of the disclosed compounds, or separately, such as by reacting the free base or free acid of a parent compound with a suitable base or acid, respectively. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N⁺(Ci-4alkyl)⁴ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt can be chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0031] In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable ester. As used herein, the term "pharmaceutically acceptable ester" refers to esters that hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Such esters can act as a prodrug as defined herein. Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfinic acids, sulfonic acids and boronic acids. Examples of esters include formates, acetates, propionates, butyrates, acrylates and ethyl succinates. The esters can be formed with a hydroxy or carboxylic acid group of the parent compound.

[0032] In certain embodiments, the pharmaceutically acceptable form is a “solvate” (e.g., a hydrate). As used herein, the term “solvate” refers to compounds that further include a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. The solvate can be of a disclosed compound or a pharmaceutically acceptable salt thereof. Where the solvent is water, the solvate is a "hydrate". Pharmaceutically acceptable solvates and hydrates are complexes that, for example, can include 1 to about 100, or 1 to about 10, or 1 to about 2, about 3 or about 4, solvent or water molecules. It will be understood that the term "compound" as used herein encompasses the compound and solvates of the compound, as well as mixtures thereof.

[0033] In certain embodiments, the pharmaceutically acceptable form is a prodrug. As used herein, the term “prodrug” (or “pro-drug”) refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable form of the compound. A prodrug can be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis (e.g., hydrolysis in blood). In certain cases, a prodrug has improved physical and/or delivery properties over the parent compound. Prodrugs can increase the bioavailability of the compound when administered to a subject (e.g., by permitting enhanced absorption into the blood following oral administration) or which enhance delivery to a biological compartment of interest (e.g., the brain or lymphatic system) relative to the parent compound. Exemplary prodrugs include derivatives of a disclosed compound with enhanced aqueous solubility or active transport through the gut membrane, relative to the parent compound.

[0034] The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7- 9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergam on Press, 1987, both of which are incorporated in full by reference herein. Exemplary advantages of a prodrug can include, but are not limited to, its physical properties, such as enhanced water solubility for parenteral administration at physiological pH compared to the parent compound, or it can enhance absorption from the digestive tract, or it can enhance drug stability for long-term storage.

[0035] As used herein, the term “pharmaceutically acceptable” excipient, carrier, or diluent refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymer as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0036] As used herein, the term “subject” refers to any animal (e.g., a mammal), including, but not limited to humans, non-human primates, rodents, and the like, which is to be the recipient of a particular treatment. Typically, the terms “subject” and “patient” are used interchangeably herein in reference to a human subject.

[0037] As used herein, the terms “treatment” or “treating” a disease or disorder refers to a method of reducing, delaying or ameliorating such a condition before or after it has occurred. Treatment may be directed at one or more effects or symptoms of a disease and/or the underlying pathology. Treatment is aimed to obtain beneficial or desired results including, but not limited to, therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient can still be afflicted with the underlying disorder. For prophylactic benefit, the pharmaceutical compounds and/or compositions can be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. The treatment can be any reduction and can be, but is not limited to, the complete ablation of the disease or the symptoms of the disease. As compared with an equivalent untreated control, such reduction or degree of prevention is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100% as measured by any standard technique.

[0038] As used herein, the term "therapeutic effect" refers to a therapeutic benefit and/or a prophylactic benefit as described herein. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0039] Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 95% (“substantially pure”), which is then used or formulated as described herein. In certain embodiments, the compounds of the present invention are more than 99% pure.

[0040] Solvates and polymorphs of the compounds of the invention are also contemplated herein. Solvates of the compounds of the present invention include, for example, hydrates.

[0041] As used herein, the term an “isolated” or “substantially isolated” molecule (such as a polypeptide or polynucleotide) is one that has been manipulated to exist in a higher concentration than in nature or has been removed from its native environment. For example, a subject antibody is isolated, purified, substantially isolated, or substantially purified when at least 10%, or 20%, or 40%, or 50%, or 70%, or 90% of non-subject-antibody materials with which it is associated in nature have been removed. For example, a polynucleotide or a polypeptide naturally present in a living animal is not "isolated," but the same polynucleotide or polypeptide separated from the coexisting materials of its natural state is "isolated." Further, recombinant DNA molecules contained in a vector are considered isolated for the purposes of the present invention. Isolated RNA molecules include in vivo or in vitro RNA replication products of DNA and RNA molecules. Isolated nucleic acid molecules further include synthetically produced molecules. Additionally, vector molecules contained in recombinant host cells are also isolated. Thus, not all “isolated” molecules need be “purified.”

[0042] As used herein, the term “purified” when used in reference to a molecule, it means that the concentration of the molecule being purified has been increased relative to molecules associated with it in its natural environment, or environment in which it was produced, found or synthesized. Naturally associated molecules include proteins, nucleic acids, lipids and sugars but generally do not include water, buffers, and reagents added to maintain the integrity or facilitate the purification of the molecule being purified. According to this definition, a substance may be 5% or more, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 95% or more, 98% or more, 99% or more, or 100% pure when considered relative to its contaminants.

[0043] Definitions of specific functional groups and chemical terms are described in more detail below. When a range of values is listed, it is intended to encompass each value and subrange within the range. For example, “Ci-4 alkyl” is intended to encompass, C1, C2, C3, C4, C1-3, C1-2, C2-4, C3-4 and C2-3 alkyl groups.

[0044] As used herein, the term “alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms (e.g., C1-10 alkyl). Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated. In some embodiments, “alkyl” can be a C1-6 alkyl group. In some embodiments, alkyl groups have 1 to 10, 1 to 8, 1 to 6, or 1 to 3 carbon atoms. Representative saturated straight chain alkyls include, but are not limited to, -methyl, -ethyl, -n- propyl, -n-butyl, -n-pentyl, and -n-hexyl; while saturated branched alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3 -methylbutyl, 2-methylpentyl, 3 -methylpentyl, 4-methylpentyl, 2-methylhexyl, 3 -methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3 -dimethylbutyl, and the like. The alkyl is attached to the parent molecule by a single bond. Unless stated otherwise in the specification, an alkyl group is optionally substituted by one or more of substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R^a)₃ , -OR^a, -SR^a, -OC(O)-R^a, -N(R^a)₂, -C(O)R_a, -C(O)OR^a, -OC(O)N(R^a)₂, - C(O)N(R^a)₂, -N(R^a)C(O)OR^a, -N(R^a)C(O)R^a, -N(R^a)C(O)N(R^a)₂, -N(R^a)C(NR^a)N(R^a)₂, - N(R^a)S(O)_tN(R^a)₂ (where t is 1 or 2), -P(=O)(R^a)(R^a), or -O-P(=O)(OR^a)₂ where each R^a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein. In a non-limiting embodiment, a substituted alkyl can be selected from fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3 -fluoropropyl, hydroxymethyl, 2 -hydroxy ethyl, 3 -hydroxypropyl, benzyl, and phenethyl.

[0045] Unless otherwise specifically defined, the term “aromatic” or “aryl” refers to cyclic, aromatic hydrocarbon groups that have 1 to 2 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, H, halogen, -O-C₁-C₆ alkyl, C₁-C₆ alkyl, -C₁-C₆ alkenyl, -OC₁-C₆ alkynyl, -C₁-C₆ alkenyl, -C₁-C₆ alkynyl, -OH, -OP(O)(OH)₂, -OC(O)Ci-C₆ alkyl, -C(O)Ci-C₆ alkyl, -OC(O)OCi-C₆alkyl, NH₂, NH(CI-C₆ alkyl), N(CI-C₆ alkyl)₂, -S(O)₂-Ci-C₆ alkyl, -S(O)NHCi-C₆alkyl, and S(O)N(CI-C₆ alkyl)₂. The substituents can themselves be optionally substituted. Furthermore, when containing two fused rings the aryl groups herein defined may have an unsaturated or partially saturated ring fused with a fully unsaturated ring. Exemplary ring systems of these aryl groups include indanyl, indenyl, tetrahydronaphthal enyl, and tetrahydrobenzoannulenyl.

[0046] The term “halogen” or “halo” refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0047] Unless otherwise specifically defined, the terms “heteroaryl” or “hetero-aromatic” as used herein, means a monocyclic heteroaryl ring or a bicyclic heteroaryl ring. The monocyclic heteroaryl ring is a 5- or 6- membered ring. The 5-membered ring has two double bonds and contains one, two, three or four heteroatoms independently selected from the group consisting of N, O, and S. The 6-membered ring has three double bonds and contains one, two, three or four heteroatoms independently selected from the group consisting of N, O, and S. The bicyclic heteroaryl ring consists of the 5- or 6-membered heteroaryl ring fused to a phenyl group or the 5- or 6-membered heteroaryl ring fused to a cycloalkyl group or the 5- or 6-membered heteroaryl ring fused to a cycloalkenyl group or the 5- or 6-membered heteroaryl ring fused to another 5- or 6- membered heteroaryl ring. Nitrogen heteroatoms contained within the heteroaryl may be optionally oxidized to the N-oxide or optionally protected with a nitrogen protecting group known to those of skill in the art. The heteroaryl is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heteroaryl. Representative examples of heteroaryl include, but are not limited to, benzothienyl, benzoxadiazolyl, cirmolinyl, 5,6- dihydroisoquinolinyl, 7,8-dihydroisoquinolinyl, 5,6-dihydroquinolinyl, 7,8-dihydroquinolinyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, pyridinium N-oxide, quinolinyl, 5,6,7,8-tetrahydroisoquinolinyl, 5, 6,7,8- tetrahydroquinolinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienopyridinyl, thienyl, triazolyl, and triazinyl.

[0048] The terms “heteroaryl” or “hetero-aromatic” groups of the present invention are substituted with 0, 1, 2, 3, or 4 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, -NZ1Z2, and (NZ1Z2)carbonyl. The term "NZ1Z2" as used herein, means two groups, Zi and Z2, which are appended to the parent molecular moiety through a nitrogen atom. Zi and Z2 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, and formyl. Representative examples of NZ1Z2 include, but are not limited to, amino, methylamino, acetylamino, and acetylmethylamino.

Detailed Description of the Invention

[0049] The invention is based in part on the discovery of novel PI3Ky inhibitors, pharmaceutical compositions thereof and methods of their preparation and use in therapy of various diseases and conditions, such as cancers (e.g., breast, colon, endometrial, kidney, lung, melanoma, prostate, thyroid cancer and leukemia) or a related disease or condition.

[0050] In one aspect, the invention generally relates to a compound having the structural formula (I):

wherein

W is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -COR¹, - COOR¹, -CONR^¹, or -Si(R¹)3, wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R¹; wherein each of R¹, R² and R³ is independently H, halogen, NH2, OH, CN, CF3, CHO, COCi-₄alkyl, CH₂C(=O)-NR^laR^lb, C(=O)-NR^laR^lb, CH₂COOR^1C, NR^ldR^le, C_1-4 alkyl, Ci-₄ alkenyl, Ci-₄ alkynyl, O-Ci-₄ alkyl, cycloalkyl, Het, Ar, NR^lh(C=O)R¹¹, NR¹J(C=O)NR^lkR¹¹, N(SO₂)R^lm, SO₂NR^lnR¹⁰, N(C=O)C(CN)C(OH)R^1P, P(O)MeMe, or P(O)OMeOMe; and each of R^1a, R^1b, R^1c, R^ld, R^1e, R^1h, R¹ⁱ, R^1j, R^lk R^1l, R^lm, R^ln, R^1o and is R^1p independently selected from the group consisting of H, Ci-₄ alkyl, C_3-8 cycloalkyl and C_3-8 heterocycloalkyl, wherein Ci-₄ alkyl is optionally substituted with one or more substituents selected from the group consisting of OH, OMe, CN, halogen, NR^3aR^3b, C_3-8 cycloalkyl and C3- 8 heterocycloalkyl; each pair of R^la and R^lb, R^ld and R^le, R^lk and R¹¹, or R^ln and R¹⁰, optionally form a 3- to 8-membered nitrogen-containing heterocyclyl ring, wherein the heterocyclyl ring is optionally substituted with one or more R⁶;

Z is C or N;

R⁴ is H, CN, halogen, OH, NHR⁷, NHCOR⁷, NH(S=O)R⁷, or NHSO2R⁷;

refers to X ring and Y ring having exactly two atoms and one bond in common; each R⁶ is independently H, halogen, C_1-4 alkyl, OH, OMe, CN, CF3, NR^laR^lb, C_3-8 cycloalkyl, or C_3-8 heterocycloalkyl; and each R⁷ is independently H, NH2, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, or cycloalkyl; or a pharmaceutically acceptable form or an isotope derivative thereof.

[0051] In certain embodiments, Z is C, having the structural formula (la):

[0052] In certain embodiments, Z is N, having the structural formula (lb):

[0053] In certain embodiments of formula (I), (la) or (lb), X ring is a 5-membered aromatic or heteroaromatic ring.

[0054] In certain embodiments of formula (I), (la) or (lb), X ring comprises two N atoms.

[0055] In certain embodiments of formula (I), (la) or (lb), Y ring is a 5-membered unsaturated aliphatic carbocyclic or heterocyclic ring.

[0056] In certain embodiments of formula (I), (la) or (lb), Y ring is a 5-membered saturated or partially saturated aliphatic carbocyclic or heterocyclic ring.

[0057] In certain embodiments of formula (I), (la) or (lb), Y ring is a 6-membered unsaturated aliphatic carbocyclic or heterocyclic ring.

[0058] In certain embodiments of formula (I), (la) or (lb), Y ring is a 6-membered saturated or partially saturated aliphatic carbocyclic or heterocyclic ring.

[0059] In certain embodiments of formula (I), (la) or (lb), is selected from:

[0060] In certain embodiments of formula (I), (I_a) Or (lb), W is selected from:

[0061] In certain embodiments, W is phenyl.

[0062] In certain embodiments (I), (la) or (lb), the compound has the structural formula (II):

wherein each of X¹, X², X³ and X⁴ is independently selected from C, CH, N or S, provided that at least one of X¹, X², X³ and X⁴ is C and at least one of X¹, X², X³ and X⁴ is N; and

Y ring is a 5-or 6-membered aliphatic carbocyclic or heterocyclic ring.

[0063] In certain embodiments of formula (II), X³ is CH and X⁴ is N, and the compound the structural formula (Ila):

wherein each of X¹ and X² is C or N, provided that one is C and the other is N; and

Y ring is a 5-or 6-membered aliphatic carbocyclic or heterocyclic ring.

[0064] In certain embodiments of formula (Ila), X¹ is N and X² is C, and the compound the structural formula (lib) :

[0065] In certain embodiments of formula (Ila), X¹ is C and X² is N, and the compound has the following structural formular (lIc):

[0066] In certain embodiments of formula (II), X¹ is C, X² is N, X³ is CH, and X⁴ is CH, and the compound has the structural formula (lid):

Id

[0067] In certain embodiments of formula (II), X¹ is C, X² is N, X³ is N, and X⁴ is N, and the compound has the structural formula (lie):

[0068] In certain embodiments of formula (II), the compound has the structural formula (III):

Y ring is a 5-or 6-membered aliphatic carbocyclic or heterocyclic ring.

[0069] In certain embodiments of formula (III), X¹ is N, X² is N, X³ is CN and X⁴ is C, having the structural formula (Illa):

[0070] In certain embodiments of formula (III), X¹ is C or CH, X² is N, X³ is S and X⁴ is C or CH, having the structural formula (Illb) :

[0071] In certain embodiments of (I), (II), (Ila), (lib), (lie), (lid), (lie), (III), (Illa) and (Illb), Z is CH.

[0072] In certain embodiments of (I), (II), (Ila), (lib), (lie), (lid), (lie), (III), (Illa) and (Illb), Z is N. [0073] In certain embodiments of (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (lie), (III), (Illa) and (Illb), R¹ is O-methyl.

[0074] In certain embodiments of (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (lie), (III), (Illa) and (Illb), R¹ is a halogen atom. In certain embodiments of (I), (la), (lb), (II), (Ila), (lib), (lie),

(lid), (lie), (III), (Illa) and (Illb), R¹ is F. In certain embodiments of (I), (la), (lb), (II), (Ila), (lib),

(lie), (lid), (lie), (III), (Illa) and (Illb), R¹ is Cl. In certain embodiments of (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (lie), (III), (Illa) and (Illb), R¹ is F. In certain embodiments of (I), (la), (lb), (II), (Ila), (lib), (lie), (Hd), (lie), (III), (Illa) and (Illb), R¹ is H.

[0075] In certain embodiments of formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (lie), (III), (Illa) and (Illb), n is 0.

[0076] In certain embodiments of formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (lie), (III), (Illa) and (Illb), p is 0.

[0077] In certain embodiments of formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (lie), (III), (Illa) and (Illb), R⁵ is methyl.

[0078] In certain embodiments of formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (lie), (III), (Illa) and (Illb), R⁴ is NHR⁷. In certain embodiments, R⁷ is H. In certain embodiments, R⁷ is Ci-4 alkyl.

[0079] In certain embodiments of formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (lie), (III), (Illa) and (Illb), R⁴ is NHCOR⁷.

[0080] In certain embodiments of formula (I), (la), (lb), (II), (Ila), (lib), (lie), (lid), (lie), (III), (Illa) and (Illb), R⁴ is NHSO2R⁷.

[0081] Examples of compounds according to the invention include, but are not limited to:

or a pharmaceutically acceptable form or an isotope derivative thereof.

[0082] In certain embodiments, a compound of the invention has one or more (e.g., 1, 2, 3) deuterium atoms replacing one or more (e.g., 1, 2, 3) hydrogen atoms. In certain embodiments, a compound of the invention has one deuterium atom replacing one hydrogen atom.

In another aspect, the invention generally relates to a pharmaceutical composition comprising a compound disclosed herein, effective to treat or reduce one or more diseases or disorders, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent. [0083] In yet another aspect, the invention generally relates to a pharmaceutical composition comprising a compound having the structural formula (I):

wherein

W is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -COR¹, - COOR¹, -CONR^¹, or -Si(R¹)3, wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R¹; each of R¹, R² and R³ is independently H, halogen, NH2, OH, CN, CF3, CHO, COCn ₄alkyl, CH₂C(=O)-NR^laR^lb, C(=O)-NR^laR^lb, CH₂COOR^1C, NR^ldR^le, C_1-4 alkyl, Ci-₄ alkenyl, Ci-₄ alkynyl, O-Ci-₄ alkyl, cycloalkyl, Het, Ar, NR^lh(C=O)Rⁿ, NR¹J(C=O)NR^lkR¹¹, N(SO₂)R^lm, SO₂NR^lnR¹⁰, N(C=O)C(CN)C(OH)R^lp, P(O)MeMe, or P(O)OMeOMe; each of R^1a, R^1b, R^1c, R^ld, R^1e, R^1h, R¹ⁱ, R^1j, R^lk R^1l, R^lm, R^ln, R^1o and R^1p is independently selected from the group consisting of H, Ci-₄ alkyl, C_3-8 cycloalkyl and C_3-8 heterocycloalkyl, wherein Ci-₄ alkyl is optionally substituted with one or more substituents selected from the group consisting of OH, OMe, CN, halogen, NR^3aR^3b, C_3-8 cycloalkyl and C3- 8 heterocycloalkyl; each pair of R^la and R^lb, R^ld and R^le, R^lk and R¹¹, or R^ln and R¹⁰, optionally form a 3- to 8-membered nitrogen-containing heterocyclyl ring, wherein the heterocyclyl ring is optionally substituted with one or more R⁶;

Het represents a 3- to 8-membered saturated or partially saturated monocyclic, bridged or spiro heterocyclyl comprising one or more heteroatoms or groups each independently selected from O, S, S(=O), S(=O)₂ and N, wherein Het is optionally substituted with one or two substituents each independently selected from the group consisting of halogen, NR^laR^lb, Ci-₄ alkyl, OH, OMe and CN, wherein C_1-4 alkyl is unsubstituted or substituted with one or more substituent selected from the group consisting of OH, halogen, NR^ldR^le; n is 0, 1, 2 or 3; p is 0, 1, 2;

Z is C or N;

R⁴ is H, CN, halogen, OH, NHR⁷, NHCOR⁷, NH(S=O)R⁷, or NHSO2R⁷;

X ring is a 5- to 6-membered aromatic or heteroaromatic ring, Y ring is a 4- to 8-membered saturated or partially saturated aliphatic carbocyclic or heterocyclic ring, wherein X and Y ring are each optionally substituted with one or more R⁶;

refers to X ring and Y ring having exactly two atoms and one bond in common; each R⁶ is independently H, halogen, C_1-4 alkyl, OH, OMe, CN, CF3, NR^laR^lb, C_3-8 cycloalkyl, or C_3-8 heterocycloalkyl; each R⁷ is independently H, NH2, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, or cycloalkyl; or a pharmaceutically acceptable form or an isotope derivative thereof, effective to treat or reduce one or more diseases or disorders, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0084] In certain embodiments, the pharmaceutical composition is suitable for oral administration.

[0085] In certain embodiments, the pharmaceutical composition is suitable for intravenous administration.

[0086] In certain embodiments, the pharmaceutical composition is useful to treat or reduce cancer.

[0087] In certain embodiments, the pharmaceutical composition is useful to treat or reduce breast, colon, endometrial, kidney, lung, melanoma, prostate, thyroid cancer or leukemia, or a related disease or condition.

[0088] In yet another aspect, the invention generally relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.

[0089] In certain embodiments, the unit dosage form is suitable for oral administration. [0090] In certain embodiments, the unit dosage form is a tablet or a capsule.

[0091 ] In certain embodiments, the unit dosage form is suitable for intravenous administration.

[0092] In certain embodiments, the unit dosage form is in the form of a liquid formulation.

[0093] In yet another aspect, the invention generally relates to a method for treating or reducing cancer, or a related disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0094] In yet another aspect, the invention generally relates to a method for treating or reducing a disease or disorder, comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound having the structural formula (I):

wherein

W is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -COR¹, - COOR¹, -CONR^¹, or -Si(R¹)3, wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R¹; each of R¹, R² and R³ is independently H, halogen, NH2, OH, CN, CF3, CHO, COCi- ₄alkyl, CH₂C(=O)-NR^laR^lb, C(=O)-NR^laR^lb, CH₂COOR^1C, NR^ldR^le, C_1-4 alkyl, Ci-₄ alkenyl, Ci-₄ alkynyl, O-Ci-₄ alkyl, cycloalkyl, Het, Ar, NR^lh(C=O)Rⁿ, NR¹J(C=O)NR^lkR¹¹, N(SO₂)R^lm, SO₂NR^lnR¹⁰, N(C=O)C(CN)C(OH)R^lp, P(O)MeMe, or P(O)OMeOMe; each of R^1a, R^1b, R^1c, R^ld, R^1e, R^1h, R¹ⁱ, R^1j, R^lk R^1l, R^lm, R^ln, R^1o and R^1p is independently selected from the group consisting of H, Ci-₄ alkyl, C_3-8 cycloalkyl and C_3-8 heterocycloalkyl, wherein Ci-₄ alkyl is optionally substituted with one or more substituents selected from the group consisting of OH, OMe, CN, halogen, NR^3aR^3b, C_3-8 cycloalkyl and C3- 8 heterocycloalkyl; each pair of R^la and R^lb, R^ld and R^le, R^lk and R¹¹, or R^ln and R¹⁰, optionally form a 3- to 8-membered nitrogen-containing heterocyclyl ring, wherein the heterocyclyl ring is optionally substituted with one or more R⁶;

Het represents a 3- to 8-membered saturated or partially saturated monocyclic, bridged or spiro heterocyclyl comprising one or more heteroatoms or groups each independently selected from O, S, S(=O), S(=O)2 and N, wherein Het is optionally substituted with one or two substituents each independently selected from the group consisting of halogen, NR^laR^lb, Ci-4 alkyl, OH, OMe and CN, wherein Ci-4 alkyl is unsubstituted or substituted with one or more substituent selected from the group consisting of OH, halogen, NR^ldR^le; n is 0, 1, 2 or 3; p is 0, 1, 2;

Z is C or N;

R⁴ is H, CN, halogen, OH, NHR⁷, NHCOR⁷, NH(S=O)R⁷, or NHSO2R⁷;

refers to X ring and Y ring having exactly two atoms and one bond in common; each R⁶ is independently H, halogen, C_1-4 alkyl, OH, OMe, CN, CF3, NR^laR^lb, C_3-8 cycloalkyl, or C_3-8 heterocycloalkyl; each R⁷ is independently H, NH2, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, or cycloalkyl; or a pharmaceutically acceptable form or an isotope derivative thereof, effective to treat cancer, or a related disease or disorder, in a mammal, including a human.

[0095] Compounds disclosed herein may cause delays in the development of AML, decrease in the number of leukemia cells in bone marrow and peripheral blood, decrease in the number of Mac-l⁺c-Kit⁺ cells in bone marrow and peripheral blood leukemia cells, reduction in the number of leukemia granulocyte macorhage progenitors cells(L-GMPs) in bone marrow, increase in apoptosis of L-GMPs, and/or impairment of the maintenance of AML. [0096] In certain embodiments, the cancer that may be treated is selected from breast, colon, endometrial, kidney, lung, melanoma, prostate, thyroid cancer and leukemias. Other PTEN- deficient neoplasm may also be treated with the compounds and pharmaceutical compositions of the invention, for example, brain (gliomsa), glioblastomas, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, colorectal cancer, Wilm’s tumor, Ewing’s sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, head and neck cancer, liver cancer, squamous cell carcinoma, ovarian cancer, pancreatic cancer, sarcoma cancer, osteosarcoma, giant cell tumor of bone, lymphoblastic T cell, malignant lymphoma, hodykins lymphoma, non- hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt’s lymphoma, follicylar lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, cervical cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, gastrointestinal stromal tumor and testicular cancer.

[0097] In yet another aspect, the invention generally relates to use of a compound disclosed herein, and a pharmaceutically acceptable excipient, carrier, or diluent, in preparation of a medicament for treating a disease or disorder.

[0098] In certain embodiments, the disease or disorder is cancer, or a related disease or disorder.

[0099] In certain embodiments, the cancer that may be treated is selected from breast, colon, endometrial, kidney, lung, melanoma, prostate, thyroid cancer and leukemia.

[00100] In certain embodiments, the medicament is for oral administration.

[00101] In certain embodiments, the medicament is for intravenous administration.

[00102] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and /ra/z.s-i somers, R- and 5-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

[00103] Isomeric mixtures containing any of a variety of isomer ratios may be utilized in accordance with the present invention. For example, where only two isomers are combined, mixtures containing 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99: 1, or 100:0 isomer ratios are contemplated by the present invention. Those of ordinary skill in the art will readily appreciate that analogous ratios are contemplated for more complex isomer mixtures.

[00104] If, for instance, a particular enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic methods well known in the art, and subsequent recovery of the pure enantiomers.

[00105] Isotopically-labeled compounds are also within the scope of the present disclosure. As used herein, an "isotopically-labeled compound" refers to a presently disclosed compound including pharmaceutical salts and prodrugs thereof, each as described herein, in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds presently disclosed include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶C1, respectively.

[00106] By isotopically-labeling the presently disclosed compounds, the compounds may be useful in drug and/or substrate tissue distribution assays. Tritiated (³H) and carbon-14 (¹⁴C) labeled compounds are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (²H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds presently disclosed, including pharmaceutical salts, esters, and prodrugs thereof, can be prepared by any means known in the art.

[00107] Further, substitution of normally abundant hydrogen (¹H) with heavier isotopes such as deuterium can afford certain therapeutic advantages, e.g., resulting from improved absorption, distribution, metabolism and/or excretion (ADME) properties, creating drugs with improved efficacy, safety, and/or tolerability. Benefits may also be obtained from replacement of normally abundant ¹²C with ¹³C. (See, WO 2007/005643, WO 2007/005644, WO 2007/016361, and WO 2007/016431.)

[00108] Stereoisomers (e.g., cis and trans isomers) and all optical isomers of a presently disclosed compound e.g., R and S enantiomers), as well as racemic, diastereomeric and other mixtures of such isomers are within the scope of the present disclosure.

[00109] Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 95% (“substantially pure”), which is then used or formulated as described herein. In certain embodiments, the compounds of the present invention are more than 99% pure.

[00110] Solvates and polymorphs of the compounds of the invention are also contemplated herein. Solvates of the compounds of the present invention include, for example, hydrates.

[00111] Any appropriate route of administration can be employed, for example, parenteral, intravenous, subcutaneous, intramuscular, intraventricular, intracorporeal, intraperitoneal, rectal, or oral administration. Most suitable means of administration for a particular patient will depend on the nature and severity of the disease or condition being treated or the nature of the therapy being used and on the nature of the active compound.

[00112] Compositions for parenteral injection comprise pharmaceutically-acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity may be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[00113] These compositions can also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paragen, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin.

[00114] Compounds of the present invention may also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically-acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.

[00115] Total daily dose of the compositions of the invention to be administered to a human or other mammal host in single or divided doses may be in amounts, for example, from 0.0001 to 300 mg/kg body weight daily and more usually 1 to 300 mg/kg body weight. The dose, from 0.0001 to 300 mg/kg body, may be given twice a day.

[00116] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds described herein or derivatives thereof are admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (i) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (ii) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (iii) humectants, as for example, glycerol, (iv) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (v) solution retarders, as for example, paraffin, (vi) absorption accelerators, as for example, quaternary ammonium compounds, (vii) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, (viii) adsorbents, as for example, kaolin and bentonite, and (ix) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others known in the art.

[00117] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers, such as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3- butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, and fatty acid esters of sorbitan, or mixtures of these substances, and the like. Besides such inert diluents, the composition can also include additional agents, such as wetting, emulsifying, suspending, sweetening, flavoring, or perfuming agents.

[00118] Materials, compositions, and components disclosed herein can be used for, can be used in conjunction with, can be used in preparation for, or are products of the disclosed methods and compositions. It is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutations of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a method is disclosed and discussed and a number of modifications that can be made to a number of molecules including in the method are discussed, each and every combination and permutation of the method, and the modifications that are possible are specifically contemplated unless specifically indicated to the contrary. Likewise, any subset or combination of these is also specifically contemplated and disclosed. This concept applies to all aspects of this disclosure including, but not limited to, steps in methods using the disclosed compositions. Thus, if there are a variety of additional steps that can be performed, it is understood that each of these additional steps can be performed with any specific method steps or combination of method steps of the disclosed methods, and that each such combination or subset of combinations is specifically contemplated and should be considered disclosed.

Examples [00119] The following examples are given for the purpose of illustrating the invention, but not for limiting the scope or spirit of the invention.

[00120] Compounds of the invention, including those specifically disclosed herein above and herein below, may be prepared as described in the following schemes. For example, the compounds of Formula (I) may be prepared as described in Schemes below, which are known to those of skill in the art for making fragments and combinations thereof.

Scheme 1

Preparation of ethyl (Z)-3-amino-4A4-trichloro-2-cyanobut-2-enoate (Step 1 \n Scheme /)

[00121] To a solution of ethyl 2-cyanoacetate (41 g, 364 mmol) and 2,2,2-trichloroacetonitrile (100 g, 692 mmol) in ethanol (150 mL) was added triethylamine (TEA) (2.0 g, 19 mmol) at 0°C. The mixture was stirred at room temperature (RT) for 6 hours. The reaction mixture was concentrated under reduced pressure to give a red oil, which was taken up in dichloromethane (DCM), filtered through a plug of silica gel, and concentrated to give 70 g ethyl (Z)-3-amino-4,4,4- trichloro-2-cyanobut-2-enoate, as a yellow solid.

Scheme 2

Preparation of ethyl 2-cyano-2-(cyclopropylcarbamothioyl)acetate (Step 1 in Scheme 2)

[00122] A mixture of ethyl isothiocyanatocyclopropane (2.5 g, 25.21 mmol), ethyl 2- cyanoacetate (2.42 mL, 22.68 mmol) and TEA (2.8 mL, 20.2 mmol) was stirred at 50 °C for 3 hours. The mixture was quenched with 20 mL H2O and acidified to pH=7-8 with IM HC1. The mixture was extracted with DCM (50 mL * 3). The organic layers were combined, washed with saturated saline (50 mL), dried over Na2SO4, filtered and concentrated to give ethyl 2-cyano-2- (cyclopropylcarbamothioyl)acetate (5.2 g) as an oil. The crude product was used in next step without further purification.

Preparation of ethyl (2Z)-2-cyano-3-(cyclopropylamino)-3-(methylsulfanyl)prop-2-enoate (Step 2 in Scheme 2)

[00123] A mixture of ethyl 2-cyano-2-(cyclopropylcarbamothioyl)acetate (5.0 g, 23.55 mmol) and KOH(1.32 g, 23.55 mmol) in EtOH (20 mL) was stirred atRT for 0.5 hour. Then iodomethane (3.34 g, 23.55 mmol) was added. The mixture was stirred at RT overnight. The mixture was then concentrated to give the residue. The residue was diluted with 20 mL H2O and extracted with DCM (20 mL * 3). The organic layers were combined, washed with saturated saline (50 mL), dried over Na2SO4, filtered and concentrated to give crude product. The crude was purified by chromatography on silica gel eluted with petroleum ether (PE): ethyl acetate (EA) =5 : 1 to give ethyl (2Z)-2-cyano-3-(cyclopropylamino)-3-(methylsulfanyl)prop-2-enoate (3.6 g) as an oil. MS (ESI): mass calcd. For C10H14N2O2S 226.2 m/z found 227.4 [M+H]⁺.

Scheme 3

Preparation of ethyl (Z)-2-cyano-3-(methylamino)-3-(methylthio)acrylate (Step 1 in Scheme 3 )

[00124] A mixture of isothiocyanatomethane (2.0 g, 27.4 mmol), ethyl 2-cyanoacetate (6.2 g, 54.8 mmol) and potassium hydroxide (1.6 g, 27.4 mmol) in EtOH (20 mL) was stirred at 50 °C for 2 hours. Then the reaction was cooled to RT. Methyl iodide (3.9 g, 27.4mmol) was added to the mixture. The reaction mixture was stirred for 2 hours at RT. Upon completion of the reaction as indicated by TLC, the reaction was quenched with H2O (20 mL), acidified to pH=7-8 with IM HC1 and extracted with DCM (30 mL * 3). The organic layers were combined, washed with saturated saline (50 mL), dried over Na2SO4, filtered and concentrated to give crude product. The crude was recrystallized from ethanol to give ethyl (Z)-2-cyano-3-(methylamino)-3- (methylthio)acrylate (5 g) as a white solid MS (ESI): mass calcd. For C8H12N2O2S 200.2 m/z found 201.3 [M+H]⁺.

Scheme 4

General procedure for preparing compounds in Scheme 4 (Step 1 in Scheme 4)

[00125] To a solution of Ethyl 2-cyanoacrylate derivatives in dimethylformamide (DMF) was added hydrazine hydrate. The mixture was stirred at 100°C for 5 hours, cooled to RT and concentrated to give crude product. The crude was dissolved in DCM and stirred for 2 hours. The mixture was filtered and washed with DCM to give the desired product.

Preparation of ethyl 3.5-diamino- l H-pyrazole-4-carboxylate (Step 1 m Scheme 4}

[00126] To a solution of ethyl (Z)-3-amino-4,4,4-trichloro-2-cyanobut-2-enoate (20 g, 78 mmol) in DMF (100 mL) was added hydrazine hydrate (7.8 g, 156 mmol). The mixture was stirred at 100°C for 5 hours, cooled to RT and concentrated to give crude product. The crude was dissolved in DCM (200 mL) and stirred for 2 hours. The mixture was filtered and washed with DCM (200 mL) to give ethyl 3,5-diamino-lH-pyrazole-4-carboxylate (10.0 g) as a brown solid. ethyl 3-amino-5-(cyclopropylamino)-4H-pyrazole-4-carboxylate was prepared according to the procedure described herein for Step 1 in Scheme 4

[00127] The desired compound (2.9 g) was obtained as an oil. MS (ESI): mass calcd. For C9H14N4O2 210.2 m/z found 211.5 [M+H]⁺. ethyl 5-amino-3-(methylamino)-lH-pyrazole-4-carboxylate was prepared according to the procedure described herein for Step 1 in Scheme 4

[00128] The desired compound (2.1 g) was obtained as an oil.

General procedure for preparing compounds in Scheme 4 (Step 2 in Scheme 4)

[00129] To a solution of ethyl lH-pyrazole-4-carboxylate derivatives in H2O was added HC1. Then 1,1,3,3-tetramethoxypropane was added in portions. The mixture was stirred at 50°C for 6 hours. Upon completion of the reaction as indicated by thin layer chromatography (TLC), the reaction was cooled to RT. The mixture was basified with 2M NaOH to pH=8-9 and extracted with DCM. The organic layers were combined, washed with H2O (20 mL), dried over Na2SO4 and filtered. The organic layer was concentrated to give the desired product.

Preparation of ethyl 2-aminopyrazolo[L5-a]pyrimidine-3-carboxylate (Step 2 in Scheme 4}

[00130] To a solution of ethyl 3,5-diamino-lH-pyrazole-4-carboxylate (10 g, 58 mmol) in H2O (40 mL) was added HC1 (40 mL, 2mol/L). Then 1,1,3,3-tetramethoxypropane (14.3 g, 87.8 mmol) was added in portions. The mixture was stirred at 50°C for 6 hours. Upon completion of the reaction as indicated by TLC, the reaction was cooled to RT. The mixture was basified with 2M NaOH to pH=8-9 and extracted with DCM (30 mL * 3). The organic layers were combined, washed with H2O (20 mL), dried over Na2SO4 and filtered. The organic layer was concentrated to give ethyl 2-aminopyrazolo[l,5-a]pyrimidine-3-carboxylate (7.5 g) as a yellow solid. ethyl 2-(cyclopropylamino)pyrazolo[L5-a]pyrimidine-3-carboxylate was prepared according to the procedure described herein for Step 2 in Scheme 4

[00131] The desired compound (1.9 g) was obtained a yellow solid. MS (ESI): mass calcd. For C12H14N4O2 246.2 m/z found 247.1 [M+H]⁺. ethyl 2-(methylamino)pyrazolo[L5-a]pyrimidine-3-carboxylate was prepared according to the procedure described herein for Step 2 in Scheme 4

[00132] The desired compound (2.1 g) was obtained as a yellow solid. MS (ESI): mass calcd.

For C10H12N4O2 220.2 m/z found 221.5 [M+H]⁺.

General procedure for preparing compounds in Scheme 4 (Step 3 in Scheme 4)

[00133] To a solution of pyrazolo[l,5-a]pyrimidine-3-carboxylate derivatives in tetrahydrofuran (THF):MeOH:H2O = 1 : 1 : 1 was added LiOH and stirred for 10 hours. The mixture was filtered. The filtrate was acidified to pH = 4-5 and extracted with DCM. The organic layers were combined, dried over Na2SO4 and filtrated. The organic layer was concentrated to give desired product.

Preparation of 2-aminopyrazolo[L5-a]pyrimidine-3-carboxylic acid (Step 3 in Scheme 4)

[00134] To a solution of ethyl 2-aminopyrazolo[l,5-a]pyrimidine-3-carboxylate (7.5 g, 36.4 mmol) inTHF :MeOH:H2O (20 mL: 20 mL: 20 mL) was added LiOH (4.5 g, 109.2 mmol) and stirred at 45 °C for 10 hours. The mixture was filtered. The filtrate was acidified to pH 4-5 and extracted with DCM (50mL * 3). The organic layers were combined, dried over Na2SO4 and filtrated. The organic layer was concentrated to give 2-aminopyrazolo[l,5-a]pyrimidine-3- carboxylic acid (6 g), as a yellow solid . MS (ESI): mass calcd. For C7H6N4O2 178.1 m/z found 178.8[M+H]⁺.

2-(cyclopropylamino) pyrazolo[E5-a] pyrimidine-3 -carboxylic acid was prepared according to the procedure described herein for Step 3 in Scheme 4

[00135] The desired compound (410 mg, 92%) was obtained as a yellow solid. ethyl 2-(methylamino)pyrazolo[ l .5-a]pyrimidine-3-carboxylate was prepared according to the procedure described herein for Step 3 in Scheme 4

[00136] The desired compound (0.25 g) was obtained as a yellow solid.

Scheme 5

General procedure for preparing compounds in Scheme 5 (Step 1 in Scheme 5)

[00137] To a solution of 2-chloro-6-m ethylbenzoic acid and dimethylformamide (DMF) in DCM was added oxalyl chloride over 10 min at 0 °C under nitrogen atmosphere. The mixture was stirred at RT for 2 hours. The mixture was concentrated under reduced pressure to give the residue. The residue was dissolved in DCM. The resulting mixture was slowly added to a mixture of aniline (or substituted aniline) and TEA in DCM at 0 °C. After 2 hours, the reaction mixture was diluted with H2O, and extracted with DCM. The organic layers were combined, washed with saturated saline, dried over Na2SO4 and filtered. The mixture was concentrated to give crude product. The crude was purified to give the desired product.

Preparation of 2-chloro-6-methyl-N-phenylbenzamide (Step 1 in Scheme 5)

[00138] To a solution of 2-chloro-6-methylbenzoic acid (37 g, 0.22 mol) and DMF (1 mL) in DCM (250 mL) was added oxalyl chloride (20.19 mL, 0.24 mol) over 10 min at 0 °C under nitrogen atmosphere. The mixture was stirred at RT for 2 hours. The mixture was concentrated under reduced pressure to give the residue. The residue was dissolved in DCM (50 mL). The resulting mixture was slowly added to a mixture of aniline (21.2g, 0.23 mol) and TEA (44 g, 0.43 mol) in DCM (250 mL) at 0 °C. After 2 hours, the reaction mixture was diluted with LEO (100 mL) and extracted with DCM (200 mL * 3). The organic layers were combined, washed with saturated saline (150 mL), dried over Na2SO4 and filtered. The mixture was concentrated to give crude product. The crude was purified by recrystallized from n-hexane (150 mL) to give 2-chloro-6- methyl-N-phenylbenzamide (45 g, 84 %) as a white solid.

2-chloro-N-(3-chlorophenyl)-6-methylbenzamide was prepared according to the procedure described herein for Step 1 in Scheme 5

[00139] The desired compound (4.5 g) was obtained as a yellow solid.

2-chloro-N-(2-methoxyphenyl)-6-methylbenzamide was prepared according to the procedure described herein for Step 1 in Scheme 5

[00140] The desired compound (1.9 g) was obtained as a yellow solid.

2-chloro-N-(3-methoxyphenyl)-6-methylbenzamide was prepared according to the procedure described herein for Step 1 in Scheme 5

[00141] The desired compound (1.5 g) was obtained as a white solid.

2-chloro-N-(4-methoxyphenyl)-6-methylbenzamide was prepared according to the procedure described herein for Step 1 in Scheme 5

[00142] The desired compound (3.3 g) was obtained as a yellow solid.

General procedure for preparing compounds in Scheme 5 (Step 2 in Scheme 5)

[00143] To a solution of 2-chloro-6-methyl-N-phenylbenzamide derivatives in THF was added n-BuLi at -30 °C under nitrogen atmosphere. After addition, the mixture was stirred at -30 °C for 0.5 hour. Then, i-PrMgCl was added to tert-butyl N-[(1S)-1- [methoxy(methyl)carbamoyl]ethyl]carbamate in THF at -30 °C under nitrogen atmosphere. After addition, the mixture was stirred at -30 °C for 0.5 hour. The in-situ Grignard agent was added dropwise to organolithium solution under anhydrous conditions, maintaining the temperature at - 30 °C to -10 °C. After addition, the mixture was stirred at -15 °C for 1 hour. The mixture was quenched with H2O and acidified to pH=l-3 with concentrated HC1. The mixture was concentrated to give crude intermediate as a yellow solid. The residue was dissolved in MeOH and concentrated HC1. The mixture was stirred at 85 °C for 1 hour. The reaction mixture was concentrated and basified to pH=8-9 with NH3.H2O. The mixture was extracted with DCM. The organic layers were combined, washed with saturated saline, dried over Na2SO4, filtered and concentrated to give crude product. To the crude dissolved in MeOH, D-Tartaric acid was added. The mixture was stirred at RT for 3 hours. The mixture was filtered. The filter cake was dissolved in DCM. The mixture was basified to pH =8 - 9 with NH3.H2O and extracted with DCM. The organic layers were combined, washed with saturated saline, dried over Na2SO4, filtered and concentrated to give the desired product.

Preparation of 3-[(lS)-l-aminoethyl]-8-chloro-2-phenyl-L2-dihydroisoquinolin-l-one (Step 2 in Scheme 5)

[00144] To a solution of 2-chloro-6-methyl-N-phenylbenzamide (32 g, 130 mmol) in THF (160 mL) was added n-BuLi (130 mL, 326 mmol, 2.5M) at -30 °C under nitrogen atmosphere. After addition, the mixture was stirred at -30 °C for 0.5 hour. Then, i-PrMgCl (105 mL, 213 mmol, 2.0 M) was added to tert-butyl N-[(lS)-l-[methoxy(methyl)carbamoyl]ethyl]carbamate (45 g, 193.84 mmol) in THF (220 mL) at -30 °C under nitrogen atmosphere. After addition, the mixture was stirred at -30 °C for 0.5 hour. The in-situ Grignard agent was added dropwise to organolithium solution under anhydrous conditions, maintaining the temperature at -30 °C to -10 °C. After addition, the mixture was stirred at -15 °C for 1 hour. The mixture was quenched with H2O and acidified to pH=l-3 with concentrated HC1. The mixture was concentrated to give crude intermediate as a yellow solid. The residue was dissolved in MeOH (100 mL) and concentrated HC1 (150 mL). The mixture was stirred at 85 °C for 1 hour. The reaction mixture was concentrated and basified to pH=8-9 with NH3.H2O. The mixture was extracted with DCM (200 mL * 3). The organic layers were combined, washed with saturated saline (100 mL * 2), dried over Na2SO4, filtered and concentrated to give crude product. To the crude dissolved in MeOH (200 mL), D- Tartaric acid (15.5 g, 103.27 mmol) was added. The mixture was stirred at RT for 3 hours. The mixture was filtered. The filter cake was dissolved in DCM (50 mL). The mixture was basified to pH =8 - 9 with NH3.H2O and extracted with DCM 300 mL). The organic layers were combined, washed with saturated saline (300 mL), dried over Na2SO4, filtered and concentrated to give 3- [(lS)-l-aminoethyl]-8-chloro-2-phenyl-l,2-dihydroisoquinolin-l-one (20 g, 51.4%) as a white solid.

3-[(lS)-l-aminoethyl]-8-chloro-2-(3-chlorophenyl)-L2-dihydroisoquinolin-l-one was prepared according to the procedure described herein for Step 2 in Scheme 5

[00145] The desired compound (1.0 g) was obtained as a white solid. MS (ESI): mass calcd.

For C17H14CI2N2O 333.2 m/z found 334.4 [M+H]⁺.

(S)-3-(l-aminoethyl)-8-chloro-2-(2-methoxyphenyl)isoquinolin-l(2H)-one was prepared according to the procedure described herein for Step 2 in Scheme 5

[00146] The desired compound (1.2 g) was obtained as a yellow solid. MS (ESI): mass calcd.

For C18H17CIN2O2 328.8 m/z found 329.6 [M+H]⁺.

3 -[( 1 S)- 1 -aminoethyl]-8-chloro-2-(3 - methoxyphenyl)- 1 ,2-dihydroisoquinolin- 1 -one was prepared according to the procedure described herein for Step 2 in Scheme 5

[00147] The desired compound (0.7 g) was obtained as a white solid. MS (ESI): mass calcd.

For C18H17CIN2O2 328.8 m/z found 329.6 [M+H]⁺.

3-[(lS)-l-aminoethyl]-8-chloro-2-(4-methoxyphenyl)-E2-dihydroisoquinolin-l-one was prepared according to the procedure described herein for Step 2 in Scheme 5

[00148] The desired compound (2.0 g) was obtained as a yellow solid. MS (ESI): mass calcd.

For C18H17CIN2O2 328.8 m/z found 329.6 [M+H]⁺.

General procedure for preparing compounds in Scheme 5 (Step 3 in Scheme 5)

[00149] A mixture of 3-[(lS)-l-aminoethyl]-8-chloro-2-phenyl-l,2-dihydroisoquinolin-l-one derivatives, 2-aminopyrazolo[l,5-a]pyrimidine-3-carboxylic acid derivatives, 1- hydroxybenzotriazole (HOBt), 1 -(3 -Dimethylaminopropyl)-3 -ethylcarbodiimide hydrochloride (EDCI) and TEA in DMF was stirred at RT. The mixture was then poured into H2O. The suspension mixture was filtered. The filter cake was washed with EA. The organic layer was diluted with H2O and extracted with EA. The organic layers were combined, washed with saturated saline, dried over Na2SO4, filtered and concentrated to give crude product. The crude was purified to give the desired compound.

Preparation of 2-amino-N-[(lS)-l-(8-chloro-l-oxo-2-phenyl-E2-dihydroisoquinolin-3- yl)ethyl]pyrazolo[E5-a]pyrimidine-3-carboxamide (Step 3 in Scheme 5)

[00150] A mixture of 3-[(lS)-l-aminoethyl]-8-chloro-2-phenyl-l,2-dihydroisoquinolin-l-one (5.0 g, 16.74 mmol), 2-aminopyrazolo[l,5-a]pyrimidine-3-carboxylic acid (6.0 g, 33.5 mmol), HOBt (4.5 g, 33.47 mmol), EDCI (6.4 g, 33.47 mmol) and TEA (12 mL, 84 mmol) in DMF (200 mL) was stirred at RT for 16 hour. The mixture was then poured into FLO. The suspension mixture was filtered. The filter cake was washed with EA (50 mL* 3). The organic layer was diluted with H2O (30 mL) and extracted with EA (150 mL * 3). The organic layers were combined, washed with saturated saline (50 mL), dried over Na2SO4, filtered and concentrated to give crude product. The crude was purified by chromatography on silica gel eluted with DCM:MeOH=10: l to give crude product (5.0 g) as a yellow solid. The crude product was purified by crystallized from 20 mL acetonitrile to give 2-amino-N-[(lS)-l-(8-chloro-l-oxo-2-phenyl-l,2-dihydroisoquinolin-3- yl)ethyl]pyrazolo[l,5-a]pyrimidine-3-carboxamide (3.6 g, 46.88%) as a yellow solid. MS (ESI): mass calcd. For C24H19CIN6O2 458.9 m/z found 459.5 [M+H]⁺.

N-[( 1 S)- 1 -(8-chloro- 1 -oxo-2-phenyl- 1 ,2-dihydroisoquinolin-3 -yl)ethyl]-2- (cyclopropylamino)pyrazolo[L5-a]pyrimidine-3-carboxamide was prepared according to the procedure described herein for Step 3 in Scheme 5

[00151] The desired compound (180 mg, 49%) was obtained as a white solid. MS (ESI): mass calcd. For C27H23CIN6O2 498.9 m/z found 500.2 [M+H]⁺.

(S)-N-( 1 -(8-chloro- 1 -oxo-2-phenyl- 1 ,2-dihydroisoquinolin-3 -yl)ethyl)-2-(m ethylamino) pyrazolo[L5-a]pyrimidine-3-carboxamide was prepared according to the procedure described herein for Step 3 in Scheme 5

[00152] The desired compound (0.15g) was obtained as a white solid. MS (ESI): mass calcd.

For C25H21CIN6O2 472.9 m/z found 473.6 [M+H]⁺.

2-amino-N-[(l S)-l-[8-chl oro-2-(3 -chlorophenyl)- 1-oxo- 1.2-dihy droisoquinolin-3- yl]ethyl]pyrazolo[ 1,5-a]pyrimidine-3-carboxamide was prepared according to the procedure described herein for Step 3 in Scheme 5

[00153] The desired compound (0.32 g) was obtained as a yellow solid. MS (ESI): mass calcd.

For C24HI₈C12N₆O2 493.3 m/z found 494.5 [M+H]⁺.

(S)-2-amino-N-(l -(8-chloro-2-(2-methoxyphenyl)- 1 -oxo- 1 ,2-dihydroisoquinolin-3 - yl)ethyl)pyrazolo[E5-a]pyrimidine-3-carboxamide was prepared according to the procedure described herein for Step 3 in Scheme 5

[00154] The desired compound (0.25 g) was obtained as a while solid. MS (ESI): mass calcd.

For C25H21CIN6O3 488.9 m/z found 489.7 [M+H]⁺.

2-amino-N-[(l S)-l-[8-chl oro-2-(3-methoxyphenyl)-l -oxo-1, 2-dihy droisoquinolin-3- yl]ethyl]pyrazolo[E5-a]pyrimidine-3-carboxamide was prepared according to the procedure described herein for Step 3 in Scheme 5

[00155] The desired compound (0.2 g) was obtained as a white solid. MS (ESI): mass calcd.

For C25H21CIN6O3 488.9 m/z found 489.7 [M+H]⁺.

2-amino-N-[( 1 S)- 1 -[8-chloro-2-(4-methoxyphenyl)- 1 -oxo- 1 ,2-dihydroisoquinolin-3 - yl]ethyl]pyrazolo[E5-a]pyrimidine-3-carboxamide was prepared according to the procedure described herein for Step 3 in Scheme 5

[00156] The desired compound (0.35 g, 77 %) was obtained as a yellow solid. MS (ESI): mass calcd. For C25H21CIN6O3 488.9 m/z found 489.7 [M+H]⁺.

Scheme 6

Preparation of (S)-2-amino-N-(l-(8-chloro-2-(2-morpholinoethyl)-l-oxo-L2-dihydroisoquinolin- 3-yl)ethyl)pyrazolo[L5-a]pyrimidine-3-carboxamide (Step 1 m Scheme 6)

[00157] A mixture of (S)-3-(l-aminoethyl)-8-chloro-2-(2-morpholinoethyl)isoquinolin-l(2H)- one (220 mg, 0.65 mmol), 2-aminopyrazolo[l,5-a]pyrimidine-3-carboxylic acid (350 mg, 1.97 mmol), HOBt (265 mg, 1.97 mmol), EDCI (376 mg, 1.97 mmol) and TEA (328 mg, 3.25 mmol) in DMF (10 mL) was stirred at RT for 3 hours. The suspension mixture was filtered. The filter cake was washed with EA (20 mL). The organic layer was diluted with H2O (30 mL) and extracted with EA (30 mL * 3). The organic layers were combined, washed with saturated saline (50 mL), dried over Na2SO4, filtered and concentrated to give crude product. The crude was purified by chromatography on silica gel eluted with DCM:MeOH=10: l to give (S)-2-amino-N-(l-(8-chloro- 2-(2-morpholinoethyl)- 1 -oxo- 1 ,2-dihy droisoquinolin-3 -yl)ethyl)pyrazolo [1,5 -a]pyrimidine-3 - carboxamide (150 mg, 46% ) as a yellow solid.

Scheme 7

Preparation of 2-amino-N-[(lS)-l-{ l-oxo-2-phenyl-8-[2-(trimethylsilyl)ethynyl]-l,2- dihydroisoquinolin-3-yl}ethyl]pyrazolo[l,5-a]pyrimidine-3-carboxamide (Step 1 in Scheme 7)

[00158] A mixture of 2-amino-N-[(lS)-l-(8-chloro-l-oxo-2-phenyl-l,2-dihydroisoquinolin-3- yl)ethyl]pyrazolo[l,5-a]pyrimidine-3-carboxamide (400 mg, 0.87 mmol), Pd(CH3CN)2Ch (22.6 mg, 0.09 mmol), X-Phos(124 mg, 0.26 mmol) and Cs2CO3( 25 mg, 1.3 mmol) in acetonitrile (10 mL) was added ethynyltrimethylsilane (1.74mL, 12.20 mmol) under N2. The reaction mixture was stirred at 80 °C overnight. The mixture was filtered and concentrated to give crude. The crude was purified by chromatography on silica gel eluted with DCM:EA=2:1 to give 2-amino-N-[(lS)-l- { l-oxo-2-phenyl-8-[2-(trimethylsilyl)ethynyl]-l,2-dihydroisoquinolin-3-yl}ethyl]pyrazolo[l,5- a]pyrimidine-3 -carboxamide (230 mg, 51%) as a yellow solid.

Preparation of 2-amino-N-[(l S)- 1 -(8-ethynyl- 1 -oxo-2-phenyl- 1 ,2-Dihy droisoquinolin-3 - yl)ethyl]pyrazolo[l,5-a]pyrimidine-3-carboxamide (Step 2 in Scheme 7)

[00159] To a solution of 2-amino-N-[(lS)-l-{ l-oxo-2-phenyl-8-[2-(trimethylsilyl)ethynyl]- l,2-dihydroisoquinolin-3-yl}ethyl]pyrazolo[l,5-a]pyrimidine-3-carboxamide (230 mg, 0.44 mmol) in THF (10 mL) was added TBAF (0.6 mL, IM). The mixture was stirred at RT for 1 hour. Then, the mixture was diluted with H2O (20 mL) and extracted with EA (30 mL * 3). The combined organic layer was washed with brine (20 mL * 2), dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography on silica gel eluted with DCM:EA=L 1 to give 2- amino-N-[( 1 S)- 1 -(8-ethynyl- 1 -oxo-2-phenyl- 1 ,2-Dihydroisoquinolin-3 -yl)ethyl]pyrazolo[ 1,5- a]pyrimidine-3 -carboxamide (120 mg, 60.5%) as a yellow sold.

Scheme 8

Preparation of tert-butyl (S)-(l-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)ethyl)carbamate (Step 1 in Scheme 8}

[00160] To a solution of 2-amino-6-chlorobenzoic acid (5.0 g, 29.14 mmol) and (25)-2-({ l-[(2- methylprop-2-yl)oxy]vinyl}amino)propanoic acid (7.17 g, 37.88 mmol) in pyridine (20 mL) was added diphenyl phosphite (22.50 mL, 101.99 mmol). The reaction mixture was stirred at 40 °C for 1 hour. Aniline (3.19 mL, 34.97 mmol) was added to the reaction mixture. The reaction mixture was stirred at 55 °C for overnight. Upon completion of the reaction as indicated by LC-MS, the reaction mixture was cooled to RT. This mixture was diluted with EA, washed with 2N aqueous HC1, brine and dried over Na2SO4. The organics layer was filtered and concentrated in vacuum to afford residue. The residue was purified by chromatography on silica gel eluted with PE:EA=10: 1

5: 1 to give tert-butyl (S)-(l-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)ethyl)carbamate (10.33 g, 88.65%) as a white solid. MS (ESI): mass calcd. For C21H22CIN3O3 399.13 m/z found 400.1 [M+H] ⁺.

Preparation of (S)-2-(l-aminoethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (Step 2 in Scheme

[00161] To a solution of tert-butyl (S)-(l-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)ethyl)carbamate (0.83 g, 2.08 mmol) in DCM (1 mL) was added HC1ZEA (3.5 mL). The reaction mixture was stirred at RT for 1 hour. Upon completion of the reaction as indicated by LC-MS, the reaction was diluted with H2O and adjusted to pH=8 with NaHCCF and extracted with DCM/MeOH. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated to give (S)-2-(l-aminoethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (500 mg, 80.65%) as a white solid. MS (ESI): mass calcd. For C16H14CIN3O 299.08 m/z found 300.1 [M+H]

Preparation of 2-amino-N-((S)-l-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)- 3,3a-dihydropyrazolo[L5-a]pyrimidine-3-carboxamide (Step 3 m Scheme 8}

[00162] To a mixture of (S)-2-(l-aminoethyl)-5-chloro-3-phenylquinazolin-4(3H)-one (500 mg, 1.67 mmol) and 2,5-dioxopyrrolidin-l-yl 2-amino-3,3a-dihydropyrazolo[l,5-a]pyrimidine-3- carboxylate (925.98 mg, 3.34 mmol) in CH3CN (10 mL) was added DIEA (0.83 mL, 5.01 mmol). The reaction mixture was stirred at 90 °C for overnight. Upon completion of the reaction as indicated by LC-MS, the reaction mixture was cooled to RT and concentrated under vacuum. The reaction mixture was diluted with EA, washed with brine, dried over Na2SO4, filtered and concentrated. The yellow residue was purified by chromatography on silica gel eluted with DCM:EA=1 : 1 to give 2-amino-N-((S)-l-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)ethyl)-3,3a-dihydropyrazolo[l,5-a]pyrimidine-3-carboxamide (476 mg, 61.91%) as a white solid. MS (ESI): mass calcd. For C24H21CIN6O2 459.14 m/z found 460.1 [M+H] ⁺.

Scheme 9

Preparation of l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrazole (Step 1 \n Scheme 9)

[00163] To a solution of IH-pyrazole (10 g, 147 mmol) in THF (150 mL) was added NaH (7.6 g, 190 mmol) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 0.5 hour. Then (trimethyl silyl)-ethoxymethyl chloride (31 g, 176 mmol) was added to the mixture. The mixture was stirred at RT overnight, quenched with saturated saline and extracted with EA (100 mL * 3). The organic layers were combined, dried over Na2SO4, filtered and concentrated to give crude product. The crude was purified by chromatography on silica gel to give l-{[2- (trimethylsilyl)ethoxy]methyl}-lH-pyrazole (33 g) as an oil.

Preparation of 5-(3-chloropropyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole (Step 2 in

Scheme 9)

[00164] To a solution of l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrazole (33.5 g, 0.17 mol) in THF (100 mL) was added n-BuLi (87 mL, 0.22 mol) dropwise over 1.5 hour at -70 °C under nitrogen atmosphere. The resulting solution was stirred for 1 hour at this temperature. Then, a solution of l-bromo-3 -chloropropane (32.0 g, 0.2 mol) was added dropwise to the reaction mixture. After addition, the solution was warmed to RT slowly and stirred overnight under N2. The reaction was quenched with H2O (100 mL) and extracted with EA(200 mL * 3). The organic layers were combined, washed with saturated saline (50 mL), dried over Na2SO4, filtered and concentrated to give crude product (60 g) as a yellow oil. The crude was used in the next step without further purification.

Preparation of 5-(3-chloropropyl)-lH-pyrazole (Step 3 in Scheme 9)

[00165] 5-(3-chloropropyl)-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrazole (60 g) was dissolved in HC1ZEA (100 mL, 2M) at RT. The reaction was stirred at 60 °C for 2 hours. Upon completion of the reaction as indicated by TLC, the reaction was cooled to RT, diluted with H2O (100 mL), neutralized with saturated NaHCOs (200 mL) and extracted with EA (200 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated to give crude product. The crude was purified by chromatography on silica gel eluted with PE:EA=1 :1 to give 5-(3- chloropropyl)-lH-pyrazole (5.0 g, 15.84%) as an oil.

Preparation of 4H.5H.6H-pyrrolo[ l .2-b]pyrazole (Step 4 in Scheme 9)

[00166] To a solution of 5-(3-chloropropyl)-lH-pyrazole (5.0 g, 0.03 mmol) in dry DMF (10 mL) was added NaH (1.5 g, 0.04 mmol) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at RT overnight. Upon completion of the reaction as indicated by TLC, the reaction was quenched with H2O (50 mL) and extracted with EA (50 mL). The organic layers were combined, washed with saturated saline (50 mL), dried over Na2SO4, filtered and concentrated to give crude product. The crude was purified by chromatography on silica gel eluted with PE: EA=2: 1 to give 4H,5H,6H-pyrrolo[l,2-b]pyrazole (2.0 g, 53%) as an oil. MS (ESI): mass calcd. For C₆H₈N₂ 108.1 m/z found 109.2 [M+H]⁺.

Preparation of 3-iodo-4H,5H,6H-pyrrolo[L2-b]pyrazole (Step 5 in Scheme 9)

[00167] To a solution of 4H,5H,6H-pyrrolo[l,2-b]pyrazole (2.0 g, 18.69 mmol) in DMF (20 mL) was added NIS (4.2 g, 18.69 mmol) at RT under nitrogen atmosphere. Then the reaction was stirred at RT overnight. Upon completion of the reaction as indicated by TLC, the reaction was quenched with H2O (20 mL) and extracted with EA (80 mL). The organic layers were combined, washed with saturated saline (50 mL), dried over Na2SO4, filtered and concentrated to give crude product. The crude was purified by chromatography on silica gel eluted with PE:EA=2:1 to give 3-iodo-4H,5H,6H-pyrrolo[l,2-b]pyrazole (1.8 g) as a yellow solid.

Scheme 10

Preparation of ethyl 4-bromo-l-(4-ethoxy-4-oxobutyl)-lH-pyrazole-5-carboxylate (Step 1 in

Scheme 10}

[00168] To a solution of ethyl 4-bromo-lH-pyrazole-5-carboxylate (8.0 g, 36.4 mmol) in DMF (80 mL) was added K2CO3 (10 g, 72.8 mmol) and 4-bromo-butyric acid ethyl ester (10 g, 54.8 mmol). Then the suspension was stirred at RT overnight. The reaction mixture was quenched with H2O (30 mL) and extracted with EA (100 mL * 3). The organic layers were combined, washed with saturated saline (50 mL), dried over Na2SO4, filtered and concentrated to give crude product. The crude was purified by chromatography on silica gel eluted with PE:EA=10: l to give ethyl 4- bromo-l-(4-ethoxy-4-oxobutyl)-lH-pyrazole-5-carboxylate (7 g) as a colorless oil. MS (ESI): mass calcd. For CnHnBrlS CU 333.1 m/z found 334.3 [M+H]⁺.

Preparation of ethyl 3-bromo-4-oxo-4.5.6.7-tetrahydropyrazolo[ l .5-a]pyridine-5-carboxylate

(Step 2 in Scheme 10}

[00169] To a solution of ethyl 4-bromo-l-(4-ethoxy-4-oxobutyl)-lH-pyrazole-5-carboxylate (7 g, 21.1 mmol) in THF (50 mL) was added NaH (1.3 g, 31.5 mmol) at 0°C. Then the mixture was heated to reflux overnight. Upon completion of the reaction as indicated by TLC, the reaction was quenched with saturated NH4CI (20 mL). The aqueous layer was extracted with EA (50 mL). The organic layers were combined, washed with saturated saline (50 mL), dried over Na2SO4, filtered and concentrated to give ethyl 3-bromo-4-oxo-4,5,6,7-tetrahydropyrazolo[l,5-a]pyridine-5- carboxylate (5.0 g) as a white solid. MS (ESI): mass calcd. For CioHnBrlS Os 287.1 m/z found 288.1 [M+H]⁺.

Preparation of 3-bromo-6,7-dihydropyrazolo[L5-a]pyridin-4(5H)-one (Step 3 in Scheme 10

[00170] To a solution of ethyl 3-bromo-4-oxo-4,5,6,7-tetrahydropyrazolo[l,5-a]pyridine-5- carboxylate (5.0g, 17.4 mmol) in DMSO (80 mL) and H2O (2 mL) was added NaCl (6.1 g, 104 mmol). The mixture was heated to 150 °C for 2 hours. After cooled to RT, the mixture was diluted with EA (100 mL) and H2O (60 mL). The organic layer was separated. The aqueous layer was extracted with EA (100 mL). The organic layers were combined, washed with saturated saline (50 mL), dried over Na2SO4, filtered and concentrated to give crude product. The crude was purified by chromatography on silica gel eluted with PE:EA = 5: 1 to give 3-bromo-6,7- dihydropyrazolo[l,5-a]pyridin-4(5H)-one (3.2 g) as a white solid. MS (ESI): mass calcd. For C₇H₇BrN₂O 215.0 m/z found 216.3 [M+H]⁺.

Preparation of 3-bromo-4.5.6.7-tetrahydropyrazolo[ l .5-a]pyridine (Step 4 in Scheme 10}

[00171] To a solution of 3-bromo-6,7-dihydropyrazolo[l,5-a]pyridin-4(5H)-one (3.0 g, 14 mmol) in 2,2'-oxydiethanol(30 mL), was added hydrazine hydrate (4.2 mL, 83.7 mmol). The resulting mixture was stirred at 180 °C for 1 hour. Potassium hydroxide (3.4 g, 59.4 mmol) was carefully added to the mixture. The resulting suspension was stirred at 150 °C for 2 hours, and then cooled to RT. The reaction mixture was diluted with H2O (50 mL), acidified to pH=4.5 with aqueous HC1 (2N) and extracted with EA (50 mL * 3). The organic layers were combined, washed with saturated saline (50 mL), dried over Na2SO4, filtered and concentrated to give 3-bromo- 4,5,6,7-tetrahydropyrazolo[l,5-a]pyridine (0.55 g) as a clear yellow oil.

Scheme 11

Preparation of l-((l-(bromomethyl)cyclopropyl)methyl)-lH-pyrazole (Step 1 in Scheme 11}

[00172] To a solution of IH-pyrazole (5.0 g, 73.5 mmol) in DMF 20 mL was added NaH (5.8 g, 147 mmol) at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 0.5 hour. Then l,l-bis(bromomethyl)cyclopropane (16.6 g, 73.5 mmol) was added. The reaction mixture was stirred at RT overnight. The mixture was diluted with H2O (50 mL) and adjusted to pH=7-8 with 2M HC1. The mixture was extracted with EA (50 mL). The organic layers were combined, washed with saturated saline (50 mL), dried over Na2SO4, filtered and concentrated to give crude product. The crude was purified by chromatography on silica gel eluted with PE:EA=10: l to give 1-((1- (bromomethyl)cyclopropyl)methyl)-lH-pyrazole (4.8 g, 30%) as an oil.

Preparation of 4'H,6'H-spiro[cyclopropane-L5'-pyrrolo[L2-b]pyrazole] (Step 2 in Scheme 11

[00173] To a solution of l-((l-(bromomethyl)cyclopropyl)methyl)-lH-pyrazole (4.8 g, 22.4 mmol) in THF 20 mL was added lithium diisopropylamide (22.4 mL, 44.8 mmol, 2M) at -78 °C under nitrogen atmosphere. After addition the mixture was stirred at -78 °C for 0.5 hour and then was stirred at RT overnight. The mixture was diluted with H2O (20 mL) and extracted with EA (50 mL). The organic layers were combined, washed with saturated saline (50 mL), dried over Na2SO4, filtered and concentrated to give crude product. The crude was purified by chromatography on silica gel eluted with PE:EA=5: 1 to give 4'H,6'H-spiro[cyclopropane-l,5'-pyrrolo[l,2-b]pyrazole] (1.3 g, 45%) as a yellow solid.

Preparation of 3'-bromo-4TL6'H-spiro[cyclopropane-L5'-pyrrolo[L2-b]pyrazole] (Step 3 in Scheme 11}

[00174] To a solution of 4'H,6'H-spiro[cyclopropane-l,5'-pyrrolo[l,2-b]pyrazole] (1.0 g, 7.4 mmol) in DCM (10 mL) was added NBS (1.6 g, 8.8 mmol) at RT. After addition, the mixture was stirred at RT for 1 hour. The mixture was diluted with H2O (20 mL) and extracted with DCM (50 mL * 3). The organic layers were combined, washed with saturated saline (50 mL), dried over Na2SO4, filtered and concentrated to give crude product. The crude was purified by chromatography on silica gel eluted with PE:EA=5:1 to give 3'-bromo-4'H,6'H- spiro[cyclopropane-l,5'-pyrrolo[l,2-b]pyrazole] (1.2 g, 76%) as a yellow solid.

Scheme 12

Preparation of 2,3-dihydropyrazolo[5,l-b]oxazole (Step 1 in Scheme 12}

[00175] To a solution of l,2-dihydro-3H-pyrazol-3-one (2 g, 23.8 mmol) in MeCN (50 mL) was added 1,2-dibromo-ethane (13.3 g, 71.3 mmol) and K2CO3 (9.8 g, 71.4 mmol). The resulting mixture was stirred at reflux overnight. The reaction mixture was filtered. The filter cake was washed with EA (20 mL) and diluted with H2O (10 mL). The mixture was extracted with EA (20 mL * 3). The organic layers were combined, washed with saturated saline (50 mL), dried over Na2SO4, filtered and concentrated to give crude product. The crude was purified by chromatography on silica gel eluted with PE:EA=5: 1 to give 2,3-dihydropyrazolo[5,l-b]oxazole (0.8 g) as a yellow solid.

Preparation of 7-iodo-2,3-dihydropyrazolo[5,l-b]oxazole (Step 2 in Scheme 12}

[00176] To a solution of 2,3-dihydropyrazolo[5,l-b]oxazole (0.8 g, 7.3 mmol) in CEfCN (10 mL) was added NIS (2.5 g, 10.9 mmol), and the mixture was stirred at RT overnight. The mixture was quenched with H2O (10 mL) and extracted with EA (20 mL * 2). The organic layers were combined, washed with saturated saline (50 mL), dried over Na2SO4, filtered and concentrated to give crude product. The crude was purified by chromatography on silica gel eluted with PE:EA=5: 1 to give 7-iodo-2,3-dihydropyrazolo[5,l-b]oxazole (1.1 g) as a yellow solid.

Scheme 13

Preparation of tert-butyl 3-hydroxy-lH-pyrazole-l-carboxylate (Step 1 in Scheme 13}

[00177] To a solution of methyl (E)-3-methoxyacrylate (10 g, 86.2 mmol) in MeOH (60 mL) was added hydrazine hydrate (6.5 g, 129.3 mmol) at 40 °C under nitrogen atmosphere. The reaction was heated to 60°C and stirred for 1 hour. The reaction mixture was cooled RT. Triethylamine (13.2 g, 129.3 mol) was added portion-wise to the mixture, maintaining reaction temperature below 30°C. A solution of di-tert-butyl dicarbonate (18.7 g, 86.2 mmol) in MeOH (50 mL) was added to the mixture portion-wise, maintaining temperature below 40°C. The reaction mixture was stirred at RT for 16 hours. The reaction solution was concentrated, diluted with H2O (50 mL) and extracted with DCM (50 mL * 3). The organic layers were combined, washed with saturated saline (50 mL), dried over Na2SO4, filtered and concentrated to give crude product. The crude was purified by chromatography on silica gel eluted with PE:EA=1 : 1 to give tert-butyl 3 -hydroxy- IH-pyrazole-l- carboxylate (11 g) as a yellow oil .

Preparation of tert-butyl 3-((l-ethoxy-2-methyl-l-oxopropan-2-yl)oxy)-lH-pyrazole-l- carboxylate (Step 2 in Scheme 13

[00178] To a solution of tert-butyl 3-hydroxy-lH-pyrazole-l-carboxylate (3.0 g, 16.2 mmol) in acetonitrile (50 mL) was added K2CO3 (4.5 g, 32.4 mmol) at RT under nitrogen atmosphere. The reaction was heated at 80°C. After 1 hour, ethyl 2-bromo-2-methylpropanoate (3.2 g, 16.2 mmol) was added. The mixture was allowed to stir at 80°C for an additional for 16 hours. The mixture was cooled to RT, filtered and concentrated to give crude product. The crude was purified by chromatography on silica gel eluted with PE:EA=4: 1 to give tert-butyl 3 -((1 -ethoxy -2-methyl-l- oxopropan-2-yl)oxy)-lH-pyrazole-l -carboxylate (5.0 g) as a yellow oil. MS (ESI): mass calcd. For C14H22N2O5 298.3 m/z found 299.5 [M+H]⁺.

Preparation of ethyl 2-((lH-pyrazol-3-yl)oxy)-2-methylpropanoate (Step 3 in Scheme 13

[00179] To a solution of tert-butyl 3-((l-ethoxy-2-methyl-l-oxopropan-2-yl)oxy)-lH-pyrazole- l-carboxylate(5 g, 16.7 mmol) in DCM (20 mL) was added HCl/EA(10 mL, 4mol/L) at 0°C. The reaction was stirred for 3 hours. The mixture was basified with saturated aqueous Na2COs to pH=8- 9. The mixture was extracted with DCM (40 mL * 3). The organic layers were combined, washed with saturated saline (50 mL), dried over Na2SO4, filtered and concentrated to give ethyl 2-((lH- pyrazol-3-yl)oxy)-2-methylpropanoate (2.5 g) as a yellow oil. Preparation of 2-((lH-pyrazol-3-yl)oxy)-2-methylpropan-l-ol (Step 4 in Scheme 13}

[00180] To a solution of ethyl 2-((lH-pyrazol-3-yl)oxy)-2-methylpropanoate (2.5 g, 12.6 mmol) in THF (30 mL) at 0°C, was added LiAlEL (0.48 g, 12.6 mmol) under nitrogen atmosphere. Upon completion of the addition, the reaction mixture was warmed to RT and stirred for an additional 1 hour. The reaction was quenched with saturated aqueous Na2SO4. The mixture was filtered. The filter cake was washed with EA (20 mL * 3). The filtrate was diluted with H2O (10 mL) and extracted with EA (20 mL * 3). The organic layers were combined, washed with saturated saline (50 mL), dried over Na2SO4, filtered and concentrated to give the crude 2-((lH-pyrazol-3- yl)oxy)-2-methylpropan-l-ol (1.2 g). The crude product was used in the next step without further purification.

Preparation of 2-((lH-pyrazol-3-yl)oxy)-2-m ethylpropyl methanesulfonate (Step 5 in Scheme

[00181] To a stirred mixture of 2-((lH-pyrazol-3-yl)oxy)-2-methylpropan-l-ol (2.0 g, 12.8 mmol) and triethylamine (2.6 g, 25.6 mmol) in DCM (30 mL) was added methanesulfonyl chloride (MsCl) (1.4 g , 12.8 mmol) at 0°C under nitrogen atmosphere. After 2 hours, the reaction was quenched with H2O (10 mL). The aqueous layer was extracted with DCM (30 mL * 3). The organic layers were combined, washed with saturated saline (50 mL), dried over Na2SO4, filtered and concentrated to give crude 2-((lH-pyrazol-3-yl)oxy)-2-methylpropyl methanesulfonate (1.7 g, yellow oil). The crude product was used in the next step without further purification.

Preparation of 2,2-dimethyl-2,3-dihydropyrazolo[5,l-b]oxazole (Step 6 in Scheme 13

[00182] To a solution of 2-((lH-pyrazol-3-yl)oxy)-2-methylpropyl methanesulfonate (1.5 g, 6.4 mmol) in DMF (15 mL) was added NaH (60% in mineral oil, 0.38 g, 9.6 mmol) at 0°C under nitrogen atmosphere. Upon completion of the addition, the reaction was warmed to RT and stirred for an additional 10 hours. The reaction was cooled to 0°C, quenched with saturated aqueous NH4CI (5 mL)and diluted with H2O (30 mL) . The aqueous layer was extracted with EA (30 mL * 3). The organic layers were combined, washed with saturated saline (50 mL), dried over Na2SO4, filtered and concentrated to give crude product. The crude was purified by chromatography on silica gel eluted with PE:EA=4: 1 to give 2,2-dimethyl-2,3-dihydropyrazolo[5,l-b]oxazole (0.9 g) as a colorless oil.

Preparation of 7-iodo-2,2-dimethyl-2,3-dihydropyrazolo[5,l-b]oxazole (Step 7 in Scheme 13

[00183] To a solution of 2,2-dimethyl-2,3-dihydropyrazolo[5,l-b]oxazole (0.9 g, 6.5 mmol) in acetonitrile (5 mL) was added NIS (1.2 g, 6.5 mmol) at 0°C under nitrogen atmosphere. Upon completion of the addition, the reaction was warmed to RT. After 4 hours, the mixture was diluted with H2O (10 mL) and extracted with DCM (20 mL * 3). The organic layers were combined, washed with saturated saline (50 mL), dried over Na2SO4, filtered and concentrated to give crude product. The crude was purified by chromatography on silica gel eluted with PE:EA=4: 1 to give 7-iodo-2,2-dimethyl-2,3-dihydropyrazolo[5,l-b]oxazole (0.85 g) as a white solid.

Scheme 14

Preparation of 3-bromo-5,6,7,8-tetrahydroimidazo[L2-a]pyrazine (Step 1 in Scheme 14)

[00184] To a solution of tert-butyl 3-bromo-5,6-dihydroimidazo[l,2-a]pyrazine-7(8H)- carboxylate (600 mg, 1.99 mmol) in DCM (10 mL) was added HCl/dioxane (15 mL). The mixture was stirred at RT for 1 hour. The mixture was concentrated under vacuum. The residue was diluted with NaHCOs (15 mL) and extracted with EA (15 mL * 3). The combined organic layer was washed with brine (20 mL * 1), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel to give 3-bromo-5,6,7,8-tetrahydroimidazo[l,2- a]pyrazine (400 mg, 100%) as a yellow solid. Preparation of 3-bromo-7-methyl-5,6,7,8-tetrahydroimidazo[L2-a]pyrazine (Step 2 \n Scheme

[00185] To a solution of 3-bromo-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine (400 mg, 1.99 mmol) in DMF (10 mL) was added K2CO3 (823 mg, 5.97 mmol) and Mel (310 mg, 2.18 mmol). The mixture was stirred at RT for 3 hours. The mixture was diluted with H2O (10 mL) and extracted with EA (20 mL * 3). The combined organic layer was washed with brine (20 mL * 1), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 3-bromo-7-methyl-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine (380 mg, 89% as a yellow solid.

Scheme 15

Preparation of 3-iodo-4,5,6,7-tetrahydro-lH-indazole (Step 1 \n Scheme 15}

[00186] A mixture of 4,5,6,7-tetrahydro-lH-indazole (1.0 g, 8.19 mmol) and KOH (0.92 g, 16.38 mmol) in DMF 20 mL was added iodine (4.16 g, 16.38 mmol). The reaction mixture was stirred at RT for 16 hours. Upon completion of the reaction as indicated by TLC (PE:EA=3 : 1), the mixture was poured into H2O (50 mL) and filtered. The solid was dissolved in DCM (50 mL). The mixture was diluted with H2O (30 mL) and extracted with DCM (50 mL * 3). The combined organic layer was washed with brine (100 mL * 1), dried over Na2SO4, filtered and concentrated. The crude product was purified by chromatography on silica gel eluted with PE:EA=3 : 1 to give 3- iodo-4,5,6,7-tetrahydro-lH-indazole (0.7 g, 34%) as a yellow solid.

Preparation of 2-methylpropan-2-yl 3-iodo-4.5.6.7-tetrahydroindazole- l -carboxylate (Step 2 in Scheme 15}

[00187] A mixture of 3-iodo-4,5,6,7-tetrahydro-lH-indazole (0.6 g, 2.42 mmol) and DMAP (0.59 g, 4.84 mmol) in DCM 20 mL was added Di-tert butyl dicarbonate (0.79 g, 3.63 mmol). The reaction mixture was stirred at RT for 16 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with DCM (25 mL * 2). The combined organic layer was washed with brine (25 mL * 1), dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography on silica gel eluted with PE:EA=5: 1 to give 2-methylpropan-2-yl 3-iodo-4, 5,6,7- tetrahydroindazole-1 -carboxylate (0.6 g, 1.72 mmol, 71.43%) as a white solid.

Scheme 16

Preparation of 5.6.7.8-tetrahydroimidazo[3.4-a]pyridine (Step 1 in Scheme 16)

[00188] To a solution of imidazo[3,4-a]pyridine (2.0 g, 16.93 mmol) in TFA(20 mL) was added PtCL (0.23 g, 8.46 mmol) at RT under EE. The reaction mixture was stirred at RT for overnight. The reaction mixture was diluted with EA and filtered. The filter cake was washed with EA. The collected filtrate was concentrated under reduced pressure to give residue. The residue was basified to PH=8-9 and extracted with EA(50 mL * 2). The combined organic layer was washed with brine (25 mL), dried by Na2SO4, filtered and concentrated to give 5,6,7,8-tetrahydroimidazo[3,4- a]pyridine(2.0 g, 96%) as a solid.

Preparation of 3-bromo-5,6,7,8-tetrahydroimidazo[3,4-a]pyridine (Step 2 in Scheme 16)

[00189] To a solution of 5,6,7,8-tetrahydroimidazo[3,4-a]pyridine (1.8 g, 14.73 mmol) in acetonitrile (20 mL) was added cyanogen bromide (1.08 mL, 14.73 mmol) at RT for 24 hours. The reaction mixture was stirred at RT for overnight. The reaction mixture was diluted with EA (20 mL) and H2O (20 mL). The organic layer was separated. The water layer was extracted with EA ( 25 mL * 2). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was chromatography on silica gel eluted with PE: EA=2: 1 to give 3-bromo-5,6,7,8-tetrahydroimidazo[3,4-a]pyridine (960 mg, 32%) as a white solid.

Scheme 17

Preparation of 5,6-dihydro-8H-imidazo[2,l-c][L4]oxazine (Step 1 in Scheme 17)

[00190] A mixture of l,4-oxazinan-3-one (5.0 g, 49.45 mmol), 2-amino- 1,1 -di ethoxy ethane (16.30 mL, 112.62 mmol) and SnCL (3.8g, 14.83mmol) was stirred at 150 °C for 4 hours under N2. The mixture was cooled to RT. The reaction mixture was diluted with EA (100 mL) and H2O (100 mL). The suspension was filtered. The resulting solid was washed with EA (50 mL * 2). The organic layer was separated. The water layer was basified to PH=8-9 and extracted with EA (50 mL * 3). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography on silica gel eluted with DCM: MeOH=50: l to give 5,6-dihydro-8H-imidazo[2,l-c][l,4]oxazine (4.0 g, 32.22 mmol, 57.22%) as an oil.

Preparation of 3-bromo-5,6-dihydro-8H-imidazo[2,l-c][L4]oxazine (Step 2 in Scheme 17)

[00191] To a solution of 5,6-dihydro-8H-imidazo[2,l-c][l,4]oxazine (1.8 g, 14.50 mmol) in EA (25 mL) was added K2CO3 (0.40 g, 2.90 mmol), NBS (1.81 g, 10.15 mmol) at -78 °C . The reaction mixture was stirred at -78 °C for 1 hour. The reaction mixture was filtered. The mixture was diluted with H2O (25 mL) and extracted with EA (25 mL * 2). The combined organic layer and washed with brine (20mL * 1), dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography on silica gel eluted with PE: EA=2: 1/DCM: MeOH=50: l to give 3- bromo-5,6-dihydro-8H-imidazo[2,l-c][l,4]oxazine (800 mg, 3.94 mmol, 27.17%).

Scheme 18

Preparation of 2-azanylidene-L3-oxazinane (Step 1 in Scheme 18}

[00192] To a solution of 3-chloropropan-l-amine (15 g, 160.32 mmol) in H2O (30 mL) was added NaCNO (7.5 g, 115.38 mmol). The resulting mixture was stirred at 100 °C for 3 hours. The reaction mixture was cooled to RT and concentrated. The crude was dissolved in DCM: MeOH=10: 1 (100 mL). The mixture was stirred at RT for 10 mins. The mixture was filtered. The filtrate was concentrated to give crude 2-azanylidene-l,3-oxazinane (19 g, 189.77 mmol, 118.38%) as a white solid. The crude product was used next step without purification.

Preparation of 2-(2-azanylidene-L3-oxazinan-3-yl)- 1, 1 -dimethoxy ethane (Step 2 in Scheme 19

[00193] To a solution of 2-azanylidene-l,3-oxazinane (19 g, 189.77 mmol) in DMF (30 mL) was added K2CO3 (55 g, 397.95 mmol), 2-bromo- 1,1 -dimethoxy ethane (22.38 mL, 189.33 mmol) at RT under N2. The reaction mixture was stirred at 85 °C for 18 hours. The reaction was cooled to RT and filtered. The filter cake was washed with EA (50 mL). The organic layer was concentrated to give crude 2-(2-azanylidene-l, 3 -oxazinan-3-yl)- 1,1 -dimethoxy ethane (35 g). The crude was used next step without purification.

Preparation of 6,7-dihydro-5H-imidazo[2,l-b][L3]oxazine (Step 3 in Scheme 18

[00194] To a solution of 2-(2-azanylidene-l,3-oxazinan-3-yl)-l,l-dimethoxyethane (35 g, 185.94 mmol) in H2O (10 mL) was added con.HCl (100 mL) at RT under N2. The reaction mixture was stirred at 100 °C for 5 hours. The mixture was cooled to RT and quenched with Na2CO3(PH=8- 9). The mixture was extracted with DCM (100 mL * 3), dried over Na2SO4, filtered and concentrated. The residue was chromatography on silica gel eluted with DCM:MeOH=20: 1 to give 6,7-dihydro-5H-imidazo[2,l-b][l,3]oxazine (0.2 g, 1.61 mmol, 0.87%) as an oil.

Preparation of 3-iodo-6,7-dihydro-5H-imidazo[2,l-b][L3]oxazine (Step 4 in Scheme 18

[00195] To a mixture of 6,7-dihydro-5H-imidazo[2,l-b][l,3]oxazine (440 mg, 3.54 mmol) and K2CO3 (97.85 mg, 0.71 mmol) in MeCN (10 mL) was added NIS (557.50 mg, 2.48 mmol). The reaction mixture was stirred at RT for 10 min. The reaction was diluted with EA (10 mL) and H2O (10 mL). The organic layer was separated. The aqueous layer was extracted with EA (25 mL * 2). The combined organic layer was washed brine (10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography on silica gel eluted with DCM: MeOH=20: l to give 3-iodo-6,7-dihydro-5H-imidazo[2,l-b][l,3]oxazine (180 mg, 0.72 mmol, 20.34%).

Scheme 19

Preparation of 3-bromotetrahydro-4H-pyran-4-one (Step 1 in Scheme 19}

[00196] 3-bromo-3,4,5,6-tetrahydro-2H-pyran-4-one (9.9 g, 55.30 mmol) was added portionwise to the solution of tetrahydro-4H-pyran-4-one (4.00 g, 40.00 mmol) in THF (130 mL), maintaining temperature at 0°C. The reaction mixture was stirred at RT for 3 hours. The reaction mixture was filtered and concentrated. The crude product was purified by chromatography on silica gel eluted with PE:EA=2: 1 to give 3-bromotetrahydro-4H-pyran-4-one (9.9 g, 138.26%) as a yellow solid.

Preparation of 6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-amine (Step 2 in Scheme 19

[00197] To a solution of 3-bromo-3,4,5,6-tetrahydro-2H-pyran-4-one (7.1 g, 39.66 mmol) in EtOH (50 mL) was added diaminomethanethione (3.02 g, 39.66 mmol) and NaHCOs (3.33 g, 39.66 mmol). The reaction mixture was stirred at 80 °C overnight. The reaction mixture was concentrated. The residue was purified by chromatography on silica gel eluted with DCM:MeOH=20: l to give 6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-amine (4.4 g, 71.02%) as a yellow solid.

Preparation of 2-bromo-6,7-dihydro-4H-pyrano[4,3-d]thiazole (Step 3 in Scheme 10

[00198] To a solution of 6,7-dihydro-4H-pyrano[4,3-d][l,3]thiazol-2-amine (2.0 g, 12.80 mmol) in MeCN (25 mL) was added copper(l+) bromide (2.20 g, 15.36 mmol) and 3-methyl-l- (nitrosooxy)butane (2.25 g, 19.20 mmol). The reaction mixture was stirred at RT for 2 hours. The reaction mixture was diluted with H2O (30 mL) and extracted with EA (40 mL * 3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by chromatography on silica gel eluted with PE:EA=2: 1 to give 2- bromo-6,7-dihydro-4H-pyrano[4,3-d]thiazole (350 mg, 12.42%) as a yellow solid.

Scheme 20

Preparation of (benzylamino)-3H-imidazole (Step 1 in Scheme 20}

[00199] A mixture of lH-imidazol-2-amine (5.0 g, 60.18 mmol) and benzaldehyde (12.8 g, 106.12 mmol) in DCM 50 mL was added Titanium tetraisopropanolate (18 mL, 60.18 mmol) and EtsN (8.4 mL, 60.18 mmol). The mixture was stirred at RT for 16 hours. Upon completion of the reaction as indicated by TLC, the mixture was concentrated under reduced pressure to give residue. The crude product was used in next step without further purification. 2-{[(E)- phenylmethylidene]amino}-3H-imidazole (10.3 g, 60.16 mmol) was dissolved in EtOH(30 mL). Then, NaBEL (3.0 g, 6.83 mmol) was added to the mixture. The mixture was stirred at RT for 2 h, quenched with FLO (50 mL) and diluted with DCM (50 mL). The mixture was filtrated. The filter cake was washed with DCM (100 mL * 3). The collected filtrate was extracted with DCM, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography on silica gel eluted with DCMMeOH=20:l to give (benzylamino)-3H-imidazole (7.7 g, 44.45 mmol, 73.89%) as a black solid.

Preparation of ethyl [2-(benzylamino)imidazol-3-yl]acetate (Step 2 in Scheme 20)

[00200] To a solution of 2-(benzylamino)-3H-imidazole (7.7 g, 44.45 mmol) in THF (30 mL) was added ethyl bromoacetate (4.92 mL, 44.45 mmol), K2CO3 (12.29 g, 88.90 mmol). The reaction mixture was stirred at RT for overnight. The reaction mixture was diluted with EA and FLO. The organic layer was separated, washed with brine and concentrated in vacuo. The residue was purified by chromatography on silica gel eluted with PE:EA=5: 1 to give ethyl [2- (benzylamino)imidazol-3-yl]acetate (6.5 g, 25.07 mmol, 56.37%) as a yellow solid.

Preparation of 2-(benzylamino) imidazol-3-yl]acetic acid (Step 3 in Scheme 20}

[00201] A mixture of ethyl [2-(benzylamino)imidazol-3-yl]acetate (6.5 g, 25.07 mmol) in THF/H2O(30 mL/10 mL) was added NaOH (2.0 g, 50.13 mmol) at RT. The mixture was stirred at 50 °C for 1 hour. Upon completion of the reaction as indicated by TLC (DCM:MeOH=20: l), the organic solvent was removed by reduced pressure. The residue was acidified to PH=2-3 and filtrated. The resulting solid was washed with H2O (5 mL * 2), dissolved in DCM (5 mL) and concentrated to give [2-(benzylamino) imidazol-3-yl]acetic acid (4.0 g, 69 %) as an oil.

Preparation of l-benzyl-2,3-dihydro-lH-imidazo[2,3-b]imidazol-2-one (Step 4 in Scheme 20}

[00202] To a solution of [2-(benzylamino)imidazol-3-yl]acetic acid (4.0 g, 17.30 mmol) in THF (30 mL) was added EDC (5.36 g, 34.59 mmol), HOBt (4.67 g, 34.59 mmol), DMAP (4.23 g, 34.59 mmol) and TEA (11.99 mL, 86.49 mmol) at RT under N2. The reaction was stirred at RT for overnight. The reaction mixture was diluted with EA (50 mL) and H2O (50 mL). The organic layer was separated. The aqueous layer was extracted with EA (25 mL * 3). The combined organic layer was washed with brine (25 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography on silica gel eluted with DCM:MeOH=20: l to give l-benzyl-2,3- dihydro-lH-imidazo[2,3-b]imidazol-2-one (1.8 g, 8.44 mmol, 48.78%) as a yellow solid.

Preparation of l-benzyl-6-bromo-2,3-dihydro-lH-imidazo[2,3-b]imidazol-2-one (Step 5 in Scheme 2 )

[00203] A mixture of l-benzyl-2,3-dihydro-lH-imidazo[2,3-b]imidazol-2-one (1.6 g, 7.50 mmol) and K2CO3 (0.21 g, 1.50 mmol) in EA (20 mL) was added NBS (1.34 g, 7.50 mmol) at -78 °C. The reaction was stirred at 0 °C for 30 min. Upon completion of the reaction as indicated by TLC (PE:EA=2: 1), the reaction was filtrated. The mixture was diluted with EhO(30 mL). The aqueous layer was separated and extracted with EA (25 mL * 2). The combined organic layer was washed with brine (25 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography on silica gel eluted with PE:EA=3: 1 to give l-benzyl-6-bromo-2,3-dihydro- lH-imidazo[2,3-b]imidazol-2-one (0.7 g, 2.40 mmol, 31.96%) as a white solid. Preparation of 6-bromo-2,3-dihydro-lH-imidazo[2,3-b]imidazol-2-one (Step 6 in Scheme 20)

[00204] To a solution of l-benzyl-6-bromo-2,3-dihydro-lH-imidazo[2,3-b]imidazol-2-one (640 mg, 2.19 mmol) in toluene (20 mL) was added ammonium acetate (696.65 mg, 13.14 mmol) and A1CL (0.72 mL, 13.14 mmol) at RT under N2. The reaction was stirred at 70 °C for 2 hours. The reaction mixture was cooled to RT, basified with aq. NaOH to PH=8-9 and filtrated. The filter cake was washed with DCM: MeOH=20: l (50 mL * 3). The filtrate was concentrated to give the crude. The crude was purified by chromatography on silica gel eluted with DCM:MeOH=10: l to give 6-bromo-2,3-dihydro-lH-imidazo[2,3-b]imidazol-2-one (0.22 g, 1.09 mmol, 50.00%) as a yellow solid.

Scheme 21

Preparation of methyl l-(2-bromoethyl)-3-nitro-lH-pyrazole-5 -carboxylate (Step 1 in Scheme

27)

[00205] A mixture of methyl 3-nitro-lH-pyrazole-5-carboxylate (5 g, 29.22 mmol), 1,2- dibromoethane (12.65 mL, 146.10 mmol) and K2CO3(4.04 g, 29.22 mmol) in acetone (50 mL) was stirred at 50 °C for 16 hours. The resulting mixture was poured into ice-water, extracted with EA and washed with brine. The organic layer was dried over by Na2SO4 and concentrated. The residue was purified by chromatography on silica gel eluted with EA/PE to afford methyl l-(2- bromoethyl)-3-nitro-lH-pyrazole-5 -carboxylate(4.4 g), MS(ESI): mass calcd. For CTEEBrNsCU 277.0 m/z found 271.0 [M+H]⁺. ) Preparation of (l-(2-bromoethyl)-3-nitro-lH-pyrazol-5-yl)methanol (Step 2 in Scheme 21)

[00206] To a solution of methyl l-(2-bromoethyl)-3-nitro-lH-pyrazole-5-carboxylate (5.5 g, 19.78 mmol) in THF (50 mL) was added DIBAL-H (32.97 mL, 49.45 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at RT for 2 hours. The mixture was poured into ice- water and extracted with EA. The organic layer was and washed with brine, dried over Na₂SO4 and concentrated. The residue was purified by chromatography on silica gel eluted with EA/PE to afford (l-(2-bromoethyl)-3-nitro-lH-pyrazol-5-yl)methanol (3 g). MS(ESI): mass calcd. For CeHgBrNsOs 249.0 m/z found 250.0 [M+H]⁺.

Preparation of 2-nitro-6,7-dihydro-4H -pyrazolo[5,l-c][L4]oxazine (Step 3 in Scheme

21)

[00207] A solution of (l-(2-bromoethyl)-3-nitro-lH-pyrazol-5-yl)methanol (3 g, 12.0 mmol) in NMP (15 mL) was stirred at 130 °C for 16 hours under nitrogen atmosphere. The resulting mixture was poured into ice-water, extracted with EA and washed with brine. The organic layer was dried over Na₂SO4 and concentrated under vacuum. The residue was purified by flash column (eluting with EA/PE) to afford 2-nitro-6,7-dihydro-4H -pyrazolo[5,l-c][l,4]oxazine (1.5 g). MS(ESI): mass calcd. For C6H7N3O3 169.0 m/z found 170.0 [M+H]⁺.

Preparation of 6,7-dihydro-4H-pyrazolo[5,l-c][L4]oxazin-2-amine (Step 4 in Scheme 21)

[00208] A mixture of 2-nitro-6,7-dihydro-4H-pyrazolo[5,l-c][l,4]oxazine (1.5 g, 8.87 mmol) and Pd/C (0.3 g) in MeOH was stirred at RT for 16 hours under H₂ atmosphere. The mixture was filtered. The filtrate was collected and concentrated under vacuum to afford 6,7-dihydro-4H- pyrazolo[5,l-c][l,4]oxazin-2-amine (1.1 g). MS(ESI): mass calcd. For CeHvNgO 139.1 m/z found 140.1 [M+H]⁺.

Preparation of 2-bromo-6,7-dihydro-4H-pyrazolo[5,l-c][L4]oxazine (Step 5 in Scheme 21)

[00209] To a mixture of 6,7-dihydro-4H-pyrazolo[5,l-c][l,4]oxazin-2-amine (500 mg, 3.59 mmol) and sodium nitrite (496 mg, 7.19 mmol) in acetonitrile (10 mL) was added cuprous bromide (1.48 g, 7.19 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 50 °C for 3 hours. The mixture was poured into ice-water, extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by chromatography on silica gel eluted with EA/PE to afford 2-bromo-6,7-dihydro-4H- pyrazolo[5,l-c][l,4]oxazine (300 mg). MS(ESI): mass calcd. For C6H7BrN2O 202.0 m/z found 203.0 [M+H]⁺.

Scheme 22

Preparation of N-benzyl-lH-imidazol-2-amine (Step 1 in Scheme 22}

[00210] To a mixture of lH-imidazol-2-amine (10 g, 120.35 mmol), benzaldehyde (13.38 mL, 132.39 mmol) and tetraisopropyl titanate (54.01 mL, 180.53 mmol) in DCM (50 mL) was added sodium borohydride (9.11 g, 240.70 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at RT for 2 hours. The mixture was poured into ice-water, extracted with EA, washed with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by chromatography on silica gel eluted with EA/PE to afford N-benzyl-lH- imidazol-2-amine 11.2 g. MS(ESI): mass calcd. For C10H11N3 173.1 m/z found 174.1 [M+H]⁺.

Preparation of ethyl 2-(2-(benzylamino)-lH-imidazol-l-yl)acetate (Step 2 in Scheme 22}

[00211] A mixture of N-benzyl-lH-imidazol-2-amine (11.2 g, 64.66 mmol), ethyl bromoacetate (7.15 mL, 64.66 mmol) and K2CO3(8.94 g, 64.66 mmol) in THF (50 mL) was stirred at RT for 16 hours under nitrogen atmosphere. The mixture was poured into ice-water, extracted with EA, washed with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by chromatography on silica gel eluted with EA/PE to afford ethyl 2-(2- (benzylamino)-lH-imidazol-l-yl)acetate 13.5 g, MS(ESI): mass calcd. For C14H17N3O2259.1 m/z found 260.1 [M+H]⁺.

Preparation of 2-(2-(benzylamino)-lH-imidazol-l-yl)acetic acid (Step 3 in Scheme 22}

[00212] A mixture of ethyl 2-(2-(benzylamino)-lH-imidazol-l-yl)acetate (13.5 g, 52.06 mmol) and NaOH (6.25 g, 156.18 mmol) in MeOH (10 mL) and H2O (40 mL) was stirred at 40 °C for 16 hours under nitrogen atmosphere. The reaction mixture was concentrated under vacuum to afford 2-(2-(benzylamino)-lH-imidazol-l-yl)acetic acid 9.5 g, MS(ESI): mass calcd. For C12H13N3O2 231.1 m/z found 232.1 [M+H]⁺.

Preparation of l-benzyl-lH-imidazo[L2-a]imidazol-2(3H)-one (Step 4 in Scheme 22}

[00213] A mixture of 2-(2-(benzylamino)-lH-imidazol-l-yl)acetic acid (9 g, 38.92 mmol), HATU (14.8 g, 38.92 mmol) and DIPEA (6.45 mL, 38.92 mmol) in DMF (50 mL) was stirred at RT for 16 hours under nitrogen atmosphere. The resulting mixture was poured into ice-water, extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by chromatography on silica gel eluted with EA/PE to afford 1 -benzyl- lH-imidazo[l,2-a]imidazol-2(3H)-one (3.9 g). MS(ESI): mass calcd. For C12H11N3O 213.1 m/z found 214.1 [M+H]⁺.

Preparation of l-benzyl-5-bromo-lH -imidazo[E2-a]imidazol-2(3H)-one (Step 5 in Scheme 22}

[00214] To a mixture of l-benzyl-lH-imidazo[l,2-a]imidazol-2(3H)-one (1.1 g, 5.16 mmol) and K2CO3(0.14 g, 1.03 mmol) in EA was added NBS (0.73 g, 4.13 mmol) at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 2 hours. The mixture was poured into ice-water, extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by chromatography on silica gel eluted with EA/PE to afford l-benzyl-5-bromo-lH -imidazo[l,2-a]imidazol-2(3H)-one 380 mg. MS(ESI): mass calcd. For CnHwBrNsO 291.0 m/z found 292.0 [M+H]⁺.

Preparation of 5-bromo-lH-imidazo[E2-a]imidazol-2(3H)-one (Step 6 in Scheme 22

[00215] A mixture of l-benzyl-5-bromo-lH-imidazo[l,2-a]imidazol-2(3H)-one(500 mg, 1.71 mmol), ammonium acetate (792 mg, 10.27 mmol) and aluminum trichloride (1.37 g, 10.27 mmol) in toluene (10 mL) was stirred at 110 °C for 2 hours under nitrogen atmosphere. The resulting mixture was poured into ice-water, extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by chromatography on silica gel eluted with EA/PE to afford 5-bromo-lH-imidazo[l,2-a]imidazol-2(3H)-one 120 mg, MS(ESI): mass calcd. For C₅H₄BrN₃O 201.0 m/z found 202.0 [M+H]⁺.

Preparation of 5-bromo-l-methyl-lH-imidazo[E2-a] imidazol-2(3H)-one (Step 7 in Scheme 22}

[00216] A mixture of 5-bromo-lH-imidazo[l,2-a]imidazol-2(3H)-one (100 mg, 0.50 mmol), CH3l(70.26 mg, 0.50 mmol) and K2CO3 (68.41 mg, 0.50 mmol) in acetonitrile (5 mL) was stirred at 83 °C for 16 hours under nitrogen atmosphere. The resulting mixture was poured into ice-water, extracted with EA. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by chromatography on silica gel eluted with EA/PE to afford 5-bromo-l-methyl-lH-imidazo[l,2-a] imidazol-2(3H)-one 38 mg, MS(ESI): mass calcd. For CeHeBrNsO 215.0 m/z found 216.0 [M+H]⁺.

Scheme 23

Preparation of 2,3-dihydro-lH-pyrrolizin-l-one (Step 1 in Scheme 23)

[00217] A mixture of 3 -(pyrrol- l-yl)propanenitrile (5.0 g, 41.61mmol), AICI3 (18.87 g, 141.49 mmol), KC1 (4.96 g,66.58 mmol), NaCl (4.62 g,79.09 mmol) was stirred at 130 °C for 10 min. H2O (80 mL) was poured into the reaction mixture. The resulting mixture was stirred at 90 °C for 2 hours. The mixture was cooled to RT and extracted with EA (60 mL * 3). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by chromatography on silica gel eluted with PE: EA=2: 1 to give 2,3-dihydro- IH-pyrrolizin-l-one (4.5 g, 89.27%) as a gray solid.

Preparation of 5-bromo-2,3-dihydro-lH-pyrrolizin-l-one (Step 2 in Scheme 23)

[00218] To a solution of 2,3-dihydro-lH-pyrrolizin-l-one (2.0 g, 16.53 mmol) in EA (20 mL) was added NBS (2.94 mg, 16.53 mmol) and K2CO3 (457mg,3.3 Immol) portion wise, maintaining temperature at RT. The reaction mixture was stirred at RT for 4 hours. The reaction mixture was diluted with H2O (40 mL) and extracted with EA (50 mL x3). The combined organic layer was washed with brine (40 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by chromatography on silica gel eluted with PE: EA=6: 1 to give 5-bromo-2,3-dihydro- IH-pyrrolizin-l-one (3.0 g, 90.84%) as a yellow solid.

Scheme 24

General procedure for preparing compounds in Scheme 24 (Step 1 in Scheme 24}

[00219] A mixture of halogenated fused ring, trimethyl silyl acetylene, copper(I) iodide, and PdCl₂(PPh₃)₂ in TEA was stirred at 70 °C for 1 hour under nitrogen atmosphere. The mixture was then cooled to RT, quenched with H₂O and extracted with EA. The organic layers were combined, washed with saturated saline, dried over Na₂SO4, filtered and concentrated to give crude product. The crude was purified by chromatography on silica gel to give the desired compound.

Preparation of 3-((trimethylsilyl)ethynyl)-6,7-dihydro-5H-pyrrolo[L2-a] imidazole (Step 1 in

Scheme 24}

[00220] A mixture of 3-bromo-6,7-dihydro-5H-pyrrolo[l,2-a]imidazole (500 mg, 2.67 mmol), trimethyl silyl acetylene(786 mg, 8.02 mmol), copper(I) iodide (51 mg, 0.26 mmol), and PdCl₂(PPh3)₂ (187 mg, 0.26 mmol) in TEA (8 mL) was stirred at 70 °C for 1 hour under nitrogen atmosphere. The mixture was then cooled to RT, quenched with H₂O (6 mL) and extracted with EA (20 mL * 3). The organic layers were combined, washed with saturated saline (50 mL), dried over Na₂SO4, filtered and concentrated to give crude product. The crude was purified by chromatography on silica gel eluted with PE:EA=5: 1 to give 3-((trimethylsilyl)ethynyl)-6,7- dihydro-5H-pyrrolo[l,2-a] imidazole (0.35 g) as a yellow solid. MS (ESI): mass calcd. For CnHi₆N₂Si 204.3 m/z found 205.1 [M+H]⁺.

3-[2-(trimethylsilyl)ethynyl]-4H,5H,6H-pyrrolo[E2-b]pyrazole was prepared according to the procedure described herein for Step 1 in Scheme 24

[00221] The desired compound (0.4 g, 91%) was obtained as an oil. MS (ESI): mass calcd. For CnHi₆N₂Si 204.3 m/z found 205.1 [M+H]⁺.

3-((trimethylsilyl)ethynyl)-4,5,6,7-tetrahydropyrazolo[E5-a]pyridine was prepared according to the procedure described herein for Step 1 in Scheme 24

[00222] The desired compound (420 mg) was obtained as a yellow solid. MS (ESI): mass calcd. For Ci₂Hi₈N₂Si 218.3 m/z found 219.5 [M+H]⁺.

5,5-dimethyl-3-[2-(trimethylsilyl)ethynyl]-4H,5H,6H-pyrrolo[E2-b]pyrazole was prepared according to the procedure described herein for Step 1 in Scheme 24

[00223] The desired compound (0.3 g, 85%) was obtained as a yellow solid. MS (ESI): mass calcd. For Ci₃H₂₀N₂Si 232.4 m/z found 233.1 [M+H]⁺. 3'-((trimethylsilyl)ethynyl)-4'H,6'H-spiro[cyclopropane-l,5'-pyrrolo[l,2-b]pyrazole]was prepared according to the procedure described herein for Step 1 in Scheme 24

[00224] The desired compound (0.38 g, 74%) was obtained as an oil.

7-((trimethylsilyl)ethynyl)-2,3-dihydropyrazolo[5,l-b]oxazole was prepared according to the procedure described herein for Step 1 in Scheme 24

[00225] The desired compound (0.4 g) was obtained as a yellow solid. MS (ESI): mass calcd. For CioHi₄N₂OSi 206.3 m/z found 207.2 [M+H]⁺.

2,2-dimethyl-7-((trimethylsilyl)ethynyl)-2,3-dihydropyrazolo[5, l-b]oxazole was prepared according to the procedure described herein for Step 1 in Scheme 24

[00226] The desired compound (0.35 g) was obtained as a yellow solid. MS (ESI): mass calcd.

For Ci₂Hi₈N₂SiO 234.3 m/z found 235.1 [M+H]⁺.

3-((trimethylsilyl)ethynyl)- tetrahydroimidazo[E2-a]pyridine was prepared according to

the procedure described herein for Step 1 in Scheme 24

[00227] The desired compound (0.4 g) was obtained as a yellow solid. MS (ESI): mass calcd. For Ci₂Hi₈N₂Si 218.3 m/z found 219.1 [M+H]⁺. tert-butyl 3-[2-(trimethylsilyl)ethynyl]-5H,6H,7H,8H-imidazo[E2-a]pyrazine-7-carboxylate was prepared according to the procedure described herein for Step 1 in Scheme 24

[00228] The desired compound (1.0 g) was obtained as a white solid.

7-methyl-3-((trimethylsilyl)ethynyl)-5,6,7,8-tetrahydroimidazo[E2-a]pyrazine was prepared according to the procedure described herein for Step 1 in Scheme 24

[00229] The desired compound (0.4 g) was obtained as a yellow solid.

2-methylpropan-2-yl O-Ktrimethylsilyl )ethynyl]-4.5.6.7-tetrahydroindazole- l -carboxylate was prepared according to the procedure described herein for Step 1 in Scheme 24

[00230] The desired compound (0.8 g) was obtained as a yellow solid.

3-[(trimethylsilyl)ethynyl]-5 7,8-tetrahydroimidazo[3,4-a]pyridine was prepared according to the procedure described herein for Step 1 in Scheme 24

[00231] The desired compound (230 mg) was obtained as a yellow solid.

3-((trimethylsilyl)ethynyl)-5,6-dihydro-8H-imidazo[2,l-c][L4]oxazine was prepared according to the procedure described herein for Step 1 in Scheme 24

[00232] The desired compound (570 mg) was obtained as a solid.

General procedure for preparing compounds in Scheme 24 (Step 2 in Scheme 24}

[00233] To a solution of trimethylsilylation (TMS) derivatives in THF was added tetra-n- butylammonium fluoride (TBAF). The mixture was stirred at RT for 0.5 hour. The mixture was diluted with H2O and extracted with EA. The organic layers were combined, washed with saturated saline, dried over Na2SO4, filtered and concentrated to give crude product. The crude was purified to give the desired compound.

Preparation of 3-ethynyl-6,7-dihydro-5H-pyrrolo[E2-a]imidazole (Step 2 in Scheme 24}

[00234] To a solution of 3-((trimethylsilyl)ethynyl)-6,7-dihydro-5H-pyrrolo[l,2-a]imidazole (350 mg, 1.71 mmol) in THF (2 mL) was added tetra-n-butylammonium fluoride (TBAF) (0.2 mL, 1 mol/L). The mixture was stirred at RT for 0.5 hour. The mixture was diluted with H2O and extracted with EA (20 mL * 3). The organic layers were combined, washed with saturated saline (50 mL), dried over Na2SO4, filtered and concentrated to give crude product. The crude was purified by chromatography on silica gel eluted with PE:EA=5: 1 to give 3-ethynyl-6,7-dihydro- 5H-pyrrolo[l,2-a]imidazole (180 mg) as an oil. MS (ESI): mass calcd. For CgEhNi 132.1 m/z found 133.2 [M+H]⁺.

3-ethynyl-4H,5H,6H-pyrrolo[E2-b]pyrazole was prepared according to the procedure described herein for Step 2 in Scheme 24

[00235] The desired compound (0.21g, 80%) was obtained as a yellow solid.

3-ethynyl-4,5 7-tetrahydropyrazolo[E5-a]pyridine was prepared according to the procedure described herein for Step 2 in Scheme 24

[00236] The desired compound (220 mg) was obtained as an oil. MS (ESI): mass calcd. For C9H10N2 146.1 m/z found 147.3 [M+H]⁺.

3-ethynyl-5,5-dimethyl-4H,5H,6H-pyrrolo[E2-b]pyrazole was prepared according to the procedure described herein for Step 2 in Scheme 24

[00237] The desired compound (180 mg, 74%) was obtained as an oil. MS (ESI): mass calcd. For C10H12N2 160.2 m/z found 161.3 [M+H]⁺.

3'-ethynyl-4'H,6'H-spiro[cyclopropane-E5'-pyrrolo[E2-b]pyrazole]was prepared according to the procedure described herein for Step 2 in Scheme 24

[00238] The desired compound (200 mg, 76%) was obtained as a yellow solid.

7-ethynyl-2,3-dihydropyrazolo[5,l-b]oxazole was prepared according to the procedure described herein for Step 2 in Scheme 24

[00239] The desired compound (0.21 g) was obtained as an oil. MS (ESI): mass calcd. For C₇H₆N₂O 134.1 m/z found 135.2 [M+H]⁺.

7-ethynyl-2,2-dimethyl-2,3-dihydropyrazolo[5,l-b]oxazole was prepared according to the procedure described herein for Step 2 in Scheme 24

[00240] The desired compound (120 mg) was obtained as a white solid. MS (ESI): mass calcd. For C₉HioN₂0 162.1 m/z found 163.2 [M+H]⁺.

3-ethynyl-5.6.7.8-tetrahydroimidazo[ l .2-a]pyridine was prepared according to the procedure described herein for Step 2 in Scheme 24

[00241] The desired compound (150 mg) was obtained as an oil. MS (ESI): mass calcd. For C9H10N2 146.1 m/z found 147.2 [M+H]⁺. tert-butyl 3-ethynyl-5H,6H,7H,8H-imidazo[E2-a]pyrazine-7-carboxylate was prepared according to the procedure described herein for Step 2 in Scheme 24

[00242] The desired compound (560 mg) was obtained as a white solid.

3-ethynyl-7-methyl-5.6.7.8-tetrahydroimidazo[ l .2-a]pyrazine was prepared according to the procedure described herein for Step 2 in Scheme 24

[00243] The desired compound (160 mg) was obtained as a white solid.

2-methylpropan-2-yl 3-ethynyl-4.5.6.7-tetrahydroindazole- l -carboxylate was prepared according to the procedure described herein for Step 2 in Scheme 24

[00244] The desired compound (380 mg) was obtained as a yellow solid.

3-ethynyl-5.6.7.8-tetrahydroimidazo[3.4-a]pyridine was prepared according to the procedure described herein for Step 2 in Scheme 24

[00245] The desired compound (103 mg) was obtained as a yellow solid.

3-ethynyl-5,6-dihydro-8H-imidazo[2,l-c][l,4]oxazine was prepared according to the procedure described herein for Step 2 in Scheme 24

[00246] The desired compound (300 mg) was obtained as a light yellow solid.

Scheme 25

General procedure for preparing compounds in Scheme 25 (Step 1 in Scheme 25

[00247] A mixture of (S)-N-(l-(8-chloro-l-oxo-l,2-dihydroisoquinolin-3- yl)ethyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide derivatives, Ethynyl substituted heterocyclic compounds, Pd(CH3CN)2Ch, dicyclohexyl[2',4',6'-tris(propan-2-yl)[l,l'-biphenyl]-2- yl]phosphane (X-Phos) and CS2CO3 in acetonitrile was stirred at 80 °C under nitrogen atmosphere. Upon completion of the reaction as indicated by TLC, the mixture was cooled to RT and filtered. The filter cake was washed with EA. The organic layer was diluted with H2O. The mixture was extracted with EA. The organic layers were combined, washed with saturated saline, dried over Na2SO4, filtered and concentrated to give crude product. The crude was purified to give the desired compound.

Compound 1

Preparation of (S)-2-amino-N-(l-(8-((6,7-dihydro-5H-pyrrolo[E2-a1imidazol-3-yl)ethynyl)-l- oxo-2-phenyl-E2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[E5-a]pyrimidine-3-carboxamide (Step

1 in Scheme 25)

[00248] A mixture of 2-amino-N-[(lS)-l-(8-chloro-l-oxo-2-phenyl-l,2-dihydroisoquinolin-3- yl)ethyl]pyrazolo[l,5-a]pyrimidine-3-carboxamide (120 mg, 0.26 mmol), 3-ethynyl-6,7-dihydro- 5H-pyrrolo[l,2-a]imidazole (110 mg, 0.78 mmol), Pd(CH3CN)2C12 (8 mg, 0.03 mmol), X-Phos (15 mg, 0.03 mmol) and CS2CO3 (170 mg, 0.52 mmol) in acetonitrile (10 mL) was stirred at 80 °C for 5 hours under nitrogen atmosphere. Upon completion of the reaction as indicated by TLC, the reaction was cooled to RT and filtered. The filter cake was washed with EA (20 mL * 3), diluted with H2O (10 mL). The mixture was extracted with EA (20 mL * 3). The organic layers were combined, washed with saturated saline (50 mL), dried over Na2SO4, filtered and concentrated to give crude product. The crude was purified by chromatography on silica gel eluted with DCM:MeOH=10: l to give (S)-2-amino-N-(l-(8-((6,7-dihydro-5H-pyrrolo[l,2-a]imidazol-3- yl)ethynyl)-l-oxo-2-phenyl-l,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[l,5-a]pyrimidine-3- carboxamide (48 mg) as a yellow solid. 'H NMR (400 MHz, DMSO) 6 8.95 - 8.88 (m, 1H), 8.57 - 8.50 (m, 1H), 8.00 (d, J = 6.6 Hz, 1H), 7.59 (ddd, J = 16.4, 14.2, 4.4 Hz, 4H), 7.53 - 7.44 (m, 3H), 7.39 (d, J= 6.7 Hz, 1H), 7.19 (s, 1H), 7.01 (dd, J = 6.7, 4.6 Hz, 1H), 6.75 (s, 1H), 6.43 (s, 2H), 4.55 (t, J= 6.7 Hz, 1H), 3.93 (d, J= 7.1 Hz, 2H), 2.75 (t, J= 7.4 Hz, 2H), 2.51 (s, 2H), 1.34 (d, J= 6.8 Hz, 3H).MS (ESI): mass calcd. For C32H26N₈O₂ 554.6 m/z found 555.3 [M+H]⁺.

Compound 2

(S)-2-amino-N-( 1 -(8-((5,6-dihydro-4H-pyrrolo[ 1 ,2-b]pyrazol-3 -yDethynyl)- 1 -oxo-2-phenyl- 1 ,2- dihydroisoquinolin-3-yl)ethyl)pyrazolo[L5-a]pyrimidine-3-carboxamide was prepared according to the procedure described herein for Step 1 in Scheme 25

[00249] The desired compound (50 mg) was obtained as a yellow solid. ¹H NMR (400 MHz, DMSO) 8 8.92 (dd, J= 6.7, 1.6 Hz, 1H), 8.54 (dd, J= 4.5, 1.6 Hz, 1H), 7.99 (d, J= 6.7 Hz, 1H), 7.67 - 7.42 (m, 8H), 7.38 (dd, J = 5.6, 3.5 Hz, 1H), 7.00 (dd, J= 6.7, 4.5 Hz, 1H), 6.72 (s, 1H), 6.42 (s, 2H), 4.54 (t, J= 6.8 Hz, 1H), 4.08 - 4.03 (m, 2H), 2.86 (t, J = 7.3 Hz, 2H), 2.58 - 2.50 (m, 2H), 1.34 (d, J = 6.8 Hz, 3H). MS (ESI): mass calcd. For C32H26N₈O₂ 554.6 m/z found 555.3 [M+H]⁺.

Compound 3

(S)-2-amino-N-(l-(l-oxo-2-phenyl-8-((4,5 7-tetrahydropyrazolo [E5-a]pyridin-3-yl)ethynyD-

E2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[E5-a]pyrimidine-3-carboxamide was prepared according to the procedure described herein for Step 1 in Scheme 25

[00250] The desired compound (40 mg) was obtained as a yellow solid. ’H NMR (400 MHz, DMSO) 8 8.92 (dd, J= 6.7, 1.6 Hz, 1H), 8.54 (dd, J= 4.5, 1.6 Hz, 1H), 7.99 (d, J= 6.7 Hz, 1H), 7.67 - 7.40 (m, 8H), 7.37 (dd, J = 5.6, 3.4 Hz, 1H), 7.00 (dd, J= 6.7, 4.5 Hz, 1H), 6.72 (s, 1H), 6.42 (s, 2H), 4.54 (t, J= 6.8 Hz, 1H), 4.03 (t, J= 6.3 Hz, 2H), 2.78 (t, J= 6.3 Hz, 2H), 1.95 - 1.88 (m, 2H), 1.76 (dd, J = 7.6, 3.9 Hz, 2H), 1.34 (d, J = 6.8 Hz, 3H).MS (ESI): mass calcd. For C33H28N8O2 568.6 m/z found 569.1 [M+H]⁺.

Compound 4

(S)-2-amino-N-(l-(8-((5,5-dimethyl-5,6-dihydro-4H-pyrrolo[E2-b1pyrazol-3-yl)ethynyl)-l-oxo- 2-phenyl-E2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[E5-a]pyrimidine-3-carboxamide was prepared according to the procedure described herein for Step 1 in Scheme 25

[00251] The desired compound (100 mg, 45%) was obtained as a yellow solid. ’H NMR (400 MHz, DMSO) 8 8.94 (dd, J = 6.6, 1.5 Hz, 1H), 8.56 (dd, J = 4.6, 1.3 Hz, 1H), 8.00 (d, J = 6.6 Hz, 1H), 7.64 - 7.54 (m, 5H), 7.53 - 7.46 (m, 3H), 7.39 (dd, J = 5.8, 3.2 Hz, 1H), 7.02 (dd, J = 6.7, 4.6 Hz, 1H), 6.74 (s, 1H), 6.44 (s, 2H), 4.59 - 4.51 (m, 1H), 3.86 (s, 2H), 2.73 (s, 2H), 1.35 (d, J = 6.7 Hz, 3H), 1.22 (s, 6H). MS (ESI): mass calcd. For C34H30N8O2 582.2 m/z found 583.3 [M+H]⁺.

Compound 5

(S)-2-(Cyclopropylamino)-N-(l-(8-((5,6-Dihydro-4H-pyrrolo[E2-a]pyrazol-3-yl)ethynyl)-l-oxo- 2-phenyl-E2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[E5-a]pyrimidine-3-carboxamide was prepared according to the procedure described herein for Step 1 in Scheme 25

[00252] The desired compound (5 mg) was obtained as a yellow solid. ’H NMR (500 MHz, DMSO) 8 9.09 (dd, J = 6.8, 1.6 Hz, 1H), 8.60 (dd, J = 4.5, 1.6 Hz, 1H), 8.00 (d, J = 6.6 Hz, 1H), 7.66 - 7.45 (m, 8H), 7.38 (dd, J = 5.4, 3.4 Hz, 1H), 7.05 (dd, J = 6.7, 4.5 Hz, 1H), 6.77 - 6.70 (m, 2H), 4.53 (p, J = 6.7 Hz, 1H), 4.08 (t, J = 7.2 Hz, 2H), 2.88 (t, J = 7.3 Hz, 2H), 2.66 (dd, J = 6.6, 3.5 Hz, 1H), 2.55 (dd, J = 14.6, 7.4 Hz, 2H), 1.34 (d, J = 6.8 Hz, 3H), 0.74 - 0.68 (m, 2H), 0.56 (dd, J = 6.7, 3.5 Hz, 2H). MS (ESI): mass calcd. For C35H30N8O2 594.25 m/z found 595.3 [M+H]⁺

Compound 6

(S)-N-(l-(8-((5,6-dihydro-4H-pyrrolo[E2-b]pyrazol-3-yl)ethynyl)-l-oxo-2-phenyl-E2- dihydroisoquinolin-3-yl)ethyl)-2-(methylamino)pyrazolo[E5-a]pyrimidine-3-carboxamide was prepared according to the procedure described herein for Step 1 in Scheme 25

[00253] The desired compound (13 mg) was obtained as a yellow solid. ’H NMR (400 MHz, DMSO) 8 8.98 (dd, J= 6.7, 1.6 Hz, 1H), 8.54 (dd, J= 4.5, 1.6 Hz, 1H), 7.98 (d, J= 6.7 Hz, 1H), 7.52 (dddd, J = 18.6, 12.3, 9.5, 6.9 Hz, 7H), 7.38 - 7.31 (m, 1H), 6.98 (dd, J= 6.7, 4.5 Hz, 1H), 6.69 (s, 1H), 6.61 (t, J= 5.0 Hz, 1H), 4.51 (p, J= 6.8 Hz, 1H), 4.04 (dd, J = 18.1, 10.9 Hz, 2H), 2.85 (t, J= 6.6 Hz, 5H), 2.56 - 2.49 (m, 2H), 1.32 (d, J= 6.7 Hz, 3H).MS (ESI): mass calcd. For C33H28N8O2 568.6 m/z found 569.3 [M+H]⁺.

Compound 7

(S)-2-Amino-N-(l-(2-(3-chlorophenyl)-8-((5,6-dihydro-4H-pyrrolo[ 1,2-b]pyrazole-3 - yl)ethynyl)-l-oxo- 1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[ 1,5-a]pyrimidine-3-carboxamide was prepared according to the procedure described herein for Step 1 in Scheme 25

[00254] The desired compound (15 mg) was obtained as a white solid. ’H NMR (400 MHz, DMSO) δ 8.93 (dt, J = 6.7, 1.6 Hz, 1H), 8.53 (ddd, J = 6.1, 4.6, 1.6 Hz, 1H), 7.88 (dd, J = 38.3, 6.9 Hz, 1H), 7.70 - 7.44 (m, 7H), 7.35 - 7.28 (m, 1H), 7.01 (dt, J = 6.7, 4.7 Hz, 1H), 6.81 (d, J = 25.5 Hz, 1H), 6.41 (d, J = 12.8 Hz, 2H), 4.66 - 4.54 (m, 1H), 4.08 (t, J = 7.2 Hz, 2H), 2.88 (t, J = 7.3 Hz, 2H), 2.60 - 2.53 (m, 2H), 1.25 (d, J = 5.9 Hz, 3H). MS (ESI): mass calcd. For C32H25CIN8O2 589.0 m/z found 590.2 [M+H]⁺.

Compound 8

[00255] The desired compound (10 mg) was obtained as a whlie solid. ’H NMR (400 MHz, DMSO) 8 8.90 (ddd, J= 7.0, 5.5, 1.6 Hz, 1H), 8.52 (ddd, J= 10.1, 4.5, 1.6 Hz, 1H), 7.84 (dd, J= 69.1, 7.4 Hz, 2H), 7.70 - 7.20 (m, 7H), 7.12 - 6.94 (m, 3H), 6.77 (d, J= 40.3 Hz, 1H), 6.39 (d, J = 14.7 Hz, 2H), 4.60 - 4.50 (m, 1H), 4.07 (dd, J= 9.8, 4.6 Hz, 2H), 3.76 (s, 2H), 2.87 (td, J= 7.5, 3.3 Hz, 2H), 2.55 (d, J= 2.8 Hz, 2H), 1.39 - 1.27 (m, 3H).MS (ESI): mass calcd. For C33H₂₈N₈O₃ 584.6 m/z found 585.2 [M+H]⁺.

Compound 9

(S)-2-Amino-N-(l-8-((5,6-dihydro-4H-pyrrolo[ 1,2-b]pyrazol-3 -yl)ethynyl)-2-(3- methoxyphenyl)- 1 -oxo- 1 ,2-dihydroisoquinolin-3 -yl)ethyl)pyrazolo[ 1,5-a]pyrimidine-3 - carboxamide was prepared according to the procedure described herein for Step 1 in Scheme 25

[00256] The desired compound (40 mg, 25%) was obtained as a yellow solid. ’H NMR (400 MHz, DMSO) δ 8.91 (d, J = 6.7 Hz, 1H), 8.53 (d, J = 4.5 Hz, 1H), 7.96 (t, J = 6.9 Hz, 1H), 7.67 - 7.50 (m, 4H), 7.42 (dt, J = 16.9, 8.0 Hz, 1H), 6.99 (ddd, J = 35.7, 18.1, 9.4 Hz, 4H), 6.72 (d, J = 12.2 Hz, 1H), 6.41 (s, 2H), 4.60 (dd, J = 15.5, 6.9 Hz, 1H), 4.07 (t, J = 7.2 Hz, 2H), 3.72 (d, J = 53.2 Hz, 3H), 2.88 (t, J = 7.3 Hz, 2H), 2.54 (dd, J = 14.8, 7.6 Hz, 2H), 1.40 - 1.35 (m, 3H). For C33H28N8O3 584.2 m/z found 585.3 [M+H]⁺.

Compound 10

(S)-2-Amino-N-(l-8-((5,6-dihydro-4H-pyrrolo[ 1,2-b]pyrazol-3 -yl)ethynyl)-2-(4- methoxyphenyl)- 1 -oxo- 1 ,2-dihydroisoquinolin-3 -yl)ethyl)pyrazolo[ 1,5-a]pyrimidine-3 - carboxamide was prepared according to the procedure described herein for Step 1 in Scheme 25

[00257] The desired compound (30 mg) was obtained as a yellow solid. ’H NMR (400 MHz, DMSO) δ 8.92 (dd, J = 6.7, 1.6 Hz, 1H), 8.54 (dd, J = 4.5, 1.6 Hz, 1H), 7.98 (d, J = 6.8 Hz, 1H), 7.62 - 7.51 (m, 4H), 7.37 - 7.32 (m, 1H), 7.26 (dd, J = 8.6, 2.6 Hz, 1H), 7.10 - 6.98 (m, 3H), 6.69 (s, 1H), 6.42 (s, 2H), 4.59 (t, J = 6.7 Hz, 1H), 4.07 (t, J = 7.2 Hz, 2H), 3.82 (s, 3H), 2.87 (t, J = 7.4 Hz, 2H), 2.54 (dd, J = 14.7, 7.4 Hz, 2H), 1.34 (d, J = 6.8 Hz, 3H). MS (ESI): mass calcd. For C33H28N8O3 584.2 m/z found 585. 3 [M+H]⁺.

Compound 11

[00258] The desired compound (20 mg, 14%) was obtained as a yellow solid.¹ H NMR (400 MHz, DMSO) δ 8.91 (dd, J = 6.7, 1.6 Hz, 1H), 8.53 (dd, J = 4.5, 1.6 Hz, 1H), 7.98 (d, J = 6.7 Hz, 1H), 7.63 - 7.51 (m, 5H), 7.50 - 7.42 (m, 3H), 7.38 - 7.33 (m, 1H), 7.00 (dd, J = 6.7, 4.5 Hz, 1H), 6.71 (s, 1H), 6.39 (s, 1H), 4.57 - 4.48 (m, 1H), 4.02 (s, 2H), 2.89 (s, 2H), 1.33 (d, J = 6.8 Hz, 3H), 0.78 (s, 2H), 0.75 (s, 2H). MS (ESI): mass calcd. For C34H28O2580.23 m/z found 581.3 [M+H]⁺.

Compound 12

(S)-2-amino-N-(l-(8-((2,3-dihydropyrazolo[5,l-b]oxazol-7-yl)ethynyl)-l-oxo-2-phenyl- 1,2- dihydroisoquinolin-3-yl)ethyl)pyrazolo[ 1,5-a]pyrimidine-3-carboxamide was prepared according to the procedure described herein for Step 1 in Scheme 25

[00259] The desired compound (6 mg) was obtained as a yellow solid.¹H NMR (500 MHz, DMSO) δ 8.90 (dd, J= 6.7, 1.5 Hz, 1H), 8.53 (dd, J= 4.5, 1.5 Hz, 1H), 7.98 (d, J= 6.7 Hz, 1H), 7.64 - 7.51 (m, 3H), 7.48 (ddd, J= 20.6, 9.0, 4.4 Hz, 5H), 7.36 (dd, J= 5.7, 3.4 Hz, 1H), 6.99 (dd, J= 6.7, 4.5 Hz, 1H), 6.71 (s, 1H), 6.40 (s, 2H), 5.14 (d, J= 8.0 Hz, 2H), 4.53 (t, J= 6.8 Hz, 1H), 4.31 - 4.22 (m, 2H), 1.33 (d, J= 6.8 Hz, 3H).MS (ESI): mass calcd. For C31H24N8O3 556.5 m/z found 557.1 [M+H]⁺. Compound 13

(S)-2-amino-N-(l-(8-((2,2-dimethyl-2,3-dihydropyrazolo[5,l-b1oxazol-7-yl)ethynyl)-l-oxo-2- phenyl-E2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[E5-a]pyrimidine-3-carboxamide was prepared according to the procedure described herein for Step 1 in Scheme 25

[00260] The desired compound (30 mg) was obtained as a yellow solid. ^JH NMR (400 MHz, DMSO) δ 8.90 (dd, J= 6.7, 1.4 Hz, 1H), 8.53 (dd, J= 4.5, 1.5 Hz, 1H), 7.98 (d, J= 6.7 Hz, 1H), 7.64 - 7.41 (m, 9H), 7.39 - 7.30 (m, 1H), 7.00 (dd, J= 6.7, 4.5 Hz, 1H), 6.71 (s, 1H), 6.40 (d, J= 4.2 Hz, 1H), 4.54 (dd, J= 14.9, 8.2 Hz, lH), 4.10 (s, 2H), 1.58 (s, 6H), 1.33 (d, J= 6.8 Hz, 3H).MS (ESI): mass calcd. For C33H28N8O3 584.6 m/z found 585.3 [M+H]⁺.

Compound 14

(S)-2-amino-N-(l-(8-((5,6-dihydro-4H-pyrrolo[E2-b]pyrazol-3-yl)ethynyl)-2-(4-((5,6-dihydro- 4H-pyrrolo[ 1 ,2-b]pyrazol-3 -yl)ethynyl)phenyl)- 1 -oxo- 1 ,2-dihydroisoquinolin-3 - yl)ethyl)pyrazolo[E5-a]pyrimidine-3-carboxamide was prepared according to the procedure described herein for Step 1 in Scheme 25

[00261] The desired compound (30 mg) was obtained as a yellow solid. ¹H NMR (400 MHz, DMSO) 8 8.93 (dd, J = 6.7, 1.6 Hz, 1H), 8.55 (dd, J = 4.5, 1.6 Hz, 1H), 7.99 (d, J = 6.8 Hz, 1H), 7.72 (s, 1H), 7.67 - 7.60 (m, 3H), 7.60 - 7.54 (m, 3H), 7.50 (dd, J = 8.2, 2.1 Hz, 1H), 7.38 (dd, J = 8.2, 2.2 Hz, 1H), 7.02 (dd, J = 6.7, 4.5 Hz, 1H), 6.76 (s, 1H), 6.44 (s, 2H), 4.58 (p, J = 6.7 Hz, 1H), 4.11 (dt, J = 19.0, 7.2 Hz, 4H), 3.01 - 2.94 (m, 2H), 2.89 (t, J = 7.3 Hz, 2H), 2.63 - 2.53 (m, 4H), 1.37 (t, J = 6.9 Hz, 3H). MS (ESI): mass calcd. For C40H32N10O2 684.2 m/z found 685.3 [M+H]⁺.

Compound 15

(S)-2-amino-N-(l-(l-oxo-2-phenyl-8-((5,6,7,8-tetrahydroimidazo[ 1,2-a]pyridin-3-yl)ethynyl)- E2-dihydroisoquinolin-3-yl)ethyl) pyrazolo[E5-a]pyrimidine-3-carboxamide was prepared according to the procedure described herein for Step 1 in Scheme 25

[00262] The desired compound (36 mg) was obtained as a yellow solid. ’H NMR (400 MHz, DMSO) 8 8.93 (d, J= 6.6 Hz, 1H), 8.56 (d, J= 3.9 Hz, 1H), 8.01 (d, J= 6.6 Hz, 1H), 7.72 - 7.35 (m, 8H), 7.21 (s, 1H), 7.10 - 6.96 (m, 1H), 6.77 (s, 1H), 6.43 (s, 2H), 4.63 - 4.48 (m, 1H), 3.97 (d, J= 5.6 Hz, 2H), 2.74 (s, 2H), 1.91 - 1.78 (m, 4H), 1.35 (d, J= 6.7 Hz, 3H).MS (ESI): mass calcd. For C33H28N8O2 568.6 m/z found 569.3 [M+H]⁺.

Compound 16

(S)-2-amino-N-(l-(2-(2-morpholinoethyl)-l-oxo-8-((4,5,6,7-tetrahydropyrazolo[E5-a]pyridin-3- yl)ethynyl)-E2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[E5-a]pyrimidine-3-carboxamide was prepared according to the procedure described herein for Step 1 in Scheme 25

[00263] The desired compound (9.8 mg, 9%) was obtained as a yellow solid. ¹H NMR (400 MHz, DMSO) 8 8.91 (dd, J = 6.7, 1.6 Hz, 1H), 8.47 (dd, J = 4.5, 1.6 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.62 - 7.50 (m, 4H), 6.98 (dd, J = 6.7, 4.6 Hz, 1H), 6.75 (s, 1H), 6.51 (s, 2H), 5.41 (dd, J = 14.0, 6.8 Hz, 1H), 4.34 - 4.21 (m, 1H), 4.06 (t, J = 6.0 Hz, 3H), 3.55 (t, J = 4.4 Hz, 4H), 2.93 (t, J = 6.3 Hz, 2H), 2.61 (t, J = 6.8 Hz, 2H), 2.43 - 2.34 (m, 2H), 2.01 - 1.94 (m, 2H), 1.85 - 1.76 (m, 2H), 1.59 (d, J = 6.6 Hz, 3H), 1.21 (s, 2H). MS (ESI): mass calcd. For C33H35N9O3 605.29 m/z found 606.3 [M+H]⁺. tert-butyl 3-(2-{3-[(lS)-l-({2-aminopyrazolo[ 1,5-a]pyrimidin-3-yl}formamido)ethyl]-l-oxo-2- phenyl-l,2-dihydroisoquinolin-8-yl }ethynyl )5H.6H.7H.8H-imidazo[ l .2-a]pyrazine-7- carboxylate was prepared according to the procedure described herein for Step 1 in Scheme 25

[00264] The desired compound (200 mg) was obtained as a yellow solid.

Compound 20 Ill

(S)-2-amino-N-(l-(8-((7-methyl- tetrahydroimidazo[ 1,2-a]pyrazin-3-yl)ethynyl)-l-oxo-2-

phenyl- 1,2-dihydroisoquinolin-3-yl)ethyl) pyrazolo[ 1,5-a]pyrimidine-3-carboxamide was prepared according to the procedure described herein for Step 1 in Scheme 25

[00265] The desired compound (20 mg) was obtained as a yellow solid. ^XH NMR (400 MHz, DMSO) δ 8.93 (dd, J = 6.7, 1.6 Hz, 1H), 8.56 (dd, J = 4.5, 1.6 Hz, 1H), 8.01 (d, J = 6.6 Hz, 1H), 7.70 - 7.42 (m, 7H), 7.40 (dd, J = 5.5, 3.4 Hz, 1H), 7.22 (s, 1H), 7.02 (dd, J = 6.7, 4.5 Hz, 1H), 6.77 (s, 1H), 6.44 (s, 2H), 4.57 (t, J = 6.7 Hz, 1H), 3.99 (t, J = 5.4 Hz, 2H), 3.56 (d, J = 14.6 Hz, 2H), 2.77 (t, J = 5.4 Hz, 2H), 2.38 (d, J = 5.9 Hz, 3H), 1.35 (d, J = 6.8 Hz, 3H). MS (ESI): mass calcd. For C33H29N9O2 583.3 m/z found 584.1 [M+H]⁺. tert-butyl (S)-3-((3-(l-(2-aminopyrazolo[ 1,5-a]pyrimidine-3-carboxamido)ethyl)-l-oxo-2- phenyl- l .2-dihydroisoquinolin-8-yl )ethynyl )-4.5.6.7-tetrahydro- 1 H-indazole- 1 -carboxylate was prepared according to the procedure described herein for Step 1 in Scheme 25

[00266] The desired compound (170 mg) was obtained as a yellow solid. Compound 22

2-amino-N-[(lS)-l-[l-oxo-2-phenyl-8- tetrahydroimidazo[l,5-a]pyridin-3-

ylethynyl)isoquinolin-3-yl]ethyl]pyrazolo[ 1,5-a]pyrimidine-3-carboxamide was prepared according to the procedure described herein for Step 1 in Scheme 25

[00267] The desired compound (14.2 mg) was obtained as a yellow solid. ^XH NMR (400 MHz, DMSO-d6) 8 8.92 (dd, J = 6.7, 1.7 Hz, 1H), 8.55 (dd, J = 4.5, 1.7 Hz, 1H), 8.01 (d, J = 6.6 Hz, 1H), 7.69 (s, 3H), 7.57 (ddd, J = 7.4, 6.1, 2.3 Hz, 1H), 7.53 - 7.45 (m, 3H), 7.41 - 7.37 (m, 1H), 7.01 (dd, J = 6.8, 4.5 Hz, 1H), 6.76 (d, J = 9.9 Hz, 2H), 6.42 (s, 2H), 4.57 (t, J = 6.8 Hz, 1H), 4.02 (t, J = 6.1 Hz, 2H), 2.69 (t, J = 6.3 Hz, 2H), 1.86 - 1.79 (m, 2H), 1.71 (q, J = 5.8 Hz, 2H), 1.34 (d, J = 6.8 Hz, 3H), 1.23 (d, J = 6.2 Hz, 4H). MS (ESI): mass calcd. For C33H₂₈N₈O₂ 568.23 m/z found 569.1 [M+H]⁺.

Compound 23

[00268] The desired compound (70 mg) was obtained as a yellow solid. ’H NMR (400 MHz, DMSO-d6) δ 8.90 (dd, J = 6.7, 1.7 Hz, 1H), 8.52 (dd, J = 4.5, 1.7 Hz, 1H), 7.98 (d, J = 6.6 Hz, 1H), 7.65 - 7.60 (m, 3H), 7.57 - 7.52 (m, 1H), 7.50 - 7.42 (m, 3H), 7.38 - 7.34 (m, 1H), 7.22 (s, 1H), 6.98 (dd, J = 6.7, 4.5 Hz, 1H), 6.74 (s, 1H), 6.40 (s, 2H), 4.70 (s, 2H), 4.53 (t, J = 6.8 Hz, 1H), 3.99 (q, J = 3.5 Hz, 4H), 1.32 (d, J = 6.8 Hz, 3H). MS (ESI): mass calcd. For C32H₂6N₈O3 570.21 m/z found 571.1 [M+H]⁺.

Scheme 26

General procedure for preparing compounds in Scheme 26 (Step 1 in Scheme 26)

[00269] A mixture of (S)-N-(l-(8-ethynyl-l-oxo-l,2-dihydroisoquinolin-3- yl)ethyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide derivatives, halogenated heterocyclic compounds, Pd(CH3CN)2Ch, Cui and TEA in dioxane was stirred at 95 °C under nitrogen atmosphere. Upon completion of the reaction as indicated by TLC, the mixture was cooled to RT and filtered. The filter cake was washed with EA. The organic layer was diluted with H2O. The mixture was extracted with EA. The organic layers were combined, washed with saturated saline, dried over Na2SO4, filtered and concentrated to give crude product. The crude was purified to give the desired compound.

Compound 24

Preparation of (S)-2-amino-N-(l-(8-((6,7-dihydro-5H-imidazo[2,l-b][1.3]oxazin-3-yl)ethynyl)- l-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[ 1,5-a]pyrimidine-3-carboxamide

(Step 1 in Scheme 26)

[00270] To a solution of 2-amino-N-[(lS)-l-(8-ethynyl-l-oxo-2-phenylisoquinolin-3- yl)ethyl]pyrazolo[l,5-a]pyrimidine-3-carboxamide (60 mg, 0.13 mmol) in dioxane (5 mL) was added 3-iodo-6,7-dihydro-5H-imidazo[2,l-b][l,3]oxazine (22 mg, 0.09 mmol), Pd(dppf)CH2C12 (7.20 mg, 0.01 mmol), Cui (0.01 mmol) and TEA (0.04 mL, 0.26 mmol). The reaction mixture was stirred at 95 °C under N2 overnight. The mixture was concentrated to give the crude. The crude was purified by chromatography on silica gel eluted with DCM: MeOH=10: 1 to give (S)-2-amino- N-(l-(8-((6,7-dihydro-5H-imidazo[2,l-b][l,3]oxazin-3-yl)ethynyl)-l-oxo-2-phenyl-l,2- dihydroisoquinolin-3-yl)ethyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (3.4 mg, 0.01 mmol, 6.60%). ’H NMR (400 MHz, DMSO-d6) δ 8.91 (dd, J = 6.7, 1.7 Hz, 1H), 8.54 (dd, J = 4.5, 1.7 Hz, 1H), 7.99 (d, J = 6.7 Hz, 1H), 7.67 - 7.53 (m, 4H), 7.49 (td, J = 7.6, 7.1, 3.7 Hz, 3H), 7.40 - 7.34 (m, 1H), 7.00 (dd, J = 6.7, 4.5 Hz, 1H), 6.92 (s, 1H), 6.74 (s, 1H), 6.41 (s, 2H), 4.54 (p, J = 6.7 Hz, 1H), 4.32 (s, 2H), 3.96 (t, J = 6.0 Hz, 2H), 2.07 (p, J = 5.8 Hz, 2H), 1.33 (d, J = 6.9 Hz, 3H). MS (ESI): mass calcd. For C32H₂6N₈O3 570.21 m/z found 571.1 [M+H]⁺.

Compound 25

(S)-2-amino-N-(l-(8-((6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl)ethynyl)-l-oxo-2-phenyl-1,2- dihydroisoquinolin-3-yl)ethyl)pyrazolo[E5-a]pyrimidine-3-carboxamide was prepared according to the procedure described herein for Step 1 in Scheme 26

[00271] The desired compound (20 mg) was obtained as a yellow solid. ’H NMR (DMSO-d⁶ ) 6: 8.93 (dd, J=6.8, 1.7 Hz, 1H), 8.55 (dd, J=4.5, 1.7 Hz, 1H), 8.02 (d, J=6.6 Hz, 1H), 7.65-7.83 (m, 3H), 7.46-7.61 (m, 4H), 7.38-7.43 (m, 1H), 7.02 (dd, J=6.7, 4.5 Hz, 1H), 6.81 (s, 1H), 6.17-6.71 (m, 1H), 4.77 (s, 2H), 4.57 (quin, J=6.6 Hz, 1H), 3.94 (t, J=5.6 Hz, 2H), 2.81 (br t, J=5.6 Hz, 2H), 1.36 (d, J=6.7 Hz, 3H). MS (ESI): mass calcd. For C32H25N7O3S 587.2 m/z found 588.4 [M+H]⁺.

Compound 26 (S)-2-amino-N-(l-(l-oxo-8-((2-oxo-2,3-dihydro-lH-imidazo[E2-a]imidazol-5-yl)ethynyl)-2- phenyl-E2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[E5-a]pyrimidine-3-carboxamide was prepared according to the procedure described herein for Step 1 in Scheme 26

[00272] The desired compound (15 mg) was obtained as a yellow solid. ^XH NMR (400 MHz, DMSO-d⁶) 6 8.94 (dd, J = 6.7, 1.7 Hz, 1H), 8.56 (dd, J =4.5, 1.7 Hz, 1H), 8.01 (d, J = 6.7 Hz, 1H), 7.70 - 7.57 (m, 4H), 7.54 - 7.47 (m,3H), 7.42 - 7.36 (m, 1H), 7.06 (s, 1H), 7.02 (dd, J = 6.7, 4.5 Hz, 1H), 6.77 (s,lH), 6.44 (s, 2H), 4.54 (d, J = 7.1 Hz, 2H), 1.37-1.34 (m, 3H) MS (ESI): mass calcd. For C31H23N9O3 569.13 m/z found 570.1 [M+H]⁺.

Compound 27

(S)-2-amino-N-(l-(l-oxo-2-phenyl-8-((5 7,8-tetrahydro-[E2,4]triazolo[4,3-a]pyridin-3- yl)ethynyl)-E2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[E5-a]pyrimidine-3-carboxamide was prepared according to the procedure described herein for Step 1 in Scheme 26

[00273] The desired compound (50 mg) was obtained as a yellow solid. ’H NMR (400 MHz, DMSO-d6) 6 8.94 (dd, J = 6.8, 1.7 Hz, 1H), 8.56 (dd, J =4.6, 1.6 Hz, 1H), 8.03 (d, J = 6.6 Hz, 1H), 7.77 (q, J = 7.5 Hz, 3H), 7.60 - 7.48(m, 4H), 7.40 (s, 1H), 7.02 (dd, J = 6.7, 4.5 Hz, 1H), 6.82 (s, 1H), 6.44 (s, 2H),4.58 (t, J = 6.7 Hz, 1H), 4.01 (t, J = 5.4 Hz, 2H), 2.86 (s, 2H), 1.86 (s, 4H), 1.36(d, J = 6.8 Hz, 3H) MS (ESI): mass calcd. For C32H27N9O2 569.23 m/z found 570.1 [M+H]⁺.

Compound 28

(S)-2-amino-N-( 1 -(8-((6,7-dihydro-4H-pyrazolo[5, 1 -cl [ 1 ,4]oxazin-2-yl)ethynyl)- 1 -oxo-2- phenyl-E2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[E5-a]pyrimidine-3-carboxamide was prepared according to the procedure described herein for Step 1 in Scheme 26

[00274] The desired compound (3 mg) was obtained as a yellow solid. ’H NMR (DMSO-t/6) 6: 8.91 (dd, J=6.7, 1.5 Hz, 1H), 8.52-8.55 (m, 1H), 7.99 (d, J=6.7 Hz, 1H), 7.64-7.67 (m, 2H), 7.58- 7.62 (m, 1H), 7.53-7.57 (m, 1H), 7.45-7.51 (m, 3H), 7.34-7.38 (m, 1H), 6.98-7.02 (m, 1H), 6.74 (s, 1H), 6.27-6.61 (m, 2H), 6.22-6.24 (m, 1H), 4.74 (s, 2H), 4.52-4.57 (m, 1H), 4.07 (br d, J=4.4 Hz, 2H), 4.03-4.05 (m, 2H), 1.34 (d, J=6.8 Hz, 3H). MS(ESI): mass calcd. For C32H26N8O3 570.2 m/z found 571.2 [M+H]⁺.

Compound 29

(S)-2-amino-N-(l-(4-oxo-3-phenyl-5-( tetrahydropyrazolo[E5-a]pyridin-3-yl)ethynyl)-

3,4-dihydroquinazolin-2-yl)ethyl)pyrazolo[E5-a]pyrimidine-3-carboxamide was prepared according to the procedure described herein for Step 1 in Scheme 26

[00275] The desired compound (25 mg) was obtained as a white solid. ^XH NMR (DMSO-de, 400MHz) 8: 8.90 (br d, J=6.7 Hz, 1H), 8.70 (br d, J=7.5 Hz, 1H), 8.60-8.66 (m, 1H), 7.75-7.80 (m, 1H), 7.65-7.69 (m, 1H), 7.61 (br s, 5H), 7.54-7.57 (m, 2H), 7.50-7.54 (m, 1H), 7.01 (dd, J=6.6, 4.5 Hz, 1H), 4.72 (br t, J=7.0 Hz, 1H), 4.02 (br t, J=5.7 Hz, 2H), 2.74-2.83 (m, 2H), 1.92 (br d, J=3.5 Hz, 2H), 1.76 (br d, J=5.1 Hz, 2H), 1.31 (br d, J=6.6 Hz, 3H). MS (ESI): mass calcd. For C32H27N9O2 569.23 m/z found 570.2 [M+H] ⁺.

Compound 30

(S)-2-amino-N-( 1 -(8-((l -methyl-2-oxo-2,3 -dihydro- lH-imidazo[ 1 ,2-a]imidazol-5-yl)ethynyl)- 1 - oxo-2-phenyl-E2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[E5-a]pyrimidine-3-carboxamide was prepared according to the procedure described herein for Step 1 in Scheme 26

[00276] The desired compound (3 mg) was obtained as a white solid. ’H NMR (CHLOROFORM-t/J 3 8.47 (dd, J=6.6, 1.5 Hz, 1H), 8.43 (dd, J=4.4, 1.6 Hz, 1H), 7.95 (d, J=7.0 Hz, 1H), 7.52-7.61 (m, 3H), 7.46-7.52 (m, 3H), 7.43 (dd, J=7.5, 1.6 Hz, 1H), 7.33-7.38 (m, 1H), 7.13 (s, 1H), 6.82 (dd, J=6.8, 4.5Hz, 1H), 6.64 (s, 1H), 5.60 (s, 2H), 4.85 (quin, J=6.8 Hz, 1H), 4.45-4.52 (m, 2H), 3.25-3.32 (m, 3H), 1.42 (d, J=6.9 Hz, 3H). MS(ESI): mass calcd. For C32H25N9O3 583.2 m/z found 584.2 [M+H]⁺.

Compound 31

(R)-2-amino-N-( 1 -( 1 -oxo-8-(( 1 -oxo-2, 3 -dihydro- 1 H-pyrrolizin-5 -yl)ethynyl)-2-phenyl- 1 ,2- dihydroisoquinolin-3-yl)ethyl)pyrazolo[E5-a]pyrimidine-3-carboxamide was prepared according to the procedure described herein for Step 1 in Scheme 26

[00277] The desired compound (30 mg) was obtained as a white solid. ’H NMR (DMSO-d6) 6: 8.87-8.98 (m, 1H), 8.55 (s, 1H), 7.95-8.05 (m, 1H), 7.65-7.74 (m, 3H), 7.55-7.60 (m, 1H), 7.47- 7.55(m, 3H), 7.38-7.42 (m, 1H), 6.98-7.04 (m, 1H), 6.76-6.81 (m, 1H), 6.71-6.75 (m, 1H), 6.60- 6.65 (m, 1H), 6.39-6.46 (m, 2H), 4.50-4.64 (m, 1H), 4.25-4.35 (m, 2H), 2.96-3.07 (m, 2H), 0.69- 0.93 (m, 3H). MS (ESI): mass calcd. For C33H25N7O3 567.2 m/z found 568.0 [M+H] ⁺.

Scheme 27

Compound 17 Preparation of (S)-2-acetamido-N-(l-(8-((5,6-dihydro-4H-pyrrolo[L2-b]pyrazol-3-yl)ethynyl)-l- oxo-2-phenyl-L2-dihydroisoquinolin-3-yl)ethyl)pyrazolo [L5-a]pyrimidine-3-carboxamide (Step 1 in Scheme 27}

[00278] To a solution of (S)-2-amino-N-(l-(8-((5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-3- yl)ethynyl)-l-oxo-2-phenyl-l,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[l,5-a] pyrimidine-3- carboxamide (60 mg, 0.11 mmol) in DCM (3 mL) was added EtsN (23 mg, 0.22 mmol) and acetyl chloride (14 mg, 0.16 mmol). Then the suspension was stirred for 2 hours. The reaction was quenched with the addition of DCM (10 mL) and H2O (5 mL). The organic layer was separated, dried over Na2SO4 and concentrated to give crude product. The crude was purified by chromatography on silica gel eluted with DCM:CH3OH=10: l to give (S)-2-acetamido-N-(l-(8- ((5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-3-yl)ethynyl)-l-oxo-2-phenyl-l,2-dihydroisoquinolin-3- yl)ethyl)pyrazolo [l,5-a]pyrimidine-3-carboxamide (6 mg) as a yellow solid. ^JH NMR (400 MHz, DMSO) 6 10.09 (s, 1H), 9.27 (dd, J = 6.9, 1.6 Hz, 1H), 8.80 (dd, J= 4.4, 1.6 Hz, 1H), 8.15 (d, J= 6.9 Hz, 1H), 7.67 - 7.51 (m, 5H), 7.48 (dd, J = 5.8, 3.1 Hz, 3H), 7.36 (d, J= 2.6 Hz, 1H), 7.29 - 7.23 (m, 1H), 6.81 (s, 1H), 4.67 - 4.55 (m, 1H), 4.08 (t, J = 7.3 Hz, 2H), 3.3 (m, 3H), 2.88 (t, J = 13 Hz, 2H), 2.60 - 2.52 (m, 2H), 1.39 (d, J = 6.7 Hz, 3H). MS (ESI): mass calcd. For C34H28N8O3 596.6 m/z found 597.4 [M+H]⁺.

Scheme 28

Preparation of tert-butyl N-[(3-{[(lS)-l-[l-oxo-2-phenyl-8-(2-{4H,5H,6H-pyrrolo[L2- b]pyrazol-3-yl}ethynyl)-L2-dihydroiso quinolin-3-yl]ethyl]carbamoyl}pyrazolo[L5- a]pyrimidin-2-yl)sulfamoyl] carbamate (Step 1 in Scheme 28}

[00279] To a solution of tert-butanol (120 mg, 1.62 mmol) in DCM (5 mL) was added chlorosulfonyl isocyanate (230 mg, 1.62 mmol) at 0°C under nitrogen atmosphere. The mixture was stirred at RT for 10 min. Then 2-amino-N-[(lS)-l-[l-oxo-2-phenyl-8-(2-{4H,5H,6H- pyrrolof 1 ,2-b]pyrazol-3 -yl } ethynyl)- 1 ,2-dihydroisoquinolin-3 -yl]ethyl]pyrazolo[ 1 ,5-a] pyrimidine-3 -carboxamide (150 mg, 0.27 mmol) in DCM (5 mL) was added to the mixture at 0 °C. The mixture was stirred at RT for 0.5 hour. Upon completion of the reaction as indicated by TLC, the reaction was quenched with H2O and extracted with DCM (20 mL * 3). The organic layers were combined, washed with saturated saline (50 mL), dried over Na2SO4, filtered and concentrated to give crude product. The crude was purified by chromatography on silica gel eluted with DCM: MeOH=20: l to give tert-butyl N-[(3-{[(lS)-l-[l-oxo-2-phenyl-8-(2-{4H,5H,6H- pyrrolof 1 ,2-b]pyrazol-3 -yl } ethynyl)- 1 ,2-dihydroisoquinolin-3 -yl]ethyl]carbamoyl } pyrazolof 1,5- a]pyrimidin-2-yl)sulfamoyl] carbamate (76 mg, 38%) as a yellow solid. MS (ESI): mass calcd. For C37H35N9O6S 733.8 m/z found 734.5 [M+H]⁺ . Compound 18

Preparation of (S -N-( 1 -(8-((5,6-dihydro-4H-pyrrolo[ 1 ,2-b]pyrazol-3 -yDethynyl)- 1 -oxo-2- phenyl-E2-dihydroisoquinolin-3-yl)ethyl)-2-(sulfamoylamino)-pyrazolo[E5-a]pyrimidine-3- carboxamide (Step 2 in Scheme 28}

[00280] A mixture of tert-butyl N-[(3-{[(lS)-l-[l-oxo-2-phenyl-8-(2-{4H,5H,6H-pyrrolo[l,2- b]pyrazol-3 -yl } ethynyl)- 1 ,2-dihydroisoquinolin-3 -yl]ethyl]carbamoyl } pyrazolof 1,5- a]pyrimidin-2-yl)sulfamoyl]carbamate (50 mg, 0.07 mmol) and 2,6-dimethylpyridine (150 mg, 1.40 mmol) in DCM (5 mL) was added trimethyl silyl trifluoromethanesulfonate (60 mg, 0.27 mmol) at 0 °C. The mixture was stirred at RT for 24 hours. Upon completion of the reaction as indicated by TLC, the mixture was purified by chromatography on silica gel eluted with DCM:MeOH=10: l to give (S)-N-(l-(8-((5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-3-yl)ethynyl)-l- oxo-2-phenyl-l,2-dihydroisoquinolin-3-yl)ethyl)-2-(sulfamoylamino)-pyrazolo[l,5- a]pyrimidine-3 -carboxamide (8 mg) as a white solid. ’H NMR (400 MHz, DMSO) 6 9.43 (s, 1H), 9.15 (dd, J = 6.9, 1.3 Hz, 1H), 8.78 (dd, J = 4.4, 1.5 Hz, 1H), 7.98 (d, J = 6.9 Hz, 1H), 7.64 - 7.59 (m, 2H), 7.56 - 7.52 (m, 4H), 7.49 (dd, J = 5.9, 3.5 Hz, 3H), 7.36 - 7.30 (m, 1H), 7.24 (dd, J = 6.9, 4.5 Hz, 1H), 6.78 (s, 1H), 4.57 (dd, J = 14.0, 7.1 Hz, 1H), 4.06 (t, J = 7.2 Hz, 2H), 2.85 (d, J = 7.6 Hz, 2H), 2.53 (d, J = 7.3 Hz, 2H), 1.38 (d, J = 6.8 Hz, 3H). MS (ESI): mass calcd. For C32H27N9O4S 633.6 m/z found 634.3 [M+H]⁺.

Scheme 29

Compound 19

Preparation of (S)-2-amino-N-(l-( 1-oxo-2-phenyl-8-((5.6.7.8-tetrahydroimidazo[ 1.2-a1pyrazin- 3-yl)ethynyl)-L2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[L5-a]pyrimidine-3-carboxamide (Step

1 in Scheme 29)

[00281] To a solution of tert-butyl (S)-3-((3-(l-(2-aminopyrazolo[l,5-a]pyrimidine-3- carboxamido)ethyl)-l-oxo-2-phenyl-l,2-dihydroisoquinolin-8-yl)ethynyl)-5,6- dihydroimidazo[l,2-a]pyrazine-7(8H)-carboxylate (100 mg, 0.15 mmol) in DCM (10 mL) was added 2,6-dimethylpyridine (320 mg, 2.99 mmol) and trimethyl silyl trifluoro methane sulfonate (663 mg, 2.99 mmol) at 0 °C under N2. Then, the reaction mixture was stirred at RT for 5 hours. The mixture was quenched with aq. NaHCO₃ (10 mL). The mixture was extracted with DCM (20 mL * 2), dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography on silica gel eluted with DCM:MeOH:NH3.H2O=250:25:l to give (S)-2-amino- N-(l -( 1 -oxo-2-phenyl-8-((5,6,7, 8-tetrahydroimidazo[ 1 ,2-a]pyrazin-3 -yl)ethynyl)- 1 ,2- dihydroisoquinolin-3-yl)ethyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (40 mg, 47%) as a white solid. ’H NMR (400 MHz, DMSO) δ 8.92(dd, J=6.7, 1.6 Hz, 1H), 8.54(dd, J=4.5, 1.6 Hz, 1H), 8.00 (d, J=6.7Hz, 1H), 7.69- 7.60 (m, 3H), 7.56 (dd, J= 9.8, 5.0 Hz, 1H), 7.52-7.43 (m, 3H), 7.39(t, J=4.6 Hz, 1H), 7.18 (s, 1H), 7.01(dd, J=6.7, 4.5 Hz, 1H), 6.75 (s, 1H), 6.42(s, 2H), 4.55(p, J=6.6 Hz, 1H), 3.88 (t, J=5.3 Hz, 2H), 3.82 (s, 2H), 3.02(t, J=5.4 Hz, 2H), 1.34(d, J=6.8 Hz, 3H). MS (ESI): mass calcd. For C32H27N9O2 569.23 m/z found 570.1 [M+H]⁺.

Scheme 30

Compound 21

Preparation of (S)-2-amino-N-(l-(l-oxo-2-phenyl-8-((4,5,6,7-tetrahydro-lH-indazol-3- yl)ethynyl)-L2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[L5-a]pyrimidine-3-carboxamide (Step 1 in Scheme 30}

[00282] To a solution of 2-methylpropan-2-yl 3-({3-[(lS)-l-{[(2-aminopyrazolo[l,5- a]pyrimidin-3-yl)carbonyl]amino}ethyl]- l-oxo-2-phenylisoquinolin-8-yl}ethynyl)-4, 5,6,7- tetrahydroindazole-1 -carboxylate (170 mg, 0.25 mmol) in DCM (10 mL) was added trimethyl silyl trifluoromethan (0.84 mL, 5.08 mmol), 2,6-dimethylpyridine (0.59 mL, 5.08 mmol) at 0 °C. The reaction mixture was stirred at RT for 3 hours. The reaction was diluted with H2O (10 mL) and extracted with DCM (10 mL * 3). The combined organic layer was washed with brine (10 mL * 1), dried over Na₂SO4, filtered and concentrated. The residue was purified by chromatography on silica gel eluted with DCM:MeOH=20: l to give (S)-2-amino-N-(l-(l-oxo-2-phenyl-8-((4,5,6,7- tetrahydro-lH-indazol-3-yl)ethynyl)-l,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[l,5- a]pyrimidine-3 -carboxamide (22.2 mg, 15.36%) as a yellow solid. ¹H NMR (400 MHz, DMSO- d⁶) 8 8.93 (dd, J = 6.7, 1.6 Hz, 1H), 8.56 (dd, J = 4.5, 1.7 Hz, 1H), 8.02 (d, J = 6.7 Hz, 1H), 7.67 (d, J = 5.4 Hz, 2H), 7.63 - 7.55 (m, 2H), 7.53 - 7.45 (m, 3H), 7.43 - 7.38 (m, 1H), 7.02 (dd, J = 6.7, 4.5 Hz, 1H), 6.76 (s, 1H), 6.44 (s, 2H), 4.57 (t, J = 6.7 Hz, 1H), 2.54 (t, J = 6.0 Hz, 2H), 2.46 (s, 2H), 1.67 (dd, J = 23.5, 7.2 Hz, 4H), 1.36 (d, J = 6.8 Hz, 3H). MS (ESI): mass calcd. For C₃₃H₂₈N₈O₂ 568.23 m/z found 569.1 [M+H]⁺.

Cellular assays

[00283] Cellular activity of PI3Ky inhibitor_was determined by quantifying the phosphorylation of AKT in THP1 cell line (monocyte). AKT phosphorylated at Ser473 and Thr308 were measured using western blotting and specific primary antibodies from Cell Signaling (CST). THP-l(Otwo Biotech #HTX1621) monocytes were grown in serum-free RMPA-1640 (RPMI-1640, Thermal Fisher #C1187550BT) with 0.004% BME (Solarbio #M8210) under 5% CO₂ at 1,000,000 cells/ml for 16 hrs, incubated with inhibitors at 500nM or DMSO for 15 min, and stimulated with 20ng/ml MCP-l(PeproTech #300-04) for 5 min. At the end of the cell treatment period, media were removed by aspiration and adherent cells were lysed in 100 uL RIPA buffer (Sigma Aldrich # R0278). Equal volume (15 uL) of proteins was resolved by SDS-PAGE and transferred to PVDF (Millipore #IPFL00010) membrane for immunoblot analysis. Primary antibodies to the following proteins were used for immunoblotting: phosphor-AKT (Ser473) (CST #4060), phosphor-AKT (Thr308) (CST #2965), total AKT (CST #9272). Secondary goat anti-rabbit IgG fluorophore- conjugated antibody (Invitrogen #A21109) was used to visualize the indicated proteins on an Odyssey CLx imaging system (Li-Cor). Quantification of band intensities was performed using Odyssey 3.0 software. The intensity of each band was measured three times. Data represent mean+SD. The remaining Akt activity in treated cells over control cells was calculated by band intensities using the tormula: Compound

p-AKT (Ser 473)or p-AKT(Thr 308)

) DMSO )x100%. Total AKT Table 1. Biological data - Cellular assay

Enzyme Binding Assays (KINOMEscan. ) [00284] Kinase enzyme binding affinities of compounds disclosed herein were determined using the KINOMEscan technology performed by Eurofins DiscoveRx Corporation, San Diego, California, USA (www.eurofmsdiscoveryservices.com). Table 2 reports the obtained PI3Ky Kd values (nM), with the PIK3g Kd being the inhibitor binding constant:

Table 2. Biological data - PfK3y Binding Activity and Cellular assay

[00285] Applicant’s disclosure is described herein in preferred embodiments with reference to the Figures, in which like numbers represent the same or similar elements. Reference throughout this specification to “one embodiment,” “an embodiment,” or similar language means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases “in one embodiment,” “in an embodiment,” and similar language throughout this specification may, but do not necessarily, all refer to the same embodiment.

[00286] The described features, structures, or characteristics of Applicant’s disclosure may be combined in any suitable manner in one or more embodiments. In the description, herein, numerous specific details are recited to provide a thorough understanding of embodiments of the invention. One skilled in the relevant art will recognize, however, that Applicant’s composition and/or method may be practiced without one or more of the specific details, or with other methods, components, materials, and so forth. In other instances, well-known structures, materials, or operations are not shown or described in detail to avoid obscuring aspects of the disclosure.

[00287] In this specification and the appended claims, the singular forms "a," "an," and "the" include plural reference, unless the context clearly dictates otherwise.

[00288] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Methods recited herein may be carried out in any order that is logically possible, in addition to a particular order disclosed.

Incorporation by Reference

[00289] References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made in this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes. Any material, or portion thereof, that is said to be incorporated by reference herein, but which conflicts with existing definitions, statements, or other disclosure material explicitly set forth herein is only incorporated to the extent that no conflict arises between that incorporated material and the present disclosure material. In the event of a conflict, the conflict is to be resolved in favor of the present disclosure as the preferred disclosure.

Equivalents

[00290] The representative examples are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples and the references to the scientific and patent literature included herein. The examples contain important additional information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.

Claims

What is claimed is: CLAIMS

1. A compound having the structural formula (I):

wherein

W is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, - COR¹, -COOR¹, -CONR^¹, or -Si(R¹)3, wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R¹; each of R¹, R² and R³ is independently H, halogen, NH2, OH, CN, CF3, CHO, COCi-₄alkyl, CH₂C(=O)-NR^laR^lb, C(=O)-NR^laR^lb, CH₂COOR^1C, NR^ldR^le, C_1-4 alkyl, Ci-₄ alkenyl, Ci-₄ alkynyl, O-Ci-₄ alkyl, cycloalkyl, Het, Ar, NR^lh(C=O)R^h, NR¹J(C=O)NR^lkR¹¹, N(SO₂)R^lm , SO₂NR^lnR¹⁰, N(C=O)C(CN)C(OH)R¹P, P(O)MeMe, or P(O)OMeOMe; wherein each of R^1a, R^1b, R^1c, R^1d, R^1e, R^1h, 1ⁱⁱ, R^1j, R^1k R^1l, R^1m, R¹ⁿ, R^1O and R^lp is independently selected from the group consisting of H, C_1-4 alkyl, C_3-8 cycloalkyl and C_3-8 heterocycloalkyl, wherein Ci-₄ alkyl is optionally substituted with one or more substituents selected from the group consisting of OH, OMe, CN, halogen, NR^3aR^3b, C_3-8 cycloalkyl and C_3-8 heterocycloalkyl; and each pair of R^la and R^lb, R^ld and R^le, R^lk and R¹¹, or R^ln and R¹⁰, optionally form a 3- to 8-membered nitrogen-containing heterocyclyl ring, wherein the heterocyclyl ring is optionally substituted with one or more R⁶; Het represents a 3- to 8-membered saturated or partially saturated monocyclic, bridged or spiro heterocyclyl comprising one or more heteroatoms or groups each independently selected from O, S, S(=O), S(=O)2 and N, wherein Het is optionally substituted with one or two substituents each independently selected from the group consisting of halogen, NR^laR^lb, Ci-4 alkyl, OH, OMe and CN, wherein Ci-4 alkyl is unsubstituted or substituted with one or more substituent selected from the group consisting of OH, halogen, NR^ldR^le; n is 0, 1, 2 or 3; p is 0, 1, 2;

Z is C or N;

R⁴ is H, CN, halogen, OH, NHR⁷, NHCOR⁷, NH(S=O)R⁷, or NHSO2R⁷;

R⁵ is H, C_1-4 alkyl , C_1-4 alkoxyl, C_1-4 alkyl-NR^ldR^le, C_1-4 alkyl-cycloalkyl, C_1-4 alkyl-O-cycloalkyl, C_1-4 alkyl-NH-cycloalkyl, C_1-4 alkyl-heterocycle, C_1-4 alkyl-O- heterocycle, or C_1-4 alkyl-NH- heterocycle;

X ring is a 5- to 6-membered aromatic or heteroaromatic ring, Y ring is a 4- to 8- membered aliphatic carbocyclic or heterocyclic ring, wherein X and Y ring are each optionally substituted with one or more R⁶; refers to X ring and Y ring having exactly two atoms and one bond in common; each R⁶ is independently H, halogen, C_1-4 alkyl, OH, OMe, CN, CF3, NR^laR^lb, C3- 8 cycloalkyl, or C_3-8 heterocycloalkyl; and each R⁷ is independently H, NH2, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, or cycloalkyl; or a pharmaceutically acceptable form or an isotope derivative thereof. The compound of claim 1, wherein Z is C, having the structural formula (la):

The compound of claim 1, wherein Z is N, having the structural formula (lb):

The compound of any one of claims 1-3, wherein X ring is a 5-membered aromatic or heteroaromatic ring. The compound of claim 4, wherein X ring comprises two N atoms. The compound of claim 4, wherein X ring comprise one N atom. The compound of claim 4, wherein X ring comprises three N atoms. The compound of claim 4, wherein X ring comprised one N atom and one S atom. The compound of any one of claims 1-8, wherein Y ring is a 5-membered aliphatic carbocyclic or heterocyclic ring. The compound of any one of claims 1-8, wherein Y ring is a 6-membered aliphatic carbocyclic or heterocyclic ring. The compound of claim 9 or 10, wherein Y ring is unsaturated. The compound of claim 9 or 10, wherein Y ring is saturated or partially saturated. The compound of any one of claims 1-12, wherein

is selected from:

Y ring is a 5-or 6-membered aliphatic carbocyclic or heterocyclic ring. The compound of claim 16, wherein X³ is CH and X⁴ is N, having the structural formula

(Ila):

wherein each of X¹ and X² is C or N, provided that one is C and the other is N; and Y ring is a 5-or 6-membered aliphatic carbocyclic or heterocyclic ring. The compound of claim 17, wherein X¹ is N and X² is C, having the following structural formular (lib) :

The compound of claim 17, wherein X¹ is C and X² is N, having the following structural formular (lie):

The compound of claim 16, wherein X¹ is C, X² is N, X³ is CH, and X⁴ is CH, having the structural formula (lid) :

The compound of claim 16, wherein X¹ is C, X² is N, X³ is N, and X⁴ is N, having the structural formula (lie):

The compound of any one of claims 1-4, having the structural formula (III):

Y ring is a 5-or 6-membered aliphatic carbocyclic or heterocyclic ring. The compound of claim 22, wherein X¹ is N, X² is N, X³ is CN and X⁴ is C, having the structural formula (Illa):

The compound of claim 22, wherein X¹ is C or CH, X² is N, X³ is S and X⁴ is C or CH, having the structural formula (ITIb):

The compound of any one of claims 16-24, wherein Z is CH. The compound of any one of claims 16-24, wherein Z is N. The compound of any one of claims 1-26, wherein R¹ is OCH3. The compound of any one of claims 1-26, wherein R¹ is F or Cl. The compound of any one of claims 1-26, wherein R¹ is H. The compound of any one of claims 1-29, wherein n is 0. The compound of any one of claims 1-30, wherein p is 0. The compound of any one of claims 1-31, wherein R⁵ is methyl. The compound of any one of claims 1-32, wherein R⁴ is NHR⁷. The compound of claim 33, wherein R⁷ is H. The compound of claim 33, wherein R⁷ is C_1-4 alkyl. The compound of any one of claims 1-32, wherein R⁴ is NHCOR⁷. The compound of any one of claims 1-32, wherein R⁴ is NHSO2R⁷. A compound selected from the group consisting of:

or a pharmaceutically acceptable form or an isotope derivative thereof. A pharmaceutical composition comprising a compound according to any of claims 1-38, effective to treat or reduce one or more diseases or disorders, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent. A pharmaceutical composition comprising a compound having the structural formula (I):

wherein

W is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, - COR¹, -COOR¹, -CONR^¹, or -Si(R¹)3, wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R¹; each of R¹, R² and R³ is independently H, halogen, NH2, OH, CN, CF3, CHO, COCi-₄alkyl, CH₂C(=O)-NR^laR^lb, C(=O)-NR^laR^lb, CH₂COOR^1C, NR^ldR^le, C_1-4 alkyl, Ci-₄ alkenyl, Ci-₄ alkynyl, O-Ci-₄ alkyl, cycloalkyl, Het, Ar, NR^lh(C=O)R^h, NR¹j(C=O)NR^lkR¹¹, N(SO₂)R^lm , SO₂NR^lnR¹⁰, N(C=O)C(CN)C(OH)R¹P, P(O)MeMe, or P(O)OMeOMe; wherein each of R^la, R^lb, R^lc, R^ld, R^le, R^lh, Rⁿ, Rh, R^lk R¹¹, R^lm, R^ln, R¹⁰ and R^lp is independently selected from the group consisting of H, C_1-4 alkyl, C_3-8 cycloalkyl and C_3-8 heterocycloalkyl, wherein C_1-4 alkyl is optionally substituted with one or more substituents selected from the group consisting of OH, OMe, CN, halogen, NR^3aR^3b, C_3-8 cycloalkyl and C_3-8 heterocycloalkyl; and each pair of R^la and R^lb, R^ld and R^le, R^lk and R¹¹, or R^ln and R¹⁰, optionally form a 3- to 8-membered nitrogen-containing heterocyclyl ring, wherein the heterocyclyl ring is optionally substituted with one or more R⁶;

Z is C or N;

R⁴ is H, CN, halogen, OH, NHR⁷, NHCOR⁷, NH(S=O)R⁷, or NHSO₂R⁷;

R⁵ is H, C_1-4 alkyl, C_1-4 alkoxyl, C_1-4 alkyl-NR^ldR^le, C_1-4 alkyl-cycloalkyl, C_1-4 alkyl-O-cycloalkyl, C_1-4 alkyl-NH-cycloalkyl, C_1-4 alkyl-heterocycle, C_1-4 alkyl-O- heterocycle, or C_1-4 alkyl-NH- heterocycle;

X ring is a 5- to 6-membered aromatic or heteroaromatic ring, Y ring is a 4- to 8- membered aliphatic carbocyclic or heterocyclic ring, wherein X and Y ring are each optionally substituted with one or more R⁶;

( X A Y ) v — refers to X ring and Y ring having exactly two atoms and one bond in common; each R⁶ is independently H, halogen, C_1-4 alkyl, OH, OMe, CN, CF3, NR^laR^lb, C3- 8 cycloalkyl, or C_3-8 heterocycloalkyl; and each R⁷ is independently H, NH2, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, or cycloalkyl; or a pharmaceutically acceptable form or an isotope derivative thereof. The pharmaceutical composition of claim 39 or 40, being suitable for oral administration. The pharmaceutical composition of claim 39 or 40, being suitable for intravenous administration. The pharmaceutical composition of any one of claims 39-42, being useful to treat or reduce cancer, or a related disease or condition. The pharmaceutical composition of any one of claims 39-42, being useful to treat or reduce breast, colon, endometrial, kidney, lung, melanoma, prostate, thyroid cancer or leukemia, or a related disease or condition. A unit dosage form comprising a pharmaceutical composition of any one of claims 39-40. The unit dosage form of claim 45, being suitable for oral administration. The unit dosage form of claim 45 or 46, being a tablet or a capsule. The unit dosage form of claim 45, being suitable for intravenous administration. The unit dosage form of claim 45 or 48, being in the form of a liquid formulation. A method for treating or reducing cancer, or a related disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-38. A method for treating or reducing a disease or disorder, comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound having the structural formula (I):

(I) wherein

W is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, - COR¹, -COOR¹, -CONR^¹, or -Si(R¹)3, wherein each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R¹; each of R¹, R² and R³ is independently H, halogen, NH2, OH, CN, CF3, CHO, COCi-4alkyl, CH₂C(=O)-NR^laR^lb, C(=O)-NR^laR^lb, CH₂COOR^1C, NR^ldR^le, Ci-₄ alkyl, C_1-4 alkenyl, C_1-4 alkynyl, O-C_1-4 alkyl, cycloalkyl, Het, Ar, NR^lh(C=O)R¹¹, NR¹J(C=O)NR^lkR¹¹, N(SO₂)R^lm , SO₂NR^lnR¹⁰, N(C=O)C(CN)C(OH)R¹P, P(O)MeMe, or P(O)OMeOMe; wherein each of R^la, R^lb, R^lc, R^ld, R^le, R^lh, Rⁿ, Rb, R^lk R¹¹, R^lm, R^ln, R¹⁰ and R^lp is independently selected from the group consisting of H, C_1-4 alkyl, C_3-8 cycloalkyl and C_3-8 heterocycloalkyl, wherein C_1-4 alkyl is optionally substituted with one or more substituents selected from the group consisting of OH, OMe, CN, halogen, NR^3aR^3b, C_3-8 cycloalkyl and C_3-8 heterocycloalkyl; and each pair of R^la and R^lb, R^ld and R^le, R^lk and R¹¹, or R^ln and R¹⁰, optionally form a 3- to 8-membered nitrogen-containing heterocyclyl ring, wherein the heterocyclyl ring is optionally substituted with one or more R⁶;

Z is C or N;

R⁴ is H, CN, halogen, OH, NHR⁷, NHCOR⁷, NH(S=O)R⁷, or NHSO₂R⁷;

refers to X ring and Y ring having exactly two atoms and one bond in common; each R⁶ is independently H, halogen, Ci-4 alkyl, OH, OMe, CN, CF3, NR^laR^lb, C3- 8 cycloalkyl, or C_3-8 heterocycloalkyl; and each R⁷ is independently H, NH2, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, or cycloalkyl; or a pharmaceutically acceptable form or an isotope derivative thereof, effective to treat cancer, or a related disease or disorder, in a mammal, including a human. The method of claim 50 or 51, wherein the cancer is selected from breast, colon, endometrial, kidney, lung, melanoma, prostate, thyroid cancer, pancreatic ductal adenocarcinoma, hepatocellular carcinoma, and leukemia, or a related disease or condition. The method of claim 52, wherein the leukemia is acute myeloid leukemia (AML). Use of a compound of any one of claims 1-38, and a pharmaceutically acceptable excipient, carrier, or diluent, in preparation of a medicament for treating a disease or disorder. The use of claim 54, wherein the disease or disorder is cancer, or a related disease or disorder. The use of claim 55, wherein the cancer is selected from breast, colon, endometrial, kidney, lung, melanoma, prostate, thyroid cancer, pancreatic ductal adenocarcinoma, helatocellular carcinoma, and leukemia. The use of claim 56, wherein the leukemia is AML. The use of any one of claims 54-57, wherein the medicament is for oral administration. The use of any one of claims 54-57, wherein the medicament is for intravenous administration.